Evaluation of Tumor Response to Ipilimumab in the Treatment of Melanoma With Brain Metastases

This study has been completed.
Sponsor:
Collaborator:
Medarex
Information provided by (Responsible Party):
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT00623766
First received: February 19, 2008
Last updated: May 27, 2014
Last verified: May 2014
  Purpose

To assess the response of melanoma with brain metastases to ipilimumab treatment while maintaining acceptable tolerability.


Condition Intervention Phase
Melanoma
Drug: Ipilimumab
Drug: Corticosteroid: Betamethasone
Drug: Corticosteroid: Dexamethasone
Drug: Corticosteroid: Fludrocortisone
Drug: Corticosteroid: Hydrocortisone
Drug: Corticosteroid: Meprednisone
Drug: Corticosteroid: Methylprednisolone
Drug: Corticosteroid: Prednisolone
Drug: Corticosteroid: Prednisone
Drug: Corticosteroid: Triamcinolone
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Multi-Center Phase II Study to Evaluate Tumor Response to Ipilimumab (BMS-734016) Monotherapy in Subjects With Melanoma Brain Metastases

Resource links provided by NLM:


Further study details as provided by Bristol-Myers Squibb:

Primary Outcome Measures:
  • Disease Control Rate by Modified World Health Organization (mWHO) Tumor Assessment Criteria [ Time Frame: From Day 1, first dose to end of Week 12 ] [ Designated as safety issue: No ]
    Disease control rate is defined as the number of patients with a best overall response of complete response (CR), partial response (PR), or stable disease (SD) (global, in brain, or outside of brain) based on mWHO criteria divided by the number of patients who received treatment. By mWHO criteria: CR=complete disappearance of all index lesions. PR=decrease, relative to baseline, of 50% or greater in the sum of the 2 largest perpendicular diameters of all index lesions. SD=does not meet criteria for CR or PR, in the absence of progressive disease (PD). Patients with PR or CR not confirmed after at least 4 weeks are scored as SD unless they have new primary lesions. PD=at least 25% increase in the sum of the diameters of all index lesions (taking as reference the smallest sum recorded at or following baseline) and/or the appearance of any new lesions. CNS=central nervous system.


Secondary Outcome Measures:
  • Disease Control Rate by Immune-related Response Criteria (irRC) [ Time Frame: From Day 1, first dose to end of Week 12 ] [ Designated as safety issue: No ]
    Disease control rate is defined as the number of patients with a best overall response of immune-related (ir) complete response (irCR), partial response (irPR), or stable disease (irSD) divided by the total number of patients who received treatment. By irRC definition: irCR=complete disappearance of all index lesions. irPR=decrease, relative to baseline, of 50% or greater in the sum of the products of the 2 largest perpendicular diameters of all index lesions. irSD=does not meet criteria for irCR or irPR, in the absence of ir progressive disease (irPD). irPD=at least 25% increase in the sum of the products of all index lesions (taking as reference the smallest sum recorded at or following baseline). CNS=central nervous system; non-CNS compartment=extracranial, or outside of the brain.

  • Best Overall Response Rate (BORR) by Modified World Health Organization (mWHO) Criteria and by Immune-relate Response Criteria (irRC) [ Time Frame: From Day 1, first dose until the last tumor assessment, Week 12 ] [ Designated as safety issue: Yes ]
    BORR is defined as the number of patients whose global best overall response (BOR) was complete (CR) or partial response (PR), divided by the total number of participants who received treatment. CR=complete disappearance of all index lesions. PR=decrease, relative to baseline, of 50% or greater in the sum of the products of the 2 largest perpendicular diameters of all index lesions. The global BOR is the best overall response (OR) designation over the study as a whole for an individual in the study based on overall tumor burden. Both central nervous system (CNS) (brain lesions) and non-CNS compartments (lesions outside the brain) are considered for the global BOR. For the analysis of global BOR of CR or PR (by both modified WHO criteria and immune-related response criteria [irRC]), the OR assessment must be confirmed by a second (confirmatory) evaluation meeting the criteria for response and must be performed no less than 4 weeks after the criteria for response are first met.

  • Duration of Response (DOR) by Modified World Health Organization (mWHO) Criteria and by Immune-related Response Criteria (irRC) [ Time Frame: From Day 1, first dose to last tumor assessment up to 18.2 months ] [ Designated as safety issue: Yes ]
    DOR is defined in patients whose global best overall response is complete (CR) or partial response (PR) as the time between the date of response of confirmed CR or PR, whichever occurs first, and the date of progressive disease or death, whichever occurs first. For patients who remain alive and have not progressed following response, duration of response will be censored on the date of last evaluable tumor assessment.

  • Progression-free Survival (PFS) by Modified World Health Organization (mWHO) Criteria and by Immune-related Response Criteria (irRC) [ Time Frame: From Day 1, first dose to the date of progression or death, whichever occurred first up to 22 months ] [ Designated as safety issue: No ]
    PFS is defined as the time between the date of the first dose of study therapy and the date of progression or death, whichever occurs first. A patient who dies without reported prior progression will be considered to have progressed on the date of death. For those who remain alive and have not progressed, PFS will be censored on the date of last evaluable tumor assessment. Participants who have not died and have no recorded postbaseline tumor assessment will be censored on the date of first dose of study therapy. Those who die without any recorded postbaseline tumor assessment will be considered to have progressed on the date of death.

  • Number of Participants Surviving at 6, 12, 18, 24, and 36 Months (Overall Survival [OS] Rate) [ Time Frame: From first dose to Months 6, 12, 18, 24, and 36 months ] [ Designated as safety issue: No ]
    OS is defined as the time from the first dose of study drug until the date of death. Overall survival rate is the percentage of participants known to be alive at a timepoint. For those patients who did not die, OS was censored at the recorded last date of patient contact, and those with a missing recorded last date of contact will be censored at the last date the patient was known to be alive. The survival rate at a specified time-point is the probability that a patient is alive at that time following randomization. The rate is calculated for each treatment group using the Kaplan-Meier product-limit method. A corresponding 2-sided 95% bootstrap confidence interval will be calculated.

  • Number of Participants Who Died or Had a Treatment-related Adverse Event (AE), Immune-related AE, Immune-related Serious Adverse Event (SAE), Nervous System Disorder, Treatment-related Nervous System Disorder, SAE, and AE Leading to Discontinuation [ Time Frame: Continuously from Day 1, first dose, to 70 days following last dose of ipilimumab ] [ Designated as safety issue: Yes ]
    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=Life-threatening or disabling, Gr 5=Death.

  • Onset of Response by Modified World Health Organization (mWHO) Criteria and Immune-related Response Criteria (irRC) [ Time Frame: From Day 1, first dose to a maximum of 4.2 months ] [ Designated as safety issue: Yes ]
    Onset of response is defined as the time between the first dose of study therapy and the date when measurement criteria are first met for global best overall response of partial (PR) or complete (CR), whichever occurs first. CR=complete disappearance of all index lesions. PR=decrease, relative to baseline, of 50% or greater in the sum of the 2 largest perpendicular diameters of all index lesions.

  • Overall Survival (OS) [ Time Frame: From first dose to 24 months ] [ Designated as safety issue: No ]
    OS is defined as the time from date of first dose of study drug until the date of death. For those patients who did not die, OS was censored at the recorded last date of patient contact, and those missing a recorded last date of contact will be censored at the last date the patient was known to be alive.


Enrollment: 99
Study Start Date: July 2008
Study Completion Date: October 2012
Primary Completion Date: September 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Ipilimumab, 10 mg/kg, IV in corticosteroid-free patients
Participants who had not received corticosteroid therapy for at least 10 days before starting study drug received ipilimumab,10 mg/kg, as a 90-minute intravenous (IV) infusion every 3 weeks (Weeks 1, 4, 7, and 10) during the Induction Phase. Those eligible (patients who did not discontinue due to toxicity, did not show progression at 24 weeks, and who remained clinically stable) for the Maintenance Phase continued to receive ipilimumab, 10 mg/kg IV, every 12 weeks, beginning at Week 24.
Drug: Ipilimumab
10 mg/kg, administered as an intravenous infusion every 3 weeks during induction and every 12 weeks during maintenance
Other Names:
  • BMS-734016
  • MDX-010
Experimental: Ipilimumab, 10 mg/kg, IV in corticosteroid-dependent patients
Participants who were dependent on corticosteroid therapy received ipilimumab, 10 mg/kg, as a 90-minute intravenous (IV) infusion every 3 weeks (Weeks 1, 4, 7, and 10) during the Induction Phase. Those eligible (patients who did not discontinue due to toxicity, did not show progression at 24 weeks, and who remained clinically stable) for the Maintenance Phase continued to receive ipilimumab, 10 mg/kg IV, every 12 weeks, beginning at Week 24.
Drug: Ipilimumab
10 mg/kg, administered as an intravenous infusion every 3 weeks during induction and every 12 weeks during maintenance
Other Names:
  • BMS-734016
  • MDX-010
Drug: Corticosteroid: Betamethasone
Participants in the corticosteroid-dependent arm for whom adequate control of metastatic brain lesion-related neurologic signs and symptoms required concurrent corticosteroid therapy with betamethasone
Drug: Corticosteroid: Dexamethasone
Participants in the corticosteroid-dependent arm for whom adequate control of metastatic brain lesion-related neurologic signs and symptoms required concurrent corticosteroid therapy with dexamethasone
Drug: Corticosteroid: Fludrocortisone
Participants in the corticosteroid-dependent arm for whom adequate control of metastatic brain lesion-related neurologic signs and symptoms required concurrent corticosteroid therapy with fludrocortisone
Drug: Corticosteroid: Hydrocortisone
Participants in the corticosteroid-dependent arm for whom adequate control of metastatic brain lesion-related neurologic signs and symptoms required concurrent corticosteroid therapy with hydrocortisone
Drug: Corticosteroid: Meprednisone
Participants in the corticosteroid-dependent arm for whom adequate control of metastatic brain lesion-related neurologic signs and symptoms required concurrent corticosteroid therapy with meprednisone
Drug: Corticosteroid: Methylprednisolone
Participants in the corticosteroid-dependent arm for whom adequate control of metastatic brain lesion-related neurologic signs and symptoms required concurrent corticosteroid therapy with methylprednisolone
Drug: Corticosteroid: Prednisolone
Participants in the corticosteroid-dependent arm for whom adequate control of metastatic brain lesion-related neurologic signs and symptoms required concurrent corticosteroid therapy with prednisolone
Drug: Corticosteroid: Prednisone
Participants in the corticosteroid-dependent arm for whom adequate control of metastatic brain lesion-related neurologic signs and symptoms required concurrent corticosteroid therapy with prednisone
Drug: Corticosteroid: Triamcinolone
Participants in the corticosteroid-dependent arm for whom adequate control of metastatic brain lesion-related neurologic signs and symptoms required concurrent corticosteroid therapy with triamcinolone

  Eligibility

Ages Eligible for Study:   16 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Key inclusion criteria

  • Histologically confirmed malignant melanoma
  • At least 1 measurable index brain metastasis >0.5 cm and no larger than 3 cm in diameter that had not been previously irradiated, and/or 2 measurable lesions >0.3 cm visible on contrast magnetic resonance
  • Index brain lesion must have resolved consequences of prior therapy that could have confounded attribution of tumor response including edema and hemorrhage
  • Participants in ipilimumab monotherapy arm (including the first 21 who were enrolled in Stage 1) were to be free of neurologic symptoms related to metastatic brain lesions and must not have required or received systemic corticosteroid therapy in the 10 days prior to beginning ipilimumab therapy
  • Eastern Cooperative Oncology Group performance status of 0 or 1
  • Required values for initial laboratory tests:

    • White blood cell count ≥2000/μL

      • Absolute neutrophil count ≥1000/μL
      • Platelets ≥100*10^3/μL
      • Hemoglobin level ≥9 g/dL (may have been transfused)
      • Aspartate aminotransferase/alanine aminotransferase (AST/ALT) level ≤2.5*ULN for participants without liver metastasis
      • AST/ALT level ≤5*ULN for those with liver metastasis
      • Bilirubin level ≤2*ULN (except participants with Gilbert's Syndrome, who must have had a total bilirubin level less than 3.0 mg/dL)
  • Age 16 years and older
  • Males and females
  • Women of childbearing potential (WOBP) must be using an adequate method of contraception to avoid pregnancy throughout the study (and for up to 26 weeks after the last dose of investigational product) in such a manner that the risk of pregnancy is minimized. WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal.

Key exclusion criteria

  • History of carcinomatous meningitis, with prior stereotactic or highly conformal radiotherapy and/or whole brain irradiation within 14 days before the first dose of ipilimumab, and documented history of autoimmune disease
  • Prior stereotactic or highly conformal radiotherapy and/or whole brain irradiation within 14 days prior to start of ipilimumab dosing for this study. Note the stereotactic radiotherapy field must not have included the brain index lesion or the lesion must have been detected and confirmed to be active and progressing after receiving whole brain irradiation.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00623766

Locations
United States, Arizona
Mayo Clinic Arizona
Scottsdale, Arizona, United States, 85259
United States, California
City Of Hope
Duarte, California, United States, 91010-3000
The Angeles Clinic & Research Institute
Los Angeles, California, United States, 90025
United States, Connecticut
Yale University School Of Medicine
New Haven, Connecticut, United States, 06520
United States, Illinois
Loyola University Medical Center
Maywood, Illinois, United States, 60153
Oncology Specialists, S.C.
Park Ridge, Illinois, United States, 60068
United States, Indiana
Indiana University Cancer Center
Indianapolis, Indiana, United States, 46202
United States, Massachusetts
Dana Farber Cancer Institute
Boston, Massachusetts, United States, 02215
United States, New Hampshire
Dartmouth Hitchcock Medical Center
Lebanon, New Hampshire, United States, 03756
United States, New York
Local Institution
Bronx, New York, United States, 10466
Memorial Sloan Kettering Cancer Center
New York, New York, United States, 10065
United States, Oregon
Providence Portland Med Ctr
Portland, Oregon, United States, 97213
United States, Tennessee
Vanderbilt-Ingram Cancer Ctr
Nashville, Tennessee, United States, 37232
United States, Washington
Seattle Cancer Care Alliance
Seattle, Washington, United States, 98109-1023
Sponsors and Collaborators
Bristol-Myers Squibb
Medarex
Investigators
Study Director: Bristol-Myers Squibb Bristol-Myers Squibb
  More Information

Additional Information:
No publications provided by Bristol-Myers Squibb

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT00623766     History of Changes
Other Study ID Numbers: CA184-042
Study First Received: February 19, 2008
Results First Received: December 17, 2013
Last Updated: May 27, 2014
Health Authority: United States: Food and Drug Administration

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
Dexamethasone acetate
Methylprednisolone acetate
Prednisolone acetate
Triamcinolone hexacetonide
Hydrocortisone acetate
Hydrocortisone 17-butyrate 21-propionate
Cortisol succinate
Dexamethasone
Prednisone
Prednisolone
Methylprednisolone
Methylprednisolone Hemisuccinate
Triamcinolone
Triamcinolone Acetonide
Hydrocortisone
Betamethasone
Fludrocortisone
Dexamethasone 21-phosphate
Prednisolone hemisuccinate
Prednisolone phosphate
BB 1101
Triamcinolone diacetate

ClinicalTrials.gov processed this record on September 18, 2014