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

Prostate Cancer Clinical Trial

Official title:

A Phase I/II, Open-label, Dose-escalation Study of MDX-010 Administered Every 3 Weeks for 4 Doses in Patients With Metastatic Hormone-Refractory Prostate Cancer

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00323882
• Other study ID #: CA184-017 ST
• Secondary ID: CA184-017
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: May 8, 2006
• Last updated: August 14, 2014
• Start date: January 2006
• Est. completion date: July 2013

Study information

• Verified date: August 2014
• Source: Bristol-Myers Squibb
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

Multicenter study in which patients with metastatic hormone refractory prostate cancer (HRPC), who have not had previous chemotherapy or immunotherapy treatments, received MDX-010 every 3 weeks for 4 doses (12 weeks total duration of induction). MDX-010 was administered at escalating dosage levels of 3, 5, and 10 mg/kg/dose infusions. At least 6 patients were to be enrolled in each dosage level. Patients who tolerated and responded to treatment or who had stable disease for 3 months or longer and who subsequently progressed during the follow up phase of the study had the option to receive additional treatment with MDX-010, up to 4 cycles. Patients were followed in the study for response up to 2 years and were followed for survival status for up to 5 years after enrollment.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 75
• Est. completion date: July 2013
• Est. primary completion date: September 2009
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Histologic diagnosis of adenocarcinoma of the prostate

• Metastatic prostate cancer (positive bone scan or measurable disease)

• Total testosterone of less than 50 ng/dL, except for patients with prior orchiectomy, where testosterone does not need to be measured.

• Patients who are receiving an antiandrogen as part of primary androgen ablation must demonstrate disease progression following discontinuation of antiandrogen and completion of a washout period and then observe disease progression.

• Patients must stop using any herbal product known to decrease PSA levels (eg., saw palmetto and PC-SPES) or any systemic or topical corticosteroid at least 4 weeks prior to screening. Progressive disease must be documented after discontinuation of these products.

• Progressive disease after androgen deprivation (or hormone therapy). For patients with measurable disease, progression will be defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. For patients with progression in, or without any measurable disease, a positive bone scan and elevated PSA will be required.

• Patients receiving bisphosphate therapy must have been on stable doses for at least 4 weeks with stable symptoms prior to enrollment.

• No prior chemotherapy or immunotherapy (tumor vaccine, cytokine, or growth factor given to control prostate cancer).

• Prior radiation therapy completed at least 4 weeks prior to enrollment. No prior radiopharmaceuticals (strontium, samarium) within 8 weeks prior to enrollment.

Exclusion Criteria:

• Bone pain due to metastatic bone disease severe enough to require routine narcotic analgesic use.

• History of severe hypersensitivity reactions to drugs formulated with polysorbate 80.

• Patients with active autoimmune disease or a history of autoimmune disease that required systemic steroids or immunosuppressive medications, except for patients with vitiligo.

• Prior therapy with any anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA-4) antibody.

• Active infection requiring therapy.

• Concurrent medical condition requiring the use of systemic or topical corticosteroids; systemic or topical corticosteroids must be discontinued at least 4 weeks prior to enrollment. The use of inhaled corticosteroids is acceptable.

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Neoplasm Metastasis
• Prostate Cancer
• Prostatic Neoplasms

Intervention

Drug:
• MDX-010
selected dose administered IV every 3 weeks

Locations

Country	Name	City	State
United States	Josephine Ford Cancer Center-Downriver	Brownstown	Michigan
United States	Henry Ford Medical Center-Fairlane	Dearborn	Michigan
United States	Henry Ford Hospital	Detroit	Michigan
United States	Carolina BioOncology Institute	Huntersville	North Carolina
United States	The Angeles Clinic and Research Institute	Los Angeles	California
United States	The Angeles Clinic and Research Institute	Los Angeles	California
United States	Yale University School of Medicine	New Haven	Connecticut
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	Oregon Health and Science University	Portland	Oregon
United States	UCSF Helen Diller Family Comprehensive Cancer Center	San Francisco	California
United States	Seattle Cancer Care Alliance	Seattle	Washington
United States	University of Washington Medical Center	Seattle	Washington
United States	Washington University School of Medicine	St. Louis	Missouri
United States	Henry Ford Medical Center-West Bloomfield	West Bloomfield	Michigan

Sponsors (1)

Lead Sponsor	Collaborator
Bristol-Myers Squibb

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Serious AEs (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Immune-related AEs - Treated Participants	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.	Day 1 to last day of study treatment (+70 days) up to 2 years	Yes
Primary	Number of Participants With Best PSA Response at Day 85 by Category - PSA Evaluable Participants	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.	Day 85	No
Secondary	Number of Participants With Best Overall PSA Response by Category - PSA Evaluable Participants	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.	Day 1 to last day of study treatment (+70 days) up to 2 years	No
Secondary	Number of Participants With Best Overall Tumor Response by Category - Tumor Evaluable Participants	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.	Day 1 to last day of study treatment (+70 days) up to 2 years	No
Secondary	Time to PSA Response at Day 85 in Participants With Complete Response (CR) or Confirmed Partial Response (PR) at Day 85	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.	Day 1 to Day 85	No
Secondary	Overall Tumor Response Rate in 10 mg/kg Ipilimumab Monotherapy and Ipilimumab/XRT Combination Therapy	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	Day 1 to last day of study treatment (+70 days) up to 2 years	No
Secondary	PSA Response Rate at Day 85 and Overall PSA Response Rate in 10 mg/kg Monotherapy and Combination Therapy	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.	Day 85, Day 1 to last day of study treatment (+70 days) up to 2 years	No
Secondary	Number of Participants Who Died by Date of Primary Analysis and by Date of Completion of Follow Up - All Treated Participants	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.	Day 1 to 5 years post treatment	Yes
Secondary	Overall Survival at Completion of Follow Up Period - Treated Participants	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.	Day 1 to 5 years post treatment	No
Secondary	Number of Participants With On-Study Hematology Laboratory Tests Worst Common Terminology Criteria (CTC) Grade - Treated Participants	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.	Day 1 to last day of study treatment (+70 days) up to 2 years	Yes
Secondary	Number of Participants With On-Study Serum Chemistry Laboratory Tests Worst Common Terminology Criteria (CTC) Grade - Treated Participants	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.	Day 1 to last day of study treatment (+70 days) up to 2 years	Yes
Secondary	Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities at Baseline and During Treatment Period - Treated Participants	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).	Baseline up to 2 years	Yes
Secondary	Number of Participants Positive for Human Anti-Human Antibodies (HAHA) - Treated Participants	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.	Day 1 up to 2 years	Yes

External Links

•   BMS Clinical Trials Disclosure
•   For FDA Safety Alerts and Recalls refer to the following link www.fda.gov/MEDWATCH/safety.htm