Study of MDX-010 in Patients With Metastatic Hormone-Refractory Prostate Cancer

AEs graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. 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. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4= Potentially Life-threatening or disabling, Gr 5=Death. Related=relationship to study drug reported as certain, probable, possible, or missing. Immune-related AE (irAE) was defined as a clinically significant AE of any organ that is associated with drug exposure, of unknown etiology, and is consistent with an immune-mediated mechanism. Day 1=first day of study treatment.

Response by investigator using National Cancer Institute (NCI) PSA Working Group recommendations= PSA < 50% of PSA reference value occurring on or before Day 85; response confirmed at least 4 weeks after the first measurement. PSA reference=PSA measured immediately prior to treatment. Complete response (CR)=PSA < 2 nanograms per milliliter (ng/mL), confirmed at least 4 weeks after 1st value; Partial response (PR)=PSA ≤ 50% of PSA reference, confirmed at least 4 weeks after 1st value; Unconfirmed=not confirmed by repeat measurements; Stable disease(SD)=No change from PSA reference; Progressive disease (PD) defined: If PSA nadir was ≥ 100% of the reference: PSA ≥ 125% of PSA reference and with a difference of absolute value of ≥ 5 ng/mL; If PSA nadir was < 100% and ≥ 50% of the reference: PSA ≥ 125% of PSA nadir and with a difference of absolute value of ≥ 5 ng/mL: If PSA nadir was < 50% of the reference: PSA ≥ 150% of PSA nadir and with a difference of absolute value of ≥ 5 ng/mL.

Best Overall PSA response per investigator, using NCI PSA Working Group: PSA with CR or PR at any time after treatment initiation and was confirmed at least 4 weeks after the first measurement. PSA reference=PSA measured immediately prior to treatment. CR=PSA concentration < 2 nanograms per milliliter (ng/mL), confirmed at least 4 weeks after 1st value; PR=PSA concentration ≤ 50% of PSA reference, confirmed at least 4 weeks after 1st value; Unconfirmed=not confirmed by repeat measurements; SD=No change from PSA reference value; PD = If PSA nadir was ≥ 100% of the reference value: PSA ≥ 125% of PSA reference and with a difference of absolute value of ≥ 5 ng/mL; If PSA nadir was < 100% and ≥ 50% of the reference value: PSA ≥ 125% of PSA nadir and with a difference of absolute value of ≥ 5 ng/mL: If PSA nadir was < 50% of the reference value: PSA ≥ 150% of PSA nadir and with a difference of absolute value of ≥ 5 ng/mL.

For those with measurable disease, tumor response based upon tumor lesions (per investigator) using Response Evaluation Criteria in Solid Tumors (RECIST). Best Overall=Participants with a best tumor response of CR or PR at anytime during the study. CR=Disappearance of all target lesions; PR=At least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference, baseline sum LD. For a status of CR or PR, changes in tumor measurements were confirmed by repeat studies no less than 4 weeks after the criteria for response were first met; Unconfirmed=not confirmed by repeat measurements; SD=Neither sufficient decrease to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum LD since the treatment started; PD=At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.

Time to PSA response was measured in months. Time to PSA response was analyzed in those participants with CR or PR at Day 85. CR=PSA concentration < 2 ng/mL, confirmed at least 4 weeks after 1st value; PR=PSA concentration ≤ 50% of PSA reference, confirmed at least 4 weeks after 1st value.

Tumor response rate was defined as the number of participants with a best response of partial or complete response divided by the total number of tumor evaluable participants. Overall Tumor Response was defined as participants with a tumor response of CR or PR at anytime during the study. CR=Disappearance of all target lesions; PR=At least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference, baseline sum LD. For a status of CR or PR, changes in tumor measurements were confirmed by repeat studies no less than 4 weeks after the criteria for response were first met

PSA response rate was defined as the number of participants with a PSA response (PR or CR) divided by the total number of PSA evaluable participants. PSA response at Day 85, as reported by the investigator, was defined as a PSA concentration < 50% of the PSA reference value occurring on or before Day 85 and this response was confirmed at least 4 weeks after the first determination. The PSA reference value was the PSA concentration measured immediately prior to treatment. Overall Response is < 50% of the PSA reference value occurring anytime after treatment was initiated and this response was confirmed at least 4 weeks after the first determination. Complete response=PSA concentration < 2 ng/mL, confirmed at least 4 weeks after first value; Partial response=PSA concentration ≤ 50% of PSA reference value, confirmed at least 4 weeks after first determination.

Primary analysis was conducted on data from Day 1 up to 2 years post treatment, data available as of September 2009. Final Follow-Up analysis was conducted on data up to 5 years post treatment, data available as of September 2013 (minimum time of eligibility 54 months to a maximum of 85 months). Primary causes of deaths are listed under each timepoint.

Overall Survival (OS) was defined as the time from the first date of study treatment until the date of death and was measured in months. For those participants who have not died, OS was censored at the last date the participant was known to be alive. Completion of follow-up for OS was a minimum time of eligibility 54 months to a maximum of 85 months.

NCI CTC version(v) 3.0 was used to determine Grade (Gr). Screening was Day -28 to Day -1. On-study laboratories were reported after the first dose date, every 21 days during a treatment cycle, and within 70 days of last dose of study therapy (ie, Days 1, 22, 43, 64, 85, etc). Hemoglobin grams per liter (g/L): 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. White blood cells(WBC) 10^9 cells per liter (c/L): Gr1: 3.0 - < LLN; Gr 2: 2.0 - < 3.0; Gr 3: 1.0 - < 2.0; Gr4: < 1.0. Lymphocytes (absolute) 10^9 c/L: Gr1: 0.8 - < 1.5; Gr 2: 0.5 - < 0.8; Gr 3): 0.2 - < 0.5; Gr 4: < 0.2. Neutrophils (absolute) 10^9 c/L: Gr 1: 1.5 - < 2.0; Gr 2: 1.0 - < 1.5; Gr 3: 0.5 - < 1.0; Gr 4: < 0.5. Platelets 10^9 c/L: 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.

CTC v3.0 used. On-study serum chemistry laboratories were reported after first dose date, every 21 days during a treatment cycle, and within 70 days of last dose of study therapy (ie, Days 1, 22, 43, 64, 85, etc). Alanine Aminotransferase (ALT) Units per Liter (U/L) 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. Aspartate Aminotransferase (AST) U/L: Gr 1: > 1.0 - 2.5 * ULN; Gr 2: > 2.5 - 5.0 * ULN; Gr 3: > 5.0 - 20.0 * ULN; Gr 4: > 20.0 * ULN. Total Bilirubin micromoles per liter (µmol/L): Gr 1: > 1.0 - 1.5 * ULN; Gr 2: > 1.5 - 3.0 * ULN; Gr 3: > 3.0 - 10.0 * ULN; Gr 4: > 10.0 * ULN. Alkaline Phosphatase U/L: Gr 1: > 1.0 - 2.5 * ULN; Gr 2: > 2.5 - 5.0 * ULN; Gr 3: > 5.0 - 20.0 * ULN; Gr 4: > 20.0 * ULN. Amylase U/L: Gr1: > 1.0 - 1.5 * ULN; Gr 2: > 1.5 - 2.0 * ULN; Gr 3: > 2.0 - 5.0 * ULN; Gr4: > 5.0 * ULN. Creatinine µmol/L: Gr1: > 1.0 - 1.5*ULN; Gr2: > 1.5 - 3.0*ULN; Gr3: > 3.0 - 6.0*ULN; Gr4: > 6.0*ULN.

12 Lead Electrocardiograms (ECGs) were performed at screening (Day -28 to Day -1), and on Day 85 during a treatment cycle, and at the end of treatment period. Clinically significant abnormalities could include atrial fibrillation, anterior fascicular block, marked sinus bradycardia, possible lateral infarct, and T-wave abnormality (other potential abnormalities were not excluded from consideration).

HAHA was measured by electrochemiluminescent (ECL) immunoassay for the detection of antibodies in human heparin plasma. Testing was performed on Days 1 (prior to ipilimumab infusion), 64, 85, and at completion of treatment.