Patient case: 81-year-old male with Prostate cancer. Genetic variant: PTEN Inactivating. Other conditions: Hypertension, Depression.

Clinical trial: Olaparib With or Without Cediranib in Treating Patients With Metastatic Hormone-Resistant Prostate Cancer

Summary: This randomized phase II trial studies how well olaparib with or without cediranib works in treating patients with hormone-resistant prostate cancer that has spread to other places in the body. Olaparib and cediranib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed description: PRIMARY OBJECTIVES:
  I. 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 metastatic castration resistant prostate cancer (mCRPC).
  SECONDARY OBJECTIVES:
  I. To assess the clinical activity of the combination of cediranib and olaparib, as measured by prostate-specific antigen (PSA) response rate, radiographic response rate by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1, and overall survival (OS), as compared to olaparib monotherapy in patients with mCRPC.
  II. To evaluate association of homologous recombination deoxyribonucleic acid (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.
  TERTIARY OBJECTIVES:
  I. 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.
  II. To characterize changes in ribonucleic acid (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.
  III. 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.
  IV. 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.
  V. To explore biomarker signatures that correlate with the clinical activity or resistance to olaparib with or without cediranib, including changes in gene expression or acquired mutations in tumor biopsies.
  OUTLINE: Patients are randomized to 1 of 2 arms.
  ARM I: Patients receive olaparib orally (PO) twice daily (BID) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  ARM II: Patients receive olaparib PO BID and cediranib PO once daily (QD) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  After completion of study treatment, patients are followed up every 6 months.

Eligibility: Inclusion Criteria:
  -  Patients must have histologically confirmed progressive, metastatic castration resistant prostate adenocarcinoma by meeting ALL the following:
  -  Pathology of prostate gland or metastatic disease must confirm the diagnosis of prostate adenocarcinoma; mixed histology with other variants such as small cell or neuroendocrine differentiation must be discussed with the study principal investigator (PI)
  -  Metastasis must be documented by radiographic evidence
  -  Castration resistance must be documented with surgical or medical castration with serum testosterone < 50ng/d (< 2.0 nM]); if the patient is being treated with luteinizing hormone-releasing hormone (LHRH) agonists (patient who has not undergone orchiectomy), this therapy must have been initiated at least 4 weeks prior to cycle 1, day 1 and must be continued throughout the study
  -  Progression must be evidenced and documented by any of the following parameters
  -  Two consecutively rising PSA values, above the baseline, at a minimum of 1-week intervals; the minimal value to enter the study is 1.0 ng/ml or greater
  -  Appearance of one or more new lesions on bone scan
  -  Progressive measurable disease by RECIST 1.1
  -  Must have a tumor lesion readily 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
  -  Must be 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
  -  Must have at least two prior lines of therapy for mCRPC; a taxane chemotherapy administered for metastatic castration sensitive disease will not count; therapy given in concurrent administration on a clinical trial will count as one line of therapy
  -  Must have no more than two prior cytotoxic chemotherapies for metastatic CRPC disease; (docetaxel administered for metastatic castration sensitive disease will not count)
  -  Prior or concurrent use of prednisone up to 5mg bid or equivalent for symptom control is allowed, as long as the treatment was initiated prior to commencing the trial medication with evidence of progression on the dose of steroids
  -  Patients must have measurable disease by RECIST v1.1; patients with bone metastases only are allowed (NOTE: nodes >= 1.5 cm (not >= 2 cm) in the short axis are considered measurable, per The Prostate Cancer Working Group 3 [PCWG3])
  -  Toxicities of prior therapy (except alopecia) should be resolved to =< grade 1 as per National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.0; patients with long-standing stable grade 2 neuropathy may be allowed after discussion with the study principal investigator (PI)
  -  Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Karnofsky >= 70%)
  -  Absolute neutrophil count >= 1,500/mcL
  -  Platelets >= 100,000/mcL
  -  Hemoglobin >= 9 g/dL
  -  Creatinine clearance: >= 45 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal; the creatinine clearance is calculated using Cockcroft-Gault formula
  -  Urine protein: creatinine ratio (UPC) of =< 1 or less than or equal to 2+ proteinuria on two consecutive dipsticks taken no less than 1 week apart; UPC is the preferred test; patients with >= 2+ proteinuria on dipstick must also have a 24 hour urine collection demonstrating =< 500mg over 24 hours
  -  Total bilirubin =< 1.5 x the institutional upper limit of normal (ULN)
  -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 times institutional ULN
  -  Coagulation parameters within 1.25 x ULN institutional limits, except where a lupus anti-coagulant has been confirmed, or except patients on anticoagulation
  -  Patients must be able to swallow oral medications and not have gastrointestinal illnesses that would preclude absorption of cediranib or olaparib
  -  Adequately controlled thyroid function, with no symptoms of thyroid dysfunction; patients can be on thyroid hormone replacement medication; asymptomatic patients with elevated thyroid-stimulating hormone (TSH) with normal T4/T3 are allowed to enroll, and recommended to follow with routine thyroid function test especially if they are randomized to cediranib/olaparib arm
  -  Adequately controlled blood pressure (BP) < 140 mmHg (systolic) and < 90 mmHg (diastolic) taken in the clinic setting by a medical professional within 2 weeks prior to starting study; patients with hypertension may be managed with up to a maximum of 3 antihypertensive medications; patients who are on 3 antihypertensive medications are highly recommended to be followed by a cardiologist or blood pressure specialist for management of BP while on protocol
  -  Patients must be willing and able to check and record daily blood pressure readings
  -  Patients who have the following risk factors are considered to be at increased risk for cardiac toxicities, and must have documented left ventricular ejection fraction (LVEF) by echocardiogram greater than institution's lower limit of normal (or 55% if threshold for normal not otherwise specified by institutional guidelines) obtained within 3 months
  -  A New York Heart Association (NYHA) classification of II controlled with treatment
  -  Prior central thoracic radiation therapy (RT), including RT to the heart
  -  History of myocardial infarction within 12 months
  -  Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception and not to donate sperm prior to the study, for the duration of study participation, and for 3 months after completion of cediranib and olaparib administration
  -  Ability to understand and the willingness to sign a written informed consent document
  Exclusion Criteria:
  -  Patients who have had chemotherapy or RT within 21 days prior to start of the study agents, or those who have not recovered from adverse events due to agents administered more than 3 weeks earlier
  -  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
  -  Patients who have received any other investigational agents within the past 28 days
  -  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
  -  For patients with known and treated brain metastases is allowed in this study if they fulfill ALL of the following criteria:
  -  The lesions have remained radiologically stable for at least six weeks after completion of brain irradiation or stereotactic brain radiosurgery, and must remain stable at the time of study entry
  -  There is no mass effect present radiologically and no steroids requirement for symptom control for more than 4 weeks
  -  Patients who 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
  -  Participants receiving any medications or substances that are strong inhibitors or inducers of CYP3A4 are ineligible; dihydropyridine calcium-channel blockers are permitted for management of hypertension
  -  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
  -  Patients with concomitant or prior invasive malignancies within the past 3 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 including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  -  Patients with corrected QT interval (QTc) (with Bazett's correction) prolongation > 470 msec or other significant electrocardiogram (ECG) abnormality noted within 14 days of treatment
  -  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
  -  Current condition requiring concurrent use of drugs or biologics with anti-arrhythmic or pro-arrhythmic potential
  -  History of hypertensive crisis or hypertensive encephalopathy within 3 years of the randomization
  -  Clinically significant peripheral vascular disease or vascular disease (abdominal aortic aneurysm [ > 5 cm] or aortic dissection); patients with known history of abdominal aortic aneurysm (AAA) with >= 4 cm in diameter, a repeat ultrasound (US) within the last 6 months will be required to document that it is =< 5 cm, and patient must be asymptomatic from the aneurysm, and the blood pressure must be well controlled as required in this protocol
  -  A major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to starting cediranib (percutaneous/endobronchial biopsies are allowed)
  -  Patients may not have current signs and/or symptoms of bowel obstruction within 1 month prior to starting study drugs, except if it was a temporary incident (improved within < 24 hrs with medical management)
  -  History of hemoptysis within the last 1 month
  -  Presence of cavitation of central pulmonary lesion
  -  History of abdominal fistula, intra-abdominal abscess, or gastrointestinal perforation with the 3 months
  -  Patients may not have current dependency on intravenous (IV) hydration or total parenteral nutrition (TPN)
  -  Patients may not have evidence of coagulopathy or bleeding diathesis; therapeutic anticoagulation for prior thromboembolic events is not permitted
  -  Patients with history of intra-abdominal bleeding or retroperitoneal bleeding within the last 3 years are excluded
  -  Patients may not have features suggestive of myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) on peripheral blood smear or bone marrow biopsy, if clinically indicated
  -  Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with cediranib or olaparib; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated; HIV-positive patients with undetectable viral loads and CD4 counts > 300, and not on any antiretroviral therapy may be allowed after discussing with the principal investigator

Relevance to patient case: not relevant