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Clinical Trial Results:
A Phase 1b/2, Open Label, Dose Finding Study to Evaluate Safety, Efficacy, Pharmacokinetics and Pharmacodynamics of Avelumab (MSB0010718C) in Combination With Either Crizotinib or PF-06463922 in Patients With Advanced or Metastatic Non Small Cell Lung Cancer

Summary
EudraCT number	2015-001879-43
Trial protocol	ES
Global end of trial date	13 Jul 2022

Results information
Results version number	v1(current)
This version publication date	08 Jul 2023
First version publication date	08 Jul 2023
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

B9991005

ISRCTN number

US NCT number

NCT02584634

WHO universal trial number (UTN)

Sponsor organisation name

Pfizer Inc.

Sponsor organisation address

235 E 42nd Street, New York, United States, NY 10017

Public contact

Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., +1 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com

Scientific contact

Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., +1 8007181021, ClinicalTrials.gov_Inquiries@pfizer.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

13 Jul 2022

Is this the analysis of the primary completion data?

Yes

Primary completion date

02 Feb 2021

Global end of trial reached?

Yes

Global end of trial date

13 Jul 2022

Was the trial ended prematurely?

Yes

Main objective of the trial

The purpose of this study is to evaluate the safety and efficacy of avelumab when combined with either crizotinib or lorlatinib (PF-06463922).

Protection of trial subjects

This study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines. In addition, all local regulatory requirements were followed, in particular, those affording greater protection to the safety of trial subjects.

Background therapy

Evidence for comparator

Actual start date of recruitment

18 Dec 2015

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

24 Months

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 11

Country: Number of subjects enrolled

Japan: 7

Country: Number of subjects enrolled

Korea, Republic of: 10

Country: Number of subjects enrolled

Spain: 6

Country: Number of subjects enrolled

United States: 9

Worldwide total number of subjects

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

Screening details

A total of 66 subjects were screened, and 43 subjects were enrolled into the study.

Period 1 title

Treatment (overall period)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Group A: Avelumab + Crizotinib

Arm description

Subjects with locally advanced or metastatic Anaplastic Lymphoma Kinase (ALK)-negative non-small cell lung cancer (NSCLC) received avelumab 10 mg/kg as a 1-hour intravenous (IV) infusion once every 2 weeks (Day 1 of each cycle) and crizotinib 250 mg orally twice a day (BID) on a continuous daily dosing schedule.

Arm type

Experimental

Investigational medicinal product name

Avelumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

The subjects received avelumab 10 mg/kg as a 1-hour intravenous (IV) infusion once every 2 weeks (Day 1 of each cycle)

Investigational medicinal product name

Crizotinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

The subjects received crizotinib 250 mg (starting dose) orally twice a day (BID).

Group B: Avelumab + Lorlatinib

Arm description

Subjects with locally advanced or metastatic ALK-positive NSCLC received avelumab 10 mg/kg as a 1-hour IV infusion once every 2 weeks (Day 1 of each cycle) and lorlatinib 100 mg orally once a day (QD) on a continuous daily dosing schedule.

Arm type

Experimental

Investigational medicinal product name

PF-06463922

Investigational medicinal product code

Other name

Lorlatinib

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

The subjects received PF-06463922 100 mg (starting dose) orally once a day (QD).

Investigational medicinal product name

Avelumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

The subjects received avelumab 10 mg/kg as a 1-hour intravenous (IV) infusion once every 2 weeks (Day 1 of each cycle)

Number of subjects in period 1	Group A: Avelumab + Crizotinib	Group B: Avelumab + Lorlatinib
Started	12	31
Completed	0	0
Not completed	12	31
Adverse event, not serious	1	4
Adverse event, serious fatal	-	1
Physician decision	1	2
Consent withdrawn by subject	1	1
Death	-	1
Adverse event, serious non-fatal	2	-
Unspecified	-	6
Progressive disease	7	15
Lost to follow-up	-	1

Baseline characteristics

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Reporting group title

Group A: Avelumab + Crizotinib

Reporting group description

Reporting group title

Group B: Avelumab + Lorlatinib

Reporting group description

Reporting group values	Group A: Avelumab + Crizotinib	Group B: Avelumab + Lorlatinib	Total
Number of subjects	12	31	43
Age Categorical
Units: Subjects
Adults (18-64 years)	9	25	34
Adults (65-84 years)	3	6	9
Adults (85 years and over)	0	0	0
Age Continuous
Units: Years
arithmetic mean (standard deviation)	58.67 ± 10.43	53.32 ± 11.59	-
Sex: Female, Male
Units: Subjects
Female	6	19	25
Male	6	12	18
Race
Units: Subjects
American Indian or Alaska Native	0	1	1
Asian	8	17	25
White	4	13	17
Black or African American	0	0	0
Native Hawaiian or Other Pacific Islander	0	0	0
Other	0	0	0
Unknown	0	0	0
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	0	1	1
Not Hispanic or Latino	11	30	41
Not Reported	1	0	1
Unknown	0	0	0
Age Range
Units: Years
median (full range (min-max))	59.5 (43 to 76)	54 (30 to 77)	-

End points

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Reporting group title

Group A: Avelumab + Crizotinib

Reporting group description

Reporting group title

Group B: Avelumab + Lorlatinib

Reporting group description

Primary: Number of Subjects With Dose-limiting Toxicities (DLTs): Phase 1b

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End point title

Number of Subjects With Dose-limiting Toxicities (DLTs): Phase 1b ^[1]

End point description

Any of the following adverse events occurring during the primary DLT observation period (the first 28 days [D]) were classified as DLTs: Grade (G) 4 neutropenia if >7 D; febrile neutropenia; G >=3 neutropenic infection; G >=3 thrombocytopenia with bleeding; G4 thrombocytopenia >7 D; G4 anemia; any G >=3 toxicity, except for any of the following: transient (<=6 h) G3 flu like symptoms or fever; transient (<=24 h) G3 fatigue, local reactions, or headache resolved to G <=1; G3 nausea and/or vomiting, diarrhea or skin toxicity resolved to G <=1 within 7 D; any G >=3 amylase or lipase abnormality; tumor flare phenomenon; single laboratory values out of normal range that weren’t related to treatment, didn’t have any clinical correlate, and resolve to Grade <=1 within 7 D. The analysis population included all subjects enrolled in Phase 1b who received at least 1 dose of study drug, and either experienced DLT during, or completed the observation period.

End point type

Primary

End point timeframe

First 2 cycles (1 cycle = 14 days)

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 statistical analysis was planned for this endpoint

End point values	Group A: Avelumab + Crizotinib	Group B: Avelumab + Lorlatinib
Number of subjects analysed	12	28
Units: Subjects	5	2

No statistical analyses for this end point

Primary: Percentage of Subjects With Objective Response (OR): Phase 2

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End point title

Percentage of Subjects With Objective Response (OR): Phase 2 ^[2]

End point description

OR is defined as complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 from the start date until disease progression or death. Both CR and PR were confirmed by repeat assessments performed >=4 weeks after the criteria for response are first met. Per RECIST v1.1: CR was defined as the disappearance of all target or non-target lesions; any pathological lymph nodes (whether target or non-target) had reduction in short axis to <10 mm and all lymph nodes were non-pathological in size (<10 mm short axis). PR was defined as a >=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions. The analysis population included all subjects who received at least 1 dose of study drug. Subjects were classified according to the study treatment received. If a subject received more than 1 treatment, the subject was classified according to the first treatment received.

End point type

Primary

End point timeframe

Screening, Day 1 of each cycle starting Cycle 3, up to end of treatment/withdrawal (maximum of 5 years)

Notes
[2] - 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 statistical analysis was planned for this endpoint

End point values	Group A: Avelumab + Crizotinib	Group B: Avelumab + Lorlatinib
Number of subjects analysed	12	31
Units: Percentage of subjects
number (confidence interval 95%)	25.0 (5.5 to 57.2)	51.6 (33.1 to 69.8)

No statistical analyses for this end point

Primary: Percentage of Subjects With CR for Group B: Phase 2

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End point title

Percentage of Subjects With CR for Group B: Phase 2 ^[3] ^[4]

End point description

Per RECIST v1.1: CR was defined as the disappearance of all target or non-target lesions; any pathological lymph nodes (whether target or non-target) had reduction in short axis to <10 mm and all lymph nodes were non-pathological in size (<10 mm short axis). The analysis population included all subjects who received at least one dose of study drug in Group B. Subjects were classified according to the study treatment actually received. If a subject received more than one treatment the subject was classified according to the first treatment received. Results for Group A are not reported for this end point according to the protocol.

End point type

Primary

End point timeframe

Baseline up to 60 months

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 statistical analysis was planned for this endpoint
[4] - 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: Statistics were reported for the arms specified

End point values	Group B: Avelumab + Lorlatinib
Number of subjects analysed	31
Units: Percentage of subjects
number (not applicable)	3.2

No statistical analyses for this end point

Secondary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs)

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End point title

Number of Subjects With Treatment-Emergent Adverse Events (TEAEs)

End point description

TEAEs are those adverse events (AEs) with onset dates during the on-treatment period for the first time or if the worsening of an AE is during the on-treatment period. Treatment-related (TR) AEs was any untoward medical occurrence attributed to study drug in a subject who received study drug. Per NCI CTCAE v4.03: Grade 3 (G3) events=severe AEs; G4 events=life-threatening consequences, urgent intervention indicated; G5 events=death related to an AE. A serious AE (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in subject hospitalization; life-threatening experience; persistent or significant disability/incapacity; congenital anomaly. The analysis population included all subjects who received at least 1 dose of study drug. Subjects were classified according to the study drug received. If a subject received more than 1 study treatment, the subject was classified according to the first treatment received.

End point type

Secondary

End point timeframe

Baseline up to 30 days after last dose of study treatment or the day before start day of new anti-cancer therapy (maximum of 5 years)

End point values	Group A: Avelumab + Crizotinib	Group B: Avelumab + Lorlatinib
Number of subjects analysed	12 ^[5]	31 ^[6]
Units: Subjects
Subjects with TEAEs (n=12, 31)	12	30
Subjects with G >=3 TEAEs (n=12, 31)	7	23
Subjects with TR TEAEs (n=12, 31)	12	28
Subjects with G >=3 TR TEAEs (n=12, 31)	6	16
Subjects with SAEs (n=12, 31)	5	21
Subjects with TR SAEs (n=12, 31)	2	6
Subjects Discont A due to TEAEs (n=12, 31)	3	10
Subjects Discont C due to TEAEs (n=12, 0)	6	99999
Subjects Discont L due to TEAEs (n=0, 31)	99999	2
Subjects Discont A, C, or L due to TEAE (n=12, 31)	6	10
Subjects Discont A, C, and L due to TEAE(n=12, 31)	3	1
Subjects Discont A due to TR TEAE (n=12, 31)	2	9
Subjects Discont C due to TR TEAE (n=12, 0)	5	99999
Subjects Discont L due to TR TEAE (n=0, 31)	99999	2
Subjects with TEAEs leading to death (n=12, 31)	1	4
Subjects with TR TEAEs leading to death (n=12, 31)	0	1
Subjects with infusion-related reactions (n=12,31)	5	9

Notes
[5] - 99999=not applicable; Discont.=discontinued; A = avelumab; C= crizotinib; L= lorlatinib
[6] - 99999=not applicable; Discont.=discontinued; A = avelumab; C= crizotinib; L= lorlatinib

No statistical analyses for this end point

Secondary: Number of Subjects with Baseline Laboratory Abnormalities Grade <=2 and Post-Baseline Laboratory Abnormalities of Grades 3 or 4 per NCI CTCAE v4.03

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End point title

Number of Subjects with Baseline Laboratory Abnormalities Grade <=2 and Post-Baseline Laboratory Abnormalities of Grades 3 or 4 per NCI CTCAE v4.03

End point description

The laboratory (lab) results were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03 severity grade. G1=mild AE. G2=moderate AE. G3=severe AE. G4=life-threatening consequences; urgent intervention indicated. Shift tables were provided to examine the distribution of lab toxicities. The parameters met the criteria of CTCAE grade shift change from G <=2 at baseline to G3 or 4 post baseline were presented. The analysis population included all subjects who received at least one dose of study drug and who could be evaluated for CTCAE criteria for each parameter in each treatment group. Subjects were classified according to the study treatment received. If a subject received more than 1 study treatment, the subject was classified according to the first treatment received.

End point type

Secondary

End point timeframe

Screening up to end of treatment/withdrawal (maximum of 5 years)

End point values	Group A: Avelumab + Crizotinib	Group B: Avelumab + Lorlatinib
Number of subjects analysed	12	31
Units: Subjects
Anemia	0	3
Lymphocyte count decreased	1	2
Lymphocyte count increased	0	2
Neutrophil count decreased	1	0
White blood cell decreased	1	0
Alanine aminotransferase increased	3	0
Aspartate aminotransferase increased	2	1
Blood bilirubin increased	0	1
Cholesterol high	0	5
Creatine phosphokinase increased	0	2
GGT increased	1	5
Hypercalcemia	0	2
Hyperglycemia	1	1
Hypermagnesemia	0	1
Hypertriglyceridemia	0	7
Hypoalbuminemia	0	1
Hyponatremia	1	3
Lipase increased	1	5
Serum amylase increased	0	1
Hemoglobin increased	0	0
Platelet count decreased	0	0
Alkaline phosphatase increased	0	0
Creatinine increased	0	0
Hyperkalemia	0	0
Hypernatremia	0	0
Hypocalcemia	0	0
Hypoglycemia	0	0
Hypokalemia	0	0
Hypomagnesemia	0	0
Hypophosphatemia	0	0

No statistical analyses for this end point

Secondary: Number of Subjects With Vital Signs Meeting Pre-defined Criteria

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End point title

Number of Subjects With Vital Signs Meeting Pre-defined Criteria

End point description

Pre-defined criteria in vital signs: pulse rate <50 beats per minute (bpm), pulse rate >120 bpm, sitting diastolic blood pressure (DBP) increase and decrease in change from baseline of >= 20 millimeter of mercury (mmHg), sitting systolic blood pressure(SBP) < 90 mmHg, increase and decrease in change from baseline of >= 30mmHg. Baseline is defined as the last assessment prior to the date/time of the first dose of study treatment. The analysis population included all subjects who received at least 1 dose of study drug. Subjects were classified according to the study treatment actually received. If a subject received more than 1 study treatment, the subject was classified according to the first treatment received.

End point type

Secondary

End point timeframe

Screening up to end of treatment/withdrawal (maximum of 5 years)

End point values	Group A: Avelumab + Crizotinib	Group B: Avelumab + Lorlatinib
Number of subjects analysed	12	31
Units: Subjects
Pulse rate <50 bpm	2	0
Pulse rate >120 bpm	0	4
Sitting DBP change >= 20 mmHg increase	2	13
Sitting DBP change >= 20 mmHg decrease	5	8
Sitting SBP <90 mmHg	1	4
Sitting SBP change >= 30 mmHg increase	1	11
Sitting SBP change >= 30 mmHg decrease	3	2

No statistical analyses for this end point

Secondary: Time to Tumor Response (TTR)

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End point title

Time to Tumor Response (TTR)

End point description

TTR is defined, for subjects with an objective response (CR or PR), as the time from the start date (the date of first dose of treatment) to the first documentation of objective response (CR or PR) which is subsequently confirmed. Per RECIST v1.1: CR: disappearance of all non-nodal target lesions and of all non-target lesions. In addition, any pathological lymph nodes assigned as target lesions/ non-target lesions must have a reduction in short axis to <10 mm. PR: at least a 30% decrease in sum of diameter of all target lesions, taking as reference baseline sum of diameters. The analysis population included all subjects who received at least one dose of study drug and who had confirmed complete response or partial response. Subjects were classified according to the study treatment actually received. If a subject received more than one treatment the subject was classified according to the first treatment received.

End point type

Secondary

End point timeframe

Screening, Day 1 of each cycle starting Cycle 3, up to end of treatment/withdrawal (maximum of 5 years)

End point values	Group A: Avelumab + Crizotinib	Group B: Avelumab + Lorlatinib
Number of subjects analysed	3	16
Units: Months
median (full range (min-max))	1.4 (1.4 to 6.9)	1.8 (1.3 to 3.7)

No statistical analyses for this end point

Secondary: Disease Control Rate (DCR)

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End point title

Disease Control Rate (DCR)

End point description

DC is defined as OR (CR or PR) or stable disease (SD) per RECIST v.1.1 from the date of first dose of study treatment until disease progression or death due to any cause. The DCR is the proportion of patients with DC. Per RECIST v1.1: SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD). PD is defined as a >=20% increase in the sum of the longest dimensions of the target lesions taking as a reference the smallest sum of the longest dimensions recorded since the treatment started, or the appearance of one or more new lesions. The analysis population included all subjects who received at least 1 dose of study drug. Subjects were classified according to the study treatment received. If a subject received more than 1 study treatment, the subject was classified according to the first treatment received.

End point type

Secondary

End point timeframe

Screening, Day 1 of each cycle starting Cycle 3, up to end of treatment/withdrawal (maximum of 5 years)

End point values	Group A: Avelumab + Crizotinib	Group B: Avelumab + Lorlatinib
Number of subjects analysed	12	31
Units: Percentage of subjects
number (confidence interval 95%)	58.3 (27.7 to 84.8)	71.0 (52.0 to 85.8)

No statistical analyses for this end point

Secondary: Duration of Response (DR)

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End point title

Duration of Response (DR)

End point description

DR: time from first documented occurrence of response (PR or CR) until date of first documented PD or death due to underlying cancer. Subjects with no PD and were still alive by 02 Feb 2020, were censored at last adequate tumor assessment. Kaplan-Meier method was used for DR analysis. The analysis population included all subjects who received at least 1 dose of study drug and who had confirmed complete response or partial response. Subjects were classified according to the study treatment received. If a subject received more than one treatment the subject was classified according to the first treatment received. 99999 = not estimable

End point type

Secondary

End point timeframe

Screening, Day 1 of each cycle starting Cycle 3, up to end of treatment/withdrawal (maximum of 5 years)

End point values	Group A: Avelumab + Crizotinib	Group B: Avelumab + Lorlatinib
Number of subjects analysed	3	16
Units: Month
median (confidence interval 95%)	3.7 (3.7 to 4.6)	14.7 (3.7 to 99999)

No statistical analyses for this end point

Secondary: Progression-free Survival (PFS)

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End point title

Progression-free Survival (PFS)

End point description

PFS is defined as the time from start date (the date of first dose of treatment) to the date of the first documentation of PD per RECIST v1.1 or death due to any cause, whichever occurs first. Per RECIST v1.1: PD: a >=20% increase in the sum of the longest dimensions of the target lesions taking as a reference the smallest sum of the longest dimensions recorded since the treatment started, or the appearance of one or more new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The analysis population included all subjects who received at least 1 dose of study drug. Subjects were classified according to the study treatment actually received. If a subject received more than 1 study treatment, the subject was classified according to the first treatment received.

End point type

Secondary

End point timeframe

Screening, Day 1 of each cycle starting Cycle 3, up to end of treatment/withdrawal (maximum of 5 years)

End point values	Group A: Avelumab + Crizotinib	Group B: Avelumab + Lorlatinib
Number of subjects analysed	12	31
Units: Months
median (confidence interval 95%)	3.7 (1.5 to 5.5)	6.4 (3.7 to 9.2)

No statistical analyses for this end point

Secondary: Kaplan-Meier Estimates of Overall Survival (OS)

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End point title

Kaplan-Meier Estimates of Overall Survival (OS)

End point description

OS is defined as the time from start date (the date of first dose of treatment) to the date of death due to any cause. The analysis population included all subjects who received at least 1 dose of study drug. Subjects were classified according to the study treatment actually received. If a subject received more than 1 study treatment, the subject was classified according to the first treatment received. 99999 = not estimable

End point type

Secondary

End point timeframe

Screening, Day 1 of each cycle starting Cycle 3, up to end of treatment/withdrawal (maximum of 5 years)

End point values	Group A: Avelumab + Crizotinib	Group B: Avelumab + Lorlatinib
Number of subjects analysed	12	31
Units: Months
median (confidence interval 95%)	16.4 (5.4 to 27.6)	32.9 (10.7 to 99999)

No statistical analyses for this end point

Secondary: Maximum Plasma Concentration (Cmax) of Crizotinib in The Presence of Avelumab

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End point title

Maximum Plasma Concentration (Cmax) of Crizotinib in The Presence of Avelumab ^[7]

End point description

Cmax of crizotinib in the presence of avelumab was observed directly from data. The analysis population included subjects who received at least 1 dose of study drug and who had at least 1 of the pharmacokinetic (PK) parameters of interest for crizotinib in Group A. Group B was not evaluable for this end point.

End point type

Secondary

End point timeframe

Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Day 1 of Cycle 2

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: Statistics were reported for the arms specified

End point values	Group A: Avelumab + Crizotinib
Number of subjects analysed	10
Units: nanograms per millilitre (ng/mL)
geometric mean (geometric coefficient of variation)	281 ± 74

No statistical analyses for this end point

Secondary: Cmax of Crizotinib Metabolite PF-06260182 in The Presence of Avelumab

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End point title

Cmax of Crizotinib Metabolite PF-06260182 in The Presence of Avelumab ^[8]

End point description

Cmax of crizotinib metabolite PF-06260182 in the presence of avelumab was observed directly from data. The analysis population included subjects who received at least one dose of study drug and who had at least one of the PK parameters of interest for crizotinib in Group A. Group B was not evaluable for this end point.

End point type

Secondary

End point timeframe

Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Day 1 of Cycle 2

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: Statistics were reported for the arms specified

End point values	Group A: Avelumab + Crizotinib
Number of subjects analysed	10
Units: ng/mL
geometric mean (geometric coefficient of variation)	84.11 ± 91

No statistical analyses for this end point

Secondary: Area Under The Plasma Concentration‑time Curve During The Dosing Interval Time Course (AUCtau) of Crizotinib in The Presence of Avelumab

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End point title

Area Under The Plasma Concentration‑time Curve During The Dosing Interval Time Course (AUCtau) of Crizotinib in The Presence of Avelumab ^[9]

End point description

AUCtau of crizotinib in the presence of avelumab was caculated by Linear/Log trapezoidal method. Dose interval is defined as after single dose from time zero to the next dose (after single dose and at steady state). The analysis population included subjects who received at least one dose of study drug and who had at least one of the PK parameters of interest for crizotinib in Group A. Group B was not evaluable for this end point.

End point type

Secondary

End point timeframe

Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Day 1 of Cycle 2

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: Statistics were reported for the arms specified

End point values	Group A: Avelumab + Crizotinib
Number of subjects analysed	10
Units: nanogramshours per millilitre (ngh/mL)
geometric mean (geometric coefficient of variation)	2755 ± 82

No statistical analyses for this end point

Secondary: Apparent Plasma Clearance (CL/F) of Crizotinib in The Presence of Avelumab

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End point title

Apparent Plasma Clearance (CL/F) of Crizotinib in The Presence of Avelumab ^[10]

End point description

Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. The analysis population included subjects who received at least one dose of study drug and who had at least one of the PK parameters of interest for crizotinib in Group A. Group B was not evaluable for this end point.

End point type

Secondary

End point timeframe

Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Day 1 of Cycle 2

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: Statistics were reported for the arms specified

End point values	Group A: Avelumab + Crizotinib
Number of subjects analysed	10
Units: Liters per hour (L/h)
geometric mean (geometric coefficient of variation)	90.76 ± 82

No statistical analyses for this end point

Secondary: Time to Cmax (Tmax) of Crizotinib in The Presence of Avelumab

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End point title

Time to Cmax (Tmax) of Crizotinib in The Presence of Avelumab ^[11]

End point description

Tmax of crizotinib in the presence of avelumab was observed directly from data as time of first occurrence. The analysis population included subjects who received at least one dose of study drug and who had at least one of the PK parameters of interest for crizotinib in Group A. Group B was not evaluable for this end point.

End point type

Secondary

End point timeframe

Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Day 1 of Cycle 2

Notes
[11] - 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: Statistics were reported for the arms specified

End point values	Group A: Avelumab + Crizotinib
Number of subjects analysed	10
Units: Hours
median (full range (min-max))	2.03 (0.00 to 8.08)

No statistical analyses for this end point

Secondary: Metabolite to Parent Ratio for Cmax (MRCmax) of PF-06260182 in The Presence of Avelumab

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End point title

Metabolite to Parent Ratio for Cmax (MRCmax) of PF-06260182 in The Presence of Avelumab ^[12]

End point description

MRCmax of metabolite PF-06260182 in the presence of avelumab was caculated (MRCmax=Metabolite Cmax/parent Cmax). Parent=crizotinib, metabolite=PF-06260182. The analysis population included subjects who received at least one dose of study drug and who had at least one of the PK parameters of interest for crizotinib in Group A. Group B was not evaluable for this end point.

End point type

Secondary

End point timeframe

Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Day 1 of Cycle 2

Notes
[12] - 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: Statistics were reported for the arms specified

End point values	Group A: Avelumab + Crizotinib
Number of subjects analysed	10
Units: Ratio
geometric mean (geometric coefficient of variation)	0.2902 ± 25

No statistical analyses for this end point

Secondary: Metabolite to Parent Ratio for AUCtau (MRAUCtau) of PF-06260182 in The Presence of Avelumab

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End point title

Metabolite to Parent Ratio for AUCtau (MRAUCtau) of PF-06260182 in The Presence of Avelumab ^[13]

End point description

MRAUCtau of metabolite PF-06260182 in the presence of avelumab was caculated (MRAUCtau=Metabolite AUCtau/parent AUCtau). Parent=crizotinib, metabolite=PF-06260182. The analysis population included subjects who received at least one dose of study drug and who had at least one of the PK parameters of interest for crizotinib in Group A. Group B was not evaluable for this end point.

End point type

Secondary

End point timeframe

Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Day 1 of Cycle 2

Notes
[13] - 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: Statistics were reported for the arms specified

End point values	Group A: Avelumab + Crizotinib
Number of subjects analysed	10
Units: Ratio
geometric mean (geometric coefficient of variation)	0.2779 ± 33

No statistical analyses for this end point

Secondary: Tmax of Crizotinib Metabolite PF-06260182 in The Presence of Avelumab

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End point title

Tmax of Crizotinib Metabolite PF-06260182 in The Presence of Avelumab ^[14]

End point description

Tmax of crizotinib metabolite PF-06260182 in the presence of avelumab was observed directly from data as time of first occurrence. The analysis population included subjects who received at least one dose of study drug and who had at least one of the PK parameters of interest for crizotinib in Group A. Group B was not evaluable for this end point.

End point type

Secondary

End point timeframe

Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Day 1 of Cycle 2

Notes
[14] - 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: Statistics were reported for the arms specified

End point values	Group A: Avelumab + Crizotinib
Number of subjects analysed	10
Units: Hours
median (full range (min-max))	3.02 (0.00 to 8.08)

No statistical analyses for this end point

Secondary: AUCtau of Crizotinib Metabolite PF-06260182 in The Presence of Avelumab

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End point title

AUCtau of Crizotinib Metabolite PF-06260182 in The Presence of Avelumab ^[15]

End point description

AUCtau of crizotinib metabolite PF-06260182 in the presence of avelumab was caculated by Linear/Log trapezoidal method. Dose interval: single dose from time zero to the next dose (after single dose and at steady state). The analysis population included subjects who received at least one dose of study drug and who had at least one of the PK parameters of interest for crizotinib in Group A. Group B was not evaluable for this end point.

End point type

Secondary

End point timeframe

Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Day 1 of Cycle 2

Notes
[15] - 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: Statistics were reported for the arms specified

End point values	Group A: Avelumab + Crizotinib
Number of subjects analysed	10
Units: ng*h/mL
geometric mean (geometric coefficient of variation)	789.1 ± 116

No statistical analyses for this end point

Secondary: Cmax of Lorlatinib in The Presence of Avelumab

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End point title

Cmax of Lorlatinib in The Presence of Avelumab ^[16]

End point description

Cmax of lorlatinib in the presence of avelumab was observed directly from data. The analysis population included subjects who received at least one dose of study drug and who had at least one of the PK parameters of interest for lorlatinib in Group B. Group A is not evaluable for this end point.

End point type

Secondary

End point timeframe

Pre-dose, 1, 2, 4, 6, 8, and 24 hours (prior to Day 2 lorlatinib dose) post dose on Day 1 of Cycle 2

Notes
[16] - 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: Statistics were reported for the arms specified

End point values	Group B: Avelumab + Lorlatinib
Number of subjects analysed	26
Units: ng/mL
geometric mean (geometric coefficient of variation)	596.9 ± 33

No statistical analyses for this end point

Secondary: Tmax of Lorlatinib in The Presence of Avelumab

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End point title

Tmax of Lorlatinib in The Presence of Avelumab ^[17]

End point description

Tmax of lorlatinib in the presence of avelumab was observed directly from data. The analysis population included subjects who received at least one dose of study drug and who had at least one of the PK parameters of interest for lorlatinib in Group B. Group A is not evaluable for this end point.

End point type

Secondary

End point timeframe

Pre-dose, 1, 2, 4, 6, 8, and 24 hours (prior to Day 2 lorlatinib dose) post dose on Day 1 of Cycle 2

Notes
[17] - 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: Statistics were reported for the arms specified

End point values	Group B: Avelumab + Lorlatinib
Number of subjects analysed	26
Units: Hours
median (full range (min-max))	1.23 (0.933 to 4.33)

No statistical analyses for this end point

Secondary: Area Under The Plasma Concentration Time Curve From Time of Dosing to The Last Collection Time Point (AUClast) of Lorlatinib in The Presence of Avelumab

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End point title

Area Under The Plasma Concentration Time Curve From Time of Dosing to The Last Collection Time Point (AUClast) of Lorlatinib in The Presence of Avelumab ^[18]

End point description

AUClast of lorlatinib in the presence of avelumab. The analysis population included subjects who received at least one dose of study drug and who had at least one of the PK parameters of interest for lorlatinib in Group B. Group A is not evaluable for this end point.

End point type

Secondary

End point timeframe

Pre-dose, 1, 2, 4, 6, 8, and 24 hours (prior to Day 2 lorlatinib dose) post dose on Day 1 of Cycle 2

Notes
[18] - 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: Statistics were reported for the arms specified

End point values	Group B: Avelumab + Lorlatinib
Number of subjects analysed	26
Units: ng*h/mL
geometric mean (geometric coefficient of variation)	4872 ± 52

No statistical analyses for this end point

Secondary: CL/F of Lorlatinib in The Presence of Avelumab

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End point title

CL/F of Lorlatinib in The Presence of Avelumab ^[19]

End point description

Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population PK modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. The analysis population included subjects who received at least one dose of study drug and who had at least one of the PK parameters of interest for lorlatinib in Group B. Group A is not evaluable for this end point.

End point type

Secondary

End point timeframe

Pre-dose, 1, 2, 4, 6, 8, and 24 hours (prior to Day 2 lorlatinib dose) post dose on Day 1 of Cycle 2

Notes
[19] - 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: Statistics were reported for the arms specified

End point values	Group B: Avelumab + Lorlatinib
Number of subjects analysed	19
Units: L/h
geometric mean (geometric coefficient of variation)	16.97 ± 44

No statistical analyses for this end point

Secondary: Cmax of Avelumab in The Presence of Crizotinib (Group A) or Lorlatinib (Group B) After Single Dose of Avelumab

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End point title

Cmax of Avelumab in The Presence of Crizotinib (Group A) or Lorlatinib (Group B) After Single Dose of Avelumab

End point description

Cmax of avelumab in the presence of crizotinib was observed directly from the data in Group A. Cmax of avelumab in the presence of lorlatinib was observed directly from the data in Group B. The analysis population included subjects who received at least one dose of study drug and who had at least one post-dose concentration measurement above the lower limit of quantification for avelumab.

End point type

Secondary

End point timeframe

Pre-dose, 1, and 168 hours post dose of avelumab on Cycle 1 Day 1.

End point values	Group A: Avelumab + Crizotinib	Group B: Avelumab + Lorlatinib
Number of subjects analysed	8	16
Units: micrograms/milliliter (ug/mL)
geometric mean (geometric coefficient of variation)	193.2 ± 14	195.7 ± 28

No statistical analyses for this end point

Secondary: AUCtau of Lorlatinib in The Presence of Avelumab

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End point title

AUCtau of Lorlatinib in The Presence of Avelumab ^[20]

End point description

AUCtau of lorlatinib in the presence of avelumab was caculated by Linear/Log trapezoidal method. Dose interval: single dose from time zero to the next dose (after single dose and at steady state). The analysis population included subjects who received at least one dose of study drug and who had at least one of the PK parameters of interest for lorlatinib in Group B. Group A is not evaluable for this end point.

End point type

Secondary

End point timeframe

Pre-dose, 1, 2, 4, 6, 8, and 24 hours (prior to Day 2 lorlatinib dose) post dose on Day 1 of Cycle 2

Notes
[20] - 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: Statistics were reported for the arms specified

End point values	Group B: Avelumab + Lorlatinib
Number of subjects analysed	19
Units: ng*h/mL
geometric mean (geometric coefficient of variation)	5807 ± 42

No statistical analyses for this end point

Secondary: Cmax of Avelumab in The Presence of Crizotinib (Group A) or Lorlatinib (Group B) After Multiple Doses of Avelumab

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End point title

Cmax of Avelumab in The Presence of Crizotinib (Group A) or Lorlatinib (Group B) After Multiple Doses of Avelumab

End point description

End point type

Secondary

End point timeframe

Pre-dose, 1, and 168 hours post dose of avelumab on Cycle 2 Day 1

End point values	Group A: Avelumab + Crizotinib	Group B: Avelumab + Lorlatinib
Number of subjects analysed	8	17
Units: ug/mL
geometric mean (geometric coefficient of variation)	174.5 ± 35	169.4 ± 68

No statistical analyses for this end point

Secondary: Trough Serum Concentration (Ctrough) of Avelumab in The Presence of Crizotinib (Group A) Following Multiple Doses of Avelumab

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End point title

Trough Serum Concentration (Ctrough) of Avelumab in The Presence of Crizotinib (Group A) Following Multiple Doses of Avelumab ^[21]

End point description

Ctrough is defined as predose concentration following multiple doses. Ctrough of avelumab in the presence of crizotinib was observed directly from the data in Group A. The analysis population included subjects who received at least one dose of study drug and who had least one observation. Number of Subjects Analyzed represents the total number of subjects in the analysis population for this end point. "n" represents the number of subjects with concentration measurement above lower limit of quantification at each visit. Group B was not evaluable for this end point.

End point type

Secondary

End point timeframe

Pre-dose on Day 1 of Cycles 2-5, 11, 17, 23, 29, 35, and 47.

Notes
[21] - 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: Statistics were reported for the arms specified

End point values	Group A: Avelumab + Crizotinib
Number of subjects analysed	12
Units: ug/mL
geometric mean (geometric coefficient of variation)
Cycle 2 Day 1 (n=7)	11.76 ± 68
Cycle 3 Day 1 (n=6)	16.26 ± 53
Cycle 4 Day 1 (n=7)	16.71 ± 34
Cycle 5 Day 1 (n=5)	14.21 ± 46
Cycle 11 Day 1 (n=2)	26.64 ± 4
Cycle 17 Day 1 (n=2)	30.59 ± 9
Cycle 23 Day 1 (n=2)	30.63 ± 15
Cycle 29 Day 1 (n=2)	30.72 ± 55
Cycle 35 Day 1 (n=2)	37.31 ± 27
Cycle 47 Day 1 (n=2)	40.91 ± 15

No statistical analyses for this end point

Secondary: Trough Serum Concentration (Ctrough) of Avelumab in The Presence of Lorlatinib (Group B) Following Multiple Doses of Avelumab

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End point title

Trough Serum Concentration (Ctrough) of Avelumab in The Presence of Lorlatinib (Group B) Following Multiple Doses of Avelumab ^[22]

End point description

Ctrough is defined as predose concentration following multiple doses. Ctrough of avelumab in the presence of lorlatinib was observed directly from the data in Group B. The analysis population included subjects who received at least one dose of study drug and who had least one observation. Number of Subjects Analyzed represents the total number of subjects in the analysis population for this end point. "n" represents the number of subjects with concentration measurement above lower limit of quantification at each visit. Group A was not evaluable for this end point.

End point type

Secondary

End point timeframe

Pre-dose on Day 1 of Cycles 2-5, 11, 17, 23, 29, 35, 41, and 47.

Notes
[22] - 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: Statistics were reported for the arms specified

End point values	Group B: Avelumab + Lorlatinib
Number of subjects analysed	25
Units: ug/mL
geometric mean (geometric coefficient of variation)
Cycle 2 Day 1 (n=22)	16.86 ± 88
Cycle 3 Day 1 (n=19)	16.99 ± 116
Cycle 4 Day 1 (n=21)	23.71 ± 80
Cycle 5 Day 1 (n=16)	26.74 ± 68
Cycle 11 Day 1 (n=15)	31.31 ± 71
Cycle 17 Day 1 (n=13)	32.69 ± 60
Cycle 23 Day 1 (n=11)	33.20 ± 56
Cycle 29 Day 1 (n=10)	25.77 ± 66
Cycle 35 Day 1 (n=10)	31.27 ± 47
Cycle 41 Day 1 (n=7)	30.81 ± 59
Cycle 47 Day 1 (n=8)	39.63 ± 64

No statistical analyses for this end point

Secondary: Number of Subjects With Anti-Drug Antibodies (ADA) Against Avelumab by Never and Ever Positive Status

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End point title

Number of Subjects With Anti-Drug Antibodies (ADA) Against Avelumab by Never and Ever Positive Status

End point description

ADA never-positive was defined as no positive ADA results at any time point. ADA ever-positive was defined as at least one positive ADA result at any time point. Baseline is defined as the last assessment on or prior to the date/time of the first dose of avelumab. The analysis population was a subset of the safety analysis set (all subjects who received at least one dose of study drug) and included subjects who had at least one ADA sample collected for avelumab.

End point type

Secondary

End point timeframe

Day 1 of Cycles 1-5, then every 12 weeks thereafter, end of treatment/withdrawal, and 30 days after last avelumab dose (up to a maximum of 5 years)

End point values	Group A: Avelumab + Crizotinib	Group B: Avelumab + Lorlatinib
Number of subjects analysed	12	31
Units: Subjects
ADA never-positive	9	25
ADA ever-positive	3	6

No statistical analyses for this end point

Secondary: Number of Subjects With Positive Programmed Death Ligand-1 (PD-L1) Biomarker Expression

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End point title

Number of Subjects With Positive Programmed Death Ligand-1 (PD-L1) Biomarker Expression

End point description

PD-L1 protein expression is determined by using Combined Positive Score (CPS), which is the percentage of viable tumor and tumor-infiltrated immune cells (restricted to lymphocytes and macrophages) within or directly associated with tumor cell strands showing partial or complete membrane staining using the SP263 antibody. Positive is defined as CPS>=1% and negative is defined as CPS <1%. The analysis population was a subset of the safety analysis set (all subjects who received at least one dose of study drug) and included subjects who had at least one biomarker parameter of PD-L1 from the corresponding assay sample with at least one baseline biomarker measurement.

End point type

Secondary

End point timeframe

Baseline

End point values	Group A: Avelumab + Crizotinib	Group B: Avelumab + Lorlatinib
Number of subjects analysed	9	24
Units: Subjects
Positive	7	20
Negative	2	4

No statistical analyses for this end point

Secondary: Number of Subjects With Positive Tumor Infiltrating CD8+ Lymphocytes

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End point title

Number of Subjects With Positive Tumor Infiltrating CD8+ Lymphocytes

End point description

Tumor infiltrating CD8+ lymphocytes is defined as the number of CD8+ cells per unit area and the percent of counted cells. Positive is defined as >=1% and negative is defined as <1%. The analysis population was a subset of the safety analysis set (all subjects who received at least one dose of study drug) and included subjects who had at least one biomarker parameter of tumor infiltrating CD8+ lymphocytes from the corresponding assay sample with at least one baseline biomarker measurement.

End point type

Secondary

End point timeframe

Baseline

End point values	Group A: Avelumab + Crizotinib	Group B: Avelumab + Lorlatinib
Number of subjects analysed	10	22
Units: Subjects
Positive	6	4
Negative	4	18

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Baseline up to 30 days post lost dose of study treatment with a maximum of 5 years.

Adverse event reporting additional description

The same event may appear as both an AE and an SAE. An event may be categorized as serious in 1 subject and as non-serious in another subject, or 1 subject may have experienced both a serious and non-serious event during the study. Total number at risk below refers to the number of subjects evaluable for SAEs or AEs.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

25.0

Reporting group title

Group B: Avelumab + Lorlatinib

Reporting group description

Reporting group title

Group A: Avelumab + Crizotinib

Reporting group description

Serious adverse events	Group B: Avelumab + Lorlatinib	Group A: Avelumab + Crizotinib
Total subjects affected by serious adverse events
subjects affected / exposed	21 / 31 (67.74%)	5 / 12 (41.67%)
number of deaths (all causes)	15	10
number of deaths resulting from adverse events	4	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Non-small cell lung cancer
subjects affected / exposed	1 / 31 (3.23%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Tongue neoplasm malignant stage unspecified
subjects affected / exposed	1 / 31 (3.23%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Superior vena cava occlusion
subjects affected / exposed	1 / 31 (3.23%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	1 / 31 (3.23%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	1 / 31 (3.23%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Disease progression
subjects affected / exposed	0 / 31 (0.00%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Chest pain
subjects affected / exposed	1 / 31 (3.23%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sudden death
subjects affected / exposed	1 / 31 (3.23%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	1 / 31 (3.23%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Pneumonitis
subjects affected / exposed	2 / 31 (6.45%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	2 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	0 / 31 (0.00%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	2 / 31 (6.45%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Confusional state
subjects affected / exposed	2 / 31 (6.45%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Delirium
subjects affected / exposed	1 / 31 (3.23%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Aspartate aminotransferase increased
subjects affected / exposed	1 / 31 (3.23%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Road traffic accident
subjects affected / exposed	1 / 31 (3.23%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	1 / 31 (3.23%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Femoral neck fracture
subjects affected / exposed	1 / 31 (3.23%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Pericardial effusion
subjects affected / exposed	1 / 31 (3.23%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac tamponade
subjects affected / exposed	1 / 31 (3.23%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Central nervous system vasculitis
subjects affected / exposed	1 / 31 (3.23%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebral haemorrhage
subjects affected / exposed	1 / 31 (3.23%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Cerebral infarction
subjects affected / exposed	1 / 31 (3.23%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Seizure
subjects affected / exposed	1 / 31 (3.23%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Febrile neutropenia
subjects affected / exposed	0 / 31 (0.00%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	1 / 31 (3.23%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Immune-mediated hepatitis
subjects affected / exposed	0 / 31 (0.00%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	0 / 31 (0.00%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Nephrolithiasis
subjects affected / exposed	1 / 31 (3.23%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Tonsillitis
subjects affected / exposed	1 / 31 (3.23%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sepsis
subjects affected / exposed	1 / 31 (3.23%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Postoperative wound infection
subjects affected / exposed	1 / 31 (3.23%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	3 / 31 (9.68%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Clostridium difficile infection
subjects affected / exposed	1 / 31 (3.23%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	1 / 31 (3.23%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	Group B: Avelumab + Lorlatinib	Group A: Avelumab + Crizotinib
Total subjects affected by non serious adverse events
subjects affected / exposed	29 / 31 (93.55%)	12 / 12 (100.00%)
General disorders and administration site conditions
Oedema peripheral
subjects affected / exposed	12 / 31 (38.71%)	1 / 12 (8.33%)
occurrences all number	18	1
Peripheral swelling
subjects affected / exposed	2 / 31 (6.45%)	0 / 12 (0.00%)
occurrences all number	5	0
Pyrexia
subjects affected / exposed	5 / 31 (16.13%)	3 / 12 (25.00%)
occurrences all number	7	5
Swelling face
subjects affected / exposed	1 / 31 (3.23%)	1 / 12 (8.33%)
occurrences all number	1	1
Oedema
subjects affected / exposed	1 / 31 (3.23%)	1 / 12 (8.33%)
occurrences all number	1	1
Mucosal inflammation
subjects affected / exposed	0 / 31 (0.00%)	2 / 12 (16.67%)
occurrences all number	0	2
Localised oedema
subjects affected / exposed	2 / 31 (6.45%)	0 / 12 (0.00%)
occurrences all number	2	0
Hypothermia
subjects affected / exposed	0 / 31 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	1
Fatigue
subjects affected / exposed	4 / 31 (12.90%)	1 / 12 (8.33%)
occurrences all number	4	3
Chills
subjects affected / exposed	2 / 31 (6.45%)	3 / 12 (25.00%)
occurrences all number	2	3
Chest pain
subjects affected / exposed	4 / 31 (12.90%)	0 / 12 (0.00%)
occurrences all number	4	0
Asthenia
subjects affected / exposed	3 / 31 (9.68%)	2 / 12 (16.67%)
occurrences all number	4	4
Reproductive system and breast disorders
Vaginal discharge
subjects affected / exposed	0 / 31 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	3
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	5 / 31 (16.13%)	2 / 12 (16.67%)
occurrences all number	6	3
Cough
subjects affected / exposed	7 / 31 (22.58%)	1 / 12 (8.33%)
occurrences all number	15	1
Dyspnoea exertional
subjects affected / exposed	2 / 31 (6.45%)	0 / 12 (0.00%)
occurrences all number	8	0
Lung opacity
subjects affected / exposed	0 / 31 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	1
Nasal congestion
subjects affected / exposed	4 / 31 (12.90%)	0 / 12 (0.00%)
occurrences all number	4	0
Oropharyngeal pain
subjects affected / exposed	2 / 31 (6.45%)	0 / 12 (0.00%)
occurrences all number	2	0
Pneumonitis
subjects affected / exposed	2 / 31 (6.45%)	0 / 12 (0.00%)
occurrences all number	3	0
Productive cough
subjects affected / exposed	0 / 31 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	1
Haemoptysis
subjects affected / exposed	4 / 31 (12.90%)	0 / 12 (0.00%)
occurrences all number	4	0
Psychiatric disorders
Insomnia
subjects affected / exposed	6 / 31 (19.35%)	0 / 12 (0.00%)
occurrences all number	7	0
Hallucination, visual
subjects affected / exposed	2 / 31 (6.45%)	0 / 12 (0.00%)
occurrences all number	3	0
Hallucination
subjects affected / exposed	2 / 31 (6.45%)	0 / 12 (0.00%)
occurrences all number	4	0
Confusional state
subjects affected / exposed	2 / 31 (6.45%)	0 / 12 (0.00%)
occurrences all number	2	0
Restlessness
subjects affected / exposed	2 / 31 (6.45%)	0 / 12 (0.00%)
occurrences all number	2	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	9 / 31 (29.03%)	4 / 12 (33.33%)
occurrences all number	27	10
Amylase increased
subjects affected / exposed	3 / 31 (9.68%)	1 / 12 (8.33%)
occurrences all number	9	2
Aspartate aminotransferase increased
subjects affected / exposed	7 / 31 (22.58%)	3 / 12 (25.00%)
occurrences all number	25	5
Blood alkaline phosphatase increased
subjects affected / exposed	2 / 31 (6.45%)	1 / 12 (8.33%)
occurrences all number	2	1
Blood cholesterol increased
subjects affected / exposed	19 / 31 (61.29%)	0 / 12 (0.00%)
occurrences all number	72	0
Blood creatine phosphokinase increased
subjects affected / exposed	4 / 31 (12.90%)	1 / 12 (8.33%)
occurrences all number	11	2
Blood creatinine increased
subjects affected / exposed	0 / 31 (0.00%)	2 / 12 (16.67%)
occurrences all number	0	2
Blood lactate dehydrogenase increased
subjects affected / exposed	0 / 31 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	1
Electrocardiogram QT prolonged
subjects affected / exposed	0 / 31 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	3
Gamma-glutamyltransferase increased
subjects affected / exposed	3 / 31 (9.68%)	1 / 12 (8.33%)
occurrences all number	11	1
Hypophonesis
subjects affected / exposed	0 / 31 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	1
Lipase increased
subjects affected / exposed	5 / 31 (16.13%)	1 / 12 (8.33%)
occurrences all number	14	1
Neutrophil count decreased
subjects affected / exposed	0 / 31 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	2
Weight decreased
subjects affected / exposed	1 / 31 (3.23%)	1 / 12 (8.33%)
occurrences all number	1	1
Weight increased
subjects affected / exposed	8 / 31 (25.81%)	0 / 12 (0.00%)
occurrences all number	12	0
White blood cell count decreased
subjects affected / exposed	0 / 31 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	3
Blood triglycerides increased
subjects affected / exposed	2 / 31 (6.45%)	0 / 12 (0.00%)
occurrences all number	3	0
Injury, poisoning and procedural complications
Infusion related reaction
subjects affected / exposed	6 / 31 (19.35%)	2 / 12 (16.67%)
occurrences all number	8	2
Procedural pain
subjects affected / exposed	2 / 31 (6.45%)	1 / 12 (8.33%)
occurrences all number	2	1
Fall
subjects affected / exposed	2 / 31 (6.45%)	0 / 12 (0.00%)
occurrences all number	2	0
Cardiac disorders
Pericardial effusion
subjects affected / exposed	1 / 31 (3.23%)	1 / 12 (8.33%)
occurrences all number	1	3
Atrioventricular block first degree
subjects affected / exposed	2 / 31 (6.45%)	0 / 12 (0.00%)
occurrences all number	2	0
Nervous system disorders
Dizziness
subjects affected / exposed	4 / 31 (12.90%)	1 / 12 (8.33%)
occurrences all number	5	2
Carpal tunnel syndrome
subjects affected / exposed	2 / 31 (6.45%)	0 / 12 (0.00%)
occurrences all number	2	0
Peripheral sensory neuropathy
subjects affected / exposed	5 / 31 (16.13%)	0 / 12 (0.00%)
occurrences all number	5	0
Paraesthesia
subjects affected / exposed	2 / 31 (6.45%)	0 / 12 (0.00%)
occurrences all number	3	0
Neuropathy peripheral
subjects affected / exposed	7 / 31 (22.58%)	0 / 12 (0.00%)
occurrences all number	8	0
Migraine
subjects affected / exposed	0 / 31 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	1
Memory impairment
subjects affected / exposed	3 / 31 (9.68%)	0 / 12 (0.00%)
occurrences all number	4	0
Lethargy
subjects affected / exposed	3 / 31 (9.68%)	0 / 12 (0.00%)
occurrences all number	5	0
Hemiparesis
subjects affected / exposed	1 / 31 (3.23%)	1 / 12 (8.33%)
occurrences all number	1	1
Headache
subjects affected / exposed	4 / 31 (12.90%)	1 / 12 (8.33%)
occurrences all number	5	2
Dysgeusia
subjects affected / exposed	2 / 31 (6.45%)	0 / 12 (0.00%)
occurrences all number	2	0
Somnolence
subjects affected / exposed	1 / 31 (3.23%)	1 / 12 (8.33%)
occurrences all number	1	1
Hyperaesthesia
subjects affected / exposed	2 / 31 (6.45%)	0 / 12 (0.00%)
occurrences all number	2	0
Blood and lymphatic system disorders
Thrombocytopenia
subjects affected / exposed	0 / 31 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	1
Anaemia
subjects affected / exposed	6 / 31 (19.35%)	3 / 12 (25.00%)
occurrences all number	8	7
Ear and labyrinth disorders
Tinnitus
subjects affected / exposed	1 / 31 (3.23%)	1 / 12 (8.33%)
occurrences all number	1	1
Eye disorders
Keratitis
subjects affected / exposed	0 / 31 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	1
Dry eye
subjects affected / exposed	1 / 31 (3.23%)	1 / 12 (8.33%)
occurrences all number	1	1
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	2 / 31 (6.45%)	1 / 12 (8.33%)
occurrences all number	2	1
Abdominal pain
subjects affected / exposed	5 / 31 (16.13%)	1 / 12 (8.33%)
occurrences all number	5	1
Constipation
subjects affected / exposed	7 / 31 (22.58%)	2 / 12 (16.67%)
occurrences all number	10	4
Dry mouth
subjects affected / exposed	0 / 31 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	1
Gastrooesophageal reflux disease
subjects affected / exposed	2 / 31 (6.45%)	0 / 12 (0.00%)
occurrences all number	2	0
Nausea
subjects affected / exposed	5 / 31 (16.13%)	7 / 12 (58.33%)
occurrences all number	6	13
Oesophageal pain
subjects affected / exposed	0 / 31 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	1
Stomatitis
subjects affected / exposed	3 / 31 (9.68%)	1 / 12 (8.33%)
occurrences all number	3	1
Vomiting
subjects affected / exposed	6 / 31 (19.35%)	6 / 12 (50.00%)
occurrences all number	8	12
Diarrhoea
subjects affected / exposed	7 / 31 (22.58%)	3 / 12 (25.00%)
occurrences all number	12	4
Proctalgia
subjects affected / exposed	2 / 31 (6.45%)	0 / 12 (0.00%)
occurrences all number	2	0
Abdominal distension
subjects affected / exposed	2 / 31 (6.45%)	0 / 12 (0.00%)
occurrences all number	2	0
Hepatobiliary disorders
Immune-mediated hepatitis
subjects affected / exposed	0 / 31 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	2
Skin and subcutaneous tissue disorders
Skin disorder
subjects affected / exposed	2 / 31 (6.45%)	0 / 12 (0.00%)
occurrences all number	2	0
Skin hypertrophy
subjects affected / exposed	2 / 31 (6.45%)	0 / 12 (0.00%)
occurrences all number	2	0
Rash
subjects affected / exposed	5 / 31 (16.13%)	4 / 12 (33.33%)
occurrences all number	13	5
Pruritus
subjects affected / exposed	2 / 31 (6.45%)	1 / 12 (8.33%)
occurrences all number	2	2
Dry skin
subjects affected / exposed	4 / 31 (12.90%)	1 / 12 (8.33%)
occurrences all number	4	1
Renal and urinary disorders
Proteinuria
subjects affected / exposed	3 / 31 (9.68%)	0 / 12 (0.00%)
occurrences all number	4	0
Nephropathy toxic
subjects affected / exposed	0 / 31 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	1
Haematuria
subjects affected / exposed	2 / 31 (6.45%)	0 / 12 (0.00%)
occurrences all number	3	0
Endocrine disorders
Hypothyroidism
subjects affected / exposed	8 / 31 (25.81%)	0 / 12 (0.00%)
occurrences all number	10	0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	4 / 31 (12.90%)	0 / 12 (0.00%)
occurrences all number	5	0
Groin pain
subjects affected / exposed	2 / 31 (6.45%)	0 / 12 (0.00%)
occurrences all number	2	0
Joint swelling
subjects affected / exposed	2 / 31 (6.45%)	0 / 12 (0.00%)
occurrences all number	4	0
Muscle spasms
subjects affected / exposed	4 / 31 (12.90%)	0 / 12 (0.00%)
occurrences all number	4	0
Muscular weakness
subjects affected / exposed	3 / 31 (9.68%)	0 / 12 (0.00%)
occurrences all number	3	0
Musculoskeletal pain
subjects affected / exposed	2 / 31 (6.45%)	0 / 12 (0.00%)
occurrences all number	2	0
Myalgia
subjects affected / exposed	6 / 31 (19.35%)	3 / 12 (25.00%)
occurrences all number	7	3
Pain in extremity
subjects affected / exposed	4 / 31 (12.90%)	0 / 12 (0.00%)
occurrences all number	4	0
Arthralgia
subjects affected / exposed	13 / 31 (41.94%)	0 / 12 (0.00%)
occurrences all number	17	0
Infections and infestations
Urinary tract infection
subjects affected / exposed	3 / 31 (9.68%)	0 / 12 (0.00%)
occurrences all number	5	0
Cellulitis
subjects affected / exposed	3 / 31 (9.68%)	1 / 12 (8.33%)
occurrences all number	4	1
Conjunctivitis
subjects affected / exposed	2 / 31 (6.45%)	0 / 12 (0.00%)
occurrences all number	3	0
Cystitis
subjects affected / exposed	2 / 31 (6.45%)	0 / 12 (0.00%)
occurrences all number	2	0
Gastroenteritis
subjects affected / exposed	1 / 31 (3.23%)	1 / 12 (8.33%)
occurrences all number	1	1
Lower respiratory tract infection
subjects affected / exposed	2 / 31 (6.45%)	0 / 12 (0.00%)
occurrences all number	3	0
Nasopharyngitis
subjects affected / exposed	3 / 31 (9.68%)	0 / 12 (0.00%)
occurrences all number	3	0
Rhinitis
subjects affected / exposed	2 / 31 (6.45%)	0 / 12 (0.00%)
occurrences all number	2	0
Tooth abscess
subjects affected / exposed	2 / 31 (6.45%)	0 / 12 (0.00%)
occurrences all number	2	0
Upper respiratory tract infection
subjects affected / exposed	5 / 31 (16.13%)	1 / 12 (8.33%)
occurrences all number	9	1
Metabolism and nutrition disorders
Acidosis
subjects affected / exposed	0 / 31 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	1
Decreased appetite
subjects affected / exposed	2 / 31 (6.45%)	5 / 12 (41.67%)
occurrences all number	2	6
Hypokalaemia
subjects affected / exposed	2 / 31 (6.45%)	0 / 12 (0.00%)
occurrences all number	2	0
Hypoglycaemia
subjects affected / exposed	1 / 31 (3.23%)	1 / 12 (8.33%)
occurrences all number	1	1
Hypocalcaemia
subjects affected / exposed	1 / 31 (3.23%)	1 / 12 (8.33%)
occurrences all number	1	1
Hypoalbuminaemia
subjects affected / exposed	2 / 31 (6.45%)	1 / 12 (8.33%)
occurrences all number	3	5
Hypertriglyceridaemia
subjects affected / exposed	18 / 31 (58.06%)	0 / 12 (0.00%)
occurrences all number	86	0
Hyperglycaemia
subjects affected / exposed	2 / 31 (6.45%)	0 / 12 (0.00%)
occurrences all number	4	0
Hypercholesterolaemia
subjects affected / exposed	6 / 31 (19.35%)	0 / 12 (0.00%)
occurrences all number	27	0

More information

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Were there any global substantial amendments to the protocol? Yes

10 Aug 2015

Per request from the United States Food and Drug Administration (US FDA), add statement that patients should have their tumors evaluated for epidermal growth factor receptor (EGFR) mutations and have exhausted appropriate therapy, if positive. Corrected typographical errors within the protocol. Corrected an error on the SOA referring to PF 06463922 PK analysis that was added in error. Corrected an error for hematology and blood chemistry collection in the SOA (Both should occur on Cycles 1 and 2 on Days 1 and 8). Clarified efficiency of decision rules based on mTPI design over traditional 3+3 design. Removed non applicable text related to medical device safety reporting from the Serious Adverse Event section.

24 Mar 2016

Revised Background, PF-06463922 Dose Modification and Electrocardiograms sections, Exclusion Criteria, and added a new Appendix to address any potential cardiac issues related to PF-06463922. Revised exclusion criteria. Clarified in the inclusion criteria and indication section that Group A patients should be previously treated. Modified inclusion criterion #9 to only include patients with estimated creatinine clearance >30 mL/min. Clarified modified Toxicity Probability Interval dose finding rules including Table 3 and removed previous Appendix 2. Removed Exploratory Objective “To explore changes to the tumor tissue and biomarkers”. Revised procedure information, visit time window, and timepoints in the Schedule of Activities and Pharmacokinetic Sample Collection Table. Clarified that baseline signs and symptoms should be collected on the Medical History Case Report Form. Clarified requirements for eye exams, urinalysis, Banked Blood Biospecimen for Exploratory Biomarker Assessments, and Pharmacokinetic sampling. Changed teratogenic risk of PF-06463922 from unknown to known in Section 4.3. Consolidated information for required Banked Biospecimens in Schedule of Assessment and Sections 7.4, 7.5, and 7.5.1. Removed requirement for antineutrophil cytoplasmic antibody, antinuclear antibody and rheumatoid factor testing. Added screening HBV and HCV tests to the Schedule of Activities table. Revised frequency of adrenocorticotropic hormone, Free thyroxine, and thyroid stimulating hormone assessments. Removed requirement for 2 blood pressure readings to be taken 1 hour apart. Updated the Recommended Dose Modifications section. Updated the Management of Avelumab + PF-06463922 Treatment-Related Toxicity guidelines. Combined Sections “Other Prohibited Concomitant Medications and Treatments” and “Other Prohibited Concomitant Medications and Therapies”. Additional guidance for use of inhibitors, inducers, and substrates of CYP3A enzymes for Group A was provided.

30 Jun 2017

Schedule of Assessments and Pharmacokinetic Sample Collection Table: Revised to include tumor sample and blood biospecimes for Group B Phase 2 including new footnote; removed Follow-up Day 30 avelumab PK sample; other clarifications included. Objectives, Endpoints, Study Overview, Study Schema, Sample size calculation, and Efficacy Analyses revised for Group B Phase 2. Inclusion Criterion 2 revised to include requirement of no prior treatment for Group B Phase 2. Inclusion Criterion 6 corrected to state “0 to 2” vs “0 or 2”. Exclusion Criterion 3 revised to not apply for Group B Phase 2. Exclusion Criterion 16 revised to update restrictions on cardiovascular disease. Exclusion Criterion 19 updated to restrict listed conditions to within the past 1 year. Exclusion Criterion 22 clarified and Exclusion criteria 24 and 25 added due to emerging data on potential drug interactions with PF-06463922. Administration section for PF-06463922 revised due to emerging food effect data on PF-06463922. Updated Tables 6 and 7 for the management of treatment-related toxicities. Added that PF-06463922 treatment should be interrupted during palliative radiotherapy, stopping 1 day before and resuming treatment after recovery from acute radiation toxicities to baseline. Revised Section 5.7.1.2 and Table 8 to remove maximum infusion time of 120 minutes. Updated guidance for Inhibitors and Inducers of CYP Enzymes for Group B. Clarification added re: steroid use to specify the guidelines only apply if patient is still receiving avelumab. Table 12: Required Laboratory Tests revised to include corrections and remove redundant language. Clarification of ECG assessment and eliminated redundant language. Collection of Avelumab Pharmacokinetic Samples (Both Groups A and B) and Immunogenicity Assessment sections revised to provide better guidance on collection of avelumab PK and ADA samples, as well as proper sample management.

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.

Enrollment in the study was terminated early based on the changing landscape in treatment options. All subjects on active treatment at the time of the termination could continue treatment and follow up per the protocol.

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Clinical trials

Clinical Trial Results: A Phase 1b/2, Open Label, Dose Finding Study to Evaluate Safety, Efficacy, Pharmacokinetics and Pharmacodynamics of Avelumab (MSB0010718C) in Combination With Either Crizotinib or PF-06463922 in Patients With Advanced or Metastatic Non Small Cell Lung Cancer

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of Subjects With Dose-limiting Toxicities (DLTs): Phase 1b

Primary: Number of Subjects With Dose-limiting Toxicities (DLTs): Phase 1b

Primary: Percentage of Subjects With Objective Response (OR): Phase 2

Primary: Percentage of Subjects With Objective Response (OR): Phase 2

Primary: Percentage of Subjects With CR for Group B: Phase 2

Primary: Percentage of Subjects With CR for Group B: Phase 2

Secondary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs)

Secondary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs)

Secondary: Number of Subjects with Baseline Laboratory Abnormalities Grade <=2 and Post-Baseline Laboratory Abnormalities of Grades 3 or 4 per NCI CTCAE v4.03

Secondary: Number of Subjects with Baseline Laboratory Abnormalities Grade <=2 and Post-Baseline Laboratory Abnormalities of Grades 3 or 4 per NCI CTCAE v4.03

Secondary: Number of Subjects With Vital Signs Meeting Pre-defined Criteria

Secondary: Number of Subjects With Vital Signs Meeting Pre-defined Criteria

Secondary: Time to Tumor Response (TTR)

Secondary: Time to Tumor Response (TTR)

Secondary: Disease Control Rate (DCR)

Secondary: Disease Control Rate (DCR)

Secondary: Duration of Response (DR)

Secondary: Duration of Response (DR)

Secondary: Progression-free Survival (PFS)

Secondary: Progression-free Survival (PFS)

Secondary: Kaplan-Meier Estimates of Overall Survival (OS)

Secondary: Kaplan-Meier Estimates of Overall Survival (OS)

Secondary: Maximum Plasma Concentration (Cmax) of Crizotinib in The Presence of Avelumab

Secondary: Maximum Plasma Concentration (Cmax) of Crizotinib in The Presence of Avelumab

Secondary: Cmax of Crizotinib Metabolite PF-06260182 in The Presence of Avelumab

Secondary: Cmax of Crizotinib Metabolite PF-06260182 in The Presence of Avelumab

Secondary: Area Under The Plasma Concentration‑time Curve During The Dosing Interval Time Course (AUCtau) of Crizotinib in The Presence of Avelumab

Secondary: Area Under The Plasma Concentration‑time Curve During The Dosing Interval Time Course (AUCtau) of Crizotinib in The Presence of Avelumab

Secondary: Apparent Plasma Clearance (CL/F) of Crizotinib in The Presence of Avelumab

Secondary: Apparent Plasma Clearance (CL/F) of Crizotinib in The Presence of Avelumab

Secondary: Time to Cmax (Tmax) of Crizotinib in The Presence of Avelumab

Secondary: Time to Cmax (Tmax) of Crizotinib in The Presence of Avelumab

Secondary: Metabolite to Parent Ratio for Cmax (MRCmax) of PF-06260182 in The Presence of Avelumab

Secondary: Metabolite to Parent Ratio for Cmax (MRCmax) of PF-06260182 in The Presence of Avelumab

Secondary: Metabolite to Parent Ratio for AUCtau (MRAUCtau) of PF-06260182 in The Presence of Avelumab

Secondary: Metabolite to Parent Ratio for AUCtau (MRAUCtau) of PF-06260182 in The Presence of Avelumab

Secondary: Tmax of Crizotinib Metabolite PF-06260182 in The Presence of Avelumab

Secondary: Tmax of Crizotinib Metabolite PF-06260182 in The Presence of Avelumab

Secondary: AUCtau of Crizotinib Metabolite PF-06260182 in The Presence of Avelumab

Secondary: AUCtau of Crizotinib Metabolite PF-06260182 in The Presence of Avelumab

Secondary: Cmax of Lorlatinib in The Presence of Avelumab

Secondary: Cmax of Lorlatinib in The Presence of Avelumab

Secondary: Tmax of Lorlatinib in The Presence of Avelumab

Secondary: Tmax of Lorlatinib in The Presence of Avelumab

Secondary: Area Under The Plasma Concentration Time Curve From Time of Dosing to The Last Collection Time Point (AUClast) of Lorlatinib in The Presence of Avelumab

Secondary: Area Under The Plasma Concentration Time Curve From Time of Dosing to The Last Collection Time Point (AUClast) of Lorlatinib in The Presence of Avelumab

Secondary: CL/F of Lorlatinib in The Presence of Avelumab

Secondary: CL/F of Lorlatinib in The Presence of Avelumab

Secondary: Cmax of Avelumab in The Presence of Crizotinib (Group A) or Lorlatinib (Group B) After Single Dose of Avelumab

Secondary: Cmax of Avelumab in The Presence of Crizotinib (Group A) or Lorlatinib (Group B) After Single Dose of Avelumab

Secondary: AUCtau of Lorlatinib in The Presence of Avelumab

Secondary: AUCtau of Lorlatinib in The Presence of Avelumab

Secondary: Cmax of Avelumab in The Presence of Crizotinib (Group A) or Lorlatinib (Group B) After Multiple Doses of Avelumab

Secondary: Cmax of Avelumab in The Presence of Crizotinib (Group A) or Lorlatinib (Group B) After Multiple Doses of Avelumab

Secondary: Trough Serum Concentration (Ctrough) of Avelumab in The Presence of Crizotinib (Group A) Following Multiple Doses of Avelumab

Secondary: Trough Serum Concentration (Ctrough) of Avelumab in The Presence of Crizotinib (Group A) Following Multiple Doses of Avelumab

Secondary: Trough Serum Concentration (Ctrough) of Avelumab in The Presence of Lorlatinib (Group B) Following Multiple Doses of Avelumab

Secondary: Trough Serum Concentration (Ctrough) of Avelumab in The Presence of Lorlatinib (Group B) Following Multiple Doses of Avelumab

Secondary: Number of Subjects With Anti-Drug Antibodies (ADA) Against Avelumab by Never and Ever Positive Status

Secondary: Number of Subjects With Anti-Drug Antibodies (ADA) Against Avelumab by Never and Ever Positive Status

Secondary: Number of Subjects With Positive Programmed Death Ligand-1 (PD-L1) Biomarker Expression

Secondary: Number of Subjects With Positive Programmed Death Ligand-1 (PD-L1) Biomarker Expression

Secondary: Number of Subjects With Positive Tumor Infiltrating CD8+ Lymphocytes

Secondary: Number of Subjects With Positive Tumor Infiltrating CD8+ Lymphocytes

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Clinical Trial Results:
A Phase 1b/2, Open Label, Dose Finding Study to Evaluate Safety, Efficacy, Pharmacokinetics and Pharmacodynamics of Avelumab (MSB0010718C) in Combination With Either Crizotinib or PF-06463922 in Patients With Advanced or Metastatic Non Small Cell Lung Cancer