- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04336943
Durvalumab and Olaparib for the Treatment of Prostate Cancer in Men Predicted to Have a High Neoantigen Load
Durvalumab (MEDI4736) and Olaparib (AZD2281) for Treatment of Biochemically Recurrent Prostate Cancer in Men Predicted to Have a High Neoantigen Load: A Multicenter Pilot Study
Study Overview
Status
Intervention / Treatment
Detailed Description
OUTLINE:
All patients receive durvalumab IV over 1 hour on day 1 of each cycle, total 6 cycles. Starting cycle 4, patients with CDK12 mutations and mismatch repair deficiency (MMRd)/microsatellite instability (MSI)-high will also receive olaparib orally (PO) twice daily (BID) on days 1- 28 of cycles 4-6. Patients with homologous recombination mutation will also receive olaparib PO BID on days 1-28 of cycles 1-6. Cycles repeat every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 2 weeks, and then every 12 weeks to complete 24 months (at 9, 12, 15, 18, 21 and 24 months).
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Contact
- Name: Michael Schweizer
- Phone Number: 206-606-6252
- Email: schweize@uw.edu
Study Locations
-
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Washington
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Seattle, Washington, United States, 98109
- Fred Hutch/University of Washington Cancer Consortium
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-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- Histologic confirmation of adenocarcinoma of the prostate
- The patient must have received definitive local therapy for prostate cancer, consisting of either radiation therapy and/or prostatectomy (salvage or adjuvant radiation post-prostatectomy is not exclusionary)
PSA must be >= 2 ng/ml if received only prior definitive radiation (no PSA threshold required if prior prostatectomy was performed) with a PSA doubling time (PSADT) =< 10 months:
- PSADT calculation must include all recorded PSA values > 0.2 ng/ml over the past 6 months prior to randomization, with a minimum of 3 values spaced at least 2 weeks apart, with each included value preferably measured at the same laboratory. PSA values obtained prior to localized therapy will be excluded
- The calculation of PSADT is based on the natural log of PSA
- Prior salvage radiation or not a candidate for localized salvage radiation due to subject preference or clinical assessment based upon disease characteristics and/or subject co-morbidities
- Prior hormonal therapy (i.e. androgen deprivation therapy) when given as neoadjuvant/concurrent/adjuvant therapy along with definitive radiation is allowed, provided this was stopped >= 6 months prior to starting treatment per protocol AND testosterone is >= 150 ng/dl
No evidence of metastatic disease on imaging by whole body bone scan and computed tomography (CT) or magnetic resonance imaging (MRI) of the chest/abdomen/pelvis within 6 weeks before study therapy start day. PSMA positron emission tomography (PET) or fluciclovine scan within 6 weeks of start day may substitute other imaging studies.
- Patients with oligometastatic disease (i.e. =< 3 sites) detectable on advanced imaging only (e.g. PSMA or fluciclovine PET) are eligible
- Abdominal or pelvic lymph nodes measuring =< 2 cm in short axis are allowed
Biomarker positive:
- Biallelic CDK12 inactivating mutations as documented using a clinical grade sequencing assay performed in a Clinical Laboratory Improvement Act (CLIA)/College of American Pathologists (CAP) certified laboratory or
- MMRd/MSI-high as documented using a clinical grade assay performed in a CLIA/CAP certified laboratory or
- Loss of function mutations in homologous recombination genes (i.e. homologous recombination deficiency; HRD) as documented using a clinical grade sequencing assay performed in a CLIA/CAP certified laboratory. Homologous recombination genes include, but not limited to BRCA1, BRCA2, ATM, CHEK2, PALB2, RAD51D, NBN, GEN1, RAD51C, MRE11A, BRIP11A, FAM175A.
- Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent and any locally required authorization (e.g., Health Insurance Portability and Accountability Act) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations
- Age > 18 years at time of study entry.
- Eastern Cooperative Oncology Group (ECOG) performance status of =< 1
- Hemoglobin >= 10.0 g/dL with no blood transfusion in the past 28 days (within 28 days prior to administration of study treatment)
- Absolute neutrophil count (ANC) be >= 1.5 x 10^9/L (within 28 days prior to administration of study treatment)
- Platelet count >= 100 x 10^9/L (within 28 days prior to administration of study treatment)
- Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN) (within 28 days prior to administration of study treatment). This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be =< 5 x ULN (within 28 days prior to administration of study treatment)
- Patient must have creatinine clearance (CL) >= 51 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance (within 28 days prior to administration of study treatment)
- Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up
- Patients must have a life expectancy >= 16 weeks
- Body weight > 30 kg
- Male patients must use a condom during treatment and for 3 months after the last dose of olaparib when having sexual intercourse with a pregnant woman or with a woman of childbearing potential. Female partners of male patients should also use a highly effective form of contraception if they are of childbearing potential
Exclusion Criteria:
- Prior chemotherapy for prostate cancer, unless done in the neoadjuvant setting, and if the last dose was > 6 months prior to enrollment
- Any prior treatment with a PD1 or PD-L1 inhibitor, including durvalumab
- Any prior treatment with a PARP inhibitor, including olaparib
History of another primary malignancy except for
- Malignancy treated with curative intent and with no known active disease >= 3 years before the first dose of durvalumab and of low potential risk for recurrence
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
- Adequately treated carcinoma in situ without evidence of disease
- History of leptomeningeal carcinomatosis
- Resting electrocardiogram (ECG) indicating uncontrolled, potentially reversible cardiac conditions, as judged by the treating physician (e.g., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, corrected QT interval by Fridericia [QTcF] prolongation > 470 ms, electrolyte disturbances, etc.), or patients with congenital long QT syndrome
Any unresolved toxicity National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade >= 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria
- Patients with grade >= 2 neuropathy will be evaluated on a case-by-case basis after consultation with the study physician
- Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or olaparib may be included only after consultation with the study physician
- Patients with myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of MDS/AML
- Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, extensive bilateral lung disease on high resolution computed tomography (HRCT) scan, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea or any psychiatric disorder that prohibits obtaining informed consent
- Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication
Immunocompromised patients, e.g., patients with uncontrolled human immunodeficiency virus (HIV). HIV+ patients will be allowed on the study if on highly active antiretroviral therapy (HAART) and disease is controlled: CD4 >= 350 cell/mcl, undetectable viral load, and no prophylactic (PPX) antibiotics
- Note: HIV screening is not required to be eligible for this study
- Active infection including tuberculosis (TB testing only performed if deemed necessary per standard clinical practice), hepatitis B (known positive hepatitis B virus [HBV] surface antigen [HBsAg] result), hepatitis C. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA)
Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion:
- Patients with vitiligo or alopecia
- Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
- Any chronic skin condition that does not require systemic therapy
- Patients without active disease in the last 5 years may be included but only after consultation with the sponsor investigator
- Patients with celiac disease controlled by diet alone
Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion:
- Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
- Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
- Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
- Receipt of live attenuated vaccine within 30 days prior to the first dose of durvalumab. Note: Patients, if enrolled, should not receive live vaccine whilst receiving durvalumab and up to 30 days after the last dose of durvalumab
- Patients receiving any chemotherapy, immunotherapy, biologic, radiotherapy or hormonal therapy for cancer treatment concurrently or within 3 weeks of study treatment. Concurrent use of hormonal therapy for non-cancer related conditions (e.g., hormone replacement therapy) is acceptable
- Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug
- Concomitant use of known strong CYP3A inhibitors (e.g. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting study treatment is 2 weeks
- Concomitant use of known strong (e.g. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's wort) or moderate CYP3A inducers (e.g. bosentan, efavirenz, modafinil). The required washout period prior to starting study treatment is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents
- Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery
- Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT)
- Participation in another clinical study with an investigational product administered in the last 3 months
- Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) or supportive care, while on the clinical study or during the follow-up period of this interventional study
- Patients with a known hypersensitivity to olaparib or durvalumab or any of the excipients of the product
- Involvement in the planning and/or conduct of the study
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Treatment (durvalumab, olaparib)
All patients receive durvalumab IV over 1 hour on day 1 of each cycle.
Patients with CDK12 mutation and MMRd/MSI-high also receive olaparib PO BID on days 1- 28 of cycles 3-6.
Patients with homologous recombination mutation also receive olaparib PO BID on days 1-28 of cycles 1-6.
Cycles repeat every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity.
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Ancillary studies
Other Names:
Ancillary studies
Given IV
Other Names:
Given PO
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Undetectable prostate specific antigen (PSA)
Time Frame: At 12 months after initiation of therapy
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Will assess if patients achieve undetectable PSA for post-prostatectomy patients (including those that also received salvage radiation) or PSA < 0.5 ng/ml for post-definitive radiation patients.
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At 12 months after initiation of therapy
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Incidence of adverse events (AEs) during durvalumab monotherapy
Time Frame: Up to 3 months
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Will be assessed per Common Terminology Criteria for Adverse Events CTCAE version (v) 5.0 guidelines.
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Up to 3 months
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Incidence of AEs during durvalumab and olaparib combination therapy
Time Frame: Up to 6 months
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Will be assessed per CTCAE v5.0 guidelines.
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Up to 6 months
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PSA50 response
Time Frame: At 3 and 6 months
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A descriptive summary (including the percentage and 90% confidence interval [CI]) of PSA50 response rate (proportion of patients with a decline in PSA > 50% from baseline) will be provided at 3- and 6-month timepoints.
The response rate will be reported with exact binomial two-sided 90% CI.
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At 3 and 6 months
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Change in quality of life: RANDSF-36
Time Frame: At the time of enrollment and then every three months for 24 months
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Will be assessed using the RANDSF-36 score calculation
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At the time of enrollment and then every three months for 24 months
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Change in quality of life: IIEF
Time Frame: At the time of enrollment and then every three months for 24 months
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Will be assessed using the International Index of Erectile Function (IIEF) score calculation
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At the time of enrollment and then every three months for 24 months
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Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Michael Schweizer, Fred Hutch/University of Washington Cancer Consortium
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Estimated)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Neoplasms by Histologic Type
- Neoplasms
- Urogenital Neoplasms
- Neoplasms by Site
- Carcinoma
- Neoplasms, Glandular and Epithelial
- Genital Neoplasms, Male
- Prostatic Diseases
- Urogenital Diseases
- Male Urogenital Diseases
- Genital Diseases, Male
- Genital Diseases
- Prostatic Neoplasms
- Adenocarcinoma
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Antineoplastic Agents
- Immunologic Factors
- Antineoplastic Agents, Immunological
- Olaparib
- Immunoglobulins
- Durvalumab
- Antibodies, Monoclonal
- Immunoglobulin G
- Poly(ADP-ribose) Polymerase Inhibitors
Other Study ID Numbers
- RG1007001
- 10509 (Other Identifier: CTEP)
- NCI-2020-01860 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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