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

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

Status

Terminated

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01127178

Enrollment

Registered

2010-05-20

Start date

2010-03-29

Completion date

2011-02-24

Last updated

2024-10-10

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Solid Tumors

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.

Interventions

DRUGE7016 + TMZ

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.

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
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

Measure	Time frame	Description
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.
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

Countries

United States

Participant flow

Recruitment details

Participants took part in the study at 2 investigative sites in the United States from 29 March 2010 to 24 February 2011.

Pre-assignment details

A total of 13 participants were screened, of which 1 was screen failure and 12 were enrolled to receive study treatment in Dose Escalation Part. The study was terminated due to sponsor's strategic decision, which is unrelated to safety, therefore no participants were enrolled in the Dose Expansion part. Hence, no data collection and analysis were done during Dose Expansion part of this study.

Participants by arm

Arm	Count
Dose Escalation Part: E7016 4 mg/kg/Day + Temozolomide 150 mg/m^2 Participants received single oral dose of 4 mg/kg/day E7016 capsule on Day -7 for PK analysis, followed by once daily dose from days 1 to 5 in combination with temozolomide 150 mg/m\^2 capsule and alone on days 6 and 7 of Cycle 1 (cycle length=28 days) in Treatment Phase. Participants who completed the Treatment Phase entered the Extension Phase of Dose Escalation Part and continued the treatment in Extension Phase in same manner of Treatment Phase until unacceptable toxicity, disease progression, termination by the treating investigator, withdrawal of consent, termination of the program by the sponsor, or treatment delay \>2 weeks for recovery of toxicity.	9
Dose Escalation Part: E7016 8 mg/kg/Day + Temozolomide 150 mg/m^2 Participants received single oral dose of 8 mg/kg/day E7016 capsule on Day -7 for PK analysis, followed by once daily dose from days 1 to 5 in combination with temozolomide 150 mg/m\^2 capsule and alone on days 6 and 7 of Cycle 1 (cycle length=28 days) in Treatment Phase. Participants who completed the Treatment Phase entered the Extension Phase of Dose Escalation Part and continued the treatment in Extension Phase in same manner of Treatment Phase until unacceptable toxicity, disease progression, termination by the treating investigator, withdrawal of consent, termination of the program by the sponsor, or treatment delay \>2 weeks for recovery of toxicity.	3
Total	12

Withdrawals & dropouts

Period	Reason	FG000	FG001
Dose Escalation: Extension Phase	Adverse Event	0	1
Dose Escalation: Extension Phase	Other	1	0
Dose Escalation: Extension Phase	Withdrawal by Subject	1	0
Dose Escalation: Treatment Phase	Adverse Event	1	0
Dose Escalation: Treatment Phase	Other	2	0
Dose Escalation: Treatment Phase	Withdrawal by Subject	1	0

Baseline characteristics

Characteristic	Dose Escalation Part: E7016 8 mg/kg/Day + Temozolomide 150 mg/m^2	Total	Dose Escalation Part: E7016 4 mg/kg/Day + Temozolomide 150 mg/m^2
Age, Continuous	57.0 Years STANDARD_DEVIATION 8.19	55.3 Years STANDARD_DEVIATION 7.85	54.8 Years STANDARD_DEVIATION 8.17
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants	2 Participants	2 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	3 Participants	10 Participants	7 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	1 Participants	2 Participants	1 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	2 Participants	10 Participants	8 Participants
Sex: Female, Male Female	1 Participants	8 Participants	7 Participants
Sex: Female, Male Male	2 Participants	4 Participants	2 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	4 / 9	0 / 3
other Total, other adverse events	9 / 9	3 / 3
serious Total, serious adverse events	5 / 9	1 / 3

Outcome results

Primary

Alternative Dose of Interest (ADI) for E7016 in Combination With Temozolomide

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.

Time frame: Cycle 1 (Cycle length = 28 days)

Population: An ADI was not pursued due to the limited sample size. No data was collected and analyzed to report in this outcome measure.

Primary

Maximum Tolerated Dose (MTD) for E7016 in Combination With Temozolomide

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).

Time frame: Cycle 1 (Cycle length = 28 days)