Study of Poly (ADP-Ribose) Polymerase (PARP) Inhibitor E7016 in Combination With Temozolomide in Subjects With Advanced Solid Tumors

Study Overview
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Brief Summary
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The purpose of this study is to determine the maximum tolerated dose (MTD) of poly (ADP-Ribose) polymerase inhibitor E7016 when used with temozolomide (TMZ) in patients with advanced solid tumors and gliomas.

Official Title
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Phase 1 Study of the Poly (ADP-Ribose) Polymerase Inhibitor E7016 in Combination With Temozolomide in Subjects With Advanced Solid Tumors

Conditions
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Solid Tumors

Intervention / Treatment
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* Drug: E7016 + TMZ


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects who meet all of the following criteria may be included in the study. Histopathologically confirmed melanoma or other solid tumors (excluding malignant brain tumors) for which no standard therapy is available (Dose-Escalation Component only). During the Expansion Component, enrollment will be restricted to subjects with histopathologically proven gliomas and will include subjects eligible for TMZ therapy as well as those who have failed TMZ therapy; and those who are either not appropriate candidates for radiation therapy or who refuse radiation therapy. Subjects who are taking either strong cytochrome P450 (CYP) inhibitors or inducers may be enrolled. Life expectancy greater than or equal to 3 months after starting E7016. Performance status (PS) 1 to 2 on the Eastern Cooperative Oncology Group (ECOG) scale. Adequate renal function indicated by serum creatinine less than 1.5 mg/dL or calculated creatinine clearance greater than 50 mL/minute. Adequate bone marrow reserve: ANC greater than or equal to 1500/mm3, Platelets greater than or equal to 100,000/mm3 (without transfusion), Hemoglobin greater than or equal to 10 g/dL (less than 10.0 g/dL is acceptable if corrected by growth factor or transfusion). Adequate liver function: Bilirubin less than or equal to 1.5x the upper limit of normal (ULN) (less than or equal to 3 x ULN if subject has liver metastases), Alkaline phosphatase, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) less than or equal to 3 times ULN (less than or equal to 5 x ULN if subject has liver metastases). Males and females age greater than or equal to 18 years at the time of informed consent. Female subjects of childbearing potential must have a negative serum beta human chorionic gonadotropin (BhCG) test at Visit 1 (Screening) and a negative urine pregnancy test prior to the first dose of E7016 capsules in the Single-Dose PK Period and again prior to the first dose of E7016 in Cycle 1. Male subjects who are partners of women of childbearing potential must use or their partners must use a highly effective method of contraception (eg, condom + spermicide, condom + diaphragm with spermicide, IUD) beginning at least 1 menstrual cycle prior to starting study drug(s), throughout the entire study period, and for 30 days after the last dose of study drug. Exclusion Criteria: Subjects who meet any of the following criteria will be excluded from participation in the study: Subjects with primary or metastatic brain tumors are excluded from the Dose-Escalation Component. Subjects with active malignancies other than gliomas are excluded from the Expansion Component. Subjects taking medications which are either strong CYP inhibitors or inducers will be excluded from the Dose-Escalation Component. Prior treatment with a PARP inhibitor. Inability to tolerate 150 mg/m2/d TMZ during previous therapy with TMZ. Known allergy, hypersensitivity, or other contraindication to E7016, TMZ, or dacarbazine or any of the other components of the formulations. Known human immunodeficiency virus infection, active hepatitis B or C. Active infections requiring specific anti-infective therapy Subjects who have had a major surgical procedure (including tumor resection) within 4 weeks prior to initiating E7016 treatment. Subjects scheduled for surgery during the projected course of the study. Females who are pregnant (positive B-hCG test) or breastfeeding. Chemotherapy, radiation therapy, or immunotherapy within 4 weeks prior to initiating E7016 treatment (6 weeks for mitomycin C or nitrosoureas). Prolongation of QTc interval (500 msec). Achlorhydria or use of antacids, proton-pump inhibitors, or other drugs known to raise gastric pH within 2 weeks prior to study drug administration. Any history of or concomitant medical condition or clinically significant disease making the subject medically unfit to receive the study drug or, in the opinion of the investigator, unsuitable for any other reason. Unable to swallow multiple capsules. History of drug or alcohol dependency or abuse within approximately the last 2 years.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: E7016 + TMZ<br> | Drug: E7016 + TMZ<br>* Single-Dose PK Period (single oral dose of E7016 on Day -7) in the Dose-Escalation Component; Multiple-Dose Treatment Cycles (7 days of oral E7016 + 5 days of oral TMZ) added in Cycle 1 of the Dose-Escalation Component and in Cycles 1 through 6 of the Expansion Component.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine dose-limiting toxicities (DLTs) for E7016 in combination with temozolomide (TMZ) in subjects with advanced solid tumors and gliomas. |  | 18 months | 
| Determine alternative dose of interest (ADI) for E7016 in combination with temozolomide (TMZ) in subjects with advanced solid tumors and gliomas. |  | 18 months | 
| Determine the maximum tolerated dose (MTD) for E7016 in combination with temozolomide (TMZ) in subjects with advanced solid tumors and gliomas. |  | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the overall safety and tolerability of E7016 in combination with TMZ. |  | 18 months | 
| Determine the plasma pharmacokinetics (PK) of E7016 and of TMZ. |  | 18 months | 
| Assess the pharmacodynamic (PD) activity of E7016, including inhibition of poly(ADP-ribose) polymerase (PARP) |  | 18 months |