A Study of Avelumab, Binimetinib and Talazoparib in Patients With Locally Advanced or Metastatic RAS-mutant Solid Tumors

A PHASE 1B/2 STUDY TO EVALUATE SAFETY AND CLINICAL ACTIVITY OF COMBINATIONS OF AVELUMAB, BINIMETINIB AND TALAZOPARIB IN PATIENTS WITH LOCALLY ADVANCED OR METASTATIC RAS-MUTANT SOLID TUMORS

This Phase 1b/2 study will examine the effects of the study drugs, avelumab, binimetinib and talazoparib when given in a 2 (doublet) or 3 (triplet) drug combination, in patients with locally advanced or metastatic RAS-mutant solid tumors. The Phase 1b part of the study will assess if the different study drugs can be given together safely and which doses to use for further research. Phase 2 will test if the study treatments have an effect on tumor size and growth, and gather more information about potential side effects.

This is a Phase 1b/2, open label, multi-center, safety, clinical activity, pharmacokinetic (PK), and pharmacodynamics (PD) study of combinations of avelumab, binimetinib and talazoparib in adult patients with metastatic pancreatic ductal adenocarcinoma and other locally advanced or metastatic KRAS- or NRAS-mutant solid tumors.

The Phase 1b part of this study will initially assess doublet drug combinations to determine a recommended dose for further investigation. Following this, the recommended dose for the combination of avelumab, binimetinib and talazoparib (triplet) will be determined. The recommended doses for the doublet and triplet combinations will be used in the Phase 2 part of the study, which will assess the safety and preliminary anti-tumor activity of the study treatments.

Inclusion Criteria:

• Histological diagnosis of locally advanced (primary or recurrent) or metastatic solid tumors that are not amenable for treatment with curative intent as follows:

  1. Metastatic pancreatic ductal adenocarcinoma; or
  2. Phase 2 only: Stage IIIb/IV NSCLC or 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).

• Have had disease progression during or following at least 1 and not more than 2 prior lines of treatment for advanced or metastatic disease.

• Patients with NSCLC must have previously received treatment with an anti-PD-1 or anti-PD-L1 agent for advanced disease.

• Measurable disease as per RECIST v1.1 criteria.

• Provision of a baseline tumor sample.

• Age ≥18 years (Japanese patients must be ≥20 years old)

• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1.

• Adequate bone marrow, renal and liver functions.

• Adequate cardiac function.

• Informed consent provided.

Exclusion Criteria:

• Prior treatment with avelumab, a PARP inhibitor or MEK inhibitor.
• Prior systemic anti-cancer therapy within 2 weeks prior to study enrollment.
• Persisting toxicity related to prior therapy.
• Current use of immunosuppressive medication.
• Known history of immune-mediated colitis, inflammatory bowel disease, pneumonitis, pulmonary fibrosis, uveitis or iritis.
• Active or prior autoimmune disease that might deteriorate when receiving an immunostimulatory agent.
• Diagnosis of myelodysplastic syndrome (MDS).
• Known symptomatic brain metastases requiring steroids.
• Known history of testing positive for HIV or hepatitis.
• Clinically significant (ie, active) cardiovascular disease.
• History of thromboembolic or cerebrovascular events.
• Current or anticipated use of a P-gp inhibitor, inducer, or inhibitor of breast cancer resistance protein (BCRP)
• Uncontrolled hypertension.
• Concurrent neuromuscular disorder that is associated with the potential of elevated creatinine kinase.
• Known history of Gilbert's syndrome.
• History or current evidence of retinal degenerative disease, retinal vein occlusion (RVO) or current risk factors for RVO.
• Other acute or chronic medical or psychiatric condition.