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

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

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.

Study Overview

• Status: Completed
• Conditions: Recurrent Prostate Cancer; Hormone Refractory Prostate Cancer
• Intervention / Treatment: Drug: dasatinib; Drug: cediranib maleate

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.

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 4E6
      • BCCA-Vancouver Cancer Centre
  • Ontario
    • Hamilton, Ontario, Canada, L8V 5C2
      • Juravinski Cancer Centre at Hamilton Health Sciences
    • Toronto, Ontario, Canada, M5G 2M9
      • University Health Network-Princess Margaret Hospital
• United States
  • Illinois
    • Peoria, Illinois, United States, 61615
      • Illinois CancerCare-Peoria
    • Springfield, Illinois, United States, 60702
      • Central Illinois Hematology Oncology Center
  • Indiana
    • Fort Wayne, Indiana, United States, 46845
      • Fort Wayne Medical Oncology and Hematology Inc - State Boulevard
  • Maryland
    • Baltimore, Maryland, United States, 21287-8936
      • Johns Hopkins University
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: dasatinib; Given orally; Other Names: BMS-354825; Drug: cediranib maleate; Given orally; Other Names: Recentin
Experimental: Arm II; 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; Given orally; 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

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Sebastien Hotte, University Health Network-Princess Margaret Hospital

Publications and helpful links

General Publications

• Spreafico A, Chi KN, Sridhar SS, Smith DC, Carducci MA, Kavsak P, Wong TS, Wang L, Ivy SP, Mukherjee SD, Kollmannsberger CK, Sukhai MA, Takebe N, Kamel-Reid S, Siu LL, Hotte SJ. A randomized phase II study of cediranib alone versus cediranib in combination with dasatinib in docetaxel resistant, castration resistant prostate cancer patients. Invest New Drugs. 2014 Oct;32(5):1005-16. doi: 10.1007/s10637-014-0106-5. Epub 2014 May 3.

Study record dates

Study Major Dates

• Study Start: October 1, 2010
• Primary Completion (Actual): January 1, 2013
• Study Completion (Actual): February 1, 2014

Study Registration Dates

• First Submitted: December 14, 2010
• First Submitted That Met QC Criteria: December 14, 2010
• First Posted (Estimate): December 15, 2010

Study Record Updates

• Last Update Posted (Actual): August 8, 2018
• Last Update Submitted That Met QC Criteria: July 9, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Prostatic Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Dasatinib; Cediranib
• Other Study ID Numbers: NCI-2011-02544; U01CA070095 (U.S. NIH Grant/Contract); U01CA132123 (U.S. NIH Grant/Contract); N01CM00071 (U.S. NIH Grant/Contract); 8476 (Other Identifier: NIH protocol number); PMH-PJC-002 (Other Identifier: University Health Network); PJC-002 (Other Identifier: Local protocol number)