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

Melanoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00246012
• Other study ID #: CR006004
• Secondary ID: C1034T022004-002
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: October 28, 2005
• Last updated: July 17, 2013
• Start date: May 2005
• Est. completion date: February 2009

Study information

• Verified date: July 2013
• Source: Centocor, Inc.
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 144
• Est. completion date: February 2009
• Est. primary completion date: June 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 a? 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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Melanoma

Intervention

Drug:
• Intetumumab
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.
• Dacarbazine
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.
• Placebo
Placebo will be administered intravenously over a period of 2 hours (+15 minutes/-15 minutes).

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
Centocor, Inc.	Janssen-Cilag Farmaceutica, S.R.L.

Countries where clinical trial is conducted

United States,  Germany,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Area Under the Concentration Versus Time Curve Between Zero to Infinite Time (AUCinf) of Intetumumab - Phase 1 (Part 1)	The AUCinf = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - 8). It is obtained from AUC (0 - t) plus AUC (t - 8).	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	No
Other	Percentage of Participants Who Achieved a Best Overall Response as CR, PR, or SD - Phase 2	The CR: complete disappearance of all measurable and non-measurable target lesions and PR: 50% 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.	Within 28 days of first infusion of study medication, within 1 week of the end of Cycles 2, 4, 6, 8; 3 months and 6 months post-last dose of study medication	No
Primary	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	Yes
Primary	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	No
Primary	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	No
Primary	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	No
Primary	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	No
Primary	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	No
Primary	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	No
Primary	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	No
Secondary	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)	No
Secondary	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)	No
Secondary	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)	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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)	No
Secondary	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)	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No