Hormone Refractory Prostate Cancer, Recurrent Prostate Cancer
Conditions
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.
Interventions
DRUGcediranib maleate
Given orally
DRUGdasatinib
Given orally
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 12-week Progression-free Survival as Per the Prostate Cancer Clinical Trials Working Group (PCWG2) | 3 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Qualtiy of Life Assessment Number of Participants With a Score ≥2 on the Present Pain Intensity (PPI) Scale | After every cycle (median duration on study = 4 cycles) | 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. |
| Number Who Experienced Study Medication Dose Intensity | Cycle 1 (an average of 28 days) | Number of patients who experienced study medication dose of over 80% during Cycle 1 was assessed. |
| Treatment Discontinuation | Cycle 1 (average of 28 days) | Discontinuation of treatment in cycle 1 (average of 28 days) |
| Treatment Discontinuation Due to Adverse Events (AEs) | Through study completion (median duration on study = 4 cycles) | Treatment discontinuation due to Adverse Events |
| Non-AE Related Treatment Discontinuation | Through study completion (median duration on study = 4 cycles) | Non-Adverse Event related Treatment Discontinuation |
| Overall Response Rate | Duration of Study (median duration on study = 4 cycles) | Best overall response rate of each evaluable patient |
| Number of Participants With Toxicities | Up to 30 days after last dose of study drugs | Incidence of toxicities graded according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) v4.0 |
| Participants for Which Bone Biomarkers for Beta-C Telopeptide Was Reduced | Through study completion (median duration on study = 4 cycles) | Participants for which beta-C telopeptide was reduced |
| Number of Participants With Increased Alkaline Phosphatase BAP | Through study completion (median duration on study = 4 cycles) | Number of participants with increased alkaline phosphatase BAP |
| Dose Interruption Due to AEs | Through study completion (median duration on study = 4 cycles) | The number of participants with dose-interruptions in each arm due to adverse events |
| Dose Reductions | Duration of Study (median duration on study = 4 cycles) | The number of participants with dose reductions in each arm |
| Quality of Life Assessment Using Functional Assessment of Cancer Therapy - Prostate (FACT-P) Questionnaire | Up to 16 weeks | Scale is measured on a range from 0 (worst quality of life) to 156 (best quality of life). |
| Treatment Related Deaths | Through study completion (median duration on study = 4 cycles) | Number of treatment related deaths |
Countries
Canada, United States
Participant flow
Recruitment details
Study was open to recruitment on October 25, 2010 and closed to accrual on July 31, 2012. Study participants were identified in clinic. The target enrolment was 50 study participants; however only 22 participants enrolled as the study was terminated due to discontinuation of cediranib drug supply due to clinical development discontinuation.
Participants by arm
| Arm | Count |
|---|---|
| Arm I - Cediranib Plus Dasatinib 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. | 11 |
| Arm II - Cediranib Alone Patients receive cediranib maleate as in arm I. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | 11 |
| Total | 22 |
Baseline characteristics
| Characteristic | Arm I - Cediranib Plus Dasatinib | Arm II - Cediranib Alone | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 9 Participants | 10 Participants | 19 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 1 Participants | 3 Participants |
| Age, Continuous | 65.4 years STANDARD_DEVIATION 7.1 | 72.7 years STANDARD_DEVIATION 6.5 | 69 years STANDARD_DEVIATION 7.6 |
| Region of Enrollment Canada | 9 participants | 8 participants | 17 participants |
| Region of Enrollment United States | 2 participants | 3 participants | 5 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 11 Participants | 11 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 11 / 11 | 11 / 11 |
| serious Total, serious adverse events | 5 / 11 | 7 / 11 |
Outcome results
Primary
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.
Time frame: 3 months
Population: All patients were included in the analysis for 12-week PFS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I - Cediranib Plus Dasatinib | 12-week Progression-free Survival as Per the Prostate Cancer Clinical Trials Working Group (PCWG2) | 2 participants |
| Arm II - Cediranib Alone | 12-week Progression-free Survival as Per the Prostate Cancer Clinical Trials Working Group (PCWG2) | 8 participants |
Secondary
Dose Interruption Due to AEs
The number of participants with dose-interruptions in each arm due to adverse events
Time frame: Through study completion (median duration on study = 4 cycles)
Population: Analysis was performed on study participants assessing the number of participants with dose-interruptions due to adverse events.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I - Cediranib Plus Dasatinib | Dose Interruption Due to AEs | 8 Participants |
| Arm II - Cediranib Alone | Dose Interruption Due to AEs | 6 Participants |
Secondary
Dose Reductions
The number of participants with dose reductions in each arm
Time frame: Duration of Study (median duration on study = 4 cycles)
Population: Analysis conducted on the number of participants with dose reductions in each arm of the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I - Cediranib Plus Dasatinib | Dose Reductions | 5 Participants |
| Arm II - Cediranib Alone | Dose Reductions | 4 Participants |
Secondary
Non-AE Related Treatment Discontinuation
Non-Adverse Event related Treatment Discontinuation
Time frame: Through study completion (median duration on study = 4 cycles)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm I - Cediranib Plus Dasatinib | Non-AE Related Treatment Discontinuation | Progressive Disease | 4 participants |
| Arm I - Cediranib Plus Dasatinib | Non-AE Related Treatment Discontinuation | Death | 0 participants |
| Arm I - Cediranib Plus Dasatinib | Non-AE Related Treatment Discontinuation | Other | 5 participants |
| Arm II - Cediranib Alone | Non-AE Related Treatment Discontinuation | Progressive Disease | 4 participants |
| Arm II - Cediranib Alone | Non-AE Related Treatment Discontinuation | Death | 2 participants |
| Arm II - Cediranib Alone | Non-AE Related Treatment Discontinuation | Other | 4 participants |
Secondary
Number of Participants With Increased Alkaline Phosphatase BAP
Number of participants with increased alkaline phosphatase BAP
Time frame: Through study completion (median duration on study = 4 cycles)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I - Cediranib Plus Dasatinib | Number of Participants With Increased Alkaline Phosphatase BAP | 5 participants |
| Arm II - Cediranib Alone | Number of Participants With Increased Alkaline Phosphatase BAP | 10 participants |
Secondary
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
Time frame: Up to 30 days after last dose of study drugs
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I - Cediranib Plus Dasatinib | Number of Participants With Toxicities | 11 participants |
| Arm II - Cediranib Alone | Number of Participants With Toxicities | 11 participants |
Secondary
Number Who Experienced Study Medication Dose Intensity
Number of patients who experienced study medication dose of over 80% during Cycle 1 was assessed.
Time frame: Cycle 1 (an average of 28 days)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I - Cediranib Plus Dasatinib | Number Who Experienced Study Medication Dose Intensity | 6 participant |
| Arm II - Cediranib Alone | Number Who Experienced Study Medication Dose Intensity | 9 participant |
Secondary
Overall Response Rate
Best overall response rate of each evaluable patient
Time frame: Duration of Study (median duration on study = 4 cycles)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I - Cediranib Plus Dasatinib | Overall Response Rate | 2.6 months |
| Arm II - Cediranib Alone | Overall Response Rate | 6.4 months |
Secondary
Overall Response Rate
Response Rate of Stable Disease and Progressive Disease
Time frame: Duration of Study (median duration on study = 4 cycles)
Population: Analysis of number of participants who experienced response rates of SD and PD.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm I - Cediranib Plus Dasatinib | Overall Response Rate | Stable Disease | 22 percentage of participants |
| Arm I - Cediranib Plus Dasatinib | Overall Response Rate | Progressive Disease | 45 percentage of participants |
| Arm II - Cediranib Alone | Overall Response Rate | Stable Disease | 77 percentage of participants |
| Arm II - Cediranib Alone | Overall Response Rate | Progressive Disease | 18 percentage of participants |
Secondary
Participants for Which Bone Biomarkers for Beta-C Telopeptide Was Reduced
Participants for which beta-C telopeptide was reduced
Time frame: Through study completion (median duration on study = 4 cycles)
Population: Analysis was done on study participatns for which beta-C telopeptide was reduced.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I - Cediranib Plus Dasatinib | Participants for Which Bone Biomarkers for Beta-C Telopeptide Was Reduced | 7 Participants |
| Arm II - Cediranib Alone | Participants for Which Bone Biomarkers for Beta-C Telopeptide Was Reduced | 6 Participants |
Secondary
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).
Time frame: Up to 16 weeks
Population: Some participants (overall and post-baseline) did not complete the questionnaire or failed to answer more than 7 questions and could not be included in the analysis (a summary score could not be calculated).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm I - Cediranib Plus Dasatinib | Quality of Life Assessment Using Functional Assessment of Cancer Therapy - Prostate (FACT-P) Questionnaire | Cycle 3 (12 weeks) | 109.1 units on a scale |
| Arm I - Cediranib Plus Dasatinib | Quality of Life Assessment Using Functional Assessment of Cancer Therapy - Prostate (FACT-P) Questionnaire | Baseline | 117.5 units on a scale |
| Arm I - Cediranib Plus Dasatinib | Quality of Life Assessment Using Functional Assessment of Cancer Therapy - Prostate (FACT-P) Questionnaire | Cycle 4 (16 weeks) | 114.5 units on a scale |
| Arm I - Cediranib Plus Dasatinib | Quality of Life Assessment Using Functional Assessment of Cancer Therapy - Prostate (FACT-P) Questionnaire | Cycle 2 (8 weeks) | 120.6 units on a scale |
| Arm II - Cediranib Alone | Quality of Life Assessment Using Functional Assessment of Cancer Therapy - Prostate (FACT-P) Questionnaire | Cycle 4 (16 weeks) | 93.8 units on a scale |
| Arm II - Cediranib Alone | Quality of Life Assessment Using Functional Assessment of Cancer Therapy - Prostate (FACT-P) Questionnaire | Cycle 3 (12 weeks) | 105.8 units on a scale |
| Arm II - Cediranib Alone | Quality of Life Assessment Using Functional Assessment of Cancer Therapy - Prostate (FACT-P) Questionnaire | Cycle 2 (8 weeks) | 107 units on a scale |
| Arm II - Cediranib Alone | Quality of Life Assessment Using Functional Assessment of Cancer Therapy - Prostate (FACT-P) Questionnaire | Baseline | 108.5 units on a scale |
Secondary
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.
Time frame: After every cycle (median duration on study = 4 cycles)
Population: Analysis was performed patients receiving single agent cediranib or combination of cediranib plus dasatinib.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I - Cediranib Plus Dasatinib | Qualtiy of Life Assessment Number of Participants With a Score ≥2 on the Present Pain Intensity (PPI) Scale | 4 Participants |
| Arm II - Cediranib Alone | Qualtiy of Life Assessment Number of Participants With a Score ≥2 on the Present Pain Intensity (PPI) Scale | 8 Participants |
Secondary
Treatment Discontinuation
Discontinuation of treatment in cycle 1 (average of 28 days)
Time frame: Cycle 1 (average of 28 days)
Population: Analysis was performed on study participants enrolled on the trial assessing number of patients who discontinued treatment in cycle 1.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I - Cediranib Plus Dasatinib | Treatment Discontinuation | 7 Participants |
| Arm II - Cediranib Alone | Treatment Discontinuation | 6 Participants |
Secondary
Treatment Discontinuation Due to Adverse Events (AEs)
Treatment discontinuation due to Adverse Events
Time frame: Through study completion (median duration on study = 4 cycles)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I - Cediranib Plus Dasatinib | Treatment Discontinuation Due to Adverse Events (AEs) | 2 participants |
| Arm II - Cediranib Alone | Treatment Discontinuation Due to Adverse Events (AEs) | 1 participants |
Secondary
Treatment Related Deaths
Number of treatment related deaths
Time frame: Through study completion (median duration on study = 4 cycles)
Population: In Arm II (Cediranib alone), 1 patient presented retroperitoneal hemorrhage (Grade 5).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I - Cediranib Plus Dasatinib | Treatment Related Deaths | 0 participants |
| Arm II - Cediranib Alone | Treatment Related Deaths | 1 participants |