Clinical Trials /

Olaparib With or Without Cediranib in Treating Patients With Metastatic Castration-Resistant Prostate Cancer

NCT02893917

Description:

This randomized phase II trial studies how well olaparib with or without cediranib works in treating patients with castration-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.

Related Conditions:
  • Prostate Adenocarcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Olaparib With or Without Cediranib in Treating Patients With Metastatic Hormone-Resistant Prostate Cancer
  • Official Title: A Randomized Phase 2 Study of Cediranib in Combination With Olaparib Versus Olaparib Alone in Men With Metastatic Castration Resistant Prostate Cancer

Clinical Trial IDs

  • ORG STUDY ID: NCI-2016-01346
  • SECONDARY ID: NCI-2016-01346
  • SECONDARY ID: 9984
  • SECONDARY ID: 9984
  • SECONDARY ID: P30CA016359
  • SECONDARY ID: UM1CA186689
  • NCT ID: NCT02893917

Conditions

  • Castration-Resistant Prostate Carcinoma
  • Hormone-Resistant Prostate Cancer
  • Metastatic Prostate Carcinoma
  • Prostate Adenocarcinoma With Focal Neuroendocrine Differentiation
  • Prostate Carcinoma Metastatic in the Bone
  • Prostate Small Cell Carcinoma
  • Stage IV Prostate Adenocarcinoma

Interventions

DrugSynonymsArms
CediranibAZD2171Arm II (olaparib, cediranib)
OlaparibAZD2281, KU-0059436, Lynparza, PARP Inhibitor AZD2281Arm I (olaparib)

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (olaparib)Active ComparatorPatients receive olaparib PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Olaparib
Arm II (olaparib, cediranib)ExperimentalPatients receive olaparib PO BID and cediranib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Cediranib
  • Olaparib

Eligibility Criteria

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:rPFS
Time Frame:Time interval from random assignment to the date when the first site of disease is found to progress, or death, whichever occurs first, assessed up to 2 years
Safety Issue:
Description:The two study arms will be compared for rPFS survival with Kaplan-Meier estimates and log-rank tests. The Rothman confidence interval (CI), which is based on Greenwood's variance, Thomas and Grunkemeier CI, and the simultaneous confidence bands by Nair and Hall and Wellner, will be reported. In addition, the possible risk factors will be compared for survival with log-rank test. For multivariate analysis, the proportional hazards Cox model will be applied to investigate potential prognostic factors, such as age of the rPFS data. The adjusted p-values of the hazard ratios and the adjusted 95% c

Secondary Outcome Measures

Measure:Correlation between HRD status and rPFS by BROCA-homologous recombination (BROCA-HR) test
Time Frame:Up to 2 weeks prior to start of therapy
Safety Issue:
Description: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. The data analysis will be completed using Fisher's exact test. The multivariate data analysis will be completed using the generalized non-linear model.
Measure:Incidence of genomic alterations by whole exome sequencing and transcriptome sequencing
Time Frame:Up to 2 years
Safety Issue:
Description:The biomarker data analysis will be completed using Lasso-based elastic net method.
Measure:Objective response rate (ORR) assessed by RECIST v1.1
Time Frame:Up to 2 years
Safety Issue:
Description:The exact 95% confidence interval of ORR will be reported based on the binomial distribution. The multivariate data analysis will be completed using the logistic regression model. The adjusted p-value and adjusted 95% confidence interval will also be reported.
Measure:OS
Time Frame:Time between randomization and death due to any cause (or last contact for surviving patients and those lost to follow-up), assessed up to 2 years
Safety Issue:
Description:The two study arms will be compared for OS with Kaplan-Meier estimates and log-rank tests.
Measure:PSA response rate
Time Frame:Up to 2 years
Safety Issue:
Description:PSA response will be defined by PSA decline from baseline > 50%, confirmed by a second value at 3-4 weeks later. PSA response rate analysis will be based on a subset of patients who had PSA progression prior to enrollment. The multivariate data analysis will be completed using the logistic regression model.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

April 12, 2017