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Clinical Trial 19568

Cancer Type:
Interventions:AZD2171 (Cediranib); Cediranib (Recentin); Olaparib (Lynparza)

Study Type: Treatment
Phase of Study: Phase II
Investigators:

  • Jingsong Zhang

Call 813-745-6100
or 1-800-679-0775
Overview

Study Title

A Randomized Phase 2 Study of Cediranib in Combination with Olaparib versus Olaparib Alone in Men with Metastatic Castration Resistant Prostate Cancer.

Summary

The purpose of this study is to compare any good and bad effects of using the combination of cediranib and olaparib to the use of olaparib by itself, for men with metastatic castration resistant prostate cancer.

Objective

Primary Objectives: 1.1.1 To assess the clinical activity of the combination of cediranib and olaparib, as measured by radiographic progression free survival (rPFS), as compared to olaparib monotherapy in patients with mCRPC. 1.2 Secondary Objectives: 1.2.1 To assess the clinical activity of the combination of cediranib and olaparib, as measured by PSA response rate, radiographic response rate by RECIST v1.1, and overall survival (OS), as compared to olaparib monotherapy in patients with mCRPC. PSA response is defined by PSA decline > 50% from the baseline, confirmed by a second value 3-4 weeks later. 1.2.2 To evaluate association of homologous recombination DNA repair deficiency (HRD) with the clinical activity of the combination of cediranib and olaparib or olaparib monotherapy, as measured by rPFS, in mCRPC patients. HRD positive status is defined by presence of homozygous deletion or deleterious mutations in key homologous recombination genes of DNA repair genes as analyzed by BROCA-HR test. 1.2.3 To evaluate the safety the combination of cediranib and olaparib and olaparib monotherapy in patients with metastatic prostate cancer. 1.3 Exploratory Objectives: 1.3.1 To characterize genomic alterations by whole exome sequencing in mCRPC patients and correlate that with clinical activity or resistance to olaparib with or without cediranib. 1.3.2 To characterize changes in RNA expression of DNA repair genes, angiogenesis markers, and immune markers, by whole transcriptome sequencing and correlate with clinical activity or resistance to olaparib with or without cediranib. 1.3.3 To characterize changes in immune tumor microenvironment in mCRPC patients by profiling expression of co-stimulatory and co-inhibitory molecules and tumor infiltrating lymphocytes, and correlate with clinical activity or resistance to olaparib with or without cediranib. 1.3.4 To identify baseline predictive biomarkers for rPFS or response and to identify on-treatment markers of acquired resistance in men with mCRPC receiving either olaparib plus cediranib or olaparib alone. 1.3.5 To explore biomarker signatures that correlate with the clinical activity or resistance to olaparib with or with cediranib, including changes in gene expression or acquired mutations in tumor biopsies.

Inclusion Criteria

  • Males, age 18 years or older
  • Participants must have histologically confirmed progressive, metastatic castration resistant prostate adenocarcinoma as outlined in study documentation.
  • Two consecutively rising PSA values, above the baseline, at a minimum of 1-week intervals
  • Appearance of one or more new lesions on bone scan
  • Progressive disease by RECIST 1.1
  • Have a tumor lesion safely accessible for biopsy per the investigator's discretion; while a soft tissue metastasis is preferred for a biopsy, a bone metastasis is allowed for biopsy as long as enough cores can be obtained; a biopsied lesion cannot be used for target lesion for response assessment
  • Agreeable to the mandatory research tumor biopsies (pre-treatment and on-treatment); tumor biopsies are mandatory at pre-treatment and at on-treatment; there is an optional biopsy at post-progression
  • Have received at least 2 one prior line of therapy for mCRPC; a taxane chemotherapy administered for metastatic castration sensitive disease will not count, unless patient develops disease progression within 12 months from the last dose chemotherapy
  • A life expectancy greater than or equal to 16 weeks
  • If currently on prednisone or other corticosteroids for palliation, the dose must be less than or equal to 10 mg a day or its equivalent dose and it must have been started at least 4 weeks prior to cycle 1 day 1
  • Must have measurable disease by RECIST v1.1, or evaluable disease with bone metastases demonstrated by Tc99 bone scan; patients with bone metastases only are allowed
  • Toxicities of prior therapy (except alopecia) should be resolved to as outlined in study documentationEastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Karnofsky >= 70%)
  • Within 28 days prior to administration of study treatment: Adequate bone marrow, hepatic and renal function.
  • White blood count (WBC) > 3 x 10^9/L
  • Able to swallow oral medications and not have gastrointestinal illnesses that would preclude absorption of cediranib or olaparib
  • Adequately controlled thyroid function and blood pressure
  • Male participants and their female partners, who are sexually active and of childbearing potential, must agree to the use of two highly effective forms of contraception as outlined in study guidelines
  • Additional criteria may apply

  • Exclusion Criteria

  • Have had chemotherapy, hormonal therapy (except LHRH agonist or antagonist), immunotherapy, radioisotope therapy, or RT within 21 days prior to start of the study agents
  • Initiating bisphosphonate, or RANKL antibody therapy or adjusting the dose/regimen within 30 days prior to cycle 1 day 1 is prohibited; patients on a stable bisphosphonate regimen are eligible and may continue
  • Have received any other investigational agents within the past 28 days prior to cycle 1 day 1
  • Patients with untreated brain metastases, spinal cord compression, or evidence of symptomatic brain metastases or leptomeningeal disease as noted on computed tomography (CT) or magnetic resonance imaging (MRI) scans are excluded from this clinical trial; while screening brain MRI is not required, it should be performed if clinically indicated at the discretion of the treating investigator; should patient found to have brain metastasis, treatment of brain metastasis must precede the participation in this study
  • Patients with known and treated brain metastases are allowed in this study if they fulfill additional criteria
  • Have received a prior inhibitor of vascular endothelial growth factor (VEGF) signaling inhibitor, or a poly adenosine diphosphate-ribose polymerase (PARP) inhibitor administered
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to cediranib or olaparib
  • Concomitant use of known strong CYP3A inhibitors, moderate CYP3A inhibitors, strong CYP3A inducers, or moderate CYP3A inducers. Minimu washout periods would apply.
  • Current use of natural herbal products or other "folk remedies"; if using previously, patients must stop using natural herbal products while participating in this study; multivitamin, calcium (Ca)/vitamin D (Vit D) and other vitamin complex supplements are allowed
  • Concomitant or prior invasive malignancies within the past 5 years; subjects with limited stage basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the breast, or non-muscle invasive bladder cancer, are eligible as long as they received curative intent therapy
  • Uncontrolled intercurrent illness that would limit compliance with study requirements
  • Resting ECG with corrected QT (QTc) > 470 msec on two or more time points within a 24 hour period, noted within 14 days of treatment, or family history of long QT syndrome
  • History of myocardial infarction within 6 months of the randomization
  • History of stroke or transient ischemic attack within 6 months of the randomization
  • NYHA classification of III or IV
  • History of hypertensive crisis or hypertensive encephalopathy within 3 years of the randomization
  • Clinically significant peripheral vascular disease or known abdominal aortic aneurysm
  • A major surgical procedure, open biopsy, or significant traumatic injury within 3 months prior to cycle 1 day 1 (percutaneous/endobronchial/endoscopic biopsies are allowed)
  • History of bowel obstruction within 1 month prior to starting study drugs
  • History of hemoptysis within the last 1 month prior to randomization
  • Presence of cavitation of central pulmonary lesion, or radiographic evidence of pneumonitis or other extensive bilateral lung disease such as interstitial lung disease
  • History of gastrointestinal (GI) perforation, history of intra-abdominal abscess within 3 months prior to starting treatment, or history of abdominal fistula unless the fistula history meets all the following: (a) the fistula was surgically repaired, (b) there has been no evidence of fistula for at least 6 months prior to starting treatment, (c) patient is deemed to be at low risk of recurrent fistula, and (d) the case must be discussed with the study PI
  • Current dependency on intravenous (IV) hydration or total parenteral nutrition (TPN)
  • Additional criteria may apply.