E7080 in Combination With Carboplatin + Gemcitabine Versus Carboplatin + Gemcitabine Alone as Second Line Therapy in Patients With Platinum-Sensitive Recurrent Ovarian Cancer by CA125

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.

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).

Eligibility Criteria:
Inclusion Criteria:

Participants may be in the study only if they meet all of the following criteria.

1. Female participants greater than or equal to 18 years of age.
2. 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.
3. 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:

   1. 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
   2. greater than or equal to 2 X nadir value for participants with an elevated pre-treatment CA125 that never normalizes).
4. Gynecological Oncology Group performance status of 0 or 1
5. Life expectancy greater than or equal to 3 months
6. Participants must have recovered from effects of any major surgery within 28 days from the first dose of study treatment.
7. Adequate hematologic, renal, liver, and coagulation system function as defined by laboratory values performed within 21 days prior to initiation of dosing.

   1. Absolute neutrophil count (ANC) greater than or equal to 1.5 x 109/L
   2. Platelet count greater than or equal to 100 x 109/L
   3. Hemoglobin greater than or equal to 9 g/dL
   4. Serum creatinine less than or equal to 1.5 X ULN and/or creatinine clearance 50 dL/min
   5. Total serum bilirubin less than or equal to 1.5 X ULN
   6. Serum aspartate transaminase (AST/SGOT) or serum alanine transaminase (ALT/SGPT) less than or equal to 2.5 X ULN, and less than or equal to 5 X ULN in cases of liver metastasis
   7. PT/International normalized ratio (INR) less than or equal to 1.5 X ULN
   8. h. PTT less than or equal to 1.1 X ULN
8. Blood pressure must be well-controlled (less than or equal to 140/90 mmHg at screening) with or without antihypertensive medication. Participants must have no history of hypertensive crisis or hypertensive encephalopathy;
9. Participants should have a negative pregnancy test at screening in pre-menopausal women and women less than 2 years after the onset of menopause. Pre-menopausal women must agree to use an acceptable method of birth control from the time of the negative pregnancy test up to 90 days after the last dose of study drug. Women of non-childbearing potential may be included if they are either surgically sterile or have been postmenopausal for greater than or equal to 1 year;
10. Before study entry, written informed consent must be obtained from participant prior to performing any study-related procedures.

Exclusion Criteria:

Participants will not be entered in the study for any of the following reasons:

1. Pregnant, breast-feeding, or refusing double barrier contraception, oral contraceptives or avoidance of pregnancy measures;
2. Prior anti-angiogenic therapy with anti-VEGFR inhibitors; bevacizumab is allowed;
3. Prior gemcitabine;
4. 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.
5. Ovarian nonepithelial cancer, including malignant mixed Mullerian tumors and borderline tumors (e.g., tumors of low malignant potential);
6. 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;
7. History of, or known carcinomatous meningitis;
8. Are currently receiving any other treatment for the tumor (including palliative radiotherapy) aside from control of symptoms;
9. 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;
10. Received chemotherapy, biological therapy, hormonal therapy, targeted therapy, or radiotherapy within the 30 days prior to commencing study treatment or have not recovered from all treatment-related toxicities to Grade less than or equal to 1, except for peripheral neuropathy (Grade 1 or 2 are permitted) or alopecia;
11. Serious non-healing wound, ulcer, bone fracture, or have undergone a major surgical procedure, open biopsy, or significant traumatic injury within the 28 days prior to commencing study treatment. Minor surgery such as Portacath placement or skin biopsy is permitted if greater than or equal to 7 days have passed;
12. The use of anti-coagulants such as Vitamin K antagonists, unfractionated heparin, or low molecular weight heparin;
13. Refractory nausea and vomiting, malabsorption, significant bowel resection, or any other medical condition that would preclude adequate absorption or result in the inability to take oral medication;
14. Significant cardiovascular impairment (history of congestive heart failure) New York Heart Association (NYHA) Grade II, unstable angina or myocardial infarction within the past 6 months, or serious cardiac arrhythmia);
15. Any history of cerebral vascular accident (CVA) or transient ischemic attack (TIA) unless they have had no evidence of active disease for at least 6 months prior to randomization
16. Active hemoptysis (defined as bright red blood of 1/2 teaspoon or more) within the 30 days prior to study entry;
17. History of abdominal fistula, gastrointestinal perforation, or intrabdominal abscess within the 6 months prior to enrolment;
18. History of bleeding diathesis or coagulopathy;
19. History of an allograft requiring immunosuppression;
20. Known positive human immunodeficiency virus (HIV), known surface antigen positive for hepatitis B hepatitis or C positive;
21. Hypersensitivity to E7080 and/or E7080 chemical derivative; or
22. Have any other uncontrolled infection or medical condition which would interfere with the conduct of the study.