A Phase 2 Study to Evaluate Safety and Anti-tumor Activity of Avelumab in Combination with Talazoparib In Patients with BRCA or ATM Mutant Tumors

Patients must meet all of the following inclusion criteria to be eligible for enrollment into the study:
1. Pathogenic or likely pathogenic germline or somatic gene defect as determined by local assessment and classification:
* One or more BRCA1 or BRCA2 gene defect (Cohort 1);
* ATM gene defect in the absence of concurrent BRCA 1/2 defect (Cohort 2).
Note: in the event that a patient has concomitant defects in more than 1 of the three genes (BRCA1 or BRCA2 or ATM), they will be enrolled in Cohort 1.
The presence of gene defects must have been determined by local assessment and classification using a test of either germline or tumor DNA which was performed in a CAP/CLIA certified (or comparable local or regional certification) laboratory.
2. Histological diagnosis of locally advanced (primary or recurrent) or metastatic solid tumors that are not amenable for treatment with curative intent, as follows:
a. Recurrent Epithelial Ovarian Cancer:
* Patients must have received at least 1 but no more than 5 total prior cytotoxic chemotherapy regimens, including at least 1 course of platinum based therapy;
* Patients must not have progressed during or within 1 month after the last dose of the most recent platinum based chemotherapy;
* Platinum sensitivity requirements:
* If previously treated with *2 prior cytotoxic chemotherapy regimens, patients must have had disease progression within 6 months after the last dose of platinum based chemotherapy, also termed *platinum resistant recurrent disease*;
* If previously treated with >2 prior cytotoxic chemotherapy regimens, platinum sensitive recurrent disease is allowed.
* Any treatment regimen that began with cytotoxic chemotherapy and continued with another regimen for maintenance therapy following best response to initial cytotoxic regimen will count as one line of prior therapy.
b. TNBC (defined as ER and PgR negative [IHC nuclear staining <5%] and HER2 negative [IHC 0, 1+, or 2+ and/or ISH non amplified with ratio less than 2.0]) or hormone receptor positive (HR+), HER2 negative breast cancer:
* Have been previously treated with no more than 3 prior chemotherapy regimens for locally advanced or metastatic breast cancer;
* There is no limit on the number of prior endocrine therapies or targeted anti cancer therapies such as mammalian target of rapamycin (mTOR) or cyclin dependent kinase (CDK)4/6 inhibitors, or vascular endothelial growth factor inhibitors (VEGF);
* Previous neo adjuvant/adjuvant treatment counts as 1 line of prior chemotherapy if disease progression occurred while on treatment or within 6 months after the last treatment dose;
* Patients must have received treatment with a taxane or anthracycline containing chemotherapy regimen in the neo adjuvant, adjuvant, or advanced setting, unless deemed unsuitable for these treatments;
* Patients that have previously been treated with platinum based chemotherapy in the neo adjuvant/adjuvant setting must not have had disease progression while on treatment or within 6 months after the last dose of platinum based chemotherapy;
* Patients that have previously been treated with platinum based chemotherapy in the advanced/metastatic setting must not have had disease progression within 6 months of initiation of a platinum-containing regimen;
* Patients with HR+ breast cancer must have received at least 1 prior endocrine therapy (adjuvant or metastatic), unless deemed not suitable for endocrine therapy.
c. Metastatic castration resistant prostate cancer (mCRPC) without small cell features:
* Patients with disease spread limited to regional pelvic lymph nodes (below the aortic bifurcation) are not eligible unless bone metastasis is present on bone scan;
* Progressed on at least 1 line of second generation anti androgen therapy (enzalutamide and/or abiraterone acetate/prednisone) for treatment of mCRPC;
* Have received no more than 2 prior chemotherapy regimens for mCRPC. Patients may have received radium 223, which does not count for a line of prior chemotherapy regimen;
* Serum testosterone *1.73 nmol/L (50 ng/dL);
* Bilateral orchiectomy or ongoing androgen deprivation therapy with a gonadotropin releasing hormone (GnRH) agonist/antagonist (surgical or medical castration);
* Progressive disease at enrollment defined as 1 or more of the following 3 criteria:
* A minimum of 3 consecutive rising PSA values with an interval of at least 1 week between determinations. The screening PSA value must be *2 *g/L (2 ng/mL) if qualifying solely by PSA progression;
* Disease progression as defined by RECIST v1.1;
* Bone disease progression defined by Prostate Cancer Working Group 3 (PCWG3) with 2 or more new metastatic lesions on bone scan (confirm ambiguous results by other imaging modalities).
d. Metastatic ductal adenocarcinoma of the pancreas:
* Have been previously treated with at least 1 but no more than 2 prior cytotoxic chemotherapy regimens (including at least one of the following: FOLFIRINOX or a gemcitabine containing regimen) unless deemed unsuitable or patient declined these therapies;
* Patients must not have had disease progression within 6 months of initiation of a platinum containing regimen.
e. Any other advanced solid tumor:
* Have received at least 1 prior SOC regimen, if it exists, as appropriate for the respective tumor type unless deemed unsuitable, or declined these therapies;
* Patients must not have had disease progression within 6 months of initiation of a platinum-containing regimen;
* Patients with NSCLC harboring B Raf proto oncogene (BRAF)V600 mutations or ALK and c Ros oncogene 1 (ROS1) translocations/rearrangements must have received the appropriate targeted therapy as approved by the relevant health care authority. Patients with activating EGFR mutations are not eligible; non squamous cell histologies require testing if EGFR status is unknown.
3. Availability of a fresh or recent tumor tissue sample from a diagnostic biopsy/surgery or a metastatic tumor biopsy; the sample must have been obtained within 24 months prior to study enrollment. When only bone disease is present, an archival tumor tissue sample obtained within 5 years prior to study enrollment may be accepted for non-prostate cancer patients and a fresh bone biopsy may be accepted for prostate cancer patients only). (See Section 7.4.1 for details).
4. Have progressive disease at study enrollment as defined by RECIST v1.1 (except for mCRPC, who must meet criterion 2c above).
5. Must have measurable disease by RECIST v1.1 with at least 1 measurable lesion that has not been previously irradiated (patients with mCRPC may have only non measurable disease).
6. Age *18 years (except in Japan, where patients must be *20 years old).
7. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.
8. Adequate bone marrow function (without hematopoietic growth factor or transfusion support within 14 days prior to study enrollment), including:
a. Absolute Neutrophil Count (ANC) *1,500/mm3 or *1.5 x 109/L.
b. Platelets *100,000/mm3 or *100 x 109/L.
c. Hemoglobin *9 g/dL (*5.6 mmol/L).
9. Adequate renal function defined by an estimated creatinine clearance *30 mL/min according to the Cockcroft Gault formula as:
* CLCR<={[(140*age) × weight)]/(72 x SCR)} × 0.85 (if female), where CLCR (creatinine clearance) is measured in mL/min, age is expressed in years, weight in kilograms (kg), and SCR (serum creatinine) in mg/dL;
* Or as measured by 24h urine assessment.
NOTE: Patients with moderate renal impairment (30 59 mL/min) will receive a reduced starting dose for talazoparib (see section 5.4.2).
10. Adequate liver function, including:
a. Total serum bilirubin *1.5 × the upper limit of normal range (ULN);
b. Aspartate and Alanine aminotransferase (AST and ALT) *2.5 x ULN.
11. Female patients of childbearing potential must have negative serum pregnancy or urine pregnancy test at screening.
Women in the following categories are not considered to be women of child-bearing potential (WOCBP):
1. Premenopausal female with 1 of the following :
* Documented hysterectomy;
* Documented bilateral salpingectomy;
* Documented bilateral oophorectomy.
For individuals with permanent infertility due to an alternate medical cause other than the above, (eg, mullerian agenesis, androgen insensitivity),
investigator discretion should be applied to determining study entry. Note: Documentation for any of the above categories can come from the site
personnel*s review of the participant*s medical records, medical examination, or medical history interview. The method of documentation should be
recorded in the participant*s medical record for the study.;2. Postmenopausal female: ;* A postmenopausal state is defined as age 60 years or older or no menses for 12 months without an alternative medical cause.
* A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormone replacement therapy (HRT).
* Females on HRT and whose menopausal status is in doubt will be required to use one of the nonestrogen hormonal highly effective contraception
methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of postmenopausal
status before study enrollment.;12. Evidence of a personally signed and dated informed consent document indicating that the patient has been informed of all pertinent aspects of the study.
13. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.

1. Prior treatment with a PARP inhibitor.;2. Prior immunotherapy with anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody.;3. Prior anti-cancer therapy within 2 weeks prior to study enrollment or prior radiation therapy within 2 weeks prior to study enrollment. Prior palliative radiotherapy to metastatic lesion(s) is permitted, provided it has been completed at least 2 days prior to study enrollment and no clinically significant toxicities are expected (eg, mucositis, esophagitis).;4. Major surgery within 4 weeks prior to study enrollment.;5. Current use of immunosuppressive medication at the time of study enrollment, EXCEPT for the following permitted steroids: see Section 4.2.;6. Known prior severe hypersensitivity to investigational products or any component in their formulations, including known severe hypersensitivity reactions to monoclonal antibodies ([NCI CTCAE] v4.03 Grade * 3).;7. Known history of immune-mediated colitis, inflammatory bowel disease, pneumonitis, pulmonary fibrosis.;8. Active or prior autoimmune disease that might deteriorate when receiving an immunostimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypoor hyperthyroid disease not requiring immunosuppressive treatment are eligible.;9. Prior organ transplantation including allogenic stem-cell transplantation.;10. Administration of live attenuated vaccines within 4 weeks of study enrollment.;11. Diagnosis of myelodysplastic syndrome (MDS).;12. Known symptomatic brain metastases requiring steroids. Patients with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to study enrollment, have discontinued corticosteroid treatment for these metastases for at least 4 weeks, and are neurologically stable.;13. Participation in other studies involving investigational drug(s) within 4 weeks prior to study entry and/or during study participation.;14. Persisting toxicity related to prior therapy (NCI CTCAE v4.03 Grade >1); however, alopecia and sensory neuropathy Grade * 2, or other Grade * 2 AEs not constituting a safety risk, based on investigator's judgment, are acceptable.;15. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).;16. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive).;17. Active infection requiring systemic therapy. Minor infections, eg, periodontal or urinary tract infection (UTI) infection, which may be treated with short term oral antibiotics are allowed.;18. Clinically significant (ie, active) cardiovascular disease: cerebral vascular;accident/stroke (<6 months prior to study enrollment), myocardial infarction;(<6 months prior to study enrollment), unstable angina, congestive heart failure (* New York Heart Association Classification Class II), or a serious cardiac arrhythmia requiring medication.;19. Current or anticipated use of strong P-gp inhibitors within 7 days prior to enrollment,or anticipated use during the study. For a list of strong P-gp inhibitors, refer to Section 5.7.10.;20. Inability to swallow capsules, known intolerance to talazoparib or its excipients, known malabsorption syndrome, or other condition that may impair absorption of talazoparib.;21. Bisphosphonate or denosumab dosage that was not stable (ie, not the same) for at least 2 weeks before study enrollment for patients receiving these therapies.;22. Other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.;23. Diagnosis of any other malignancy within 2 years prior to study enrollment, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the breast, bladder, or cervix, or low-grade (Gleason * 6) prostate cancer on surveillance without any plans for treatment intervention (eg, surgery, radiation, or castration), or other early-stage low-risk cancers.;24. Pregnant female patients, breastfeeding female patients, and female patients of childbearing potential who are unwilling or unable to use a method of highly effective contraception as outlined in this protocol during treatment and for at least 30 days after the last dose of avelumab and for at least 7 months after the last dose of talazoparib; fertile male patients with female partners of reproductive potential or pregnant partners, unwilling to use a condom (even after vasectomy) during treatment and for at least 4 months after the last dose of talazoparib.;25. Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or patients who are Pfizer employees, including their family members, directly involved in the conduct of the study.