A Study of Subcutaneous Nivolumab Monotherapy With or Without Recombinant Human Hyaluronidase PH20 (rHuPH20)

Phase I/II Pharmacokinetic Multi-Tumor Study of Subcutaneous Formulation of Nivolumab Monotherapy

Status

Completed

Phases

Phase 1Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03656718

Enrollment

139

Registered

2018-09-04

Start date

2018-10-29

Completion date

2024-09-12

Last updated

2025-11-12

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Neoplasms by Site

Keywords

Subcutaneous, Nivolumab, rHuPH20

Brief summary

The purpose of this study is to investigate the effects of nivolumab when given under the skin with or without rHuPH20. This study will include participants with 1 of the following advanced or metastatic tumors approved for treatment with nivolumab monotherapy: * non-small cell lung cancer (NSCLC) * renal cell carcinoma (RCC) * unresectable or metastatic melanoma * hepatocellular carcinoma (HCC) * microsatellite instability-high or mismatch repair deficient colorectal cancer (MSI-H/dMMR CRC) * in Part B, other solid tumors may be considered at the discretion of the Clinical Trial Physician * In addition to the above tumors, Part E will also include participants with metastatic urothelial carcinoma (mUC).

Interventions

BIOLOGICALnivolumab

(Subcutaneous) Specified dose on specified days

DRUGrHuPH20

Specified dose on specified days Permeation enhancer

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* Histologic or cytologic confirmation of advanced (metastatic and/or unresectable) solid tumors of one of the following tumor types: 1. Metastatic squamous or non-squamous NSCLC 2. RCC, advanced or metastatic 3. Melanoma 4. HCC 5. CRC, metastatic (MSI-H or dMMR) 6. In Part B, other solid tumor types may be considered at the discretion of the Medical Monitor 7. In Part E, Metastatic urothelial carcinoma * Measurable disease as per RECIST version 1.1 criteria * ECOG performance status of 0 or 1

Exclusion criteria

* Active brain metastases or leptomeningeal metastases * Ocular melanoma * Active, known, or suspected autoimmune disease Other protocol defined inclusion/

Design outcomes

Primary

Measure	Time frame	Description
Maximum Observed Serum Nivolumab Concentration (Cmax) - Parts A, B, D, and E	From first dose until approximately 21 days post first dose.	Cmax is the maximum observed serum nivolumab concentration. Collected for Arm A, B, and D on Cycle 1 Day 1, Cycle 1 Day 2, Cycle 1 Day 4, Cycle 1 Day 8, Cycle 1 Day 15, and Cycle 1 Day 21. Collected for Arm E on Cycle 1 Day 1, Cycle 1 Day 2, Cycle 1 Day 4, Cycle 1 Day 8, Cycle 1 Day 15.
Time Taken to Reach Cmax (Tmax) - Parts A, B, D, and E	From first dose until approximately 21 days post first dose.	Tmax is the time taken to reach the maximum observed serum nivolumab concentration (Cmax). Collected for Arm A, B, and D on Cycle 1 Day 1, Cycle 1 Day 2, Cycle 1 Day 4, Cycle 1 Day 8, Cycle 1 Day 15, and Cycle 1 Day 21. Collected for Arm E on Cycle 1 Day 1, Cycle 1 Day 2, Cycle 1 Day 4, Cycle 1 Day 8, Cycle 1 Day 15.
Area Under the Time-Serum Nivolumab Concentration Curve (AUC (TAU)) - Parts A, B, D, and E	From first dose until approximately 21 days post first dose.	AUC (TAU) is the area measured under the concentration-time curve taken over the dosing interval. Collected for Arm A, B, and D on Cycle 1 Day 1, Cycle 1 Day 2, Cycle 1 Day 4, Cycle 1 Day 8, Cycle 1 Day 15, and Cycle 1 Day 21. Collected for Arm E on Cycle 1 Day 1, Cycle 1 Day 2, Cycle 1 Day 4, Cycle 1 Day 8, Cycle 1 Day 15.
Observed Serum Nivolumab Concentration at the End of Dosing (Ctau) - Parts A, B, D, and E	At the end of dosing interval of Cycle 1 - first dose (Day 21 for Parts A, B and D; Day 15 for Part E)	Ctau is the observed serum nivolumab concentration at the end of the dosing interval. Collected for Arma A, B, and D.
Lowest Observed Serum Nivolumab Concentration (Ctrough) During Part C - Part A and B Crossover Participants to Part C	On Day 1 of Cycles 2, 3, 5, 9, 13, and 19 of Part C (Day 1 of Part C: up to 14 months from Baseline; each cycle was 28 days)	Ctrough assessed during Part C. Ctrough is the lowest observed serum nivolumab concentration.

Secondary

Measure	Time frame	Description
Number of Participants Experiencing Treatment Related Adverse Events (TRAEs) Leading to Discontinuation	From first dose until 100 days post last dose (up to approximately 70 months).	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 treatment 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 treatment, whether or not considered related to the study treatment. TRAEs are AEs where a reasonable causal relationship exists between study treatment administration and the AE.
Number of Participants With Select Laboratory Changes From Baseline	From first dose until 30 days post last dose (up to approximately 67 months and 20 days).	Laboratory parameters including hematology, chemistry, liver function, and renal function summarized using worst grade NCI CTCAE v.5 criteria. Baseline refers to evaluations with a date on or prior to the day of first dose of study treatment.
Number of Participants Who Died	From randomization until data cutoff (up to approximately 70 months).	Number of participants who died due to any cause.
Number of Participants With Anti-Nivolumab Antibodies (ADAs) and Neutralizing Antibodies	At baseline and up to 100 days post last dose (up to approximately 70 months).	Anti-drug antibody (ADA) Positive: A participant with at least one ADA-positive sample relative to baseline (ADA negative at baseline or ADA titer to be at least 4-fold or greater (\>=) than baseline positive titer) at any time after initiation of treatment; Neutralizing Positive: At least one ADA-positive sample with neutralizing antibodies detected post-baseline. Baseline ADA Positive: A participant with a baseline ADA-positive sample. Baseline refers to evaluations with a date on or prior to the day of first dose of study treatment.
Number of Participants Experiencing Any Select Adverse Events Within the Hypersensitivity/Infusion Reaction Category and Broad Standardized MedDRA Query (SMQ) of Anaphylactic Reaction Occurring Within 2 Days of Study Drug Administration	From first dose until 2 days post last dose (up to approximately 66 months and 22 days).	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 treatment 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 treatment, whether or not considered related to the study treatment.
Number of Participants Experiencing Adverse Events (AEs)	From first dose until 100 days post last dose (up to approximately 70 months).	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 treatment 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 treatment, whether or not considered related to the study treatment.
Number of Participants Experiencing Treatment Related Adverse Events (TRAEs)	From first dose until 100 days post last dose (up to approximately 70 months).	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 treatment 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 treatment, whether or not considered related to the study treatment. TRAEs are AEs where a reasonable causal relationship exists between study treatment administration and the AE.
Number of Participants Experiencing Serious Adverse Events (SAEs)	From first dose until 100 days post last dose (up to approximately 70 months).	A Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any dose: (a) results in death, (b) 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), and/ or (c) requires inpatient hospitalization or causes prolongation of existing hospitalization.
Number of Participants Experiencing Treatment Related Serious Adverse Events (TRSAEs)	From first dose until 100 days post last dose (up to approximately 70 months).	A Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any dose: (a) results in death, (b) 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), and/ or (c) requires inpatient hospitalization or causes prolongation of existing hospitalization. TRSAEs are SAEs where a reasonable causal relationship exists between study treatment administration and the SAE.

Countries

Argentina, Brazil, Chile, France, Italy, Mexico, Netherlands, New Zealand, Poland, Spain, United Kingdom, United States

Participant flow

Pre-assignment details

28 participants from Part A and Part B crossed over after completing treatment in their originally assigned Arms to form Part C.

Participants by arm

Arm	Count
Part A - Group 1: Nivolumab + rHuPH20 SC 720mg Single dose of nivolumab (BMS-986298) 720 mg administered subcutaneously (SC) with recombinant human hyaluronidase (rHuPH20) manually by syringe. Four weeks after the single nivolumab SC (BMS-986298) dose participants received IV nivolumab (BMS-936558) 480 mg Q4W dosing until Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 progression, unacceptable toxicity, withdrawal of consent, completion of 104 weeks of treatment, cross over to nivolumab SC dosing in Part C whichever occurred first. In certain circumstances, participants with progressive disease per RECIST v1.1 but with otherwise stable or improved performance and clinical status could continue to be treated in the event of a perceived benefit per Investigator.	22
Part B - Group 2: Nivolumab SC 720mg Single dose of nivolumab (BMS-986298) 720 mg administered subcutaneously (SC) without recombinant human hyaluronidase (rHuPH20) by syringe pump. Four weeks after the single nivolumab SC (BMS-986298) dose participants received IV nivolumab (BMS-936558) 480 mg Q4W dosing until Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 progression, unacceptable toxicity, withdrawal of consent, completion of 104 weeks of treatment, cross over to nivolumab SC dosing in Part C, whichever occurred first. In certain circumstances, participants with progressive disease per RECIST v1.1 but with otherwise stable or improved performance and clinical status could continue to be treated in the event of a perceived benefit per Investigator.	18
Part B - Group 3: Nivolumab + rHuPH20 SC 960mg Single dose of nivolumab (BMS-986298) 960 mg administered subcutaneously (SC) with recombinant human hyaluronidase (rHuPH20) manually by syringe. Four weeks after the single nivolumab SC (BMS-986298) dose participants received IV nivolumab (BMS-936558) 480 mg Q4W dosing until Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 progression, unacceptable toxicity, withdrawal of consent, completion of 104 weeks of treatment, cross over to nivolumab SC dosing in Part C, whichever occurred first. In certain circumstances, participants with progressive disease per RECIST v1.1 but with otherwise stable or improved performance and clinical status could continue to be treated in the event of a perceived benefit per Investigator.	10
Part B - Group 4: Nivolumab SC 960mg Single dose of nivolumab (BMS-986298) 960 mg administered subcutaneously (SC) without recombinant human hyaluronidase (rHuPH20) by syringe pump. Four weeks after the single nivolumab SC (BMS-986298) dose participants received IV nivolumab (BMS-936558) 480 mg Q4W dosing until Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 progression, unacceptable toxicity, withdrawal of consent, completion of 104 weeks of treatment, cross over to nivolumab SC dosing in Part C, whichever occurred first. In certain circumstances, participants with progressive disease per RECIST v1.1 but with otherwise stable or improved performance and clinical status could continue to be treated in the event of a perceived benefit per Investigator.	17
Part D: Nivolumab SC + rHuPH20 SC 1200mg Q4W Nivolumab (BMS-986298) 1200 mg administered subcutaneously (SC) with recombinant human hyaluronidase (rHuPH20) manually by syringe every 4 weeks. Treatment continued until Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 progression, unacceptable toxicity, withdrawal of consent, or completion of 104 weeks of treatment, whichever occurred first. In certain circumstances, participants with progressive disease per RECIST v1.1 but with otherwise stable or improved performance and clinical status could continue to be treated in the event of a perceived benefit per Investigator.	36
Part E: Nivolumab SC Co-Formulated With rHuPH20 600mg Q2W Nivolumab (BMS-986298) 600 mg coformulated with recombinant human hyaluronidase (rHuPH20) administered subcutaneously (SC) manually by syringe every 2 weeks. Treatment continued until Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 progression, unacceptable toxicity, withdrawal of consent, or completion of 104 weeks of treatment, whichever occurred first. In certain circumstances, participants with progressive disease per RECIST v1.1 but with otherwise stable or improved performance and clinical status could continue to be treated in the event of a perceived benefit per Investigator.	36
Total	139

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004	FG005	FG006
Treatment Period Part C	Death	0	0	0	0	1	0	0
Treatment Period Part C	Disease progression	0	0	0	0	12	0	0
Treatment Period Part C	Maximum clinical benefit	0	0	0	0	1	0	0
Treatment Period Part C	Other reasons	0	0	0	0	1	0	0
Treatment Period Part C	Participant requested to discontinue study treatment	0	0	0	0	1	0	0
Treatment Period Parts A, B, D, and E	Adverse event unrelated to study drug	0	0	0	0	0	4	1
Treatment Period Parts A, B, D, and E	Death	1	0	0	0	0	0	2
Treatment Period Parts A, B, D, and E	Disease progression	8	11	4	6	0	20	21
Treatment Period Parts A, B, D, and E	Other reasons	0	0	0	0	0	1	3
Treatment Period Parts A, B, D, and E	Participant requested to discontinue study treatment	1	0	0	0	0	0	2
Treatment Period Parts A, B, D, and E	Study drug toxicity	2	1	1	2	0	4	1

Baseline characteristics

Characteristic	Part A - Group 1: Nivolumab + rHuPH20 SC 720mg	Total	Part E: Nivolumab SC Co-Formulated With rHuPH20 600mg Q2W	Part D: Nivolumab SC + rHuPH20 SC 1200mg Q4W	Part B - Group 4: Nivolumab SC 960mg	Part B - Group 3: Nivolumab + rHuPH20 SC 960mg	Part B - Group 2: Nivolumab SC 720mg
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	16 Participants	77 Participants	17 Participants	22 Participants	11 Participants	5 Participants	6 Participants
Age, Categorical Between 18 and 65 years	6 Participants	62 Participants	19 Participants	14 Participants	6 Participants	5 Participants	12 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants	6 Participants	1 Participants	4 Participants	0 Participants	0 Participants	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	4 Participants	56 Participants	22 Participants	16 Participants	7 Participants	2 Participants	5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	17 Participants	77 Participants	13 Participants	16 Participants	10 Participants	8 Participants	13 Participants
Race/Ethnicity, Customized Asian	0 Participants	2 Participants	1 Participants	1 Participants	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Black or African American	2 Participants	3 Participants	0 Participants	1 Participants	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Not Reported	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Other	2 Participants	8 Participants	1 Participants	3 Participants	0 Participants	2 Participants	0 Participants
Race/Ethnicity, Customized White	18 Participants	126 Participants	34 Participants	31 Participants	17 Participants	8 Participants	18 Participants
Sex: Female, Male Female	12 Participants	47 Participants	9 Participants	10 Participants	5 Participants	6 Participants	5 Participants
Sex: Female, Male Male	10 Participants	92 Participants	27 Participants	26 Participants	12 Participants	4 Participants	13 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk	EG006 affected / at risk	EG007 affected / at risk	EG008 affected / at risk	EG009 affected / at risk
deaths Total, all-cause mortality	18 / 22	6 / 9	14 / 18	2 / 6	8 / 10	4 / 5	14 / 17	5 / 8	25 / 36	30 / 36
other Total, other adverse events	22 / 22	9 / 9	18 / 18	6 / 6	10 / 10	5 / 5	17 / 17	8 / 8	34 / 36	35 / 36
serious Total, serious adverse events	12 / 22	4 / 9	10 / 18	1 / 6	4 / 10	2 / 5	11 / 17	4 / 8	19 / 36	25 / 36

Outcome results

Primary

Area Under the Time-Serum Nivolumab Concentration Curve (AUC (TAU)) - Parts A, B, D, and E

AUC (TAU) is the area measured under the concentration-time curve taken over the dosing interval. Collected for Arm A, B, and D on Cycle 1 Day 1, Cycle 1 Day 2, Cycle 1 Day 4, Cycle 1 Day 8, Cycle 1 Day 15, and Cycle 1 Day 21. Collected for Arm E on Cycle 1 Day 1, Cycle 1 Day 2, Cycle 1 Day 4, Cycle 1 Day 8, Cycle 1 Day 15.

Time frame: From first dose until approximately 21 days post first dose.

Population: All treated participants with available cycle 1 PK results in Parts A, B, D, and E. Pre-specified for data to be reported for Parts A, B, D, and E only.

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Part A - Group 1: Nivolumab + rHuPH20 SC 720mg	Area Under the Time-Serum Nivolumab Concentration Curve (AUC (TAU)) - Parts A, B, D, and E	24908 h*ug/mL	Geometric Coefficient of Variation 53
Part B - Group 2: Nivolumab SC 720mg	Area Under the Time-Serum Nivolumab Concentration Curve (AUC (TAU)) - Parts A, B, D, and E	27909 h*ug/mL	Geometric Coefficient of Variation 36
Part B - Group 3: Nivolumab + rHuPH20 SC 960mg	Area Under the Time-Serum Nivolumab Concentration Curve (AUC (TAU)) - Parts A, B, D, and E	40264 h*ug/mL	Geometric Coefficient of Variation 45
Part B - Group 4: Nivolumab SC 960mg	Area Under the Time-Serum Nivolumab Concentration Curve (AUC (TAU)) - Parts A, B, D, and E	32702 h*ug/mL	Geometric Coefficient of Variation 31
Part D: Nivolumab SC + rHuPH20 SC 1200mg Q4W	Area Under the Time-Serum Nivolumab Concentration Curve (AUC (TAU)) - Parts A, B, D, and E	53561 h*ug/mL	Geometric Coefficient of Variation 40
Part E: Nivolumab SC Co-Formulated With rHuPH20 600mg Q2W	Area Under the Time-Serum Nivolumab Concentration Curve (AUC (TAU)) - Parts A, B, D, and E	15857 h*ug/mL	Geometric Coefficient of Variation 30

Primary

Lowest Observed Serum Nivolumab Concentration (Ctrough) During Part C - Part A and B Crossover Participants to Part C

Ctrough assessed during Part C. Ctrough is the lowest observed serum nivolumab concentration.

Time frame: On Day 1 of Cycles 2, 3, 5, 9, 13, and 19 of Part C (Day 1 of Part C: up to 14 months from Baseline; each cycle was 28 days)

Population: All participants in Part C (who crossed over from Part A or B) with available PK results for each visit. Pre-specified for data to be reported for Part C crossover participants only. Participants are presented under their original treatment assignment.

Arm	Measure	Group	Value (GEOMETRIC_MEAN)	Dispersion
Part A - Group 1: Nivolumab + rHuPH20 SC 720mg	Lowest Observed Serum Nivolumab Concentration (Ctrough) During Part C - Part A and B Crossover Participants to Part C	Cycle 13 Day 1	183 ug/mL	Geometric Coefficient of Variation 34
Part A - Group 1: Nivolumab + rHuPH20 SC 720mg	Lowest Observed Serum Nivolumab Concentration (Ctrough) During Part C - Part A and B Crossover Participants to Part C	Cycle 9 Day 1	170 ug/mL	Geometric Coefficient of Variation 55
Part A - Group 1: Nivolumab + rHuPH20 SC 720mg	Lowest Observed Serum Nivolumab Concentration (Ctrough) During Part C - Part A and B Crossover Participants to Part C	Cycle 5 Day 1	149 ug/mL	Geometric Coefficient of Variation 55
Part A - Group 1: Nivolumab + rHuPH20 SC 720mg	Lowest Observed Serum Nivolumab Concentration (Ctrough) During Part C - Part A and B Crossover Participants to Part C	Cycle 3 Day 1	119 ug/mL	Geometric Coefficient of Variation 51
Part A - Group 1: Nivolumab + rHuPH20 SC 720mg	Lowest Observed Serum Nivolumab Concentration (Ctrough) During Part C - Part A and B Crossover Participants to Part C	Cycle 2 Day 1	115 ug/mL	Geometric Coefficient of Variation 58
Part B - Group 2: Nivolumab SC 720mg	Lowest Observed Serum Nivolumab Concentration (Ctrough) During Part C - Part A and B Crossover Participants to Part C	Cycle 3 Day 1	118 ug/mL	Geometric Coefficient of Variation 34
Part B - Group 2: Nivolumab SC 720mg	Lowest Observed Serum Nivolumab Concentration (Ctrough) During Part C - Part A and B Crossover Participants to Part C	Cycle 5 Day 1	144 ug/mL	Geometric Coefficient of Variation 66
Part B - Group 2: Nivolumab SC 720mg	Lowest Observed Serum Nivolumab Concentration (Ctrough) During Part C - Part A and B Crossover Participants to Part C	Cycle 9 Day 1	138 ug/mL	Geometric Coefficient of Variation 81
Part B - Group 2: Nivolumab SC 720mg	Lowest Observed Serum Nivolumab Concentration (Ctrough) During Part C - Part A and B Crossover Participants to Part C	Cycle 13 Day 1	113 ug/mL	Geometric Coefficient of Variation 48
Part B - Group 2: Nivolumab SC 720mg	Lowest Observed Serum Nivolumab Concentration (Ctrough) During Part C - Part A and B Crossover Participants to Part C	Cycle 19 Day 1	74.7 ug/mL	—
Part B - Group 2: Nivolumab SC 720mg	Lowest Observed Serum Nivolumab Concentration (Ctrough) During Part C - Part A and B Crossover Participants to Part C	Cycle 2 Day 1	106 ug/mL	Geometric Coefficient of Variation 42
Part B - Group 3: Nivolumab + rHuPH20 SC 960mg	Lowest Observed Serum Nivolumab Concentration (Ctrough) During Part C - Part A and B Crossover Participants to Part C	Cycle 3 Day 1	149 ug/mL	Geometric Coefficient of Variation 42
Part B - Group 3: Nivolumab + rHuPH20 SC 960mg	Lowest Observed Serum Nivolumab Concentration (Ctrough) During Part C - Part A and B Crossover Participants to Part C	Cycle 2 Day 1	124 ug/mL	Geometric Coefficient of Variation 38
Part B - Group 3: Nivolumab + rHuPH20 SC 960mg	Lowest Observed Serum Nivolumab Concentration (Ctrough) During Part C - Part A and B Crossover Participants to Part C	Cycle 9 Day 1	228 ug/mL	—
Part B - Group 3: Nivolumab + rHuPH20 SC 960mg	Lowest Observed Serum Nivolumab Concentration (Ctrough) During Part C - Part A and B Crossover Participants to Part C	Cycle 13 Day 1	246 ug/mL	—
Part B - Group 3: Nivolumab + rHuPH20 SC 960mg	Lowest Observed Serum Nivolumab Concentration (Ctrough) During Part C - Part A and B Crossover Participants to Part C	Cycle 5 Day 1	192 ug/mL	Geometric Coefficient of Variation 16
Part B - Group 4: Nivolumab SC 960mg	Lowest Observed Serum Nivolumab Concentration (Ctrough) During Part C - Part A and B Crossover Participants to Part C	Cycle 2 Day 1	85.7 ug/mL	Geometric Coefficient of Variation 48
Part B - Group 4: Nivolumab SC 960mg	Lowest Observed Serum Nivolumab Concentration (Ctrough) During Part C - Part A and B Crossover Participants to Part C	Cycle 5 Day 1	171 ug/mL	Geometric Coefficient of Variation 8
Part B - Group 4: Nivolumab SC 960mg	Lowest Observed Serum Nivolumab Concentration (Ctrough) During Part C - Part A and B Crossover Participants to Part C	Cycle 13 Day 1	217 ug/mL	Geometric Coefficient of Variation 16
Part B - Group 4: Nivolumab SC 960mg	Lowest Observed Serum Nivolumab Concentration (Ctrough) During Part C - Part A and B Crossover Participants to Part C	Cycle 3 Day 1	104 ug/mL	Geometric Coefficient of Variation 44
Part B - Group 4: Nivolumab SC 960mg	Lowest Observed Serum Nivolumab Concentration (Ctrough) During Part C - Part A and B Crossover Participants to Part C	Cycle 19 Day 1	212 ug/mL	—
Part B - Group 4: Nivolumab SC 960mg	Lowest Observed Serum Nivolumab Concentration (Ctrough) During Part C - Part A and B Crossover Participants to Part C	Cycle 9 Day 1	208 ug/mL	Geometric Coefficient of Variation 38

Primary

Maximum Observed Serum Nivolumab Concentration (Cmax) - Parts A, B, D, and E

Cmax is the maximum observed serum nivolumab concentration. Collected for Arm A, B, and D on Cycle 1 Day 1, Cycle 1 Day 2, Cycle 1 Day 4, Cycle 1 Day 8, Cycle 1 Day 15, and Cycle 1 Day 21. Collected for Arm E on Cycle 1 Day 1, Cycle 1 Day 2, Cycle 1 Day 4, Cycle 1 Day 8, Cycle 1 Day 15.

Time frame: From first dose until approximately 21 days post first dose.

Population: All treated participants with available Cycle 1 PK results in Parts A, B, D, and E. Pre-specified for data to be reported for Parts A, B, D, and E only.

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Part A - Group 1: Nivolumab + rHuPH20 SC 720mg	Maximum Observed Serum Nivolumab Concentration (Cmax) - Parts A, B, D, and E	54.8 ug/mL	Geometric Coefficient of Variation 51
Part B - Group 2: Nivolumab SC 720mg	Maximum Observed Serum Nivolumab Concentration (Cmax) - Parts A, B, D, and E	56.6 ug/mL	Geometric Coefficient of Variation 34
Part B - Group 3: Nivolumab + rHuPH20 SC 960mg	Maximum Observed Serum Nivolumab Concentration (Cmax) - Parts A, B, D, and E	81.4 ug/mL	Geometric Coefficient of Variation 41
Part B - Group 4: Nivolumab SC 960mg	Maximum Observed Serum Nivolumab Concentration (Cmax) - Parts A, B, D, and E	63.9 ug/mL	Geometric Coefficient of Variation 30
Part D: Nivolumab SC + rHuPH20 SC 1200mg Q4W	Maximum Observed Serum Nivolumab Concentration (Cmax) - Parts A, B, D, and E	106.0 ug/mL	Geometric Coefficient of Variation 46
Part E: Nivolumab SC Co-Formulated With rHuPH20 600mg Q2W	Maximum Observed Serum Nivolumab Concentration (Cmax) - Parts A, B, D, and E	57.8 ug/mL	Geometric Coefficient of Variation 31

Primary

Observed Serum Nivolumab Concentration at the End of Dosing (Ctau) - Parts A, B, D, and E

Ctau is the observed serum nivolumab concentration at the end of the dosing interval. Collected for Arma A, B, and D.

Time frame: At the end of dosing interval of Cycle 1 - first dose (Day 21 for Parts A, B and D; Day 15 for Part E)

Population: All treated participants with available cycle 1 PK results in Parts A, B, D, and E. Pre-specified for data to be collected only in Parts A, B, D, and E.

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Part A - Group 1: Nivolumab + rHuPH20 SC 720mg	Observed Serum Nivolumab Concentration at the End of Dosing (Ctau) - Parts A, B, D, and E	22.2 ug/mL	Geometric Coefficient of Variation 86
Part B - Group 2: Nivolumab SC 720mg	Observed Serum Nivolumab Concentration at the End of Dosing (Ctau) - Parts A, B, D, and E	26.9 ug/mL	Geometric Coefficient of Variation 65
Part B - Group 3: Nivolumab + rHuPH20 SC 960mg	Observed Serum Nivolumab Concentration at the End of Dosing (Ctau) - Parts A, B, D, and E	39.2 ug/mL	Geometric Coefficient of Variation 67
Part B - Group 4: Nivolumab SC 960mg	Observed Serum Nivolumab Concentration at the End of Dosing (Ctau) - Parts A, B, D, and E	34.8 ug/mL	Geometric Coefficient of Variation 41
Part D: Nivolumab SC + rHuPH20 SC 1200mg Q4W	Observed Serum Nivolumab Concentration at the End of Dosing (Ctau) - Parts A, B, D, and E	54.4 ug/mL	Geometric Coefficient of Variation 49
Part E: Nivolumab SC Co-Formulated With rHuPH20 600mg Q2W	Observed Serum Nivolumab Concentration at the End of Dosing (Ctau) - Parts A, B, D, and E	43.6 ug/mL	Geometric Coefficient of Variation 36

Primary

Time Taken to Reach Cmax (Tmax) - Parts A, B, D, and E

Tmax is the time taken to reach the maximum observed serum nivolumab concentration (Cmax). Collected for Arm A, B, and D on Cycle 1 Day 1, Cycle 1 Day 2, Cycle 1 Day 4, Cycle 1 Day 8, Cycle 1 Day 15, and Cycle 1 Day 21. Collected for Arm E on Cycle 1 Day 1, Cycle 1 Day 2, Cycle 1 Day 4, Cycle 1 Day 8, Cycle 1 Day 15.

Time frame: From first dose until approximately 21 days post first dose.

Population: All treated participants with available cycle 1 PK results in Parts A, B, D, and E. Pre-specified for data to be reported for Parts A, B, D, and E only.

Arm	Measure	Value (MEDIAN)
Part A - Group 1: Nivolumab + rHuPH20 SC 720mg	Time Taken to Reach Cmax (Tmax) - Parts A, B, D, and E	167 hours
Part B - Group 2: Nivolumab SC 720mg	Time Taken to Reach Cmax (Tmax) - Parts A, B, D, and E	167 hours
Part B - Group 3: Nivolumab + rHuPH20 SC 960mg	Time Taken to Reach Cmax (Tmax) - Parts A, B, D, and E	141 hours
Part B - Group 4: Nivolumab SC 960mg	Time Taken to Reach Cmax (Tmax) - Parts A, B, D, and E	168 hours
Part D: Nivolumab SC + rHuPH20 SC 1200mg Q4W	Time Taken to Reach Cmax (Tmax) - Parts A, B, D, and E	130 hours
Part E: Nivolumab SC Co-Formulated With rHuPH20 600mg Q2W	Time Taken to Reach Cmax (Tmax) - Parts A, B, D, and E	130 hours

Secondary

Number of Participants Experiencing Adverse Events (AEs)

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 treatment 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 treatment, whether or not considered related to the study treatment.

Time frame: From first dose until 100 days post last dose (up to approximately 70 months).