Metastatic Castration-resistant Prostrate Cancer, Metastatic Melanoma, Non-small Cell Lung Cancer, Renal Cell Carcinoma
Conditions
Brief summary
The purpose of this study is to determine the safety and effectiveness of MDX-1106 in patients with certain types of cancer. Another purpose is to determine how MDX-1106 is absorbed and distributed within the body, and how it's eventually eliminated.
Interventions
BIOLOGICALBMS-936558 (MDX-1106)
Solution, Intravenous, 0.1 mg/kg - 10 mg/kg, Every 2 weeks, 3 years depending on response
Sponsors
Ono Pharmaceutical Co. Ltd
Bristol-Myers Squibb
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com Inclusion Criteria: * Subjects must have mCRPC,RCC, MEL, Non-small-cell lung cancer (NSCLC), or Colorectal Cancer (CRC), that is advanced (non-resectable), or recurrent and for which no alternative, curative standard exists * Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2 * Must have at least 1 measurable lesion * Subjects with mCRPC and with only non-measurable bone lesions must have either progression new lesions or have Prostate-specific antigen (PSA) progression within the 6-week period before study administration * At least 1 and up to 5 prior systemic therapies for advanced/recurrent disease * Prior treated brain or meningeal metastases must be without Magnetic resonance imaging (MRI) evidence of progression for at least 8 weeks and off immunosuppressive doses of systemic steroids for at least 2 weeks before study drug administration * Prior systemic radiation therapy must have been completed at least 4 weeks before study drug administration. Prior focal radiotherapy completed at least 2 weeks prior to study drug administration * Immunosuppressive doses of systemic medications, such as steroids or absorbed topical steroids must be discontinued at least 2 weeks before study drug administration * Prior surgery that required general anesthesia must be completed at least 2 weeks before study drug administration. Surgery requiring local/epidural anesthesia must be completed at least 72 hours before study drug administration
Exclusion criteria
* History of severe hypersensitivity reactions to other Monoclonal antibody (mAb)s * Subjects with any active autoimmune disease or a documented history of autoimmune disease, or history of syndrome that required systemic steroids or immunosuppressive medications, except for subjects with vitiligo or resolved childhood asthma/atopy * Prior therapy with an anti-Programmed death-1 (PD-1), anti-PD-L1, anti-PD-L2, or anti- Cytotoxic t-lymphocyte antigen-4 (CTLA-4) antibody (or any other antibody targeting T cell co-stimulation pathways) * Known history of Human Immunodeficiency Virus * Active infection requiring therapy, positive tests for Hepatitis B surface antigen or Hepatitis C ribonucleic acid (RNA) * Underlying medical conditions that will make the administration of study drug hazardous * Concurrent medical condition requiring the use of immunosuppressive medications, or immunosuppressive doses of systemic or absorbable topical corticosteroids * Use of other investigational drugs (drugs not marketed for any indication) within 28 days or at least 5 half-lives (whichever is longer) before study drug administration
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Severe Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment-Related AEs, Deaths, Discontinuation of Study Drug Due to AEs | Day 1 to 70 days following last dose of study drug up to June 2013, approximately 4 years | AE=any new unfavorable symptom, sign or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity or drug dependency/abuse; is life-threatening, an important medical event or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=having certain, probable, possible or missing relationship to study drug. Death=during the study and up to 28 days past study discontinuation. The select AEs were determined using the Medical Dictionary for Regulatory Activities (MedDRA, v15.1) and graded using the Cancer Therapy Evaluation Program Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0. |
| Number of Participants With Abnormal Serum Chemistry Laboratory Values | Day 1 up to June 2013, approximately 4 years | Alkaline phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatinine and Total Bilirubin. National Cancer Institute Common Terminology Criteria (CTC) version (v) 3.0 was used to determine Grade (Gr). Abnormal values for ALP, ALT and AST were based on grades; Gr 1: \> 1.0 - 2.5 \* upper limits of normal (ULN); Gr 2: \> 2.5 - 5.0 \* ULN; Gr 3: \> 5.0 - 20.0 \* ULN; Gr 4: \> 20.0 \* ULN. Abnormal values for Creatinine were based on Gr 1: \> 1.0 - 1.5\*ULN; Gr 2: \> 1.5 - 3.0\*ULN; Gr 3: \> 3.0 - 6.0\*ULN; Gr 4: \> 6.0\*ULN. Abnormal values for Total Bilirubin were based on Gr 1: \> 1.0 - 1.5 \* upper limits of normal (ULN); Gr 2: \> 1.5 - 3.0 \* ULN; Gr 3: \> 3.0 - 10.0 \* ULN; Gr 4: \> 10.0 \* ULN. |
| Number of Participants With Abnormal Hematology Laboratory Values | Day 1 up to June 2013, approximately 4 years | Hemoglobin, Lymphocytes, Neutrophils, Platelets and Leukocytes. National Cancer Institute Common Terminology Criteria (CTC) version (v) 3.0 was used to determine Grade (Gr). Abnormal values for Hemoglobin were based on Gr 1: 10.0 - less than (\<) lower limit of normal (LLN); Gr 2: 8.0 - \< 10.0; Gr 3: 6.5 - \< 8.0; Gr 4: \< 6.5. Abnormal values for Lymphocytes were based on Gr 1: 0.8 - \< 1.5; Gr 2: 0.5 - \< 0.8; Gr 3): 0.2 - \< 0.5; Gr 4: \< 0.2. Abnormal values for Neutrophils were based on Gr 1: 1.5 - \< 2.0; Gr 2: 1.0 - \< 1.5; Gr 3: 0.5 - \< 1.0; Gr 4: \< 0.5. Abnormal values for Platelets were based on Gr 1: 75.0 - \< lower limits of normal (LLN); Gr 2: 50.0 - \< 75.0; Gr 3: 25.0 - \< 50.0; Gr 4: \< 25.0. Abnormal values for Leukocytes were based on Gr 1: 3.0 - \< LLN; Gr 2: 2.0 - \< 3.0; Gr 3: 1.0 - \< 2.0; Gr4: \< 1.0. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Geometric Mean Maximum Serum Concentration (Cmax) | 1,4,8,24,48 and 96 hours post-dose timepoints on Day 1 of cycles 1 and 3 | Nivolumab in human serum was assayed by PPD® (Richmond, Virginia) using a cross-validated enzyme-linked immunosorbent assay (ELISA). Blood samples were assessed at all doses from a subset of participants. The pharmacokinetic (PK) parameter of Cmax was measured in micrograms per milliliter (µg/mL). |
| Median Time of Maximum Serum Concentration (Tmax) | 1,4,8,24,48 and 96 hours post-dose timepoints on Day 1 of cycles 1 and 3 | Nivolumab in human serum was assayed by PPD® (Richmond, Virginia) using a cross-validated ELISA. Blood samples were assessed Blood samples were assessed at all doses from a subset of participants. The PK parameter of Tmax was measured in hours (h). |
| Immunogenicity Assessment | Day 1 up to June 2013, approximately 4 years | Classification of participants host immune response was based on the following definitions: Anti-Drug Antibody (ADA) Positive Subjects have with at least one ADA positive sample at any time after initiation of treatment. ADA positive subjects were further classified into categories with Persistent Positive defined as an ADA positive sample at 2 or more sequential timepoints at least 8 weeks apart. |
| Geometric Mean Total Body Clearance of Drug From Serum (CLT) | 1,4,8,24,48 and 96 hours post-dose timepoints on Day 1 of cycle 3 | Nivolumab in human serum was assayed by PPD® (Richmond, Virginia) using a cross-validated ELISA. Blood samples Blood samples were assessed at all doses from a subset of participants. The PK parameter of CLT was measured in milliliters per hour (mL/h). |
| Mean Effective Half-life (T-HALFeff) | 1,4,8,24,48 and 96 hours post-dose timepoints on Day 1 of cycle 3 | Nivolumab in human serum was assayed by PPD® (Richmond, Virginia) using a cross-validated ELISA. Blood samples were assessed at all doses from a subset of participants. The PK parameter of T-HALFeff was measured in hours (h). |
| Geometric Mean Area Under the Curve (AUC[TAU]) in One Dosing Interval Observed Post-Single Dose | 1,4,8,24,48 and 96 hours post-dose timepoints on Day 1 of cycles 1 and 3 | Nivolumab in human serum was assayed by PPD® (Richmond, Virginia) using a cross-validated ELISA. Blood samples were assessed at all doses from a subset of participants. The PK parameter of AUC was measured in micrograms\*hours per milliliter (μg\*h/mL). |
| Objective Response Rate | Day 1 up to June 2013, approximately 4 years | Tumor response was evaluated by the sponsor based on tumor assessments by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.0. Objective response rate (ORR) was defined as the proportion of participants who's confirmed best overall response (BOR) is either complete (CR) or partial (PR), where the denominator is the number of treated participants in the population of interest. Response was based on tumor measurements. Responders= complete response (CR) or partial response (PR). CR=disappearance of all target and non-target lesions; PR=at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the screening sum longest diameter. 95% Confidence intervals (CIs) were computed using the Clopper Pearson method. |
| Duration of Tumor Response | Day 1 up to June 2013, approximately 4 years | Duration of tumor response (DOR) was calculated from the first date of response of complete response (CR) or partial response (PR) to the date of the first progressive disease (PD) or the date of death. Duration of response was censored at the last tumor assessment date if a responder did not have PD or death. Nonresponders were not included in the analysis. Median DOR was estimated by Kaplan-Meier analysis. |
Countries
United States
Participant flow
Pre-assignment details
395 participants were enrolled and 306 were treated. 89 were not treated because they failed to meet study eligibility criteria or died prior to the initiation of treatment. All participants had received at least 1 prior cancer therapy. Study is on-going.
Participants by arm
| Arm | Count |
|---|---|
| 0.1 mg/kg Nivolumab Intravenous (IV) solution of 0.1 milligram nivolumab per kilogram of body weight (mg/kg) was administered every 2 weeks; Dosing on Days 1, 15, 29, and 43 of each treatment cycle. | 17 |
| 0.3 mg/kg Nivolumab 0.3 mg/kg nivolumab was administered every 2 weeks; Dosing on Days 1, 15, 29, and 43 of each treatment cycle. | 18 |
| 1.0 mg/kg Nivolumab 1.0 mg/kg nivolumab was administered every 2 weeks; Dosing on Days 1, 15, 29, and 43 of each treatment cycle. | 86 |
| 3.0 mg/kg Nivolumab 3.0 mg/kg nivolumab was administered every 2 weeks; Dosing on Days 1, 15, 29, and 43 of each treatment cycle. | 54 |
| 10 mg/kg Nivolumab 10 mg/kg nivolumab was administered every 2 weeks; Dosing on Days 1, 15, 29, and 43 of each treatment cycle. | 131 |
| Total | 306 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 0 | 9 | 8 | 23 |
| Overall Study | Completed Maximum Cycles | 0 | 0 | 11 | 3 | 6 |
| Overall Study | Complete Response | 0 | 0 | 2 | 2 | 1 |
| Overall Study | Death | 0 | 0 | 0 | 0 | 2 |
| Overall Study | Disease Progression | 12 | 13 | 48 | 32 | 88 |
| Overall Study | non-specified | 0 | 0 | 4 | 2 | 3 |
| Overall Study | Protocol Violation | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Treatment on-going | 2 | 5 | 5 | 4 | 4 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 6 | 3 | 4 |
Baseline characteristics
| Characteristic | Total | 0.1 mg/kg Nivolumab | 0.3 mg/kg Nivolumab | 1.0 mg/kg Nivolumab | 3.0 mg/kg Nivolumab | 10 mg/kg Nivolumab |
|---|---|---|---|---|---|---|
| Age, Continuous | 62.2 years | 57.5 years | 60.8 years | 61.8 years | 62.7 years | 63.1 years |
| Age, Customized Greater than or equal to (>)= 65 years | 138 participants | 4 participants | 9 participants | 37 participants | 24 participants | 64 participants |
| Age, Customized Less than (<) 65 years | 168 participants | 13 participants | 9 participants | 49 participants | 30 participants | 67 participants |
| Sex: Female, Male Female | 103 Participants | 4 Participants | 9 Participants | 26 Participants | 21 Participants | 43 Participants |
| Sex: Female, Male Male | 203 Participants | 13 Participants | 9 Participants | 60 Participants | 33 Participants | 88 Participants |
| Tumor Type Castrate-Resistant Prostate Cancer (CRC) | 19 participants | 0 participants | 0 participants | 0 participants | 0 participants | 19 participants |
| Tumor Type MCRPC | 17 participants | 0 participants | 0 participants | 0 participants | 0 participants | 17 participants |
| Tumor Type Melanoma | 107 participants | 17 participants | 18 participants | 35 participants | 17 participants | 20 participants |
| Tumor Type Non-Squamous NSCLC (NSQ NSCLC) | 74 participants | 0 participants | 0 participants | 18 participants | 19 participants | 37 participants |
| Tumor Type NSCLC of Unspecified Histology | 1 participants | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants |
| Tumor Type Renal Cell Carcinoma (RCC) | 34 participants | 0 participants | 0 participants | 18 participants | 0 participants | 16 participants |
| Tumor Type Squamous Non-Small Cell Lung Cancer (SQ NSCLC) | 54 participants | 0 participants | 0 participants | 15 participants | 18 participants | 21 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 17 / 17 | 17 / 18 | 83 / 86 | 51 / 54 | 130 / 131 |
| serious Total, serious adverse events | 9 / 17 | 8 / 18 | 37 / 86 | 26 / 54 | 79 / 131 |
Outcome results
Primary
Number of Participants With Abnormal Hematology Laboratory Values
Hemoglobin, Lymphocytes, Neutrophils, Platelets and Leukocytes. National Cancer Institute Common Terminology Criteria (CTC) version (v) 3.0 was used to determine Grade (Gr). Abnormal values for Hemoglobin were based on Gr 1: 10.0 - less than (\<) lower limit of normal (LLN); Gr 2: 8.0 - \< 10.0; Gr 3: 6.5 - \< 8.0; Gr 4: \< 6.5. Abnormal values for Lymphocytes were based on Gr 1: 0.8 - \< 1.5; Gr 2: 0.5 - \< 0.8; Gr 3): 0.2 - \< 0.5; Gr 4: \< 0.2. Abnormal values for Neutrophils were based on Gr 1: 1.5 - \< 2.0; Gr 2: 1.0 - \< 1.5; Gr 3: 0.5 - \< 1.0; Gr 4: \< 0.5. Abnormal values for Platelets were based on Gr 1: 75.0 - \< lower limits of normal (LLN); Gr 2: 50.0 - \< 75.0; Gr 3: 25.0 - \< 50.0; Gr 4: \< 25.0. Abnormal values for Leukocytes were based on Gr 1: 3.0 - \< LLN; Gr 2: 2.0 - \< 3.0; Gr 3: 1.0 - \< 2.0; Gr4: \< 1.0.
Time frame: Day 1 up to June 2013, approximately 4 years
Population: All participants who received at least 1 dose or any partial dose of nivolumab who underwent the laboratory test.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 0.1 mg/kg Nivolumab | Number of Participants With Abnormal Hematology Laboratory Values | Lymphocytes (Grades 1-2) | 9 participants |
| 0.1 mg/kg Nivolumab | Number of Participants With Abnormal Hematology Laboratory Values | Leukocytes (Grades 3-4) | 0 participants |
| 0.1 mg/kg Nivolumab | Number of Participants With Abnormal Hematology Laboratory Values | Lymphocytes (Grades 3-4) | 3 participants |
| 0.1 mg/kg Nivolumab | Number of Participants With Abnormal Hematology Laboratory Values | Leukocytes (Grades 1-2) | 4 participants |
| 0.1 mg/kg Nivolumab | Number of Participants With Abnormal Hematology Laboratory Values | Platelets (Grades 3-4) | 0 participants |
| 0.1 mg/kg Nivolumab | Number of Participants With Abnormal Hematology Laboratory Values | Hemoglobin (Grades 3-4) | 0 participants |
| 0.1 mg/kg Nivolumab | Number of Participants With Abnormal Hematology Laboratory Values | Hemoglobin (Grades 1-2) | 12 participants |
| 0.1 mg/kg Nivolumab | Number of Participants With Abnormal Hematology Laboratory Values | Platelets (Grades 1-2) | 2 participants |
| 0.1 mg/kg Nivolumab | Number of Participants With Abnormal Hematology Laboratory Values | Neutrophils (Grades 3-4) | 0 participants |
| 0.1 mg/kg Nivolumab | Number of Participants With Abnormal Hematology Laboratory Values | Neutrophils (Grades 1-2) | 4 participants |
| 0.3 mg/kg Nivolumab | Number of Participants With Abnormal Hematology Laboratory Values | Hemoglobin (Grades 3-4) | 0 participants |
| 0.3 mg/kg Nivolumab | Number of Participants With Abnormal Hematology Laboratory Values | Hemoglobin (Grades 1-2) | 12 participants |
| 0.3 mg/kg Nivolumab | Number of Participants With Abnormal Hematology Laboratory Values | Lymphocytes (Grades 1-2) | 15 participants |
| 0.3 mg/kg Nivolumab | Number of Participants With Abnormal Hematology Laboratory Values | Lymphocytes (Grades 3-4) | 3 participants |
| 0.3 mg/kg Nivolumab | Number of Participants With Abnormal Hematology Laboratory Values | Neutrophils (Grades 1-2) | 4 participants |
| 0.3 mg/kg Nivolumab | Number of Participants With Abnormal Hematology Laboratory Values | Neutrophils (Grades 3-4) | 0 participants |
| 0.3 mg/kg Nivolumab | Number of Participants With Abnormal Hematology Laboratory Values | Platelets (Grades 1-2) | 1 participants |
| 0.3 mg/kg Nivolumab | Number of Participants With Abnormal Hematology Laboratory Values | Platelets (Grades 3-4) | 0 participants |
| 0.3 mg/kg Nivolumab | Number of Participants With Abnormal Hematology Laboratory Values | Leukocytes (Grades 1-2) | 4 participants |
| 0.3 mg/kg Nivolumab | Number of Participants With Abnormal Hematology Laboratory Values | Leukocytes (Grades 3-4) | 0 participants |
| 1.0 mg/kg Nivolumab | Number of Participants With Abnormal Hematology Laboratory Values | Neutrophils (Grades 3-4) | 1 participants |
| 1.0 mg/kg Nivolumab | Number of Participants With Abnormal Hematology Laboratory Values | Leukocytes (Grades 1-2) | 11 participants |
| 1.0 mg/kg Nivolumab | Number of Participants With Abnormal Hematology Laboratory Values | Lymphocytes (Grades 1-2) | 64 participants |
| 1.0 mg/kg Nivolumab | Number of Participants With Abnormal Hematology Laboratory Values | Lymphocytes (Grades 3-4) | 8 participants |
| 1.0 mg/kg Nivolumab | Number of Participants With Abnormal Hematology Laboratory Values | Hemoglobin (Grades 3-4) | 6 participants |
| 1.0 mg/kg Nivolumab | Number of Participants With Abnormal Hematology Laboratory Values | Neutrophils (Grades 1-2) | 13 participants |
| 1.0 mg/kg Nivolumab | Number of Participants With Abnormal Hematology Laboratory Values | Platelets (Grades 1-2) | 9 participants |
| 1.0 mg/kg Nivolumab | Number of Participants With Abnormal Hematology Laboratory Values | Hemoglobin (Grades 1-2) | 58 participants |
| 1.0 mg/kg Nivolumab | Number of Participants With Abnormal Hematology Laboratory Values | Leukocytes (Grades 3-4) | 1 participants |
| 1.0 mg/kg Nivolumab | Number of Participants With Abnormal Hematology Laboratory Values | Platelets (Grades 3-4) | 0 participants |
| 3.0 mg/kg Nivolumab | Number of Participants With Abnormal Hematology Laboratory Values | Hemoglobin (Grades 3-4) | 0 participants |
| 3.0 mg/kg Nivolumab | Number of Participants With Abnormal Hematology Laboratory Values | Leukocytes (Grades 3-4) | 0 participants |
| 3.0 mg/kg Nivolumab | Number of Participants With Abnormal Hematology Laboratory Values | Hemoglobin (Grades 1-2) | 46 participants |
| 3.0 mg/kg Nivolumab | Number of Participants With Abnormal Hematology Laboratory Values | Lymphocytes (Grades 1-2) | 43 participants |
| 3.0 mg/kg Nivolumab | Number of Participants With Abnormal Hematology Laboratory Values | Neutrophils (Grades 3-4) | 1 participants |
| 3.0 mg/kg Nivolumab | Number of Participants With Abnormal Hematology Laboratory Values | Platelets (Grades 3-4) | 0 participants |
| 3.0 mg/kg Nivolumab | Number of Participants With Abnormal Hematology Laboratory Values | Leukocytes (Grades 1-2) | 10 participants |
| 3.0 mg/kg Nivolumab | Number of Participants With Abnormal Hematology Laboratory Values | Platelets (Grades 1-2) | 10 participants |
| 3.0 mg/kg Nivolumab | Number of Participants With Abnormal Hematology Laboratory Values | Lymphocytes (Grades 3-4) | 8 participants |
| 3.0 mg/kg Nivolumab | Number of Participants With Abnormal Hematology Laboratory Values | Neutrophils (Grades 1-2) | 6 participants |
| 10 mg/kg Nivolumab | Number of Participants With Abnormal Hematology Laboratory Values | Lymphocytes (Grades 3-4) | 19 participants |
| 10 mg/kg Nivolumab | Number of Participants With Abnormal Hematology Laboratory Values | Leukocytes (Grades 1-2) | 13 participants |
| 10 mg/kg Nivolumab | Number of Participants With Abnormal Hematology Laboratory Values | Neutrophils (Grades 1-2) | 12 participants |
| 10 mg/kg Nivolumab | Number of Participants With Abnormal Hematology Laboratory Values | Neutrophils (Grades 3-4) | 3 participants |
| 10 mg/kg Nivolumab | Number of Participants With Abnormal Hematology Laboratory Values | Leukocytes (Grades 3-4) | 3 participants |
| 10 mg/kg Nivolumab | Number of Participants With Abnormal Hematology Laboratory Values | Platelets (Grades 1-2) | 19 participants |
| 10 mg/kg Nivolumab | Number of Participants With Abnormal Hematology Laboratory Values | Hemoglobin (Grades 1-2) | 101 participants |
| 10 mg/kg Nivolumab | Number of Participants With Abnormal Hematology Laboratory Values | Platelets (Grades 3-4) | 0 participants |
| 10 mg/kg Nivolumab | Number of Participants With Abnormal Hematology Laboratory Values | Lymphocytes (Grades 1-2) | 101 participants |
| 10 mg/kg Nivolumab | Number of Participants With Abnormal Hematology Laboratory Values | Hemoglobin (Grades 3-4) | 6 participants |
Primary
Number of Participants With Abnormal Serum Chemistry Laboratory Values
Alkaline phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatinine and Total Bilirubin. National Cancer Institute Common Terminology Criteria (CTC) version (v) 3.0 was used to determine Grade (Gr). Abnormal values for ALP, ALT and AST were based on grades; Gr 1: \> 1.0 - 2.5 \* upper limits of normal (ULN); Gr 2: \> 2.5 - 5.0 \* ULN; Gr 3: \> 5.0 - 20.0 \* ULN; Gr 4: \> 20.0 \* ULN. Abnormal values for Creatinine were based on Gr 1: \> 1.0 - 1.5\*ULN; Gr 2: \> 1.5 - 3.0\*ULN; Gr 3: \> 3.0 - 6.0\*ULN; Gr 4: \> 6.0\*ULN. Abnormal values for Total Bilirubin were based on Gr 1: \> 1.0 - 1.5 \* upper limits of normal (ULN); Gr 2: \> 1.5 - 3.0 \* ULN; Gr 3: \> 3.0 - 10.0 \* ULN; Gr 4: \> 10.0 \* ULN.
Time frame: Day 1 up to June 2013, approximately 4 years
Population: All participants who received at least 1 dose or any partial dose of nivolumab who underwent the laboratory test.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 0.1 mg/kg Nivolumab | Number of Participants With Abnormal Serum Chemistry Laboratory Values | ALT (Grades 1-2) | 6 participants |
| 0.1 mg/kg Nivolumab | Number of Participants With Abnormal Serum Chemistry Laboratory Values | Total Bilirubin (Grades 3-4) | 0 participants |
| 0.1 mg/kg Nivolumab | Number of Participants With Abnormal Serum Chemistry Laboratory Values | ALT (Grades 3-4) | 0 participants |
| 0.1 mg/kg Nivolumab | Number of Participants With Abnormal Serum Chemistry Laboratory Values | Total Bilirubin (Grades 1-2) | 2 participants |
| 0.1 mg/kg Nivolumab | Number of Participants With Abnormal Serum Chemistry Laboratory Values | Creatinine (Grades 3-4) | 0 participants |
| 0.1 mg/kg Nivolumab | Number of Participants With Abnormal Serum Chemistry Laboratory Values | ALP (Grades 3-4) | 0 participants |
| 0.1 mg/kg Nivolumab | Number of Participants With Abnormal Serum Chemistry Laboratory Values | ALP (Grades 1-2) | 8 participants |
| 0.1 mg/kg Nivolumab | Number of Participants With Abnormal Serum Chemistry Laboratory Values | Creatinine (Grades 1-2) | 5 participants |
| 0.1 mg/kg Nivolumab | Number of Participants With Abnormal Serum Chemistry Laboratory Values | AST (Grades 3-4) | 0 participants |
| 0.1 mg/kg Nivolumab | Number of Participants With Abnormal Serum Chemistry Laboratory Values | AST (Grades 1-2) | 6 participants |
| 0.3 mg/kg Nivolumab | Number of Participants With Abnormal Serum Chemistry Laboratory Values | ALP (Grades 3-4) | 0 participants |
| 0.3 mg/kg Nivolumab | Number of Participants With Abnormal Serum Chemistry Laboratory Values | ALP (Grades 1-2) | 7 participants |
| 0.3 mg/kg Nivolumab | Number of Participants With Abnormal Serum Chemistry Laboratory Values | ALT (Grades 1-2) | 3 participants |
| 0.3 mg/kg Nivolumab | Number of Participants With Abnormal Serum Chemistry Laboratory Values | ALT (Grades 3-4) | 0 participants |
| 0.3 mg/kg Nivolumab | Number of Participants With Abnormal Serum Chemistry Laboratory Values | AST (Grades 1-2) | 4 participants |
| 0.3 mg/kg Nivolumab | Number of Participants With Abnormal Serum Chemistry Laboratory Values | AST (Grades 3-4) | 2 participants |
| 0.3 mg/kg Nivolumab | Number of Participants With Abnormal Serum Chemistry Laboratory Values | Creatinine (Grades 1-2) | 9 participants |
| 0.3 mg/kg Nivolumab | Number of Participants With Abnormal Serum Chemistry Laboratory Values | Creatinine (Grades 3-4) | 0 participants |
| 0.3 mg/kg Nivolumab | Number of Participants With Abnormal Serum Chemistry Laboratory Values | Total Bilirubin (Grades 1-2) | 1 participants |
| 0.3 mg/kg Nivolumab | Number of Participants With Abnormal Serum Chemistry Laboratory Values | Total Bilirubin (Grades 3-4) | 2 participants |
| 1.0 mg/kg Nivolumab | Number of Participants With Abnormal Serum Chemistry Laboratory Values | AST (Grades 3-4) | 2 participants |
| 1.0 mg/kg Nivolumab | Number of Participants With Abnormal Serum Chemistry Laboratory Values | Total Bilirubin (Grades 1-2) | 3 participants |
| 1.0 mg/kg Nivolumab | Number of Participants With Abnormal Serum Chemistry Laboratory Values | ALT (Grades 1-2) | 25 participants |
| 1.0 mg/kg Nivolumab | Number of Participants With Abnormal Serum Chemistry Laboratory Values | ALT (Grades 3-4) | 1 participants |
| 1.0 mg/kg Nivolumab | Number of Participants With Abnormal Serum Chemistry Laboratory Values | ALP (Grades 3-4) | 3 participants |
| 1.0 mg/kg Nivolumab | Number of Participants With Abnormal Serum Chemistry Laboratory Values | AST (Grades 1-2) | 26 participants |
| 1.0 mg/kg Nivolumab | Number of Participants With Abnormal Serum Chemistry Laboratory Values | Creatinine (Grades 1-2) | 21 participants |
| 1.0 mg/kg Nivolumab | Number of Participants With Abnormal Serum Chemistry Laboratory Values | ALP (Grades 1-2) | 21 participants |
| 1.0 mg/kg Nivolumab | Number of Participants With Abnormal Serum Chemistry Laboratory Values | Total Bilirubin (Grades 3-4) | 0 participants |
| 1.0 mg/kg Nivolumab | Number of Participants With Abnormal Serum Chemistry Laboratory Values | Creatinine (Grades 3-4) | 0 participants |
| 3.0 mg/kg Nivolumab | Number of Participants With Abnormal Serum Chemistry Laboratory Values | ALP (Grades 3-4) | 2 participants |
| 3.0 mg/kg Nivolumab | Number of Participants With Abnormal Serum Chemistry Laboratory Values | Total Bilirubin (Grades 3-4) | 0 participants |
| 3.0 mg/kg Nivolumab | Number of Participants With Abnormal Serum Chemistry Laboratory Values | ALP (Grades 1-2) | 11 participants |
| 3.0 mg/kg Nivolumab | Number of Participants With Abnormal Serum Chemistry Laboratory Values | ALT (Grades 1-2) | 13 participants |
| 3.0 mg/kg Nivolumab | Number of Participants With Abnormal Serum Chemistry Laboratory Values | AST (Grades 3-4) | 3 participants |
| 3.0 mg/kg Nivolumab | Number of Participants With Abnormal Serum Chemistry Laboratory Values | Creatinine (Grades 3-4) | 0 participants |
| 3.0 mg/kg Nivolumab | Number of Participants With Abnormal Serum Chemistry Laboratory Values | Total Bilirubin (Grades 1-2) | 4 participants |
| 3.0 mg/kg Nivolumab | Number of Participants With Abnormal Serum Chemistry Laboratory Values | Creatinine (Grades 1-2) | 9 participants |
| 3.0 mg/kg Nivolumab | Number of Participants With Abnormal Serum Chemistry Laboratory Values | ALT (Grades 3-4) | 2 participants |
| 3.0 mg/kg Nivolumab | Number of Participants With Abnormal Serum Chemistry Laboratory Values | AST (Grades 1-2) | 13 participants |
| 10 mg/kg Nivolumab | Number of Participants With Abnormal Serum Chemistry Laboratory Values | ALT (Grades 3-4) | 2 participants |
| 10 mg/kg Nivolumab | Number of Participants With Abnormal Serum Chemistry Laboratory Values | Total Bilirubin (Grades 1-2) | 3 participants |
| 10 mg/kg Nivolumab | Number of Participants With Abnormal Serum Chemistry Laboratory Values | AST (Grades 1-2) | 41 participants |
| 10 mg/kg Nivolumab | Number of Participants With Abnormal Serum Chemistry Laboratory Values | AST (Grades 3-4) | 2 participants |
| 10 mg/kg Nivolumab | Number of Participants With Abnormal Serum Chemistry Laboratory Values | Total Bilirubin (Grades 3-4) | 2 participants |
| 10 mg/kg Nivolumab | Number of Participants With Abnormal Serum Chemistry Laboratory Values | Creatinine (Grades 1-2) | 34 participants |
| 10 mg/kg Nivolumab | Number of Participants With Abnormal Serum Chemistry Laboratory Values | ALP (Grades 1-2) | 38 participants |
| 10 mg/kg Nivolumab | Number of Participants With Abnormal Serum Chemistry Laboratory Values | Creatinine (Grades 3-4) | 1 participants |
| 10 mg/kg Nivolumab | Number of Participants With Abnormal Serum Chemistry Laboratory Values | ALT (Grades 1-2) | 18 participants |
| 10 mg/kg Nivolumab | Number of Participants With Abnormal Serum Chemistry Laboratory Values | ALP (Grades 3-4) | 3 participants |
Primary
Number of Participants With Severe Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment-Related AEs, Deaths, Discontinuation of Study Drug Due to AEs
AE=any new unfavorable symptom, sign or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity or drug dependency/abuse; is life-threatening, an important medical event or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=having certain, probable, possible or missing relationship to study drug. Death=during the study and up to 28 days past study discontinuation. The select AEs were determined using the Medical Dictionary for Regulatory Activities (MedDRA, v15.1) and graded using the Cancer Therapy Evaluation Program Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0.
Time frame: Day 1 to 70 days following last dose of study drug up to June 2013, approximately 4 years
Population: All participants who received at least 1 dose or any partial dose of nivolumab were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 0.1 mg/kg Nivolumab | Number of Participants With Severe Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment-Related AEs, Deaths, Discontinuation of Study Drug Due to AEs | Treatment-Related Deaths | 0 participants |
| 0.1 mg/kg Nivolumab | Number of Participants With Severe Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment-Related AEs, Deaths, Discontinuation of Study Drug Due to AEs | SAE | 9 participants |
| 0.1 mg/kg Nivolumab | Number of Participants With Severe Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment-Related AEs, Deaths, Discontinuation of Study Drug Due to AEs | Discontinuation of Study Drug due to AEs | 3 participants |
| 0.1 mg/kg Nivolumab | Number of Participants With Severe Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment-Related AEs, Deaths, Discontinuation of Study Drug Due to AEs | Treatment-Related AE | 13 participants |
| 0.1 mg/kg Nivolumab | Number of Participants With Severe Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment-Related AEs, Deaths, Discontinuation of Study Drug Due to AEs | All Deaths (within 100 days of last dose) | 4 participants |
| 0.3 mg/kg Nivolumab | Number of Participants With Severe Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment-Related AEs, Deaths, Discontinuation of Study Drug Due to AEs | Treatment-Related Deaths | 0 participants |
| 0.3 mg/kg Nivolumab | Number of Participants With Severe Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment-Related AEs, Deaths, Discontinuation of Study Drug Due to AEs | All Deaths (within 100 days of last dose) | 4 participants |
| 0.3 mg/kg Nivolumab | Number of Participants With Severe Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment-Related AEs, Deaths, Discontinuation of Study Drug Due to AEs | Treatment-Related AE | 14 participants |
| 0.3 mg/kg Nivolumab | Number of Participants With Severe Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment-Related AEs, Deaths, Discontinuation of Study Drug Due to AEs | Discontinuation of Study Drug due to AEs | 0 participants |
| 0.3 mg/kg Nivolumab | Number of Participants With Severe Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment-Related AEs, Deaths, Discontinuation of Study Drug Due to AEs | SAE | 8 participants |
| 1.0 mg/kg Nivolumab | Number of Participants With Severe Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment-Related AEs, Deaths, Discontinuation of Study Drug Due to AEs | All Deaths (within 100 days of last dose) | 18 participants |
| 1.0 mg/kg Nivolumab | Number of Participants With Severe Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment-Related AEs, Deaths, Discontinuation of Study Drug Due to AEs | SAE | 37 participants |
| 1.0 mg/kg Nivolumab | Number of Participants With Severe Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment-Related AEs, Deaths, Discontinuation of Study Drug Due to AEs | Treatment-Related AE | 70 participants |
| 1.0 mg/kg Nivolumab | Number of Participants With Severe Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment-Related AEs, Deaths, Discontinuation of Study Drug Due to AEs | Treatment-Related Deaths | 1 participants |
| 1.0 mg/kg Nivolumab | Number of Participants With Severe Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment-Related AEs, Deaths, Discontinuation of Study Drug Due to AEs | Discontinuation of Study Drug due to AEs | 12 participants |
| 3.0 mg/kg Nivolumab | Number of Participants With Severe Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment-Related AEs, Deaths, Discontinuation of Study Drug Due to AEs | Discontinuation of Study Drug due to AEs | 12 participants |
| 3.0 mg/kg Nivolumab | Number of Participants With Severe Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment-Related AEs, Deaths, Discontinuation of Study Drug Due to AEs | SAE | 26 participants |
| 3.0 mg/kg Nivolumab | Number of Participants With Severe Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment-Related AEs, Deaths, Discontinuation of Study Drug Due to AEs | Treatment-Related Deaths | 0 participants |
| 3.0 mg/kg Nivolumab | Number of Participants With Severe Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment-Related AEs, Deaths, Discontinuation of Study Drug Due to AEs | All Deaths (within 100 days of last dose) | 9 participants |
| 3.0 mg/kg Nivolumab | Number of Participants With Severe Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment-Related AEs, Deaths, Discontinuation of Study Drug Due to AEs | Treatment-Related AE | 40 participants |
| 10 mg/kg Nivolumab | Number of Participants With Severe Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment-Related AEs, Deaths, Discontinuation of Study Drug Due to AEs | All Deaths (within 100 days of last dose) | 40 participants |
| 10 mg/kg Nivolumab | Number of Participants With Severe Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment-Related AEs, Deaths, Discontinuation of Study Drug Due to AEs | Treatment-Related Deaths | 1 participants |
| 10 mg/kg Nivolumab | Number of Participants With Severe Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment-Related AEs, Deaths, Discontinuation of Study Drug Due to AEs | SAE | 79 participants |
| 10 mg/kg Nivolumab | Number of Participants With Severe Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment-Related AEs, Deaths, Discontinuation of Study Drug Due to AEs | Discontinuation of Study Drug due to AEs | 30 participants |
| 10 mg/kg Nivolumab | Number of Participants With Severe Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment-Related AEs, Deaths, Discontinuation of Study Drug Due to AEs | Treatment-Related AE | 93 participants |
Secondary
Duration of Tumor Response
Duration of tumor response (DOR) was calculated from the first date of response of complete response (CR) or partial response (PR) to the date of the first progressive disease (PD) or the date of death. Duration of response was censored at the last tumor assessment date if a responder did not have PD or death. Nonresponders were not included in the analysis. Median DOR was estimated by Kaplan-Meier analysis.
Time frame: Day 1 up to June 2013, approximately 4 years
Population: All participants who received at least 1 dose or any partial dose of nivolumab with a measurable tumor response were analyzed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| 0.1 mg/kg Nivolumab | Duration of Tumor Response | NSQ NSCLC (n=0,0,18,19,37,74) | NA months |
| 0.1 mg/kg Nivolumab | Duration of Tumor Response | SQ NSCLC (n=0,0,15,18,21,54) | NA months |
| 0.1 mg/kg Nivolumab | Duration of Tumor Response | All NSCLC (n=0,0,33,37,59,129) | NA months |
| 0.1 mg/kg Nivolumab | Duration of Tumor Response | Mel (n=17,18,35,17,20,107) | NA months |
| 0.1 mg/kg Nivolumab | Duration of Tumor Response | RCC (n=0,0,18,0,16,34) | NA months |
| 0.3 mg/kg Nivolumab | Duration of Tumor Response | SQ NSCLC (n=0,0,15,18,21,54) | NA months |
| 0.3 mg/kg Nivolumab | Duration of Tumor Response | RCC (n=0,0,18,0,16,34) | NA months |
| 0.3 mg/kg Nivolumab | Duration of Tumor Response | Mel (n=17,18,35,17,20,107) | 20.7 months |
| 0.3 mg/kg Nivolumab | Duration of Tumor Response | All NSCLC (n=0,0,33,37,59,129) | NA months |
| 0.3 mg/kg Nivolumab | Duration of Tumor Response | NSQ NSCLC (n=0,0,18,19,37,74) | NA months |
| 1.0 mg/kg Nivolumab | Duration of Tumor Response | All NSCLC (n=0,0,33,37,59,129) | 14.7 months |
| 1.0 mg/kg Nivolumab | Duration of Tumor Response | NSQ NSCLC (n=0,0,18,19,37,74) | 14.7 months |
| 1.0 mg/kg Nivolumab | Duration of Tumor Response | SQ NSCLC (n=0,0,15,18,21,54) | NA months |
| 1.0 mg/kg Nivolumab | Duration of Tumor Response | RCC (n=0,0,18,0,16,34) | 12.9 months |
| 1.0 mg/kg Nivolumab | Duration of Tumor Response | Mel (n=17,18,35,17,20,107) | 24.0 months |
| 3.0 mg/kg Nivolumab | Duration of Tumor Response | All NSCLC (n=0,0,33,37,59,129) | 17 months |
| 3.0 mg/kg Nivolumab | Duration of Tumor Response | NSQ NSCLC (n=0,0,18,19,37,74) | 13.6 months |
| 3.0 mg/kg Nivolumab | Duration of Tumor Response | SQ NSCLC (n=0,0,15,18,21,54) | NA months |
| 3.0 mg/kg Nivolumab | Duration of Tumor Response | Mel (n=17,18,35,17,20,107) | 17.5 months |
| 3.0 mg/kg Nivolumab | Duration of Tumor Response | RCC (n=0,0,18,0,16,34) | NA months |
| 10 mg/kg Nivolumab | Duration of Tumor Response | All NSCLC (n=0,0,33,37,59,129) | 19.1 months |
| 10 mg/kg Nivolumab | Duration of Tumor Response | RCC (n=0,0,18,0,16,34) | 12.9 months |
| 10 mg/kg Nivolumab | Duration of Tumor Response | Mel (n=17,18,35,17,20,107) | 25.7 months |
| 10 mg/kg Nivolumab | Duration of Tumor Response | SQ NSCLC (n=0,0,15,18,21,54) | 19.1 months |
| 10 mg/kg Nivolumab | Duration of Tumor Response | NSQ NSCLC (n=0,0,18,19,37,74) | NA months |
| All Dose Groups | Duration of Tumor Response | All NSCLC (n=0,0,33,37,59,129) | 17.0 months |
| All Dose Groups | Duration of Tumor Response | NSQ NSCLC (n=0,0,18,19,37,74) | 14.2 months |
| All Dose Groups | Duration of Tumor Response | RCC (n=0,0,18,0,16,34) | 12.9 months |
| All Dose Groups | Duration of Tumor Response | Mel (n=17,18,35,17,20,107) | 22.9 months |
| All Dose Groups | Duration of Tumor Response | SQ NSCLC (n=0,0,15,18,21,54) | NA months |
Secondary
Geometric Mean Area Under the Curve (AUC[TAU]) in One Dosing Interval Observed Post-Single Dose
Nivolumab in human serum was assayed by PPD® (Richmond, Virginia) using a cross-validated ELISA. Blood samples were assessed at all doses from a subset of participants. The PK parameter of AUC was measured in micrograms\*hours per milliliter (μg\*h/mL).
Time frame: 1,4,8,24,48 and 96 hours post-dose timepoints on Day 1 of cycles 1 and 3
Population: All participants who received at least 1 dose or any partial dose of nivolumab and had adequate PK profiles.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 0.1 mg/kg Nivolumab | Geometric Mean Area Under the Curve (AUC[TAU]) in One Dosing Interval Observed Post-Single Dose | Cycle 1/Day 1 (n=13,15,10,13,12) | 279.4 micrograms*hours per milliliter (μg*h/mL | Geometric Coefficient of Variation 32.5 |
| 0.1 mg/kg Nivolumab | Geometric Mean Area Under the Curve (AUC[TAU]) in One Dosing Interval Observed Post-Single Dose | Cycle 3/Day 1 (n=4,2,9,5,3) | 1101.4 micrograms*hours per milliliter (μg*h/mL | Geometric Coefficient of Variation 26.6 |
| 0.3 mg/kg Nivolumab | Geometric Mean Area Under the Curve (AUC[TAU]) in One Dosing Interval Observed Post-Single Dose | Cycle 1/Day 1 (n=13,15,10,13,12) | 954.7 micrograms*hours per milliliter (μg*h/mL | Geometric Coefficient of Variation 26.9 |
| 0.3 mg/kg Nivolumab | Geometric Mean Area Under the Curve (AUC[TAU]) in One Dosing Interval Observed Post-Single Dose | Cycle 3/Day 1 (n=4,2,9,5,3) | 3406.1 micrograms*hours per milliliter (μg*h/mL | Geometric Coefficient of Variation 12.8 |
| 1.0 mg/kg Nivolumab | Geometric Mean Area Under the Curve (AUC[TAU]) in One Dosing Interval Observed Post-Single Dose | Cycle 1/Day 1 (n=13,15,10,13,12) | 3589.6 micrograms*hours per milliliter (μg*h/mL | Geometric Coefficient of Variation 23.8 |
| 1.0 mg/kg Nivolumab | Geometric Mean Area Under the Curve (AUC[TAU]) in One Dosing Interval Observed Post-Single Dose | Cycle 3/Day 1 (n=4,2,9,5,3) | 10190.4 micrograms*hours per milliliter (μg*h/mL | Geometric Coefficient of Variation 25.8 |
| 3.0 mg/kg Nivolumab | Geometric Mean Area Under the Curve (AUC[TAU]) in One Dosing Interval Observed Post-Single Dose | Cycle 3/Day 1 (n=4,2,9,5,3) | 30640.3 micrograms*hours per milliliter (μg*h/mL | Geometric Coefficient of Variation 17.5 |
| 3.0 mg/kg Nivolumab | Geometric Mean Area Under the Curve (AUC[TAU]) in One Dosing Interval Observed Post-Single Dose | Cycle 1/Day 1 (n=13,15,10,13,12) | 8785.8 micrograms*hours per milliliter (μg*h/mL | Geometric Coefficient of Variation 22.7 |
| 10 mg/kg Nivolumab | Geometric Mean Area Under the Curve (AUC[TAU]) in One Dosing Interval Observed Post-Single Dose | Cycle 1/Day 1 (n=13,15,10,13,12) | 31095.1 micrograms*hours per milliliter (μg*h/mL | Geometric Coefficient of Variation 25.4 |
| 10 mg/kg Nivolumab | Geometric Mean Area Under the Curve (AUC[TAU]) in One Dosing Interval Observed Post-Single Dose | Cycle 3/Day 1 (n=4,2,9,5,3) | 99621.7 micrograms*hours per milliliter (μg*h/mL | Geometric Coefficient of Variation 26 |
Secondary
Geometric Mean Maximum Serum Concentration (Cmax)
Nivolumab in human serum was assayed by PPD® (Richmond, Virginia) using a cross-validated enzyme-linked immunosorbent assay (ELISA). Blood samples were assessed at all doses from a subset of participants. The pharmacokinetic (PK) parameter of Cmax was measured in micrograms per milliliter (µg/mL).
Time frame: 1,4,8,24,48 and 96 hours post-dose timepoints on Day 1 of cycles 1 and 3
Population: All participants who received at least 1 dose or any partial dose of nivolumab and had adequate PK profiles.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 0.1 mg/kg Nivolumab | Geometric Mean Maximum Serum Concentration (Cmax) | Cycle 1/Day 1 (n=15,17,17,13,14) | 1.9 micrograms per milliliter (µg/mL) | Geometric Coefficient of Variation 23.6 |
| 0.1 mg/kg Nivolumab | Geometric Mean Maximum Serum Concentration (Cmax) | Cycle 3/Day 1 (n=5,2,10,7,5) | 3.7 micrograms per milliliter (µg/mL) | Geometric Coefficient of Variation 42.2 |
| 0.3 mg/kg Nivolumab | Geometric Mean Maximum Serum Concentration (Cmax) | Cycle 1/Day 1 (n=15,17,17,13,14) | 7.0 micrograms per milliliter (µg/mL) | Geometric Coefficient of Variation 32.3 |
| 0.3 mg/kg Nivolumab | Geometric Mean Maximum Serum Concentration (Cmax) | Cycle 3/Day 1 (n=5,2,10,7,5) | 17.8 micrograms per milliliter (µg/mL) | Geometric Coefficient of Variation 26.6 |
| 1.0 mg/kg Nivolumab | Geometric Mean Maximum Serum Concentration (Cmax) | Cycle 1/Day 1 (n=15,17,17,13,14) | 19.6 micrograms per milliliter (µg/mL) | Geometric Coefficient of Variation 29.5 |
| 1.0 mg/kg Nivolumab | Geometric Mean Maximum Serum Concentration (Cmax) | Cycle 3/Day 1 (n=5,2,10,7,5) | 46.9 micrograms per milliliter (µg/mL) | Geometric Coefficient of Variation 26.1 |
| 3.0 mg/kg Nivolumab | Geometric Mean Maximum Serum Concentration (Cmax) | Cycle 3/Day 1 (n=5,2,10,7,5) | 132.0 micrograms per milliliter (µg/mL) | Geometric Coefficient of Variation 19.8 |
| 3.0 mg/kg Nivolumab | Geometric Mean Maximum Serum Concentration (Cmax) | Cycle 1/Day 1 (n=15,17,17,13,14) | 61.3 micrograms per milliliter (µg/mL) | Geometric Coefficient of Variation 26.4 |
| 10 mg/kg Nivolumab | Geometric Mean Maximum Serum Concentration (Cmax) | Cycle 1/Day 1 (n=15,17,17,13,14) | 191.2 micrograms per milliliter (µg/mL) | Geometric Coefficient of Variation 40 |
| 10 mg/kg Nivolumab | Geometric Mean Maximum Serum Concentration (Cmax) | Cycle 3/Day 1 (n=5,2,10,7,5) | 475.0 micrograms per milliliter (µg/mL) | Geometric Coefficient of Variation 24.6 |
Secondary
Geometric Mean Total Body Clearance of Drug From Serum (CLT)
Nivolumab in human serum was assayed by PPD® (Richmond, Virginia) using a cross-validated ELISA. Blood samples Blood samples were assessed at all doses from a subset of participants. The PK parameter of CLT was measured in milliliters per hour (mL/h).
Time frame: 1,4,8,24,48 and 96 hours post-dose timepoints on Day 1 of cycle 3
Population: All participants who received at least 1 dose or any partial dose of nivolumab and had adequate PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 0.1 mg/kg Nivolumab | Geometric Mean Total Body Clearance of Drug From Serum (CLT) | 8.3 milliliters per hour (mL/h) | Geometric Coefficient of Variation 40 |
| 0.3 mg/kg Nivolumab | Geometric Mean Total Body Clearance of Drug From Serum (CLT) | 6.9 milliliters per hour (mL/h) | Geometric Coefficient of Variation 17.8 |
| 1.0 mg/kg Nivolumab | Geometric Mean Total Body Clearance of Drug From Serum (CLT) | 8.0 milliliters per hour (mL/h) | Geometric Coefficient of Variation 31.1 |
| 3.0 mg/kg Nivolumab | Geometric Mean Total Body Clearance of Drug From Serum (CLT) | 10.3 milliliters per hour (mL/h) | Geometric Coefficient of Variation 18.1 |
| 10 mg/kg Nivolumab | Geometric Mean Total Body Clearance of Drug From Serum (CLT) | 8.5 milliliters per hour (mL/h) | Geometric Coefficient of Variation 6.4 |
Secondary
Immunogenicity Assessment
Classification of participants host immune response was based on the following definitions: Anti-Drug Antibody (ADA) Positive Subjects have with at least one ADA positive sample at any time after initiation of treatment. ADA positive subjects were further classified into categories with Persistent Positive defined as an ADA positive sample at 2 or more sequential timepoints at least 8 weeks apart.
Time frame: Day 1 up to June 2013, approximately 4 years
Population: All participants who received at least 1 dose or any partial dose of nivolumab and were ADA-evaluable were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 0.1 mg/kg Nivolumab | Immunogenicity Assessment | ADA Positive | 6 participants |
| 0.1 mg/kg Nivolumab | Immunogenicity Assessment | Persistant Positive | 1 participants |
| 0.3 mg/kg Nivolumab | Immunogenicity Assessment | ADA Positive | 2 participants |
| 0.3 mg/kg Nivolumab | Immunogenicity Assessment | Persistant Positive | 0 participants |
| 1.0 mg/kg Nivolumab | Immunogenicity Assessment | ADA Positive | 7 participants |
| 1.0 mg/kg Nivolumab | Immunogenicity Assessment | Persistant Positive | 1 participants |
| 3.0 mg/kg Nivolumab | Immunogenicity Assessment | Persistant Positive | 0 participants |
| 3.0 mg/kg Nivolumab | Immunogenicity Assessment | ADA Positive | 2 participants |
| 10 mg/kg Nivolumab | Immunogenicity Assessment | ADA Positive | 4 participants |
| 10 mg/kg Nivolumab | Immunogenicity Assessment | Persistant Positive | 0 participants |
Secondary
Mean Effective Half-life (T-HALFeff)
Nivolumab in human serum was assayed by PPD® (Richmond, Virginia) using a cross-validated ELISA. Blood samples were assessed at all doses from a subset of participants. The PK parameter of T-HALFeff was measured in hours (h).
Time frame: 1,4,8,24,48 and 96 hours post-dose timepoints on Day 1 of cycle 3
Population: All participants who received at least 1 dose or any partial dose of nivolumab and had adequate PK profiles.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 0.1 mg/kg Nivolumab | Mean Effective Half-life (T-HALFeff) | 622 hours (h) | Standard Deviation 235 |
| 0.3 mg/kg Nivolumab | Mean Effective Half-life (T-HALFeff) | 555 hours (h) | Standard Deviation 42 |
| 1.0 mg/kg Nivolumab | Mean Effective Half-life (T-HALFeff) | 636 hours (h) | Standard Deviation 267 |
| 3.0 mg/kg Nivolumab | Mean Effective Half-life (T-HALFeff) | 661 hours (h) | Standard Deviation 202 |
| 10 mg/kg Nivolumab | Mean Effective Half-life (T-HALFeff) | 595 hours (h) | Standard Deviation 80 |
Secondary
Median Time of Maximum Serum Concentration (Tmax)
Nivolumab in human serum was assayed by PPD® (Richmond, Virginia) using a cross-validated ELISA. Blood samples were assessed Blood samples were assessed at all doses from a subset of participants. The PK parameter of Tmax was measured in hours (h).
Time frame: 1,4,8,24,48 and 96 hours post-dose timepoints on Day 1 of cycles 1 and 3
Population: All participants who received at least 1 dose or any partial dose of nivolumab and had adequate PK profiles.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| 0.1 mg/kg Nivolumab | Median Time of Maximum Serum Concentration (Tmax) | Cycle 1/Day 1 (n=15,17,17,13,14) | 1.1 hours (h) |
| 0.1 mg/kg Nivolumab | Median Time of Maximum Serum Concentration (Tmax) | Cycle 3/Day 1 (n=5,2,10,7,5) | 8.0 hours (h) |
| 0.3 mg/kg Nivolumab | Median Time of Maximum Serum Concentration (Tmax) | Cycle 1/Day 1 (n=15,17,17,13,14) | 1.2 hours (h) |
| 0.3 mg/kg Nivolumab | Median Time of Maximum Serum Concentration (Tmax) | Cycle 3/Day 1 (n=5,2,10,7,5) | 24.7 hours (h) |
| 1.0 mg/kg Nivolumab | Median Time of Maximum Serum Concentration (Tmax) | Cycle 1/Day 1 (n=15,17,17,13,14) | 1.2 hours (h) |
| 1.0 mg/kg Nivolumab | Median Time of Maximum Serum Concentration (Tmax) | Cycle 3/Day 1 (n=5,2,10,7,5) | 1.0 hours (h) |
| 3.0 mg/kg Nivolumab | Median Time of Maximum Serum Concentration (Tmax) | Cycle 3/Day 1 (n=5,2,10,7,5) | 4.0 hours (h) |
| 3.0 mg/kg Nivolumab | Median Time of Maximum Serum Concentration (Tmax) | Cycle 1/Day 1 (n=15,17,17,13,14) | 2.1 hours (h) |
| 10 mg/kg Nivolumab | Median Time of Maximum Serum Concentration (Tmax) | Cycle 1/Day 1 (n=15,17,17,13,14) | 3.9 hours (h) |
| 10 mg/kg Nivolumab | Median Time of Maximum Serum Concentration (Tmax) | Cycle 3/Day 1 (n=5,2,10,7,5) | 22.3 hours (h) |
Secondary
Objective Response Rate
Tumor response was evaluated by the sponsor based on tumor assessments by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.0. Objective response rate (ORR) was defined as the proportion of participants who's confirmed best overall response (BOR) is either complete (CR) or partial (PR), where the denominator is the number of treated participants in the population of interest. Response was based on tumor measurements. Responders= complete response (CR) or partial response (PR). CR=disappearance of all target and non-target lesions; PR=at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the screening sum longest diameter. 95% Confidence intervals (CIs) were computed using the Clopper Pearson method.
Time frame: Day 1 up to June 2013, approximately 4 years
Population: All participants who received at least 1 dose or any partial dose of nivolumab with an evaluable tumor response were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 0.1 mg/kg Nivolumab | Objective Response Rate | Melanoma (n=17,18,35,17,20,107) | 35.3 percentage of participants |
| 0.1 mg/kg Nivolumab | Objective Response Rate | NSQ NSCLC (n=0,0,18,19,37,74) | 0 percentage of participants |
| 0.1 mg/kg Nivolumab | Objective Response Rate | TOTAL NSCLC (n=0,0,33,37,59,129) | 0 percentage of participants |
| 0.1 mg/kg Nivolumab | Objective Response Rate | SQ NSCLC (n=0,0,15,18,21,54) | 0 percentage of participants |
| 0.1 mg/kg Nivolumab | Objective Response Rate | Renal Cell Carcinoma (RCC) (n=0,0,18,0,16,34) | 0 percentage of participants |
| 0.3 mg/kg Nivolumab | Objective Response Rate | SQ NSCLC (n=0,0,15,18,21,54) | 0 percentage of participants |
| 0.3 mg/kg Nivolumab | Objective Response Rate | Melanoma (n=17,18,35,17,20,107) | 27.8 percentage of participants |
| 0.3 mg/kg Nivolumab | Objective Response Rate | Renal Cell Carcinoma (RCC) (n=0,0,18,0,16,34) | 0 percentage of participants |
| 0.3 mg/kg Nivolumab | Objective Response Rate | NSQ NSCLC (n=0,0,18,19,37,74) | 0 percentage of participants |
| 0.3 mg/kg Nivolumab | Objective Response Rate | TOTAL NSCLC (n=0,0,33,37,59,129) | 0 percentage of participants |
| 1.0 mg/kg Nivolumab | Objective Response Rate | Renal Cell Carcinoma (RCC) (n=0,0,18,0,16,34) | 27.8 percentage of participants |
| 1.0 mg/kg Nivolumab | Objective Response Rate | Melanoma (n=17,18,35,17,20,107) | 31.4 percentage of participants |
| 1.0 mg/kg Nivolumab | Objective Response Rate | SQ NSCLC (n=0,0,15,18,21,54) | 0 percentage of participants |
| 1.0 mg/kg Nivolumab | Objective Response Rate | TOTAL NSCLC (n=0,0,33,37,59,129) | 3.0 percentage of participants |
| 1.0 mg/kg Nivolumab | Objective Response Rate | NSQ NSCLC (n=0,0,18,19,37,74) | 5.6 percentage of participants |
| 3.0 mg/kg Nivolumab | Objective Response Rate | SQ NSCLC (n=0,0,15,18,21,54) | 22.2 percentage of participants |
| 3.0 mg/kg Nivolumab | Objective Response Rate | NSQ NSCLC (n=0,0,18,19,37,74) | 26.3 percentage of participants |
| 3.0 mg/kg Nivolumab | Objective Response Rate | TOTAL NSCLC (n=0,0,33,37,59,129) | 24.3 percentage of participants |
| 3.0 mg/kg Nivolumab | Objective Response Rate | Melanoma (n=17,18,35,17,20,107) | 41.2 percentage of participants |
| 3.0 mg/kg Nivolumab | Objective Response Rate | Renal Cell Carcinoma (RCC) (n=0,0,18,0,16,34) | 0 percentage of participants |
| 10 mg/kg Nivolumab | Objective Response Rate | Melanoma (n=17,18,35,17,20,107) | 20.0 percentage of participants |
| 10 mg/kg Nivolumab | Objective Response Rate | SQ NSCLC (n=0,0,15,18,21,54) | 23.8 percentage of participants |
| 10 mg/kg Nivolumab | Objective Response Rate | Renal Cell Carcinoma (RCC) (n=0,0,18,0,16,34) | 31.3 percentage of participants |
| 10 mg/kg Nivolumab | Objective Response Rate | NSQ NSCLC (n=0,0,18,19,37,74) | 18.9 percentage of participants |
| 10 mg/kg Nivolumab | Objective Response Rate | TOTAL NSCLC (n=0,0,33,37,59,129) | 20.3 percentage of participants |
| All Dose Groups | Objective Response Rate | SQ NSCLC (n=0,0,15,18,21,54) | 16.7 percentage of participants |
| All Dose Groups | Objective Response Rate | Melanoma (n=17,18,35,17,20,107) | 30.8 percentage of participants |
| All Dose Groups | Objective Response Rate | NSQ NSCLC (n=0,0,18,19,37,74) | 17.6 percentage of participants |
| All Dose Groups | Objective Response Rate | Renal Cell Carcinoma (RCC) (n=0,0,18,0,16,34) | 29.4 percentage of participants |
| All Dose Groups | Objective Response Rate | TOTAL NSCLC (n=0,0,33,37,59,129) | 17.1 percentage of participants |