Advanced Melanoma
Conditions
Brief summary
The purpose of this clinical research study is to compare pharmacokinetics of ipilimumab manufactured by two different processes
Interventions
BIOLOGICALIpilimumab
Solution, Intravenous, 10 mg/kg, Every 3 weeks (up to 4 doses) in induction phase, every 12 weeks in maintenance phase, 48 weeks
Sponsors
Medarex
Bristol-Myers Squibb
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologic diagnosis of malignant melanoma * Eastern Cooperative Oncology Group (ECOG) performance status 0-1 * Measurable/evaluable disease per modified World Health Organization (mWHO) criteria
Exclusion criteria
* Active Brain Metastasis * Primary ocular or mucosal melanoma * Prior Autoimmune disease * Inadequate hematologic, hepatic or renal function * Use of immunosuppressants * Prior treatment with a CD137 agonist or cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitor
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Serum Concentration (Cmax) of Ipilimumab Manufactured by Process C Relative to the Cmax of Ipilimumab Manufactured by Process B - Evaluable Pharmacokinetic Population | Day 1 to Day 84 | Single-dose Pharmacokinetic (PK) parameters of ipilimumab were derived from serum concentration versus time data. Cmax was measured from first dose to end of the induction period (4 doses) as micrograms per milliliter (μg/mL). Samples were obtained at 0 hour (predose) on Days 1, 2, 3, 4, and Weeks 2, 3, 4, 7, and 10; Day 1, samples were also obtained 1 h 30 minutes (min), 2 h, 2 h 30 min, 3 h 30 min, 4 h 30 min, and 6 h post dose. In calculating PK parameters, predose concentrations and concentrations prior to first quantifiable concentration below the lower limit of quantitation (LLOQ) were treated as missing for the calculation of summary statistics. Drug was quantitatively determined in serum by an enzyme-linked immunosorbent assay (ELISA). Individual PK parameter values were derived by non-compartmental methods using a validated PK analysis program (Kinetica™ 4.4.1 within eToolbox \[version 2.6.1\]). |
| Area Under the Serum Concentration-time Curve (AUC) From Time Zero to Day 21, AUC(0-21d), of Ipilimumab Manufactured by Process C Relative to the AUC(0-21d) of Ipilimumab Manufactured by Process B - Evaluable Pharmacokinetic Population | Day 1 to Day 84 | The single-dose pharmacokinetic parameters of ipilimumab were derived from serum concentration versus time data. AUC(0-21d) was measured from first dose to end of the induction period as micrograms\*hours per milliliter (μg\*h/mL). Samples were obtained at 0 hour (predose) on Days 1, 2, 3, 4, and Weeks 2, 3, 4, 7, and 10; Day 1, samples were also obtained 1 h 30 minutes (min), 2 h, 2 h 30 min, 3 h 30 min, 4 h 30 min, and 6 h post dose. In calculating PK parameters, predose concentrations and concentrations prior to first quantifiable concentration below the lower limit of quantitation (LLOQ) were treated as missing for the calculation of summary statistics. Drug was quantitatively determined in serum by an enzyme-linked immunosorbent assay (ELISA). Individual PK parameter values were derived by non-compartmental methods using a validated PK analysis program (Kinetica™ 4.4.1 within eToolbox \[version 2.6.1\]). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clearance (CLT) of Ipilimumab Manufactured by Process C Relative to the CLT of Ipilimumab Manufactured by Process B - Evaluable Pharmacokinetic Population | Day 1 to Day 84 | The single-dose Pharmacokinetic parameters of ipilimumab were derived from serum concentration versus time data. CLT was measured from first dose to end of the induction period (4 doses) in milliliters per hour (mL/h). Samples were obtained at 0 hour (predose) on Days 1, 2, 3, 4, and Weeks 2, 3, 4, 7, and 10; Day 1, samples were also obtained 1 h 30 minutes (min), 2 h, 2 h 30 min, 3 h 30 min, 4 h 30 min, and 6 h post dose. In calculating PK parameters, predose concentrations and concentrations prior to first quantifiable concentration below the lower limit of quantitation (LLOQ) were treated as missing for the calculation of summary statistics. Drug was quantitatively determined in serum by an enzyme-linked immunosorbent assay (ELISA). Individual PK parameter values were derived by non-compartmental methods using a validated PK analysis program (Kinetica™ 4.4.1 within eToolbox \[version 2.6.1\]). |
| Volume of Distribution at Steady State (Vss) of Ipilimumab Manufactured by Process C Relative to the Vss of Ipilimumab Manufactured by Process B - Evaluable Pharmacokinetic Population | Day 1 to Day 84 | The single-dose Pharmacokinetic parameters of ipilimumab were derived from serum concentration versus time data. Vss was measured from first dose to end of the induction period (4 doses) in liter(s) (L). Samples were obtained at 0 hour (predose) on Days 1, 2, 3, 4, and Weeks 2, 3, 4, 7, and 10; Day 1, samples were also obtained 1 h 30 minutes (min), 2 h, 2 h 30 min, 3 h 30 min, 4 h 30 min, and 6 h post dose. In calculating PK parameters, predose concentrations and concentrations prior to first quantifiable concentration below the lower limit of quantitation (LLOQ) were treated as missing for the calculation of summary statistics. Drug was quantitatively determined in serum by an enzyme-linked immunosorbent assay (ELISA). Individual PK parameter values were derived by non-compartmental methods using a validated PK analysis program (Kinetica™ 4.4.1 within eToolbox \[version 2.6.1\]). |
| Best Overall Tumor Response Per Investigator Based on Modified World Health Organization (mWHO) Criteria - All Randomized Participants | Day 1 to last patient, last visit, approximately 3 years | Overall Response (OR) was determined as the combination of assessments of index and non-index lesions using mWHO criteria which were: Complete Response=complete disappearance of all lesions; Partial Response=decrease, relative to baseline, of 50% or greater in the sum of the products of the two largest perpendicular diameters of all index lesions, in the absence of Complete Response; Stable Disease=does not meet criteria for complete or partial response, in the absence of progressive disease, or a decrease or tumor stabilization of one or more non-index lesions; Progressive Disease (Progression)=at least 25% increase in the sum of the products of all index lesions (taking as reference the smallest sum recorded at or following baseline) and/or the appearance of any new lesion(s), or progression of non-index lesion(s). OR was measured across the entire study from Day 1 to the last patient, last visit (2009 to 2012) |
| Best Overall Tumor Response Per Investigator Based on Immune-related (ir) Response Criteria (RC) - All Randomized Participants | Day 1 to last patient, last visit, approximately 3 years | ir RC=modifications of mWHO criteria reflecting clinical experience with ipilimumab in over 20 completed and/or ongoing clinical studies. irRC were designed to capture clinical activity of ipilimumab immunotherapy that may not be adequately addressed by the mWHO criteria. irComplete Response (irCR): Complete disappearance of all index and non-index lesions. irPartial Response (irPR): Decrease, relative to baseline, of 50% or greater in the sum of the products of the two largest perpendicular diameters of all index and all new measurable lesions in the absence of irCR, non-index lesions not considered. irStable Disease (irSD): Does not meet criteria for irCR or irPR, in the absence of progressive disease (irPD). irProgressive Disease (irPD): At least 25% increase in Tumor Burden when compared to sum of the products of diameters of lesions at nadir. |
| Median Overall Survival Following First Ipilimumab Dose - All Treated Participants | Week 1 (first dose) to last patient, last visit, approximately 3 years | Overall survival (OS) was defined as the time between the first dose of study treatment and death and was analyzed using Kaplan-Meier methods, with participants who had not died censored at the last date known to be alive. Overall survival was measured in months. |
| Model Estimates of Mean Absolute Lymphocyte Count at Each Nominal Ipilimumab Induction Dose and at End of the Induction Dosing Period | Day 0 (prior to first dose) to Day 84 | Absolute lymphocyte counts (ALC) were obtained throughout the study as part of the hematology panel. Results collected from 28 days prior to the first infusion of ipilimumab through the end of the Induction-Dosing Period were included in the analyses of ALC. Mean ALC was estimated via an extended linear model, with linear splines and a spatial exponential within-patient correlation structure. Lymphocytes were measured as 1000 cells per micro liter (c/µL). |
| Time of Maximum Observed Serum Concentration (Tmax) of Ipilimumab Manufactured by Process C Relative to the Tmax of Ipilimumab Manufactured by Process B - Evaluable Pharmacokinetic Population | Day 1 to Day 84 | The single-dose Pharmacokinetic parameters of ipilimumab were derived from serum concentration versus time data. Tmax was measured from first dose to end of the induction period (4 doses) in hours (h). Samples were obtained at 0 h (predose) on Days 1, 2, 3, 4, and Weeks 2, 3, 4, 7, and 10; Day 1, samples were also obtained 1 h 30 minutes (min), 2 h, 2 h 30 min, 3 h 30 min, 4 h 30 min, and 6 h post dose. In calculating PK parameters, predose concentrations and concentrations prior to first quantifiable concentration below the lower limit of quantitation (LLOQ) were treated as missing for the calculation of summary statistics. Drug was quantitatively determined in serum by an enzyme-linked immunosorbent assay (ELISA). Individual PK parameter values were derived by non-compartmental methods using a validated PK analysis program (Kinetica™ 4.4.1 within eToolbox \[version 2.6.1\]). |
| Number of Participants Who Developed Antibodies and Neutralizing Antibodies | Prior to start of drug Week 1 to Week 24 on treatment or end of treatment | Electrochemiluminescent (ECL) Immunoassay was used to detect human anti-human ipilimumab antibodies (HAHA) in serum. Blood samples were collected prior to the start of each ipilimumab infusion at Weeks 1, 4, 7, 10, 24, and at end of treatment. Those participants who were positive HAHA on treatment were then tested for presence of neutralizing antibodies. |
| Mean Change From Baseline in Sitting Systolic and Diastolic Blood Pressure - All Treated Participants up to Data Cutoff | Screening to data cut off for July 2010, approximately 36 Weeks | Systolic and Diastolic blood pressure were measured in millimeters of mercury (mmHg) and were obtained after the participant had been seated for 5 minutes. Vital sign measurements were collected at Screening (baseline), Weeks 1, 4, 7, 10, 12, 24 and every 12 weeks thereafter in the Maintenance Phase, and at the End of Treatment visit. The change from baseline in blood pressure one hour post end of infusion at the end of induction Period, Week 36 of Maintenance Period, and end of treatment, up to data cutoff for July 2010 are presented below. |
| Mean Change From Baseline in Sitting Pulse Rate - All Treated Participants up to Data Cutoff | Screening to data cut off for July 2010, approximately 36 Weeks | Pulse Rate was measured in beats per minute (bpm) and was obtained after the participant had been seated for 5 minutes. Vital sign measurements were collected at Screening (baseline), Weeks 1, 4, 7, 10, 12, 24 and every 12 weeks thereafter in the Maintenance Phase, and at the End of Treatment visit. The change from baseline in blood pressure one hour post end of infusion at the end of induction Period, Week 36 of Maintenance Period, and end of treatment, up to data cutoff for July 2010 are presented below. |
| Number of Participants With 2-Grade or Greater Shift From Baseline (Worsening) in Hematology Laboratory Safety Tests - All Treated Participants | Screening to data cut off for July 2010, approximately 36 Weeks | Common Terminology Criteria (CTC), Version 3 used to assess parameters. Lower limit of normal (LLN); grams per deciliter (g/dL); Grade (GR); cells per microliter (c/µL). Hemoglobin Gr 1:\<LLN to 10.0 g/dL, Gr 2:\<10.0 to 8.0 g/dL, Gr 3:\<8.0 to 6.5 g/dL, Gr 4:\<6.5 g/dL. Absolute neutrophil (ANC) and ANC plus bands: Gr 1:\<LLN to 1.5\*10\^3 c/µL, Gr 2:\<1.5 to 1.0\*10\^3 c/µL, Gr 3:\<1.0 to 0.5\*10\^3 c/µL, Gr 4:\<0.5\*10\^3 c/µL. Platelet count Gr 1:LLN to 75.0\*10\^9 c/L, Gr 2:\<75.0 to 50.0\*10\^9 c/L, Gr 3:\<50.0 to 25.0\*10\^9 c/L, Gr 4:\<25.0 to 10\^9 c/L. Lymphocytes Gr 1: \<1.5 to 0.8 \*10\^3 c/µL, Gr 2 \<0.8 to 0.5 \*10\^3 c/µL, Gr 3: \<0.5 to 0.2 \*10\^3 c/µL, Gr 4: \<0.2\*10\^3 c/µL. Leukocytes Gr 1:\<LLN to 3.0 \*10\^3 c/µL, Gr 2; \<3.0 to 2.0 \*10\^3 c/µL, Gr 3: \<2.0 to 1.0 \*10\^3 c/µL, Gr 4: \<1.0 \*10\^3 c/µL. Baseline is screening or Day 1, prior to dosing. |
| Number of Participants With 2-Grade or Greater Shift From Baseline (Worsening) in Chemistry Laboratory Safety Tests (Non-electrolyte) - All Treated Participants | Screening to data cut off for July 2010, approximately 36 Weeks | Alanine transaminase (ALT); Aspartate aminotransferase (AST); Alkaline phosphatase (ALP); upper limits of normal (ULN). ALT Gr 1:\>1.0 to 2.5\*ULN; Gr 2: \>2.5 to 5.0\*ULN; Gr 3: \>5.0 to 20.0\*ULN; Gr 4: \>20.0\*ULN. AST Gr 1: \>1.0 to 2.5\*ULN; Gr 2: \>2.5 to 5.0\*ULN; Gr 3: \>5.0 to 20.0\*ULN; Gr 4: \>20.0\*ULN. Total bilirubin Gr 1: \>1.0 to 1.5\*ULN; Gr 2: \>1.5 to 3.0\*ULN; Gr 3: \>3.0 to 10..0\*ULN; Gr 4: \>10.0.0\*ULN. ALP (U/L) Gr1:\>1.0 to 2.5\*ULN, Gr2:\>2.5 to 5.0\*ULN, Gr3:\>5.0 to 20.0\*ULN, Gr4:\>20.0\*ULN. Albumin (low) Gr 1:\<LLN to 3 g/dL; Gr 2: \<3.0 - 2.0 g/L; Gr 3: \< 2 g/dL. Creatinine Gr 1: \>1 - 1.5\*ULN; Gr 2: \>1.5 - 3.0\*ULN; Gr 3: \>3.0- 6.0\*ULN; Gr 4: \>6.0\*ULN. Lipase (U/L) Gr 1: 1.0 to 1.5\*ULN; Gr 2: \>1.5 to 2.0\*ULN; Gr 3: 2.0 to 5; Gr 4: \>5\*ULN. Amylase (U/L) Gr 1: \>ULN to 1.5\*ULN; Grade 2 \>1.5 to 2.0\*ULN, Grade 3 \>2.0 to 5.0\*ULN, Grade 4 \>5.0\*ULN. Baseline was screening or Day 1, prior to first dose of drug. |
| Number of Participants With 2-Grade or Greater Shift From Baseline (Worsening) in Electrolyte Laboratory Safety Tests - All Treated Participants | Screening to data cut off for July 2010, approximately 36 Weeks | Sodium high (H) Gr 1:\>ULN - 150; Gr 2: \>150 - 155; Gr 3: \>155 - 160; Gr 4: \>160 mmol/L; Sodium low(L) Gr 1:\<LLN - 130; Gr 3: \<130 - 120; Gr 4: \<120 mmol/L. Potassium (H) Gr 1: \>ULN - 5.5; Gr 2: \>5.5 - 6.0; Gr 3: \> 6.0 - 7.0; Gr 4: \>7.0 mmol/L; Potassium (L) Gr 1: \<LLN - 3.0; Gr 2: \<LLN - 3.0; Gr 3: \< 3.0 - 2.5; Gr 4: \<2.5 mmol/L. Bicarbonate Gr1: 16-\<LLN, Gr2: 11-16, Gr3, 8-11, Gr4: \<8 milliequivalents per liter (mEq/L). Phosphorus Gr 1: 2.5 - \<LLN, Gr2 2.0-\<2.5, Gr3: 1.0-\<2.0, Gr4: \<1.0. Calcium (L) Gr 1: \<LLN to 8.0; Gr2: 7.0 - 8.0; Gr3: 6.0-7.0; Gr 4: \<6.0 mg/dL; calcium (H) Gr1:\>ULN - 11.5, Gr2:\>11.5 - 12.5, Gr3: 12.5 - 13.5, Gr4: \>13.5. Baseline is screening or Day 1, prior to first dose of drug. |
| Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and AEs Leading to Discontinuation | Day 1 to last patient, last visit, approximately 3 years | Adverse events (AEs) and Serious AEs (SAEs) were graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse events version 3.0. Medical Dictionary for Regulatory Activities (MedDRA) version 15.1 was used. Note there is a difference in number of participants with an SAE in this outcome measure and the number listed in the Adverse Events Section of this document. This is because the SAEs reported in the xml upload of the Adverse Events section includes additional participants who reported SAEs after the clinical study report database was closed. |
| Terminal Elimination Half Life (T-HALF) of Ipilimumab Manufactured by Process C Relative to the T-HALF of Ipilimumab Manufactured by Process B - Evaluable Pharmacokinetic Population | Day 1 to Day 84 | The single-dose Pharmacokinetic parameters of ipilimumab were derived from serum concentration versus time data. T-HALF was measured from first dose to end of the induction period (4 doses) in day(s). Samples were obtained at 0 hour (predose) on Days 1, 2, 3, 4, and Weeks 2, 3, 4, 7, and 10; Day 1, samples were also obtained 1 h 30 minutes (min), 2 h, 2 h 30 min, 3 h 30 min, 4 h 30 min, and 6 h post dose. In calculating PK parameters, predose concentrations and concentrations prior to first quantifiable concentration below the lower limit of quantitation (LLOQ) were treated as missing for the calculation of summary statistics. Drug was quantitatively determined in serum by an enzyme-linked immunosorbent assay (ELISA). Individual PK parameter values were derived by non-compartmental methods using a validated PK analysis program (Kinetica™ 4.4.1 within eToolbox \[version 2.6.1\]). |
Countries
United States
Participant flow
Recruitment details
Study started August 3, 2009, ended October 31, 2012; Induction Phase (Weeks 1, 4, 7, 10), Maintenance Phase (participants without immune-related progressive disease (irPD) received ipilimumab every 12 weeks until disease progression, toxicity, pregnancy, death, withdrew consent, lost to follow up); Patients followed for 10 weeks post last dose.
Pre-assignment details
99 participants enrolled; 75 participants randomized and treated. 24 participants not treated due to violations of inclusion or exclusion criteria.
Participants by arm
| Arm | Count |
|---|---|
| Ipilimumab (Process B) 10 mg/kg ipilimumab was given IV once every 3 weeks (up to 4 doses) in the induction phase (Weeks 1, 4, 7, and 10); it was given once every 12 weeks in the maintenance phase for 48 weeks. In Process B, ipilimumab was manufactured by Lonza using material from transfectoma cell line. | 37 |
| Ipilimumab (Process C) 10 mg/kg ipilimumab was given IV once every 3 weeks (up to 4 doses) in the induction phase (Weeks 1, 4, 7, and 10); it was given once every 12 weeks in the maintenance phase for 48 weeks. In Process C, ipilimumab was manufactured by the Sponsor using material from a sub-clone of the original transfectoma cell line, modified cell culture and purification steps. | 38 |
| Total | 75 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Induction Period | Adverse Event | 0 | 2 |
| Induction Period | Death | 1 | 1 |
| Induction Period | Disease Progression | 12 | 11 |
| Induction Period | No longer meets study criteria | 0 | 1 |
| Induction Period | Study Drug Toxicity | 8 | 6 |
| Induction Period | Withdrawal by Subject | 1 | 1 |
| Maintenance Period | Administrative (study closure) | 7 | 2 |
| Maintenance Period | Adverse Event | 0 | 1 |
| Maintenance Period | Death | 1 | 1 |
| Maintenance Period | Disease Progression | 3 | 7 |
| Maintenance Period | Study Drug Toxicity | 0 | 2 |
| Maintenance Period | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Ipilimumab (Process B) | Ipilimumab (Process C) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 12 Participants | 14 Participants | 26 Participants |
| Age, Categorical Between 18 and 65 years | 25 Participants | 24 Participants | 49 Participants |
| Age, Continuous | 57 years STANDARD_DEVIATION 14 | 59 years STANDARD_DEVIATION 12 | 58 years STANDARD_DEVIATION 13 |
| Body Weight | 81.3 kg STANDARD_DEVIATION 13.4 | 80.7 kg STANDARD_DEVIATION 13.3 | 81.0 kg STANDARD_DEVIATION 13.3 |
| Eastern Cooperative Oncology Group (ECOG) ECOG=0 | 25 participants | 21 participants | 46 participants |
| Eastern Cooperative Oncology Group (ECOG) ECOG=1 | 12 participants | 17 participants | 29 participants |
| Region of Enrollment United States | 37 participants | 38 participants | 75 participants |
| Sex: Female, Male Female | 12 Participants | 14 Participants | 26 Participants |
| Sex: Female, Male Male | 25 Participants | 24 Participants | 49 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 37 / 37 | 38 / 38 |
| serious Total, serious adverse events | 24 / 37 | 26 / 38 |
Outcome results
Primary
Area Under the Serum Concentration-time Curve (AUC) From Time Zero to Day 21, AUC(0-21d), of Ipilimumab Manufactured by Process C Relative to the AUC(0-21d) of Ipilimumab Manufactured by Process B - Evaluable Pharmacokinetic Population
The single-dose pharmacokinetic parameters of ipilimumab were derived from serum concentration versus time data. AUC(0-21d) was measured from first dose to end of the induction period as micrograms\*hours per milliliter (μg\*h/mL). Samples were obtained at 0 hour (predose) on Days 1, 2, 3, 4, and Weeks 2, 3, 4, 7, and 10; Day 1, samples were also obtained 1 h 30 minutes (min), 2 h, 2 h 30 min, 3 h 30 min, 4 h 30 min, and 6 h post dose. In calculating PK parameters, predose concentrations and concentrations prior to first quantifiable concentration below the lower limit of quantitation (LLOQ) were treated as missing for the calculation of summary statistics. Drug was quantitatively determined in serum by an enzyme-linked immunosorbent assay (ELISA). Individual PK parameter values were derived by non-compartmental methods using a validated PK analysis program (Kinetica™ 4.4.1 within eToolbox \[version 2.6.1\]).
Time frame: Day 1 to Day 84
Population: PK evaluable Population: All participants who received at least one dose of drug and had adequate PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Ipilimumab (Process B) | Area Under the Serum Concentration-time Curve (AUC) From Time Zero to Day 21, AUC(0-21d), of Ipilimumab Manufactured by Process C Relative to the AUC(0-21d) of Ipilimumab Manufactured by Process B - Evaluable Pharmacokinetic Population | 40374.47 μg*h/mL | Geometric Coefficient of Variation 25 |
| Ipilimumab (Process C) | Area Under the Serum Concentration-time Curve (AUC) From Time Zero to Day 21, AUC(0-21d), of Ipilimumab Manufactured by Process C Relative to the AUC(0-21d) of Ipilimumab Manufactured by Process B - Evaluable Pharmacokinetic Population | 40085.9 μg*h/mL | Geometric Coefficient of Variation 29 |
Comparison: Biocomparability of ipilimumab Process C to ipilimumab Process B was to be concluded if the 90% confidence intervals (CIs) for the ratio of geometric means for ipilimumab Cmax were contained within 80% to 125%. Point estimates and 90% CIs were constructed for the ratio of geometric means (Process C/Process B) for ipilimumab Cmax.90% CI: [0.922, 1.156]Least squared linear regression
Primary
Maximum Observed Serum Concentration (Cmax) of Ipilimumab Manufactured by Process C Relative to the Cmax of Ipilimumab Manufactured by Process B - Evaluable Pharmacokinetic Population
Single-dose Pharmacokinetic (PK) parameters of ipilimumab were derived from serum concentration versus time data. Cmax was measured from first dose to end of the induction period (4 doses) as micrograms per milliliter (μg/mL). Samples were obtained at 0 hour (predose) on Days 1, 2, 3, 4, and Weeks 2, 3, 4, 7, and 10; Day 1, samples were also obtained 1 h 30 minutes (min), 2 h, 2 h 30 min, 3 h 30 min, 4 h 30 min, and 6 h post dose. In calculating PK parameters, predose concentrations and concentrations prior to first quantifiable concentration below the lower limit of quantitation (LLOQ) were treated as missing for the calculation of summary statistics. Drug was quantitatively determined in serum by an enzyme-linked immunosorbent assay (ELISA). Individual PK parameter values were derived by non-compartmental methods using a validated PK analysis program (Kinetica™ 4.4.1 within eToolbox \[version 2.6.1\]).
Time frame: Day 1 to Day 84
Population: Pharmacokinetic (PK) evaluable Population: All participants who received at least one dose of drug and had adequate PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Ipilimumab (Process B) | Maximum Observed Serum Concentration (Cmax) of Ipilimumab Manufactured by Process C Relative to the Cmax of Ipilimumab Manufactured by Process B - Evaluable Pharmacokinetic Population | 252.68 μg/mL | Geometric Coefficient of Variation 29 |
| Ipilimumab (Process C) | Maximum Observed Serum Concentration (Cmax) of Ipilimumab Manufactured by Process C Relative to the Cmax of Ipilimumab Manufactured by Process B - Evaluable Pharmacokinetic Population | 251.26 μg/mL | Geometric Coefficient of Variation 24 |
Comparison: Biocomparability of ipilimumab Process C to ipilimumab Process B was concluded if the 90% confidence intervals (CIs) for the ratio of geometric means for Cmax were contained within 80% to 125%.90% CI: [0.916, 1.114]Least squared linear regression
Secondary
Best Overall Tumor Response Per Investigator Based on Immune-related (ir) Response Criteria (RC) - All Randomized Participants
ir RC=modifications of mWHO criteria reflecting clinical experience with ipilimumab in over 20 completed and/or ongoing clinical studies. irRC were designed to capture clinical activity of ipilimumab immunotherapy that may not be adequately addressed by the mWHO criteria. irComplete Response (irCR): Complete disappearance of all index and non-index lesions. irPartial Response (irPR): Decrease, relative to baseline, of 50% or greater in the sum of the products of the two largest perpendicular diameters of all index and all new measurable lesions in the absence of irCR, non-index lesions not considered. irStable Disease (irSD): Does not meet criteria for irCR or irPR, in the absence of progressive disease (irPD). irProgressive Disease (irPD): At least 25% increase in Tumor Burden when compared to sum of the products of diameters of lesions at nadir.
Time frame: Day 1 to last patient, last visit, approximately 3 years
Population: All participants randomized to a treatment arm who received at least 1 dose of ipilimumab as randomized with measurable disease at baseline, at least one baseline assessment and one on-treatment tumor assessment, no resection of index lesions, and for irRC, no resection of new lesions.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ipilimumab (Process B) | Best Overall Tumor Response Per Investigator Based on Immune-related (ir) Response Criteria (RC) - All Randomized Participants | ir Partial Response | 2 participants |
| Ipilimumab (Process B) | Best Overall Tumor Response Per Investigator Based on Immune-related (ir) Response Criteria (RC) - All Randomized Participants | ir Progression | 14 participants |
| Ipilimumab (Process B) | Best Overall Tumor Response Per Investigator Based on Immune-related (ir) Response Criteria (RC) - All Randomized Participants | ir Stable Disease | 11 participants |
| Ipilimumab (Process B) | Best Overall Tumor Response Per Investigator Based on Immune-related (ir) Response Criteria (RC) - All Randomized Participants | Unable to determine | 6 participants |
| Ipilimumab (Process B) | Best Overall Tumor Response Per Investigator Based on Immune-related (ir) Response Criteria (RC) - All Randomized Participants | ir Complete Response | 0 participants |
| Ipilimumab (Process C) | Best Overall Tumor Response Per Investigator Based on Immune-related (ir) Response Criteria (RC) - All Randomized Participants | Unable to determine | 2 participants |
| Ipilimumab (Process C) | Best Overall Tumor Response Per Investigator Based on Immune-related (ir) Response Criteria (RC) - All Randomized Participants | ir Complete Response | 1 participants |
| Ipilimumab (Process C) | Best Overall Tumor Response Per Investigator Based on Immune-related (ir) Response Criteria (RC) - All Randomized Participants | ir Partial Response | 9 participants |
| Ipilimumab (Process C) | Best Overall Tumor Response Per Investigator Based on Immune-related (ir) Response Criteria (RC) - All Randomized Participants | ir Stable Disease | 8 participants |
| Ipilimumab (Process C) | Best Overall Tumor Response Per Investigator Based on Immune-related (ir) Response Criteria (RC) - All Randomized Participants | ir Progression | 14 participants |
Secondary
Best Overall Tumor Response Per Investigator Based on Modified World Health Organization (mWHO) Criteria - All Randomized Participants
Overall Response (OR) was determined as the combination of assessments of index and non-index lesions using mWHO criteria which were: Complete Response=complete disappearance of all lesions; Partial Response=decrease, relative to baseline, of 50% or greater in the sum of the products of the two largest perpendicular diameters of all index lesions, in the absence of Complete Response; Stable Disease=does not meet criteria for complete or partial response, in the absence of progressive disease, or a decrease or tumor stabilization of one or more non-index lesions; Progressive Disease (Progression)=at least 25% increase in the sum of the products of all index lesions (taking as reference the smallest sum recorded at or following baseline) and/or the appearance of any new lesion(s), or progression of non-index lesion(s). OR was measured across the entire study from Day 1 to the last patient, last visit (2009 to 2012)
Time frame: Day 1 to last patient, last visit, approximately 3 years
Population: All participants randomized to a treatment arm who received at least 1 dose of ipilimumab as randomized with measurable disease at baseline, at least one baseline assessment and one on-treatment tumor assessment, no resection of index lesions.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ipilimumab (Process B) | Best Overall Tumor Response Per Investigator Based on Modified World Health Organization (mWHO) Criteria - All Randomized Participants | Stable Disease mWHO | 11 participants |
| Ipilimumab (Process B) | Best Overall Tumor Response Per Investigator Based on Modified World Health Organization (mWHO) Criteria - All Randomized Participants | Unable to determine mWHO | 7 participants |
| Ipilimumab (Process B) | Best Overall Tumor Response Per Investigator Based on Modified World Health Organization (mWHO) Criteria - All Randomized Participants | Progression mWHO | 14 participants |
| Ipilimumab (Process B) | Best Overall Tumor Response Per Investigator Based on Modified World Health Organization (mWHO) Criteria - All Randomized Participants | Complete Response mWHO | 0 participants |
| Ipilimumab (Process B) | Best Overall Tumor Response Per Investigator Based on Modified World Health Organization (mWHO) Criteria - All Randomized Participants | Partial Response mWHO | 4 participants |
| Ipilimumab (Process C) | Best Overall Tumor Response Per Investigator Based on Modified World Health Organization (mWHO) Criteria - All Randomized Participants | Complete Response mWHO | 1 participants |
| Ipilimumab (Process C) | Best Overall Tumor Response Per Investigator Based on Modified World Health Organization (mWHO) Criteria - All Randomized Participants | Stable Disease mWHO | 7 participants |
| Ipilimumab (Process C) | Best Overall Tumor Response Per Investigator Based on Modified World Health Organization (mWHO) Criteria - All Randomized Participants | Partial Response mWHO | 10 participants |
| Ipilimumab (Process C) | Best Overall Tumor Response Per Investigator Based on Modified World Health Organization (mWHO) Criteria - All Randomized Participants | Progression mWHO | 17 participants |
| Ipilimumab (Process C) | Best Overall Tumor Response Per Investigator Based on Modified World Health Organization (mWHO) Criteria - All Randomized Participants | Unable to determine mWHO | 2 participants |
Secondary
Clearance (CLT) of Ipilimumab Manufactured by Process C Relative to the CLT of Ipilimumab Manufactured by Process B - Evaluable Pharmacokinetic Population
The single-dose Pharmacokinetic parameters of ipilimumab were derived from serum concentration versus time data. CLT was measured from first dose to end of the induction period (4 doses) in milliliters per hour (mL/h). Samples were obtained at 0 hour (predose) on Days 1, 2, 3, 4, and Weeks 2, 3, 4, 7, and 10; Day 1, samples were also obtained 1 h 30 minutes (min), 2 h, 2 h 30 min, 3 h 30 min, 4 h 30 min, and 6 h post dose. In calculating PK parameters, predose concentrations and concentrations prior to first quantifiable concentration below the lower limit of quantitation (LLOQ) were treated as missing for the calculation of summary statistics. Drug was quantitatively determined in serum by an enzyme-linked immunosorbent assay (ELISA). Individual PK parameter values were derived by non-compartmental methods using a validated PK analysis program (Kinetica™ 4.4.1 within eToolbox \[version 2.6.1\]).
Time frame: Day 1 to Day 84
Population: PK evaluable Population: All participants who received at least one dose of drug and had adequate PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Ipilimumab (Process B) | Clearance (CLT) of Ipilimumab Manufactured by Process C Relative to the CLT of Ipilimumab Manufactured by Process B - Evaluable Pharmacokinetic Population | 12.590 mL/h | Geometric Coefficient of Variation 45 |
| Ipilimumab (Process C) | Clearance (CLT) of Ipilimumab Manufactured by Process C Relative to the CLT of Ipilimumab Manufactured by Process B - Evaluable Pharmacokinetic Population | 12.934 mL/h | Geometric Coefficient of Variation 53 |
Secondary
Mean Change From Baseline in Sitting Pulse Rate - All Treated Participants up to Data Cutoff
Pulse Rate was measured in beats per minute (bpm) and was obtained after the participant had been seated for 5 minutes. Vital sign measurements were collected at Screening (baseline), Weeks 1, 4, 7, 10, 12, 24 and every 12 weeks thereafter in the Maintenance Phase, and at the End of Treatment visit. The change from baseline in blood pressure one hour post end of infusion at the end of induction Period, Week 36 of Maintenance Period, and end of treatment, up to data cutoff for July 2010 are presented below.
Time frame: Screening to data cut off for July 2010, approximately 36 Weeks
Population: All participants who received at least 1 dose of ipilimumab and had available data at baseline and the specific timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ipilimumab (Process B) | Mean Change From Baseline in Sitting Pulse Rate - All Treated Participants up to Data Cutoff | Pulse Rate at End of Induction (N=10, 24) | -4.3 bpm | Standard Deviation 11.1 |
| Ipilimumab (Process B) | Mean Change From Baseline in Sitting Pulse Rate - All Treated Participants up to Data Cutoff | Pulse Rate at Week 36 (N=7,7)) | -7.7 bpm | Standard Deviation 15.3 |
| Ipilimumab (Process B) | Mean Change From Baseline in Sitting Pulse Rate - All Treated Participants up to Data Cutoff | Pulse Rate at end of treatment (N=6,7) | 25.5 bpm | Standard Deviation 15.8 |
| Ipilimumab (Process C) | Mean Change From Baseline in Sitting Pulse Rate - All Treated Participants up to Data Cutoff | Pulse Rate at End of Induction (N=10, 24) | -3.3 bpm | Standard Deviation 11.1 |
| Ipilimumab (Process C) | Mean Change From Baseline in Sitting Pulse Rate - All Treated Participants up to Data Cutoff | Pulse Rate at Week 36 (N=7,7)) | -7.1 bpm | Standard Deviation 8.8 |
| Ipilimumab (Process C) | Mean Change From Baseline in Sitting Pulse Rate - All Treated Participants up to Data Cutoff | Pulse Rate at end of treatment (N=6,7) | 12.3 bpm | Standard Deviation 10.5 |
Secondary
Mean Change From Baseline in Sitting Systolic and Diastolic Blood Pressure - All Treated Participants up to Data Cutoff
Systolic and Diastolic blood pressure were measured in millimeters of mercury (mmHg) and were obtained after the participant had been seated for 5 minutes. Vital sign measurements were collected at Screening (baseline), Weeks 1, 4, 7, 10, 12, 24 and every 12 weeks thereafter in the Maintenance Phase, and at the End of Treatment visit. The change from baseline in blood pressure one hour post end of infusion at the end of induction Period, Week 36 of Maintenance Period, and end of treatment, up to data cutoff for July 2010 are presented below.
Time frame: Screening to data cut off for July 2010, approximately 36 Weeks
Population: All participants who received at least 1 dose of ipilimumab and had available data at baseline and the specific timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ipilimumab (Process B) | Mean Change From Baseline in Sitting Systolic and Diastolic Blood Pressure - All Treated Participants up to Data Cutoff | Diastolic at End of Induction (N=10, 12) | -1.6 mmHg | Standard Deviation 10.1 |
| Ipilimumab (Process B) | Mean Change From Baseline in Sitting Systolic and Diastolic Blood Pressure - All Treated Participants up to Data Cutoff | Diastolic at Week 36 of Maintenance (N=7, 7) | -7.0 mmHg | Standard Deviation 14.1 |
| Ipilimumab (Process B) | Mean Change From Baseline in Sitting Systolic and Diastolic Blood Pressure - All Treated Participants up to Data Cutoff | Diastolic at End of Treatment (N=6,7) | 7.5 mmHg | Standard Deviation 7.1 |
| Ipilimumab (Process B) | Mean Change From Baseline in Sitting Systolic and Diastolic Blood Pressure - All Treated Participants up to Data Cutoff | Systolic at End of Induction (N=10, 12) | -4.1 mmHg | Standard Deviation 19.6 |
| Ipilimumab (Process B) | Mean Change From Baseline in Sitting Systolic and Diastolic Blood Pressure - All Treated Participants up to Data Cutoff | Systolic at Week 36 of Maintenance (N=7, 7) | -5.7 mmHg | Standard Deviation 31.5 |
| Ipilimumab (Process B) | Mean Change From Baseline in Sitting Systolic and Diastolic Blood Pressure - All Treated Participants up to Data Cutoff | Systolic at End of Treatment (N=6,7) | 11.5 mmHg | Standard Deviation 13.3 |
| Ipilimumab (Process C) | Mean Change From Baseline in Sitting Systolic and Diastolic Blood Pressure - All Treated Participants up to Data Cutoff | Systolic at Week 36 of Maintenance (N=7, 7) | -8.3 mmHg | Standard Deviation 18.3 |
| Ipilimumab (Process C) | Mean Change From Baseline in Sitting Systolic and Diastolic Blood Pressure - All Treated Participants up to Data Cutoff | Diastolic at End of Induction (N=10, 12) | -1.4 mmHg | Standard Deviation 9.7 |
| Ipilimumab (Process C) | Mean Change From Baseline in Sitting Systolic and Diastolic Blood Pressure - All Treated Participants up to Data Cutoff | Systolic at End of Induction (N=10, 12) | -8.6 mmHg | Standard Deviation 21 |
| Ipilimumab (Process C) | Mean Change From Baseline in Sitting Systolic and Diastolic Blood Pressure - All Treated Participants up to Data Cutoff | Diastolic at Week 36 of Maintenance (N=7, 7) | -5.6 mmHg | Standard Deviation 6.8 |
| Ipilimumab (Process C) | Mean Change From Baseline in Sitting Systolic and Diastolic Blood Pressure - All Treated Participants up to Data Cutoff | Systolic at End of Treatment (N=6,7) | -2.1 mmHg | Standard Deviation 14.7 |
| Ipilimumab (Process C) | Mean Change From Baseline in Sitting Systolic and Diastolic Blood Pressure - All Treated Participants up to Data Cutoff | Diastolic at End of Treatment (N=6,7) | 2.3 mmHg | Standard Deviation 12.4 |
Secondary
Median Overall Survival Following First Ipilimumab Dose - All Treated Participants
Overall survival (OS) was defined as the time between the first dose of study treatment and death and was analyzed using Kaplan-Meier methods, with participants who had not died censored at the last date known to be alive. Overall survival was measured in months.
Time frame: Week 1 (first dose) to last patient, last visit, approximately 3 years
Population: All participants who received at least one dose of ipilimumab.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ipilimumab (Process B) | Median Overall Survival Following First Ipilimumab Dose - All Treated Participants | 20.58 months |
| Ipilimumab (Process C) | Median Overall Survival Following First Ipilimumab Dose - All Treated Participants | 24.79 months |
Secondary
Model Estimates of Mean Absolute Lymphocyte Count at Each Nominal Ipilimumab Induction Dose and at End of the Induction Dosing Period
Absolute lymphocyte counts (ALC) were obtained throughout the study as part of the hematology panel. Results collected from 28 days prior to the first infusion of ipilimumab through the end of the Induction-Dosing Period were included in the analyses of ALC. Mean ALC was estimated via an extended linear model, with linear splines and a spatial exponential within-patient correlation structure. Lymphocytes were measured as 1000 cells per micro liter (c/µL).
Time frame: Day 0 (prior to first dose) to Day 84
Population: All participants in the Pharmacodynamic data set with: (1) a baseline ALC evaluation; and (2) at least 1 post-baseline ALC evaluation (after the date of first dose).
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Ipilimumab (Process B) | Model Estimates of Mean Absolute Lymphocyte Count at Each Nominal Ipilimumab Induction Dose and at End of the Induction Dosing Period | 0 days since first dose | 1.26 1000 c/µL |
| Ipilimumab (Process B) | Model Estimates of Mean Absolute Lymphocyte Count at Each Nominal Ipilimumab Induction Dose and at End of the Induction Dosing Period | 21 days since first dose | 1.67 1000 c/µL |
| Ipilimumab (Process B) | Model Estimates of Mean Absolute Lymphocyte Count at Each Nominal Ipilimumab Induction Dose and at End of the Induction Dosing Period | 42 days since first dose | 1.79 1000 c/µL |
| Ipilimumab (Process B) | Model Estimates of Mean Absolute Lymphocyte Count at Each Nominal Ipilimumab Induction Dose and at End of the Induction Dosing Period | 84 days since first dose | 1.89 1000 c/µL |
| Ipilimumab (Process B) | Model Estimates of Mean Absolute Lymphocyte Count at Each Nominal Ipilimumab Induction Dose and at End of the Induction Dosing Period | 63 days since first dose | 2.07 1000 c/µL |
| Ipilimumab (Process C) | Model Estimates of Mean Absolute Lymphocyte Count at Each Nominal Ipilimumab Induction Dose and at End of the Induction Dosing Period | 42 days since first dose | 1.86 1000 c/µL |
| Ipilimumab (Process C) | Model Estimates of Mean Absolute Lymphocyte Count at Each Nominal Ipilimumab Induction Dose and at End of the Induction Dosing Period | 0 days since first dose | 1.18 1000 c/µL |
| Ipilimumab (Process C) | Model Estimates of Mean Absolute Lymphocyte Count at Each Nominal Ipilimumab Induction Dose and at End of the Induction Dosing Period | 63 days since first dose | 1.94 1000 c/µL |
| Ipilimumab (Process C) | Model Estimates of Mean Absolute Lymphocyte Count at Each Nominal Ipilimumab Induction Dose and at End of the Induction Dosing Period | 21 days since first dose | 1.74 1000 c/µL |
| Ipilimumab (Process C) | Model Estimates of Mean Absolute Lymphocyte Count at Each Nominal Ipilimumab Induction Dose and at End of the Induction Dosing Period | 84 days since first dose | 2.01 1000 c/µL |
Comparison: Time-by-process interaction. Null hypothesis that the pattern of mean ALC values over time is the same for both processes.p-value: 0.85F-test
Comparison: Overall time effect. Null hypothesis of no mean ALC changes over time in either process group (treatment arm).p-value: <0.0001F-test
Secondary
Number of Participants Who Developed Antibodies and Neutralizing Antibodies
Electrochemiluminescent (ECL) Immunoassay was used to detect human anti-human ipilimumab antibodies (HAHA) in serum. Blood samples were collected prior to the start of each ipilimumab infusion at Weeks 1, 4, 7, 10, 24, and at end of treatment. Those participants who were positive HAHA on treatment were then tested for presence of neutralizing antibodies.
Time frame: Prior to start of drug Week 1 to Week 24 on treatment or end of treatment
Population: Participants who received study drug and had HAHA data prior to infusion in Week 1 and while on treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ipilimumab (Process B) | Number of Participants Who Developed Antibodies and Neutralizing Antibodies | Positive HAHA on treatment | 0 participants |
| Ipilimumab (Process B) | Number of Participants Who Developed Antibodies and Neutralizing Antibodies | Neutralizing antibodies present | 0 participants |
| Ipilimumab (Process C) | Number of Participants Who Developed Antibodies and Neutralizing Antibodies | Positive HAHA on treatment | 2 participants |
| Ipilimumab (Process C) | Number of Participants Who Developed Antibodies and Neutralizing Antibodies | Neutralizing antibodies present | 0 participants |
Secondary
Number of Participants With 2-Grade or Greater Shift From Baseline (Worsening) in Chemistry Laboratory Safety Tests (Non-electrolyte) - All Treated Participants
Alanine transaminase (ALT); Aspartate aminotransferase (AST); Alkaline phosphatase (ALP); upper limits of normal (ULN). ALT Gr 1:\>1.0 to 2.5\*ULN; Gr 2: \>2.5 to 5.0\*ULN; Gr 3: \>5.0 to 20.0\*ULN; Gr 4: \>20.0\*ULN. AST Gr 1: \>1.0 to 2.5\*ULN; Gr 2: \>2.5 to 5.0\*ULN; Gr 3: \>5.0 to 20.0\*ULN; Gr 4: \>20.0\*ULN. Total bilirubin Gr 1: \>1.0 to 1.5\*ULN; Gr 2: \>1.5 to 3.0\*ULN; Gr 3: \>3.0 to 10..0\*ULN; Gr 4: \>10.0.0\*ULN. ALP (U/L) Gr1:\>1.0 to 2.5\*ULN, Gr2:\>2.5 to 5.0\*ULN, Gr3:\>5.0 to 20.0\*ULN, Gr4:\>20.0\*ULN. Albumin (low) Gr 1:\<LLN to 3 g/dL; Gr 2: \<3.0 - 2.0 g/L; Gr 3: \< 2 g/dL. Creatinine Gr 1: \>1 - 1.5\*ULN; Gr 2: \>1.5 - 3.0\*ULN; Gr 3: \>3.0- 6.0\*ULN; Gr 4: \>6.0\*ULN. Lipase (U/L) Gr 1: 1.0 to 1.5\*ULN; Gr 2: \>1.5 to 2.0\*ULN; Gr 3: 2.0 to 5; Gr 4: \>5\*ULN. Amylase (U/L) Gr 1: \>ULN to 1.5\*ULN; Grade 2 \>1.5 to 2.0\*ULN, Grade 3 \>2.0 to 5.0\*ULN, Grade 4 \>5.0\*ULN. Baseline was screening or Day 1, prior to first dose of drug.
Time frame: Screening to data cut off for July 2010, approximately 36 Weeks
Population: All participants who received at least 1 dose of ipilimumab and had available data at baseline and post baseline.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ipilimumab (Process B) | Number of Participants With 2-Grade or Greater Shift From Baseline (Worsening) in Chemistry Laboratory Safety Tests (Non-electrolyte) - All Treated Participants | ALT (N=36, 37) | 2 participants |
| Ipilimumab (Process B) | Number of Participants With 2-Grade or Greater Shift From Baseline (Worsening) in Chemistry Laboratory Safety Tests (Non-electrolyte) - All Treated Participants | AST (N=36, 37) | 2 participants |
| Ipilimumab (Process B) | Number of Participants With 2-Grade or Greater Shift From Baseline (Worsening) in Chemistry Laboratory Safety Tests (Non-electrolyte) - All Treated Participants | Alkaline Phosphatase (N=36, 37) | 2 participants |
| Ipilimumab (Process B) | Number of Participants With 2-Grade or Greater Shift From Baseline (Worsening) in Chemistry Laboratory Safety Tests (Non-electrolyte) - All Treated Participants | Amylase (N=35, 35) | 0 participants |
| Ipilimumab (Process B) | Number of Participants With 2-Grade or Greater Shift From Baseline (Worsening) in Chemistry Laboratory Safety Tests (Non-electrolyte) - All Treated Participants | Lipase (N=10, 14) | 0 participants |
| Ipilimumab (Process B) | Number of Participants With 2-Grade or Greater Shift From Baseline (Worsening) in Chemistry Laboratory Safety Tests (Non-electrolyte) - All Treated Participants | Albumin (N=36, 37) | 7 participants |
| Ipilimumab (Process B) | Number of Participants With 2-Grade or Greater Shift From Baseline (Worsening) in Chemistry Laboratory Safety Tests (Non-electrolyte) - All Treated Participants | Creatinine (N= 37, 37) | 2 participants |
| Ipilimumab (Process B) | Number of Participants With 2-Grade or Greater Shift From Baseline (Worsening) in Chemistry Laboratory Safety Tests (Non-electrolyte) - All Treated Participants | Bilirubin (N=36, 37) | 2 participants |
| Ipilimumab (Process C) | Number of Participants With 2-Grade or Greater Shift From Baseline (Worsening) in Chemistry Laboratory Safety Tests (Non-electrolyte) - All Treated Participants | Bilirubin (N=36, 37) | 0 participants |
| Ipilimumab (Process C) | Number of Participants With 2-Grade or Greater Shift From Baseline (Worsening) in Chemistry Laboratory Safety Tests (Non-electrolyte) - All Treated Participants | ALT (N=36, 37) | 1 participants |
| Ipilimumab (Process C) | Number of Participants With 2-Grade or Greater Shift From Baseline (Worsening) in Chemistry Laboratory Safety Tests (Non-electrolyte) - All Treated Participants | Lipase (N=10, 14) | 1 participants |
| Ipilimumab (Process C) | Number of Participants With 2-Grade or Greater Shift From Baseline (Worsening) in Chemistry Laboratory Safety Tests (Non-electrolyte) - All Treated Participants | AST (N=36, 37) | 1 participants |
| Ipilimumab (Process C) | Number of Participants With 2-Grade or Greater Shift From Baseline (Worsening) in Chemistry Laboratory Safety Tests (Non-electrolyte) - All Treated Participants | Creatinine (N= 37, 37) | 1 participants |
| Ipilimumab (Process C) | Number of Participants With 2-Grade or Greater Shift From Baseline (Worsening) in Chemistry Laboratory Safety Tests (Non-electrolyte) - All Treated Participants | Alkaline Phosphatase (N=36, 37) | 1 participants |
| Ipilimumab (Process C) | Number of Participants With 2-Grade or Greater Shift From Baseline (Worsening) in Chemistry Laboratory Safety Tests (Non-electrolyte) - All Treated Participants | Albumin (N=36, 37) | 8 participants |
| Ipilimumab (Process C) | Number of Participants With 2-Grade or Greater Shift From Baseline (Worsening) in Chemistry Laboratory Safety Tests (Non-electrolyte) - All Treated Participants | Amylase (N=35, 35) | 2 participants |
Secondary
Number of Participants With 2-Grade or Greater Shift From Baseline (Worsening) in Electrolyte Laboratory Safety Tests - All Treated Participants
Sodium high (H) Gr 1:\>ULN - 150; Gr 2: \>150 - 155; Gr 3: \>155 - 160; Gr 4: \>160 mmol/L; Sodium low(L) Gr 1:\<LLN - 130; Gr 3: \<130 - 120; Gr 4: \<120 mmol/L. Potassium (H) Gr 1: \>ULN - 5.5; Gr 2: \>5.5 - 6.0; Gr 3: \> 6.0 - 7.0; Gr 4: \>7.0 mmol/L; Potassium (L) Gr 1: \<LLN - 3.0; Gr 2: \<LLN - 3.0; Gr 3: \< 3.0 - 2.5; Gr 4: \<2.5 mmol/L. Bicarbonate Gr1: 16-\<LLN, Gr2: 11-16, Gr3, 8-11, Gr4: \<8 milliequivalents per liter (mEq/L). Phosphorus Gr 1: 2.5 - \<LLN, Gr2 2.0-\<2.5, Gr3: 1.0-\<2.0, Gr4: \<1.0. Calcium (L) Gr 1: \<LLN to 8.0; Gr2: 7.0 - 8.0; Gr3: 6.0-7.0; Gr 4: \<6.0 mg/dL; calcium (H) Gr1:\>ULN - 11.5, Gr2:\>11.5 - 12.5, Gr3: 12.5 - 13.5, Gr4: \>13.5. Baseline is screening or Day 1, prior to first dose of drug.
Time frame: Screening to data cut off for July 2010, approximately 36 Weeks
Population: All participants who received at least 1 dose of ipilimumab and had available data at baseline and post baseline.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ipilimumab (Process B) | Number of Participants With 2-Grade or Greater Shift From Baseline (Worsening) in Electrolyte Laboratory Safety Tests - All Treated Participants | Calcium (low) (N=37, 37) | 1 participants |
| Ipilimumab (Process B) | Number of Participants With 2-Grade or Greater Shift From Baseline (Worsening) in Electrolyte Laboratory Safety Tests - All Treated Participants | Bicarbonate (N=37, 37) | 0 participants |
| Ipilimumab (Process B) | Number of Participants With 2-Grade or Greater Shift From Baseline (Worsening) in Electrolyte Laboratory Safety Tests - All Treated Participants | Potassium (high) (N=36, 37) | 0 participants |
| Ipilimumab (Process B) | Number of Participants With 2-Grade or Greater Shift From Baseline (Worsening) in Electrolyte Laboratory Safety Tests - All Treated Participants | Sodium (low) (N=37, 37) | 4 participants |
| Ipilimumab (Process B) | Number of Participants With 2-Grade or Greater Shift From Baseline (Worsening) in Electrolyte Laboratory Safety Tests - All Treated Participants | Inorganic Phosphorus (N=37,37) | 9 participants |
| Ipilimumab (Process B) | Number of Participants With 2-Grade or Greater Shift From Baseline (Worsening) in Electrolyte Laboratory Safety Tests - All Treated Participants | Potassium (low) (N=36, 37) | 1 participants |
| Ipilimumab (Process C) | Number of Participants With 2-Grade or Greater Shift From Baseline (Worsening) in Electrolyte Laboratory Safety Tests - All Treated Participants | Inorganic Phosphorus (N=37,37) | 7 participants |
| Ipilimumab (Process C) | Number of Participants With 2-Grade or Greater Shift From Baseline (Worsening) in Electrolyte Laboratory Safety Tests - All Treated Participants | Potassium (high) (N=36, 37) | 1 participants |
| Ipilimumab (Process C) | Number of Participants With 2-Grade or Greater Shift From Baseline (Worsening) in Electrolyte Laboratory Safety Tests - All Treated Participants | Calcium (low) (N=37, 37) | 7 participants |
| Ipilimumab (Process C) | Number of Participants With 2-Grade or Greater Shift From Baseline (Worsening) in Electrolyte Laboratory Safety Tests - All Treated Participants | Potassium (low) (N=36, 37) | 2 participants |
| Ipilimumab (Process C) | Number of Participants With 2-Grade or Greater Shift From Baseline (Worsening) in Electrolyte Laboratory Safety Tests - All Treated Participants | Bicarbonate (N=37, 37) | 1 participants |
| Ipilimumab (Process C) | Number of Participants With 2-Grade or Greater Shift From Baseline (Worsening) in Electrolyte Laboratory Safety Tests - All Treated Participants | Sodium (low) (N=37, 37) | 6 participants |
Secondary
Number of Participants With 2-Grade or Greater Shift From Baseline (Worsening) in Hematology Laboratory Safety Tests - All Treated Participants
Common Terminology Criteria (CTC), Version 3 used to assess parameters. Lower limit of normal (LLN); grams per deciliter (g/dL); Grade (GR); cells per microliter (c/µL). Hemoglobin Gr 1:\<LLN to 10.0 g/dL, Gr 2:\<10.0 to 8.0 g/dL, Gr 3:\<8.0 to 6.5 g/dL, Gr 4:\<6.5 g/dL. Absolute neutrophil (ANC) and ANC plus bands: Gr 1:\<LLN to 1.5\*10\^3 c/µL, Gr 2:\<1.5 to 1.0\*10\^3 c/µL, Gr 3:\<1.0 to 0.5\*10\^3 c/µL, Gr 4:\<0.5\*10\^3 c/µL. Platelet count Gr 1:LLN to 75.0\*10\^9 c/L, Gr 2:\<75.0 to 50.0\*10\^9 c/L, Gr 3:\<50.0 to 25.0\*10\^9 c/L, Gr 4:\<25.0 to 10\^9 c/L. Lymphocytes Gr 1: \<1.5 to 0.8 \*10\^3 c/µL, Gr 2 \<0.8 to 0.5 \*10\^3 c/µL, Gr 3: \<0.5 to 0.2 \*10\^3 c/µL, Gr 4: \<0.2\*10\^3 c/µL. Leukocytes Gr 1:\<LLN to 3.0 \*10\^3 c/µL, Gr 2; \<3.0 to 2.0 \*10\^3 c/µL, Gr 3: \<2.0 to 1.0 \*10\^3 c/µL, Gr 4: \<1.0 \*10\^3 c/µL. Baseline is screening or Day 1, prior to dosing.
Time frame: Screening to data cut off for July 2010, approximately 36 Weeks
Population: All participants who received at least 1 dose of ipilimumab and had available data at baseline and post baseline.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ipilimumab (Process B) | Number of Participants With 2-Grade or Greater Shift From Baseline (Worsening) in Hematology Laboratory Safety Tests - All Treated Participants | Hemoglobin (N=37, 38) | 2 participants |
| Ipilimumab (Process B) | Number of Participants With 2-Grade or Greater Shift From Baseline (Worsening) in Hematology Laboratory Safety Tests - All Treated Participants | Lymphocytes (N=37, 38) | 3 participants |
| Ipilimumab (Process B) | Number of Participants With 2-Grade or Greater Shift From Baseline (Worsening) in Hematology Laboratory Safety Tests - All Treated Participants | Neutrophils, Absolute (N=31, 36) | 0 participants |
| Ipilimumab (Process B) | Number of Participants With 2-Grade or Greater Shift From Baseline (Worsening) in Hematology Laboratory Safety Tests - All Treated Participants | Neutrophils + bands, Absolute (N=31, 36) | 0 participants |
| Ipilimumab (Process B) | Number of Participants With 2-Grade or Greater Shift From Baseline (Worsening) in Hematology Laboratory Safety Tests - All Treated Participants | Platelet Count (N=37, 38) | 0 participants |
| Ipilimumab (Process C) | Number of Participants With 2-Grade or Greater Shift From Baseline (Worsening) in Hematology Laboratory Safety Tests - All Treated Participants | Platelet Count (N=37, 38) | 1 participants |
| Ipilimumab (Process C) | Number of Participants With 2-Grade or Greater Shift From Baseline (Worsening) in Hematology Laboratory Safety Tests - All Treated Participants | Hemoglobin (N=37, 38) | 3 participants |
| Ipilimumab (Process C) | Number of Participants With 2-Grade or Greater Shift From Baseline (Worsening) in Hematology Laboratory Safety Tests - All Treated Participants | Neutrophils + bands, Absolute (N=31, 36) | 1 participants |
| Ipilimumab (Process C) | Number of Participants With 2-Grade or Greater Shift From Baseline (Worsening) in Hematology Laboratory Safety Tests - All Treated Participants | Lymphocytes (N=37, 38) | 3 participants |
| Ipilimumab (Process C) | Number of Participants With 2-Grade or Greater Shift From Baseline (Worsening) in Hematology Laboratory Safety Tests - All Treated Participants | Neutrophils, Absolute (N=31, 36) | 2 participants |
Secondary
Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and AEs Leading to Discontinuation
Adverse events (AEs) and Serious AEs (SAEs) were graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse events version 3.0. Medical Dictionary for Regulatory Activities (MedDRA) version 15.1 was used. Note there is a difference in number of participants with an SAE in this outcome measure and the number listed in the Adverse Events Section of this document. This is because the SAEs reported in the xml upload of the Adverse Events section includes additional participants who reported SAEs after the clinical study report database was closed.
Time frame: Day 1 to last patient, last visit, approximately 3 years
Population: All participants who received at least 1 dose of ipilimumab.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ipilimumab (Process B) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and AEs Leading to Discontinuation | Participants with at least 1 treatment related AE | 33 participants |
| Ipilimumab (Process B) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and AEs Leading to Discontinuation | Participants with at least 1 SAE | 22 participants |
| Ipilimumab (Process B) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and AEs Leading to Discontinuation | Participants with at least 1 treatment related SAE | 10 participants |
| Ipilimumab (Process B) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and AEs Leading to Discontinuation | AE leading to discontinuation | 14 participants |
| Ipilimumab (Process B) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and AEs Leading to Discontinuation | Participants who died | 17 participants |
| Ipilimumab (Process B) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and AEs Leading to Discontinuation | Participants with at least 1 AE | 37 participants |
| Ipilimumab (Process C) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and AEs Leading to Discontinuation | Participants who died | 20 participants |
| Ipilimumab (Process C) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and AEs Leading to Discontinuation | Participants with at least 1 treatment related AE | 36 participants |
| Ipilimumab (Process C) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and AEs Leading to Discontinuation | AE leading to discontinuation | 12 participants |
| Ipilimumab (Process C) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and AEs Leading to Discontinuation | Participants with at least 1 SAE | 24 participants |
| Ipilimumab (Process C) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and AEs Leading to Discontinuation | Participants with at least 1 AE | 38 participants |
| Ipilimumab (Process C) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and AEs Leading to Discontinuation | Participants with at least 1 treatment related SAE | 13 participants |
Secondary
Terminal Elimination Half Life (T-HALF) of Ipilimumab Manufactured by Process C Relative to the T-HALF of Ipilimumab Manufactured by Process B - Evaluable Pharmacokinetic Population
The single-dose Pharmacokinetic parameters of ipilimumab were derived from serum concentration versus time data. T-HALF was measured from first dose to end of the induction period (4 doses) in day(s). Samples were obtained at 0 hour (predose) on Days 1, 2, 3, 4, and Weeks 2, 3, 4, 7, and 10; Day 1, samples were also obtained 1 h 30 minutes (min), 2 h, 2 h 30 min, 3 h 30 min, 4 h 30 min, and 6 h post dose. In calculating PK parameters, predose concentrations and concentrations prior to first quantifiable concentration below the lower limit of quantitation (LLOQ) were treated as missing for the calculation of summary statistics. Drug was quantitatively determined in serum by an enzyme-linked immunosorbent assay (ELISA). Individual PK parameter values were derived by non-compartmental methods using a validated PK analysis program (Kinetica™ 4.4.1 within eToolbox \[version 2.6.1\]).
Time frame: Day 1 to Day 84
Population: PK evaluable Population: All participants who received at least one dose of drug and had adequate PK profiles.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ipilimumab (Process B) | Terminal Elimination Half Life (T-HALF) of Ipilimumab Manufactured by Process C Relative to the T-HALF of Ipilimumab Manufactured by Process B - Evaluable Pharmacokinetic Population | 15.45 days | Standard Deviation 6.93 |
| Ipilimumab (Process C) | Terminal Elimination Half Life (T-HALF) of Ipilimumab Manufactured by Process C Relative to the T-HALF of Ipilimumab Manufactured by Process B - Evaluable Pharmacokinetic Population | 15.23 days | Standard Deviation 8.73 |
Secondary
Time of Maximum Observed Serum Concentration (Tmax) of Ipilimumab Manufactured by Process C Relative to the Tmax of Ipilimumab Manufactured by Process B - Evaluable Pharmacokinetic Population
The single-dose Pharmacokinetic parameters of ipilimumab were derived from serum concentration versus time data. Tmax was measured from first dose to end of the induction period (4 doses) in hours (h). Samples were obtained at 0 h (predose) on Days 1, 2, 3, 4, and Weeks 2, 3, 4, 7, and 10; Day 1, samples were also obtained 1 h 30 minutes (min), 2 h, 2 h 30 min, 3 h 30 min, 4 h 30 min, and 6 h post dose. In calculating PK parameters, predose concentrations and concentrations prior to first quantifiable concentration below the lower limit of quantitation (LLOQ) were treated as missing for the calculation of summary statistics. Drug was quantitatively determined in serum by an enzyme-linked immunosorbent assay (ELISA). Individual PK parameter values were derived by non-compartmental methods using a validated PK analysis program (Kinetica™ 4.4.1 within eToolbox \[version 2.6.1\]).
Time frame: Day 1 to Day 84
Population: PK evaluable Population: All participants who received at least one dose of drug and had adequate PK profiles.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ipilimumab (Process B) | Time of Maximum Observed Serum Concentration (Tmax) of Ipilimumab Manufactured by Process C Relative to the Tmax of Ipilimumab Manufactured by Process B - Evaluable Pharmacokinetic Population | 2.00 h |
| Ipilimumab (Process C) | Time of Maximum Observed Serum Concentration (Tmax) of Ipilimumab Manufactured by Process C Relative to the Tmax of Ipilimumab Manufactured by Process B - Evaluable Pharmacokinetic Population | 2.50 h |
Secondary
Volume of Distribution at Steady State (Vss) of Ipilimumab Manufactured by Process C Relative to the Vss of Ipilimumab Manufactured by Process B - Evaluable Pharmacokinetic Population
The single-dose Pharmacokinetic parameters of ipilimumab were derived from serum concentration versus time data. Vss was measured from first dose to end of the induction period (4 doses) in liter(s) (L). Samples were obtained at 0 hour (predose) on Days 1, 2, 3, 4, and Weeks 2, 3, 4, 7, and 10; Day 1, samples were also obtained 1 h 30 minutes (min), 2 h, 2 h 30 min, 3 h 30 min, 4 h 30 min, and 6 h post dose. In calculating PK parameters, predose concentrations and concentrations prior to first quantifiable concentration below the lower limit of quantitation (LLOQ) were treated as missing for the calculation of summary statistics. Drug was quantitatively determined in serum by an enzyme-linked immunosorbent assay (ELISA). Individual PK parameter values were derived by non-compartmental methods using a validated PK analysis program (Kinetica™ 4.4.1 within eToolbox \[version 2.6.1\]).
Time frame: Day 1 to Day 84
Population: PK evaluable Population: All participants who received at least one dose of drug and had adequate PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Ipilimumab (Process B) | Volume of Distribution at Steady State (Vss) of Ipilimumab Manufactured by Process C Relative to the Vss of Ipilimumab Manufactured by Process B - Evaluable Pharmacokinetic Population | 6.06 L | Geometric Coefficient of Variation 21 |
| Ipilimumab (Process C) | Volume of Distribution at Steady State (Vss) of Ipilimumab Manufactured by Process C Relative to the Vss of Ipilimumab Manufactured by Process B - Evaluable Pharmacokinetic Population | 5.96 L | Geometric Coefficient of Variation 32 |