Saracatinib and Paclitaxel in Platinum-resistant Ovarian Cancer

Study Overview
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Brief Summary
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The purpose of this study is to investigate whether the addition of the Src inhibitor saracatinib (AZD0530) to weekly paclitaxel improves efficacy, compared with paclitaxel plus placebo, in patients with relapsed platinum-resistant ovarian cancer. The trial will also determine toxicity and ascertain whether the combination of paclitaxel plus saracatinib should proceed to a phase III trial.

Detailed Description
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A multicentre, randomised, double-blind, placebo-controlled Phase II trial will be conducted. The overall aim of the trial is to investigate whether the addition of saracatinib to weekly paclitaxel improves efficacy, as measured by progression free survival, compared with paclitaxel plus placebo. The trial will also determine toxicity and ascertain whether the combination of paclitaxel plus saracatinib should proceed to a phase III trial. The toxicity data from Study NCT00610714 (D8180C00015) suggests that a small number of patients could experience febrile neutropaenia during their first chemotherapy cycle. To combat this, saracatinib (175 mg OD)/matched placebo will begin 1 week prior to commencement of chemotherapy, and be given continuously until progression. All patients will receive cycles of weekly paclitaxel chemotherapy. One cycle will consist of weekly paclitaxel (80 mg/m2) for 6 weeks followed by 2 weeks rest. If there is evidence of on-going response after 4 cycles, 3 further cycles of saracatinib/placebo plus weekly paclitaxel will be given, unless there is dose-limiting toxicity or the patient requests to discontinue treatment. If best response is stable disease after 4 cycles, treatment should be discontinued but may continue at the discretion of the Investigator.

Official Title
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A Randomised Placebo-controlled Trial of Saracatinib (AZD0530) Plus Weekly Paclitaxel in Platinum Resistant Ovarian, Fallopian Tube or Primary Peritoneal Cancer

Conditions
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Ovarian Cancer, Fallopian Tube Cancer, Primary Peritoneal Cancer

Intervention / Treatment
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* Drug: Paclitaxel
* Drug: Saracatinib
* Drug: Matched placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Confirmed relapsed ovarian, fallopian tube or primary peritoneal cancer AND relapse within the platinum-resistant (progression must not be based on Cancer Antigen 125 (CA125) alone) time-frame, i.e. have progressed within 6 months of platinum therapy. Patients need not have received prior taxane; if patients have received prior taxane, the interval since treatment must be known. Patients will be stratified as <6 months or 6+ months taxane interval/no prior taxane. Patients will generally have received at least 2 lines of prior chemotherapy, but may enter if they have relapsed within 6 months of first line therapy. Patients may have received prior liposomal doxorubicin, although this is NOT a requirement. The treatment immediately prior to study entry need not be platinum-based. Measurable or evaluable disease (if not measurable by Response Evaluation Criteria In Solid Tumours (RECIST) v1.1 criteria, patients must be evaluable by Gynecologic Cancer InterGroup (GCIG) CA125 criteria). Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-2 Adequate haematological and biochemical function. Exclusion criteria Prior administration of weekly paclitaxel. Tumours of malignant mixed mesodermal (MMMT) or mucinous subtypes, or non-epithelial ovarian cancers (e.g. Brenner tumours, Sex-cord tumours). Unresolved bowel obstruction. Chemotherapy within the preceding 3 weeks. Radiotherapy within the preceding 3 weeks. Treatment with any investigational agent within the preceding 4 weeks or within 5 half-lives of the investigational agent, whichever is longer. Known leptomeningeal involvement or intracranial disease. Evidence of interstitial lung disease (bilateral, diffuse, parenchymal lung disease). Resting ECG with measurable QTc interval of >480 msec at 2 or more time points within a 24 hour period. Pregnant or lactating females. Fertile women of childbearing potential not willing to use highly effective contraception for the duration of trial treatment and for at least 6 months after the last administration of saracatinib +/- paclitaxel. Inability or unwillingness to give informed consent. Ongoing active infection or a documented history of HIV infection, Hepatitis B or C. Concurrent congestive heart failure or prior history of New York Heart Association (NYHA) class III/IV cardiac disease. Concurrent autoimmune disorder, e.g. systemic lupus or any demyelinating disease. Use of immunosuppressive therapy or corticosteroids taken within the 4 weeks prior to study entry and during the treatment period.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Saracatinib plus weekly paclitaxel<br> | Drug: Paclitaxel<br>* Paclitaxel 80 mg/m2 weekly for 6 weeks followed by a 2 week break (1 cycle), for 4 cycles initially (32 weeks). If there is evidence of on-going response after 4 cycles, 3 further cycles will be given, unless there is dose-limiting toxicity or the patient requests to discontinue treatment. If best response is stable disease after 4 cycles, treatment should be discontinued but may continue at the discretion of the Investigator.<br>Drug: Saracatinib<br>* Saracatinib 175 mg PO once daily, to begin 1 week prior to commencement of chemotherapy, taken continuously until progression<br>|
| Placebo Comparator: Placebo plus weekly paclitaxel<br> | Drug: Paclitaxel<br>* Paclitaxel 80 mg/m2 weekly for 6 weeks followed by a 2 week break (1 cycle), for 4 cycles initially (32 weeks). If there is evidence of on-going response after 4 cycles, 3 further cycles will be given, unless there is dose-limiting toxicity or the patient requests to discontinue treatment. If best response is stable disease after 4 cycles, treatment should be discontinued but may continue at the discretion of the Investigator.<br>Drug: Matched placebo<br>* Matched placebo PO once daily, to begin 1 week prior to commencement of chemotherapy, taken continuously until progression<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 6 Month Progression-free Survival Rate (PFS) (Based on Combined Response Evaluation Criteria In Solid Tumours (RECIST) v1.1 +/- Gynecologic Cancer Intergroup (GCIG) CA125 Criteria) | Where a patient's disease is not measurable by RECIST v1.1, response may be based on GCIG CA125 criteria plus symptoms. The 6 month progression-free survival rate will be calculated by the trial statistician during the final analysis. | Using RECIST v1.1 at baseline; at Week 7 or 8 of each chemotherapy cycle; and 3 monthly during follow up. CA125 response will be assessed at baseline, weeks 1, 3 and 6 of each chemotherapy cycle, and at every follow up visit. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival |  | First saracatinib/placebo dose until death, assessed up to 36 months | 
| Objective Response Rate Based on Investigator Assessment Based on RECIST v1.1 +/- GCIG CA125 Criteria | Where a patient's disease is not measurable by RECIST v1.1, response may be based on GCIG CA125 criteria plus symptoms. | Using RECIST v1.1 at baseline; at Week 7 or 8 of each chemotherapy cycle; and 3 monthly during follow up. CA125 response will be assessed at baseline, weeks 1, 3 and 6 of each chemotherapy cycle, and at every follow up visit. | 
| Median Duration of Response | Where a patient's disease is not measurable by RECIST v1.1, response may be based on GCIG CA125 criteria plus symptoms. Duration of Response will be calculated by the trial statistician during the final analysis. | Using RECIST v1.1 at baseline; at Week 7 or 8 of each chemotherapy cycle; and 3 monthly during follow up. CA125 response will be assessed at baseline, weeks 1, 3 and 6 of each chemotherapy cycle, and at every follow up visit. | 
| Quality of Life: Trial Outcome Index (TOI) Based on FACT-O | The TOI value for each patient is derived at each timepoint by calculating the sum of 3 subscales: Physical Well-Being (PWB), Functional Well-Being (FWB), Additional Concerns. Each subscale score is derived from questions with 4 answers (0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, 4=very much). In each subscale reversals are performed and the individual question scores added together. This value is then multiplied by the number of questions within the subscale, and divided by the number of questions answered to derive a subscale score. The higher each subscale score, the better the QoL. PWB 7 questions, lower values=better QoL. FWB 7 questions, higher values=better QoL. Additional concerns 11 questions (higher values in 6 questions=better QoL; higher values in 5 questions=worse QoL) The TOI is reported for each arm based on the average TOI score of each patient calculated across the outcome measure time frame. The higher the TOI, the better the QoL. | Patients will fill in FACT-O questionnaires at the following timepoints: baseline; Weeks 1, 3 and 6 of every chemotherapy cycle; at every follow up visit | 
| Median Time To Progression Based on RECIST v1.1 and GCIG CA125 Criteria | Where a patient's disease is not measurable by RECIST v1.1, response may be based on GCIG CA125 criteria plus symptoms. Time To Progression will be calculated by the trial statistician during the final analysis. | Using RECIST v1.1 at baseline; at Week 7 or 8 of each chemotherapy cycle; and 3 monthly during follow up. CA125 response will be assessed at baseline, weeks 1, 3 and 6 of each chemotherapy cycle, and at every follow up visit. | 
| Median PFS |  | From first saracatinib/placebo dose to first documented progression and/or death, assessed up to 36 months |