A Safety and Efficacy Study of Intetumumab, Alone and in Combination With Dacarbazine, in Participants With Stage 4 Melanoma

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and effectiveness of the intetumumab, alone and in combination with dacarbazine, in patients with stage 4 melanoma.

Detailed Description
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This is a Phase 1/2, multi-center, randomized (the study medication is assigned by chance) study. This study will be conducted in 2 Phases (Phase 1 and Phase 2). Phase 1 of this study will be non-randomized, open-label (all people know the identity of the intervention) and dose-escalation phase. It includes screening period and treatment period, which consists of 2 parts (Part 1 and Part 2). In Part 1, participants will receive 1 of 3 single dose levels of intetumumab [3 milligram per kilogram (mg/kg), 5 mg/kg or 10 mg/kg]. Part 2 will include 2 dose cohorts: dacarbazine plus intetumumab (5 mg/kg) or dacarbazine plus intetumumab (10 mg/kg). Phase 2 of this study will be randomized, blinded (neither physician nor participant knows the intervention which the participant will receive) and controlled (an inactive substance and other medication is compared with a study medication to test whether the medication has a real effect in this clinical study). This phase of the study will include screening period, treatment period (8 cycles of treatment with every cycle once in 3 weeks) and follow-up period (24 weeks). During the treatment period, participants will be randomly assigned to 1 of 4 treatment groups, Group 1: dacarbazine plus placebo, Group 2: intetumumab (5 mg/kg), Group 3: intetumumab (10 mg/kg) and Group 4: dacarbazine plus intetumumab. Randomization will be further based on the site of metastases and Eastern Cooperative Oncology Group performance status at Baseline. Single-medication intetumumab treatment groups will be open-label, while the dacarbazine plus intetumumab or placebo groups will be blinded. The total duration of the Phase 2 of this study will be up to 52 weeks or up to 76 weeks in case of extended dosing (extended administrations [up to 8 additional cycles] of the same assigned treatment will be allowed for participants that are responding to therapy with stable disease or better). Participants will be assessed for incidence of dose limiting toxicities, pharmacokinetics and tumor responses. Participants' safety will be monitored throughout the study.

Official Title
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A Phase 1/2, Multi-Center, Blinded, Randomized, Controlled Study of the Safety and Efficacy of the Human Monoclonal Antibody to Human α ν Integrins (CNTO 95), Alone and in Combination With Dacarbazine, in Subjects With Stage IV Melanoma

Conditions
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Melanoma

Intervention / Treatment
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* Drug: Intetumumab
* Drug: Dacarbazine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed melanoma including ocular and mucosal Documented AJCC (American Joint Committee on Cancer) Stage 3 unresectable or Stage 4 melanoma (Phase 1); AJCC Stage 4 melanoma (Phase 2) Radiographically measurable disease or measurable skin lesions Prior chemotherapy for metastatic melanoma will be allowed for Phase 1, while previously untreated for melanoma by chemotherapy will be allowed for Phase 2 Agrees to protocol-defined use of effective contraception Exclusion Criteria: History of receiving murine or human/murine recombination products of human αν integrins Known human immunodeficiency virus (HIV) positivity and clinically important active infection Presence of bone metastases or malignant effusions (non-measurable lesions) and central nervous system metastases Prior radiation to target lesions Concurrent immunotherapy, biotherapy, radiotherapy, chemotherapy, or investigational therapy and therapeutic use of anticoagulation

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intetumumab 3 mg/kg [Phase 1 (Part 1)]<br>Intetumumab will be administered at the dose of 3 milligram per kilogram (mg/kg) as intravenous infusion (a fluid or a medicine delivered into a vein by way of a needle) over a period of 2 hours (hr) (± 15 minutes) once every 3 weeks until the occurrence of dose limiting toxicities (DLTs). If after an evaluation of the preliminary single-dose pharmacokinetics, receptor saturation is not observed at the 3 mg/kg or 5 mg/kg dose level, that dose of intetumumab will be discontinued in Part 1 and participants will be treated at the highest, documented safe dose level at which receptor saturation is observed. | Drug: Intetumumab<br>* Intetumumab will be administered at the dose of 3 milligram per kilogram (mg/kg) as intravenous infusion (a fluid or a medicine delivered into a vein by way of a needle) over a period of 2 hours (hr) (± 15 minutes) once every 3 weeks until the occurrence of dose limiting toxicities (DLTs). In Phase 2, intetumumab (5 mg/kg or 10 mg/kg) will be administered for 8 cycles until no evidence of disease progression or unacceptable toxicity. If a participant responds to therapy with stable disease (SD) or better, the participant will be eligible to receive up to 8 cycles of extended administrations.<br>|
| Experimental: Intetumumab 5 mg/kg [Phase 1 (Part 1)]<br>Intetumumab will be administered at the dose of 5 mg/kg as intravenous infusion over a period of 2 hr (± 15 minutes) once every 3 weeks until the occurrence of DLTs. If after an evaluation of the preliminary single-dose pharmacokinetics, receptor saturation is not observed at the 3 mg/kg or 5 mg/kg dose level, that dose of intetumumab will be discontinued in Part 1 and participants will be treated at the highest, documented safe dose level at which receptor saturation is observed. | Drug: Intetumumab<br>* Intetumumab will be administered at the dose of 3 milligram per kilogram (mg/kg) as intravenous infusion (a fluid or a medicine delivered into a vein by way of a needle) over a period of 2 hours (hr) (± 15 minutes) once every 3 weeks until the occurrence of dose limiting toxicities (DLTs). In Phase 2, intetumumab (5 mg/kg or 10 mg/kg) will be administered for 8 cycles until no evidence of disease progression or unacceptable toxicity. If a participant responds to therapy with stable disease (SD) or better, the participant will be eligible to receive up to 8 cycles of extended administrations.<br>|
| Experimental: Intetumumab 10 mg/kg [Phase 1 (Part 1)]<br>Intetumumab will be administered at the dose of 10 mg/kg as intravenous infusion over a period of 2 hr (± 15 minutes) once every 3 weeks until the occurrence of DLTs. | Drug: Intetumumab<br>* Intetumumab will be administered at the dose of 3 milligram per kilogram (mg/kg) as intravenous infusion (a fluid or a medicine delivered into a vein by way of a needle) over a period of 2 hours (hr) (± 15 minutes) once every 3 weeks until the occurrence of dose limiting toxicities (DLTs). In Phase 2, intetumumab (5 mg/kg or 10 mg/kg) will be administered for 8 cycles until no evidence of disease progression or unacceptable toxicity. If a participant responds to therapy with stable disease (SD) or better, the participant will be eligible to receive up to 8 cycles of extended administrations.<br>|
| Experimental: Dacarbazine + intetumumab 5 mg/kg [Phase 1 (Part 2)]<br>Intetumumab will be administered at the dose of 5 mg/kg as intravenous infusion over a period of 2 hr (± 15 minutes) once every 3 weeks for 8 cycles until no evidence of disease progression or unacceptable toxicity. If participants respond to therapy with stable disease (SD) or better, they will be considered eligible to receive up to 8 cycles of extended administrations. Commercially available dacarbazine will be administered at the dose of 1000 milligram per meter-square (mg/m^2) intravenously over a period of 60 minutes (± 30 minutes) prior to intetumumab infusion. | Drug: Intetumumab<br>* Intetumumab will be administered at the dose of 3 milligram per kilogram (mg/kg) as intravenous infusion (a fluid or a medicine delivered into a vein by way of a needle) over a period of 2 hours (hr) (± 15 minutes) once every 3 weeks until the occurrence of dose limiting toxicities (DLTs). In Phase 2, intetumumab (5 mg/kg or 10 mg/kg) will be administered for 8 cycles until no evidence of disease progression or unacceptable toxicity. If a participant responds to therapy with stable disease (SD) or better, the participant will be eligible to receive up to 8 cycles of extended administrations.<br>Drug: Dacarbazine<br>* Commercially available dacarbazine will be administered intravenously over a 60-minute period (+30 minutes/-30 minutes) and prior to the intetumumab/placebo infusion. In case participants are unable to tolerate dacarbazine even after 2 dose reductions, they will be given the option to continue on intetumumab alone.<br>|
| Experimental: Dacarbazine + intetumumab 10 mg/kg [Phase 1 (Part 2)]<br>Intetumumab will be administered at the dose of 10 mg/kg as intravenous infusion over a period of 2 hr (± 15 minutes) once every 3 weeks for 8 cycles until no evidence of disease progression or unacceptable toxicity. If participants respond to therapy with SD or better, they will be considered eligible to receive up to 8 cycles of extended administrations. Commercially available dacarbazine will be administered at the dose of 1000 mg/m^2 intravenously over a period of 60 minutes (± 30 minutes) prior to intetumumab infusion. | Drug: Intetumumab<br>* Intetumumab will be administered at the dose of 3 milligram per kilogram (mg/kg) as intravenous infusion (a fluid or a medicine delivered into a vein by way of a needle) over a period of 2 hours (hr) (± 15 minutes) once every 3 weeks until the occurrence of dose limiting toxicities (DLTs). In Phase 2, intetumumab (5 mg/kg or 10 mg/kg) will be administered for 8 cycles until no evidence of disease progression or unacceptable toxicity. If a participant responds to therapy with stable disease (SD) or better, the participant will be eligible to receive up to 8 cycles of extended administrations.<br>Drug: Dacarbazine<br>* Commercially available dacarbazine will be administered intravenously over a 60-minute period (+30 minutes/-30 minutes) and prior to the intetumumab/placebo infusion. In case participants are unable to tolerate dacarbazine even after 2 dose reductions, they will be given the option to continue on intetumumab alone.<br>|
| Experimental: Dacarbazine + placebo [Phase 2]<br>Placebo will be administered intravenously over a period of 2 hr (±15 minutes). Commercially available dacarbazine will be administered at the dose of 1000 mg/m^2 intravenously over a period of 60 minutes (± 30 minutes) prior to placebo infusion. In case participants are unable to tolerate dacarbazine even after 2 dose reductions, they will be given the option to continue with 10 mg/kg intetumumab alone. | Drug: Dacarbazine<br>* Commercially available dacarbazine will be administered intravenously over a 60-minute period (+30 minutes/-30 minutes) and prior to the intetumumab/placebo infusion. In case participants are unable to tolerate dacarbazine even after 2 dose reductions, they will be given the option to continue on intetumumab alone.<br>Drug: Placebo<br>* Placebo will be administered intravenously over a period of 2 hours (+15 minutes/-15 minutes).<br>|
| Experimental: Intetumumab 5 mg/kg [Phase 2]<br>Intetumumab will be administered at the dose of 5 mg/kg as intravenous infusion over a period of 2 hr (± 15 minutes) once every 3 weeks for 8 cycles until no evidence of disease progression or unacceptable toxicity. If participants respond to therapy with SD or better, they are considered eligible to receive up to 8 cycles of extended administrations. | Drug: Intetumumab<br>* Intetumumab will be administered at the dose of 3 milligram per kilogram (mg/kg) as intravenous infusion (a fluid or a medicine delivered into a vein by way of a needle) over a period of 2 hours (hr) (± 15 minutes) once every 3 weeks until the occurrence of dose limiting toxicities (DLTs). In Phase 2, intetumumab (5 mg/kg or 10 mg/kg) will be administered for 8 cycles until no evidence of disease progression or unacceptable toxicity. If a participant responds to therapy with stable disease (SD) or better, the participant will be eligible to receive up to 8 cycles of extended administrations.<br>|
| Experimental: Intetumumab 10 mg/kg [Phase 2]<br>Intetumumab will be administered at the dose of 10 mg/kg as intravenous infusion over a period of 2 hr (± 15 minutes) once every 3 weeks for 8 cycles until no evidence of disease progression or unacceptable toxicity. If participants respond to therapy with SD or better, they are considered eligible to receive up to 8 cycles of extended administrations. | Drug: Intetumumab<br>* Intetumumab will be administered at the dose of 3 milligram per kilogram (mg/kg) as intravenous infusion (a fluid or a medicine delivered into a vein by way of a needle) over a period of 2 hours (hr) (± 15 minutes) once every 3 weeks until the occurrence of dose limiting toxicities (DLTs). In Phase 2, intetumumab (5 mg/kg or 10 mg/kg) will be administered for 8 cycles until no evidence of disease progression or unacceptable toxicity. If a participant responds to therapy with stable disease (SD) or better, the participant will be eligible to receive up to 8 cycles of extended administrations.<br>|
| Experimental: Dacarbazine + intetumumab 10 mg/kg [Phase 2]<br>Intetumumab will be administered at the dose of 10 mg/kg as intravenous infusion over a period of 2 hr (± 15 minutes) once every 3 weeks for 8 cycles until no evidence of disease progression or unacceptable toxicity. If participants respond to therapy with SD or better, they are considered eligible to receive up to 8 cycles of extended administrations. Commercially available dacarbazine will be administered at the dose of 1000 mg/m^2 intravenously over a period of 60 minutes (± 30 minutes) prior to intetumumab infusion. | Drug: Intetumumab<br>* Intetumumab will be administered at the dose of 3 milligram per kilogram (mg/kg) as intravenous infusion (a fluid or a medicine delivered into a vein by way of a needle) over a period of 2 hours (hr) (± 15 minutes) once every 3 weeks until the occurrence of dose limiting toxicities (DLTs). In Phase 2, intetumumab (5 mg/kg or 10 mg/kg) will be administered for 8 cycles until no evidence of disease progression or unacceptable toxicity. If a participant responds to therapy with stable disease (SD) or better, the participant will be eligible to receive up to 8 cycles of extended administrations.<br>Drug: Dacarbazine<br>* Commercially available dacarbazine will be administered intravenously over a 60-minute period (+30 minutes/-30 minutes) and prior to the intetumumab/placebo infusion. In case participants are unable to tolerate dacarbazine even after 2 dose reductions, they will be given the option to continue on intetumumab alone.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose Limiting Toxicities (DLTs) - Phase 1 | The DLT is defined as any Grade 3 or higher adverse event identified by the safety data monitoring committee as attributable to intetumumab except for hypersensitivity reactions, which are not considered DLTs unless there are 2 or more occurrences of greater than or equal to Grade 3 hypersensitivity reaction within a group. | Up to 21 days post-first infusion from the last treated participant in Phase 1 | 
| Maximum Observed Serum Concentration (Cmax) of Intetumumab - Phase 1 (Part 1) | The maximum observed analyte concentration in serum was reported. | Pre-infusion, post-infusion at 2, 4, 8, 24 hour, Day 8, Day 15, post-last dose (3 weeks or 1 week) and 3 months post-last dose | 
| Area Under the Serum Concentration Versus Time Curve (AUC) of Intetumumab - Phase 1 (Part 1) | The AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. | Pre-infusion, post-infusion at 2, 4, 8, 24 hour, Day 8, Day 15, post-last dose (3 weeks or 1 week) and 3 months post-last dose | 
| Half-life of Intetumumab - Phase 1 (Part 1) | Plasma decay half-life is the time measured for the plasma concentration of the drug to decrease by one half. | Pre-infusion, post-infusion at 2, 4, 8, 24 hour, Day 8, Day 15, post-last dose (3 weeks or 1 week) and 3 months post-last dose | 
| Total Clearance (CL) of Intetumumab After Intravenous Administration - Phase 1 (Part 1) | The CL is a quantitative measure of the rate at which a drug substance is removed from the body. | Pre-infusion, post-infusion at 2, 4, 8, 24 hour, Day 8, Day 15, post-last dose (3 weeks or 1 week) and 3 months post-last dose | 
| Volume of Distribution (Vz) of Intetumumab - Phase 1 (Part 1) | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. | Pre-infusion, post-infusion at 2, 4, 8, 24 hour, Day 8, Day 15, post-last dose (3 weeks or 1 week) and 3 months post-last dose | 
| Accumulation Ratio (R) of Intetumumab - Phase 1 (Part 1) | The R is obtained by dividing AUC at two different time points. | Pre-infusion, post-infusion at 2, 4, 8, 24 hour, Day 8, Day 15, post-last dose (3 weeks or 1 week) and 3 months post-last dose | 
| Progression-Free Survival (PFS) - Phase 2 | The PFS was defined as the time from the date of randomization to the date of initial documented progressive disease (PD), or the date of initial documented symptomatic deterioration, or the date of death, whichever occurred first. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as at least a 20% increase in the sum of the longest diameter of target lesions, taking as a reference the smallest sum longest diameter recorded since the treatment started or the appearance of 1 or more new lesions. | From the date of randomization to date of initial documented progressive disease or death, whichever occured first, as assessed upto 6 months after last dose of study medication | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieved a Best Overall Tumor Response as Complete Response (CR) or Partial Response (PR) - Phase 2 | The CR: complete disappearance of all measurable and non-measurable target lesions and PR: 50 percent (%) or more decrease in sum of the longest diameters of target lesion(s), with at least stable disease (SD) in all other evaluable disease in the absence of treatment failure. The best response achieved among all the evaluated time points was reported. | Screening, within 1 week of the end of Cycles 2, 4, 6, 8 (but prior to the next cycle dose), and follow-up (3 and 6 months post-last dose where applicable) | 
| Percentage of Participants Who Achieved CR - Phase 2 | The CR: complete disappearance of all measurable and non-measurable target lesions. The participants who achieved CR as the best response were reported. | Screening, within 1 week of the end of Cycles 2, 4, 6, 8 (but prior to the next cycle dose), and follow-up (3 and 6 months post-last dose where applicable) | 
| Percentage of Participants Who Achieved Stable Disease (SD) - Phase 2 | The SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Progressive disease (PD), taking as a reference the smallest sum longest diameter since the treatment started. The participants who achieved SD as the best response were reported. | Screening, within 1 week of the end of Cycles 2, 4, 6, 8 (but prior to the next cycle dose), and follow-up (3 and 6 months post-last dose where applicable) | 
| Overall Survival (OS) - Phase 2 | The OS is defined as the time from the date of randomization to the date of death due to any cause and was to be censored at the date that the subject is last known to be alive. | Every 3 months until death, until lost to follow-up, until withdrawal of consent, or until the Sponsor ends the study, as assessed up to 6 months post-last dose of study medication | 
| Duration of Response - Phase 2 | Time duration required to achieve a CR or PR. | From the time of initial documented response (CR or PR) to the first documented sign of progression, assessed up to 6 months post-last dose of study medication | 
| Time to Worsening in Eastern Cooperative Oncology Group (ECOG) Performance Status - Phase 2 | Eastern Cooperative Oncology (ECOG) performance status: Participants will be graded from 0 (Fully active, able to carry on all pre-disease activities without restriction) to 4 (Completely disabled, cannot carry on any self-care, totally confined to bed or chair). Worsening in ECOG score was defined as ≥ 1 point increase in ECOG score from baseline. | Baseline (within 7 days of first infusion of study medication), Day 1 of all 8 cycles, 3 weeks or 1 week post-last dose, 3 months and 6 months post-last dose of study medication | 
| Maximum Observed Serum Concentration (Cmax) of Intetumumab - Phase 2 | The maximum observed analyte concentration in serum was reported. | Pre-infusion, post-infusion at 2, 4, 8, 24 hour, Day 8, Day 15, post-last dose (3 weeks or 1 week) and 3 months post-last dose | 
| Change From Baseline in Functional Assessment of Cancer Therapy-Melanoma Subscale (FACT-MS) Score - Phase 2 | The FACT-MS subscale is used to evaluate health related quality of life. It consists of 16 items: 12 items related to physical well-being, 3 to emotional well-being and 1 to social well-being. Scores for all items will range from 0 to 4. Total score ranges from 0-64; higher score indicates a more positive quality of life. | Day 1 (pre-dose) of Cycles 1, 2, 3; and final visit (3 weeks post-last dose of study medication) | 
| Change From Baseline in Brief Pain Inventory (BPI) Score - Phase 2 | The BPI questionnaire is used to evaluate heath related quality of life. BPI allows participants to rate the severity of their pain on a scale of 0 (no pain) to 10 (pain as bad as you can imagine). | Day 1 (pre-dose) of Cycles 1, 2, 3; and final visit (3 weeks post-last dose of study medication) | 
| Maximum Observed Serum Concentration (Cmax) of Intetumumab - Phase 1 (Part 2) | The maximum observed analyte concentration in serum was reported. | Pre-infusion, post-infusion at 2, 4, 8, 24 hour, Day 8, Day 15, post-last dose (3 weeks or 1 week) and 3 months post-last dose | 
| Area Under the Serum Concentration Versus Time Curve (AUC) of Intetumumab - Phase 1 (Part 2) | The AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. | Pre-infusion, post-infusion at 2, 4, 8, 24 hour, Day 8, Day 15, post-last dose (3 weeks or 1 week) and 3 months post-last dose | 
| Half-life of Intetumumab - Phase 1 (Part 2) | Plasma decay half-life is the time measured for the plasma concentration of the drug to decrease by one half. | Pre-infusion, post-infusion at 2, 4, 8, 24 hour, Day 8, Day 15, post-last dose (3 weeks or 1 week) and 3 months post-last dose | 
| Total Clearance (CL) of Intetumumab After Intravenous Administration - Phase 1 (Part 2) | The CL is a quantitative measure of the rate at which a drug substance is removed from the body. | Pre-infusion, post-infusion at 2, 4, 8, 24 hour, Day 8, Day 15, post-last dose (3 weeks or 1 week) and 3 months post-last dose | 
| Volume of Distribution (Vz) of Intetumumab - Phase 1 (Part 2) | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. | Pre-infusion, post-infusion at 2, 4, 8, 24 hour, Day 8, Day 15, post-last dose (3 weeks or 1 week) and 3 months post-last dose | 
| Accumulation Ratio (R) of Intetumumab - Phase 1 (Part 2) | The R is obtained by dividing AUC at two different time points. | Pre-infusion, post-infusion at 2, 4, 8, 24 hour, Day 8, Day 15, post-last dose (3 weeks or 1 week) and 3 months post-last dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Melanoma, Neoplasm, CNTO 95, Dacarbazine, Intetumumab