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

Melanoma Clinical Trial

Official title:

A Multi-Center Phase II Study to Evaluate Tumor Response to Ipilimumab (BMS-734016) Monotherapy in Subjects With Melanoma Brain Metastases

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00623766
• Other study ID #: CA184-042
• Status: Completed
• Phase: Phase 2
• First received: February 19, 2008
• Last updated: May 27, 2014
• Start date: July 2008
• Est. completion date: October 2012

Study information

• Verified date: May 2014
• Source: Bristol-Myers Squibb
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 99
• Est. completion date: October 2012
• Est. primary completion date: September 2009
• Accepts healthy volunteers: No
• Gender: All
• Age group: 16 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Melanoma

Intervention

Drug:
• Ipilimumab
10 mg/kg, administered as an intravenous infusion every 3 weeks during induction and every 12 weeks during maintenance
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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

Locations

Country	Name	City	State
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Local Institution	Bronx	New York
United States	City Of Hope	Duarte	California
United States	Indiana University Cancer Center	Indianapolis	Indiana
United States	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire
United States	The Angeles Clinic & Research Institute	Los Angeles	California
United States	Loyola University Medical Center	Maywood	Illinois
United States	Vanderbilt-Ingram Cancer Ctr	Nashville	Tennessee
United States	Yale University School Of Medicine	New Haven	Connecticut
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Oncology Specialists, S.C.	Park Ridge	Illinois
United States	Providence Portland Med Ctr	Portland	Oregon
United States	Mayo Clinic Arizona	Scottsdale	Arizona
United States	Seattle Cancer Care Alliance	Seattle	Washington

Sponsors (2)

Lead Sponsor	Collaborator
Bristol-Myers Squibb	Medarex

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Disease Control Rate by Modified World Health Organization (mWHO) Tumor Assessment Criteria	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.	From Day 1, first dose to end of Week 12
Secondary	Disease Control Rate by Immune-related Response Criteria (irRC)	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.	From Day 1, first dose to end of Week 12
Secondary	Best Overall Response Rate (BORR) by Modified World Health Organization (mWHO) Criteria and by Immune-relate Response Criteria (irRC)	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.	From Day 1, first dose until the last tumor assessment, Week 12
Secondary	Duration of Response (DOR) by Modified World Health Organization (mWHO) Criteria and by Immune-related Response Criteria (irRC)	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.	From Day 1, first dose to last tumor assessment up to 18.2 months
Secondary	Progression-free Survival (PFS) by Modified World Health Organization (mWHO) Criteria and by Immune-related Response Criteria (irRC)	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.	From Day 1, first dose to the date of progression or death, whichever occurred first up to 22 months
Secondary	Number of Participants Surviving at 6, 12, 18, 24, and 36 Months (Overall Survival [OS] Rate)	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.	From first dose to Months 6, 12, 18, 24, and 36 months
Secondary	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	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.	Continuously from Day 1, first dose, to 70 days following last dose of ipilimumab
Secondary	Onset of Response by Modified World Health Organization (mWHO) Criteria and Immune-related Response Criteria (irRC)	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.	From Day 1, first dose to a maximum of 4.2 months
Secondary	Overall Survival (OS)	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.	From first dose to 24 months

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