Clinical Trials /

Olaparib in Treating Patients With Metastatic Biliary Tract Cancer With Aberrant DNA Repair Gene Mutations

NCT04042831

Description:

This phase II trial studies how well olaparib works in treating patients with biliary tract cancer that has spread to other places in the body (metastatic) and with aberrant DNA repair gene mutations. Olaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Related Conditions:
  • Biliary Tract Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Olaparib in Treating Patients With Metastatic Biliary Tract Cancer With Aberrant DNA Repair Gene Mutations
  • Official Title: A Phase II Study of Olaparib in Patients With Advanced Biliary Tract Cancer With Aberrant DNA Repair Gene Mutations

Clinical Trial IDs

  • ORG STUDY ID: ACCRU-ICRN-1702
  • SECONDARY ID: NCI-2019-04434
  • SECONDARY ID: ACCRU-ICRN-1702
  • SECONDARY ID: P30CA015083
  • NCT ID: NCT04042831

Conditions

  • ARID1A Gene Mutation
  • ATM Gene Mutation
  • ATR Gene Mutation
  • Bile Duct Adenocarcinoma
  • BRCA1 Gene Mutation
  • BRCA2 Gene Mutation
  • BRIP1 Gene Mutation
  • CHEK2 Gene Mutation
  • EMSY Gene Mutation
  • Fanconi Anemia Complementation Group Gene Mutation
  • Metastatic Bile Duct Carcinoma
  • MRE11 Gene Mutation
  • NBN Gene Mutation
  • PALB2 Gene Mutation
  • PTEN Gene Deletion
  • RAD51 Gene Mutation

Interventions

DrugSynonymsArms
OlaparibAZD 2281, AZD-2281, AZD2281, KU-0059436, Lynparza, PARP Inhibitor AZD2281Treatment (olaparib)

Purpose

This phase II trial studies how well olaparib works in treating patients with biliary tract cancer that has spread to other places in the body (metastatic) and with aberrant DNA repair gene mutations. Olaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the efficacy (objective response rate) of olaparib monotherapy in advanced
      biliary tract cancer (BTC) with mutations in deoxyribonucleic acid (DNA) repair genes.

      SECONDARY OBJECTIVES:

      I. To determine the overall survival of patients with advanced biliary tract cancer with
      mutations in DNA repair genes treated with olaparib.

      II. To determine the progression free survival of patients with advanced biliary tract cancer
      with mutations in DNA repair genes treated with olaparib.

      III. To assess the frequency and severity of adverse events in advanced biliary tract cancer
      patients treated with olaparib.

      IV. To assess the duration of response for patients with advanced biliary tract cancer with
      mutations in DNA repair genes treated with olaparib who experience an objective response.

      CORRELATIVE RESEARCH OBJECTIVES:

      I. Determine the prevalence of mutations including those targeting DNA repair pathways.

      II. Identify mutational signatures associated with pathogenic process in advanced biliary
      tract cancer samples.

      III. Correlate the presence of mutations and mutational signatures linked to mutations in DNA
      repair genes and homologous recombinant repair with clinical responses to olaparib.

      IV. To evaluate putative biomarkers related to:

      Iva. De novo sensitivity. IVb. Tumor evolution and resistance, to PARP inhibition from
      olaparib in BTC.

      OUTLINE:

      Patients receive olaparib orally (PO) twice daily (BID) on days 1-28. Treatment repeats every
      28 days for up to 36 cycles in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 days and then every 3
      months for up to 3 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (olaparib)ExperimentalPatients receive olaparib PO BID on days 1-28. Treatment repeats every 28 days for up to 36 cycles in the absence of disease progression or unacceptable toxicity.
  • Olaparib

Eligibility Criteria

        Inclusion Criteria:

          -  Histological or cytological documentation of metastatic adenocarcinoma of the biliary
             tract

          -  Patients with previously identified genetic aberrations that are associated with
             homologous recombinant repair pathway will be eligible [e.g. somatic mutations in ATM,
             ATR, CHEK2, BRCA 1/2, RAD51, BRIP1, PALB2, PTEN, FANC, NBN, EMSY, MRE11, ARID1A] or
             germline mutations in the above genes. Clinical Laboratory Improvement Act
             (CLIA)-certified assays including commercial tests (Foundation Medicine, Caris,
             Tempus) will be allowed

          -  Measurable disease

          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1. (Form is
             available on the Academic and Community Cancer Research United [ACCRU] web site)

          -  Life expectancy of >= 16 weeks per estimation of investigator

          -  Absolute neutrophil count (ANC) >= 1500/mm^3 (obtained =< 7 days prior to
             registration)

          -  Platelet count >= 75,000/mm^3 (obtained =< 7 days prior to registration)

          -  Hemoglobin >= 9.0 g/dL with no blood transfusion in the past 28 days (obtained =< 7
             days prior to registration)

          -  Total bilirubin =< 1.5 x upper limit of normal (ULN) (obtained =< 7 days prior to
             registration)

          -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN (=< 5
             x ULN for subjects with liver involvement of their cancer) (obtained =< 7 days prior
             to registration)

          -  Serum creatinine =< 1.5 x ULN (obtained =< 7 days prior to registration)

          -  Institutional normalized ratio (INR)/partial thromboplastin time (PTT) =< 1.5 x ULN
             (obtained =< 7 days prior to registration)

               -  Exception: Patients who are therapeutically treated with anticoagulant agents
                  (excluding warfarin) will be allowed to participate provided that no prior
                  evidence of underlying abnormality in coagulation parameters exists. Close
                  monitoring of at least weekly evaluations will be performed until INR/PTT is
                  stable based on a measurement that is pre-dose as defined by the local standard
                  of care

          -  Alkaline phosphatase limit =< 2.5 x ULN (=< 5 x ULN for patients with liver
             involvement of their cancer) (obtained =< 7 days prior to registration)

          -  Creatinine clearance estimated of >= 51 mL/min using the Cockcroft-Gault equation
             (obtained =< 7 days prior to registration)

          -  Negative serum pregnancy test done =< 28 days prior to registration and confirmed
             prior to treatment on day 1, for women of childbearing potential, postmenopausal women
             or women of childbearing potential with evidence of non-childbearing status.

               -  Postmenopausal is defined as:

                    -  Amenorrheic for 1 year or more following cessation of exogenous hormonal
                       treatments

                    -  Luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in
                       the post-menopausal range for women under 50

                    -  Radiation-induced oophorectomy with last menses > 1 year ago

                    -  Chemotherapy-induced menopause with > 1 year interval since last menses

                    -  Surgical sterilization (bilateral oophorectomy or hysterectomy)

          -  Provide informed written consent

          -  Willing to return to enrolling institution for follow-up (during the active monitoring
             phase of the study)

          -  Willing to provide blood and tissue for correlative purposes

          -  Prior exposure or completion of platinum based chemotherapy

        Exclusion Criteria:

          -  Platinum refractory disease (evidence disease progression on platinum based
             chemotherapy regimen or =< 6 months of completion of platinum based chemotherapy
             regimen)

          -  Patient has received prior systemic anti-cancer therapy, tumor embolization or
             radiotherapy =< 4 weeks prior to registration

          -  Major surgical procedure, open biopsy, or significant traumatic injury =< 28 days
             prior to registration

               -  NOTE: Patients must have recovered from any effects of any major surgery

          -  Congestive heart failure - New York Heart Association (NYHA) >= class II

          -  Resting electrocardiogram (ECG) indicating uncontrolled, potentially reversible
             cardiac conditions, as judged by the investigator (eg. unstable ischemia, uncontrolled
             symptomatic arrhythmia, corrected QT interval by Fridericia's correction formula
             [QTcF] prolongation > 500 ms, electrolyte disturbances, etc.), or patients with
             congenital long QT syndrome. Cardiac arrhythmias requiring anti-arrhythmic therapy.

               -  NOTE: Pacemaker, beta blockers or digoxin are permitted

          -  Uncontrolled hypertension. (Systolic blood pressure > 140 mmHg or diastolic pressure >
             90 mmHg despite optimal medical management)

          -  History of or current pheochromocytoma

          -  Arterial or venous thrombotic or embolic events such as cerebrovascular accident
             (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism =<
             6 months prior to registration

          -  Ongoing infection > grade 2 National Cancer Institute (NCI)-Common Terminology
             Criteria for Adverse Events (CTCAE) version (v)5.0

          -  Known active hepatitis B or C

          -  Seizure disorder requiring medication

          -  Symptomatic metastatic brain or meningeal tumors unless the patient is > 6 months from
             definitive therapy, has a negative imaging study =< 4 weeks of registration and is
             clinically stable with respect to the tumor at the time of registration. Patients with
             spinal cord compression unless considered to have received definitive treatment for
             this and evidence of clinically stable disease for 28 days prior to registration

               -  NOTE: The patient can receive a stable dose of corticosteroids before and during
                  the study as long as these were started =< 4 weeks prior to registration

          -  History of organ allograft (including corneal transplant) or allogenic bone marrow
             transplant or double umbilical cord blood transplantation (dUCBT)

          -  Evidence or history of bleeding diathesis or any hemorrhage or bleeding event > CTCAE
             v5.0 grade 3, =< 4 weeks prior to registration

          -  Non-healing wound, ulcer, or bone fracture

          -  Renal failure requiring hemo-or peritoneal dialysis

          -  Dehydration CTCAE v5.0 grade >= 1

          -  Substance abuse, medical, psychological or social conditions that may interfere with
             the patient?s participation in the study or evaluation of the study results

          -  Known hypersensitivity to any of the study drugs, study drug classes, or excipients in
             the formulation

          -  Interstitial lung disease with ongoing signs and symptoms at the time of informed
             consent

          -  Persistent proteinuria of CTCAE v5.0 grade 3 or higher (>= 3.5 g/24 hours [hrs])

          -  Unable to swallow orally administered medications

          -  Any malabsorption condition and/or patients with gastrointestinal disorders likely to
             interfere with absorption of the study medication

          -  Unresolved toxicity greater than CTCAE v5.0 grade 2 attributed to any prior
             therapy/procedure excluding alopecia and oxaliplatin induced neurotoxicity =< grade 2

          -  Albumin levels < 2.5 g/dl

          -  Any of the following because this study involves an investigational agent whose
             genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are
             unknown.

               -  Pregnant women

               -  Nursing women

               -  Men or women of childbearing potential who are unwilling to employ adequate
                  contraception

               -  NOTE: Women of childbearing potential and their partners, who are sexually
                  active, must agree to the use of TWO highly effective forms of contraception in
                  combination. This should be started from the time of registration and continue
                  throughout the period of taking study treatment and for at least 1 month after
                  last dose of study drug(s), or they must totally/truly abstain from any form of
                  sexual intercourse.

               -  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.
                  Male patients should not donate sperm throughout the period of taking olaparib
                  and for 3 months following the last dose of olaparib

          -  Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment
             of the investigator, would make the patient inappropriate for entry into this study or
             interfere significantly with the proper assessment of safety and toxicity of the
             prescribed regimens. 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, uncontrolled ventricular
             arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure
             disorder, unstable spinal cord compression, superior vena cava syndrome, extensive
             interstitial bilateral lung disease on high resolution computed tomography (HRCT) scan
             or any psychiatric disorder that prohibits obtaining informed consent

          -  Immunocompromised patients and patients known to be human immunodeficiency virus (HIV)
             serologically positive and currently receiving antiretroviral therapy.

               -  NOTE: Patients known to be HIV positive, but without clinical evidence of an
                  immunocompromised state, are eligible for this trial

          -  Receiving any other investigational agent which would be considered as a treatment for
             the primary neoplasm

          -  Other malignancy unless curatively treated with no evidence of disease for >= 5 years
             prior to registration, except: adequately treated non-melanoma skin cancer, curatively
             treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS), stage 1, grade
             1 endometrial carcinoma.

               -  NOTE: All cancer treatments for cancers that were distinct in a primary site
                  other than biliary tract cancer must be completed >= 5 years prior to
                  registration

          -  Pleural effusion or ascites that causes respiratory compromise (>= CTCAE v5.0 grade 2
             dyspnea)

          -  Previous enrollment in the present study

          -  Prior exposure to any PARP inhibitor including olaparib

          -  Known hypersensitivity reaction to olaparib or any of the excipients of the product

          -  Myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of
             myelodysplastic syndrome/acute myeloid leukemia (MDS/AML)

          -  Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin,
             clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir,
             saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg.
             ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil).

               -  NOTE: The required washout period prior to registration is 2 weeks

          -  Concomitant use of known strong (eg. phenobarbital, enzalutamide, phenytoin,
             rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John?s Wort) or
             moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil).

               -  NOTE: The required washout period prior to registration is 5 weeks for
                  enzalutamide or phenobarbital and 3 weeks for other agents

          -  Patient taking medications or herbal products including grapefruits, grapefruit
             hybrids, pomelos, star fruits, Seville oranges, pomegranates, or the juice from any of
             these. Note: Patients must discontinue the drug/product >= 7 days prior to
             registration

          -  Patient taking medications with a known risk to prolong the QTc interval and/or cause
             Torsades de Pointes. Note: Patients must be discontinued >= 7 days of registration.
             Treating physicians may wish to replace the drug(s) that do not carry this risk with
             safe alternative(s)

          -  Concurrent use of warfarin or other warfarin-derived anticoagulant.

               -  NOTE: Concurrent use of heparin, direct oral anticoagulants, low molecular weight
                  heparin (LMWH), or fondaparinux is allowed

          -  Whole blood transfusions in the last 120 days prior to entry to the study (packed red
             blood cells and platelet transfusions are acceptable outside of 28 days prior to
             treatment)

          -  Involvement in the planning and/or conduct of the study

          -  Judgment by the investigator that the patient should not participate in the study if
             the patient is unlikely to comply with study procedures, restrictions and requirements
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Best objective response rate
Time Frame:Up to 24 weeks after registration
Safety Issue:
Description:Will be defined as the percentage of patients with advanced biliary cancer treated with olaparib with aberrant deoxyribonucleic acid (DNA) repair/homologous recombination repair (HRR) genes, among evaluable patients, who had a response =< 24 weeks of registration. Response is defined as either complete response (CR) or partial response (PR), per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

Secondary Outcome Measures

Measure:Overall survival (OS)
Time Frame:From study entry to death from any cause, assessed up to 3 years
Safety Issue:
Description:OS will be estimated using the Kaplan-Meier method. The median OS and 95% confidence interval will be reported.
Measure:Progression-free survival (PFS)
Time Frame:From study entry to the first of either disease progression or death from any cause, assessed up to 3 years
Safety Issue:
Description:Disease progression will be determined based on RECIST 1.1 criteria. PFS will be estimated using the Kaplan-Meier method. The median PFS and 95% confidence interval will be reported.
Measure:Incidence of adverse events
Time Frame:Up to 3 years
Safety Issue:
Description:Adverse events by patient will be summarized by frequencies and severity using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Measure:Duration of response (DoR)
Time Frame:Up to 3 years
Safety Issue:
Description:Will be defined for all evaluable patients who have achieved an objective response as the date at which the patient?s earliest best objective status is first noted to be either a complete response or partial response to the earliest date progression is documented, or death if no prior evidence of disease progression. The distribution of DoR will be estimated using the method of Kaplan-Meier (Kaplan and Meier 1958).

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Academic and Community Cancer Research United

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