A Safety and Effectiveness Study of CNTO 95, Alone and in Combination With Dacarbazine, in Patients With Stage IV Melanoma - Full Text View

Purpose

The purpose of this study is to evaluate the safety and effectiveness of the CNTO 95, alone and in combination with dacarbazine, in patients with stage IV melanoma.

Condition	Intervention	Phase
Melanoma Stage IV	Drug: CNTO 95 Drug: DTIC Drug: Placebo	Phase 1 Phase 2

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

Resource links provided by NLM:

MedlinePlus related topics: Cancer Melanoma

Drug Information available for: Dacarbazine

U.S. FDA Resources

Further study details as provided by Centocor, Inc.:

Primary Outcome Measures:

Phase I (Part 1): Incidence of dose limiting toxicities (DLTs) [ Time Frame: Up to 21 days post first infusion from the last treated patient in Part 1 of Phase I ] [ Designated as safety issue: Yes ]
Incidence of DLTs when a single-agent CNTO 95 (3 mg/kg, 5 mg/kg, or 10 mg/kg) will be administered to patients. DLT is defined as any Grade 3 or higher adverse event identified by the safety data monitoring committee as attributable to CNTO 95 except for hypersensitivity reactions, which will not be considered DLTs unless there are 2 or more occurrences of greater than or equal to Grade 3 hypersensitivity. reaction within a cohort.
Phase I (Part 2): Incidence of dose limiting toxicities (DLTs) [ Time Frame: Up to 21 days post first infusion from the last treated patient in Part 2 of Phase I ] [ Designated as safety issue: Yes ]
Incidence of DLTs when Dacarbazine (DTIC) is administered in combination with either 5 mg/kg CNTO 95 or 10 mg/kg CNTO 95.
Phase I (Part 1): Maximum observed serum concentration (Cmax) of CNTO 95 [ Time Frame: 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 ] [ Designated as safety issue: No ]
Phase I (Part 1): Area under the serum concentration versus time curve (AUC) of CNTO 95 [ Time Frame: 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 ] [ Designated as safety issue: No ]
Phase l (Part 1): Area under the concentration versus time curve between 2 sampling times; t1 and t2 (AUC t1-t2) of CNTO 95 [ Time Frame: 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 ] [ Designated as safety issue: No ]
Phase l (Part 1): Half-life of CNTO 95 [ Time Frame: 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 ] [ Designated as safety issue: No ]
Phase l (Part 1): Total clearance of CNTO 95 after intravenous administration [ Time Frame: 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 ] [ Designated as safety issue: No ]
Phase l (Part 1): Volume of distribution (Vz) of CNTO 95 [ Time Frame: 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 ] [ Designated as safety issue: No ]
Phase l (Part 1): Accumulation ratio of CNTO 95 [ Time Frame: 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 ] [ Designated as safety issue: No ]
Phase ll: Progression-free survival (PFS) [ Time Frame: 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 ] [ Designated as safety issue: No ]
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.

Secondary Outcome Measures:

Phase II: Number of patients who achieve a best overall tumor response as: complete response (CR) or partial response (PR) [ Time Frame: 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 ] [ Designated as safety issue: No ]
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.
Phase ll: Number of patients who achieve a best overall response as CR [ Time Frame: 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 ] [ Designated as safety issue: No ]
Phase ll: Number of patients who achieve a best overall response as CR, PR, or SD [ Time Frame: 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 ] [ Designated as safety issue: No ]
Overall survival (OS) [ Time Frame: 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 ] [ Designated as safety issue: No ]
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.
Phase ll: Duration of response [ Time Frame: 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 ] [ Designated as safety issue: No ]
Time duration required to achieve a CR or PR
Phase ll: Change in Eastern Cooperative Oncology (ECOG) performance status from baseline [ Time Frame: 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. ] [ Designated as safety issue: No ]
Eastern Cooperative Oncology (ECOG) performance status: Patients 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).
Phase II: Change from baseline in Functional Assessment of Cancer Therapy-Melanoma Subscale (FACT-MS) score [ Time Frame: Baseline (screening, within 28 days before treatment), prior to cycles 1, 2, and 3 on Day 1, 3 weeks post last dose of study medication ] [ Designated as safety issue: No ]
FACT-MS subscale is used to evaluate health related quality of life. It consists of 20 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 and a high score indicates a more positive quality of life.
Phase II: Change from baseline in Brief Pain Inventory (BPI) score [ Time Frame: Baseline (screening, within 28 days before treatment), prior to cycles 1, 2, and 3 on Day 1, 3 weeks post last dose of study medication ] [ Designated as safety issue: No ]
BPI questionnaire is used to evaluate heath related quality of life. BPI allows patients to rate the severity of their pain on a scale of 0 (no pain) to 10 (pain as bad as you can imagine) and the degree to which their pain interferes with common dimensions of feeling and function (general activity, walking, work, mood, enjoyment of life, relations with others, and sleep) on a scale of 0 (no interference) to 10 (interferes completely).

Enrollment:	130
Study Start Date:	May 2005
Study Completion Date:	February 2009
Primary Completion Date:	June 2008 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Phase I (Part 1): CNTO 95 Patients will receive CNTO 95 (3 mg/kg, 5 mg/kg, or 10 mg/kg)	Drug: CNTO 95 CNTO 95 will be administered intravenously over a period of 2 hours (+15 minutes/-15 minutes) once every 3 weeks. In Phase I, CNTO 95 (3 mg/kg, 5 mg/kg or 10 mg/kg) will be administered until the occurrence of dose limiting toxicities. In Phase II, CNTO 95 (5 mg/kg or 10 mg/kg) will be administered for 8 cycles until no evidence of disease progression or unacceptable toxicity. If a patient responds to therapy with stable disease (SD) or better, the patient will be eligible to receive up to 8 cycles of extended administrations
Experimental: Phase I (Part 2): DTIC+5 mg/kg CNTO 95 Patients will receive dacarbazine (DTIC; 1000 mg/m2) in combination with CNTO 95 (5 mg/kg)	Drug: CNTO 95 CNTO 95 will be administered intravenously over a period of 2 hours (+15 minutes/-15 minutes) once every 3 weeks. In Phase I, CNTO 95 (3 mg/kg, 5 mg/kg or 10 mg/kg) will be administered until the occurrence of dose limiting toxicities. In Phase II, CNTO 95 (5 mg/kg or 10 mg/kg) will be administered for 8 cycles until no evidence of disease progression or unacceptable toxicity. If a patient responds to therapy with stable disease (SD) or better, the patient will be eligible to receive up to 8 cycles of extended administrations Drug: DTIC Commercially available DTIC will be administered intravenously over a 60-minute period (+30 minutes/-30 minutes) and prior to the CNTO 95/placebo infusion. In case patients are unable to tolerate DTIC even after 2 dose reductions, they will be given the option to continue on CNTO 95 alone.
Experimental: Phase I (Part 2): DTIC+10 mg/kg CNTO 95 Patients will receive DTIC (1000 mg/m2) in combination with CNTO 95 (10 mg/kg)	Drug: CNTO 95 CNTO 95 will be administered intravenously over a period of 2 hours (+15 minutes/-15 minutes) once every 3 weeks. In Phase I, CNTO 95 (3 mg/kg, 5 mg/kg or 10 mg/kg) will be administered until the occurrence of dose limiting toxicities. In Phase II, CNTO 95 (5 mg/kg or 10 mg/kg) will be administered for 8 cycles until no evidence of disease progression or unacceptable toxicity. If a patient responds to therapy with stable disease (SD) or better, the patient will be eligible to receive up to 8 cycles of extended administrations Drug: DTIC Commercially available DTIC will be administered intravenously over a 60-minute period (+30 minutes/-30 minutes) and prior to the CNTO 95/placebo infusion. In case patients are unable to tolerate DTIC even after 2 dose reductions, they will be given the option to continue on CNTO 95 alone.
Active Comparator: Phase II: DTIC + placebo Patients will receive DTIC in combination with placebo once every 3 weeks	Drug: DTIC Commercially available DTIC will be administered intravenously over a 60-minute period (+30 minutes/-30 minutes) and prior to the CNTO 95/placebo infusion. In case patients are unable to tolerate DTIC even after 2 dose reductions, they will be given the option to continue on CNTO 95 alone. Drug: Placebo Placebo will be administered intravenously over a period of 2 hours (+15 minutes/-15 minutes).
Experimental: Phase II: 5 mg/kg CNTO 95 Patients will receive CNTO 95 (5 mg/kg)	Drug: CNTO 95 CNTO 95 will be administered intravenously over a period of 2 hours (+15 minutes/-15 minutes) once every 3 weeks. In Phase I, CNTO 95 (3 mg/kg, 5 mg/kg or 10 mg/kg) will be administered until the occurrence of dose limiting toxicities. In Phase II, CNTO 95 (5 mg/kg or 10 mg/kg) will be administered for 8 cycles until no evidence of disease progression or unacceptable toxicity. If a patient responds to therapy with stable disease (SD) or better, the patient will be eligible to receive up to 8 cycles of extended administrations
Experimental: Phase II: 10 mg/kg CNTO 95 Patients will receive CNTO 95 (10 mg/kg)	Drug: CNTO 95 CNTO 95 will be administered intravenously over a period of 2 hours (+15 minutes/-15 minutes) once every 3 weeks. In Phase I, CNTO 95 (3 mg/kg, 5 mg/kg or 10 mg/kg) will be administered until the occurrence of dose limiting toxicities. In Phase II, CNTO 95 (5 mg/kg or 10 mg/kg) will be administered for 8 cycles until no evidence of disease progression or unacceptable toxicity. If a patient responds to therapy with stable disease (SD) or better, the patient will be eligible to receive up to 8 cycles of extended administrations
Experimental: Phase II: DTIC+10 mg/kg CNTO 95 Patients will receive DTIC in combination with CNTO 95 (10 mg/kg)	Drug: CNTO 95 CNTO 95 will be administered intravenously over a period of 2 hours (+15 minutes/-15 minutes) once every 3 weeks. In Phase I, CNTO 95 (3 mg/kg, 5 mg/kg or 10 mg/kg) will be administered until the occurrence of dose limiting toxicities. In Phase II, CNTO 95 (5 mg/kg or 10 mg/kg) will be administered for 8 cycles until no evidence of disease progression or unacceptable toxicity. If a patient responds to therapy with stable disease (SD) or better, the patient will be eligible to receive up to 8 cycles of extended administrations Drug: DTIC Commercially available DTIC will be administered intravenously over a 60-minute period (+30 minutes/-30 minutes) and prior to the CNTO 95/placebo infusion. In case patients are unable to tolerate DTIC even after 2 dose reductions, they will be given the option to continue on CNTO 95 alone.

Detailed Description:

This is a Phase 1/2, multi-center, randomized (the study medication is assigned by chance) study. This study is conducted in 2 Phases (Phase 1 and Phase 2). Phase 1 of this study is nonrandomized, open-label (all people know the identity of the intervention), dose-escalation phase. It includes screening period and treatment period, which consists of 2 parts (Part 1 and Part 2). In Part 1, patients will receive 1 of 3 single dose levels of CNTO 95 [3 mg/kg, 5 mg/kg, or 10 mg/kg]. Part 2 will include 2 dose cohorts, Cohort 1: dacarbazine (DTIC) plus CNTO 95 [5 mg/kg] and Cohort 2: DTIC plus CNTO 95 [10 mg/kg]. Phase 2 of this study is randomized, blinded (neither physician nor patient knows the intervention which the patient will receive nor any 1 of them does not know the intervention), 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 includes 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, patients will be randomly assigned to 1 of 4 treatment groups, Group 1: DTIC plus placebo, Group 2: CNTO 95 (5 mg/kg), Group 3: CNTO 95 (10 mg/kg), and Group 4: DTIC plus CNTO 95. Randomization will be further based on the site of metastases at baseline and baseline Eastern Cooperative Oncology Group performance status. Single-medication CNTO 95 treatment groups will be open-label, while the DTIC plus CNTO 95 or placebo groups will be blinded. The total duration of the Phase 2 of this study is 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 patients that are responding to therapy with stable disease or better). Safety evaluations will include adverse events, infusion reactions, clinical laboratory tests, electrocardiogram, vital signs, and physical examination.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Histologically confirmed melanoma including ocular and mucosal (Stage III unresectable or Stage IV)
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
Adequate values of bone marrow, liver function tests, and renal function tests

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) only and presence of central nervous system metastases
Prior radiation to target lesions
Concurrent immunotherapy, biotherapy, radiotherapy, chemotherapy, or investigational therapy and therapeutic use of anticoagulation
History of bleeding diathesis, recurrent deep vein thrombosis and uveitis
Planned surgery (except for minor surgical procedures) during study period

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00246012

Show 38 Study Locations

Sponsors and Collaborators

Centocor, Inc.

Janssen-Cilag Farmaceutica, S.R.L.

Investigators

Study Director:

Centocor, Inc Clinical Trial

Centocor, Inc.

More Information

No publications provided

Responsible Party:	Centocor, Inc.
ClinicalTrials.gov Identifier:	NCT00246012 History of Changes
Other Study ID Numbers:	CR006004, C1034T02, 2004-002130-18
Study First Received:	October 28, 2005
Last Updated:	December 4, 2012
Health Authority:	United States: Food and Drug Administration

Keywords provided by Centocor, Inc.:

Melanoma Stage IV
Cancer
CNTO 95

Dacarbazine
Intetumumab
Human Monoclonal Antibody

Additional relevant MeSH terms:

Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Antibodies, Monoclonal

Dacarbazine
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on May 21, 2013