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Clinical Trial Results:
A Study to Evaluate the Safety and Efficacy of the CD40 Agonistic Antibody APX005M Administered in Combination with Nivolumab in Subjects with Non-small Cell Lung Cancer and Subjects with Metastatic Melanoma

Summary
EudraCT number	2018-003866-14
Trial protocol	ES FR
Global end of trial date	16 Nov 2020

Results information
Results version number	v1(current)
This version publication date	19 Jan 2024
First version publication date	19 Jan 2024
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

APX005M-002

ISRCTN number

US NCT number

NCT03123783

WHO universal trial number (UTN)

Sponsor organisation name

Pyxis Oncology, Inc.

Sponsor organisation address

321 Harrison Avenue, Boston, United States, MA 02118

Public contact

Clinical Operations, Pyxis Oncology, Inc., 1 (339) 545 8252, clinicaltrials@pyxisoncology.com

Scientific contact

Ken Kobayashi, Pyxis Oncology, Inc., 1 (816) 830-5408, kkobayashi@pyxisoncology.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

16 Nov 2020

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

16 Nov 2020

Was the trial ended prematurely?

Main objective of the trial

Phase 1b: •Determine the maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D) of APX005M when given in combination with nivolumab. Phase 2: •Evaluate the objective response rate (ORR) by Response Evaluation Criteria In Solid Tumors (RECIST 1.1) in each cohort/group.

Protection of trial subjects

Written informed consent was required from each participant prior to any testing under this protocol, including screening tests and evaluations. The informed consent form, as specified by the clinical site’s institutional review board/independent ethics committee, followed the Protection of Human Subjects regulations listed in the Code of Federal Regulations, Title 21, Part 50.

Background therapy

Evidence for comparator

Actual start date of recruitment

17 May 2017

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Spain: 76

Country: Number of subjects enrolled

United States: 64

Worldwide total number of subjects

140

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

In Phase 1b dose-escalation portion of the study, a total of 10 participants were enrolled at 3 dose levels. Nine participants received at least one dose of both study drugs. 0.3 mg/kg was determined as the RP2D. The 3 participants treated in DL3 of Phase 1b are at the RP2D and are also included in Phase 2 results.

Screening details

For the Phase 2 cohorts 1, 2, 3A, 3B, a total of 133 participants were enrolled in 4 cohorts to receive APX005M at 0.3 mg/kg (RP2D) plus nivolumab at 360 mg intravenously (IV). Three participants who were treated at the RP2D in the Phase 1b dose-escalation portion of the study were included in Phase 2 of the relevant disease-specific cohort.

Period 1 title

Enrollment to Treatment

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

DL1 - APX005M 0.03 mg/kg + Nivolumab (Phase 1b)

Arm description

Participants were to receive 0.03 mg/kg of APX005M administered every 21 days in combination with nivolumab 360 mg IV.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

DL2 - APX005M 0.1 mg/kg + Nivolumab (Phase 1b)

Arm description

Participants were to receive 0.1 mg/kg of APX005M administered every 21 days in combination with nivolumab 360 mg IV.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

DL3 - APX005M 0.3 mg/kg + Nivolumab (Phase 1b)

Arm description

Participants were to receive 0.3 mg/kg of APX005M administered every 21 days in combination with nivolumab 360 mg IV.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Cohort 1 (Arm)/ inNSCLC (Phase 2)

Arm description

Participants with immunotherapy naïve metastatic or locally advanced non-small cell lung cancer (inNSCLC) were to receive 0.3 mg/kg of APX005M administered every 21 days in combination with nivolumab 360 mg IV. One participant from DL3 was also included.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Cohort 2 (Arm)/ PD1-MM (Phase 2)

Arm description

Participants with anti-programmed cell death protein 1 (PD-1) or anti-programmed death-ligand 1 (PD-L1) resistant or pretreated unresectable or metastatic melanoma (PD1-MM) were to receive 0.3 mg/kg of APX005M administered every 21 days in combination with nivolumab 360 mg IV. Two participants from DL3 were also included.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Cohort 3A (Arm)/ PD1-NSCLC (Phase 2)

Arm description

Participants with PD1 or PD-L1 resistant or pretreated-non-small cell lung cancer (PD1-NSCLC) metastatic or locally advanced NSCLC not amenable to curative treatment were to receive 0.3 mg/kg of APX005M administered every 21 days in combination with nivolumab 360 mg IV.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Cohort 3B (Arm)/ PD1-NSCLC (Phase 2)

Arm description

Participants with PD1-NSCLC metastatic or locally advanced NSCLC not amenable to curative treatment that progressed during prior treatment with anti-PD-1/ PD-L1 therapy were to receive 0.3 mg/kg of APX005M administered every 21 days in combination with nivolumab 360 mg IV.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 1	DL1 - APX005M 0.03 mg/kg + Nivolumab (Phase 1b)	DL2 - APX005M 0.1 mg/kg + Nivolumab (Phase 1b)	DL3 - APX005M 0.3 mg/kg + Nivolumab (Phase 1b)	Cohort 1 (Arm)/ inNSCLC (Phase 2)	Cohort 2 (Arm)/ PD1-MM (Phase 2)	Cohort 3A (Arm)/ PD1-NSCLC (Phase 2)	Cohort 3B (Arm)/ PD1-NSCLC (Phase 2)
Started	3	4	3	53	38	14	28
Completed	3	3	3	53	38	14	28
Not completed	0	1	0	0	0	0	0
Removed prior to APX005M administration	-	1	-	-	-	-	-

Period 2 title

Treatment to End of Study

Is this the baseline period?

Yes ^[1]

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

DL1 - APX005M 0.03 mg/kg + Nivolumab (Phase 1b)

Arm description

Participants received 0.03 mg/kg of APX005M administered every 21 days in combination with nivolumab 360 mg IV.

Arm type

Experimental

Investigational medicinal product name

APX005M

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

APX005M was administered at the assigned dose as a 60-minute IV infusion on Day 1 of each 3-week treatment cycle approximately 30 minutes following nivolumab.

Investigational medicinal product name

nivolumab

Investigational medicinal product code

Other name

Optivo

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Nivolumab 360 mg was administered as a 30-minute IV infusion on Day 1 of each 3-week treatment cycle. It was not to be administered as an IV push or bolus injection.

DL2 - APX005M 0.1 mg/kg + Nivolumab (Phase 1b)

Arm description

Participants received 0.1 mg/kg of APX005M administered every 21 days in combination with nivolumab 360 mg IV.

Arm type

Experimental

Investigational medicinal product name

APX005M

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

APX005M was administered at the assigned dose as a 60-minute IV infusion on Day 1 of each 3-week treatment cycle approximately 30 minutes following nivolumab.

Investigational medicinal product name

nivolumab

Investigational medicinal product code

Other name

Optivo

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Nivolumab 360 mg was administered as a 30-minute IV infusion on Day 1 of each 3-week treatment cycle. It was not to be administered as an IV push or bolus injection.

DL3 - APX005M 0.3 mg/kg + Nivolumab (Phase 1b)

Arm description

Participants received 0.3 mg/kg of APX005M administered every 21 days in combination with nivolumab 360 mg IV.

Arm type

Experimental

Investigational medicinal product name

APX005M

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

APX005M was administered at the assigned dose as a 60-minute IV infusion on Day 1 of each 3-week treatment cycle approximately 30 minutes following nivolumab.

Investigational medicinal product name

nivolumab

Investigational medicinal product code

Other name

Optivo

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Nivolumab 360 mg was administered as a 30-minute IV infusion on Day 1 of each 3-week treatment cycle. It was not to be administered as an IV push or bolus injection.

Cohort 1 (Arm)/ inNSCLC (Phase 2)

Arm description

Participants with inNSCLC received 0.3 mg/kg of APX005M administered every 21 days in combination with nivolumab 360 mg IV. One participant from DL3 was also included.

Arm type

Experimental

Investigational medicinal product name

APX005M

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

APX005M was administered at the assigned dose as a 60-minute IV infusion on Day 1 of each 3-week treatment cycle approximately 30 minutes following nivolumab.

Investigational medicinal product name

nivolumab

Investigational medicinal product code

Other name

Optivo

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Nivolumab 360 mg was administered as a 30-minute IV infusion on Day 1 of each 3-week treatment cycle. It was not to be administered as an IV push or bolus injection.

Cohort 2 (Arm)/ PD1-MM (Phase 2)

Arm description

Participants with PD-1 or anti-PD-L1 resistant or PD1-MM were to receive 0.3 mg/kg of APX005M administered every 21 days in combination with nivolumab 360 mg IV. Two participants from DL3 were also included.

Arm type

Experimental

Investigational medicinal product name

APX005M

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

APX005M was administered at the assigned dose as a 60-minute IV infusion on Day 1 of each 3-week treatment cycle approximately 30 minutes following nivolumab.

Investigational medicinal product name

nivolumab

Investigational medicinal product code

Other name

Optivo

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Nivolumab 360 mg was administered as a 30-minute IV infusion on Day 1 of each 3-week treatment cycle. It was not to be administered as an IV push or bolus injection.

Cohort 3A (Arm)/ PD1-NSCLC (Phase 2)

Arm description

Participants with PD1-NSCLC metastatic or locally advanced NSCLC not amenable to curative treatment were to receive 0.3 mg/kg of APX005M administered every 21 days in combination with nivolumab 360 mg IV.

Arm type

Experimental

Investigational medicinal product name

APX005M

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

APX005M was administered at the assigned dose as a 60-minute IV infusion on Day 1 of each 3-week treatment cycle approximately 30 minutes following nivolumab.

Investigational medicinal product name

nivolumab

Investigational medicinal product code

Other name

Optivo

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Nivolumab 360 mg was administered as a 30-minute IV infusion on Day 1 of each 3-week treatment cycle. It was not to be administered as an IV push or bolus injection.

Cohort 3B (Arm)/ PD1-NSCLC (Phase 2)

Arm description

Participants with PD1-NSCLC metastatic or locally advanced NSCLC not amenable to curative treatment that progressed during prior treatment with anti-PD-1/PD-L1 therapy received 0.3 mg/kg of APX005M administered every 21 days in combination with nivolumab 360 mg IV.

Arm type

Experimental

Investigational medicinal product name

APX005M

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

APX005M was administered at the assigned dose as a 60-minute IV infusion on Day 1 of each 3-week treatment cycle approximately 30 minutes following nivolumab.

Investigational medicinal product name

nivolumab

Investigational medicinal product code

Other name

Optivo

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Nivolumab 360 mg was administered as a 30-minute IV infusion on Day 1 of each 3-week treatment cycle. It was not to be administered as an IV push or bolus injection.

Notes
[1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
Justification: Baseline characteristics are presented for the Safety Population.

Number of subjects in period 2	DL1 - APX005M 0.03 mg/kg + Nivolumab (Phase 1b)	DL2 - APX005M 0.1 mg/kg + Nivolumab (Phase 1b)	DL3 - APX005M 0.3 mg/kg + Nivolumab (Phase 1b)	Cohort 1 (Arm)/ inNSCLC (Phase 2)	Cohort 2 (Arm)/ PD1-MM (Phase 2)	Cohort 3A (Arm)/ PD1-NSCLC (Phase 2)	Cohort 3B (Arm)/ PD1-NSCLC (Phase 2)
Started	3	3	3	53	38	14	28
Completed	3	3	3	48	33	12	25
Not completed	0	0	0	5	5	2	3
No post baseline tumor assessment	-	-	-	5	2	2	3
Prior systemic therapy not allowed	-	-	-	-	3	-	-

Baseline characteristics

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Reporting group title

Treatment to End of Study

Reporting group description

All participants in the safety population who received at least 1 dose of study drug.

Notes
[1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same.
Justification: The 3 participants treated in DL3 of Phase 1b are at the RP2D and are also included in Phase 2 results. One participant was rolled over to Cohort 1 (Phase 2) and 2 participants were rolled over into Cohort 2 (Phase 2) to continue treatment.

Reporting group values	Treatment to End of Study	Total
Number of subjects	139	139
Age categorical
Units: Subjects
<=18 years	0	0
Between 18 and 65 years	61	61
>=65 years	78	78
Gender categorical
Units: Subjects
Female	52	52
Male	87	87
Ethnicity
Units: Subjects
Hispanic or Latino	30	30
Not Hispanic or Latino	109	109
Unknown or Not Reported	0	0
Race
Units: Subjects
American Indian or Alaska Native	1	1
Asian	1	1
Native Hawaiian or Other Pacific Islander	0	0
Black or African American	5	5
White	132	132
More than one race	0	0
Unknown or Not Reported	0	0
Region of Enrollment
Units: Subjects
United States	75	75
Spain	64	64
ECOG Performance Status
Grade 0 - Normal activity, fully active, able to carry on all pre-disease performance without restriction. Grade 1 - Symptoms, but fully ambulatory, restricted in physically strenuous but ambulatory and able to carry out work of a light or sedentary nature (e.g., light housework, office work). Grade 0 is better than Grade 1.
Units: Subjects
ECOG Score 0	61	61
ECOG Score 1	78	78

End points

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Reporting group title

DL1 - APX005M 0.03 mg/kg + Nivolumab (Phase 1b)

Reporting group description

Participants were to receive 0.03 mg/kg of APX005M administered every 21 days in combination with nivolumab 360 mg IV.

Reporting group title

DL2 - APX005M 0.1 mg/kg + Nivolumab (Phase 1b)

Reporting group description

Participants were to receive 0.1 mg/kg of APX005M administered every 21 days in combination with nivolumab 360 mg IV.

Reporting group title

DL3 - APX005M 0.3 mg/kg + Nivolumab (Phase 1b)

Reporting group description

Participants were to receive 0.3 mg/kg of APX005M administered every 21 days in combination with nivolumab 360 mg IV.

Reporting group title

Cohort 1 (Arm)/ inNSCLC (Phase 2)

Reporting group description

Reporting group title

Cohort 2 (Arm)/ PD1-MM (Phase 2)

Reporting group description

Reporting group title

Cohort 3A (Arm)/ PD1-NSCLC (Phase 2)

Reporting group description

Reporting group title

Cohort 3B (Arm)/ PD1-NSCLC (Phase 2)

Reporting group description

Reporting group title

DL1 - APX005M 0.03 mg/kg + Nivolumab (Phase 1b)

Reporting group description

Participants received 0.03 mg/kg of APX005M administered every 21 days in combination with nivolumab 360 mg IV.

Reporting group title

DL2 - APX005M 0.1 mg/kg + Nivolumab (Phase 1b)

Reporting group description

Participants received 0.1 mg/kg of APX005M administered every 21 days in combination with nivolumab 360 mg IV.

Reporting group title

DL3 - APX005M 0.3 mg/kg + Nivolumab (Phase 1b)

Reporting group description

Participants received 0.3 mg/kg of APX005M administered every 21 days in combination with nivolumab 360 mg IV.

Reporting group title

Cohort 1 (Arm)/ inNSCLC (Phase 2)

Reporting group description

Participants with inNSCLC received 0.3 mg/kg of APX005M administered every 21 days in combination with nivolumab 360 mg IV. One participant from DL3 was also included.

Reporting group title

Cohort 2 (Arm)/ PD1-MM (Phase 2)

Reporting group description

Reporting group title

Cohort 3A (Arm)/ PD1-NSCLC (Phase 2)

Reporting group description

Reporting group title

Cohort 3B (Arm)/ PD1-NSCLC (Phase 2)

Reporting group description

Subject analysis set title

Phase 1b Escalation

Subject analysis set type

Safety analysis

Subject analysis set description

Participants received IV infusions of APX005M starting at DL 0.03, 0.1 or 0.3 mg/kg administered every 21 days in combination with nivolumab 360 mg IV.

Primary: Number of Participants Experiencing Dose-limiting Toxicities (DLTs)

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End point title

Number of Participants Experiencing Dose-limiting Toxicities (DLTs) ^[1]

End point description

All toxicities were graded according to the NCI-CTCAE version 4.03. DLT was defined as any of the following events attributed to APX005M and nivolumab combination: - Grade 4 hematologic toxicity lasting ≥ 7 days (except asymptomatic lymphopenia) - Grade 3 or 4 neutropenia with a single temperature of >38.3◦ C (101◦ F) or a sustained temperature of ≥38◦ C (100.4◦ F) for more than one hour - Grade 4 thrombocytopenia or Grade ≥3 thrombocytopenia with signs or symptoms of bleeding or requiring platelet transfusion - Grade 4 non-hematologic toxicity - Grade 3 non-hematologic toxicity lasting >3 days despite optimal supportive care - Any Grade ≥ 3 non-hematologic laboratory value if: medical intervention is required to treat the participant, abnormality leads to hospitalization, or abnormality persists for >1 week - Failure to recover from a treatment-related adverse event to baseline or ≤ Grade 1 within 12 weeks of last dose of investigational product - Grade 5 toxicity.

End point type

Primary

End point timeframe

Up to 21 days following first dose of APX005M and nivolumab

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No additional statistical analyses were pre-specified for this endpoint.

End point values	Phase 1b Escalation
Number of subjects analysed	9 ^[2]
Units: participants	0

Notes
[2] - All participants in the safety population who received at least 1 dose of study drug in Phase 1b.

No statistical analyses for this end point

Primary: MTD of APX005M + Nivolumab (Phase 1b)

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End point title

MTD of APX005M + Nivolumab (Phase 1b) ^[3]

End point description

Establish the MTD dose of APX005M combined with 360 mg of nivolumab for which < 33% of DLT- evaluable participants experience a DLT. In Phase 1b, the RP2D was based on the overall safety and tolerability of the combination of APX005M and nivolumab by testing increasing doses up to 0.3 mg/kg APX005M + nivolumab. All participants in the safety population who received at least 1 dose of study drug in the escalation cohorts (APX005M 0.03 mg/kg + nivolumab; APX005M 0.1 mg/kg + nivolumab; APX005M 0.3 mg/kg + nivolumab). Values of "99999" indicate the MTD was formally not reached.

End point type

Primary

End point timeframe

Up to 21 days following first dose of APX005M and nivolumab

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No additional statistical analyses were pre-specified for this endpoint.

End point values	Phase 1b Escalation
Number of subjects analysed	9 ^[4]
Units: mg/kg
number (not applicable)	99999

Notes
[4] - All participants in the safety population who received at least 1 dose of study drug in Phase 1b.

No statistical analyses for this end point

Primary: Evaluate the ORR by RECIST 1.1 and iRECIST in Each Cohort / Group (Phase 2)

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End point title

Evaluate the ORR by RECIST 1.1 and iRECIST in Each Cohort / Group (Phase 2) ^[5] ^[6]

End point description

ORR defined as the rate of participants who show as best overall response; either a complete response (CR) or a partial response (PR). The ORR can be evaluated by RECIST v1.1 using computed tomography scans/magnetic resonance imaging. Per RECIST v1.1, for target lesions and assessed by imaging: CR, Disappearance of all target lesions and non-target (NT) lesions; PR, >30% decrease in the sum of the longest diameter of target lesions and no PD in NT lesions or new lesions; ORR = CR + PR. Cohort 1: inNSCLC, Cohort 2: unresectable or MM that progressed during treatment with anti-PD-1/PD-L1 therapy and had confirmation of PD ≥4 weeks, Cohort 3: PD1-NSCLC metastatic or locally advanced NSCLC not amenable to curative treatment that progressed during prior treatment with anti-PD-1/PD-L1 therapy. Cohort 3A: best response of PD or with SD <16 weeks, Cohort 3B includes PD1-NSCLC with tumor response or with SD ≥ 16 weeks.

End point type

Primary

End point timeframe

From start of the treatment (Day 1) until disease progression, withdrawal of consent, death, initiation of any anticancer therapy, lost to follow-up, or termination by the Sponsor, whichever comes first (for Phase 2: maximum up to 27 months)

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No additional statistical analyses were pre-specified for this endpoint.
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: ORR analysis was pre-specified for Phase 2 only.

End point values	Cohort 1 (Arm)/ inNSCLC (Phase 2)	Cohort 2 (Arm)/ PD1-MM (Phase 2)	Cohort 3A (Arm)/ PD1-NSCLC (Phase 2)	Cohort 3B (Arm)/ PD1-NSCLC (Phase 2)
Number of subjects analysed	48	33	12	25
Units: percentage of participants
number (confidence interval 90%)	16.67 (8.57 to 28.07)	15.15 (6.17 to 29.25)	0.00 (0.00 to 22.09)	0.00 (0.00 to 11.29)

No statistical analyses for this end point

Secondary: Safety of the APX005M and Nivolumab Combination (Phase 2)

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End point title

Safety of the APX005M and Nivolumab Combination (Phase 2) ^[7]

End point description

Number of participants with treatment emergent adverse events are reported. Any adverse event a participant has with 2 or more events in that category is counted only once.

End point type

Secondary

End point timeframe

Day 1 up to 30 days (or 100 days for serious adverse events and adverse events with potential immunologic etiology) following the after the last dose of APX005M and/or nivolumab (from start of treatment up to 27 months)

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Secondary safety analysis was pre-specified for Phase 2 only.

End point values	Cohort 1 (Arm)/ inNSCLC (Phase 2)	Cohort 2 (Arm)/ PD1-MM (Phase 2)	Cohort 3A (Arm)/ PD1-NSCLC (Phase 2)	Cohort 3B (Arm)/ PD1-NSCLC (Phase 2)
Number of subjects analysed	53	38	14	28
Units: participants	52	36	14	28

No statistical analyses for this end point

Secondary: Duration of Response (DOR) as Per RECIST 1.1 (Phase 2)

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End point title

Duration of Response (DOR) as Per RECIST 1.1 (Phase 2) ^[8]

End point description

Duration of Response is defined as the time from the first evidence of confirmed PR or better by per RECIST v1.1 to PD or death due to any cause; in participants alive without PD, DOR was censored on the date of the last tumor assessment. PD is defined using RECIST v1.1, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Four/Five participants in Cohort 2 had ongoing responses at the time of study closure. Cohort 1: inNSCLC, Cohort 2: unresectable or MM that progressed during treatment with anti-PD-1/PD-L1 therapy and had confirmation of PD ≥4 week. Cohort 3A/PD1-NSCLC and Cohort 3B/PD1 NSCLC had no objective response and therefore DOR could not be assessed. Values of "9.9999" indicate the median duration of response not reached.

End point type

Secondary

End point timeframe

Maximum up to 25 months

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: DOR analysis was pre-specified for Phase 2 only. Cohort 3A/PD1-NSCLC and Cohort 3B/PD1 NSCLC had no objective response and therefore DOR could not be assessed.

End point values	Cohort 1 (Arm)/ inNSCLC (Phase 2)	Cohort 2 (Arm)/ PD1-MM (Phase 2)
Number of subjects analysed	8	5
Units: months
median (full range (min-max))	9.9999 (3.9 to 21.4)	9.9999 (4.2 to 24.7)

No statistical analyses for this end point

Secondary: Median Progression-free Survival (PFS) (Phase 2)

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End point title

Median Progression-free Survival (PFS) (Phase 2) ^[9]

End point description

PFS in each cohort, measured from first dose to the earlier of PD (by RECIST 1.1) or death due to any cause, whichever occurs first. Cohort 1: inNSCLC, Cohort 2: unresectable or MM that progressed during treatment with anti-PD-1/PD-L1 therapy and had confirmation of PD ≥4 weeks, Cohort 3: PD1-NSCLC metastatic or locally advanced NSCLC not amenable to curative treatment that progressed during prior treatment with anti-PD-1/PD-L1 therapy. Cohort 3A: best response of PD or with SD <16 weeks, Cohort 3B includes PD1-NSCLC with tumor response or with SD ≥ 16 weeks.

End point type

Secondary

End point timeframe

From start of treatment (Day 1) up to 27 months

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: PFS analysis was pre-specified for Phase 2 only.

End point values	Cohort 1 (Arm)/ inNSCLC (Phase 2)	Cohort 2 (Arm)/ PD1-MM (Phase 2)	Cohort 3A (Arm)/ PD1-NSCLC (Phase 2)	Cohort 3B (Arm)/ PD1-NSCLC (Phase 2)
Number of subjects analysed	48	33	12	25
Units: months
median (confidence interval 90%)	4.11 (3.45 to 5.52)	1.97 (1.87 to 3.61)	3.43 (2.00 to 3.88)	3.65 (1.84 to 3.81)

No statistical analyses for this end point

Secondary: 6-month PFS Rate (Phase 2)

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End point title

6-month PFS Rate (Phase 2) ^[10]

End point description

PFS rate in each cohort, measured from first dose to the earlier of PD (by RECIST 1.1) or death due to any cause, whichever occurs first. Cohort 1: inNSCLC, Cohort 2: unresectable or MM that progressed during treatment with anti-PD-1/PD-L1 therapy and had confirmation of PD ≥4 weeks, Cohort 3: PD1-NSCLC metastatic or locally advanced NSCLC not amenable to curative treatment that progressed during prior treatment with anti-PD-1/PD-L1 therapy. Cohort 3A: best response of PD or with SD <16 weeks, Cohort 3B includes PD1-NSCLC with tumor response or with SD ≥ 16 weeks.

End point type

Secondary

End point timeframe

From start of treatment (Day 1) to 6 months

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: PFS analysis was pre-specified for Phase 2 only.

End point values	Cohort 1 (Arm)/ inNSCLC (Phase 2)	Cohort 2 (Arm)/ PD1-MM (Phase 2)	Cohort 3A (Arm)/ PD1-NSCLC (Phase 2)	Cohort 3B (Arm)/ PD1-NSCLC (Phase 2)
Number of subjects analysed	48	33	12	25
Units: percentage of participants
number (confidence interval 90%)	33.10 (20.10 to 46.68)	21.21 (9.35 to 36.25)	25.00 (6.01 to 50.48)	12.92 (3.27 to 29.41)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Day 1 through 30 days (or 100 days for serious adverse events (SAEs) and adverse events (AEs) with potential immunologic etiology) after the last dose of study drug (up to 27 months)

Adverse event reporting additional description

An AE considered "serious" if it results in any of the following outcomes: - Death - A life-threatening AE - Inpatient hospitalization or prolongation of existing hospitalization - A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions - A congenital anomaly/birth defect.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

18.00

Reporting group title

DL1 - APX005M 0.03 mg/kg + Nivolumab (Phase 1b escalation)

Reporting group description

Participants received 0.03 mg/kg of APX005M administered every 21 days in combination with nivolumab 360 mg IV.

Reporting group title

DL2 - APX005M 0.1 mg/kg + Nivolumab (Phase 1b escalation)

Reporting group description

Participants received 0.1 mg/kg of APX005M administered every 21 days in combination with nivolumab 360 mg IV.

Reporting group title

DL3 - APX005M 0.3 mg/kg + Nivolumab (Phase 1b escalation)

Reporting group description

Participants received 0.3 mg/kg of APX005M administered every 21 days in combination with nivolumab 360 mg IV. Note: The 3 participants in DL3 are at the RP2D and are also included in Phase 2 results. One participant was rolled over to Cohort 1 (Phase 2) and 2 participants were rolled over into Cohort 2 (Phase 2).

Reporting group title

Cohort 1 (Arm)/ inNSCLC (Phase 2)

Reporting group description

Participants with inNSCLC received 0.3 mg/kg of APX005M administered every 21 days in combination with nivolumab 360 mg IV. Includes data from 1 participant from DL3.

Reporting group title

Cohort 2 (Arm)/ PD1-MM (Phase 2)

Reporting group description

Reporting group title

Cohort 3A (Arm)/ PD1-NSCLC (Phase 2)

Reporting group description

Participants with PD1-NSCLC metastatic or locally advanced NSCLC not amenable to curative treatment received 0.3 mg/kg of APX005M administered every 21 days in combination with nivolumab 360 mg IV.

Reporting group title

Cohort 3B (Arm)/ PD1-NSCLC (Phase 2)

Reporting group description

Serious adverse events	DL1 - APX005M 0.03 mg/kg + Nivolumab (Phase 1b escalation)	DL2 - APX005M 0.1 mg/kg + Nivolumab (Phase 1b escalation)	DL3 - APX005M 0.3 mg/kg + Nivolumab (Phase 1b escalation)	Cohort 1 (Arm)/ inNSCLC (Phase 2)	Cohort 2 (Arm)/ PD1-MM (Phase 2)	Cohort 3A (Arm)/ PD1-NSCLC (Phase 2)	Cohort 3B (Arm)/ PD1-NSCLC (Phase 2)
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	25 / 53 (47.17%)	6 / 38 (15.79%)	6 / 14 (42.86%)	13 / 28 (46.43%)
number of deaths (all causes)	1	1	0	18	4	4	9
number of deaths resulting from adverse events	0	0	0	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bone neoplasm
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 53 (1.89%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cancer pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	1 / 14 (7.14%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	1 / 14 (7.14%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Facial pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 53 (1.89%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 53 (1.89%)	0 / 38 (0.00%)	0 / 14 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	1 / 38 (2.63%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 53 (1.89%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Cytokine release syndrome
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	0 / 14 (0.00%)	2 / 28 (7.14%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 53 (1.89%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 53 (3.77%)	0 / 38 (0.00%)	1 / 14 (7.14%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 4	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chronic respiratory failure
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 53 (1.89%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 53 (3.77%)	0 / 38 (0.00%)	1 / 14 (7.14%)	2 / 28 (7.14%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 53 (1.89%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 53 (1.89%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary artery thrombosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 53 (1.89%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 53 (5.66%)	0 / 38 (0.00%)	1 / 14 (7.14%)	2 / 28 (7.14%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 53 (1.89%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Confusional state
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 53 (1.89%)	1 / 38 (2.63%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Blood bilirubin increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 53 (1.89%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Weight decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 53 (1.89%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	0 / 14 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Femur fraction
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 53 (1.89%)	0 / 38 (0.00%)	0 / 14 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hip fracture
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 53 (1.89%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Radius fracture
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	1 / 38 (2.63%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Toxicity to various agents
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	1 / 38 (2.63%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute coronary syndrome
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 53 (3.77%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 53 (1.89%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	1 / 14 (7.14%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Cardio-respiratory arrest
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 53 (1.89%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Pericardial effusion
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	1 / 14 (7.14%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Brain oedema
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	1 / 14 (7.14%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 53 (3.77%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Encephalitis autoimmune
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	1 / 14 (7.14%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 53 (3.77%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 53 (1.89%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Optic ischaemic neuropathy
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Colitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 53 (3.77%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 53 (1.89%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	0 / 14 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	1 / 38 (2.63%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	0 / 14 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 53 (1.89%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	0 / 14 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Back pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 53 (1.89%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myositis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	0 / 14 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	1 / 38 (2.63%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	1 / 38 (2.63%)	0 / 14 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	0 / 14 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	1 / 38 (2.63%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung abscess
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 53 (1.89%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 53 (1.89%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	4 / 53 (7.55%)	0 / 38 (0.00%)	2 / 14 (14.29%)	2 / 28 (7.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 5	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 53 (1.89%)	0 / 38 (0.00%)	0 / 14 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Streptococcal bacteraemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 53 (1.89%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Diabetic ketoacidosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 53 (1.89%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	0 / 14 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	0 / 14 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	DL1 - APX005M 0.03 mg/kg + Nivolumab (Phase 1b escalation)	DL2 - APX005M 0.1 mg/kg + Nivolumab (Phase 1b escalation)	DL3 - APX005M 0.3 mg/kg + Nivolumab (Phase 1b escalation)	Cohort 1 (Arm)/ inNSCLC (Phase 2)	Cohort 2 (Arm)/ PD1-MM (Phase 2)	Cohort 3A (Arm)/ PD1-NSCLC (Phase 2)	Cohort 3B (Arm)/ PD1-NSCLC (Phase 2)
Total subjects affected by non serious adverse events
subjects affected / exposed	3 / 3 (100.00%)	3 / 3 (100.00%)	3 / 3 (100.00%)	52 / 53 (98.11%)	36 / 38 (94.74%)	14 / 14 (100.00%)	28 / 28 (100.00%)
Vascular disorders
Flushing
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	6 / 53 (11.32%)	3 / 38 (7.89%)	0 / 14 (0.00%)	2 / 28 (7.14%)
occurrences all number	0	1	0	8	3	0	2
Hypertention
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	11 / 53 (20.75%)	2 / 38 (5.26%)	0 / 14 (0.00%)	3 / 28 (10.71%)
occurrences all number	0	0	0	16	2	0	5
Hypotension
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	10 / 53 (18.87%)	4 / 38 (10.53%)	1 / 14 (7.14%)	3 / 28 (10.71%)
occurrences all number	0	2	0	16	5	1	4
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	7 / 53 (13.21%)	6 / 38 (15.79%)	4 / 14 (28.57%)	12 / 28 (42.86%)
occurrences all number	0	0	0	8	10	6	17
Chest discomfort
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	2 / 14 (14.29%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	2	0
Chest pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 53 (3.77%)	1 / 38 (2.63%)	0 / 14 (0.00%)	5 / 28 (17.86%)
occurrences all number	0	0	0	2	1	0	8
Chills
subjects affected / exposed	0 / 3 (0.00%)	2 / 3 (66.67%)	3 / 3 (100.00%)	30 / 53 (56.60%)	19 / 38 (50.00%)	5 / 14 (35.71%)	13 / 28 (46.43%)
occurrences all number	0	3	5	65	51	14	24
Discomfort
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	1 / 14 (7.14%)	1 / 28 (3.57%)
occurrences all number	0	0	0	0	0	1	1
Fatigue
subjects affected / exposed	3 / 3 (100.00%)	2 / 3 (66.67%)	0 / 3 (0.00%)	18 / 53 (33.96%)	15 / 38 (39.47%)	5 / 14 (35.71%)	4 / 28 (14.29%)
occurrences all number	4	8	0	41	36	12	4
Influenza like illness
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 3 (66.67%)	2 / 53 (3.77%)	1 / 38 (2.63%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	2	2	1	0	0
Malaise
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	2 / 53 (3.77%)	4 / 38 (10.53%)	3 / 14 (21.43%)	0 / 28 (0.00%)
occurrences all number	0	0	1	2	4	3	0
Non-cardiac chest pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	5 / 53 (9.43%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	5	0	0	0
Oedema peripheral
subjects affected / exposed	0 / 3 (0.00%)	2 / 3 (66.67%)	0 / 3 (0.00%)	4 / 53 (7.55%)	3 / 38 (7.89%)	3 / 14 (21.43%)	2 / 28 (7.14%)
occurrences all number	0	4	0	7	3	3	2
Pain
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	5 / 53 (9.43%)	1 / 38 (2.63%)	0 / 14 (0.00%)	1 / 28 (3.57%)
occurrences all number	1	1	0	6	1	0	1
Performance status decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	1 / 14 (7.14%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Pyrexia
subjects affected / exposed	0 / 3 (0.00%)	2 / 3 (66.67%)	2 / 3 (66.67%)	28 / 53 (52.83%)	26 / 38 (68.42%)	7 / 14 (50.00%)	12 / 28 (42.86%)
occurrences all number	0	3	4	56	57	34	24
Immune system disorders
Cytokine release syndrome
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	3 / 53 (5.66%)	0 / 38 (0.00%)	0 / 14 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	1	0	4	0	0	1
Hypersensitivity
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 53 (1.89%)	0 / 38 (0.00%)	1 / 14 (7.14%)	0 / 28 (0.00%)
occurrences all number	0	0	0	1	0	1	0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 53 (5.66%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	7	0	0	0
Cough
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 3 (33.33%)	13 / 53 (24.53%)	3 / 38 (7.89%)	3 / 14 (21.43%)	10 / 28 (35.71%)
occurrences all number	1	1	1	16	4	3	13
Dysphonia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 53 (3.77%)	2 / 38 (5.26%)	0 / 14 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	0	0	2	2	0	1
Dyspnoea
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	21 / 53 (39.62%)	3 / 38 (7.89%)	6 / 14 (42.86%)	8 / 28 (28.57%)
occurrences all number	1	0	0	30	3	8	9
Dyspnoea at rest
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Dyspnoea exertional
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 53 (5.66%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	3	0	0	0
Epistaxis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 53 (3.77%)	0 / 38 (0.00%)	0 / 14 (0.00%)	2 / 28 (7.14%)
occurrences all number	0	0	0	3	0	0	3
Haemoptysis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	3 / 53 (5.66%)	0 / 38 (0.00%)	1 / 14 (7.14%)	1 / 28 (3.57%)
occurrences all number	0	0	1	3	0	3	1
Hypoxia
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 53 (3.77%)	0 / 38 (0.00%)	0 / 14 (0.00%)	1 / 28 (3.57%)
occurrences all number	1	0	0	2	0	0	1
Lung infiltration
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Nasal congestion
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 53 (1.89%)	2 / 38 (5.26%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	2	1	1	2	0	0
Pleural effusion
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 53 (7.55%)	1 / 38 (2.63%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0	4	1	0	0
Pneumonitis
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	2 / 38 (5.26%)	0 / 14 (0.00%)	1 / 28 (3.57%)
occurrences all number	6	0	0	0	4	0	2
Productive cough
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 53 (3.77%)	0 / 38 (0.00%)	0 / 14 (0.00%)	1 / 28 (3.57%)
occurrences all number	4	0	0	2	0	0	1
Pulmonary embolism
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 53 (5.66%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	3	0	0	0
Rhinorrhoea
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	2 / 53 (3.77%)	0 / 38 (0.00%)	0 / 14 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	0	1	2	0	0	1
Upper-airway cough syndrome
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	2 / 14 (14.29%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	2	0
Wheezing
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	5 / 53 (9.43%)	1 / 38 (2.63%)	1 / 14 (7.14%)	1 / 28 (3.57%)
occurrences all number	0	0	0	5	1	1	2
Psychiatric disorders
Anxiety
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	5 / 53 (9.43%)	1 / 38 (2.63%)	1 / 14 (7.14%)	0 / 28 (0.00%)
occurrences all number	1	0	0	5	1	1	0
Confusional state
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 53 (5.66%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0	4	0	0	0
Depression
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 53 (5.66%)	1 / 38 (2.63%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	3	1	0	0
Depressive symptom
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	1 / 14 (7.14%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Disorientation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	1 / 14 (7.14%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Insomnia
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	13 / 53 (24.53%)	1 / 38 (2.63%)	1 / 14 (7.14%)	0 / 28 (0.00%)
occurrences all number	0	2	0	14	1	1	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	11 / 53 (20.75%)	11 / 38 (28.95%)	4 / 14 (28.57%)	8 / 28 (28.57%)
occurrences all number	0	3	0	33	19	6	34
Amylase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 53 (5.66%)	2 / 38 (5.26%)	1 / 14 (7.14%)	2 / 28 (7.14%)
occurrences all number	0	0	0	5	4	2	3
Aspartate aminotransferase increased
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	12 / 53 (22.64%)	9 / 38 (23.68%)	4 / 14 (28.57%)	8 / 28 (28.57%)
occurrences all number	1	5	0	23	16	5	17
Blood alkaline phosphatase
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	2 / 14 (14.29%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	2	0
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	9 / 53 (16.98%)	7 / 38 (18.42%)	1 / 14 (7.14%)	3 / 28 (10.71%)
occurrences all number	0	3	0	34	12	1	5
Blood bilirubin increased
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	3 / 53 (5.66%)	3 / 38 (7.89%)	0 / 14 (0.00%)	1 / 28 (3.57%)
occurrences all number	1	0	1	4	5	0	4
Blood cortisol decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	1 / 14 (7.14%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Blood creatinine increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	5 / 53 (9.43%)	1 / 38 (2.63%)	1 / 14 (7.14%)	1 / 28 (3.57%)
occurrences all number	0	0	0	8	5	2	1
Blood glucose increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	1 / 38 (2.63%)	1 / 14 (7.14%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	2	2	0
Blood lactate dehydrogenase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	3 / 38 (7.89%)	0 / 14 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	0	0	0	3	0	2
Blood urea increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	1 / 14 (7.14%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	8 / 53 (15.09%)	7 / 38 (18.42%)	4 / 14 (28.57%)	5 / 28 (17.86%)
occurrences all number	0	0	0	19	18	10	15
Haemoglobin
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 53 (1.89%)	1 / 38 (2.63%)	0 / 14 (0.00%)	3 / 28 (10.71%)
occurrences all number	0	0	0	1	7	0	3
Lipase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	5 / 53 (9.43%)	1 / 38 (2.63%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	9	2	0	0
Lymphocyte count decreased
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	2	0	0	0	0	0
Monocyte count decreased
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences all number	2	0	0	0	0	0	0
Platelet count decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 53 (7.55%)	1 / 38 (2.63%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	10	1	0	0
Weight decreased
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	14 / 53 (26.42%)	0 / 38 (0.00%)	1 / 14 (7.14%)	3 / 28 (10.71%)
occurrences all number	0	2	0	21	0	1	3
Weight increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 53 (1.89%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	2	0	1	0	0	0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Fall
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 53 (7.55%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	6	0	0	0
Infusion related reaction
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	5 / 53 (9.43%)	3 / 38 (7.89%)	2 / 14 (14.29%)	3 / 28 (10.71%)
occurrences all number	0	0	0	6	4	2	6
Ligament sprain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	1 / 14 (7.14%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 53 (3.77%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	1	0	2	0	0	0
Palpitations
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 53 (1.89%)	2 / 38 (5.26%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	1	2	0	0
Pericardial effusion
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	1 / 14 (7.14%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Sinus tachycardia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 53 (5.66%)	1 / 38 (2.63%)	0 / 14 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	0	0	3	1	0	1
Tachycardia
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	7 / 53 (13.21%)	2 / 38 (5.26%)	1 / 14 (7.14%)	2 / 28 (7.14%)
occurrences all number	0	1	1	7	2	1	2
Nervous system disorders
Dizziness
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	3 / 53 (5.66%)	2 / 38 (5.26%)	1 / 14 (7.14%)	0 / 28 (0.00%)
occurrences all number	0	1	0	3	2	1	0
Dysgeusia
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	3 / 53 (5.66%)	2 / 38 (5.26%)	1 / 14 (7.14%)	0 / 28 (0.00%)
occurrences all number	1	0	1	4	2	1	0
Headache
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 3 (33.33%)	8 / 53 (15.09%)	8 / 38 (21.05%)	2 / 14 (14.29%)	4 / 28 (14.29%)
occurrences all number	1	2	1	13	20	4	4
Hypoaesthesia
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	1 / 38 (2.63%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0	0	1	0	0
Lethargy
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	1 / 14 (7.14%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Neuralgia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	1 / 14 (7.14%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Presyncope
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 53 (1.89%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	1	0	0	0
Somnolence
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	2 / 14 (14.29%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	2	0
Tremor
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	1 / 38 (2.63%)	1 / 14 (7.14%)	1 / 28 (3.57%)
occurrences all number	0	0	0	0	1	1	1
Vocal cord paralysis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	1 / 14 (7.14%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 3 (0.00%)	2 / 3 (66.67%)	0 / 3 (0.00%)	13 / 53 (24.53%)	4 / 38 (10.53%)	0 / 14 (0.00%)	6 / 28 (21.43%)
occurrences all number	0	2	0	31	8	0	10
Lymph node pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	1 / 14 (7.14%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 53 (1.89%)	2 / 38 (5.26%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	1	2	0	0
Vertigo
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 53 (0.00%)	2 / 38 (5.26%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	0	2	0	0
Eye disorders
Asthenopia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	1 / 14 (7.14%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Dry eye
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	1 / 38 (2.63%)	1 / 14 (7.14%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	1	1	0
Eye pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	1 / 14 (7.14%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Retinal exudates
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	1 / 14 (7.14%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Vision blurred
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 53 (3.77%)	1 / 38 (2.63%)	1 / 14 (7.14%)	0 / 28 (0.00%)
occurrences all number	0	0	0	2	1	1	0
Vitreous floaters
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	3 / 53 (5.66%)	2 / 38 (5.26%)	2 / 14 (14.29%)	0 / 28 (0.00%)
occurrences all number	0	2	0	7	2	3	0
Abdominal pain upper
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	1 / 38 (2.63%)	3 / 14 (21.43%)	1 / 28 (3.57%)
occurrences all number	0	0	0	0	3	3	1
Constipation
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	10 / 53 (18.87%)	5 / 38 (13.16%)	3 / 14 (21.43%)	0 / 28 (0.00%)
occurrences all number	1	0	1	15	5	3	0
Diarrhoea
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	2 / 3 (66.67%)	12 / 53 (22.64%)	6 / 38 (15.79%)	2 / 14 (14.29%)	2 / 28 (7.14%)
occurrences all number	0	1	3	37	8	8	2
Dry mouth
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	6 / 53 (11.32%)	2 / 38 (5.26%)	2 / 14 (14.29%)	1 / 28 (3.57%)
occurrences all number	0	0	0	6	2	2	1
Dyspepsia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	2 / 38 (5.26%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	3	0	0
Dysphagia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	1 / 38 (2.63%)	0 / 14 (0.00%)	2 / 28 (7.14%)
occurrences all number	0	0	0	0	1	0	2
Nausea
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	3 / 3 (100.00%)	24 / 53 (45.28%)	18 / 38 (47.37%)	7 / 14 (50.00%)	8 / 28 (28.57%)
occurrences all number	1	7	5	54	22	13	13
Odynophagia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	0 / 14 (0.00%)	2 / 28 (7.14%)
occurrences all number	0	0	0	0	0	0	2
Stomatitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 53 (7.55%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	5	0	0	0
Toothache
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	1 / 38 (2.63%)	1 / 14 (7.14%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	1	1	0
Vomiting
subjects affected / exposed	1 / 3 (33.33%)	2 / 3 (66.67%)	3 / 3 (100.00%)	18 / 53 (33.96%)	10 / 38 (26.32%)	2 / 14 (14.29%)	5 / 28 (17.86%)
occurrences all number	1	3	4	46	19	3	8
Hepatobiliary disorders
Autoimmune hepatitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Skin and subcutaneous tissue disorders
Blister
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 53 (1.89%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	1	0	1	0	0	0
Dry skin
subjects affected / exposed	0 / 3 (0.00%)	2 / 3 (66.67%)	1 / 3 (33.33%)	2 / 53 (3.77%)	2 / 38 (5.26%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	3	1	2	2	0	0
Hyperhidrosis
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	3 / 53 (5.66%)	0 / 38 (0.00%)	2 / 14 (14.29%)	2 / 28 (7.14%)
occurrences all number	0	1	1	3	0	3	3
Lichenoid keratosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	1 / 14 (7.14%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Night sweats
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	2 / 53 (3.77%)	0 / 38 (0.00%)	1 / 14 (7.14%)	0 / 28 (0.00%)
occurrences all number	0	0	1	2	0	1	0
Pruritus generalised
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 53 (1.89%)	0 / 38 (0.00%)	1 / 14 (7.14%)	0 / 28 (0.00%)
occurrences all number	0	0	0	1	0	1	0
Pruritus
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	3 / 3 (100.00%)	16 / 53 (30.19%)	13 / 38 (34.21%)	4 / 14 (28.57%)	4 / 28 (14.29%)
occurrences all number	0	1	3	34	15	7	7
Rash
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	2 / 3 (66.67%)	9 / 53 (16.98%)	10 / 38 (26.32%)	1 / 14 (7.14%)	1 / 28 (3.57%)
occurrences all number	2	1	3	13	13	3	1
Rash maculo-papular
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	4 / 53 (7.55%)	1 / 38 (2.63%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	1	0	9	1	0	0
Skin hypopigmentation
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Urticaria
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 53 (1.89%)	0 / 38 (0.00%)	1 / 14 (7.14%)	0 / 28 (0.00%)
occurrences all number	0	0	1	1	0	1	0
Renal and urinary disorders
Chromaturia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	2 / 38 (5.26%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	7	0	0
Dysuria
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	2 / 38 (5.26%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	2	0	0
Haematuria
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 53 (1.89%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	1	0	1	0	0	0
Pollakiuria
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 53 (1.89%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	3	0	1	0	0	0
Endocrine disorders
Hyperthyroidism
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 53 (7.55%)	1 / 38 (2.63%)	0 / 14 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	0	0	4	1	0	1
Hypothyroidism
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	5 / 53 (9.43%)	2 / 38 (5.26%)	1 / 14 (7.14%)	0 / 28 (0.00%)
occurrences all number	1	0	1	5	2	1	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 3 (33.33%)	12 / 53 (22.64%)	6 / 38 (15.79%)	3 / 14 (21.43%)	5 / 28 (17.86%)
occurrences all number	1	1	5	23	16	3	6
Back pain
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	8 / 53 (15.09%)	4 / 38 (10.53%)	1 / 14 (7.14%)	2 / 28 (7.14%)
occurrences all number	1	1	0	11	6	1	2
Bone pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 53 (5.66%)	0 / 38 (0.00%)	0 / 14 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	0	0	3	0	0	3
Flank pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 53 (5.66%)	0 / 38 (0.00%)	0 / 14 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	0	0	3	0	0	2
Muscular weakness
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 53 (7.55%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	4	0	0	0
Musculoskeletal chest pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 53 (3.77%)	2 / 38 (5.26%)	1 / 14 (7.14%)	1 / 28 (3.57%)
occurrences all number	0	0	0	2	2	1	1
Musculoskeletal pain
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 53 (3.77%)	1 / 38 (2.63%)	2 / 14 (14.29%)	2 / 28 (7.14%)
occurrences all number	1	0	0	4	1	2	2
Myalgia
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	4 / 53 (7.55%)	6 / 38 (15.79%)	1 / 14 (7.14%)	1 / 28 (3.57%)
occurrences all number	0	2	1	4	10	2	1
Neck pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 53 (3.77%)	0 / 38 (0.00%)	1 / 14 (7.14%)	2 / 28 (7.14%)
occurrences all number	0	0	0	3	0	1	2
Ostenonecrosis of jaw
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	1 / 14 (7.14%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Pain in extremity
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 53 (3.77%)	3 / 38 (7.89%)	0 / 14 (0.00%)	5 / 28 (17.86%)
occurrences all number	0	0	0	3	6	0	5
Pain in jaw
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 53 (1.89%)	0 / 38 (0.00%)	1 / 14 (7.14%)	0 / 28 (0.00%)
occurrences all number	0	0	0	2	0	1	0
Muscle rigidity
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 53 (0.00%)	1 / 38 (2.63%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	0	1	0	0
Infections and infestations
Anorectal infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	1 / 14 (7.14%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Candida infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 53 (3.77%)	0 / 38 (0.00%)	1 / 14 (7.14%)	0 / 28 (0.00%)
occurrences all number	0	0	0	2	0	1	0
Fungal infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 53 (0.00%)	1 / 38 (2.63%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	0	1	0	0
Gingivitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	1 / 14 (7.14%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Herpes zoster
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 53 (1.89%)	0 / 38 (0.00%)	1 / 14 (7.14%)	1 / 28 (3.57%)
occurrences all number	0	0	0	2	0	1	1
Localised infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 53 (1.89%)	1 / 38 (2.63%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	1	1	0	0
Lung infection
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Nasopharyngitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 53 (5.66%)	1 / 38 (2.63%)	0 / 14 (0.00%)	2 / 28 (7.14%)
occurrences all number	0	0	0	3	1	0	2
Pharyngitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 53 (0.00%)	0 / 38 (0.00%)	1 / 14 (7.14%)	1 / 28 (3.57%)
occurrences all number	0	0	0	0	0	1	1
Pneumonia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	6 / 53 (11.32%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	8	0	0	0
Respiratory tract infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 53 (1.89%)	0 / 38 (0.00%)	0 / 14 (0.00%)	4 / 28 (14.29%)
occurrences all number	0	0	0	1	0	0	4
Sinusitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 53 (1.89%)	0 / 38 (0.00%)	0 / 14 (0.00%)	2 / 28 (7.14%)
occurrences all number	0	0	0	3	0	0	2
Skin infection
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 53 (1.89%)	0 / 38 (0.00%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	1	0	2	0	0	0
Upper respiratory tract infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 53 (3.77%)	4 / 38 (10.53%)	2 / 14 (14.29%)	0 / 28 (0.00%)
occurrences all number	0	0	0	3	4	2	0
Urinary tract infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 53 (3.77%)	2 / 38 (5.26%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	2	2	0	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	1 / 3 (33.33%)	2 / 3 (66.67%)	1 / 3 (33.33%)	14 / 53 (26.42%)	4 / 38 (10.53%)	4 / 14 (28.57%)	7 / 28 (25.00%)
occurrences all number	1	9	2	15	4	5	8
Dehydration
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	5 / 53 (9.43%)	0 / 38 (0.00%)	0 / 14 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	1	0	10	0	0	1
Hypercalcaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 53 (1.89%)	0 / 38 (0.00%)	0 / 14 (0.00%)	2 / 28 (7.14%)
occurrences all number	0	0	0	1	0	0	3
Hyperglycaemia
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	4 / 53 (7.55%)	1 / 38 (2.63%)	0 / 14 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	1	0	4	1	0	0
Hypokalaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 53 (7.55%)	0 / 38 (0.00%)	0 / 14 (0.00%)	2 / 28 (7.14%)
occurrences all number	0	0	0	4	0	0	5
Hypomagnesaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 53 (5.66%)	0 / 38 (0.00%)	0 / 14 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	0	0	3	0	0	3
Hyponatraemia
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 53 (7.55%)	1 / 38 (2.63%)	0 / 14 (0.00%)	1 / 28 (3.57%)
occurrences all number	1	0	0	6	1	0	1

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Were there any global substantial amendments to the protocol? Yes

10 Oct 2019

- Provide clarification regarding optional biopsies. - Provide clarification regarding confirm. - Regroup the Eligibility Criteria for easier reference. - Relax the requirement to discuss minor study treatment delays with the Medical Monitor. - Provide additional guidance regarding the infusion rate following infusion-related reactions and premedication regimen. - Modify the supportive care guidelines related to elevated liver function tests and cytokine release syndrome. - Add supportive care guidelines for myocarditis toxicity. - Add definition of correlative laboratory testing. - Specify that the dose modification regarding neutropenia related to Grade 3-4 and not Grades 2 to 4. - Remove summary of changes appendices as redline tracked changes versions of the amendment will be provided. - Remove summary of changes appendices as redline versions will be provided.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results:
A Study to Evaluate the Safety and Efficacy of the CD40 Agonistic Antibody APX005M Administered in Combination with Nivolumab in Subjects with Non-small Cell Lung Cancer and Subjects with Metastatic Melanoma

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of Participants Experiencing Dose-limiting Toxicities (DLTs)

Primary: Number of Participants Experiencing Dose-limiting Toxicities (DLTs)

Primary: MTD of APX005M + Nivolumab (Phase 1b)

Primary: MTD of APX005M + Nivolumab (Phase 1b)

Primary: Evaluate the ORR by RECIST 1.1 and iRECIST in Each Cohort / Group (Phase 2)

Primary: Evaluate the ORR by RECIST 1.1 and iRECIST in Each Cohort / Group (Phase 2)

Secondary: Safety of the APX005M and Nivolumab Combination (Phase 2)

Secondary: Safety of the APX005M and Nivolumab Combination (Phase 2)

Secondary: Duration of Response (DOR) as Per RECIST 1.1 (Phase 2)

Secondary: Duration of Response (DOR) as Per RECIST 1.1 (Phase 2)

Secondary: Median Progression-free Survival (PFS) (Phase 2)

Secondary: Median Progression-free Survival (PFS) (Phase 2)

Secondary: 6-month PFS Rate (Phase 2)

Secondary: 6-month PFS Rate (Phase 2)

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical trials

Clinical Trial Results: A Study to Evaluate the Safety and Efficacy of the CD40 Agonistic Antibody APX005M Administered in Combination with Nivolumab in Subjects with Non-small Cell Lung Cancer and Subjects with Metastatic Melanoma

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of Participants Experiencing Dose-limiting Toxicities (DLTs)

Primary: Number of Participants Experiencing Dose-limiting Toxicities (DLTs)

Primary: MTD of APX005M + Nivolumab (Phase 1b)

Primary: MTD of APX005M + Nivolumab (Phase 1b)

Primary: Evaluate the ORR by RECIST 1.1 and iRECIST in Each Cohort / Group (Phase 2)

Primary: Evaluate the ORR by RECIST 1.1 and iRECIST in Each Cohort / Group (Phase 2)

Secondary: Safety of the APX005M and Nivolumab Combination (Phase 2)

Secondary: Safety of the APX005M and Nivolumab Combination (Phase 2)

Secondary: Duration of Response (DOR) as Per RECIST 1.1 (Phase 2)

Secondary: Duration of Response (DOR) as Per RECIST 1.1 (Phase 2)

Secondary: Median Progression-free Survival (PFS) (Phase 2)

Secondary: Median Progression-free Survival (PFS) (Phase 2)

Secondary: 6-month PFS Rate (Phase 2)

Secondary: 6-month PFS Rate (Phase 2)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Study to Evaluate the Safety and Efficacy of the CD40 Agonistic Antibody APX005M Administered in Combination with Nivolumab in Subjects with Non-small Cell Lung Cancer and Subjects with Metastatic Melanoma