Clinical Trials /

Olaparib in People With Malignant Mesothelioma

NCT03531840

Description:

Background: The drug olaparib may stop cancer cells from fixing damage to their DNA. It has been approved to treat certain cancers in people that were born with a mutation in the BRCA gene. It has not been approved for treating mesothelioma. But some people with mesothelioma have mutations in a gene, BAP1 related to BRCA. Researchers want to see if olaparib can work in patients with mutations in this gene. They also want to see if works on mutations in other genes or patients without any mutations. They want to see if olaparib causes mesothelioma tumors to shrink. Objective: To study the effect of olaparib on mesothelioma. Eligibility: People ages 18 and older with malignant mesothelioma that has already been treated Design: Participants will be screened with Sample of tumor tissue or fluid Medical history Physical exam Blood, heart, and urine tests Scans and x-rays Participants will give blood and tissue samples. These will be genetically tested. The study will be done in 21-day cycles. Participants will take tables of the study drug 2 times each day. They will get information on what food and drugs to avoid during the study. They will get information about birth control. They will keep a diary of doses and symptoms. Participants will have blood and urine tests and scans every few weeks. Participants will be told any important genetic testing results. Participants will stay in the study until their disease gets worse or the participant or their doctor chooses to stop it. About 30 days after stopping the study drug, participants will have a follow-up visit. They will have a medical history, physical exam, blood tests, and scans. Some participants will continue to have scans every 6 weeks. ...

Related Conditions:
  • Malignant Mesothelioma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Olaparib in People With Malignant Mesothelioma
  • Official Title: Phase II Study of Olaparib in Subjects With Malignant Mesothelioma

Clinical Trial IDs

  • ORG STUDY ID: 180097
  • SECONDARY ID: 18-C-0097
  • NCT ID: NCT03531840

Conditions

  • Mesothelioma

Interventions

DrugSynonymsArms
Olaparib1/Olaparib

Purpose

Background: The drug olaparib may stop cancer cells from fixing damage to their DNA. It has been approved to treat certain cancers in people that were born with a mutation in the BRCA gene. It has not been approved for treating mesothelioma. But some people with mesothelioma have mutations in a gene, BAP1 related to BRCA. Researchers want to see if olaparib can work in patients with mutations in this gene. They also want to see if works on mutations in other genes or patients without any mutations. They want to see if olaparib causes mesothelioma tumors to shrink. Objective: To study the effect of olaparib on mesothelioma. Eligibility: People ages 18 and older with malignant mesothelioma that has already been treated Design: Participants will be screened with Sample of tumor tissue or fluid Medical history Physical exam Blood, heart, and urine tests Scans and x-rays Participants will give blood and tissue samples. These will be genetically tested. The study will be done in 21-day cycles. Participants will take tables of the study drug 2 times each day. They will get information on what food and drugs to avoid during the study. They will get information about birth control. They will keep a diary of doses and symptoms. Participants will have blood and urine tests and scans every few weeks. Participants will be told any important genetic testing results. Participants will stay in the study until their disease gets worse or the participant or their doctor chooses to stop it. About 30 days after stopping the study drug, participants will have a follow-up visit. They will have a medical history, physical exam, blood tests, and scans. Some participants will continue to have scans every 6 weeks. ...

Detailed Description

      Background:

        -  Malignant mesothelioma is an invasive and often fatal neoplasm that arises from
           mesothelium that lines several organs.

        -  Recent studies have identified germline mutations in the gene encoding BRCA1 associated
           protein-1 (BAP1) which can predispose to mesothelioma

        -  In addition to mesothelioma, germline BAP1 mutations confer increased susceptibility for
           the development of several other tumors including uveal melanoma, cutaneous melanoma,
           renal cell cancers and possibly other cancers

        -  In addition to BAP1, we found several novel germline variants that have previously not
           been associated with risk of developing mesothelioma.

        -  As evidenced by recent data derived from ovarian and prostate cancer patients, mutations
           in DNA repair genes can define subgroups of cancer patients with distinct
           vulnerabilities to DNA damage response inhibitors.

        -  Olaparib is a PARP inhibitor indicated as monotherapy in patients with deleterious or
           suspected deleterious germline BRCA mutated

        -  Both established and patient derived mesothelioma cell lines with mutated DNA repair
           genes are sensitive to olaparib.

      Objective:

      -Determine the efficacy with respect to objective response rate of olaparib in patients with
      malignant mesothelioma based on somatic or germline mutation status of DNA repair genes

      Eligibility:

        -  Patients must have progressive, histologically or cytologically confirmed malignant
           mesothelioma.

        -  Age greater than or equal to 18 years

        -  Patients must have received prior platinum and pemetrexed based therapies

        -  Adequate organ and bone marrow function

      Design:

        -  This is a phase II, single center study of olaparib in subjects with malignant
           mesothelioma

        -  All subjects will take olaparib by mouth twice daily until disease progression or
           intolerable side effects

        -  Subjects will be assessed for safety (continuously) and efficacy (every 6 weeks)

        -  Subjects will be analyzed in 3 separate comparison groups according to their mutation
           status

             -  Comparison Group 1: Patients with a germline mutation in DNA repair genes

             -  Comparison Group 2: Patients with BAP1 somatic mutations

             -  Comparison Group 3: Patients with neither germline mutations nor BAP 1 somatic
                mutations

        -  Up to 30 evaluable subjects will be enrolled
    

Trial Arms

NameTypeDescriptionInterventions
1/OlaparibExperimentalTwice daily oral olaparib
  • Olaparib

Eligibility Criteria

        -  INCLUSION CRITERIA:

          -  Patients must have histologically or cytologically malignant mesothelioma confirmed by
             the NCI Laboratory of Pathology. Patients with pleural, peritoneal, pericardial or
             tunica vaginalis mesothelioma are eligible.

          -  Archival tumor samples must be available and sufficient for diagnostic and genetic
             testing; if archival sample insufficient for testing, subject must have lesions
             amenable to biopsy and be willing to undergo biopsy.

          -  Patients must have measurable disease.

          -  Patients must have progressive disease at study entry

          -  Patients must have received prior platinum and pemetrexed based therapies. Response to
             platinum is not an eligibility criterion for enrollment.

          -  Age greater than or equal to 18 years. Because no dosing or adverse event data are
             currently available on the use of olaparib in patients <18 years of age, children are
             excluded from this study, but may be eligible for future pediatric trials.

          -  ECOG performance status less than or equal to 1.

          -  Patients must have a life expectancy of greater than or equal to 16 weeks

          -  Patients must have adequate organ and marrow function less than or equal to 5days
             prior to C1D1 as defined below:

               -  leukocytes greater than or equal to 3,000/mcL

               -  absolute neutrophil count greater than or equal to greater than or equal to
                  1,500/mcL without growth factor support

               -  platelets greater than or equal to 100,000/mcL

               -  hemoglobin greater than or equal to 10 g/dL with no blood transfusion in the past
                  28 days

               -  total bilirubin less than or equal to 1.5 x ULN (unless Gilbert s Disease)

               -  AST(SGOT)/ALT(SGPT) less than or equal to 2.5 X institutional upper limit of
                  normal (less than or equal to 5X ULN in the presence of liver metastases)

               -  creatinine clearance greater than or equal to 51 mL/min (calculated using the
                  -Cockcroft-Gault formula.

          -  Pre-clinical data indicate that olaparib can have adverse effects on embryofetal
             survival and development. It is further not known whether olaparib or its metabolites
             are found in seminal fluid. For these reasons:

          -  Women of childbearing potential and their partners, who are sexually active, must
             agree to the use of 2 highly effective forms of contraception in combination (male
             condom plus one other method or must totally/truly abstain from any form of sexual
             intercourse. This should be started from the signing of the informed consent,
             throughout their participation in the study and for at least 1 month after the last
             dose of olaparib.

          -  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.

          -  Acceptable birth control methods:

               -  Total sexual abstinence i.e., refrain from any form of sexual intercourse in line
                  with the patients usual and/or preferred lifestyle. Abstinence must be for the
                  total duration of the study treatment and for at least 1month (for female
                  patients) or 3 months (for male patients) after the last dose of study treatment.
                  Periodic abstinence (e.g., calendar ovulation, symptothermal, post-ovulation
                  methods) and withdrawal are not acceptable methods of contraception.

               -  Vasectomised sexual partner PLUS male condom. With participant assurance that
                  partner received post-vasectomy confirmation of azoospermia.

               -  Tubal occlusion PLUS male condom

               -  Intrauterine Device PLUS male condom. Provided coils are copper-banded.

               -  Etonogestrel implants (e.g., Implanon , Norplant ) PLUS male condom

               -  Normal and low dose combined oral pills PLUS male condom

               -  Hormonal shot or injection (e.g., Depo-Provera) PLUS male condom

               -  Intrauterine system device (e.g., levonorgestrel-releasing intrauterine system
                  -Mirena ) PLUS male condom

               -  Norelgestromin/ethinyl estradiol transdermal system PLUS male condom

               -  Intravaginal device (e.g., ethinyl estradiol and etonogestrel) PLUS male condom

               -  Cerazette (desogestrel) PLUS male condom. Cerazette is currently the only highly
                  efficacious progesterone based pill.

          -  Ability of subject to understand and the willingness to sign a written informed
             consent document.

        EXCLUSION CRITERIA:

          -  Patients who are receiving any other investigational agents.

          -  Patients who have received any previous treatment with a PARP inhibitor, including
             olaparib.

          -  Patients receiving any systemic chemotherapy or radiotherapy (except for palliative
             reasons) within 3 weeks prior to study treatment

          -  Patients with other malignancy documented as occurring within the last 1 year except:
             adequately treated nonmelanoma skin cancer, curatively treated in situ cancer of the
             cervix, ductal carcinoma in situ (DCIS), Stage 1, grade 1 endometrial carcinoma, or
             other solid tumors includinglymphomas (without bone marrow involvement) documented as
             curatively treated or under control for greater than or equal to 1 year.

          -  Patients with features suggestive of MDS/AML on peripheral blood smear.

          -  Patients with symptomatic uncontrolled brain metastases. A scan to confirm the absence
             of brain metastases is not required. The patient can receive a stable dose of
             corticosteroids before and during the study as long as these were started at least 4
             weeks prior to treatment. Patients with spinal cord compression unless considered to
             have received definitive treatment for this and evidence of clinically stable disease
             for 28 days.

          -  History of allergic reactions or hypersensitivity attributed to compounds of similar
             chemical or biologic composition to olaparib or its excipients.

          -  Patients who have had a whole blood transfusion within 120 days prior to enrollment.
             (Packed red blood cells and platelet transfusions are acceptable)

          -  Patients with persistent toxicities (greater than or equal to CTCAE grade 2) with the
             exception of alopecia,caused by previous cancer therapy

          -  Concomitant use of known strong or moderate 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 olaparib is 2 weeks.

          -  Concomitant use of known strong CYP3A inducers (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 olaparib is 5 weeks for enzalutamide or phenobarbital
             and 3 weeks for other agents.

          -  Resting ECG with QTcF > 470 msec on 2 or more time points within a 24-hour period or
             family history of long QT syndrome

          -  Patients that have had major surgery within 2 weeks of starting study treatment and
             patients must have recovered from any effects of any major surgery.

          -  Patients unable to swallow orally administered medication and patients with
             gastrointestinal disorders likely to interfere with absorption of the study
             medication.

          -  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.

          -  Pregnant women are excluded from this study because olaparib has the potential for
             teratogenic or abortifacient effects. Women must either be post-menopausal or must
             have a negative pregnancy test (urine or serum) less than or equal to 28 days prior to
             enrollment and confirmed on day 1 of cycle 1 of study therapy. Postmenopausal is
             defined as:

        Amenorrheic for 1 year or more following cessation of exogenous hormonaltreatments

        Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in the
        post-menopausal range for women under 50 years of age

        radiation-induced oophorectomy with last menses >1 year ago

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

        surgical sterilisation (bilateral oophorectomy or hysterectomy)

          -  Because there is an unknown but potential risk for adverse events in nursing infants
             secondary to treatment of the mother with olaparib, breastfeeding should be
             discontinued if the mother is treated with olaparib.

          -  Immunocompromised patients are excluded.

          -  Patients who are known to be serologically positive for human immunodeficiency virus
             (HIV). This includes HIV patients on antiretroviral therapy due to the potential for
             pharmacokinetic interactions with olaparib.

          -  Patients with known active hepatitis (i.e. Hepatitis B or C) due to risk of
             transmitting the infection through blood or other body fluids

          -  Previous allogeneic hematopoietic stem cell transplant, allogeneic bone marrow
             transplant or double umbilical cord blood transplant (duCBT)
      
Maximum Eligible Age:99 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:objective response rate
Time Frame:6 months after enrollment of last patient
Safety Issue:
Description:Percentage of subjects overall who experienced partial or complete response. Percentage of subjects with germline DNA repair mutation who experienced partial or complete response. Percentage of subjects with BAP1 somatic mutations who experienced partial or complete response. Percentage of subjects with neither germline DNA repair mutations nor somatic BAP1 mutations who experienced partial or complete response.

Details

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

Trial Keywords

  • DNA Mismatch Repair
  • BAP1
  • BRCA

Last Updated

September 19, 2019