A Phase I Study of MK-4827 in Combination with Temozolomide in Patients with Advanced Cancer
The goal of this clinical research study is to find the highest tolerable dose of the combination of MK-4827 and temozolomide that can be given to patients with advanced solid cancers. The effects of the study drugs at different dose levels and the safety of the study drugs will also be studied. You are also being asked to take part in optional procedures, which are described in a separate consent form.
Disease Group: Advanced Cancers
Treatment Agent: MK-4827,Temozolomide
Treatment Location: Both at MD Anderson & Other Sites
Sponsor: Merck & Co, Inc.
Primary To define the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of MK-4827 + TMZ administered to adult patients with solid tumors. Hypothesis: The DLTs observed in adult patients with locally advanced or metastatic solid tumors after administration of MK-4827 + TMZ will be dose-dependent and allow for definition of a MTD in disease-specific cohorts. Secondary To explore the anti-tumor activity of MK-4827 + TMZ doublet in patients with solid tumors. Exploratory To investigate the interaction of genotype, transcription profile, and / or protein in archival tumor tissue with potential predictors of response in patients treated with MK-4827 and temozolomide. To assess pharmacokinetic properties of MK-4827 administered orally to patients with solid tumors (Part A only). The samples will be archived for potential analysis.
IRB Review and Approval Date: 02/23/2011
Recruitment Status: Not Accepting
Projected Accrual: 64
1) In Part A of the Study: Patients must have a histologically-confirmed
metastatic or locally advanced solid tumor that has failed to respond to
standard therapy, progressed despite standard therapy, for which
standard therapy does not exist, or for which subject is not a candidate
or is unwilling to undergo standard therapy. Patient may have received
up to 3 prior treatment regimens for Part A.
2) In Part B of the Study (Dose Expansion Cohorts): Patients must have a histologically-confirmed recurrent glioblastoma multiforme with radiographic evidence of progression/recurrence of disease as defined by the Response Assessment in Neuro-Oncology (RANO). Patients may have received up to two prior treatment regimens for their recurrent disease. Adjuvant treatment of primary glioblastoma multiform (GBM) is not considered a prior treatment. Patients may NOT have received prior temozolomide or bevacizumab for their recurrent disease, although these treatments are allowed if received in the adjuvant setting. Patients receiving adjuvant treatment must have a treatment-free interval of > 3 months from the completion of adjuvant treatment without GBM progression. Patients with secondary glioblastoma multiforme are allowed.
3) (Inclusion #2 cont'd) OR Patients must have histologically-confirmed recurrent or metastatic melanoma. Patients may have received up to two prior therapies. Adjuvant treatment of melanoma is not considered a prior treatment. Patients who have received prior treatment with cytotoxic chemotherapy for their recurrent or metastatic melanoma are excluded. Patients may NOT have received prior temozolomide, Dacarbazine (DTIC), or Parp inhibitors.
4) Patient is male or female, and >/=18 years of age on day of signing informed consent.
5) Patients must have performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.
6) Patients must have adequate organ function as defined by the following:Absolute neutrophil count (ANC) >/= 1,500 /mcL; Platelets >/= 100,000 /mcL; Hemoglobin >/= 9 g/dL – without transfusion or erythrocyte stimulating agents (ESA) support; serum creatinine or calculated creatinine clearance </= 1.5 X upper limit of normal (ULN) OR >/= 60 mL/min for patients with creatinine levels > 1.5 X institutional ULN; serum total bilirubin </= 1.5 X ULN OR direct bilirubin </= ULN for patients with total bilirubin levels > 1.5 ULN; AST (SGOT) and ALT (SGPT) </= 2.5 X ULN (</= 5 X ULN for patients with liver metastases); International Normalized Ratio (INR) or Prothrombin Time (PT) </= 1.2 X ULN; activated Partial Thromboplastin Time (aPTT) </= 1.2 X ULN
7) Women enrolled in the study, who are not free from menses for > 1 year, posthysterectomy/oophorectomy, or surgically sterilized, are willing to use two adequate barrier methods of contraception to prevent pregnancy or to abstain from heterosexual activity throughout the study, starting with Visit 1 through 30 days after the last dose of study drug. Approved contraceptive methods include for example, intra uterine device, diaphragm with spermicide, cervical cap with spermicide, male condom or female condom with spermicide. Spermicides alone are not an acceptable method of contraception.
8) Male patient agrees to use an adequate method of contraception starting with the first dose of study drug through 90 days after the last dose of study drugs.
9) Patient has voluntarily agreed to participate by giving written informed consent.
10) Patient is able to swallow capsules and has no surgical or anatomical condition that will preclude the patient from swallowing and absorbing oral medications on an ongoing basis.
11) Patient has no history of a prior malignancy with the exception of gliomas (as secondary GBM is allowed), cervical intraepithelial neoplasia; basal cell carcinoma of the skin; adequately treated localized prostate carcinoma with Prostate-Specific Antigen (PSA) < 1.0; or who has undergone potentially curative therapy with no evidence of that disease for five years, or who is deemed at low risk for recurrence by his/her treating physician.
12) Patient has at least one measurable metastatic or recurrent lesion according to RECIST (if a solitary lesion, histological/cytological confirmation of its neoplastic nature is required). For GBM patients, patients must have at least one measurable lesion defined by the RANO criteria.
13) Female patient of childbearing potential has a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine pregnancy test is positive or borderline, a serum pregnancy test will be required.
1) Patient who has had chemotherapy, radiotherapy, or biological therapy
(including monoclonal antibodies) within four weeks prior to study Day 1
(six weeks for nitrosoureas & mitomycin C) or who has not recovered
(</= Grade 1 or baseline) from adverse events due to agents
administered more than four weeks earlier. (Patients with prostate
cancer who are currently taking hormonal agents as part of their
treatment are eligible for this study and may continue to take the
hormonal agents while participating in this study.)
2) Patient is currently participating or has participated in a study with an investigational compound or device within 28 days, or 5X half-life of the investigational compound (excluding monoclonal antibodies), whichever is longer, of Day 1 of this study.
3) Patients with known symptomatic or progressive Central Nervous System (CNS) metastases and/or carcinomatous meningitis are excluded. However, patients with CNS metastases who are asymptomatic and have completed a course of therapy are eligible for the study provided they are clinically stable for three months prior to entry as defined as: (1) no evidence of new or enlarging CNS metastasis (2) off steroids or on a stable dose of steroids. Patients with a primary brain tumor are eligible for the study.
4) Patient has known hypersensitivity to the components of study drug or its analogs.
5) Patient has a previous or current condition, therapy, or laboratory abnormality that may confound the results of the study, interfere with the patient’s participation for the full duration of the study, or increase the risk to the patient such that participation is not in his/her best interest.
6) Patient has prior exposure to PARP inhibitors. Prior exposure to temozolomide is allowed only for patients with GBM, provided it was received in the adjuvant setting with GBM progression after completion of adjuvant temozolomide treatment and a treatment-free interval of >/= 3 months.
7) Patient has significant or uncontrolled cardiovascular disease, including New York Heart Association (NYHA) Class III-IV heart failure, unstable angina, or a myocardial infarction within the last six months.
8) Patient has known psychiatric or substance abuse disorders that would interfere with compliance with study requirements.
9) Patient is, at the time of signing informed consent, a regular user (including "recreational use") of any illicit drugs or had a recent history (within the last year) of drug or alcohol abuse.
10) Patient is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study.
11) Patient is known to be Human Immunodeficiency Virus (HIV)-positive.
12) Patient has active Hepatitis B or C.
13) Patient has symptomatic ascites or pleural effusion. A patient who is clinically stable following treatment for these conditions is eligible.
14) Patient has a requirement for concurrent treatment with immunosuppressive agents other than prescribed corticosteroids at stable doses for >/= 2 weeks prior to first planned dose of study drug.
15) Patient must not have prior radiation therapy to more than 30 % of the bone marrow and must have recovered for at least 3 weeks from the hematologic toxicity of prior radiotherapy.
16) Patient has had a prior stem cell or bone marrow transplant.
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