BrUOG 390: Neoadjuvant Treatment With Talazoparib
Condition: BRCA1 Mutation; BRCA2 Mutation; Ovarian Cancer; Fallopian Tube Cancer; High Grade Serous Carcinoma
MeSH terms: Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Fallopian Tube Neoplasms; Cystadenocarcinoma, Serous
Intervention: Talazoparib Oral Capsule
Intervention description: An orally available PARP inhibitor for the treatment of advanced breast cancer with germline BRCA mutations.
Intervention MeSH terms: Talazoparib
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 1.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      Ovarian cancer is the most fatal gynecologic cancer; in the US alone an estimated 22,000
      women will be diagnosed in 2019, with over 13,000 dying of the disease. Approximately half of
      epithelial ovarian cancers (EOC) exhibit defective DNA repair through alterations in the
      homologous recombination (HR) pathway, with 14% accounted for by germline mutations in BRCA
      genes (mBRCA); this goes up to about one in five (20%) women when one includes
      tumor-associated (somatic) mBRCA.The approach to women with mBRCA-associated ovarian cancer
      has heralded precision treatment in our field with the availability of PARP inhibitors. Now
      indicated as treatment for women with documented mBRCA (genomic or somatic), it also has
      shown significant benefits for women with recurrent EOC who respond to platinum-based therapy
      when administered as maintenance treatment.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Volunteers must have clinical and radiographic evidence of newly detected FIGO stage
             II, III or IV epithelial ovarian, primary peritoneal or fallopian tube cancer, deemed
             by a gynecologic oncologist as not amenable to an R0 resection at presentation.

          2. Institutional confirmation of Müllerian epithelial adenocarcinoma

          3. Histologic epithelial cell types: high grade serous carcinoma, high grade endometrioid
             carcinoma, or a combination of these.

          4. Documented mutation in BRCA1 or BRCA2 by genetic or commercial somatic testing.
             Reports will require submission at the time of enrollment.

          5. Measurable disease as defined by RECIST 1.1. Measurable disease is defined as at least
             one lesion that can be accurately measured in at least one dimension (longest diameter
             to be recorded). Each lesion must be ≥ 10 mm when measured by CT, MRI or caliper
             measurement by clinical exam; or ≥ 20 mm when measured by chest x-ray. Lymph nodes
             must be ≥ 15 mm in short axis when measured by CT or MRI.14

          6. Age ≥ 18

          7. Adequate hematologic function determined within 28 days of consent as follows:

               -  ANC greater than or equal to 1,500/mcl. NOTE: ANC cannot have been induced by
                  granulocyte colony stimulating factors.

               -  Platelets greater than or equal to 100,000/mcl

               -  Hemoglobin greater than 10 mg/dl (NOTE: While transfusions are permitted to
                  achieve baseline hemoglobin level, patients must not have transfusion within 14
                  days prior to obtaining baseline screening labs)

          8. Creatinine Clearance > 15 mL/min. (NOTE: Please see Section 6.2.1 for dosing
             requirements for patients with renal insufficiency)

             CrCl = (140- age in years) x weight in kg x 0.85/ 72 x serum creatinine in mg/ dL

          9. Adequate hepatic function within 14 days prior to registration defined as follows:

               -  Bilirubin ≤ 1.5 x ULN

               -  ALT and AST < 2.5 x ULN

               -  Alkaline phosphatase ≤ 2.5 x ULN

         10. Neurologic function: Neuropathy (sensory and motor) less than or equal to CTCAE v5.0
             Grade 1.

         11. Ability to swallow and retain oral medication. Adequate gastrointestinal absorption
             with no use of parenteral nutrition within two weeks of trial enrollment and no
             evidence of bowel obstruction.

         12. The volunteer must provide study-specific informed consent prior to study entry.

        Exclusion Criteria:

          1. Suspected non-gynecologic malignancy, evidenced by tumor markers and/or histologic
             evaluation.

          2. Prior history of other invasive malignancies, with the exception of nonmelanoma skin
             cancer and other specific malignancies as noted in Section 4.2.4 and Section 4.2.5 are
             excluded if there is any evidence of other malignancy being present within the last
             three years (2 years for breast cancer, see Section 4.2.4). Volunteers are also
             excluded if their previous cancer treatment contraindicates this protocol therapy.

          3. Prior chemotherapy for any abdominal or pelvic tumor within the last three years is
             excluded. Volunteers may have received prior adjuvant chemotherapy and radiotherapy
             for localized breast cancer, provided that it was completed more than 2 years prior to
             registration, the volunteer remains free of recurrent or metastatic disease and
             hormonal therapy has been discontinued.

          4. Prior radiotherapy to any portion of the abdominal cavity or pelvis or thoracic cavity
             within the last three years are excluded. Prior radiation for localized cancer of the
             head and neck or skin is permitted, provided that it was completed more than three
             years prior to registration, and the volunteer remains free of recurrent or metastatic
             disease.

          5. Synchronous primary endometrial cancer, or a past history of primary endometrial
             cancer, unless all of the following conditions are met: Stage not greater than I-A,
             grade 1 or 2, no more than superficial myometrial invasion, without vascular or
             lymphatic invasion; no poorly differentiated subtypes, including serous, clear cell or
             other FIGO grade 3 lesions.

          6. Severe, active co-morbidity defined as follows:

               -  Chronic or current active infectious disease requiring systemic antibiotics,
                  antifungal or antiviral treatment

               -  Known brain or central nervous system metastases or history of uncontrolled
                  seizures

               -  Clinically significant cardiac disease including unstable angina, acute
                  myocardial infarction within 6 months from enrollment, New York Heart Association
                  Class III or IV congestive heart failure, and serious arrhythmia requiring
                  medication (this does not include asymptomatic atrial fibrillation with
                  controlled ventricular rate).

               -  Partial or complete gastrointestinal obstruction

          7. Volunteers who are not candidates for major abdominal surgery due to known medical
             comorbidities.

          8. Volunteers with any condition that in the judgment of the investigator would
             jeopardize safety or volunteer compliance with the protocol.

          9. Concurrent anticancer therapy (e.g. chemotherapy, radiation therapy, biologic therapy,
             immunotherapy, hormonal therapy, investigational therapy).

         10. Receipt of an investigational study drug for any indication within 30 days or 5
             half-lives (whichever is longer) prior to Day 1 of protocol therapy.

         11. Prior exposure to a PARP inhibitor.

         12. People of child-bearing potential (WOCB). This includes:

               -  Any volunteer who has experienced menarche and who has not undergone surgical
                  sterilization (hysterectomy and/or bilateral oophorectomy) or who is not
                  postmenopausal. Menopause is defined clinically as 12-month amenorrhea in a woman
                  over 45 in the absence of other biological or physiological causes.

               -  Volunteers who are pregnant or nursing. Volunteers must agree to use adequate
                  contraception (hormonal or barrier method of birth control; abstinence) prior to
                  study entry, for the duration of study participation, and for at least 7 months
                  after completing therapy.

             People with an intact uterus and ovaries must have a screening negative serum or urine
             pregnancy test within 14 days of registration. A second pregnancy test must be done
             within 24 hours prior to the start of the first cycle of study treatment

         13. Potent P-gp inhibitors that result in ≥ 2-fold increase in the exposure of an in vivo
             probe P-gp substrate, including: amiodarone, carvedilol, clarithromycin, cobicistat,
             dronedarone, erythromycin, glecaprevir/pibrentasvir, indinavir, itraconazole,
             ketoconazole, lapatinib, lopinavir, propafenone, quinidine, ranolazine, ritonavir,
             saquinavir, sofosbuvir/velpatasvir/voxilaprevir, telaprevir, tipranavir, valspodar and
             verapamil.