A Study Evaluating Efficacy of ABT-888 in Combination With Temozolomide in Metastatic Melanoma

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy of ABT-888 in combination with temozolomide versus temozolomide alone in subjects with metastatic melanoma.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study Evaluating the Efficacy of ABT-888 in Combination With Temozolomide Versus Temozolomide Alone in Subjects With Metastatic Melanoma

Conditions
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Melanoma, Metastatic Melanoma, Skin Cancer

Intervention / Treatment
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* Drug: temozolomide
* Drug: ABT-888
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically (or cytologically) confirmed metastatic melanoma. Unresectable Stage III or Stage IV metastatic melanoma. Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Subjects with no history of brain metastases demonstrated by a baseline MRI, or subjects with a history of previously treated brain metastases who have history of operable/SRS treatable brain metastases and completed surgical resection/stereotactic radiosurgery with or without adjuvant whole brain radiation at least 28 days prior to Day 1; have baseline MRI that shows no evidence of active intercranial disease; have discontinued taking medications for symptom management of brain metastases at least 7 days prior to Day 1 28 days since prior anti-cancer therapy. Eastern Cooperative Oncology Group (ECOG) Performance Score of 0-1. Adequate hematologic, renal and hepatic function. Partial Thromboplastin Time (PTT) is <= 1.5 x upper normal limit of institution's normal range and international normalized ratio (INR) < 1.5. Subject's with significant fluid retention may be allowed at the discretion of the investigator. Life expectancy > 12 weeks. Females must not be pregnant. Voluntarily signed informed consent. Exclusion Criteria: Lactate Dehydrogenase (LDH) > 2 x Upper Limit of Normal (ULN). Ocular malignant melanoma. History of central nervous system metastases or leptomeningeal disease. Prior treatment with Dacarbazine (DTIC) or Temozolomide (TMZ). Prior DNA damaging agents or cytotoxic chemotherapy. Prior Whole Brain Radiation Therapy (with exceptions). Received an investigational agent within 28 days of study. History of seizure disorder and/or taking medication for seizure disorder. Active malignancy within the past 5 years, except cervical cancer in situ, in situ carcinoma of the bladder or non-melanoma carcinoma of the skin. Medical condition that would cause a high risk for toxicities.

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo for ABT-888 BID + TMZ QD<br>Placebo for ABT-888 twice daily (BID) for 7 days every 28 days plus temozolomide (TMZ; by body surface area) 150 mg/m2 once daily (QD) for 5 days every 28 days. | Drug: temozolomide<br>* temozolomide capsule administered orally once daily for 5 days every 28 days<br>* Other names: Temodal;Other: Placebo<br>* Placebo for ABT-888 capsule administered orally twice daily for 7 days every 28 days<br>|
| Active Comparator: ABT-888 20 mg BID + TMZ QD<br>ABT-888 20 mg twice daily (BID) for 7 days every 28 days plus temozolomide (TMZ; by body surface area) 150 mg/m2 once daily (QD) for 5 days every 28 days. | Drug: temozolomide<br>* temozolomide capsule administered orally once daily for 5 days every 28 days<br>* Other names: Temodal;Drug: ABT-888<br>* ABT-888 capsule administered orally twice daily for 7 days every 28 days<br>* Other names: veliparib;|
| Active Comparator: ABT-888 40 mg BID + TMZ QD<br>ABT-888 40 mg twice daily (BID) for 7 days every 28 days plus temozolomide (TMZ; by body surface area) 150 mg/m2 once daily (QD) for 5 days every 28 days. | Drug: temozolomide<br>* temozolomide capsule administered orally once daily for 5 days every 28 days<br>* Other names: Temodal;Drug: ABT-888<br>* ABT-888 capsule administered orally twice daily for 7 days every 28 days<br>* Other names: veliparib;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS): Time to Event | PFS: the number of days from the date that the participant was randomized to the date the participant experienced a confirmed event of disease progression (radiological, as determined by the central imaging center; or clinical, as determined by the investigator), or to the date of death (all causes of mortality) if disease progression was not reached. All events were included whether the participant was still taking or had discontinued study drug. Events of death were included for participants who had not experienced a confirmed event of disease progression, provided the death occurred within 8 weeks of the last available disease progression assessment. The distribution of PFS, as determined by the central imaging center (radiological)/ investigator (clinical), was estimated for each treatment group using Kaplan-Meier methodology. Point estimates and 95% confidence intervals (95% CIs) for the quartiles for the PFS distribution are provided. | Every Cycle (28 Days) until disease progression was observed or another reason for discontinuation of assessments was identified by the investigator. The maximum observed followup duration at the progression-free survival analysis time was 9.7 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS): Time to Event | OS was defined as the number of days from the date the participant was randomized to the date of death. All deaths were included, whether the participant was still taking or had discontinued study drug. If a participant had not died and was lost to follow-up, then data were censored at the last study visit or contact date, or date the participant was last known to be alive, whichever was later; if the participant was not lost to follow-up, then data were censored at the last study visit or contact date, whichever was later. The distribution of OS was estimated for each treatment group using Kaplan-Meier methodology. Point estimates and 95% CIs for the quartiles for the OS distribution are provided. Per protocol, because neither the ABT-888 20 mg BID + TMZ nor ABT-888 40 mg BID + TMZ groups were statistically significantly better than the Placebo + TMZ group for the primary endpoint of PFS, confirmatory statistical testing was not continued for any secondary endpoints. | Per protocol, survival follow-up information was to be obtained every 3 months for up to 18 months after the final visit for the subject. The maximum observed follow-up at the overall survival analysis time was 21.0 months. | 
| 12-Month Overall Survival (OS) Rate | The 12-month overall survival rate was defined as the percentage of participants surviving at 12 months. The distribution of 12-month OS rate was estimated using Kaplan-Meier methodology. Point estimates and 95% CIs for the quartiles for the PFS distribution are provided. Per protocol, because neither the ABT-888 20 mg BID + TMZ nor ABT-888 40 mg BID + TMZ treatment groups were statistically significantly better than the Placebo + TMZ treatment group for the primary endpoint of PFS, confirmatory statistical testing was not continued for any secondary endpoints, regardless of the observed P values. | Per protocol, survival was to be assessed every 4 weeks or as needed after participant is registered as off-study for up to 18 months. The maximum observed follow-up at the overall survival analysis time was 21.0 months. | 
| 6-month Progression-Free Survival Rate | The 6-month progression-free survival rate was defined as the percentage of participants without disease progression at 6 months.The distribution of 6-month progression-free survival rate, as determined by the central imaging center (radiological)/ investigator (clinical), was estimated using Kaplan-Meier methodology. Point estimates and 95% CIs for the quartiles for the PFS distribution are provided. Per protocol, because neither the ABT-888 20 mg BID + TMZ nor ABT-888 40 mg BID + TMZ treatment groups were statistically significantly better than the Placebo + TMZ treatment group for the primary endpoint of PFS, confirmatory statistical testing was not continued for any secondary endpoints, regardless of the observed P values. | Every Cycle (28 Days) until disease progression was observed or another reason for discontinuation of assessments was identified by the investigator. The maximum observed followup duration at the progression-free survival analysis time was 9.7 months. | 
| Objective Response Rate | The objective response rate was defined as the percentage of participants with a confirmed CR or PR per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by computed tomography (CT) scan: complete response (CR), disappearance of all target lesions; partial response (PR), ≥30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. Per protocol, because neither the ABT-888 20 mg BID + TMZ nor ABT-888 40 mg BID + TMZ treatment groups were statistically significantly better than the Placebo + TMZ treatment group for the primary endpoint of PFS, confirmatory statistical testing was not continued for any secondary endpoints, regardless of the observed P values. | Every 2 cycles (8 weeks) until disease progression was observed or another reason for discontinuation of assessments was identified by the investigator. The maximum observed followup duration at the progression-free survival analysis time was 9.7 months. | 
| Time to Disease Progression | The distribution of time to disease progression, as determined by the central imaging center (radiological)/ investigator (clinical), was estimated for each treatment group using Kaplan-Meier methodology. Point estimates and 95% CIs for the quartiles for the PFS distribution are provided. Per protocol, because neither the ABT-888 20 mg BID + TMZ nor ABT-888 40 mg BID + TMZ treatment groups were statistically significantly better than the Placebo + TMZ treatment group for the primary endpoint of PFS, confirmatory statistical testing was not continued for any secondary endpoints, regardless of the observed P values. | Every Cycle (28 Days), until disease progression was observed or another reason for discontinuation of assessments was identified by the investigator. The maximum observed followup duration at the progression-free survival analysis time was 9.7 months. | 
| Disease Control Rate | The disease control rate was defined as the percentage of participants who had at least stable disease (complete response, partial response, or stable disease) through the end of Week 8. Per protocol, because neither the ABT-888 20 mg BID + TMZ nor ABT-888 40 mg BID + TMZ treatment groups were statistically significantly better than the Placebo + TMZ treatment group for the primary endpoint of PFS, confirmatory statistical testing was not continued for any secondary endpoints, regardless of the observed P values. | Week 8 | 
| Time to Neurological/Brain Metastases Progression | Time to neurological/brain metastases progression, defined as the number of days from the date of randomization to the date the participant experienced an event of neurological/brain metastases progression, was estimated using Kaplan-Meier methodology. Point estimates and 95% CIs for the quartiles for the distribution are provided. All events of progression were included, regardless of whether the event occurred while the participant was still taking study drug. If a participant did not experience an event, data were censored at the date of the last available brain CT scan. For participants with no postbaseline brain CT scans, data were censored at randomization. Per protocol, because neither the ABT-888 20 mg BID + TMZ nor ABT-888 40 mg BID + TMZ groups were statistically significantly better than the Placebo + TMZ group for the primary endpoint of PFS, confirmatory statistical testing was not continued for any secondary endpoints, regardless of the observed P values. | Every 2 cycles (8 weeks) until disease progression was observed or another reason for discontinuation of assessments was identified by the investigator. The maximum observed followup duration at the progression-free survival analysis time was 9.7 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ABT-888, Temozolomide, Skin cancer, Melanoma, Metastatic Melanoma, MM