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

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

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00441337

Acronym

MDX1106-01

Enrollment

Registered

2007-02-28

Start date

2006-08-31

Completion date

2009-11-30

Last updated

2015-02-20

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

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

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.

Interventions

BIOLOGICALMDX-1106

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

Study design

Allocation

NON_RANDOMIZED

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
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	Day 1 to 70 days post last dose of study drug; 28 days past study discontinuation	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	Day 1 to Day 85	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	Day 1 to Day 85	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	Day 1 to Day 85	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	Day 1 to Day 85	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 T-HALF was measured in days.
Geometric Mean Total Body Clearance of Drug From Serum (CLT) Post-Single Dose	Day 1 to Day 85	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 CLT was measured in milliliters per hour per kilogram body weight (mL/h/kg).
Mean Volume of Distribution (Vz) Post-Single Dose	Day 1 to Day 85	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 Vz was measured in milliliters per kilogram of body weight (mL/kg).
Percent of Participants With Best Overall Response Rate in Safety Population and in Tumor Evaluable Population	Day 1 up to 2 Years.	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)	Day 1 to Day 85	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

Measure	Time frame	Description
Mean Diastolic Blood Pressure at Baseline and Post-Infusion Day 1 (Cycle 1) in 1mg, 3mg, and 10 mg Cohorts - Safety Population	Baseline, Day 1	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.
Number of Participants With Best Overall Response (BOR) by Category in Safety Population	Day 1 to Day 85	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.
Mean Systolic Blood Pressure at Baseline and Post-Infusion Day 1 (Cycle 1) in in 1mg, 3mg, and 10 mg Cohorts - Safety Population	Baseline, Day 1	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.
Percentage of Participants With Disease Control and Major Durable Disease Control	Day 1 to 2 Years	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	Day 1 to 2 Years	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	Day 1 to 2 Years	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	Day 1 to 2 Years	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	Day 29, Day 57, Day 85	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	Baseline, Day 2, Day 85, Day 113	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	Baseline, Day 1	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	Baseline, Day 1	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.

Countries

United States

Participant flow

Recruitment details

Study from 25 October 2006 to 27 November 2009. After completion of a single dose (cycle 1), those meeting criteria could be re-treated with 2 additional doses (cycle 2); and additional cycles. Participants who had a complete response (CR) or partial response (PR) at end of re-treatment were followed-up until disease progression for 2 years.

Pre-assignment details

39 participants were enrolled and 39 were treated with at least 1 dose or a partial dose of study drug.

Participants by arm

Arm	Count
0.3 mg/kg Nivolumab 0.3 mg of nivolumab per kg of body weight (mg/kg) was administered in a single IV infusion on Day 1 with 10% of the dose infused over 6 minutes and after a 1 hour observation period, the balance was administered over 60 minutes. Eligible participants could be re-treated and receive 2 more doses (1 dose every 4 weeks) at same dose as the single dose if: disease was stable, no drug intolerance was observed, no complete response (CR) or partial response (PR) was observed, or they had a positive immunogenicity sample within 4 weeks prior to re-treatment. Those who responded to therapy with a CR or PR were eligible for long-term follow-up until either progressive disease (PD) or 2 years elapsed.	6
1 mg/kg Nivolumab 1 mg of nivolumab per kg of body weight was administered in a single IV infusion over 60 minutes on Day 1. Eligible participants could be re-treated and receive 2 more doses (1 dose every 4 weeks) at same dose as the single dose if: disease was stable, no drug intolerance was observed, no complete response (CR) or partial response (PR) was observed, or they had a positive immunogenicity sample within 4 weeks prior to re-treatment. Those who responded to therapy with a CR or PR were eligible for long-term follow-up until either progressive disease (PD) or 2 years elapsed.	6
3 mg/kg Nivolumab 3 mg of nivolumab per kg of body weight was administered in a single IV infusion over 60 minutes on Day 1. Eligible participants could be re-treated and receive 2 more doses (1 dose every 4 weeks) at same dose as the single dose if: disease was stable, no drug intolerance was observed, no complete response (CR) or partial response (PR) was observed, or they had a positive immunogenicity sample within 4 weeks prior to re-treatment. Those who responded to therapy with a CR or PR were eligible for long-term follow-up until either progressive disease (PD) or 2 years elapsed.	6
10 mg/kg Nivolumab 10 mg of nivolumab per kg of body weight was administered in a single IV infusion over 60 minutes on Day 1. Eligible participants could be re-treated and receive 2 more doses (1 dose every 4 weeks) at same dose as the single dose if: disease was stable, no drug intolerance was observed, no complete response (CR) or partial response (PR) was observed, or they had a positive immunogenicity sample within 4 weeks prior to re-treatment. Those who responded to therapy with a CR or PR were eligible for long-term follow-up until either progressive disease (PD) or 2 years elapsed.	21
Total	39

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003
Overall Study	Did not meet inclusion criteria	0	0	1	0
Overall Study	Disease Progression	6	6	4	18
Overall Study	Lost to Follow-up	0	0	0	1
Overall Study	Sponsor Decision	0	0	1	2

Baseline characteristics

Characteristic	Total	10 mg/kg Nivolumab	0.3 mg/kg Nivolumab	3 mg/kg Nivolumab	1 mg/kg Nivolumab
Age, Continuous	62.6 years STANDARD_DEVIATION 9.7	63.2 years STANDARD_DEVIATION 10	56.5 years STANDARD_DEVIATION 5.7	61.0 years STANDARD_DEVIATION 10.4	68.3 years STANDARD_DEVIATION 9.4
Body Weight in kilograms (kg)	81.3 kg	81.3 kg	96.8 kg	81.9 kg	73.9 kg
Race/Ethnicity, Customized Black	10 participants	3 participants	2 participants	2 participants	3 participants
Race/Ethnicity, Customized White	29 participants	18 participants	4 participants	4 participants	3 participants
Region of Enrollment United States	39 participants	21 participants	6 participants	6 participants	6 participants
Sex: Female, Male Female	17 Participants	10 Participants	2 Participants	2 Participants	3 Participants
Sex: Female, Male Male	22 Participants	11 Participants	4 Participants	4 Participants	3 Participants
Stage of Malignancy at Screening Diagnosis Stage I	0 participants	0 participants	0 participants	0 participants	0 participants
Stage of Malignancy at Screening Diagnosis Stage II	0 participants	0 participants	0 participants	0 participants	0 participants
Stage of Malignancy at Screening Diagnosis Stage III	1 participants	0 participants	1 participants	0 participants	0 participants
Stage of Malignancy at Screening Diagnosis Stage IV	38 participants	21 participants	5 participants	6 participants	6 participants
Time since initial diagnosis (years)	3.8 Years	4.1 Years	3.7 Years	5.6 Years	2.7 Years
Type of Malignancy Colorectal cancer	14 participants	5 participants	5 participants	2 participants	2 participants
Type of Malignancy Melanoma	10 participants	8 participants	0 participants	0 participants	2 participants
Type of Malignancy Non-small cell lung cancer	6 participants	2 participants	1 participants	2 participants	1 participants
Type of Malignancy Prostate Cancer	8 participants	5 participants	0 participants	2 participants	1 participants
Type of Malignancy Renal cell cancer	1 participants	1 participants	0 participants	0 participants	0 participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —
other Total, other adverse events	6 / 6	6 / 6	6 / 6	21 / 21
serious Total, serious adverse events	3 / 6	5 / 6	4 / 6	11 / 21

Outcome results

Primary

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).

Time frame: Day 1 to Day 85