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Clinical Trial Results:
A Phase I/II open-label, multi-center, dose-escalation study of safety, tolerability, pharmacokinetics, dosimetry, and response to repeat dosing of 177Lu-PSMA-R2 radio-ligand therapy in patients with prostate specific membrane antigen (PSMA) positive (68Ga-PSMA-R2) progressive metastatic castration-resistant prostate cancer, following previous systemic treatment.

Summary
EudraCT number	2017-004034-29
Trial protocol	GB ES
Global end of trial date	02 Jun 2022

Results information
Results version number	v1(current)
This version publication date	09 Mar 2023
First version publication date	09 Mar 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

A206T-G01-001

ISRCTN number

US NCT number

NCT03490838

WHO universal trial number (UTN)

Other trial identifiers

CAAA602A12101: Novartis

Sponsor organisation name

Novartis Pharma AG

Sponsor organisation address

Novartis Campus, Basel, Switzerland, 4002

Public contact

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@Novartis.com

Scientific contact

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@Novartis.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

02 Jun 2022

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

02 Jun 2022

Was the trial ended prematurely?

Yes

Main objective of the trial

This Phase I/II study was intended to investigate the safety, tolerability, and radiation dosimetry of 177Lu-PSMA-R2 and further assess preliminary efficacy data in patients with Metastatic Castration-resistant Prostate Cancer (mCRPC). The Phase I portion of the study aimed to determine the recommended dose or Maximum Tolerated Dose (MTD) of 177Lu-PSMA-R2 for Radio-Ligand Therapy (RLT) of mCRPC, and the Phase II portion was planned to expand into approximately 60 patients documenting the preliminary activity (anti-tumor response) of repeated treatments administered, continuing safety assessments and collecting Quality of Life (QoL) data.

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.

Background therapy

Evidence for comparator

Actual start date of recruitment

24 May 2018

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Spain: 6

Country: Number of subjects enrolled

United States: 21

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

This study was conducted at 11 centers in 2 countries: Spain (2) and USA (9).

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Phase I: Dose Escalation Cohort 1

Arm description

Phase I: Dose Escalation Cohort 1 (3 cycles at 100 mCi)

Arm type

Experimental

Investigational medicinal product name

177Lu-PSMA-R2

Investigational medicinal product code

Other name

Pharmaceutical forms

Kit for radiopharmaceutical preparation

Routes of administration

Intravenous use

Dosage and administration details

3 cycles at 100 mCi

Phase I: Dose Escalation Cohort 2

Arm description

Phase I: Dose Escalation Cohort 2 (3 cycles at 200 mCi)

Arm type

Experimental

Investigational medicinal product name

177Lu-PSMA-R2

Investigational medicinal product code

Other name

Pharmaceutical forms

Kit for radiopharmaceutical preparation

Routes of administration

Intravenous use

Dosage and administration details

3 cycles at 200 mCi

Phase I: Dose Escalation Cohort 3A

Arm description

Phase I: Dose Escalation Cohort 3A (4 cycles at 200 mCi)

Arm type

Experimental

Investigational medicinal product name

177Lu-PSMA-R2

Investigational medicinal product code

Other name

Pharmaceutical forms

Kit for radiopharmaceutical preparation

Routes of administration

Intravenous use

Dosage and administration details

4 cycles at 200 mCi

Phase I: Dose Escalation Cohort 3B

Arm description

Phase I: Dose Escalation Cohort 3B (3 cycles at 300 mCi)

Arm type

Experimental

Investigational medicinal product name

177Lu-PSMA-R2

Investigational medicinal product code

Other name

Pharmaceutical forms

Kit for radiopharmaceutical preparation

Routes of administration

Intravenous use

Dosage and administration details

3 cycles at 300 mCi

Phase I: Dose Escalation Cohort 4B

Arm description

Phase I: Dose Escalation Cohort 4B (4 cycles at 300 mCi)

Arm type

Experimental

Investigational medicinal product name

177Lu-PSMA-R2

Investigational medicinal product code

Other name

Pharmaceutical forms

Kit for radiopharmaceutical preparation

Routes of administration

Intravenous use

Dosage and administration details

4 cycles at 300 mCi

Phase I: Dose Escalation Cohort 4C

Arm description

Phase I: Dose Escalation Cohort 4C (3 cycles at 400 mCi)

Arm type

Experimental

Investigational medicinal product name

177Lu-PSMA-R2

Investigational medicinal product code

Other name

Pharmaceutical forms

Kit for radiopharmaceutical preparation

Routes of administration

Intravenous use

Dosage and administration details

3 cycles at 400 mCi

Phase I: Dose Escalation Cohort 5C

Arm description

Phase I: Dose Escalation Cohort 5C (4 cycles at 400 mCi)

Arm type

Experimental

Investigational medicinal product name

177Lu-PSMA-R2

Investigational medicinal product code

Other name

Pharmaceutical forms

Kit for radiopharmaceutical preparation

Routes of administration

Intravenous use

Dosage and administration details

4 cycles at 400 mCi

Phase I: Dose Escalation Cohort 5D

Arm description

Phase I: Dose Escalation Cohort 5D (2 cycles at 500 mCi)

Arm type

Experimental

Investigational medicinal product name

177Lu-PSMA-R2

Investigational medicinal product code

Other name

Pharmaceutical forms

Kit for radiopharmaceutical preparation

Routes of administration

Intravenous use

Dosage and administration details

2 cycles at 500 mCi

Phase I: Dose Escalation Cohort 6E

Arm description

Phase I: Dose Escalation Cohort 6E (3 cycles at 500 mCi)

Arm type

Experimental

Investigational medicinal product name

177Lu-PSMA-R2

Investigational medicinal product code

Other name

Pharmaceutical forms

Kit for radiopharmaceutical preparation

Routes of administration

Intravenous use

Dosage and administration details

3 cycles at 500 mCi

Number of subjects in period 1	Phase I: Dose Escalation Cohort 1	Phase I: Dose Escalation Cohort 2	Phase I: Dose Escalation Cohort 3A	Phase I: Dose Escalation Cohort 3B	Phase I: Dose Escalation Cohort 4B	Phase I: Dose Escalation Cohort 4C	Phase I: Dose Escalation Cohort 5C	Phase I: Dose Escalation Cohort 5D	Phase I: Dose Escalation Cohort 6E
Started	3	3	3	3	3	3	3	3	3
Completed	0	0	0	0	0	0	0	0	0
Not completed	3	3	3	3	3	3	3	3	3
Adverse event, serious fatal	1	1	1	3	3	2	1	1	-
Consent withdrawn by subject	2	2	1	-	-	-	-	-	-
Physician decision	-	-	-	-	-	-	-	2	1
Other pre-specified reason defined in the protocol	-	-	-	-	-	-	-	-	1
Sponsor Decision	-	-	1	-	-	1	1	-	1
Lost to follow-up	-	-	-	-	-	-	1	-	-

Baseline characteristics

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Reporting group title

Phase I: Dose Escalation Cohort 1

Reporting group description

Phase I: Dose Escalation Cohort 1 (3 cycles at 100 mCi)

Reporting group title

Phase I: Dose Escalation Cohort 2

Reporting group description

Phase I: Dose Escalation Cohort 2 (3 cycles at 200 mCi)

Reporting group title

Phase I: Dose Escalation Cohort 3A

Reporting group description

Phase I: Dose Escalation Cohort 3A (4 cycles at 200 mCi)

Reporting group title

Phase I: Dose Escalation Cohort 3B

Reporting group description

Phase I: Dose Escalation Cohort 3B (3 cycles at 300 mCi)

Reporting group title

Phase I: Dose Escalation Cohort 4B

Reporting group description

Phase I: Dose Escalation Cohort 4B (4 cycles at 300 mCi)

Reporting group title

Phase I: Dose Escalation Cohort 4C

Reporting group description

Phase I: Dose Escalation Cohort 4C (3 cycles at 400 mCi)

Reporting group title

Phase I: Dose Escalation Cohort 5C

Reporting group description

Phase I: Dose Escalation Cohort 5C (4 cycles at 400 mCi)

Reporting group title

Phase I: Dose Escalation Cohort 5D

Reporting group description

Phase I: Dose Escalation Cohort 5D (2 cycles at 500 mCi)

Reporting group title

Phase I: Dose Escalation Cohort 6E

Reporting group description

Phase I: Dose Escalation Cohort 6E (3 cycles at 500 mCi)

Reporting group values	Phase I: Dose Escalation Cohort 1	Phase I: Dose Escalation Cohort 2	Phase I: Dose Escalation Cohort 3A	Phase I: Dose Escalation Cohort 3B	Phase I: Dose Escalation Cohort 4B	Phase I: Dose Escalation Cohort 4C	Phase I: Dose Escalation Cohort 5C	Phase I: Dose Escalation Cohort 5D	Phase I: Dose Escalation Cohort 6E	Total
Number of subjects	3	3	3	3	3	3	3	3	3	27
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0	0	0	0	0
Adults (18-64 years)	2	2	0	0	0	1	1	1	1	8
From 65-84 years	1	1	2	3	3	2	2	2	2	18
85 years and over	0	0	1	0	0	0	0	0	0	1
Age Continuous
Units: Years
arithmetic mean (standard deviation)	58.3 ( 12.01 )	61.0 ( 5.57 )	74.0 ( 10.44 )	72.7 ( 6.03 )	72.0 ( 2.00 )	65.7 ( 2.31 )	67.0 ( 6.08 )	64.7 ( 5.86 )	64.3 ( 8.14 )	-
Sex: Female, Male
Units: Participants
Female	0	0	0	0	0	0	0	0	0	0
Male	3	3	3	3	3	3	3	3	3	27
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0	0	0	0	0	0
Asian	0	0	0	0	0	0	0	0	0	0
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0	0	0	0	0
Black or African American	0	0	0	0	1	0	0	0	0	1
White	2	3	3	3	2	3	3	3	3	25
More than one race	1	0	0	0	0	0	0	0	0	1
Unknown or Not Reported	0	0	0	0	0	0	0	0	0	0
ECOG Performance Status
The Eastern Cooperative Oncology Group Performance Status (ECOG PS) score classifies participants according to their functional impairment, with scores ranging from 0 (fully active) to 5 (dead). ECOG PS: 0 = Fully active, able to carry on all pre-disease performance without restriction; 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work.
Units: Subjects
Grade 0	3	3	1	0	2	3	1	2	3	18
Grade 1	0	0	2	3	1	0	2	1	0	9
Number of participants by Total Gleason score (>=6)
Gleason score can range from 2-10. The higher the Gleason Score, the more likely that the cancer will grow and spread quickly. Scores of 6 (or less) describe cancer cells that look similar to normal cells and suggest that the cancer is likely to grow slowly. A score of 7 suggests an intermediate risk for aggressive cancer. Scores of 8 (or higher) describe cancers that are likely to spread more rapidly, these cancers are often referred to as poorly differentiated or high grade.
Units: Subjects
Gleason score = 6	0	0	0	0	1	0	0	0	0	1
Gleason score = 7	1	1	1	0	1	1	0	3	2	10
Gleason score = 8	1	0	0	1	0	1	1	0	1	5
Gleason score = 9	0	2	1	1	1	1	1	0	0	7
Gleason score = 10	0	0	0	1	0	0	1	0	0	2
Gleason score = Missing	1	0	1	0	0	0	0	0	0	2
Time since first prostate cancer diagnosis
Time since first prostate cancer diagnosis is defined as (date of screening – date of first prostate cancer diagnosis + 1) / 30.4375.
Units: Months
arithmetic mean (standard deviation)	70.5 ( 52.95 )	76.7 ( 26.44 )	176.6 ( 132.16 )	75.3 ( 54.27 )	89.4 ( 49.80 )	40.0 ( 15.47 )	129.5 ( 78.29 )	76.1 ( 32.37 )	120.2 ( 49.29 )	-

End points

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Reporting group title

Phase I: Dose Escalation Cohort 1

Reporting group description

Phase I: Dose Escalation Cohort 1 (3 cycles at 100 mCi)

Reporting group title

Phase I: Dose Escalation Cohort 2

Reporting group description

Phase I: Dose Escalation Cohort 2 (3 cycles at 200 mCi)

Reporting group title

Phase I: Dose Escalation Cohort 3A

Reporting group description

Phase I: Dose Escalation Cohort 3A (4 cycles at 200 mCi)

Reporting group title

Phase I: Dose Escalation Cohort 3B

Reporting group description

Phase I: Dose Escalation Cohort 3B (3 cycles at 300 mCi)

Reporting group title

Phase I: Dose Escalation Cohort 4B

Reporting group description

Phase I: Dose Escalation Cohort 4B (4 cycles at 300 mCi)

Reporting group title

Phase I: Dose Escalation Cohort 4C

Reporting group description

Phase I: Dose Escalation Cohort 4C (3 cycles at 400 mCi)

Reporting group title

Phase I: Dose Escalation Cohort 5C

Reporting group description

Phase I: Dose Escalation Cohort 5C (4 cycles at 400 mCi)

Reporting group title

Phase I: Dose Escalation Cohort 5D

Reporting group description

Phase I: Dose Escalation Cohort 5D (2 cycles at 500 mCi)

Reporting group title

Phase I: Dose Escalation Cohort 6E

Reporting group description

Phase I: Dose Escalation Cohort 6E (3 cycles at 500 mCi)

Subject analysis set title

Phase I: Dose Escalation Cohort 1 (Cycle 1)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Phase I: Dose Escalation Cohort 1 (Cycle 1 at 100 mCi)

Subject analysis set title

Phase I: Dose Escalation Cohorts 2 & 3A (Cycle 1)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Phase I: Dose Escalation Cohorts 2 & 3A (Cycle 1 at 200 mCi)

Subject analysis set title

Phase I: Dose Escalation Cohorts 3B & 4B (Cycle 1)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Phase I: Dose Escalation Cohorts 3B & 4B (Cycle 1 at 300 mCi)

Subject analysis set title

Phase I: Dose Escalation Cohorts 4C & 5C (Cycle 1)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Phase I: Dose Escalation Cohorts 4C & 5C (Cycle 1 at 400 mCi)

Subject analysis set title

Phase I: Dose Escalation Cohorts 5D & 6E (Cycle 1)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Phase I: Dose Escalation Cohorts 5D & 6E (Cycle 1 at 500 mCi)

Primary: Phase I: Incidence of dose limiting toxicities (DLTs) during first cycle of study treatment.

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End point title

Phase I: Incidence of dose limiting toxicities (DLTs) during first cycle of study treatment. ^[1]

End point description

A dose-limiting toxicity (DLT) was defined as any toxicity not attributable to the disease or disease-related processes under investigation, the time window for DLT assessment period was Cycle 1. To be considered a DLT, it was to be related to the IP (attributions: possible, probable, and definite) while fulfilling one of the following criteria as per the NCI Common Toxicity Criteria for Adverse Events (CTCAE) version 5.0.

End point type

Primary

End point timeframe

Up to 8 weeks after the first 177Lu-PSMA-R2 dose

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: Only descriptive analysis performed

End point values	Phase I: Dose Escalation Cohort 1	Phase I: Dose Escalation Cohort 2	Phase I: Dose Escalation Cohort 3A	Phase I: Dose Escalation Cohort 3B	Phase I: Dose Escalation Cohort 4B	Phase I: Dose Escalation Cohort 4C	Phase I: Dose Escalation Cohort 5C	Phase I: Dose Escalation Cohort 5D	Phase I: Dose Escalation Cohort 6E
Number of subjects analysed	3	3	3	3	3	3	3	3	3
Units: Participants	0	0	0	0	0	0	0	0	0

No statistical analyses for this end point

Secondary: Phase I: Number of Participants with Treatment Emergent Adverse Events (TEAEs)

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End point title

Phase I: Number of Participants with Treatment Emergent Adverse Events (TEAEs)

End point description

The distribution of adverse events was done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs) and Serious Adverse Event (TESAEs), through the monitoring of relevant clinical and laboratory safety parameters.

End point type

Secondary

End point timeframe

From randomization till 30 days safety follow-up, assessed up to approximately 4 years

End point values	Phase I: Dose Escalation Cohort 1	Phase I: Dose Escalation Cohort 2	Phase I: Dose Escalation Cohort 3A	Phase I: Dose Escalation Cohort 3B	Phase I: Dose Escalation Cohort 4B	Phase I: Dose Escalation Cohort 4C	Phase I: Dose Escalation Cohort 5C	Phase I: Dose Escalation Cohort 5D	Phase I: Dose Escalation Cohort 6E
Number of subjects analysed	3	3	3	3	3	3	3	3	3
Units: Participants
At least one TEAE	3	3	3	3	3	3	3	3	3
TEAE rel. to 68Ga-PSMA-R2	0	0	1	1	0	1	2	0	0
TEAE rel. to 177Lu-PSMA-R2	2	2	2	3	2	2	3	3	3
TEAE rel. to the study procedure	0	3	1	1	0	0	0	0	1
Serious TEAE	1	1	1	1	2	0	0	0	0
Serious TEAE rel. to 68Ga-PSMA-R2	0	0	0	0	0	0	0	0	0
Serious TEAE rel. to 177Lu-PSMA-R2	0	0	1	0	0	0	0	0	0
Serious TEAE rel. to the study procedure	0	0	0	0	0	0	0	0	0
TEAE leading to study discontinuation	1	0	0	0	0	0	0	0	0
Mild TEAE	3	3	3	3	3	3	3	3	3
Moderate TEAE	2	3	2	1	3	1	2	1	1
Severe TEAE	0	1	1	2	2	0	0	0	0
Life threatening TEAE	1	1	0	0	0	0	0	0	0
TEAE leading to death	1	0	0	0	0	0	0	0	0
At least one DLT	0	0	0	0	0	0	0	0	0

No statistical analyses for this end point

Secondary: Phase I: Number of participants with an Objective Response Rate (ORR)

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End point title

Phase I: Number of participants with an Objective Response Rate (ORR)

End point description

The objective response rate (ORR) was defined as the proportion of participants with Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR), as assessed per RECIST 1.1 by the investigator.

End point type

Secondary

End point timeframe

From date of randomization until date of progression or date of death from any cause, whichever comes first, assessed up to approximately 4 years

End point values	Phase I: Dose Escalation Cohort 1	Phase I: Dose Escalation Cohort 2	Phase I: Dose Escalation Cohort 3A	Phase I: Dose Escalation Cohort 3B	Phase I: Dose Escalation Cohort 4B	Phase I: Dose Escalation Cohort 4C	Phase I: Dose Escalation Cohort 5C	Phase I: Dose Escalation Cohort 5D	Phase I: Dose Escalation Cohort 6E
Number of subjects analysed	3	3	3	3	3	3	3	3	3
Units: Participants
ORR in overall population	0	0	0	0	0	0	0	0	1
ORR in patients with visceral disease at Baseline	0	0	0	0	0	0	0	0	0

No statistical analyses for this end point

Secondary: Phase I: Duration of Response (DoR)

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End point title

Phase I: Duration of Response (DoR)

End point description

Duration of Response (DOR) according to RECIST v1.1 was defined as the time that measurement criteria were met for objective response (BOR of Complete Response (CR) or Partial Response (PR)) (whichever status was recorded first) until the first date of progression or death was documented.

End point type

Secondary

End point timeframe

From first documented evidence of CR or PR (the response prior to confirmation) until time of documented disease progression or death due to any cause, whichever comes first, assessed up to approximately 4 years

End point values	Phase I: Dose Escalation Cohort 1	Phase I: Dose Escalation Cohort 2	Phase I: Dose Escalation Cohort 3A	Phase I: Dose Escalation Cohort 3B	Phase I: Dose Escalation Cohort 4B	Phase I: Dose Escalation Cohort 4C	Phase I: Dose Escalation Cohort 5C	Phase I: Dose Escalation Cohort 5D	Phase I: Dose Escalation Cohort 6E
Number of subjects analysed	0 ^[2]	0 ^[3]	0 ^[4]	0 ^[5]	0 ^[6]	0 ^[7]	0 ^[8]	0 ^[9]	1
Units: Months
median (confidence interval 95%)	( to )	( to )	( to )	( to )	( to )	( to )	( to )	( to )	2.63 (0 to 999)

Notes
[2] - No participants with BOR of Complete Response (CR) or Partial Response (PR)
[3] - No participants with BOR of Complete Response (CR) or Partial Response (PR)
[4] - No participants with BOR of Complete Response (CR) or Partial Response (PR)
[5] - No participants with BOR of Complete Response (CR) or Partial Response (PR)
[6] - No participants with BOR of Complete Response (CR) or Partial Response (PR)
[7] - No participants with BOR of Complete Response (CR) or Partial Response (PR)
[8] - No participants with BOR of Complete Response (CR) or Partial Response (PR)
[9] - No participants with BOR of Complete Response (CR) or Partial Response (PR)

No statistical analyses for this end point

Secondary: Phase I: Number of participants with a Prostate-Specific Antigen (PSA) response rate 30

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End point title

Phase I: Number of participants with a Prostate-Specific Antigen (PSA) response rate 30

End point description

PSA response rate 30 was defined as the proportion of participants who had a greater or equal 30% in PSA from Baseline that was confirmed by a second PSA measurement 4 weeks later, as per Prostate Cancer Working Group 3 (PCWG3) criteria.

End point type

Secondary

End point timeframe

Week 13 (12 weeks after the first 177Lu-PSMA-R2 injection)

End point values	Phase I: Dose Escalation Cohort 1	Phase I: Dose Escalation Cohort 2	Phase I: Dose Escalation Cohort 3A	Phase I: Dose Escalation Cohort 3B	Phase I: Dose Escalation Cohort 4B	Phase I: Dose Escalation Cohort 4C	Phase I: Dose Escalation Cohort 5C	Phase I: Dose Escalation Cohort 5D	Phase I: Dose Escalation Cohort 6E
Number of subjects analysed	3	3	3	3	3	3	3	3	3
Units: Participants	0	0	0	1	0	0	0	0	2

No statistical analyses for this end point

Secondary: Phase I: Number of participants with a Prostate-Specific Antigen (PSA) response rate 50

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End point title

Phase I: Number of participants with a Prostate-Specific Antigen (PSA) response rate 50

End point description

PSA response rate 50 was defined as the proportion of participants who had a greater or equal 50% in PSA from Baseline that was confirmed by a second PSA measurement 4 weeks later, as per Prostate Cancer Working Group 3 (PCWG3) criteria.

End point type

Secondary

End point timeframe

Week 13 (12 weeks after the first 177Lu-PSMA-R2 injection)

End point values	Phase I: Dose Escalation Cohort 1	Phase I: Dose Escalation Cohort 2	Phase I: Dose Escalation Cohort 3A	Phase I: Dose Escalation Cohort 3B	Phase I: Dose Escalation Cohort 4B	Phase I: Dose Escalation Cohort 4C	Phase I: Dose Escalation Cohort 5C	Phase I: Dose Escalation Cohort 5D	Phase I: Dose Escalation Cohort 6E
Number of subjects analysed	3	3	3	3	3	3	3	3	3
Units: Participants	0	0	0	0	0	0	0	0	1

No statistical analyses for this end point

Secondary: Phase I: Maximum plasma concentration (Cmax) of 177Lu-PSMA-R2

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End point title

Phase I: Maximum plasma concentration (Cmax) of 177Lu-PSMA-R2

End point description

Venous whole blood samples was collected in a subset of 18 patients (3 patients from each cohort testing a new dose strength) for activity-based pharmacokinetics characterization. Cmax was listed and summarized using descriptive statistics.

End point type

Secondary

End point timeframe

Day 1 (before the start of infusion, at the mid-point, and just before the end of infusion, then at post infusion at approximately 5, 15, 30 minutes, 1, 2, 4, 6, 8, 24, 40 (+/- 4 hours), 48 hours), Day 4 (+2 days) and Day 8 post end of infusion

End point values	Phase I: Dose Escalation Cohort 1	Phase I: Dose Escalation Cohort 2	Phase I: Dose Escalation Cohort 3A	Phase I: Dose Escalation Cohort 3B	Phase I: Dose Escalation Cohort 4B	Phase I: Dose Escalation Cohort 4C	Phase I: Dose Escalation Cohort 5C	Phase I: Dose Escalation Cohort 5D	Phase I: Dose Escalation Cohort 6E
Number of subjects analysed	3	3	0 ^[10]	3	0 ^[11]	3	0 ^[12]	3	3
Units: ng/mL
geometric mean (geometric coefficient of variation)	7.16 ( 46.9 )	12.8 ( 33.8 )	( )	21.7 ( 31.2 )	( )	21.9 ( 25.2 )	( )	32.8 ( 8.17 )	43.7 ( 41.2 )

Notes
[10] - PK assessments done in 3 patients from each cohort testing a new dose strength
[11] - PK assessments done in 3 patients from each cohort testing a new dose strength
[12] - PK assessments done in 3 patients from each cohort testing a new dose strength

No statistical analyses for this end point

Secondary: Phase I: Area under the serum concentration-time curve from time zero to the time of last quantifiable concentration (AUCtlast) of 177Lu-PSMA-R2

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End point title

Phase I: Area under the serum concentration-time curve from time zero to the time of last quantifiable concentration (AUCtlast) of 177Lu-PSMA-R2

End point description

Venous whole blood samples was collected in a subset of 18 patients (3 patients from each cohort testing a new dose strength) for activity-based pharmacokinetics characterization. AUCtlast was listed and summarized using descriptive statistics.

End point type

Secondary

End point timeframe

End point values	Phase I: Dose Escalation Cohort 1	Phase I: Dose Escalation Cohort 2	Phase I: Dose Escalation Cohort 3A	Phase I: Dose Escalation Cohort 3B	Phase I: Dose Escalation Cohort 4B	Phase I: Dose Escalation Cohort 4C	Phase I: Dose Escalation Cohort 5C	Phase I: Dose Escalation Cohort 5D	Phase I: Dose Escalation Cohort 6E
Number of subjects analysed	3	3	0 ^[13]	3	0 ^[14]	3	0 ^[15]	3	3
Units: hr*ng/mL
geometric mean (geometric coefficient of variation)	21.3 ( 53.8 )	36.3 ( 35.2 )	( )	85.9 ( 4.81 )	( )	82.7 ( 39.5 )	( )	126 ( 32.7 )	207 ( 17.6 )

Notes
[13] - PK assessments done in 3 patients from each cohort testing a new dose strength
[14] - PK assessments done in 3 patients from each cohort testing a new dose strength
[15] - PK assessments done in 3 patients from each cohort testing a new dose strength

No statistical analyses for this end point

Secondary: Phase I: Area under the serum concentration-time curve from time zero to (AUCinf) of 177Lu-PSMA-R2

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End point title

Phase I: Area under the serum concentration-time curve from time zero to (AUCinf) of 177Lu-PSMA-R2

End point description

Venous whole blood samples was collected in a subset of 18 patients (3 patients from each cohort testing a new dose strength) for activity-based pharmacokinetics characterization. AUCinf was listed and summarized using descriptive statistics.

End point type

Secondary

End point timeframe

End point values	Phase I: Dose Escalation Cohort 1	Phase I: Dose Escalation Cohort 2	Phase I: Dose Escalation Cohort 3A	Phase I: Dose Escalation Cohort 3B	Phase I: Dose Escalation Cohort 4B	Phase I: Dose Escalation Cohort 4C	Phase I: Dose Escalation Cohort 5C	Phase I: Dose Escalation Cohort 5D	Phase I: Dose Escalation Cohort 6E
Number of subjects analysed	3	3	0 ^[16]	3	0 ^[17]	3	0 ^[18]	3	3
Units: hr*ng/mL
geometric mean (geometric coefficient of variation)	21.3 ( 53.8 )	37.9 ( 37.5 )	( )	86.6 ( 4.59 )	( )	83.1 ( 39.8 )	( )	127 ( 32.7 )	207 ( 17.5 )

Notes
[16] - PK assessments done in 3 patients from each cohort testing a new dose strength
[17] - PK assessments done in 3 patients from each cohort testing a new dose strength
[18] - PK assessments done in 3 patients from each cohort testing a new dose strength

No statistical analyses for this end point

Secondary: Phase I: Absorbed doses of 177Lu-PSMA-R2 by critical organs

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End point title

Phase I: Absorbed doses of 177Lu-PSMA-R2 by critical organs

End point description

Absorbed doses of 177Lu-PSMA-R2 were assessed by critical organs and summarized using descriptive statistics.

End point type

Secondary

End point timeframe

Days 1 through 8 post-treatment

End point values	Phase I: Dose Escalation Cohort 1 (Cycle 1)	Phase I: Dose Escalation Cohorts 2 & 3A (Cycle 1)	Phase I: Dose Escalation Cohorts 3B & 4B (Cycle 1)	Phase I: Dose Escalation Cohorts 4C & 5C (Cycle 1)	Phase I: Dose Escalation Cohorts 5D & 6E (Cycle 1)
Number of subjects analysed	3	6	6	6	6
Units: Gy/GBq
arithmetic mean (standard deviation)
Adrenal Gland	0.0054 ( 0.00090 )	0.062 ( 0.020 )	0.010 ( 0.0037 )	0.0083 ( 0.0019 )	0.0087 ( 0.0024 )
Bladder Wall	0.43 ( 0.029 )	0.37 ( 0.036 )	0.29 ( 0.067 )	0.038 ( 0.052 )	0.36 ( 0.042 )
Bone Marrow	0.0087 ( 0.0038 )	0.052 ( 0.016 )	0.016 ( 0.0026 )	0.011 ( 0.0042 )	0.012 ( 0.0026 )
Brain	0.0014 ( 0.00080 )	0.0044 ( 0.0017 )	0.0025 ( 0.00078 )	0.0023 ( 0.00052 )	0.0027 ( 0.00078 )
Colon, Left	0.17 ( 0.050 )	0.37 ( 0.14 )	0.61 ( 0.14 )	0.38 ( 0.14 )	0.33 ( 0.12 )
Colon, Right	0.092 ( 0.026 )	0.22 ( 0.084 )	0.33 ( 0.075 )	0.20 ( 0.076 )	0.18 ( 0.063 )
Esophagus	0.0019 ( 0.00041 )	0.059 ( 0.019 )	0.0044 ( 0.0021 )	0.0037 ( 0.0013 )	0.0039 ( 0.0016 )
Eye	0.0012 ( 0.00040 )	0.058 ( 0.018 )	0.0032 ( 0.0016 )	0.0028 ( 0.00096 )	0.0029 ( 0.0015 )
Gallbladder	0.0028 ( 0.00052 )	0.061 ( 0.019 )	0.0068 ( 0.0026 )	0.0053 ( 0.00094 )	0.0055 ( 0.0019 )
Heart, Ventricular Wall	0.059 ( 0.047 )	0.046 ( 0.015 )	0.096 ( 0.046 )	0.051 ( 0.031 )	0.071 ( 0.037 )
Kidney	0.025 ( 0.035 )	0.15 ( 0.046 )	0.34 ( 0.15 )	0.28 ( 0.15 )	0.27 ( 0.14 )
Lacrimal Gland	0.060 ( 0.035 )	0.096 ( 0.097 )	0.096 ( 0.043 )	0.069 ( 0.011 )	0.094 ( 0.034 )
Liver	0.020 ( 0.0055 )	0.014 ( 0.0066 )	0.032 ( 0.014 )	0.026 ( 0.010 )	0.034 ( 0.014 )
Lung	0.0092 ( 0.00014 )	0.017 ( 0.0054 )	0.026 ( 0.019 )	0.023 ( 0.019 )	0.020 ( 0.012 )
Osteogenic Cells	0.0056 ( 0.0022 )	0.070 ( 0.022 )	0.011 ( 0.0025 )	0.0082 ( 0.0028 )	0.0088 ( 0.0019 )
Pancreas	0.0026 ( 0.00044 )	0.062 ( 0.020 )	0.0066 ( 0.0025 )	0.0051 ( 0.00072 )	0.0051 ( 0.0018 )
Prostate Gland	0.0047 ( 0.00025 )	0.064 ( 0.019 )	0.0075 ( 0.0018 )	0.0067 ( 0.00055 )	0.0066 ( 0.0015 )
Rectum	0.16 ( 0.047 )	0.35 ( 0.14 )	0.58 ( 0.13 )	0.36 ( 0.14 )	0.31 ( 0.11 )
Salivary Gland	0.025 ( 0.010 )	0.069 ( 0.028 )	0.050 ( 0.021 )	0.040 ( 0.011 )	0.051 ( 0.022 )
Small Intestine	0.16 ( 0.0040 )	0.087 ( 0.029 )	0.055 ( 0.013 )	0.035 ( 0.011 )	0.031 ( 0.010 )
Spleen	0.012 ( 0.014 )	0.048 ( 0.032 )	0.030 ( 0.023 )	0.080 ( 0.063 )	0.091 ( 0.066 )
Stomach	0.0020 ( 0.00042 )	0.061 ( 0.019 )	0.0049 ( 0.0022 )	0.0041 ( 0.0010 )	0.0042 ( 0.0016 )
Testis	0.0019 ( 0.00037 )	0.060 ( 0.019 )	0.0037 ( 0.0016 )	0.0034 ( 0.00094 )	0.0035 ( 0.0015 )
Thymus Gland	0.0018 ( 0.00039 )	0.060 ( 0.019 )	0.0042 ( 0.0021 )	0.0034 ( 0.0013 )	0.0036 ( 0.0016 )
Thyroid Gland	0.066 ( 0.047 )	0.057 ( 0.027 )	0.090 ( 0.047 )	0.12 ( 0.10 )	0.12 ( 0.11 )
Whole-body	0.0074 ( 0.00069 )	0.065 ( 0.020 )	0.013 ( 0.0037 )	0.011 ( 0.00091 )	0.011 ( 0.0024 )

No statistical analyses for this end point

Secondary: Phase I: Residence times of 177Lu-PSMA-R2 in normal organs

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End point title

Phase I: Residence times of 177Lu-PSMA-R2 in normal organs

End point description

Residence times of 177Lu-PSMA-R2 were assessed in normal organs and summarized using descriptive statistics.

End point type

Secondary

End point timeframe

Days 1 through 8 post-treatment

End point values	Phase I: Dose Escalation Cohort 1 (Cycle 1)	Phase I: Dose Escalation Cohorts 2 & 3A (Cycle 1)	Phase I: Dose Escalation Cohorts 3B & 4B (Cycle 1)	Phase I: Dose Escalation Cohorts 4C & 5C (Cycle 1)	Phase I: Dose Escalation Cohorts 5D & 6E (Cycle 1)
Number of subjects analysed	3	6	6	6	6
Units: MBq-hr/MBq
median (full range (min-max))
Bladder	0.26 (0.14 to 0.59)	999 (999 to 999)	1.5 (0.63 to 2.4)	0.84 (0.32 to 0.89)	1.2 (0.46 to 2.9)
Body	5.6 (4.0 to 6.2)	51 (32 to 63)	8.7 (6.4 to 16)	7.1 (7.1 to 8.9)	8.4 (6.3 to 11)
Bone Marrow	0.12 (0.12 to 0.27)	0.12 (0.10 to 0.14)	0.30 (0.26 to 0.34)	0.17 (0.14 to 0.30)	0.22 (0.17 to 0.33)
Brain	0.026 (0.0082 to 0.033)	0.044 (0.020 to 0.053)	0.033 (0.029 to 0.053)	0.040 (0.027 to 0.041)	0.044 (0.022 to 0.058)
Heart, Ventricular Wall	0.17 (0.078 to 0.43)	0.15 (0.11 to 0.21)	0.28 (0.24 to 0.56)	0.16 (0.095 to 0.32)	0.28 (0.11 to 0.42)
Intestine	0.51 (0.45 to 0.58)	0.83 (0.44 to 0.90)	2.4 (1.3 to 6.4)	0.98 (0.89 to 1.8)	1.4 (0.61 to 2.6)
Kidney	0.92 (0.74 to 0.97)	0.48 (0.40 to 0.71)	1.1 (0.90 to 1.7)	0.90 (0.67 to 1.6)	0.97 (0.66 to 1.9)
Lacrimal Gland	0.0016 (0.0013 to 0.0036)	0.0019 (0.0010 to 0.0075)	0.0030 (0.0022 to 0.0052)	0.0025 (0.0021 to 0.0029)	0.0030 (0.0025 to 0.0058)
Liver	0.42 (0.27 to 0.49)	0.22 (0.095 to 0.31)	0.48 (0.43 to 0.92)	0.44 (0.32 to 0.72)	0.68 (0.31 to 1.1)
Lung	0.12 (0.12 to 0.13)	0.20 (0.11 to 0.22)	0.29 (0.11 to 0.64)	0.19 (0.13 to 0.61)	0.21 (0.10 to 0.50)
Salivary Gland	0.024 (0.016 to 0.036)	0.050 (0.049 to 0.095)	0.039 (0.035 to 0.074)	0.038 (0.030 to 0.051)	0.048 (0.024 to 0.080)
Spleen	0.0055 (0.0050 to 0.048)	0.060 (0.031 to 0.13)	0.030 (0.023 to 0.092)	0.11 (0.039 to 0.26)	0.15 (0.020 to 0.31)
Thyroid Gland	0.015 (0.0047 to 0.027)	0.0091 (0.0085 to 0.019)	0.016 (0.014 to 0.034)	0.022 (0.0084 to 0.054)	0.020 (0.0065 to 0.076)

No statistical analyses for this end point

Secondary: Phase I: Mean change from Baseline in Patient Reported Outcomes (PRO) of Mouth Dryness using Xerostomia Questionnaire

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End point title

Phase I: Mean change from Baseline in Patient Reported Outcomes (PRO) of Mouth Dryness using Xerostomia Questionnaire

End point description

The Xerostomia questionnaire is a questionnaire used to describe mouth dryness and its effects on daily life. It consists of 8 questions with each question score ranging from 0 ("never"/"none") to 10 ("worst"). The sum of the 8 scores produces a total score (score range from 0-80). A low score corresponds to a good quality of life while a high score means a poor quality of life due to the dry mouth.

End point type

Secondary

End point timeframe

Baseline, Cycle 1 Day 1, Cycle 3 Day 85, Follow Up 1, Follow Up 2, Follow Up 3, Follow Up 4

End point values	Phase I: Dose Escalation Cohort 1	Phase I: Dose Escalation Cohort 2	Phase I: Dose Escalation Cohort 3A	Phase I: Dose Escalation Cohort 3B	Phase I: Dose Escalation Cohort 4B	Phase I: Dose Escalation Cohort 4C	Phase I: Dose Escalation Cohort 5C	Phase I: Dose Escalation Cohort 5D	Phase I: Dose Escalation Cohort 6E
Number of subjects analysed	3	3	3	3	3	3	3	3	3
Units: Score
arithmetic mean (standard deviation)
Cycle 1 Day 1 Change from Baseline	999 ( 999 )	999 ( 999 )	999 ( 999 )	999 ( 999 )	999 ( 999 )	999 ( 999 )	999 ( 999 )	999 ( 999 )	999 ( 999 )
Cycle 3 Day 85 Change from Baseline	999 ( 999 )	-4.0 ( 999 )	4.7 ( 8.96 )	-2.5 ( 9.19 )	999 ( 999 )	-8.0 ( 999 )	14.0 ( 999 )	999 ( 999 )	-0.7 ( 3.06 )
Follow Up 1 Change from Baseline	999 ( 999 )	999 ( 999 )	-1.0 ( 999 )	0.5 ( 13.44 )	6.0 ( 999 )	-8.0 ( 999 )	2.5 ( 4.95 )	-2.3 ( 4.04 )	2.3 ( 14.64 )
Follow Up 2 Change from Baseline	999 ( 999 )	999 ( 999 )	999 ( 999 )	-4.5 ( 6.36 )	0.0 ( 999 )	18.0 ( 999 )	-2.0 ( 999 )	999 ( 999 )	3.3 ( 8.50 )
Follow Up 3 Change from Baseline	999 ( 999 )	999 ( 999 )	999 ( 999 )	21.0 ( 999 )	999 ( 999 )	-7.0 ( 4.24 )	999 ( 999 )	999 ( 999 )	4.7 ( 7.23 )
Follow Up 4 Change from Baseline	999 ( 999 )	999 ( 999 )	-1.0 ( 999 )	999 ( 999 )	999 ( 999 )	999 ( 999 )	16.0 ( 999 )	999 ( 999 )	18.5 ( 26.16 )

No statistical analyses for this end point

Secondary: Phase I: Mean change from Baseline in Patient Reported Outcomes (PRO) of Eye Dryness using Xerophthalmia Questionnaire

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End point title

Phase I: Mean change from Baseline in Patient Reported Outcomes (PRO) of Eye Dryness using Xerophthalmia Questionnaire

End point description

The Xerophthalmia questionnaire is a questionnaire used to describe eye dryness and its effects on daily life. It consists of 3 questions. The first 2 questions scores range from 1 ("never") to 4 ("constantly") and the last question is a Yes/No question about previous dry eye diagnosis. The sum of the scores of the first 2 questions produces a total score (score range from 2-8). A low score corresponds to a good quality of life while a high score means a poor quality of life due to the dry eye.

End point type

Secondary

End point timeframe

Baseline, Cycle 1 Day 1, Cycle 3 Day 85, Follow Up 1, Follow Up 2, Follow Up 3, Follow Up 4

End point values	Phase I: Dose Escalation Cohort 1	Phase I: Dose Escalation Cohort 2	Phase I: Dose Escalation Cohort 3A	Phase I: Dose Escalation Cohort 3B	Phase I: Dose Escalation Cohort 4B	Phase I: Dose Escalation Cohort 4C	Phase I: Dose Escalation Cohort 5C	Phase I: Dose Escalation Cohort 5D	Phase I: Dose Escalation Cohort 6E
Number of subjects analysed	3	3	3	3	3	3	3	3	3
Units: Score
arithmetic mean (standard deviation)
Cycle 1 Day 1 Change from Baseline	999 ( 999 )	999 ( 999 )	999 ( 999 )	999 ( 999 )	999 ( 999 )	999 ( 999 )	999 ( 999 )	999 ( 999 )	999 ( 999 )
Cycle 3 Day 85 Change from Baseline	999 ( 999 )	-2.0 ( 999 )	0.0 ( 0.00 )	-1.0 ( 1.41 )	999 ( 999 )	1.0 ( 999 )	1.0 ( 999 )	999 ( 999 )	0.0 ( 0.00 )
Follow Up 1 Change from Baseline	999 ( 999 )	999 ( 999 )	-2.0 ( 999 )	-0.5 ( 2.12 )	0.0 ( 999 )	0.0 ( 999 )	1.5 ( 0.71 )	-0.3 ( 0.58 )	-0.3 ( 0.58 )
Follow Up 2 Change from Baseline	999 ( 999 )	999 ( 999 )	999 ( 999 )	-0.5 ( 2.12 )	0.0 ( 999 )	0.0 ( 999 )	0.0 ( 999 )	999 ( 999 )	0.0 ( 0.00 )
Follow Up 3 Change from Baseline	999 ( 999 )	999 ( 999 )	999 ( 999 )	-2.0 ( 999 )	999 ( 999 )	0.0 ( 0.00 )	999 ( 999 )	999 ( 999 )	0.0 ( 0.00 )
Follow Up 4 Change from Baseline	999 ( 999 )	999 ( 999 )	-2.0 ( 999 )	999 ( 999 )	999 ( 999 )	999 ( 999 )	2.0 ( 999 )	999 ( 999 )	0.0 ( 0.00 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From informed consent signature through study completion reached at early termination date on 02-Jun-2022, assessed up to approximately 4 years.

Adverse event reporting additional description

Consistent with EudraCTdisclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

25.0

Reporting group title

Cohort 3B: 3 cycles at 300 mCi

Reporting group description

Cohort 3B: 3 cycles at 300 mCi

Reporting group title

Cohort 3A: 4 cycles at 200 mCi

Reporting group description

Cohort 3A: 4 cycles at 200 mCi

Reporting group title

Cohort 2: 3 cycles at 200 mCi

Reporting group description

Cohort 2: 3 cycles at 200 mCi

Reporting group title

Cohort 1: 3 cycles at 100 mCi

Reporting group description

Cohort 1: 3 cycles at 100 mCi

Reporting group title

Cohort 5D: 2 cycles at 500 mCi

Reporting group description

Cohort 5D: 2 cycles at 500 mCi

Reporting group title

Cohort 5C: 4 cycles at 400 mCi

Reporting group description

Cohort 5C: 4 cycles at 400 mCi

Reporting group title

Cohort 4C: 3 cycles at 400 mCi

Reporting group description

Cohort 4C: 3 cycles at 400 mCi

Reporting group title

Cohort 6E: 3 cycles at 500 mCi

Reporting group description

Cohort 6E: 3 cycles at 500 mCi

Reporting group title

Cohort 4B: 4 cycles at 300 mCi

Reporting group description

Cohort 4B: 4 cycles at 300 mCi

Serious adverse events	Cohort 3B: 3 cycles at 300 mCi	Cohort 3A: 4 cycles at 200 mCi	Cohort 2: 3 cycles at 200 mCi	Cohort 1: 3 cycles at 100 mCi	Cohort 5D: 2 cycles at 500 mCi	Cohort 5C: 4 cycles at 400 mCi	Cohort 4C: 3 cycles at 400 mCi	Cohort 6E: 3 cycles at 500 mCi	Cohort 4B: 4 cycles at 300 mCi
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 3 (66.67%)
number of deaths (all causes)	3	1	1	1	1	1	2	0	3
number of deaths resulting from adverse events	0	0	0	0	0	0	0	0	0
Investigations
Platelet count decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Squamous cell carcinoma of lung
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Cardiac disorders
Atrial flutter
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Nervous system disorders
Hypoaesthesia
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0
Gastrointestinal disorders
Vomiting
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	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 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0
Infections and infestations
Urinary tract infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0

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

Non-serious adverse events	Cohort 3B: 3 cycles at 300 mCi	Cohort 3A: 4 cycles at 200 mCi	Cohort 2: 3 cycles at 200 mCi	Cohort 1: 3 cycles at 100 mCi	Cohort 5D: 2 cycles at 500 mCi	Cohort 5C: 4 cycles at 400 mCi	Cohort 4C: 3 cycles at 400 mCi	Cohort 6E: 3 cycles at 500 mCi	Cohort 4B: 4 cycles at 300 mCi
Total subjects affected by non serious adverse events
subjects affected / exposed	3 / 3 (100.00%)	3 / 3 (100.00%)	3 / 3 (100.00%)	3 / 3 (100.00%)	3 / 3 (100.00%)	3 / 3 (100.00%)	3 / 3 (100.00%)	3 / 3 (100.00%)	3 / 3 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	2 / 3 (66.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	1	2	0	0	2
Fatigue
subjects affected / exposed	1 / 3 (33.33%)	2 / 3 (66.67%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	2 / 3 (66.67%)	1 / 3 (33.33%)
occurrences all number	1	2	1	1	0	0	1	2	1
Oedema peripheral
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Injection site pain
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Infusion site coldness
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Pyrexia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Peripheral swelling
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Reproductive system and breast disorders
Prostatic pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	1	0
Hypoxia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Productive cough
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Psychiatric disorders
Depression
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Insomnia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 3 (33.33%)
occurrences all number	0	2	0	1	0	0	1	1	1
Amylase decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Blood bilirubin increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	1	0	0	1
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	1	0	1	0	0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 3 (33.33%)
occurrences all number	0	2	1	1	0	0	1	1	1
Blood chloride increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Blood creatine increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	1	0	0	0	1	0	0	1
Blood fibrinogen decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Blood urea increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Blood lactate dehydrogenase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	1	0	0
Blood glucose increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Electrocardiogram QT prolonged
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	0	2
Eosinophil count decreased
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)
occurrences all number	1	0	0	0	0	2	0	1	1
Eosinophil count increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	2	0
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 3 (33.33%)
occurrences all number	0	1	0	0	0	0	1	2	1
Glomerular filtration rate decreased
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Immature granulocyte percentage increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Immature granulocyte count increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Lipase decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Lymphocyte count decreased
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)
occurrences all number	1	1	0	0	0	4	0	3	4
Mean cell haemoglobin increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Neutrophil count decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	2	0	0	0
Platelet count decreased
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences all number	1	0	0	0	0	1	0	0	1
Protein urine present
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	1	0	0	1
Red blood cells urine positive
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	0	1
Urinary casts
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Urine analysis abnormal
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Weight decreased
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	1	0	0	0	0	1	0	1
White blood cell count decreased
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)
occurrences all number	2	1	1	0	0	2	0	1	3
White blood cells urine positive
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	1	0	0	1
Injury, poisoning and procedural complications
Lip injury
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Nervous system disorders
Dizziness
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Dysgeusia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 3 (66.67%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	2	0	1	0	0	0	0
Headache
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	2	0	0	0	0	0	0
Peripheral sensory neuropathy
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Sciatica
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 3 (33.33%)	2 / 3 (66.67%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences all number	1	2	1	2	0	1	1	0	1
Eosinophilia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Blood loss anaemia
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Eye disorders
Dry eye
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	1	0
Xerophthalmia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Abdominal pain upper
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Constipation
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences all number	1	0	1	0	1	0	1	1	0
Diarrhoea
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Frequent bowel movements
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Dyschezia
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Dry mouth
subjects affected / exposed	1 / 3 (33.33%)	2 / 3 (66.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 3 (66.67%)	0 / 3 (0.00%)
occurrences all number	1	2	0	0	0	2	0	2	0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	1	0	0	0	0	0
Oral pruritus
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Nausea
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences all number	1	0	1	0	2	2	0	1	0
Hepatobiliary disorders
Liver injury
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	0	1
Skin and subcutaneous tissue disorders
Dry skin
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	0	1
Ingrowing nail
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Rash
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	1	0
Renal and urinary disorders
Pollakiuria
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences all number	1	0	0	0	0	1	0	0	1
Urinary incontinence
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Renal failure
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	0	1
Urinary retention
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	0	1
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	1	2	0	0	0	0	0	1
Back pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 3 (66.67%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	2	1	1	0
Coccydynia
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Bone pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	1	0	0	0	0	0
Groin pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Musculoskeletal pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Muscular weakness
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Pain in extremity
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 3 (66.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	3	0	0	0	0
Infections and infestations
COVID-19
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	1	0	0	0
Urinary tract infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	1	0	0
Staphylococcal infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	0	1
Nasopharyngitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	2 / 3 (66.67%)
occurrences all number	0	0	0	0	0	1	0	1	2
Hyperglycaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	2	0	0	0	1	0	0
Hyperkalaemia
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	2	0	1	0	0	0	0	0

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Were there any global substantial amendments to the protocol? Yes

02 Feb 2018

Changes regarding secondary endpoint PSA response rate determination, treatment discontinuation, follow-up period testing, visit schedule variations, exclusion criteria, dosimetry analysis, safety dose-limiting toxicity determination and prohibited concomitant determination.

22 Feb 2018

No major changes from version 1.1. The changes in this version are mainly formatting changes and corrections of typographical errors.

02 Jul 2018

The main purpose of this amendment was to (A) include dosimetry, pharmacokinetics and imaging assessments in cohort 2 as well as all subsequent cohorts with a dose increase (B) move salivary gland scintigraphy from Day 1 to the Screening Period in order to allow clearance of radioactive tracer Tc99m and avoid Tc-99m’s possible impact on dosimetry assessments.

29 Apr 2019

The main purpose of this amendment was to enhance the dose escalation algorithm in Phase-I to allow testing of more dosing schedules during the dose-escalation phase by increasing the strength as well as testing different cycles of 177Lu-PSMA-R2, to determine RP2D. The amendment also clarified and ensured alignment between the objectives and endpoints of both Phase I and Phase II. Certain endpoints were moved from exploratory to secondary for both Phase I and Phase II. Given the single arm design of Phase II, primary objective, was changed from assessment of rPFS to assessment of PSA reduction of 50% or higher compared to baseline and rPFS was moved to secondary endpoint. Due to its relevance for radioligand therapy Disease Control Rate (DCR), and PSA response of 30% or higher was added to the secondary endpoint for Phase II. Duration of Response (DoR), Objective Response Rate (ORR) was added as a secondary endpoint for both Phase I and Phase II. Statistical assumptions for Phase II was updated accordingly.

30 Sep 2019

Clarifications on specific sections of the study design and stopping guidelines were provided. Other administrative annotations were 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.

Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com for complete trial results.

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Phase I: Incidence of dose limiting toxicities (DLTs) during first cycle of study treatment.

Primary: Phase I: Incidence of dose limiting toxicities (DLTs) during first cycle of study treatment.

Secondary: Phase I: Number of Participants with Treatment Emergent Adverse Events (TEAEs)

Secondary: Phase I: Number of Participants with Treatment Emergent Adverse Events (TEAEs)

Secondary: Phase I: Number of participants with an Objective Response Rate (ORR)

Secondary: Phase I: Number of participants with an Objective Response Rate (ORR)

Secondary: Phase I: Duration of Response (DoR)

Secondary: Phase I: Duration of Response (DoR)

Secondary: Phase I: Number of participants with a Prostate-Specific Antigen (PSA) response rate 30

Secondary: Phase I: Number of participants with a Prostate-Specific Antigen (PSA) response rate 30

Secondary: Phase I: Number of participants with a Prostate-Specific Antigen (PSA) response rate 50

Secondary: Phase I: Number of participants with a Prostate-Specific Antigen (PSA) response rate 50

Secondary: Phase I: Maximum plasma concentration (Cmax) of 177Lu-PSMA-R2

Secondary: Phase I: Maximum plasma concentration (Cmax) of 177Lu-PSMA-R2

Secondary: Phase I: Area under the serum concentration-time curve from time zero to the time of last quantifiable concentration (AUCtlast) of 177Lu-PSMA-R2

Secondary: Phase I: Area under the serum concentration-time curve from time zero to the time of last quantifiable concentration (AUCtlast) of 177Lu-PSMA-R2

Secondary: Phase I: Area under the serum concentration-time curve from time zero to (AUCinf) of 177Lu-PSMA-R2

Secondary: Phase I: Area under the serum concentration-time curve from time zero to (AUCinf) of 177Lu-PSMA-R2

Secondary: Phase I: Absorbed doses of 177Lu-PSMA-R2 by critical organs

Secondary: Phase I: Absorbed doses of 177Lu-PSMA-R2 by critical organs

Secondary: Phase I: Residence times of 177Lu-PSMA-R2 in normal organs

Secondary: Phase I: Residence times of 177Lu-PSMA-R2 in normal organs

Secondary: Phase I: Mean change from Baseline in Patient Reported Outcomes (PRO) of Mouth Dryness using Xerostomia Questionnaire

Secondary: Phase I: Mean change from Baseline in Patient Reported Outcomes (PRO) of Mouth Dryness using Xerostomia Questionnaire

Secondary: Phase I: Mean change from Baseline in Patient Reported Outcomes (PRO) of Eye Dryness using Xerophthalmia Questionnaire

Secondary: Phase I: Mean change from Baseline in Patient Reported Outcomes (PRO) of Eye Dryness using Xerophthalmia Questionnaire

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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