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

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ClinicalTrials.gov Identifier: NCT04042831
Recruitment Status : Not yet recruiting
First Posted : August 2, 2019
Last Update Posted : January 27, 2020
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Academic and Community Cancer Research United

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
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 Drug: Olaparib Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of Olaparib in Patients With Advanced Biliary Tract Cancer With Aberrant DNA Repair Gene Mutations
Estimated Study Start Date : January 30, 2020
Estimated Primary Completion Date : September 30, 2021
Estimated Study Completion Date : September 30, 2023


Arm Intervention/treatment
Experimental: Treatment (olaparib)
Patients 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.
Drug: Olaparib
Given PO
Other Names:
  • AZD 2281
  • AZD-2281
  • AZD2281
  • KU-0059436
  • Lynparza
  • PARP Inhibitor AZD2281




Primary Outcome Measures :
  1. Best objective response rate [ Time Frame: Up to 24 weeks after registration ]
    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 :
  1. Overall survival (OS) [ Time Frame: From study entry to death from any cause, assessed up to 3 years ]
    OS will be estimated using the Kaplan-Meier method. The median OS and 95% confidence interval will be reported.

  2. 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 ]
    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.

  3. Incidence of adverse events [ Time Frame: Up to 3 years ]
    Adverse events by patient will be summarized by frequencies and severity using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

  4. Duration of response (DoR) [ Time Frame: Up to 3 years ]
    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).



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04042831


Locations
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United States, Arizona
Mayo Clinic in Arizona
Scottsdale, Arizona, United States, 85259
Contact: Peter D. Masci    480-342-6011    masci.peter@mayo.edu   
Principal Investigator: Daniel H. Ahn         
United States, Massachusetts
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02215
Contact: Norka C. Snyder    617-643-4971    nsnyder@partners.org   
Principal Investigator: Lipika Goyal         
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
Contact: ACCRU Operations    507-538-7448    ACCRU@mayo.edu   
Principal Investigator: Amit Mahipal         
United States, New York
Memorial Sloan Kettering Cancer Center
New York, New York, United States, 10065
Contact: Angemael Syldor    646-888-5334    syldora@mskcc.org   
Principal Investigator: Ghassan K. Abou-Alfa         
United States, Texas
M D Anderson Cancer Center
Houston, Texas, United States, 77030
Contact: Charles Stava    713-792-2841    cstava@mdanderson.org   
Principal Investigator: Milind Javle         
Sponsors and Collaborators
Academic and Community Cancer Research United
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Daniel H Ahn Academic and Community Cancer Research United

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Responsible Party: Academic and Community Cancer Research United
ClinicalTrials.gov Identifier: NCT04042831    
Other Study ID Numbers: ACCRU-ICRN-1702
NCI-2019-04434 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
ACCRU-ICRN-1702 ( Other Identifier: Academic and Community Cancer Research United )
P30CA015083 ( U.S. NIH Grant/Contract )
First Posted: August 2, 2019    Key Record Dates
Last Update Posted: January 27, 2020
Last Verified: December 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Biliary Tract Neoplasms
Carcinoma, Ductal
Fanconi Anemia
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Biliary Tract Diseases
Digestive System Diseases
Anemia, Hypoplastic, Congenital
Anemia, Aplastic
Anemia
Hematologic Diseases
Bone Marrow Diseases
Genetic Diseases, Inborn
DNA Repair-Deficiency Disorders
Metabolic Diseases
Neoplasms, Ductal, Lobular, and Medullary
Olaparib
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents