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

This is a Phase 1b/2, open label, multi-center, safety, clinical activity, pharmacokinetic
(PK), and pharmacodynamics (PD) study of avelumab in combination with binimetinib with or
without talazoparib in adult patients with locally advanced or metastatic KRAS- or
NRAS-mutant non-small cell lung cancer, pancreatic ductal adenocarcinoma, or other KRAS- or
NRAS-mutant solid tumors.

The Phase 1b part of this study will initially assess the combination of avelumab and
binimetinib (doublet) 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. 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

2. Metastatic pancreatic ductal adenocarcinoma; or

3. 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).

- 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.