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Title A Randomized, Double Blind, Phase 2, Dose-Ranging Study to Evaluate the Safety and Efficacy of Veliparib and Whole Brain Radiation Therapy Versus Placebo and Whole Brain Radiation Therapy in Subjects with Brain Metastases from Non-Small Cell Lung Cancer

IRB ABBT1512

CC 12-1224

Hospital Main Campus

Phase Phase 2

Disease Brain, Lung

Drug Veliparib

Description

1. The primary efficacy endpoint is overall survival

1. Secondary efficacy endpoints are best tumor response rate, time to clinical brain metastasis progression and time to intracranial progressions (radiographic).

Inclusion Criteria

1. Subject must be ≥ 18 years of age;
2. Subject must have cytologically or histologically confirmed NSCLC;
3. Subject must have brain metastases as demonstrated on a MRI brain scan. Note: CT scan of brain with or without contrast scan be obtained if subject is medically ineligible for MRI;
4. Subject must be eligible for treatment with WBRT;
5. Subject must have adequate hematologic, renal, and hepatic function as follows:
   1. Absolute Neutrophil Count (ANC > 1,000/mm^3 [1.0 x 10^9/L]);
   2. Platelets > 100,000/mm^3 (100 x 10^9/L);
   3. Hemoglobin > 9.0 g/dL (1.4 mmol/L);
   4. Serum creatinine < 1.5 x upper normal limit (ULN) range OR creatinine clearance > 45 mL/min/1.73m^2 for subjects with creatinine levels above the ULN;
   5. AST and/or ALT < 2.5 x the ULN;
   6. Bilirubin < 1.5 x the ULN. Subjects with Gilberts Syndrome may have a bilirubin ≥ 1.5 � the ULN.
6. Women of childbearing potential and men must agree to use adequate contraception prior to study entry (sufficiently long enough to ensure prevention of pregnancy), for the duration of study participation and for a minimum of 90 days following completion of therapy. Women of childbearing potential must have a negative serum pregnancy test prior to initiation of treatment. To be considered of non-child bearing potential, postmenopausal women must be amenorrheic for at least 12 months or subjects must be surgically sterile. Adequate means of contraception are considered to be:
   1. Total abstinence from sexual intercourse as the preferred life style, periodic abstinence is not acceptable;
   2. Vasectomized male subjects or vasectomized partner of female subjects; a vasectomized partner of female subjects must be an exclusive partner;
   3. Hormonal contraceptives (oral, vaginal ring, parenteral or transdermal);
   4. Double-barrier method (condoms and diaphragm or vaginal cap plus spermicidal sponge, jellies or cream);
   5. Intra-Uterine Device (IUD).
   6. Note: Additionally, male subjects (including those who are vasectomized) with partners of childbearing potential, must agree to use condoms for the duration of the Treatment Period and for 90 days following completion of therapy.
7. Subject must be able to take oral medication.
8. Subject is capable of understanding and complying with parameters as outlined in the protocol and able to sign and date the informed consent approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study-specific procedures.

Exclusion Criteria

1. Subject is diagnosed with brain metastases > 28 days prior to Treatment Day 1;
2. Subject received any prior form of cranial radiation and/or neurosurgery for their brain metastases;
3. Subjects last dose of anti-cancer therapy or investigational therapy was ≤ 7 days prior to Treatment Day 1. Subjects may continue to receive Bisphosphonates, steroids, such as inhaled steroids for asthma, topical steroids, or replacement/stress corticosteroids, and medroxyprogesterone during the study if started prior totreatment with veliparib/placebo and WBRT;
4. Subject has a Karnofsky Performance Score (KPS) of < 70;
5. Subject has clinically significant dyspnea requiring supplemental oxygen therapy;
6. Subject has liver metastases (restaging is not required for known liver metastases);
7. Subject has more than 2 sites (organ systems) of metastases from NSCLC (restaging is not required for subjects with more than 2 known sites of metastases) with the exception of the following:
   1. Intra-cranial sites of metastases from NSCLC;
   2. Thoracic sites of metastases from NSCLC; and
   3. Bone metastases.
8. Subject has leptomeningeal metastases or subarachnoid spread of tumor as demonstrated on a MRI brain scan;
9. Subject has unresolved or unstable, serious toxicity from prior administration of another investigational drug and/or prior anti-cancer treatment;
10. Subject has a known seizure disorder that is uncontrolled, or has seizures occurring greater than or equal to 3 times a week over the past month. Subjects presenting with symptoms of seizures from the brain metastases are eligible; however he/she should receive adequate anti-seizure medication prior to study treatment;
11. Subject is pregnant or lactating;
12. Subject has previously been treated with a PARP inhibitor as an investigational agent;
13. Subject has clinically significant and uncontrolled major medical condition(s) including but not limited to:
    1. Uncontrolled nausea/vomiting /diarrhea;
    2. Active uncontrolled infection requiring intravenous antibiotics;
    3. Non-cancer related neurologic or neurodegenerative condition;
    4. Symptomatic congestive heart failure;
    5. Unstable angina pectoris or cardiac arrhythmia;
    6. Psychiatric illness/social situation that would limit compliance with study requirements;
    7. Any medical condition which, in the opinion of the Investigator, places the subject at an unacceptably high risk for toxicities;
    8. Significant fluid retention, including ascites or pleural effusion, may be allowed at the discretion of the Investigator.
14. Subject has a history of another active cancer within the past 5 years except:
    1. Cervical cancer in situ;
    2. In situ carcinoma of the bladder;
    3. Basal or squamous cell carcinoma of the skin;
    4. Or other cancer in situ that is considered cured.