An Open-Label, Multicenter, Randomized, Phase Ib/II Study of E7080 in Combination With Carboplatin + Gemcitabine Versus Carboplatin + Gemcitabine Alone as Second Line Therapy in Patients With Platinum-Sensitive Recurrent Ovarian Cancer by CA125.
Overview
- Phase
- Phase 1
- Intervention
- Lenvatinib
- Conditions
- Ovarian Cancer
- Sponsor
- Eisai Inc.
- Enrollment
- 7
- Locations
- 1
- Primary Endpoint
- Number of Participants With Dose Limiting Toxicity (DLT)
- Status
- Terminated
- Last Updated
- 2 years ago
Overview
Brief Summary
The purpose of this study was to determine the maximum tolerated dose (MTD)/recommended Phase II dose of lenvatinib administered in combination with carboplatin and gemcitabine (Phase IB) and to evaluate the safety and tolerability of E7080 administered in combination with carboplatin and gemcitabine compared to carboplatin and gemcitabine alone (Phase II) in participants with platinum-sensitive recurrent ovarian cancer.
Detailed Description
This open-label, multicenter, randomized study was to consist of a Phase 1b portion: a safety run-in period with 3 doses of lenvatinib administered in combination with carboplatin + gemcitabine; and a Phase II portion: a randomized 2-arm period. Approximately 100 participants with ovarian cancer were to be enrolled in the study (10 to 20 participants in the Phase 1b portion and 80 participants in the Phase II portion). Participants were to participate in either the Phase 1b or the Phase II portion. Participants were to receive study treatment (lenvatinib plus carboplatin + gemcitabine or carboplatin + gemcitabine) for six 21-day cycles (18 weeks). Participants who receive E7080 and experience evidence of clinical benefit (CR, PR, or SD) may continue single agent E7080 beyond 18 weeks, until the occurrence of progressive disease (PD), unacceptable toxicity, withdrawal of consent, or withdrawal by investigator, whichever occurs first. Initially, an ascending dose schedule starting at lenvatinib 16 mg once daily on Day 1 to Day 21 was chosen for the Phase 1b portion to determine the MTD of lenvatinib administered once daily in combination with carboplatin + gemcitabine; however, due to hematologic toxicity observed in the first cohort, the lenvatinib administration schedule was changed to Days 2 to 21 in Protocol Amendment 2. Continued hematologic toxicity prompted a third protocol amendment, designed to evaluate a lower range of doses starting at lenvatinib 8 mg once daily in Protocol Amendment 3. After three protocol amendments, recruitment into the Phase 1b portion of the study was very limited, with only one evaluable participant enrolled during the last 5 months of recruitment. Due to the limited enrollment despite significant diligence to boost enrollment and the complex study design required to manage hematologic toxicity, the study was terminated before the initiation of Phase II. Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); vital signs; Gynecological Oncology Group performance status; clinical laboratory evaluations; physical examinations; and 12-lead electrocardiograms (ECGs).
Investigators
Eligibility Criteria
Inclusion Criteria
- •Participants may be in the study only if they meet all of the following criteria.
- •Female participants greater than or equal to 18 years of age.
- •Histologically or cytologically confirmed ovarian epithelial, fallopian tube, or primary peritoneal cavity cancer that was treated with and was sensitive to one prior platinum-based chemotherapy regimen for Stage III or Stage IV disease.
- •Documentation of biochemical relapse defined by CA125 criteria (measurable or non-measurable by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST criteria), more than six months since completion of first-line platinum-based chemotherapy requiring treatment with further platinum-based chemotherapy. CA125 criteria for relapse Gynecologic Cancer Intergroup (GCIG) criteria are the finding of 2 serum CA125 levels with samples taken at least 1 week apart and no greater than 3 months apart:
- •greater than or equal to 2 x ULN in participants with an elevated pre-treatment serum CA125 level followed by normalization on treatment and prior to progression OR
- •greater than or equal to 2 X nadir value for participants with an elevated pre-treatment CA125 that never normalizes).
- •Gynecological Oncology Group performance status of 0 or 1
- •Life expectancy greater than or equal to 3 months
- •Participants must have recovered from effects of any major surgery within 28 days from the first dose of study treatment.
- •Adequate hematologic, renal, liver, and coagulation system function as defined by laboratory values performed within 21 days prior to initiation of dosing.
Exclusion Criteria
- •Participants will not be entered in the study for any of the following reasons:
- •Pregnant, breast-feeding, or refusing double barrier contraception, oral contraceptives or avoidance of pregnancy measures;
- •Prior anti-angiogenic therapy with anti-VEGFR inhibitors; bevacizumab is allowed;
- •Prior gemcitabine;
- •Participants with proteinuria greater than 1+ on urine dipstick testing will undergo 24-hour urine collection for quantitative assessment of proteinuria. Participants with 24-hour urine protein greater than or equal to 1 g/24 hours will be ineligible.
- •Ovarian nonepithelial cancer, including malignant mixed Mullerian tumors and borderline tumors (e.g., tumors of low malignant potential);
- •Other malignancy within 5 years of randomization, with the exception of adequately treated carcinoma in situ of the cervix or non-melanoma skin cancer, with no subsequent evidence of recurrence;
- •History of, or known carcinomatous meningitis;
- •Are currently receiving any other treatment for the tumor (including palliative radiotherapy) aside from control of symptoms;
- •Received treatment in another clinical study within the 30 days prior to commencing study treatment or participants who have not recovered from side effects of an investigational drug to Grade less than or equal to 1, except for peripheral neuropathy (Grade 1 or 2 are permitted) or alopecia;
Arms & Interventions
Lenvatinib plus carboplatin + gemcitabine
Phase IB and Phase II
Intervention: Lenvatinib
Lenvatinib plus carboplatin + gemcitabine
Phase IB and Phase II
Intervention: Carboplatin
Lenvatinib plus carboplatin + gemcitabine
Phase IB and Phase II
Intervention: Gemcitabine
Carboplatin + gemcitabine
Phase II
Intervention: Carboplatin
Carboplatin + gemcitabine
Phase II
Intervention: Gemcitabine
Outcomes
Primary Outcomes
Number of Participants With Dose Limiting Toxicity (DLT)
Time Frame: Cycle 1 (21 days)
DLTs were defined as clinically significant adverse events occurring less than or equal to 21 days after commencing study treatment and considered to be possibly or probably related to study treatment by the Investigator. If 1 DLT occurred at any dose level, the cohort was to be expanded to include a maximum of six evaluable subjects. If 2 DLTs occurred at any dose level, the maximum tolerated dose (MTD) was to be either defined as the preceding dose, or an intermediate dose. To evaluate an intermediate dose, an additional dose cohort could be added to more accurately define the MTD.
Secondary Outcomes
- Biomarker CA125-based Overall Response Rate (B-ORR), Within Treatment Group(Day 1 of every cycle, at end of treatment visit and every 2 months during follow-up period for patients who complete study without progressive disease.)
- Biomarker-based Proportion of Biomarker-Progression-Free Survival (B-PFS) at Week 12, Within Treatment Group(Week 12)