Safety and clinical Activity of avelumab in combination with binimetinib with or without talazoparib in patients with advanced or metastatic Ras-Mutant Solid Tumors

Phase 1

• Conditions: locally advanced or metastatic KRAS-or NRAS-mutant NSCLC, mPDAC (regardless of KRAS status), and other KRAS-or NRAS-mutant solid tumors; MedDRA version: 20.0Level: LLTClassification code 10065147Term: Malignant solid tumorSystem Organ Class: 100000004864; MedDRA version: 20.0Level: LLTClassification code 10065252Term: Solid tumorSystem Organ Class: 100000004864; Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2018-000124-34-BE
• Lead Sponsor: Pfizer Inc, 253 East 42nd Street, New York, NY 10017

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2018-11-28
• Last Update Posted: 17 May 2021

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 127

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;

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, erythromyc

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified