Combination Therapy for Recurrent Ovarian Cancer

Study Design Overview:

This is a two-part open-label clinical trial of ASWD (Ashwagandha) administered to patients with recurrent ovarian cancer in combination with liposomal doxorubicin, (DOXIL) following at least one previous line of chemotherapy. Patients will initially be enrolled in part 1 of the study, which is the feasibility/tolerability evaluation. Once the part 1 enrollment is completed, the patients will be enrolled in part 2 of the study.

In both parts, ASWD will be administered orally daily whereas liposomal doxorubicin will be administered intravenously (IV) every 4 weeks for at least 4 cycles or until disease progression and/or unacceptable toxicity, whichever comes first. If disease progression and/or unacceptable toxicity is not encountered, study treatment will be for a maximum of 10 cycles, or until a total cumulative dose of anthracycline therapy exceeds 450 mg/m2. Continued treatment with liposomal doxorubicin and/or ASWD will be determined by the provider. Once there is a completion of 10 cycles, ASWD will be continued in a daily regimen as maintenance, without continued liposomal doxorubicin, until disease progression and/or unacceptable toxicity.

Part 1 Part 1 (Phase I) is a feasibility/tolerability evaluation in which approximately 18 patients with recurrent ovarian cancer will be enrolled. The enrolled patients will be treated with 3 doses of ASWD [1.0 g, 2.0 g or 4.0 g/twice daily (total 2.0 g, 4.0 g or 8.0 g/day) taken orally with water in the form of capsule (500 mg/capsule, containing 500 mg of active ashwagandha)] in combination with set dosage of DOXIL (40 mg/m2 over 60 min, every 4 weeks). DOXIL will be administered at an initial rate of 1 mg/min to minimize the risk of infusion reactions. If no infusion related reactions occur, infusion rate will be increased to complete administration over 1 hour. Bolus injection or undiluted solution will not be administered.

Dose Escalation:

Approximately 18 subjects will be enrolled to escalating dose levels of ASWD in combination with DOXIL the approved dose of 40 mg/m2. Each dose level will initially enroll at least 3 DLT-evaluable subjects to a maximum of 6 subjects. Subsequent subjects, if any, assigned to receive the same dose level will be enrolled in groups of at least 2 DLT-evaluable subjects. Table 1 provides the dose escalation decision with target toxicity rate of 28.5% and optimal interval of (25.6%, 32.7%).

The ASWD starting dose level is 2.0 g, administered daily orally, starting with Cycle 1. The DOXIL dose level is fixed dose of 40 mg/m2 IV for every 4 weeks. The escalation dose of ASWD will be 4.0 g/day or 8.0 g/day for second and third cohort respectively and fixed dose of DOXIL. ASWD will be given alone if patient is no longer receiving DOXIL treatments. However, it will be given along with DOXIL if the patient continues DOXIL after 4 cycles.

The DLT observation period consists of the lead-in period [7 days of ashwagandha and Cycle 1 (21 days)] for 28 days total. To be considered DLT evaluate, subjects must complete at least 75% of ASWD dosing (i.e., at least 21 days) in the lead-in period and Cycle 1 or experience a DLT. DLT non-evaluate subjects may be replaced if needed to achieve the required number of DLT-evaluable subjects for dose escalation decisions. Dose-limiting toxicities will be graded using the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 (CTCAE v5.0). https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcae_v5_quick_reference_5x7.pdf.

Ashwagandha is sold as an over-the-counter dietary supplement rich in WFA in 500 mg tablets containing 500 mg of active ashwagandha. ASWD will be provided by Marudhar Impex, Ahmedabad, India. Ashwagandha is manufactured and packed to capsules by Marudhar Impex under cGMP and analyzed by Eurofins Analytical Services India Private Limited. ASWD is extracted from the plant Withania somnifera grown under control conditions and packed in a Good Manufacturing Practices (GMPs) facility. It contains 0.71 % (w/w) Withanoside IV, 01.14% Withaferin A, 0.27% Withanoside V, 0.33% Withanone, 0.09% withanolide A, and 0.00% withanolide B determined by HPLC. The investigators will confirm the content of withaferin A using HPLC.

DOXIL is a liposomal formulation of doxorubicin hydrochloride encapsulated in liposomes with surface-bound methoxypolyethylene glycol (MPEG). Each liposomal doxorubicin vial contains pegylated liposomal doxorubicin HCl, 2 mg/mL and delivered as 10 ml (20 mg) in a concentrate for single dose intravenous infusion and is presented as sterile, translucent, and red suspension. For < 90 mg/m2, DOXIL is diluted in 250 ml Dextrose 5% in water and for > 90 mg/m2 DOXIL is diluted in 500 mL Dextrose in 5% in water. Aseptic technique must be strictly observed since no preservative or bacteriostatic agent is present in DOXIL. Diluted DOXIL should be refrigerated at 2°C to 8°C (36°F to 46°F) and administered within 24 hours.

Part 1 (Phase I) Part 1 of the study will be conducted using '3 + 3' traditional dose escalation design. Toxicities will be graded using the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 (CTCAE v5.0). Initially, 3 patients will be treated with 1.0 gram of ASWD twice daily (total of 2.0 grams/day) in combination with DOXIL, if none of them develop toxicity, then next 3 patients will be treated with 2.0 grams twice (total 4.0 grams/day) in combination with DOXIL, if none of them develop toxicity or has any issue, then next 3 patients will be treated with 4.0 grams twice daily (total 8.0 grams/day) in combination with DOXIL. If any of the patients has a Grade 3-4 hematologic or non-hematologic toxicity, the cohort will be expanded by three subjects (with a maximum of 6 patients at a given dose), prior to proceeding to the next dose. DOXIL dose will be 40 mg/m2 administered IV over a period of 60 min every 4 weeks for 4 cycles or until disease progression and/or unacceptable toxicity, whichever comes first to a maximum of 10 cycles. The total anthracycline (doxorubicin) cumulative dose should not exceed over 450 mg/m2.

AWSD will be administered on days 1-28 of each cycle. Patients will start ASWD on cycle 1, day 1 of DOXIL infusion. ASWD administration instructions will be provided to participants as follows:

"Take (appropriate number of capsules per dose escalation) tablets every 12 hours; to be initiated the day of starting chemotherapy." The medication may be taken with or without water and with or without food. If a dose is missed, it will not be re-taken. Participants will be instructed to keep a dose log. AWSD may be stored at ambient temperature protected from light at the participants' home. Plasma and urine samples will be collected for analysis of selected circulating biomarkers (proteins).

Part 2 (Phase II) Part 2 is an open label, exploration study to estimate the overall survival and response rate for participants treated daily with ASWD in the form of tablets in combination with DOXIL (40 mg/m2 IV for every 4 weeks for 4 cycles). Approximately 54 patients (including part 1 subjects treated with the highest feasible dose) will be enrolled in part 2 of the study. The enrollment for part 2 of the study will begin with the ASWD and liposomal doxorubicin dosages determined from part 1, provided no more than 2 out of 6 patients develop treatment related non-hematological toxicity in part 1 of the study. The enrolled patients will start taking ASWD capsules identified in part 1 for evaluation in part 2. Patients who participated in part 1 of the study will be offered to continue treatment to part 2, with a maximum tolerable dose. DOXIL will be administered every 4 weeks (40 mg/m2) for up to 10 cycles (limited to the standard limit of anthracycline administration, 450 mg/m2 cumulative dose of doxorubicin HCL). In the event of no progression and tolerance of the drug, patients should continue ASWD even DOXIL is stopped.

Dose Limiting Toxicities (DLT) The dose limiting toxicity window will include the first cycle of therapy (four weeks) and will be monitored prior to the initiation of cycle 2.

Laboratory values will be measured weekly during cycle one of therapy, then prior to each administration of DOXIL. These will include complete blood count (CBC) with platelets and complete metabolic panel (CMP) with liver function tests. In addition, prothrombin time and partial thromboplastin time will be monitored, simultaneously.

Hepatic Toxicity: Grade 3-4 hepatic toxicity will be defined as AST or ALT >3X upper limits of normal (ULN) and a concurrent bilirubin >2X ULN of any duration without finding of cholestasis (elevated alkaline phosphatase).

Hematologic Toxicity: Hematologic toxicity will be defined as: 1) Grade 4 neutropenia or thrombocytopenia > 7 days; 2) Grade 3 thrombocytopenia with bleeding; and 3) neutropenia fever.

Non-Hematologic Toxicity: Non-Hematologic toxicity will be defined as 1) Grade 4 alopecia, drug-related fever, and toxicities secondary to neutropenia and sepsis [with the exception of nausea and vomiting (if manageable with supportive care measures)], platelet count (< 25,000/mm3) 50 days beyond the start of the chemotherapy (not related to recurrent leukemia); 2) Grade 3 neurologic toxicity (sensory or autonomic).

Grade 3-4 non-hematologic toxicities will be considered a DLT and can be exempted from DLT if they resolve within 1 week, if they do not lead to hospitalization, and if they can be adequately managed with supportive care or conventional interventions within 72 hours.

Death: Any death not clearly due to underlying disease or extraneous causes