BrUOG 390: Neoadjuvant Treatment With Talazoparib

• Talazoparib Oral Capsule (Drug), also known as Talzenna: An orally available PARP inhibitor for the treatment of advanced breast cancer with germline BRCA mutations.

Primary outcomes

• Determine the Preliminary Effectiveness of Talazorparib [First 9 weeks of treatment]: Define the proportion of volunteers completing the planned 9 weeks of treatment without disease progression.

Secondary outcomes

• Feasibility of the Trial Design. [First 2 years of study.]: Define whether 30 volunteers can successfully be enrolled within 2 years within participating institutions.

Sex: Female, ages: 18 Years to any

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.

Participant flow

Outcome results

• Determine the Preliminary Effectiveness of Talazorparib (Primary), Count of participants, Participants: Planned Therapy 1
• Feasibility of the Trial Design. (Secondary), Count of participants, Participants: Planned Therapy 1

Adverse events

Time frame: From the time a signed and dated ICF was obtained until 30 days after the last treatment, approximately 8 months.

Serious adverse events by term

Other adverse events by term

• Study Protocol, Statistical Analysis Plan, and Informed Consent Form (PDF, 2021-06-09)

• Don S Dizon, MD, Principal investigator, Brown University