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Clinical Trial Results:
Risk-based, response-adapted, Phase II open-label trial of nivolumab + brentuximab vedotin (N+ Bv) for children, adolescents, and young adults with relapsed/refractory (R/R) CD30 + classic Hodgkin lymphoma (cHL) after failure of first-line therapy, followed by brentuximab + bendamustine (Bv + B) for participants with a suboptimal response. CheckMate 744: CHECKpoint pathway and nivolumab clinical Trial Evaluation

Summary
EudraCT number	2016-002347-41
Trial protocol	CZ ES IE DE GB NL PL Outside EU/EEA IT
Global end of trial date	28 May 2024

Results information
Results version number	v1(current)
This version publication date	17 Nov 2024
First version publication date	17 Nov 2024
Other versions

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

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Trial information

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Sponsor protocol code

CA209-744

ISRCTN number

US NCT number

NCT02927769

WHO universal trial number (UTN)

Sponsor organisation name

Bristol-Myers Squibb

Sponsor organisation address

Chaussee de la Hulpe 185, Brussels, Belgium, 1170

Public contact

EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, Clinical.Trials@bms.com

Scientific contact

Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.com

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

Yes

EMA paediatric investigation plan number(s)

EMEA-001407-PIP02-15

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?

Yes

Analysis stage

Final

Date of interim/final analysis

08 Jul 2024

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

28 May 2024

Was the trial ended prematurely?

Main objective of the trial

To describe the complete metabolic response (CMR) rate before radiation therapy/high-dose chemotherapy/autologous stem-cell transplant and event-free survival (EFS) rate at 3 years, as assessed by blinded independent central review (BICR), using Lugano 2014 response criteria.

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial participants were followed.

Background therapy

Evidence for comparator

Actual start date of recruitment

28 Mar 2017

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

France: 14

Country: Number of subjects enrolled

Germany: 10

Country: Number of subjects enrolled

Ireland: 2

Country: Number of subjects enrolled

Italy: 15

Country: Number of subjects enrolled

Netherlands: 6

Country: Number of subjects enrolled

Spain: 1

Country: Number of subjects enrolled

United Kingdom: 4

Country: Number of subjects enrolled

United States: 20

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

All participants entered the Induction phase. Participants entered the Intensification phase if they received brentuximab + bendamustine (Bv + B). Participants entered the Consolidation Phase if they received radiation therapy (C1) or high-dose chemotherapy/autologous stem cell transplant (HDCT/ASCT) (C2).

Period 1 title

Induction Phase

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Cohort 1: Relapsed/Refractory cHL - Low Risk Relapse

Arm description

Participants started in the induction phase and received nivolumab + brentuximab vedotin (N+Bv) for 2 cycles (6 weeks). Participants with radiographic progression, by Investigator at Cycle 2 entered follow-up. The rest continued in the induction phase and received 2 more cycles of N+Bv (total 4 cycles = 12 weeks). - Participants who had a complete metabolic response (CMR) by BICR after a total of 4 cycles (12 weeks) of N+Bv received 2 more cycles of treatment of N+Bv (total of 6 cycles [18 weeks]), followed by Radiation Therapy (RT) (consolidation phase). - Participants without a CMR after 4 cycles of N+Bv, by BICR, entered the intensification phase and received 2 cycles of brentuximab + bendamustine (Bv+B); participants who achieved CMR after these 2 cycles proceeded with RT (consolidation phase). - Participants who had radiographic progression after Cycle 4 N+Bv, by BICR, or those who did not achieve CMR, after 2 cycles of Bv+B were taken off study treatment and entered follow-up.

Arm type

Experimental

Investigational medicinal product name

Brentuximab Vedotin

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for injection

Routes of administration

Intravenous use

Dosage and administration details

1.8 mg/kg every 21 days

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

BMS-936558

Other name

Pharmaceutical forms

Concentrate for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

3 mg/kg every 21 days

Cohort 2: Relapsed/Refractory cHL - Standard Risk Relapse

Arm description

Participants started in the induction phase and received nivolumab + brentuximab vedotin (N+Bv) for 2 cycles (6 weeks). Those with progression at Cycle 2 entered follow-up. The rest received 2 more cycles of N+Bv (total 4 cycles = 12 weeks). - Participants with complete metabolic response (CMR) after 4 cycles of N+Bv received high-dose chemotherapy and autologous stem cell transplant (HDCT/ASCT) (consolidation phase). Participants with CMR could receive up to 2 more cycles of N+Bv if their HDCT/ASCT was postponed. - Participants without CMR after 4 cycles of N+Bv received 2 cycles of brentuximab + bendamustine (Bv+B) (intensification phase). - Participants in CMR after 2 cycles of Bv+B received HDCT/ASCT. - Participants without CMR could receive 2 more cycles of Bv+B. If they had CMR, they received HDCT/ASCT. - Participants with CMR could receive up to 2 more cycles of B+Bv if their HDCT/ASCT was postponed. - Participants with progression after Cycle 4 N+Bv were taken off treatment.

Arm type

Experimental

Investigational medicinal product name

Bendamustine

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for injection

Routes of administration

Intravenous use

Dosage and administration details

90 mg/m2/day, 21-day cycles (on Days1 and 2)

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

BMS-936558

Other name

Pharmaceutical forms

Concentrate for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

3 mg/kg every 21 days

Number of subjects in period 1	Cohort 1: Relapsed/Refractory cHL - Low Risk Relapse	Cohort 2: Relapsed/Refractory cHL - Standard Risk Relapse
Started	28	44
Completed	27	42
Not completed	1	2
Disease progression	-	1
Study drug toxicity	1	1

Period 2 title

Consolidation Phase

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Cohort 1: Relapsed/Refractory cHL - Low Risk Relapse

Arm description

Arm type

Experimental

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

BMS-936558

Other name

Pharmaceutical forms

Concentrate for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

3 mg/kg every 21 days

Investigational medicinal product name

Bendamustine

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for injection

Routes of administration

Intravenous use

Dosage and administration details

90 mg/m2/day, 21-day cycles (on Days1 and 2)

Investigational medicinal product name

Brentuximab Vedotin

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for injection

Routes of administration

Intravenous use

Dosage and administration details

1.8 mg/kg every 21 days

Cohort 2: Relapsed/Refractory cHL - Standard Risk Relapse

Arm description

Arm type

Experimental

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

BMS-936558

Other name

Pharmaceutical forms

Concentrate for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

3 mg/kg every 21 days

Investigational medicinal product name

Bendamustine

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for injection

Routes of administration

Intravenous use

Dosage and administration details

90 mg/m2/day, 21-day cycles (on Days1 and 2)

Investigational medicinal product name

Bendamustine

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for injection

Routes of administration

Intravenous use

Dosage and administration details

90 mg/m2/day, 21-day cycles (on Days1 and 2)

Number of subjects in period 2 ^[1]	Cohort 1: Relapsed/Refractory cHL - Low Risk Relapse	Cohort 2: Relapsed/Refractory cHL - Standard Risk Relapse
Started	22	32
Completed	22	32

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Not all participants who started in the induction phase entered the intensification or consolidation phase.

Period 3 title

Intensification Phase

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Cohort 1: Relapsed/Refractory cHL - Low Risk Relapse

Arm description

Arm type

Experimental

Investigational medicinal product name

Bendamustine

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for injection

Routes of administration

Intravenous use

Dosage and administration details

90 mg/m2/day, 21-day cycles (on Days1 and 2)

Investigational medicinal product name

Brentuximab Vedotin

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for injection

Routes of administration

Intravenous use

Dosage and administration details

1.8 mg/kg every 21 days

Cohort 2: Relapsed/Refractory cHL - Standard Risk Relapse

Arm description

Arm type

Experimental

Investigational medicinal product name

Bendamustine

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for injection

Routes of administration

Intravenous use

Dosage and administration details

90 mg/m2/day, 21-day cycles (on Days1 and 2)

Investigational medicinal product name

Brentuximab Vedotin

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for injection

Routes of administration

Intravenous use

Dosage and administration details

1.8 mg/kg every 21 days

Number of subjects in period 3 ^[2]	Cohort 1: Relapsed/Refractory cHL - Low Risk Relapse	Cohort 2: Relapsed/Refractory cHL - Standard Risk Relapse
Started	6	11
Completed	5	11
Not completed	1	0
Study drug toxicity	1	-

Notes
[2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Not all participants who started in the induction phase entered the intensification or consolidation phase.

Baseline characteristics

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Reporting group title

Cohort 1: Relapsed/Refractory cHL - Low Risk Relapse

Reporting group description

Reporting group title

Cohort 2: Relapsed/Refractory cHL - Standard Risk Relapse

Reporting group description

Reporting group values	Cohort 1: Relapsed/Refractory cHL - Low Risk Relapse	Cohort 2: Relapsed/Refractory cHL - Standard Risk Relapse	Total
Number of subjects	28	44	72
Age categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	3	4	7
Adolescents (12-17 years)	15	27	42
Adults (18-64 years)	10	13	23
From 65-84 years	0	0	0
85 years and over	0	0	0
Age Continuous
Units: Years
arithmetic mean (standard deviation)	17.0 ( 4.3 )	16.2 ( 3.7 )	-
Sex: Female, Male
Units: Participants
Female	18	15	33
Male	10	29	39
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0
Asian	1	0	1
Native Hawaiian or Other Pacific Islander	0	1	1
Black or African American	1	1	2
White	25	41	66
More than one race	0	0	0
Unknown or Not Reported	1	1	2
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	3	1	4
Not Hispanic or Latino	8	20	28
Unknown or Not Reported	17	23	40

End points

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Reporting group title

Cohort 1: Relapsed/Refractory cHL - Low Risk Relapse

Reporting group description

Reporting group title

Cohort 2: Relapsed/Refractory cHL - Standard Risk Relapse

Reporting group description

Reporting group title

Cohort 1: Relapsed/Refractory cHL - Low Risk Relapse

Reporting group description

Reporting group title

Cohort 2: Relapsed/Refractory cHL - Standard Risk Relapse

Reporting group description

Reporting group title

Cohort 1: Relapsed/Refractory cHL - Low Risk Relapse

Reporting group description

Reporting group title

Cohort 2: Relapsed/Refractory cHL - Standard Risk Relapse

Reporting group description

Primary: Event-free Survival (EFS) Rate at 3 Years by Blinded Independent Centralized Review (BICR) - Cohort 1

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End point title

Event-free Survival (EFS) Rate at 3 Years by Blinded Independent Centralized Review (BICR) - Cohort 1 ^[1] ^[2]

End point description

Event Free Survival (EFS) is the time from the first treatment to the earliest occurrence of composite events including: Disease progression (PD), Failure to achieve complete metabolic response (CMR) after 4 cycles of N+Bv and 2 cycles of Bv+B, Secondary malignancy, Death . PD : Lymph Nodes and Lesions: new growth or increase of >= 50% in size from nadir. New or growing lesions outside the lymph nodes. Spleen: Significant increase in spleen size, either from a previously enlarged state or from normal size. New Lesions: Yes Bone Marrow: New or returning FDG-avid disease CM): Lymph nodes/extralymphatic sites: Score 1, 2, 3 with/without residual mass on 5-point scale • New lesions: No Bone marrow: No FDG-avid disease Participants without an “event” were censored at the last tumor assessment. Those who started subsequent anticancer therapy without a prior “event” were censored at the last tumor assessment prior to or upon starting subsequent therapy. Based on Kaplan-Meier Estimates.

End point type

Primary

End point timeframe

At 3 years post first dose of study therapy

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 statistics were planned for this endpoint.
[2] - 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: Prespecified to be collected for Cohort 1 only.

End point values	Cohort 1: Relapsed/Refractory cHL - Low Risk Relapse
Number of subjects analysed	28
Units: Percent of participants
number (confidence interval 90%)	87.5 (70.6 to 95.0)

No statistical analyses for this end point

Primary: Complete Metabolic Response (CMR) Rate at Any Time Prior to High Dose Chemotherapy Followed by Autologous Stem Cell Treatment (HDCT/ASCT) by Blinded Independent Centralized Review (BICR) - Cohort 2

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End point title

Complete Metabolic Response (CMR) Rate at Any Time Prior to High Dose Chemotherapy Followed by Autologous Stem Cell Treatment (HDCT/ASCT) by Blinded Independent Centralized Review (BICR) - Cohort 2 ^[3] ^[4]

End point description

The complete metabolic response (CMR) rate is defined as the percent of all response-evaluable participants who, assessed by the BICR, achieved best response of CMR. Complete metabolic response (CMR): • Lymph nodes/extralymphatic sites: Score 1, 2, 3 with/without residual mass on 5-point scale • New lesions: No • Bone marrow: No FDG-avid disease Participants who came off study treatment early for toxicity without a CMR were evaluable. Confidence interval is based on the Clopper and Pearson method

End point type

Primary

End point timeframe

From first dose to complete metabolic response or the completion of six cycles of therapy (up to approximately 18 weeks)

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: Only descriptive statistics were 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: Prespecified to be collected for Cohort 1 only.

End point values	Cohort 2: Relapsed/Refractory cHL - Standard Risk Relapse
Number of subjects analysed	44
Units: Percent of participants
number (confidence interval 90%)	88.6 (77.6 to 95.4)

No statistical analyses for this end point

Primary: Complete Metabolic Response (CMR) Rate at Any Time Prior to Radiation Therapy by Blinded Independent Centralized Review (BICR) - Cohort 1

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End point title

Complete Metabolic Response (CMR) Rate at Any Time Prior to Radiation Therapy by Blinded Independent Centralized Review (BICR) - Cohort 1 ^[5] ^[6]

End point description

The complete metabolic response (CMR) rate is defined as the percent of all response-evaluable participants who, assessed by the BICR, achieved best response of CMR. Complete metabolic response (CMR): • Lymph nodes/extralymphatic sites: Score 1, 2, 3 with/without residual mass on 5-point scale • New lesions: No • Bone marrow: No FDG-avid disease Participants who stopped study treatment early for toxicity without a CMR were evaluable. Confidence interval is based on the Clopper and Pearson method

End point type

Primary

End point timeframe

From first dose to complete metabolic response or the completion of six cycles of therapy (up to approximately 18 weeks).

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistics were planned for this endpoint.
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Prespecified to be collected for Cohort 1 only.

End point values	Cohort 1: Relapsed/Refractory cHL - Low Risk Relapse
Number of subjects analysed	28
Units: Percent of participants
number (confidence interval 90%)	92.9 (79.2 to 98.7)

No statistical analyses for this end point

Secondary: Overall Response Rate (ORR) Following 4 Cycles of Nivolumab + Brentuximab Vedotin Treatment by Blinded Independent Centralized Review (BICR)

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End point title

Overall Response Rate (ORR) Following 4 Cycles of Nivolumab + Brentuximab Vedotin Treatment by Blinded Independent Centralized Review (BICR)

End point description

Overall response rate (ORR) is defined as the percent of all response-evaluable participants who, assessed by the BICR, achieved a best response of complete metabolic response (CMR) or partial metabolic response (PMR). Complete metabolic response (CMR): • Lymph nodes/extralymphatic sites: Score 1, 2, 3 with/without residual mass on 5-point scale • New lesions: No • Bone marrow: No FDG-avid disease Partial metabolic response (PMR): • Lymph nodes/extralymphatic: Score 4 or 5, reduced uptake from baseline • New lesions: None • Bone marrow: Residual uptake higher than normal, reduced from baseline. Participants who came off early for toxicity without CMR or PMR were evaluable.

End point type

Secondary

End point timeframe

From first dose to PMR or CMR within 4 cycles of therapy, or the completion of four cycles of therapy (N+Bv x4) (up to approximately 12 weeks).

End point values	Cohort 1: Relapsed/Refractory cHL - Low Risk Relapse	Cohort 2: Relapsed/Refractory cHL - Standard Risk Relapse
Number of subjects analysed	28	44
Units: Percent of participants
number (confidence interval 90%)	96.4 (84.1 to 99.8)	93.2 (83.3 to 98.1)

No statistical analyses for this end point

Secondary: Duration of Response (DOR) by Blinded Independent Centralized Review (BICR)

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End point title

Duration of Response (DOR) by Blinded Independent Centralized Review (BICR)

End point description

Duration of response (DOR) is from first complete metabolic response or partial metabolic response (CMR or PMR) to event free survival EFS (Cohort 1)/progression free survival PFS (Cohort 2) event. For participants with no event, the DOR was censored on the date of last tumor assessment. Participants who started subsequent anticancer therapy (not part of high-dose chemotherapy followed by autologous stem cell transplant HDCT/ASCT) without a prior reported EFS/PFS event were censored at the last tumor assessment prior to starting subsequent anticancer therapy. Complete metabolic response (CMR): • Lymph nodes/extralymphatic sites: Score 1, 2, 3 with/without residual mass on 5-point scale • New lesions: No • Bone marrow: No FDG-avid disease Partial metabolic response: • Lymph nodes/extralymphatic: Score 4 or 5, reduced uptake from baseline • New lesions: None • Bone marrow: Residual uptake higher than normal, reduced from baseline. Based on Kaplan-Meier estimates. "99999 = N/A".

End point type

Secondary

End point timeframe

From first dose until disease progression, start of subsequent anti-cancer therapy, or or death due to any cause (up to approximately 86 months)

End point values	Cohort 1: Relapsed/Refractory cHL - Low Risk Relapse	Cohort 2: Relapsed/Refractory cHL - Standard Risk Relapse
Number of subjects analysed	26	39
Units: Months
median (confidence interval 95%)	99999 (99999 to 99999)	99999 (99999 to 99999)

No statistical analyses for this end point

Secondary: Progression Free Survival (PFS) Rate at 3 Years by Blinded Independent Centralized Review (BICR)

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End point title

Progression Free Survival (PFS) Rate at 3 Years by Blinded Independent Centralized Review (BICR)

End point description

Progression Free Survival (PFS) is the time from the date of first treatment to the date of first documented disease progression by BICR or death. Progressive Disease (PD): Lymph Nodes and Lesions: new growth or increase of >= 50% in size from nadir. New or growing lesions outside the lymph nodes. Spleen: Significant increase in spleen size, either from a previously enlarged state or from normal size. New Lesions: Yes Bone Marrow: New or returning FDG-avid disease. Participants who neither progressed nor died were censored at the last adequate tumor assessment. Participants who started subsequent anticancer therapy (that is not part of high dose chemotherapy followed by autologous stem cell transplant (HDCT/ASCT) Consolidation Therapy for R2 Cohort) without a prior reported progression or death were censored at the last tumor assessment prior to initiation of the subsequent anticancer therapy. Based on Kaplan-Meier Estimates.

End point type

Secondary

End point timeframe

At 3 years post first dose of study therapy

End point values	Cohort 1: Relapsed/Refractory cHL - Low Risk Relapse	Cohort 2: Relapsed/Refractory cHL - Standard Risk Relapse
Number of subjects analysed	28	44
Units: Percent of participants
number (confidence interval 90%)	95.2 (77.7 to 99.1)	91.1 (78.4 to 96.5)

No statistical analyses for this end point

Secondary: Complete Metabolic Response (CMR) Rate at Any Time Prior to Radiation Therapy by Investigator - Cohort 1

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End point title

Complete Metabolic Response (CMR) Rate at Any Time Prior to Radiation Therapy by Investigator - Cohort 1 ^[7]

End point description

The complete metabolic response (CMR) rate is defined as the percent of all response-evaluable participants who, assessed by the investigator, achieved best response of CMR. Complete metabolic response (CMR): • Lymph nodes/extralymphatic sites: Score 1, 2, 3 with/without residual mass on 5-point scale • New lesions: No • Bone marrow: No FDG-avid disease Participants who come off early for toxicity without a CMR were evaluable. Confidence interval is based on the Clopper and Pearson method

End point type

Secondary

End point timeframe

From first dose to complete metabolic response or the completion of six cycles of therapy (up to approximately 18 weeks).

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: Prespecified to be collected for Cohort 1 only.

End point values	Cohort 1: Relapsed/Refractory cHL - Low Risk Relapse
Number of subjects analysed	28
Units: Percent of participants
number (confidence interval 90%)	89.3 (74.6 to 97.0)

No statistical analyses for this end point

Secondary: Event-free Survival (EFS) Rate at 3 Years by Investigator - Cohort 1

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End point title

Event-free Survival (EFS) Rate at 3 Years by Investigator - Cohort 1 ^[8]

End point description

Event Free Survival (EFS) is the time from the first treatment to the earliest occurrence of composite events including: Disease progression (PD), Failure to achieve complete metabolic response (CMR) after 4 cycles of N+Bv and 2 cycles of Bv+B, Secondary malignancy, Death . PD : Lymph Nodes and Lesions: new growth or increase of >= 50% in size from nadir. New or growing lesions outside the lymph nodes. Spleen: Significant increase in spleen size, either from a previously enlarged state or from normal size. New Lesions: Yes Bone Marrow: New or returning FDG-avid disease CMR: Lymph nodes/extralymphatic sites: Score 1, 2, 3 with/without residual mass on 5-point scale New lesions: No Bone marrow: No FDG-avid disease Participants without an “event” were censored at the last tumor assessment. Those who started subsequent anticancer therapy without a prior “event” were censored at the last tumor assessment prior to or upon starting subsequent therapy. Based on Kaplan-Meier Estimates.

End point type

Secondary

End point timeframe

At 3 years post first dose of study therapy

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: Prespecified to be collected for Cohort 1 only.

End point values	Cohort 1: Relapsed/Refractory cHL - Low Risk Relapse
Number of subjects analysed	28
Units: Percent of participants
number (confidence interval 90%)	88.5 (72.8 to 95.4)

No statistical analyses for this end point

Secondary: Progression Free Survival (PFS) Rate at 3 Years by Investigator

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End point title

Progression Free Survival (PFS) Rate at 3 Years by Investigator

End point description

Progression Free Survival (PFS) is the time from the date of first treatment to the date of first documented disease progression by investigator or death. Progressive Disease (PD): Lymph Nodes and Lesions: new growth or increase of >= 50% in size from nadir. New or growing lesions outside the lymph nodes. Spleen: Significant increase in spleen size, either from a previously enlarged state or from normal size. New Lesions: Yes Bone Marrow: New or returning FDG-avid disease. Participants who neither progressed nor died were be censored at the last adequate tumor assessment. Participants who started subsequent anticancer therapy (that is not part of high dose chemotherapy followed by autologous stem cell transplant (HDCT/ASCT) Consolidation Therapy forR2 Cohort) without a prior reported progression or death were censored at the last tumor assessment prior to initiation of the subsequent anticancer therapy. Based on Kaplan-Meier Estimates.

End point type

Secondary

End point timeframe

At 3 years post first dose

End point values	Cohort 1: Relapsed/Refractory cHL - Low Risk Relapse	Cohort 2: Relapsed/Refractory cHL - Standard Risk Relapse
Number of subjects analysed	28	44
Units: Percent of participants
number (confidence interval 90%)	95.8 (80.2 to 99.2)	88.1 (74.8 to 94.6)

No statistical analyses for this end point

Secondary: Complete Metabolic Response (CMR) Rate at Any Time Prior to High Dose Chemotherapy Followed by Autologous Stem Cell Treatment (HDCT/ASCT) by Investigator - Cohort 2

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End point title

Complete Metabolic Response (CMR) Rate at Any Time Prior to High Dose Chemotherapy Followed by Autologous Stem Cell Treatment (HDCT/ASCT) by Investigator - Cohort 2 ^[9]

End point description

The complete metabolic response (CMR) rate is defined as the percent of all response-evaluable participants who, assessed by the investigator, achieved best response of CMR. Complete metabolic response (CMR): • Lymph nodes/extralymphatic sites: Score 1, 2, 3 with/without residual mass on 5-point scale • New lesions: No • Bone marrow: No FDG-avid disease Participants who came off study treatment early for toxicity without a CMR were evaluable. Confidence interval is based on the Clopper and Pearson method.

End point type

Secondary

End point timeframe

From first dose to complete metabolic response or the completion of six cycles of therapy (up to approximately 18 weeks)

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: Prespecified to be collected for Cohort 2 only.

End point values	Cohort 2: Relapsed/Refractory cHL - Standard Risk Relapse
Number of subjects analysed	44
Units: Percent of participants
number (confidence interval 95%)	86.4 (74.8 to 93.9)

No statistical analyses for this end point

Secondary: Overall Response Rate (ORR) Following 4 Cycles of Nivolumab + Brentuximab Vedotin Treatment by Investigator

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End point title

Overall Response Rate (ORR) Following 4 Cycles of Nivolumab + Brentuximab Vedotin Treatment by Investigator

End point description

Overall response rate (ORR) is defined as the percent of all response-evaluable participants who, assessed by the investigator, achieve a best response of complete metabolic response (CMR) or partial metabolic response (PMR). Complete metabolic response (CMR): • Lymph nodes/extralymphatic sites: Score 1, 2, 3 with/without residual mass on 5-point scale • New lesions: No • Bone marrow: No FDG-avid disease Partial metabolic response: • Lymph nodes/extralymphatic: Score 4 or 5, reduced uptake from baseline • New lesions: None • Bone marrow: Residual uptake higher than normal, reduced from baseline Participants who came off early for toxicity without CMR or PMR were evaluable.

End point type

Secondary

End point timeframe

From first dose to PMR or CMR within 4 cycles of therapy, or the completion of four cycles of therapy (N+Bv x4) (up to approximately 12 weeks).

End point values	Cohort 1: Relapsed/Refractory cHL - Low Risk Relapse	Cohort 2: Relapsed/Refractory cHL - Standard Risk Relapse
Number of subjects analysed	28	44
Units: Percent of participants
number (confidence interval 90%)	100.0 (89.9 to 100.0)	90.9 (80.4 to 96.8)

No statistical analyses for this end point

Secondary: Duration of Response (DOR) by Investigator

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End point title

Duration of Response (DOR) by Investigator

End point description

Duration of response (DOR) is from first complete metabolic response or partial metabolic response (CMR or PMR) to event free survival EFS (Cohort 1)/progression free survival PFS (Cohort 2) event. For participants with no event, the DOR was censored on the date of last tumor assessment. Participants who started subsequent anticancer therapy (not part of high-dose chemotherapy followed by autologous stem cell transplant HDCT/ASCT) without a prior reported EFS/PFS event were censored at the last tumor assessment before starting subsequent anticancer therapy. Complete metabolic response (CMR): • Lymph nodes/extralymphatic sites: Score 1, 2, 3 with/without residual mass on 5-point scale • New lesions: No • Bone marrow: No FDG-avid disease Partial metabolic response: • Lymph nodes/extralymphatic: Score 4 or 5, reduced uptake from baseline • New lesions: None • Bone marrow: Residual uptake higher than normal, reduced from baseline. Based on Kaplan-Meier estimates. "99999=N/A".

End point type

Secondary

End point timeframe

From first dose until disease progression, start of subsequent anti-cancer therapy, or or death due to any cause (up to approximately 86 months)

End point values	Cohort 1: Relapsed/Refractory cHL - Low Risk Relapse	Cohort 2: Relapsed/Refractory cHL - Standard Risk Relapse
Number of subjects analysed	28	44
Units: Months
median (confidence interval 95%)	99999 (99999 to 99999)	99999 (99999 to 99999)

No statistical analyses for this end point

Secondary: The Number of Participants with Adverse Events (AEs)

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End point title

The Number of Participants with Adverse Events (AEs)

End point description

An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study drug and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug.

End point type

Secondary

End point timeframe

From first dose to 30 days post last dose (an average of 4 months up until a maximum of 7 months).

End point values	Cohort 1: Relapsed/Refractory cHL - Low Risk Relapse	Cohort 2: Relapsed/Refractory cHL - Standard Risk Relapse
Number of subjects analysed	28	44
Units: Participants	26	42

No statistical analyses for this end point

Secondary: The Number of Participants with Serious Adverse Events (SAEs)

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End point title

The Number of Participants with Serious Adverse Events (SAEs)

End point description

A Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any dose: - Results in death - Is life-threatening (defined as an event in which the participant was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe) - Requires inpatient hospitalization or causes prolongation of existing hospitalization - Results in persistent or significant disability/incapacity - Is a congenital anomaly/birth defect - Is an important medical event.

End point type

Secondary

End point timeframe

From first dose to 30 days post last dose (an average of 4 months up until a maximum of 7 months)

End point values	Cohort 1: Relapsed/Refractory cHL - Low Risk Relapse	Cohort 2: Relapsed/Refractory cHL - Standard Risk Relapse
Number of subjects analysed	28	44
Units: Participants	8	9

No statistical analyses for this end point

Secondary: The Number of Participants with Abnormal Laboratory Values for Specific Thyroid Tests

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End point title

The Number of Participants with Abnormal Laboratory Values for Specific Thyroid Tests

End point description

The Number of Participants with Abnormal Laboratory Values for Specific Thyroid Tests.

End point type

Secondary

End point timeframe

From first dose to 30 days post last dose (an average of 4 months up until a maximum of 7 months)

End point values	Cohort 1: Relapsed/Refractory cHL - Low Risk Relapse	Cohort 2: Relapsed/Refractory cHL - Standard Risk Relapse
Number of subjects analysed	28	44
Units: Participants
TSH > ULN	6	8
TSH > ULN WITH TSH <= ULN AT BASELINE	5	4
TSH >ULN WITH ATLEAST ONE FT3/FT4 TEST VALUE <LLN	1	0
TSH >ULN WITH ALL OTHER FT3/FT4 TEST VALUES >= LLN	4	5
TSH > ULN WITH FT3/FT4 TEST MISSING	1	3
TSH < LLN	4	1
TSH <LLN WITH TSH >= LLN AT BASELINE	4	1
TSH <LLN WITH ATLEAST ONE FT3/FT4 TEST VALUE > ULN	3	1
TSH <LLN WITH ALL OTHER FT3/FT4 TEST VALUES <= ULN	1	0
TSH < LLN WITH FT3/FT4 TEST MISSING	0	0

No statistical analyses for this end point

Secondary: The Number of Participants with Abnormal Laboratory Values for Liver Tests

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End point title

The Number of Participants with Abnormal Laboratory Values for Liver Tests

End point description

The Number of Participants with Abnormal Laboratory Values for Liver Tests.

End point type

Secondary

End point timeframe

From first dose to 30 days post last dose (an average of 4 months up until a maximum of 7 months)

End point values	Cohort 1: Relapsed/Refractory cHL - Low Risk Relapse	Cohort 2: Relapsed/Refractory cHL - Standard Risk Relapse
Number of subjects analysed	28	44
Units: Participants
ALT OR AST > 3XULN	8	5
ALT OR AST> 5XULN	3	1
ALT OR AST> 10XULN	0	0
ALT OR AST > 20XULN	0	0
TOTAL BILIRUBIN > 2XULN	1	0
ALT/AST ELEV>3XULN;TOTAL BILIRUBIN>2XULN IN 1 DAY	0	0
ALT/AST ELEV>3XULN;TOTAL BILIRUBIN>2XULN 30 DAYS	0	0

No statistical analyses for this end point

Secondary: Vital Sign Measurements

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End point title

Vital Sign Measurements

End point description

Data not collected

End point type

Secondary

End point timeframe

Data not collected

End point values	Cohort 1: Relapsed/Refractory cHL - Low Risk Relapse	Cohort 2: Relapsed/Refractory cHL - Standard Risk Relapse
Number of subjects analysed	0 ^[10]	0 ^[11]
Units: N/A

Notes
[10] - Data not collected
[11] - Data not collected

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

SAEs and Non-serious AEs were assessed from first dose to 30 days after last dose of study therapy (assessed for an average of 4 months up until a maximum of 7 months).

Adverse event reporting additional description

Serious Adverse Events and Non-Serious Adverse Events represents all participants that received at least 1 dose of study medication.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

27.0

Reporting group title

Cohort 1: Nivo + Bv

Reporting group description

Participants started in the induction phase and received nivolumab + brentuximab vedotin (N+Bv) for 2 cycles (6 weeks). Participants with radiographic progression, as assessed by Investigator at Cycle 2 entered follow-up. The rest of the participants continued in the induction phase and received 2 additional cycles of N+Bv study therapy (total 4 cycles = 12 weeks). - Participants who had a complete metabolic response (CMR) by BICR after a total of 4 cycles (12 weeks) of N+Bv received an additional 2 cycles of treatment of N+Bv (for a total of 6 cycles [18 weeks]), followed by Radiation Therapy (RT) (consolidation phase).

Reporting group title

Cohort 2: Nivo + Bv

Reporting group description

Participants started in the induction phase and received nivolumab + brentuximab vedotin (N+Bv) for 2 cycles (6 weeks). Participants with radiographic progression, as assessed by Investigator at Cycle 2 entered follow-up. The rest of the participants received 2 additional cycles of N+Bv study therapy (total 4 cycles = 12 weeks). - Participants who had complete metabolic response (CMR), by BICR, after a total of 4 cycles (12 weeks) of N+Bv proceeded with high-dose chemotherapy followed by an autologous stem cell transplant (HDCT/ASCT) (consolidation phase). Participants with CMR had the option to receive up to 2 additional cycles of N+Bv if their HDCT/ASCT was postponed for any reason.

Reporting group title

Cohort 2: (Nivo + Bv) + (Bv + B)

Reporting group description

Participants started in the induction phase with nivolumab and brentuximab vedotin (N+Bv) for 2 cycles (6 weeks). Those with radiographic progression at Cycle 2 entered follow-up. The rest received 2 more cycles of N+Bv (total 4 cycles, 12 weeks). Participants with complete metabolic response (CMR) after 4 cycles of N+Bv got with high-dose chemotherapy and autologous stem cell transplant (HDCT/ASCT). Those with CMR could receive up to 2 additional cycles of N+Bv if HDCT/ASCT was postponed. Participants without CMR after 4 cycles of N+Bv received 2 cycles of brentuximab and bendamustine (Bv+B). Those with CMR after 2 cycles of Bv+B got HDCT/ASCT. Participants without CMR could receive 2 more cycles of Bv+B and, if CMR was attained, got HDCT/ASCT. Those with CMR could receive up to 2 additional cycles of Bv+B if HDCT/ASCT was postponed. Participants with radiographic progression after Cycle 4 N+Bv or no CMR after final Bv+B were taken off study treatment and entered follow-up.

Reporting group title

Cohort 1: (Nivo + Bv) + (Bv + B)

Reporting group description

Participants started in the induction phase and received nivolumab and brentuximab vedotin (N+Bv) for 2 cycles (6 weeks). Those with radiographic progression at Cycle 2 entered follow-up. The rest continued in the induction phase for 2 additional cycles of N+Bv (total 4 cycles, 12 weeks). Participants with a complete metabolic response (CMR) after 4 cycles of N+Bv received 2 more cycles of N+Bv (total 6 cycles, 18 weeks) followed by Radiation Therapy (RT) in the consolidation phase. Participants without a CMR after 4 cycles of N+Bv entered the intensification phase and received 2 cycles of brentuximab and bendamustine (Bv+B). Those who achieved CMR after these 2 cycles proceeded with RT consolidation. Participants with radiographic progression after Cycle 4 N+Bv or those who did not achieve CMR after 2 cycles of Bv+B were taken off study treatment and entered follow-up.

Serious adverse events	Cohort 1: Nivo + Bv	Cohort 2: Nivo + Bv	Cohort 2: (Nivo + Bv) + (Bv + B)	Cohort 1: (Nivo + Bv) + (Bv + B)
Total subjects affected by serious adverse events
subjects affected / exposed	6 / 22 (27.27%)	11 / 33 (33.33%)	4 / 11 (36.36%)	3 / 6 (50.00%)
number of deaths (all causes)	0	0	1	0
number of deaths resulting from adverse events	0	0	0	0
Vascular disorders
Hypotension
subjects affected / exposed	0 / 22 (0.00%)	0 / 33 (0.00%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Chest pain
subjects affected / exposed	0 / 22 (0.00%)	0 / 33 (0.00%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	2 / 22 (9.09%)	3 / 33 (9.09%)	1 / 11 (9.09%)	3 / 6 (50.00%)
occurrences causally related to treatment / all	0 / 2	0 / 4	0 / 1	4 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Anaphylactic reaction
subjects affected / exposed	0 / 22 (0.00%)	1 / 33 (3.03%)	0 / 11 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypersensitivity
subjects affected / exposed	1 / 22 (4.55%)	1 / 33 (3.03%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	1 / 1	3 / 3	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Hypoxia
subjects affected / exposed	0 / 22 (0.00%)	0 / 33 (0.00%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 22 (0.00%)	1 / 33 (3.03%)	0 / 11 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Orthopnoea
subjects affected / exposed	0 / 22 (0.00%)	1 / 33 (3.03%)	0 / 11 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary veno-occlusive disease
subjects affected / exposed	0 / 22 (0.00%)	1 / 33 (3.03%)	0 / 11 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Activated partial thromboplastin time prolonged
subjects affected / exposed	0 / 22 (0.00%)	1 / 33 (3.03%)	0 / 11 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood phosphorus increased
subjects affected / exposed	0 / 22 (0.00%)	1 / 33 (3.03%)	0 / 11 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Infusion related reaction
subjects affected / exposed	0 / 22 (0.00%)	1 / 33 (3.03%)	0 / 11 (0.00%)	1 / 6 (16.67%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular access complication
subjects affected / exposed	0 / 22 (0.00%)	1 / 33 (3.03%)	0 / 11 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Pericardial effusion
subjects affected / exposed	0 / 22 (0.00%)	1 / 33 (3.03%)	0 / 11 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Febrile neutropenia
subjects affected / exposed	1 / 22 (4.55%)	1 / 33 (3.03%)	0 / 11 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Disseminated intravascular coagulation
subjects affected / exposed	0 / 22 (0.00%)	1 / 33 (3.03%)	0 / 11 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Enteritis
subjects affected / exposed	1 / 22 (4.55%)	0 / 33 (0.00%)	0 / 11 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Stomatitis
subjects affected / exposed	0 / 22 (0.00%)	0 / 33 (0.00%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Urticaria
subjects affected / exposed	0 / 22 (0.00%)	0 / 33 (0.00%)	0 / 11 (0.00%)	1 / 6 (16.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rash
subjects affected / exposed	1 / 22 (4.55%)	0 / 33 (0.00%)	0 / 11 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 22 (0.00%)	0 / 33 (0.00%)	0 / 11 (0.00%)	1 / 6 (16.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Synovial cyst
subjects affected / exposed	0 / 22 (0.00%)	1 / 33 (3.03%)	0 / 11 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	0 / 22 (0.00%)	0 / 33 (0.00%)	0 / 11 (0.00%)	1 / 6 (16.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Sepsis
subjects affected / exposed	0 / 22 (0.00%)	1 / 33 (3.03%)	0 / 11 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Otitis media
subjects affected / exposed	0 / 22 (0.00%)	0 / 33 (0.00%)	0 / 11 (0.00%)	1 / 6 (16.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Cohort 1: Nivo + Bv	Cohort 2: Nivo + Bv	Cohort 2: (Nivo + Bv) + (Bv + B)	Cohort 1: (Nivo + Bv) + (Bv + B)
Total subjects affected by non serious adverse events
subjects affected / exposed	18 / 22 (81.82%)	33 / 33 (100.00%)	11 / 11 (100.00%)	6 / 6 (100.00%)
Vascular disorders
Hypertension
subjects affected / exposed	0 / 22 (0.00%)	3 / 33 (9.09%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	0	4	1	0
Hypotension
subjects affected / exposed	0 / 22 (0.00%)	4 / 33 (12.12%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	0	4	1	0
General disorders and administration site conditions
Face oedema
subjects affected / exposed	0 / 22 (0.00%)	0 / 33 (0.00%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Asthenia
subjects affected / exposed	4 / 22 (18.18%)	1 / 33 (3.03%)	1 / 11 (9.09%)	1 / 6 (16.67%)
occurrences all number	6	1	2	1
Fatigue
subjects affected / exposed	4 / 22 (18.18%)	7 / 33 (21.21%)	1 / 11 (9.09%)	2 / 6 (33.33%)
occurrences all number	4	12	1	7
Oedema peripheral
subjects affected / exposed	0 / 22 (0.00%)	2 / 33 (6.06%)	0 / 11 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	2	0	0
Non-cardiac chest pain
subjects affected / exposed	1 / 22 (4.55%)	1 / 33 (3.03%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	1	2	1	0
Mucosal inflammation
subjects affected / exposed	1 / 22 (4.55%)	10 / 33 (30.30%)	5 / 11 (45.45%)	0 / 6 (0.00%)
occurrences all number	1	11	6	0
Influenza like illness
subjects affected / exposed	0 / 22 (0.00%)	1 / 33 (3.03%)	1 / 11 (9.09%)	1 / 6 (16.67%)
occurrences all number	0	1	4	2
Gait disturbance
subjects affected / exposed	0 / 22 (0.00%)	0 / 33 (0.00%)	0 / 11 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	1
Pyrexia
subjects affected / exposed	1 / 22 (4.55%)	17 / 33 (51.52%)	5 / 11 (45.45%)	2 / 6 (33.33%)
occurrences all number	1	22	8	2
Immune system disorders
Hypersensitivity
subjects affected / exposed	1 / 22 (4.55%)	6 / 33 (18.18%)	3 / 11 (27.27%)	2 / 6 (33.33%)
occurrences all number	1	6	3	3
Infusion related hypersensitivity reaction
subjects affected / exposed	0 / 22 (0.00%)	0 / 33 (0.00%)	0 / 11 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	1
Drug hypersensitivity
subjects affected / exposed	1 / 22 (4.55%)	2 / 33 (6.06%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	1	2	2	0
Reproductive system and breast disorders
Dysmenorrhoea
subjects affected / exposed	2 / 22 (9.09%)	0 / 33 (0.00%)	0 / 11 (0.00%)	0 / 6 (0.00%)
occurrences all number	3	0	0	0
Respiratory, thoracic and mediastinal disorders
Rhinorrhoea
subjects affected / exposed	0 / 22 (0.00%)	0 / 33 (0.00%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Pharyngeal inflammation
subjects affected / exposed	0 / 22 (0.00%)	2 / 33 (6.06%)	0 / 11 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	2	0	0
Oropharyngeal pain
subjects affected / exposed	5 / 22 (22.73%)	4 / 33 (12.12%)	1 / 11 (9.09%)	1 / 6 (16.67%)
occurrences all number	5	5	1	1
Nasal congestion
subjects affected / exposed	1 / 22 (4.55%)	3 / 33 (9.09%)	0 / 11 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	3	0	0
Cough
subjects affected / exposed	2 / 22 (9.09%)	8 / 33 (24.24%)	0 / 11 (0.00%)	1 / 6 (16.67%)
occurrences all number	2	9	0	1
Dyspnoea
subjects affected / exposed	1 / 22 (4.55%)	3 / 33 (9.09%)	0 / 11 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	3	0	0
Epistaxis
subjects affected / exposed	3 / 22 (13.64%)	4 / 33 (12.12%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	3	6	1	0
Hypoxia
subjects affected / exposed	0 / 22 (0.00%)	3 / 33 (9.09%)	0 / 11 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	5	0	0
Psychiatric disorders
Insomnia
subjects affected / exposed	0 / 22 (0.00%)	3 / 33 (9.09%)	0 / 11 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	3	0	0
Anxiety
subjects affected / exposed	1 / 22 (4.55%)	1 / 33 (3.03%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	1	1	1	0
Agitation
subjects affected / exposed	0 / 22 (0.00%)	0 / 33 (0.00%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	5 / 22 (22.73%)	2 / 33 (6.06%)	3 / 11 (27.27%)	2 / 6 (33.33%)
occurrences all number	6	2	4	3
Amylase increased
subjects affected / exposed	1 / 22 (4.55%)	0 / 33 (0.00%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	1	0	2	0
Aspartate aminotransferase increased
subjects affected / exposed	3 / 22 (13.64%)	3 / 33 (9.09%)	2 / 11 (18.18%)	2 / 6 (33.33%)
occurrences all number	6	5	3	4
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 22 (0.00%)	1 / 33 (3.03%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	0	1	1	0
Blood bilirubin increased
subjects affected / exposed	2 / 22 (9.09%)	0 / 33 (0.00%)	0 / 11 (0.00%)	0 / 6 (0.00%)
occurrences all number	2	0	0	0
Body temperature increased
subjects affected / exposed	0 / 22 (0.00%)	0 / 33 (0.00%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 22 (0.00%)	0 / 33 (0.00%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Heart rate increased
subjects affected / exposed	0 / 22 (0.00%)	0 / 33 (0.00%)	0 / 11 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	1
International normalised ratio increased
subjects affected / exposed	0 / 22 (0.00%)	0 / 33 (0.00%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Lipase decreased
subjects affected / exposed	0 / 22 (0.00%)	0 / 33 (0.00%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Lipase increased
subjects affected / exposed	2 / 22 (9.09%)	0 / 33 (0.00%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	2	0	2	0
Lymphocyte count decreased
subjects affected / exposed	1 / 22 (4.55%)	0 / 33 (0.00%)	0 / 11 (0.00%)	1 / 6 (16.67%)
occurrences all number	1	0	0	1
Neutrophil count decreased
subjects affected / exposed	1 / 22 (4.55%)	2 / 33 (6.06%)	0 / 11 (0.00%)	0 / 6 (0.00%)
occurrences all number	2	2	0	0
Platelet count decreased
subjects affected / exposed	0 / 22 (0.00%)	4 / 33 (12.12%)	2 / 11 (18.18%)	0 / 6 (0.00%)
occurrences all number	0	4	2	0
Weight decreased
subjects affected / exposed	1 / 22 (4.55%)	2 / 33 (6.06%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	1	2	1	0
White blood cell count decreased
subjects affected / exposed	1 / 22 (4.55%)	2 / 33 (6.06%)	2 / 11 (18.18%)	0 / 6 (0.00%)
occurrences all number	1	4	2	0
Injury, poisoning and procedural complications
Radiation skin injury
subjects affected / exposed	1 / 22 (4.55%)	0 / 33 (0.00%)	0 / 11 (0.00%)	2 / 6 (33.33%)
occurrences all number	1	0	0	2
Radiation associated pain
subjects affected / exposed	0 / 22 (0.00%)	0 / 33 (0.00%)	0 / 11 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	1
Procedural pain
subjects affected / exposed	0 / 22 (0.00%)	0 / 33 (0.00%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Post procedural complication
subjects affected / exposed	0 / 22 (0.00%)	0 / 33 (0.00%)	0 / 11 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	1
Infusion related reaction
subjects affected / exposed	4 / 22 (18.18%)	4 / 33 (12.12%)	5 / 11 (45.45%)	1 / 6 (16.67%)
occurrences all number	4	4	9	2
Vascular access site pruritus
subjects affected / exposed	0 / 22 (0.00%)	0 / 33 (0.00%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Cardiac disorders
Tachycardia
subjects affected / exposed	2 / 22 (9.09%)	1 / 33 (3.03%)	0 / 11 (0.00%)	0 / 6 (0.00%)
occurrences all number	2	1	0	0
Sinus bradycardia
subjects affected / exposed	0 / 22 (0.00%)	0 / 33 (0.00%)	2 / 11 (18.18%)	0 / 6 (0.00%)
occurrences all number	0	0	2	0
Nervous system disorders
Presyncope
subjects affected / exposed	1 / 22 (4.55%)	2 / 33 (6.06%)	0 / 11 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	2	0	0
Disturbance in attention
subjects affected / exposed	0 / 22 (0.00%)	0 / 33 (0.00%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Dizziness
subjects affected / exposed	1 / 22 (4.55%)	4 / 33 (12.12%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	1	5	1	0
Headache
subjects affected / exposed	10 / 22 (45.45%)	6 / 33 (18.18%)	4 / 11 (36.36%)	2 / 6 (33.33%)
occurrences all number	12	7	7	2
Somnolence
subjects affected / exposed	0 / 22 (0.00%)	0 / 33 (0.00%)	0 / 11 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 22 (4.55%)	6 / 33 (18.18%)	3 / 11 (27.27%)	1 / 6 (16.67%)
occurrences all number	1	6	3	2
Febrile neutropenia
subjects affected / exposed	0 / 22 (0.00%)	5 / 33 (15.15%)	4 / 11 (36.36%)	0 / 6 (0.00%)
occurrences all number	0	5	4	0
Thrombocytopenia
subjects affected / exposed	1 / 22 (4.55%)	4 / 33 (12.12%)	2 / 11 (18.18%)	0 / 6 (0.00%)
occurrences all number	1	5	2	0
Neutropenia
subjects affected / exposed	1 / 22 (4.55%)	2 / 33 (6.06%)	2 / 11 (18.18%)	1 / 6 (16.67%)
occurrences all number	1	2	2	1
Leukopenia
subjects affected / exposed	0 / 22 (0.00%)	0 / 33 (0.00%)	0 / 11 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	1
Eye disorders
Eye pain
subjects affected / exposed	0 / 22 (0.00%)	2 / 33 (6.06%)	0 / 11 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	2	0	0
Gastrointestinal disorders
Abdominal pain upper
subjects affected / exposed	1 / 22 (4.55%)	7 / 33 (21.21%)	1 / 11 (9.09%)	1 / 6 (16.67%)
occurrences all number	3	7	2	1
Abdominal pain
subjects affected / exposed	1 / 22 (4.55%)	9 / 33 (27.27%)	4 / 11 (36.36%)	0 / 6 (0.00%)
occurrences all number	1	13	7	0
Vomiting
subjects affected / exposed	2 / 22 (9.09%)	7 / 33 (21.21%)	6 / 11 (54.55%)	3 / 6 (50.00%)
occurrences all number	2	11	22	4
Stomatitis
subjects affected / exposed	1 / 22 (4.55%)	7 / 33 (21.21%)	1 / 11 (9.09%)	1 / 6 (16.67%)
occurrences all number	1	7	1	1
Paraesthesia oral
subjects affected / exposed	0 / 22 (0.00%)	0 / 33 (0.00%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Oral pain
subjects affected / exposed	0 / 22 (0.00%)	0 / 33 (0.00%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Nausea
subjects affected / exposed	9 / 22 (40.91%)	19 / 33 (57.58%)	11 / 11 (100.00%)	3 / 6 (50.00%)
occurrences all number	11	32	22	5
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 22 (4.55%)	1 / 33 (3.03%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	1	1	1	0
Enterocolitis
subjects affected / exposed	0 / 22 (0.00%)	0 / 33 (0.00%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Dysphagia
subjects affected / exposed	1 / 22 (4.55%)	0 / 33 (0.00%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	1	0	1	0
Diarrhoea
subjects affected / exposed	5 / 22 (22.73%)	13 / 33 (39.39%)	4 / 11 (36.36%)	1 / 6 (16.67%)
occurrences all number	6	24	8	1
Constipation
subjects affected / exposed	4 / 22 (18.18%)	3 / 33 (9.09%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	5	4	1	0
Coating in mouth
subjects affected / exposed	0 / 22 (0.00%)	0 / 33 (0.00%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Skin and subcutaneous tissue disorders
Erythema
subjects affected / exposed	1 / 22 (4.55%)	3 / 33 (9.09%)	2 / 11 (18.18%)	0 / 6 (0.00%)
occurrences all number	1	3	3	0
Dry skin
subjects affected / exposed	0 / 22 (0.00%)	3 / 33 (9.09%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	0	4	1	0
Dermatitis allergic
subjects affected / exposed	0 / 22 (0.00%)	3 / 33 (9.09%)	1 / 11 (9.09%)	1 / 6 (16.67%)
occurrences all number	0	3	1	2
Alopecia
subjects affected / exposed	3 / 22 (13.64%)	5 / 33 (15.15%)	1 / 11 (9.09%)	1 / 6 (16.67%)
occurrences all number	3	5	1	1
Acne
subjects affected / exposed	2 / 22 (9.09%)	0 / 33 (0.00%)	0 / 11 (0.00%)	0 / 6 (0.00%)
occurrences all number	2	0	0	0
Pruritus
subjects affected / exposed	4 / 22 (18.18%)	2 / 33 (6.06%)	3 / 11 (27.27%)	0 / 6 (0.00%)
occurrences all number	5	2	4	0
Night sweats
subjects affected / exposed	0 / 22 (0.00%)	1 / 33 (3.03%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	0	1	1	0
Hyperhidrosis
subjects affected / exposed	0 / 22 (0.00%)	0 / 33 (0.00%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	0	0	2	0
Rash maculo-papular
subjects affected / exposed	2 / 22 (9.09%)	6 / 33 (18.18%)	2 / 11 (18.18%)	1 / 6 (16.67%)
occurrences all number	3	8	4	1
Rash
subjects affected / exposed	0 / 22 (0.00%)	3 / 33 (9.09%)	4 / 11 (36.36%)	0 / 6 (0.00%)
occurrences all number	0	3	6	0
Purpura
subjects affected / exposed	0 / 22 (0.00%)	0 / 33 (0.00%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Psoriasis
subjects affected / exposed	0 / 22 (0.00%)	0 / 33 (0.00%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Urticaria
subjects affected / exposed	0 / 22 (0.00%)	0 / 33 (0.00%)	0 / 11 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	1
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 22 (0.00%)	0 / 33 (0.00%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	0	0	2	0
Haematuria
subjects affected / exposed	0 / 22 (0.00%)	2 / 33 (6.06%)	0 / 11 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	2	0	0
Endocrine disorders
Hypothyroidism
subjects affected / exposed	1 / 22 (4.55%)	0 / 33 (0.00%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	1	0	1	0
Hyperthyroidism
subjects affected / exposed	2 / 22 (9.09%)	0 / 33 (0.00%)	0 / 11 (0.00%)	0 / 6 (0.00%)
occurrences all number	2	0	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 22 (0.00%)	2 / 33 (6.06%)	3 / 11 (27.27%)	2 / 6 (33.33%)
occurrences all number	0	4	3	2
Back pain
subjects affected / exposed	1 / 22 (4.55%)	5 / 33 (15.15%)	2 / 11 (18.18%)	0 / 6 (0.00%)
occurrences all number	1	7	2	0
Bone pain
subjects affected / exposed	0 / 22 (0.00%)	4 / 33 (12.12%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	0	4	1	0
Flank pain
subjects affected / exposed	0 / 22 (0.00%)	0 / 33 (0.00%)	0 / 11 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	1
Groin pain
subjects affected / exposed	0 / 22 (0.00%)	0 / 33 (0.00%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Myalgia
subjects affected / exposed	0 / 22 (0.00%)	2 / 33 (6.06%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	0	2	1	0
Pain in extremity
subjects affected / exposed	3 / 22 (13.64%)	2 / 33 (6.06%)	2 / 11 (18.18%)	2 / 6 (33.33%)
occurrences all number	4	2	2	2
Pain in jaw
subjects affected / exposed	1 / 22 (4.55%)	2 / 33 (6.06%)	0 / 11 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	2	0	0
Infections and infestations
Cellulitis
subjects affected / exposed	0 / 22 (0.00%)	0 / 33 (0.00%)	0 / 11 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	1
Device related infection
subjects affected / exposed	0 / 22 (0.00%)	0 / 33 (0.00%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Epstein-Barr virus infection reactivation
subjects affected / exposed	0 / 22 (0.00%)	0 / 33 (0.00%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Gastroenteritis
subjects affected / exposed	1 / 22 (4.55%)	0 / 33 (0.00%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	1	0	1	0
Nasopharyngitis
subjects affected / exposed	1 / 22 (4.55%)	1 / 33 (3.03%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	3	1	1	0
Otitis media
subjects affected / exposed	0 / 22 (0.00%)	0 / 33 (0.00%)	0 / 11 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	1
Pharyngitis
subjects affected / exposed	0 / 22 (0.00%)	3 / 33 (9.09%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	0	4	1	0
Rhinitis
subjects affected / exposed	1 / 22 (4.55%)	3 / 33 (9.09%)	0 / 11 (0.00%)	2 / 6 (33.33%)
occurrences all number	1	3	0	2
Staphylococcal infection
subjects affected / exposed	0 / 22 (0.00%)	0 / 33 (0.00%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Upper respiratory tract infection
subjects affected / exposed	2 / 22 (9.09%)	2 / 33 (6.06%)	2 / 11 (18.18%)	0 / 6 (0.00%)
occurrences all number	2	3	2	0
Urinary tract infection
subjects affected / exposed	2 / 22 (9.09%)	0 / 33 (0.00%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	2	0	1	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 22 (0.00%)	8 / 33 (24.24%)	1 / 11 (9.09%)	1 / 6 (16.67%)
occurrences all number	0	9	1	1
Hyperglycaemia
subjects affected / exposed	1 / 22 (4.55%)	0 / 33 (0.00%)	1 / 11 (9.09%)	1 / 6 (16.67%)
occurrences all number	1	0	1	2
Hypochloraemia
subjects affected / exposed	0 / 22 (0.00%)	0 / 33 (0.00%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Hypoalbuminaemia
subjects affected / exposed	1 / 22 (4.55%)	0 / 33 (0.00%)	0 / 11 (0.00%)	1 / 6 (16.67%)
occurrences all number	1	0	0	1
Hyperuricaemia
subjects affected / exposed	0 / 22 (0.00%)	1 / 33 (3.03%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	0	1	4	0
Hypokalaemia
subjects affected / exposed	1 / 22 (4.55%)	0 / 33 (0.00%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	1	0	2	0
Hyponatraemia
subjects affected / exposed	1 / 22 (4.55%)	0 / 33 (0.00%)	2 / 11 (18.18%)	0 / 6 (0.00%)
occurrences all number	1	0	2	0
Hypophosphataemia
subjects affected / exposed	1 / 22 (4.55%)	0 / 33 (0.00%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	1	0	1	0
Hypouricaemia
subjects affected / exposed	0 / 22 (0.00%)	0 / 33 (0.00%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Hypocalcaemia
subjects affected / exposed	0 / 22 (0.00%)	1 / 33 (3.03%)	1 / 11 (9.09%)	0 / 6 (0.00%)
occurrences all number	0	1	1	0

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Were there any global substantial amendments to the protocol? Yes

01 Mar 2017

Per Health Authority recommendations (eg,: Add additional Safety Assessments to provide more frequent safety monitoring for this patient population during Induction Phase, update an optional lab sample and revise Section 2 Tables-due to new Safety Labs, add futility rule for R2 Cohort, amend inclusion criteria language from Direct to Total Bilirubin, simplify nivolumab dose delay criteria language and formatting, include guidance for live vaccinations, and clarify the need to follow local guidelines for opportunistic infection prophylaxis). Additionally, clarifying: R1 Consolidation Therapy may be inclusive of all types of Radiation Therapy (RT) per institutional guidelines, adds up to 2 additional cycles of Bv+B with BMS MM approval for R2 cohort consolidation therapy delays (to be consistent with the approach taken for Induction Phase, N+Bv), deletes wording “for biomarker analysis” as the biopsy isrequired per Standard of Care and provided to BMS for histologic confirmation of disease and biomarker testing, modification of requirements for FDG-PET at screening and during treatment in alignment with Standard of Care practices, and LYRIC 2016 criteria will be added as an exploratory endpoint for future data analysis according to refinement of LUGANO classification in the era of immunomodulatory therapy.

26 Mar 2021

The response assessment by investigators using Lugano 2014 response criteria was added as a secondary endpoint to allow for a comprehensive interpretation of the study data. Guidance for collection and submission of tumor assessments was added to support the evaluation of this new secondary endpoint. Contraception requirements for female participants of child bearing potential were modified to properly align with Nivolumab clinical research standard guidelines and brentuximab label. Other minor edits were made, as described in the Summary of Key Changes.

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Event-free Survival (EFS) Rate at 3 Years by Blinded Independent Centralized Review (BICR) - Cohort 1

Primary: Event-free Survival (EFS) Rate at 3 Years by Blinded Independent Centralized Review (BICR) - Cohort 1

Primary: Complete Metabolic Response (CMR) Rate at Any Time Prior to High Dose Chemotherapy Followed by Autologous Stem Cell Treatment (HDCT/ASCT) by Blinded Independent Centralized Review (BICR) - Cohort 2

Primary: Complete Metabolic Response (CMR) Rate at Any Time Prior to High Dose Chemotherapy Followed by Autologous Stem Cell Treatment (HDCT/ASCT) by Blinded Independent Centralized Review (BICR) - Cohort 2

Primary: Complete Metabolic Response (CMR) Rate at Any Time Prior to Radiation Therapy by Blinded Independent Centralized Review (BICR) - Cohort 1

Primary: Complete Metabolic Response (CMR) Rate at Any Time Prior to Radiation Therapy by Blinded Independent Centralized Review (BICR) - Cohort 1

Secondary: Overall Response Rate (ORR) Following 4 Cycles of Nivolumab + Brentuximab Vedotin Treatment by Blinded Independent Centralized Review (BICR)

Secondary: Overall Response Rate (ORR) Following 4 Cycles of Nivolumab + Brentuximab Vedotin Treatment by Blinded Independent Centralized Review (BICR)

Secondary: Duration of Response (DOR) by Blinded Independent Centralized Review (BICR)

Secondary: Duration of Response (DOR) by Blinded Independent Centralized Review (BICR)

Secondary: Progression Free Survival (PFS) Rate at 3 Years by Blinded Independent Centralized Review (BICR)

Secondary: Progression Free Survival (PFS) Rate at 3 Years by Blinded Independent Centralized Review (BICR)

Secondary: Complete Metabolic Response (CMR) Rate at Any Time Prior to Radiation Therapy by Investigator - Cohort 1

Secondary: Complete Metabolic Response (CMR) Rate at Any Time Prior to Radiation Therapy by Investigator - Cohort 1

Secondary: Event-free Survival (EFS) Rate at 3 Years by Investigator - Cohort 1

Secondary: Event-free Survival (EFS) Rate at 3 Years by Investigator - Cohort 1

Secondary: Progression Free Survival (PFS) Rate at 3 Years by Investigator

Secondary: Progression Free Survival (PFS) Rate at 3 Years by Investigator

Secondary: Complete Metabolic Response (CMR) Rate at Any Time Prior to High Dose Chemotherapy Followed by Autologous Stem Cell Treatment (HDCT/ASCT) by Investigator - Cohort 2

Secondary: Complete Metabolic Response (CMR) Rate at Any Time Prior to High Dose Chemotherapy Followed by Autologous Stem Cell Treatment (HDCT/ASCT) by Investigator - Cohort 2

Secondary: Overall Response Rate (ORR) Following 4 Cycles of Nivolumab + Brentuximab Vedotin Treatment by Investigator

Secondary: Overall Response Rate (ORR) Following 4 Cycles of Nivolumab + Brentuximab Vedotin Treatment by Investigator

Secondary: Duration of Response (DOR) by Investigator

Secondary: Duration of Response (DOR) by Investigator

Secondary: The Number of Participants with Adverse Events (AEs)

Secondary: The Number of Participants with Adverse Events (AEs)

Secondary: The Number of Participants with Serious Adverse Events (SAEs)

Secondary: The Number of Participants with Serious Adverse Events (SAEs)

Secondary: The Number of Participants with Abnormal Laboratory Values for Specific Thyroid Tests

Secondary: The Number of Participants with Abnormal Laboratory Values for Specific Thyroid Tests

Secondary: The Number of Participants with Abnormal Laboratory Values for Liver Tests

Secondary: The Number of Participants with Abnormal Laboratory Values for Liver Tests

Secondary: Vital Sign Measurements

Secondary: Vital Sign Measurements

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information