Cediranib Maleate With or Without Dasatinib in Patients With HRPC-Resistant to Treatment With Docetaxel

Study Overview
=================
Brief Summary
-----------------
This randomized phase II trial is studying the side effects and how well giving cediranib maleate together with or without dasatinib works in treating patients with hormone-resistant prostate cancer resistant to treatment with docetaxel. Cediranib maleate and dasatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth or by blocking blood flow to the tumor. It is not yet known whether giving cediranib maleate together with dasatinib or alone is an effective treatment for prostate cancer.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. To determine the progression-free survival of patients with docetaxel-resistant and castration-resistant prostate cancer treated with cediranib maleate with versus without dasatinib. SECONDARY OBJECTIVES: I. To confirm the safety and tolerability of cediranib maleate with versus without dasatinib in these patients. II. To calculate objective response rates of cediranib maleate with versus without dasatinib, according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria, in patients with measurable disease at baseline. III. To perform symptom assessment using the FACT-P questionnaire and the Present Pain Intensity (PPI) scale from the McGill-Melzack questionnaire. IV. To explore bone resorption markers (e.g., c-telopeptide and bone alkaline phosphatase), and to correlate these biomarkers with clinical outcome. OUTLINE: This is a multicenter study. Patients are stratified according to the presence of soft tissue (visceral or nodal) vs bone-only disease. Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive oral cediranib maleate once daily and oral dasatinib once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive cediranib maleate as in arm I. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study, patients are followed up for 4 weeks.

Official Title
-----------------
A Phase 2 Randomized Study of Cediranib (AZD2171) Alone Compared With the Combination of Cediranib (AZD2171) Plus BMS-354825 (Dasatinib, Sprycel) in Docetaxel Resistant, Castration Resistant Prostate Cancer

Conditions
-----------------
Hormone Refractory Prostate Cancer, Recurrent Prostate Cancer

Intervention / Treatment
-----------------
* Drug: cediranib maleate
* Drug: dasatinib


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically/cytologically confirmed prostate cancer Measurable/non-measurable disease Prior hormonal therapy with medical LHRH agonist or orchiectomy castration (Castrate level of testosterone (< 50 ng/dL) required) Clinical/radiographic evidence of progression on or after docetaxel therapy No active pleural/pericardial effusion of any grade No meningeal metastases/untreated known brain metastases Patients with treated brain metastasis with radiologic, clinical evidence of stability, with no evidence of cavitation/hemorrhage in the brain lesions allowed if asymptomatic and not requiring corticosteroids Life expectancy >3 months ECOG PS 0-2 (Karnofsky PS 60-100%) ANC >= 1,500/mm^3 Platelet count >= 100,000/mm^3 Hemoglobin >= 9 g/dL INR=< 1.3 Total bilirubin =< 1.25 times ULN AST and ALT=< 2.0 times ULN (5 x ULN if clearly attributable to liver metastasis) Creatinine normal OR creatinine clearance >= 60 mL/min LVEF> institutional normal range by ECHO/MUGA Urine dipstick for protein < 1+ OR < 1 g on 24-hour urine collection Exclusion Criteria: >5 years since any malignancy except in situ cancer, non-metastatic basal/squamous cell skin cancer, or other cancer for which the patient has been curatively treated Fertile patients must use effective contraception No condition that impairs ability to swallow/absorb No history of allergic reactions attributed to compounds of similar chemical/biologic composition to cediranib/dasatinib No systolic BP>150 mmHg and/or diastolic BP>100 mmHg QTc prolongation (>=480 msec by Fridericia correction) or other significant ECG abnormalities are ineligible No active/uncontrolled infections, serious illness, or medical conditions that would not permit patient to be managed according to protocol No known immunodeficiency syndrome No clinical/radiological evidence of severe/uncontrolled interstitial lung disease No history/concurrent idiopathic pulmonary fibrosis No concurrent combination antiretroviral therapy for HIV-positive patients No unresolved toxicity>=CTCAE grade 2 (except alopecia) from prior anticancer therapy 4 weeks since prior anti-androgens 4 weeks since prior chemotherapy following docetaxel for metastatic disease (Any number of regimens allowed) 4 weeks since prior hormonal therapy or abiraterone 3 weeks since prior radioisotopes or radiotherapy and recovered No prior therapy with angiogenesis or Src or FAK inhibitors 3 weeks since prior major surgery and recovered 1 week since prior corticosteroids Concurrent zoledronic acid allowed provided patient has been receiving it prior to start of study treatment Concurrent medications or substances known to affect or with the potential to affect the activity or pharmacokinetics of cediranib and dasatinib will be determined following review of their case by the principal investigator or co-investigator 14 days before and after study and no concurrent CYP3A4-active agents or substances (including strong inhibitors or inducers) Concurrent prophylactic low-dose warfarin (INR must be close monitored) or low-molecular weight heparin allowed No other concurrent investigational agents

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

Sexes Eligible for Study
-----------------
Male

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

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

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients receive oral cediranib maleate once daily and oral dasatinib once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: cediranib maleate<br>* Given orally<br>* Other names: Recentin;Drug: dasatinib<br>* Given orally<br>* Other names: BMS-354825;|
| Experimental: Arm II<br>Patients receive cediranib maleate as in arm I. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: cediranib maleate<br>* Given orally<br>* Other names: Recentin;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 12-week Progression-free Survival as Per the Prostate Cancer Clinical Trials Working Group (PCWG2) | Progression is defined using the Prostate Cancer Clinical Trials Working Group (PCWG2) criteria, which includes a compilation of prostate-specific antigen (PSA), bone scan, and CT-scan assessments (Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Toxicities | Incidence of toxicities graded according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) v4.0 | Up to 30 days after last dose of study drugs | 
| Qualtiy of Life Assessment Number of Participants With a Score ≥2 on the Present Pain Intensity (PPI) Scale | Present Pain Intensity (PPI) scale. Scale is measured 0-5, where 0=no pain, 1=mild pain, 2=discomforting pain, 3=distressing pain, 4=horrible pain and 5=excruciating pain Participants who were up to completing the assessment (did not decline) and who reported a score >=2 at the end of any cycle are reported. | After every cycle (median duration on study = 4 cycles) | 
| Number Who Experienced Study Medication Dose Intensity | Number of patients who experienced study medication dose of over 80% during Cycle 1 was assessed. | Cycle 1 (an average of 28 days) | 
| Treatment Discontinuation | Discontinuation of treatment in cycle 1 (average of 28 days) | Cycle 1 (average of 28 days) | 
| Treatment Discontinuation Due to Adverse Events (AEs) | Treatment discontinuation due to Adverse Events | Through study completion (median duration on study = 4 cycles) | 
| Non-AE Related Treatment Discontinuation | Non-Adverse Event related Treatment Discontinuation | Through study completion (median duration on study = 4 cycles) | 
| Overall Response Rate | Best overall response rate of each evaluable patient | Duration of Study (median duration on study = 4 cycles) | 
| Treatment Related Deaths | Number of treatment related deaths | Through study completion (median duration on study = 4 cycles) | 
| Participants for Which Bone Biomarkers for Beta-C Telopeptide Was Reduced | Participants for which beta-C telopeptide was reduced | Through study completion (median duration on study = 4 cycles) | 
| Number of Participants With Increased Alkaline Phosphatase BAP | Number of participants with increased alkaline phosphatase BAP | Through study completion (median duration on study = 4 cycles) | 
| Dose Interruption Due to AEs | The number of participants with dose-interruptions in each arm due to adverse events | Through study completion (median duration on study = 4 cycles) | 
| Dose Reductions | The number of participants with dose reductions in each arm | Duration of Study (median duration on study = 4 cycles) | 
| Overall Response Rate | Response Rate of Stable Disease and Progressive Disease | Duration of Study (median duration on study = 4 cycles) | 
| Quality of Life Assessment Using Functional Assessment of Cancer Therapy - Prostate (FACT-P) Questionnaire | Scale is measured on a range from 0 (worst quality of life) to 156 (best quality of life). | Up to 16 weeks |