Olaparib in Unresectable/Metastatic Melanoma With BRCA1/2

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Brief Title

Olaparib in Unresectable/Metastatic Melanoma With BRCA1/2

Official Title

Pilot Trial of Olaparib in Patients With Unresectable or Metastatic Melanoma With Mutations in BRCA1/2 Genes

Brief Summary

      The purpose of this study is to evaluate how effective Olaparib is when given as a treatment
      for primary or recurrent, unresectable or metastatic melanoma. This research study involves
      targeted therapy.

      -The name of the study drug involved in this study is: Olaparib (also known as Lynparza)
    

Detailed Description

      A phase II, single arm, open label pilot trial in a sample size of 15 primary or recurrent,
      unresectable or metastatic melanoma patients that have progressed on prior checkpoint
      inhibitor therapy with germline or somatic mutations in BRCA1/2.

      The research study procedures include screening for eligibility, study treatment including
      evaluations, surveys, optional biopsies, and follow up visits. This research study involves
      targeted therapy.

        -  The name of the study drug involved in this study is:

        -  Olaparib (also known as Lynparza)

      It is expected that about 15 people will take part in this research study.

      This research study is a Phase II clinical trial. Phase II clinical trials test the safety
      and effectiveness of an investigational drug to learn whether the drug works in treating a
      specific disease. "Investigational" means that the drug is being studied.

      This research study is a Pilot Study, which is the first time investigators are examining
      this drug for treatment of melanoma.

      The U.S. Food and Drug Administration (FDA) has not approved Olaparib for this specific
      disease, but it has been approved for other uses.

      AstraZeneca, a pharmaceutical company, is supporting this research study by providing funding
      for the research study and the study drug, Olaparib.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Overall response rate (ORR)

Secondary Outcome

 Progression Free Survival

Condition

Recurrent Metastatic Melanoma

Intervention

Olaparib

Study Arms / Comparison Groups

 OLAPARIB
Description:  The research study procedures include screening for eligibility, study treatment including evaluations, surveys, optional biopsies, and follow up visits
Olaparib- Each study treatment cycle lasts 28 days . This will continue for as long as the study treatment is providing clinical benefit

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

15

Start Date

February 2023

Completion Date

May 1, 2027

Primary Completion Date

May 1, 2026

Eligibility Criteria

        Inclusion Criteria:

          -  Subjects must have histologically or cytologically confirmed diagnosis of primary or
             recurrent metastatic melanoma including cutaneous, mucosal, or uveal melanoma.

          -  Participants must have a germline or somatic DNA damage repair mutation or deletion in
             BRCA1 or BRCA2. The result may have been obtained from one of the following test
             providers: OncoPanel, SNaPshot Panel, Myriad Genetics, Invitae, Ambry, Quest, Colour
             Genomics, IMPACT, Foundation Medicine (tissue or ctDNA based), Guardant, or another
             CLIA approved tissue and/or serum based next generation sequencing-based assay.
             (Variants of uncertain significance are excluded.)

          -  Participants must have measurable disease as defined by RECIST 1.1 criteria

               -  At least one lesion, not previously irradiated, that can be accurately measured
                  at baseline as ≥ 10 mm in the longest diameter (except lymph nodes which must
                  have short axis ≥ 15 mm) with computed tomography (CT) or magnetic resonance
                  imaging (MRI) (or Clinical examination) and which is suitable for accurate
                  repeated measurements.

               -  Subjects must have received prior checkpoint inhibitor therapy (defined as
                  anti-CTLA4 or anti-PD-1 or combination anti-CTLA4/anti-PD-1), either for
                  metastatic or unresectable disease or progressed on adjuvant therapy.

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

          -  Patients must have a life expectancy ≥ 16 weeks.

          -  ECOG performance status ≤1(Karnofsky ≥60%, see Appendix A).

          -  Participants must have adequate organ and marrow function measured within 28 days
             prior to administration of study treatment as defined below:

               -  Hemoglobin ≥ 10.0 g/dL with no blood transfusion in the past 28 days

               -  Absolute neutrophil count (ANC) ≥ 1.5 x 109/L

               -  Platelet count ≥ 100 x 109/L

               -  Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)

               -  Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase (SGOT))
                  / Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase (SGPT)) ≤
                  2.5 x institutional upper limit of normal unless liver metastases are present in
                  which case they must be ≤ 5x ULN

               -  Patients must have creatinine clearance estimated of ≥51 mL/min using the
                  Cockcroft-Gault equation or based on a 24 hour urine test: Estimated creatinine
                  clearance = (140-age [years]) x weight (kg) (x F)a / serum creatinine (mg/dL) x
                  72 (where F=0.85 for females and F=1 for males).

          -  Participants must have the ability to swallow pills.

          -  Participants with a prior or concurrent malignancy whose natural history or treatment
             does not have the potential to interfere with the safety or efficacy assessment of the
             investigational regimen are eligible for this trial.

          -  The effects of olaparib on the developing human fetus are unknown. For this reason and
             because similar agents are known to be teratogenic, women of child-bearing potential
             and men must agree to use adequate contraception (hormonal or barrier method of birth
             control; abstinence) prior to study entry and for the duration of study participation.
             Should a woman become pregnant or suspect she is pregnant while she or her partner is
             participating in this study, she should inform her treating physician immediately. Men
             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.

          -  Postmenopausal or evidence of non-childbearing status for women of childbearing
             potential: negative urine or serum pregnancy test within 28 days of study treatment
             and confirmed prior to treatment on day 1.

          -  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)

          -  Measurable disease as defined by RECIST 1.1 criteria

             -- At least one lesion, that can be accurately measured at baseline as ≥ 10 mm in the
             longest diameter (except lymph nodes which must have short axis ≥ 15 mm) with computed
             tomography (CT) or magnetic resonance imaging (MRI) (or Clinical examination) and
             which is suitable for accurate repeated measurements.

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

        Exclusion Criteria:

          -  Participants who have had chemotherapy or radiotherapy (except for palliative reasons)
             for melanoma within 3 weeks prior to entering the study.

          -  Participants who have not recovered from adverse events due to prior anti-cancer
             therapy (i.e., have residual toxicities CTCAE > Grade 2) with the exception of
             alopecia.

          -  Participants who are receiving any other investigational agents.

          -  Other malignancy unless curatively treated with no evidence of disease for ≥5 years
             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. Patients with a history of localized triple negative breast cancer may be
             eligible, provided they completed their adjuvant chemotherapy more than three years
             prior to registration, and that the patient remains free of recurrent or metastatic
             disease

          -  Patients with myelodysplastic syndrome/acute myeloid leukemia or with features
             suggestive of MDS/AML.

          -  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.

          -  Patients with a known hypersensitivity to olaparib or any of the excipients of the
             product.

          -  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 olaparib is 2 weeks. Because the lists of these agents are
             constantly changing, it is important to regularly consult a frequently-updated medical
             reference. As part of the enrollment/informed consent procedures, the participant will
             be counseled on the risk of interactions with other agents, and what to do if new
             medications need to be prescribed or if the participant is considering a new
             over-the-counter medicine or herbal product.

          -  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 olaparib is 5 weeks for enzalutamide or phenobarbital and 3
             weeks for other agents.

          -  Any previous treatment with a PARP inhibitor, including olaparib.

          -  Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as
             judged by the investigator (e.g., unstable ischemia, uncontrolled symptomatic
             arrhythmia, congestive heart failure, QTcF prolongation >500 ms, electrolyte
             disturbances, etc.), or patients with congenital long QT syndrome.

          -  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.

          -  Participants with psychiatric illness/social situations that would limit compliance
             with study requirements.

          -  Pregnant women are excluded from this study because olaparib is an agent with the
             potential for teratogenic or abortifacient effects. 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.

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

          -  Previous allogeneic bone marrow transplant or double umbilical cord blood
             transplantation (dUCBT).

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

          -  Known HIV or AIDS-related illness.

          -  Patients with known active hepatitis (i.e. Hepatitis B or C).

               -  Active hepatitis B virus (HBV) is defined by a known positive HBV surface antigen
                  (HBsAg) result. Patients with a past or resolved HBV infection (defined as the
                  presence of hepatitis B core antibody 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 RNA.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Tamara Sussman, MD, (617) 632-5055, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT05482074

Organization ID

22-294


Responsible Party

Principal Investigator

Study Sponsor

Dana-Farber Cancer Institute

Collaborators

 AstraZeneca

Study Sponsor

Tamara Sussman, MD, Principal Investigator, Dana-Farber Cancer Institute


Verification Date

July 2022