| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| locally advanced or metastatic KRAS-or NRAS-mutant NSCLC, mPDAC (regardless of KRAS status), and other KRAS-or NRAS-mutant solid tumors |
|
| 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 |
Phase 1: To assess the DLT rate of avelumab incombination with binimetinib with or without talazoparib in patients with locally advanced or metastatic KRAS-or NRAS-mutant NSCLC and mPDAC in order to determine the recommended Phase 2 dose (RP2D) for the combinations.
Phase 2: To assess the ORR of avelumab in combination with binimetinib with or without talazoparib, based on Investigator assessment per RECIST v1.1 in patients with locally advanced or metastatic KRAS-or NRAS-mutant NSCLC, mPDAC, and other KRAS-or NRAS-mutant advanced solid tumors |
|
| E.2.2 | Secondary objectives of the trial |
-To assess the overall safety and tolerability of avelumab in combination with binimetinib with or without talazoparib.
-To characterize the PK of avelumab, binimetinib and talazoparib when given in combination (avelumab plus binimetinib with or without talazoparib).
-To evaluate the immunogenicity of avelumab when combined with binimetinib with or without talazoparib
-To assess the anti-tumor activity of avelumab in combination with binimetinib with or without talazoparib.
-To assess the correlation of anti-tumor activity of avelumab in combination with binimetinib with or without talazoparib with PD-L1 expression, DDR gene alterations, and TMB in baseline tumor tissue.
Please see protocol for exploratory objectives |
|
| 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 as follows:
a. Stage IIIb/IV NSCLC with documented positive KRAS or NRAS mutation status as determined using a validated test performed in a College of American Pathologists (CAP)/Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory (or other comparable local or regional certification);
or
b. Metastatic pancreatic ductal adenocarcinoma; or
c. Phase 2 only: other advanced solid tumors with documented positive KRAS or NRAS mutation as determined using a validated test performed in a CAP/CLIA-certified laboratory (or other comparable local or regional certification).
2. Have had disease progression during or following at least 1 and not more than 2 prior lines of treatment for advanced or metastatic disease.
3. Patients with NSCLC must have previously received treatment with an anti-PD-1 or anti-PD-L1 agent for advanced disease.
4. Measurable disease as per RECIST v1.1 criteria (Appendix 3) with at least 1 target lesion
5. Provision of a Baseline Tumor sample:
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 formalin-fixed paraffin-embedded (FFPE) tissue to be submitted for protocol-required testing. Core needle or excisional biopsies are required, as fine needle aspirations will not yield enough tissue for protocol-specified testing
Exception: If an archival tumor tissue sample 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.
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. 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 (CLCR) ≥ 60 mL/min according to the Cockcroft-Gault formula or by 24 hour urine collection for CLCR, or according to local institutional standard method
10. Adequate Liver Function, including:
a. Total serum bilirubin ≤ 1.5 × ULN;
b. AST and ALT ≤ 2.5 × ULN.
11. Adequate Cardiac Function including:
a. Left ventricular ejection fraction (LVEF) ≥ 50% or above institutional normal value as determined by a multigated acquisition (MUGA) scan or echocardiography;
b. QTc interval ≤ 480 msec (mean from triplicate electrocardiograms [ECGs]).
12. 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:
i) 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;
ii) Have undergone a documented hysterectomy and/or bilateral oophorectomy;
iii) Have medically confirmed ovarian failure
All other female patients (including female patients with tubal ligations) are considered to be of childbearing potential
13. Evidence of a personally signed and dated informed consent document indicating that the patient has been informed of all pertinent aspects of the study.
14. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other procedures. |
|
| E.4 | Principal exclusion criteria |
1. Prior treatment with avelumab, a PARP inhibitor or MEK inhibitor.
2. Prior systemic anti-cancer therapy within 2 weeks prior to study enrollment.
3. Persisting toxicity related to prior therapy NCI CTCAE v4.0 Grade >1; however, alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 adverse events not constituting a safety risk based on the investigator’s judgment are acceptable.
4. Prior radiation therapy within 2 weeks prior to enrollment. Exception: Prior palliative radiotherapy 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).
5. Major surgery within 4 weeks prior to study enrollment.
6. Current use of immunosuppressive medication at the time of study enrollment, EXCEPT for the following permitted steroids (see Section 5.8.3 of protocol):
a. Intranasal, inhaled, topical steroids, eye drops or local steroid injection (eg, intra-articular injection);
b. Systemic corticosteroids at physiologic doses ≤10 mg/day of prednisone or equivalent;
c. Steroids as premedication for hypersensitivity reactions (eg, computed tomography (CT) scan premedication).
7. 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).
8. Known history of immune-mediated colitis, inflammatory bowel disease, pneumonitis, pulmonary fibrosis, uveitis or iritis.
9. Active or prior autoimmune disease that might deteriorate when receiving an immunostimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo-or hyperthyroid disease not requiring immunosuppressive treatment are eligible.
10. Prior organ transplantation including allogenic stem-cell transplantation.
11. Vaccination within 4 weeks of study enrollment and while on trials is prohibited except for administration of inactivated vaccines.
12. Diagnosis of Myelodysplastic Syndrome (MDS).
13. 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.
14. Participation in other studies involving investigational drug(s) within 4 weeks prior to study enrollment.
15. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immune deficiency 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: 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. History of thromboembolic or cerebrovascular events ≤6 months prior to study enrollment, including transient ischemic attacks, cerebrovascular accidents, deep vein thrombosis or pulmonary emboli
20. Current or anticipated use of a 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)
21. Inability to swallow or administer whole capsules or tablets, known intolerance to talazoparib or binimetinib or its excipients, known malabsorption syndrome, or other condition that may impair absorption of talazoparib or binimetinib.
22. Uncontrolled hypertension defined as persistent systolic blood pressure ≥150 mmHg or diastolic blood pressure ≥ 100 mmHg despite current therapy.
23. Concurrent neuromuscular disorder that is associated with the potential of elevated CK (eg, inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy).
24. Known history of Gilbert’s syndrome.
25. History or current evidence of retinal degenerative disease, RVO or current risk factors for RVO (eg, uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes).
26. 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
For Exclusion criteria 28 to 30 please see protocol section 4.2 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
-Phase 1b: DLT during the primary DLT evaluation period (Cycle 1).
-Phase 2: Confirmed OR based on Investigator assessment per RECIST v1.1 (see Appendix 3 of Protocol) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase 1- DLT evaluation period (Cycle 1)- 28 days after treatment start
Phase 2-throughout the trial
|
|
| E.5.2 | Secondary end point(s) |
-Adverse Events as characterized by type, severity (as graded by NCI CTCAE v4.03), timing, seriousness, and relationship to study treatment
-Laboratory abnormalities as characterized by type, severity (as graded by NCI CTCAE v4.03) and timing.
-PK parameters, ie, (Ctrough for binimetinib and talazoparib and Ctrough and Cmax for avelumab, at various cycles).
-Avelumab ADA levels and nAb against avelumab.
-Phase 1b: Confirmed OR based on Investigator assessment per RECIST v1.1
-TTR, DR, and PFS based on Investigator assessment per RECIST v1.1 and OS.
-PD-L1 expression level, DDR gene alterations, and TMB in baseline tumor tissue.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| 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 |
|
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Phase 2 of the study patients will be randomized in a 1:1 to receive double to triplet treament. |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 13 |
| 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 |
| France |
| Italy |
| Singapore |
| 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
|
|
| 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 | 8 |
| E.8.9.1 | In the Member State concerned days | 23 |
| 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 | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 23 |
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