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

Phase 1

Terminated

• Conditions: Solid Tumors
• Interventions: Drug: E7016 + TMZ

• Registration Number: NCT01127178
• Lead Sponsor: Eisai Inc.

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2010-03-29
• Study First Submitted: 2010-05-10
• Study First Submitted QC: 2010-05-19
• Study First Posted: 2010-05-20
• Primary Completion: 2011-02-24
• Study Completion: 2011-02-24
• Status Verified: 2015-12
• Results First Submitted: 2024-01-05
• Results First Submitted QC: 2024-07-15
• Last Update Submitted: 2024-07-15
• Results First Posted: 2024-10-10
• Last Update Posted: 2024-10-10

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 12

Inclusion Criteria

Subjects who meet all of the following criteria may be included in the study.

1. 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.

2. Life expectancy greater than or equal to 3 months after starting E7016.

3. Performance status (PS) 1 to 2 on the Eastern Cooperative Oncology Group (ECOG) scale.

4. Adequate renal function indicated by serum creatinine less than 1.5 mg/dL or calculated creatinine clearance greater than 50 mL/minute.

5. Adequate bone marrow reserve:

   1. ANC greater than or equal to 1500/mm3,
   2. Platelets greater than or equal to 100,000/mm3 (without transfusion),
   3. Hemoglobin greater than or equal to 10 g/dL (less than 10.0 g/dL is acceptable if corrected by growth factor or transfusion).

6. Adequate liver function:

   1. 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),
   2. 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).

7. Males and females age greater than or equal to 18 years at the time of informed consent.

   1. 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.
   2. 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:

1. Subjects with primary or metastatic brain tumors are excluded from the Dose-Escalation Component.
2. Subjects with active malignancies other than gliomas are excluded from the Expansion Component.
3. Subjects taking medications which are either strong CYP inhibitors or inducers will be excluded from the Dose-Escalation Component.
4. Prior treatment with a PARP inhibitor.
5. Inability to tolerate 150 mg/m2/d TMZ during previous therapy with TMZ.
6. Known allergy, hypersensitivity, or other contraindication to E7016, TMZ, or dacarbazine or any of the other components of the formulations.
7. Known human immunodeficiency virus infection, active hepatitis B or C.
8. Active infections requiring specific anti-infective therapy
9. Subjects who have had a major surgical procedure (including tumor resection) within 4 weeks prior to initiating E7016 treatment.
10. Subjects scheduled for surgery during the projected course of the study.
11. Females who are pregnant (positive B-hCG test) or breastfeeding.
12. Chemotherapy, radiation therapy, or immunotherapy within 4 weeks prior to initiating E7016 treatment (6 weeks for mitomycin C or nitrosoureas).
13. Prolongation of QTc interval (500 msec).
14. Achlorhydria or use of antacids, proton-pump inhibitors, or other drugs known to raise gastric pH within 2 weeks prior to study drug administration.
15. 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.
16. Unable to swallow multiple capsules.
17. History of drug or alcohol dependency or abuse within approximately the last 2 years.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
E7016 + TMZ	E7016 + TMZ	-

Primary Outcome Measures

Name	Time	Method
Maximum Tolerated Dose (MTD) for E7016 in Combination With Temozolomide	Cycle 1 (Cycle length = 28 days)	The MTD was defined as the highest dose of E7016 in combination with temozolomide at which no more than one of six participants experienced a dose-limiting toxicity (DLT). DLTs were defined as those adverse events (AEs) considered related to E7016 which occurred during the first cycle of study drug administration. DLTs were evaluated and graded based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE version \[v\] 4.0).
Number of Participants With Dose-limiting Toxicity (DLT)	Cycle 1 (Cycle length = 28 days)	A DLT was defined as those AEs considered related to E7016 which occurred during the first cycle of study drug administration. DLTs were evaluated and graded based on the NCI CTCAE version 4.0. The following toxicities were regarded as DLTs: a Grade 4 hematologic toxicity (lasting \[greater than or equal to\] \>=5 days); a temozolomide dose reduction for Grade \>=3 neutropenia or thrombocytopenia; or a Grade \>=3 nonhematologic toxicity (except optimally managed nausea, vomiting, or diarrhea) that was assessed by the investigator as related to study drug. A participant with two or more DLTs with the same preferred term was counted only once for that preferred term.
Alternative Dose of Interest (ADI) for E7016 in Combination With Temozolomide	Cycle 1 (Cycle length = 28 days)	The ADI determination plan was based primarily on clinical, and/or PK measurements of drug concentration and/or bioactivity as defined by preclinical studies. However, the ADI was not pursued due to the limited sample size.

Secondary Outcome Measures

Name	Time	Method
Objective Response Rate (ORR)	From Cycle 1 Day 1 up to 6 Cycles (Cycle length=28 days) of treatment, an average of 24 weeks	The ORR was defined as the percentage of participants with complete response (CR) plus partial response (PR) as determined by the investigator, using modified Response Evaluation Criteria in Solid Tumors (RECIST 1.1) in the evaluation of magnetic resonance imaging/computerized tomography (MRI/CT) scans of targeted lesions and photographs and bone scans if appropriate for the tumor type. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had to have reduction in short axis to less than 10 mm. PR was defined as at least a 30 percent (%) decrease in the sum of diameters of target lesions. ORR = CR + PR
Disease Control Rate (DCR)	From Cycle 1 Day 1 up to 6 Cycles (Cycle length=28 days) of treatment, an average of 24 weeks	DCR was defined as the percentage of participants who had BOR of CR plus PR plus stable disease (SD). The best observed response (BOR) was defined as the best response recorded from the start of the study treatment until discontinuation from the study. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had to have reduction in short axis to less than 10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions. SD was defined as nonCR/non-progressive disease (PD) (NN), for participants with nontarget lesions. The minimum duration of SD was 7 weeks of multiple dose treatment. For participants who did not have target lesions, the response category NN was used instead of SD. DCR = CR + PR + SD greater than or equal to 7 weeks
Overall Survival (OS)	From Cycle 1 Day 1 up to 6 Cycles (Cycle length=28 days) of treatment, an average of 24 weeks	OS was defined as the time from the first dose of E7016 until 6 Cycles of treatment or death whichever occurs first.