| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Locally advanced (primary or recurrent) or metastatic solid tumors, including non-small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), hormone receptor-positive (HR+) /human epidermal growth factor receptor 2-negative (HER2-) breast cancer, recurrent platinum-sensitive ovarian cancer, UC, and castration-resistant prostate cancer (CRPC).
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065147 |
| E.1.2 | Term | Malignant solid tumor |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065252 |
| E.1.2 | Term | Solid tumor |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
● Phase 1b: To assess the DLT rate of avelumab in combination with talazoparib in patients with locally advanced or metastatic solid tumors in order to select the RP2D of talazoparib for the combination.
● Phase 2: To assess ORR of avelumab in combination with talazoparib, as assessed by the Investigator, per RECIST v1.1 in patients with locally advanced or metastatic solid tumors and per RECIST v1.1 and Prostate Cancer Working Group 3 (PCWG3) in patients with mCRPC.
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| E.2.2 | Secondary objectives of the trial |
● To assess the overall safety and tolerability of avelumab in combination with talazoparib.
● To characterize the PK of avelumab and talazoparib when given in combination.
● To evaluate the immunogenicity of avelumab when given in combination with talazoparib.
● To assess the anti-tumor activity of avelumab in combination with talazoparib.
● To assess the correlation of anti-tumor activity of avelumab in combination with talazoparib with PD-L1 expression, tumor mutational burden (TMB; defined as the total number of mutations in the tumor genome, or number of mutations per megabase of DNA if derived from targeted sequencing, and potential biomarkers of PARP inhibitor sensitivity in baseline tumor tissues. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histological diagnosis of locally advanced (primary or recurrent) or metastatic solid tumors that are not amenable for treatment with curative intent (for more details refer to Protocol section 4.1).
2. Measurable disease by RECIST v1.1 with at least 1 measurable lesion; This criterion is not required for patients with metastatic CRPC.
3. Mandatory primary or metastatic tumor biopsy to be performed within 28 days (45 days for patients requiring prospective biomarker testing for eligibility evaluation) prior to study enrollment to allow FFPE tissue be submitted for protocol-required testing. Core needle or excision biopsies are required, as fine needle aspirations will not yield enough tissue for protocol-specified testing. If archival tumor tissue is available from a biopsy/surgery that was performed within 1 year prior to study enrollment and the patient did not receive any subsequent systemic anti-cancer treatment, the tumor tissue may be submitted without repeating a tumor biopsy during the screening period. For mCRPC patients with no biopsable lesion outside of bone, archival tumor tissue from a biopsy/surgery performed within 5 years prior to study enrollment must be submitted without repeating a tumor biopsy
during the screening period.
4. Age ≥ 18 years (except in Japan, where patients must be ≥ 20 years).
5. ECOG Performance Status 0 or 1.
6. Adequate Bone Marrow Function, 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).
7. Adequate renal function defined by an estimated CrCL of ≥60 mL/min for patients enrolled in Phase 1b portion of the study and ≥30mL for patients enrolled in Phase 2 portion of the study. CrCL should be estimated according to the Cockcroft-Gault formula.
8. Adequate Liver Function, including:
a. Total serum bilirubin ≤1.5 ;
b. AST and ALT ≤2.5 × ULN;
9. Female patients of childbearing potential must have negative serum pregnancy or urine pregnancy test at screening (see Protocol Section 7.1.1 for criteria to be considered not of childbearing potential).
Female patients of nonchildbearing potential must meet at least 1 of the following criteria:
● Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause and have a serum follicle-stimulating hormone (FSH) level confirming the postmenopausal state;
● Have undergone a documented hysterectomy and/or bilateral oophorectomy;
● Have medically confirmed ovarian failure.
All other female patients (including female patients with tubal ligations) are considered to be of childbearing potential.
10. Evidence of a personally signed and dated informed consent document indicating that the patient has been informed of all pertinent aspects of the study.
11. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other procedures.
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| E.4 | Principal exclusion criteria |
1. Prior treatment with a PARP inhibitor.
2. Prior immunotherapy with IL-2, IFN-α, or an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, OX-40, GITR, LAG-3, IDO, TDO, TIM-3, CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immunecheckpoint pathways. Prior treatment with Sipuleucel-T for patients with mCRPC is allowed. EXCEPTION for Cohort A2 only: Prior treatment with anit-PD-1/L1 therapy inthe metastatic setting (Stage IV only), as described in Inclusion Criterion 1 is allowed.
3. Prior anti-cancer therapy within 2 weeks prior to study enrollment. Prior radiation therapy within 2 weeks prior to enrollment. Prior palliative radiotherapy to metastatic lesion(s) is permitted, provided it has been completed 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 Protocol Section 5.7.5).
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. Vaccination within 4 weeks of study enrollment and while on trials is prohibited except for administration of inactivated vaccines.
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 enrollment 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.
18. Clinically significant (ie, active) cardiovascular disease: cerebral vascular accident/stroke (<6 months prior to enrollment), myocardial infarction (<6 months prior to 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 within 7 days prior to first dose of study drug, or anticipated use during the study of a strong P-gp inhibitor.
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 5 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 of the cervix. For patients not enrolled in Cohorts E1 and E2: low-grade (Gleason 6 or below) prostate cancer on surveillance with no plans for treatment intervention (eg, surgery, radiation, or castration) or prostate cancer that has been adequately treated with prostatectomy or radiotherapy and currently with no evidence of disease or symptoms is allowed. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
● Phase 1b: DLT during the DLT evaluation period (Cycle 1).
● Phase 2: Confirmed OR, as assessed by the Investigator using RECIST v1.1 in patients with locally advanced or metastatic solid tumors and RECIST v1.1 and PCWG3 in patients with mCRPC.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
● Phase 1b: the DLT evaluation period will be during the first cycle (28 days) of treatment.
● Phase 2: defined OR until disease progression or death due to any cause |
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| E.5.2 | Secondary end point(s) |
● AEs as characterized by type, severity (as graded by National Cancer Institute Common Terminology Criteria for AEs [NCI CTCAE] v.4.03), timing, seriousness, and relationship to study therapy.
● Laboratory abnormalities as characterized by type, severity (as graded by NCI CTCAE v.4.03) and timing.
● PK parameters for avelumab and talazoparib including: pre-dose/trough concentrations (Ctrough) and post-dose concentrations (for talazoparib) or maximum concentrations (Cmax) for avelumab.
● Avelumab anti-drug antibody (ADA) levels and neutralizing antibodies (Nab) against avelumab.
● Phase 1b: Confirmed OR, as assessed by the Investigator using RECIST v1.1 in patients with locally advanced or metastatic solid tumors and RECIST v1.1 and PCWG3 in patients with mCRPC.
● Phase 1b and Phase 2: Time-to-event endpoints including time to tumor response (TTR), duration of response (DR), and progression-free survival (PFS) as assessed by the Investigator using RECIST v1.1 for patients with solid tumors and using RECIST v1.1 and PCWG3 for patients with mCRPC, time to PSA progression for patients with mCRPC
● PSA response ≥50% for patients with mCRPC.
● CA-125 response for patients with ovarian cancer.
● PD-L1 expression level in baseline tumor tissue.
● TMB in baseline tumor tissue.
● Genomic scarring and the presence of defects in select genes, considered critical to effective DDR, in baseline tumor tissue.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| According to protocol Schedule of Activities |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
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| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 17 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Belgium |
| Canada |
| Denmark |
| Hungary |
| Korea, Republic of |
| Russian Federation |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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