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A Study of MDX-1106 in Patients With Selected Refractory or Relapsed Malignancies (MDX1106-01)

Primary Purpose

Carcinoma, Non-Small-Cell Lung, Colorectal Cancer, Malignant Melanoma

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

MDX-1106

About this trial

This is an interventional treatment trial for Carcinoma, Non-Small-Cell Lung focused on measuring malignancies, cancer, non small cell lung cancer, lung cancer, colorectal cancer, adenocarcinoma, melanoma, malignant melanoma, renal cancer, renal carcinoma, carcinoma, prostate cancer, prostate adenocarcinoma, Recurrent or treatment refractory malignancies

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Relapsed/refractory non-small cell lung cancer, colorectal adenocarcinoma, malignant melanoma, renal (clear) cell carcinoma, or hormone-refractory prostate adenocarcinoma
Prior treatment must have been completed at least 4 weeks prior to enrollment
No untreated primary or metastatic brain or meningeal tumors
ECOG PS 0 or 1
Meet all screening laboratory values

Exclusion Criteria:

History of severe hypersensitivity reactions to other monoclonal antibodies
Active autoimmune disease or a documented history of autoimmune disease
Prior therapy with an anti-PD-1 or anti-CTLA-4 antibody
Active infection
Concurrent medical condition requiring the use of immunosuppressive medications

Sites / Locations

Johns Hopkins Unv., School of Medicine
Henry Ford Health System
Washington University School of Medicine - Barnes Jewish Hospital
Carolina BioOncology Institute, PLLC

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Arm Label

0.3 mg/kg MDX-1106 drug

1 mg/kg MDX-1106 drug

3 mg/kg MDX-1106 drug

10 mg/kg MDX-1106 drug

Arm Description

0.3 milligrams (mg) MDX-1106 drug (nivolumab) per kilogram (kg) of body weight (mg/kg) was administered in a single intravenous (IV) infusion. If criteria were met, 2 additional doses could be administered (1 every 4 weeks).

1 mg MDX-1106 drug (nivolumab) per kg of body weight (mg/kg) was administered in a single IV infusion. If criteria were met, 2 additional doses could be administered (1 every 4 weeks).

3 mgs MDX-1106 drug (nivolumab) per kg of body weight (mg/kg) was administered in a single IV infusion. If criteria were met, 2 additional doses could be administered (1 every 4 weeks).

10 mgs MDX-1106 drug (nivolumab) per kg of body weight (mg/kg) was administered in a single IV infusion. If criteria were met, 2 additional doses could be administered (1 every 4 weeks).

Outcomes

Primary Outcome Measures

Number of Participants With Severe Adverse Events (AEs), Serious Adverse Events (SAEs), Drug-Related AEs, Deaths, Discontinuation of Study Drug Due to AE, Dose-Limiting Toxicity (DLT) AE and Immune-related AEs (irAEs) in Safety Population

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. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4= Potentially Life-threatening or disabling. Severe=All Grade 3 or 4 events. Death=during the study and up to 28 days past study discontinuation. AEs graded using the Cancer Therapy Evaluation Program Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0. irAEs=unknown etiology, associated with study drug and consistent with an immune phenomenon. DLT: ≥Gr 3 AE(s) or lab abnormality without alternative explanation other than drug.

Geometric Mean Maximum Serum Concentration (Cmax) Observed Post-Single Dose

Nivolumab in human serum was assayed during the period of known analyte stability and reported as final data for this study by PPD® (Richmond, Virginia) using a cross-validated enzyme-linked immunosorbent assay (ELISA) method. For the single dose (Day 1), serum concentrations of nivolumab were assessed: prior to dosing, at 30 minutes (during dosing), immediately post-dose, and 30 minutes post-infusion end time; at 1, 2, 4, 6, 8, 24, 48, and 72 hours post-infusion end time; and on Days 8, 15, 22, 29, 43, 57, 71, and 85. The pharmacokinetic (PK) parameter of Cmax was measured in micrograms per milliliter (µg/mL).

Median Time at Which the Maximum Serum Concentration Occurred (Tmax) Post-Single Dose

Nivolumab in human serum was assayed during the period of known analyte stability and reported as final data for this study by PPD® (Richmond, Virginia) using a cross-validated ELISA method. For the single dose (Day 1), serum concentrations of nivolumab were assessed: prior to dosing, at 30 minutes (during dosing), immediately post-dose, and 30 minutes post-infusion end time; at 1, 2, 4, 6, 8, 24, 48, and 72 hours post-infusion end time; and on Days 8, 15, 22, 29, 43, 57, 71, and 85. The PK parameter of Tmax was measured in hours (h).

Geometric Mean Area Under the Curve (AUC) From Time of Dosing to Time of Last Observation (0-T) and Extrapolated to Infinity (INF) Observed Post-Single Dose

AUC(0-T): Area under the concentration-time curve from the time of dosing to the time of the last observation. AUC(INF): Area under the curve from the time of dosing extrapolated to infinity. Nivolumab in human serum was assayed during the period of known analyte stability and reported as final data for this study by PPD® (Richmond, Virginia) using a cross-validated ELISA method. For the single dose (Day 1), serum concentrations of nivolumab were assessed: prior to dosing, at 30 minutes (during dosing), immediately post-dose, and 30 minutes post-infusion end time; at 1, 2, 4, 6, 8, 24, 48, and 72 hours post-infusion end time; and on Days 8, 15, 22, 29, 43, 57, 71, and 85. The PK parameters of AUC(0-T) and AUC (INF) were measured in micrograms*hours per milliliter (µg*h/mL).

Mean Elimination Half-life (T-HALF) Post-Single Dose

Geometric Mean Total Body Clearance of Drug From Serum (CLT) Post-Single Dose

Mean Volume of Distribution (Vz) Post-Single Dose

Percent of Participants With Best Overall Response Rate in Safety Population and in Tumor Evaluable Population

The Best Overall Response Rate (BORR) was defined as the number of participants who had a confirmed complete response (CR) or partial response (PR) during the study divided by the total number of participants evaluated. Response was based on tumor assessment for both target and non-target lesions using: Clinical examination; Chest X-ray; Computed Tomography and Magnetic Resonance Imaging; Bone scan; Ultrasound. Per National Cancer Institute Response Evaluation Criteria in Solid Tumors (RECIST) v1.0, best overall response (BOR) for tumors was confirmed CR or 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. Confidence intervals (CIs) were computed using the Clopper and Pearson method.

Percent of Participants With Prostate-Specific Antigen (PSA) Response After the First Dose by Day 85 In Participants With Hormone-Refractory Prostate Adenocarcinoma (HRPC)

The PSA response rate was defined as the number of participants who had at least a 50% decrease of the PSA value from the PSA reference value divided by the total number of participants evaluated (percent of participants). PSA reference value was the PSA concentration measured immediately prior to dosing on Day 1. PSA response was assessed using the Recommendations from the National Cancer Institute Prostate-Specific Antigen Working Group. A PSA response had to be confirmed at least 4 weeks after first response. 95% exact CIs were computed using the Clopper and Pearson method.

Secondary Outcome Measures

Number of Participants With Best Overall Response (BOR) by Category in Safety Population

Measurable and non-measurable disease/target lesions were evaluated according to National Cancer Institute standardized RECIST.Complete Response (CR)=disappearance of all target and non-target lesions and no new lesions; Partial Response=at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the screening sum longest diameter; Stable disease (SD)=neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum longest diameter since treatment; PD=at least a 20% increase in the sum of the longest diameter recorded since screening, or the appearance of one or more new lesions. BOR was recorded between the first tumor assessment and last tumor assessment. CR and PR had to be confirmed by repeat assessment no less than 4 weeks after the criteria were first met. SD assessment must have met the criteria at least once at or after Week 12.

Percentage of Participants With Disease Control and Major Durable Disease Control

Disease control rate was defined as number of participants whose Best Overall Response (BOR) was complete response (CR), partial response (PR), or stable disease (SD) divided by the total number of participants. Major durable disease control rate was defined as the total number of participants whose BOR was CR, PR, or SD ≥24 weeks, divided by the total number of participants. Per RECIST v 1.0, BOR for tumors was confirmed CR or 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 since treatment; SD=neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for PD. PD=at least a 20% increase in the sum of the longest diameter recorded since screening, or the appearance of one or more new lesions. 95% CIs were computed using the Clopper and Pearson method.

Median Time to Tumor Response and Duration of Tumor Response

Time to tumor response: from the date of first dose to the first date of tumor response (CR or PR confirmed at least 4 weeks later); for nonresponders, it was censored at the date of the maximum tumor assessment time in the dose cohort by the end of study. Duration of tumor response was calculated from the first date of response of CR or PR to the date of the first PD or the date of death if a participant died due to disease progression (whichever occurred first). Duration of response was censored at the last tumor assessment date by the end of study if a responder did not have PD or death. Nonresponders had the duration of response as an event of 0 days.

Time to Tumor Progression and Tumor Progression Free Survival

Time to tumor progression (TTP) was measured in days from date of the first dose to the date of the first PD or the date of death if due to PD. For those who died without PD it was censored at the date of death. TTP was censored at the last tumor assessment by the end of study if a participant did not have PD or death. Tumor progression free survival (PFS) was measured in days from the date of first dose to the date of the first disease progression or to the date of death. PFS was censored at the last tumor assessment date by the end of study if a participant did not have PD or death.

Median Time to PSA Progression in Days and Median PSA Progression Free Survival in Days in PSA Evaluable Population

Time to PSA progression: first dose to first PSA progression. Missing date of progression was censored: if death during the study, time to progression was right-censored at last PSA assessment; if no progression from first dose and still alive at end of study, time to progression was right-censored at last PSA assessment by end of study; if no PSA progression and one has discontinued from the study (other than death or PSA progression), time to progression was right-censored at last PSA assessment. PSA progression free survival (PFS): first dose to first PSA progression or death, whichever comes first. Missing date of progression was censored: if one did not have PSA progression from first dose and was still alive at end of study, PSA PFS was right-censored at last PSA assessment; if one does not have any progression and discontinued from the study for reasons other than death or progression, PFS was right-censored at last assessment. CI computed using Brookmeyer and Crowley method.

Mean Change From Baseline in PSA Relative Velocity at Days 29, 57, and 85 With Cycle 1 in PSA Evaluable Population

PSA relative velocity (PSA RV) was defined as = (d[PSA]/dt)/ [PSA], where [PSA] =concentration of PSA, and t= time, and in the limit reflects the instantaneous change in PSA levels as a fraction of total PSA level. Decreases in PSA RV may occur while measured [PSA] is still rising, and may indicate that continued therapy may lead to a treatment benefit, particularly in the setting of immunotherapy, where expansion of an effective immune response is likely to require weeks to mature. Baseline PSA RV was based on the velocity of last PSA measurement before the first infusion of study drug and the screening PSA measurement.

Mean Change From Baseline in Electrocardiogram Parameters PR, QRS and QT in Safety Population

12-lead ECGs were performed at screening, baseline, Day 2 and at completion of the dose cycle (Day 85 in first dose cycle). In those participants undergoing re-treatment, ECG was repeated at the completion of the re-treatment. Baseline was defined as the last measurement before the first dose of study drug, which was calculated from pre-dose or from screening if pre-dose was not available. PR, QRS and QT interval were measured in milliseconds (msec).

Mean Diastolic Blood Pressure at Baseline and Post-Infusion Day 1 (Cycle 1) in 0.3 mg Cohort - Safety Population

Diastolic blood pressures (DBPs) measured in millimeters of mercury (mmHg) were obtained while the participant was seated. Post infusion DBPs are presented in the 0.3 mg cohort at: 21, 36, 51, 66, 82, 97, 112, 127, 157 minutes post infusion, and at 1, 2, 3, 4, 6, 8 hours post infusion. Baseline was defined as the last measurement before the first dose of study drug, which was calculated from pre-dose or from screening if pre-dose was not available. Mean DBP on Day 1 for first dose (cycle 1) are presented below.

Mean Systolic Blood Pressure at Baseline and Post-Infusion Day 1 (Cycle 1) in 0.3 mg Cohort - Safety Population

Systolic blood pressures (SBPs) measured in millimeters of mercury (mmHg) were obtained while the participant was seated. Baseline, Infusion (0 minutes) and Post infusion SBPs are presented in the 0.3 mg cohort at: 21, 36, 51, 66, 82, 97, 112, 127, 157 minutes post infusion, and at 1, 2, 3, 4, 6, 8 hours post infusion. Baseline was defined as the last measurement before the first dose of study drug, which was calculated from pre-dose or from screening if pre-dose was not available. Mean SBP on Day 1 for first dose (cycle 1) are presented below.

Mean Diastolic Blood Pressure at Baseline and Post-Infusion Day 1 (Cycle 1) in 1mg, 3mg, and 10 mg Cohorts - Safety Population

Diastolic blood pressures (DBPs) measured in millimeters of mercury (mmHg) were obtained while the participant was seated. Baseline, Infusion (0 minutes) and Post infusion DBPs are presented in the 1 mg, 3 mg and 10 mg cohorts at: 15, 30, 45, 60, 75, and 90 minutes post infusion and at 1, 2, 3, 4, 6, 8 hours post infusion. Baseline was defined as the last measurement before the first dose of study drug, which was calculated from pre-dose or from screening if pre-dose was not available. Mean DBP on Day 1 for first dose (cycle 1) are presented below.

Mean Systolic Blood Pressure at Baseline and Post-Infusion Day 1 (Cycle 1) in in 1mg, 3mg, and 10 mg Cohorts - Safety Population

Systolic blood pressures (SBPs) measured in millimeters of mercury (mmHg) were obtained while the participant was seated. Baseline, Infusion (0 minutes) and Post infusion SBPs are presented in the 1 mg, 3 mg and 10 mg cohorts at: 15, 30, 45, 60, 75, and 90 minutes post infusion and at 1, 2, 3, 4, 6, 8 hours post infusion. Baseline was defined as the last measurement before the first dose of study drug, which was calculated from pre-dose or from screening if pre-dose was not available. Mean SBPs on Day 1 for first dose (cycle 1) are presented below.

Full Information

NCT ID

NCT00441337

First Posted

February 27, 2007

Last Updated

February 5, 2015

Sponsor

Bristol-Myers Squibb

1. Study Identification

Unique Protocol Identification Number

NCT00441337

Brief Title

A Study of MDX-1106 in Patients With Selected Refractory or Relapsed Malignancies

Acronym

MDX1106-01

Official Title

A Phase 1, Open Label, Dose-escalation, Safety and Pharmacokinetic Study of MDX-1106 in Patients With Selected or Relapsed Malignancies

Study Type

Interventional

2. Study Status

Record Verification Date

February 2015

Overall Recruitment Status

Completed

Study Start Date

August 2006 (undefined)

Primary Completion Date

November 2009 (Actual)

Study Completion Date

November 2009 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Bristol-Myers Squibb

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

To evaluate the safety, tolerability, efficacy, and pharmacokinetics of MDX-1106 when administered to patients with advanced non-small cell lung cancer, colorectal cancer, malignant melanoma, clear cell renal cell cancer or hormone refractory prostate cancer

Detailed Description

Six patients enrolled at each dose level of 0.3, 1.0, 3.0 and 10mg/kg; the remaining 10 to 15 patients may subsequently be enrolled at a dose at or below the maximum tolerated dose (MTD) during the dose-escalation portion of the study. Patients who respond may receive additional doses of drug.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Carcinoma, Non-Small-Cell Lung, Colorectal Cancer, Malignant Melanoma, Renal Cancer, Prostate Cancer

Keywords

malignancies, cancer, non small cell lung cancer, lung cancer, colorectal cancer, adenocarcinoma, melanoma, malignant melanoma, renal cancer, renal carcinoma, carcinoma, prostate cancer, prostate adenocarcinoma, Recurrent or treatment refractory malignancies

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

39 (Actual)

8. Arms, Groups, and Interventions

Arm Title

0.3 mg/kg MDX-1106 drug

Arm Type

Experimental

Arm Description

Arm Title

1 mg/kg MDX-1106 drug

Arm Type

Experimental

Arm Description

1 mg MDX-1106 drug (nivolumab) per kg of body weight (mg/kg) was administered in a single IV infusion. If criteria were met, 2 additional doses could be administered (1 every 4 weeks).

Arm Title

3 mg/kg MDX-1106 drug

Arm Type

Experimental

Arm Description

3 mgs MDX-1106 drug (nivolumab) per kg of body weight (mg/kg) was administered in a single IV infusion. If criteria were met, 2 additional doses could be administered (1 every 4 weeks).

Arm Title

10 mg/kg MDX-1106 drug

Arm Type

Experimental

Arm Description

10 mgs MDX-1106 drug (nivolumab) per kg of body weight (mg/kg) was administered in a single IV infusion. If criteria were met, 2 additional doses could be administered (1 every 4 weeks).

Intervention Type

Biological

Intervention Name(s)

MDX-1106

Other Intervention Name(s)

nivolumab

Intervention Description

patients will receive a single dose of MDX-1106 as a 60 minute infusion.

Primary Outcome Measure Information:

Title

Description

Time Frame

Day 1 to 70 days post last dose of study drug; 28 days past study discontinuation

Title

Geometric Mean Maximum Serum Concentration (Cmax) Observed Post-Single Dose

Description

Time Frame

Day 1 to Day 85

Title

Median Time at Which the Maximum Serum Concentration Occurred (Tmax) Post-Single Dose

Description

Time Frame

Day 1 to Day 85

Title

Geometric Mean Area Under the Curve (AUC) From Time of Dosing to Time of Last Observation (0-T) and Extrapolated to Infinity (INF) Observed Post-Single Dose

Description

Time Frame

Day 1 to Day 85

Title

Mean Elimination Half-life (T-HALF) Post-Single Dose

Description

Time Frame

Day 1 to Day 85

Title

Geometric Mean Total Body Clearance of Drug From Serum (CLT) Post-Single Dose

Description

Time Frame

Day 1 to Day 85

Title

Mean Volume of Distribution (Vz) Post-Single Dose

Description

Time Frame

Day 1 to Day 85

Title

Percent of Participants With Best Overall Response Rate in Safety Population and in Tumor Evaluable Population

Description

Time Frame

Day 1 up to 2 Years.

Title

Percent of Participants With Prostate-Specific Antigen (PSA) Response After the First Dose by Day 85 In Participants With Hormone-Refractory Prostate Adenocarcinoma (HRPC)

Description

Time Frame

Day 1 to Day 85

Secondary Outcome Measure Information:

Title

Number of Participants With Best Overall Response (BOR) by Category in Safety Population

Description

Time Frame

Day 1 to Day 85

Title

Percentage of Participants With Disease Control and Major Durable Disease Control

Description

Time Frame

Day 1 to 2 Years

Title

Median Time to Tumor Response and Duration of Tumor Response

Description

Time Frame

Day 1 to 2 Years

Title

Time to Tumor Progression and Tumor Progression Free Survival

Description

Time Frame

Day 1 to 2 Years

Title

Median Time to PSA Progression in Days and Median PSA Progression Free Survival in Days in PSA Evaluable Population

Description

Time Frame

Day 1 to 2 Years

Title

Mean Change From Baseline in PSA Relative Velocity at Days 29, 57, and 85 With Cycle 1 in PSA Evaluable Population

Description

Time Frame

Day 29, Day 57, Day 85

Title

Mean Change From Baseline in Electrocardiogram Parameters PR, QRS and QT in Safety Population

Description

Time Frame

Baseline, Day 2, Day 85, Day 113

Title

Mean Diastolic Blood Pressure at Baseline and Post-Infusion Day 1 (Cycle 1) in 0.3 mg Cohort - Safety Population

Description

Time Frame

Baseline, Day 1

Title

Mean Systolic Blood Pressure at Baseline and Post-Infusion Day 1 (Cycle 1) in 0.3 mg Cohort - Safety Population

Description

Time Frame

Baseline, Day 1

Title

Mean Diastolic Blood Pressure at Baseline and Post-Infusion Day 1 (Cycle 1) in 1mg, 3mg, and 10 mg Cohorts - Safety Population

Description

Time Frame

Baseline, Day 1

Title

Mean Systolic Blood Pressure at Baseline and Post-Infusion Day 1 (Cycle 1) in in 1mg, 3mg, and 10 mg Cohorts - Safety Population

Description

Systolic blood pressures (SBPs) measured in millimeters of mercury (mmHg) were obtained while the participant was seated. Baseline, Infusion (0 minutes) and Post infusion SBPs are presented in the 1 mg, 3 mg and 10 mg cohorts at: 15, 30, 45, 60, 75, and 90 minutes post infusion and at 1, 2, 3, 4, 6, 8 hours post infusion. Baseline was defined as the last measurement before the first dose of study drug, which was calculated from pre-dose or from screening if pre-dose was not available. Mean SBPs on Day 1 for first dose (cycle 1) are presented below.

Time Frame

Baseline, Day 1

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Relapsed/refractory non-small cell lung cancer, colorectal adenocarcinoma, malignant melanoma, renal (clear) cell carcinoma, or hormone-refractory prostate adenocarcinoma Prior treatment must have been completed at least 4 weeks prior to enrollment No untreated primary or metastatic brain or meningeal tumors ECOG PS 0 or 1 Meet all screening laboratory values Exclusion Criteria: History of severe hypersensitivity reactions to other monoclonal antibodies Active autoimmune disease or a documented history of autoimmune disease Prior therapy with an anti-PD-1 or anti-CTLA-4 antibody Active infection Concurrent medical condition requiring the use of immunosuppressive medications

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Bristol-Myers Squibb

Organizational Affiliation

Bristol-Myers Squibb

Official's Role

Study Director

Facility Information:

Facility Name

Johns Hopkins Unv., School of Medicine

City

Baltimore

State/Province

Maryland

ZIP/Postal Code

21231

Country

United States

Facility Name

Henry Ford Health System

City

Detroit

State/Province

Michigan

ZIP/Postal Code

48202

Country

United States

Facility Name

Washington University School of Medicine - Barnes Jewish Hospital

City

St. Louis

State/Province

Missouri

ZIP/Postal Code

63110

Country

United States

Facility Name

Carolina BioOncology Institute, PLLC

City

Huntersville

State/Province

North Carolina

ZIP/Postal Code

28078

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

21917625

Citation

George S, Pili R, Carducci MA, Kim JJ. Role of immunotherapy for renal cell cancer in 2011. J Natl Compr Canc Netw. 2011 Sep 1;9(9):1011-8. doi: 10.6004/jnccn.2011.0085.

Results Reference

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A Study of MDX-1106 in Patients With Selected Refractory or Relapsed Malignancies

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