Clinical Trials /

Durvalumab and Olaparib for the Treatment of Prostate Cancer in Men Predicted to Have a High Neoantigen Load

NCT04336943

Description:

This phase II trial studies how well durvalumab and olaparib work in treating prostate cancer in men predicted to have specific genetic mutations (a high neoantigen load). Immunotherapy with monoclonal antibodies, such as durvalumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. PARPs are proteins that help repair DNA mutations. PARP inhibitors, such as olaparib, can keep PARP from working, so tumor cells can't repair themselves, and they may stop growing. Giving durvalumab and olaparib may kill more tumor cells in patients with prostate cancer predicted to have a high neoantigen load.

Related Conditions:
  • Prostate Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Durvalumab and Olaparib for the Treatment of Prostate Cancer in Men Predicted to Have a High Neoantigen Load
  • Official Title: Durvalumab (MEDI4736) and Olaparib (AZD2281) for Treatment of Biochemically Recurrent Prostate Cancer in Men Predicted to Have a High Neoantigen Load: A Pilot Study

Clinical Trial IDs

  • ORG STUDY ID: RG1007001
  • SECONDARY ID: NCI-2020-01860
  • SECONDARY ID: 10509
  • SECONDARY ID: P30CA015704
  • NCT ID: NCT04336943

Conditions

  • Biochemically Recurrent Prostate Carcinoma
  • Prostate Adenocarcinoma

Interventions

DrugSynonymsArms
DurvalumabImfinzi, Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer, MEDI-4736, MEDI4736Treatment (durvalumab, olaparib)
OlaparibAZD 2281, AZD-2281, AZD2281, KU-0059436, Lynparza, PARP Inhibitor AZD2281Treatment (durvalumab, olaparib)

Purpose

This phase II trial studies how well durvalumab and olaparib work in treating prostate cancer in men predicted to have specific genetic mutations (a high neoantigen load). Immunotherapy with monoclonal antibodies, such as durvalumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. PARPs are proteins that help repair DNA mutations. PARP inhibitors, such as olaparib, can keep PARP from working, so tumor cells can't repair themselves, and they may stop growing. Giving durvalumab and olaparib may kill more tumor cells in patients with prostate cancer predicted to have a high neoantigen load.

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).
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (durvalumab, olaparib)ExperimentalAll 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.
  • Durvalumab
  • Olaparib

Eligibility Criteria

        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 with a PSA doubling time (PSADT) =< 10 months:

               -  PSADT calculation must include all recorded PSA values 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.

               -  Patients with oligometastatic disease (i.e. =< 3 sites) detectable on advanced
                  imaging only (e.g. PSMA or fluciclovine positron emission tomography [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

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

Primary Outcome Measures

Measure:Undetectable prostate specific antigen (PSA)
Time Frame:At 12 months after initiation of therapy
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Incidence of adverse events (AEs) during durvalumab monotherapy
Time Frame:Up to 3 months
Safety Issue:
Description:Will be assessed per Common Terminology Criteria for Adverse Events CTCAE version (v) 5.0 guidelines.
Measure:Incidence of AEs during durvalumab and olaparib combination therapy
Time Frame:Up to 6 months
Safety Issue:
Description:Will be assessed per CTCAE v5.0 guidelines.
Measure:PSA50 response
Time Frame:At 3 and 6 months
Safety Issue:
Description: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.
Measure:Change in quality of life: RANDSF-36
Time Frame:At the time of enrollment and then every three months for 24 months
Safety Issue:
Description:Will be assessed using the RANDSF-36 score calculation
Measure:Change in quality of life: IIEF
Time Frame:At the time of enrollment and then every three months for 24 months
Safety Issue:
Description:Will be assessed using the International Index of Erectile Function (IIEF) score calculation

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Washington

Last Updated

March 15, 2021