Sorafenib + Topotecan for Platinum-Resistant Recurrent Ovarian Cancer

Study Overview
=================
Brief Summary
-----------------
This multi-institutional phase I/II clinical trial will test the tolerability and efficacy of the combination sorafenib and topotecan in patients with recurrent ovarian cancer, which is platinum-resistant (recurrence within 6 months from completing platinum based therapy) or refractory (progressive disease during platinum based therapy).

Detailed Description
-----------------
OUTLINE: This is a multi-center study. Topotecan: 4mg/m2 weekly, 3 weeks on and one week off. Sorafenib: Assigned cohort dose for phase I (up to 12 patients) Maximum tolerated dose for phase II (21 total patients) Cycles will consist of 4 weeks (28 days) with disease evaluations every 8 weeks. Non-PD and acceptable toxicity: Patients will continue protocol therapy PD or unacceptable toxicity: Patients will discontinue protocol therapy ECOG performance status 0-1 Life expectancy: Three (3) months Hematopoietic: White blood cell count (WBC) > 3 K/mm3 Hemoglobin (Hgb) > 9 g/dL Platelets > 100 K/mm3 Absolute neutrophil count (ANC) > 1.5 K/mm3 INR < 1.5 or a PTT within normal limits. NOTE: Patients receiving anti-coagulation treatment with an agent such as warfarin or heparin may be allowed to participate. No evidence or history of bleeding diathesis or coagulopathy. Hepatic: Bilirubin < 1.5 x ULN Aspartate aminotransferase (AST, SGOT) < 2.5 x ULN Alanine aminotransferase (ALT, SGPT) < 2.5 x ULN Alkaline phosphate < 2.5 x ULN Renal: Creatinine < 1.5 x ULN Cardiovascular: No history of myocardial infarction or angina pectoris or angina equivalent within 6 months prior to registration for protocol therapy (the patient may not be on anti-anginal or anti-arrhythmic medications), or have uncontrolled hypertension or congestive heart failure > class II NYHA Pulmonary: No thrombolic or embolic events such as a cerebrovascular accident, including transient ischemic attacks within the past 6 months. No pulmonary hemorrhage/bleeding event > CTCAE Grade 2 within 28 days prior to registration for protocol therapy. No non-pulmonary hemorrhage/bleeding event > CTCAE Grade 3 within 28 days prior to registration for protocol therapy.

Official Title
-----------------
A Phase I/II Study of Sorafenib in Combination With Topotecan for the Treatment of Platinum-Resistant Recurrent Ovarian Cancer or Primary Peritoneal Carcinomatosis: Hoosier Oncology Group GYN06-111

Conditions
-----------------
Ovarian Cancer

Intervention / Treatment
-----------------
* Drug: Sorafenib
* Drug: Topotecan


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Have histologically-confirmed epithelial ovarian cancer, primary peritoneal carcinomatosis or fallopian tube cancer. Enrollment of patients with clear cell histology is encouraged. Have measurable disease according to RECIST or detectable disease by 1) CA-125 at least twice the ULN within 14 days prior to registration for protocol therapy; 2) Ascites and/or pleural effusion attributed to tumor; 3) solid and/or cystic abnormalities on radiographic imaging that do not meet RECIST definitions for target lesions. Have failed at least one prior platinum based chemotherapeutic regimen. No more than 3 prior treatment regimens for epithelial ovarian cancer. Prior radiation therapy is allowed to < 25% of the bone marrow. Be at least 4 weeks since last anti-cancer treatment, radiation or surgery at the time of registration for protocol therapy. No active cancer in addition to the epithelial ovarian cancer within the last 5 years, with the exception of: superficial skin cancer (basal cell or squamous cell skin carcinoma; carcinoma in situ of the cervix; Stage I endometrial cancer with less than 50% invasion of the myometrium, or other adequately treated Stage I or II cancer in complete remission. Age > 18 years at the time of consent Written informed consent and HIPAA authorization for release of personal health information. Females of childbearing potential must be willing to use an effective method of contraception (hormonal or barrier method of birth control; abstinence) from the time consent is signed until 90 days after treatment discontinuation Females of childbearing potential must have a negative pregnancy test within 7 days prior to being registered for protocol therapy. Exclusion Criteria: No known or suspected allergy to sorafenib or any agent given in the course of this trial. No prior treatment with anti-angiogenesis therapy. No active CNS metastases. No treatment with any investigational agent within 30 days prior to being registered for protocol therapy. No concurrent combination anti-retroviral therapy for the treatment of immunodeficiency. No clinically significant infections requiring antibiotic treatment. No evidence of bowel obstruction, malabsorption, or other contraindication to oral medication. No serious non-healing wound, ulcer, or bone fracture. No major surgery, open biopsy or significant traumatic injury within 28 days of registration for protocol therapy. No use of St. John's Wort or rifampin (rifampicin) while on protocol therapy. No condition that impairs patient's ability to swallow whole pills.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I<br>Topotecan 3.5 mg/m^2 + Sorafenib dose escalation: | Drug: Sorafenib<br>* Phase I: Dose Escalation, Phase II: MTD Dose level -1: 200mg po daily Dose level 1: 400mg po daily (MTD) Dose level 2: 400mg po bid<br>Drug: Topotecan<br>* 3.5mg/m2 weekly, 3 weeks on and one week off.<br>|
| Experimental: Phase II<br>Topotecan 3.5 mg/m^2 + Sorafenib 400 mg po daily. | Drug: Sorafenib<br>* Phase I: Dose Escalation, Phase II: MTD Dose level -1: 200mg po daily Dose level 1: 400mg po daily (MTD) Dose level 2: 400mg po bid<br>Drug: Topotecan<br>* 3.5mg/m2 weekly, 3 weeks on and one week off.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) | An initial 3 patients will be enrolled at dose level 1. If all 3 patients in dose level 1 complete the first cycle of therapy without a dose limiting toxicity (DLT), 3 patients will be enrolled at dose level 2. If 0 of 3 or 1 of 6 patients in dose level 2 experience a DLT, all subsequent patients will be enrolled in the Phase II cohort at dose level 2. If 2 of the first 3 or 2 of the total 6 patients experience DLT at dose level 2, then dose level 1 will be considered the MTD and used in the second phase. | Each participant was treated at their assigned dose level on 28 day cycles until disease progression or unacceptable toxicity. Participants were evaluated for toxicity every two weeks. | 
| Percentage of Participants With Response | To assess response in patients with recurrent or resistant epithelial ovarian cancer treated with Sorafenib plus Topotecan. Reponse evaluated per RECIST criteria where: Complete Response (CR): Disappearance of all target lesions Partial Response (PR): At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started | Disease assessments were conducted on the 8th week (Cycle 2, Week 4) and every eight weeks there after, until treatment discontinuation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | To determine the progression-free survival of patients treated with Sorafenib plus Topotecan. | From enrollment until treatment discontinuation. Participants may remain on study drug indefinitely | 
| Clinical Benefit | To determine the rate of clinical benefit defined as the percentage of patients experiencing an objective response or a CA125 response. | From enrollment until treatment discontinuation. Participants may remain on study drug indefinitely | 
| Duration of Stable Disease | To determine duration of stable disease, in months | From enrollment until treatment discontinuation. Participants may remain on study drug indefinitely |