| 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 with a pathogenic or likely pathogenic germline or loss-of-function somatic BRCA1, or BRCA2, or ATM gene defect |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 |
|
| 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 |
|
| 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 |
| To evaluate ORR of avelumab in combination with talazoparib, in patients with locally advanced or metastatic solid tumors harboring BRCA1, BRCA2 or ATM defect. |
|
| 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 other measures of 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 in baseline tumor tissue.
- To assess the correlation of anti-tumor activity and emergence of resistance with defects in a panel of key oncogenes, including BRCA 1/2 and ATM, and TMB in circulating tumor DNA (ctDNA) and tumor tissue at baseline, during treatment and at the end of treatment. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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).
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;
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;
c. Metastatic castration-resistant prostate cancer (mCRPC) without small cell features;
d. Metastatic ductal adenocarcinoma of the pancreas;
e. Any other advanced solid tumor.
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).
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 inkilograms (kg), and SCR (serum creatinine) in mg/dL;
- Or as measured by 24h urine assessment.
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. 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.
12. Evidence of a personally signed and dated informed consent document, within >28 days prior to enrollment, 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. |
|
| E.4 | Principal exclusion criteria |
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 a P-glycoprotein (P-gp) inhibitor (amiodarone, carvedilol, clarithromycin, cobicistat, darunavir, dronedarone, erythromycin, indinavir , itraconazole, ketoconazole, lapatinib, lopinavir, propafenone, quinidine, ranolazine, ritonavir, saquinavir, telaprevir, tipranavir, valspodar, and verapamil), P-gp inducer (avasimibe, carbamazepine, phenytoin, rifampin, and St. John’s wort), or inhibitor of breast cancer resistance protein (BCRP) (curcumin, cyclosporine, elacridar [GF120918], and eltrombopag).
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.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Confirmed OR in patients with locally advanced or metastatic solid tumors with BRCA 1/2 or ATM defect, as assessed by Blinded Independent Central Review (BICR), using RECIST v1.1 and, in patients with mCRPC, RECIST v1.1 and PCWG3 (bone). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
For patients with solid tumors, except mCRPC: Objective response (OR) is defined as a CR or PR per RECIST v1.1 from the first dose of study treatment until disease progression or death due to any cause. Both CR and PR must be confirmed by repeat assessments performed no less than 4 weeks after the criteria for response are first met.
For patients with mCRPC: Objective response (OR) is defined as the proportion of patients with a best overall soft tissue response of CR or PR per RECIST v1.1 from the first dose of study treatment until disease progression or death due to any cause. Soft tissue responses will be confirmed by a follow-up radiographic assessment at least 4 weeks later with a repeated CT or MRI with no evidence of confirmed bone disease progression per PCWG3 criteria. |
|
| E.5.2 | Secondary end point(s) |
- Adverse Events as characterized by type, severity (as graded by National Cancer Institute Common Terminology Criteria for Adverse Events [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 including: pre-dose/trough concentrations (Ctrough) for avelumab and talazoparib and post-dose concentrations (for talazoparib) and
maximum concentrations (Cmax) for avelumab.
- Avelumab Anti-drug antibody (ADA) levels and neutralizing antibodies (Nab) against avelumab.
- Confirmed OR as assessed by the investigator, using RECIST v1.1 and, in patients with mCRPC, RECIST v1.1 and PCWG3.
- Time to event endpoints: Endpoints as assessed by BICR and as assessed by the investigator, using RECIST v1.1 and in patients with mCRPC, RECIST v1.1 and PCWG3, including time to tumor response (TTR), duration of response (DR), and progression free survival (PFS). Additional time-to-event endpoints include overall survival (OS) for all patients and time to prostate-specific antigen (PSA) progression (≥ 25% increase) for mCRPC patients.
- PSA response ≥ 50% decrease and CTC count conversion for patients with mCRPC.
- Cancer antigen (CA)-125 response ≥ 50% decrease for patients with ovarian cancer.
- PD-L1 expression level in baseline tumor tissue
- Presence of defects in a panel of key oncogenes, including BRCA1/2 and ATM, and TMB in ctDNA and tumor tissue at baseline, during treatment, and at the end of treatment. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| multiple timepoints as per protocol |
|
| 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 | Yes |
| 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 |
| Tolerability, Immunogenicity |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| 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 | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| 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 |
| Argentina |
| Belgium |
| Denmark |
| France |
| Israel |
| Italy |
| Netherlands |
| Spain |
| United Kingdom |
| United States |
|
| 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
|
End of trial in a Member State of the European Union (EU) is defined as the time at which it is deemed that a sufficient number of patients have been recruited and completed the study as stated in the regulatory application and ethics application in the Member State.
End of trial in all other participating countries is defined as last subject last visit (LSLV). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 14 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 10 |
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