A Study to Evaluate eFT508 Alone and in Combination With Avelumab in Subjects With MSS Colorectal Cancer

• Drug: eFT508
  eFT508 will be taken orally (PO) twice a day (bid).
• Drug: Avelumab
  Avelumab 10 mg/kg will be administered intravenously (IV) on Day 1 and once every 2 weeks (q2wk) thereafter

• Experimental: Part 1: eFT508 plus avelumab dose finding Arm
  subjects will receive eFT508 in combination with a fixed dose of avelumab
  Interventions:

  • Drug: eFT508
  • Drug: Avelumab
• Experimental: Part 2: eFT508 plus avelumab
  subjects will receive eFT508 in combination with a fixed dose of avelumab
  Interventions:

  • Drug: eFT508
  • Drug: Avelumab
• Experimental: Part 2: eFT508 alone
  subjects will receive eFT508 alone
  Intervention: Drug: eFT508

Inclusion Criteria:

• ECOG performance status of 0, 1, or 2
• Pathologically documented diagnosis of colorectal adenocarcinoma.
• Progressed on or intolerant of at least 2 prior cancer therapy regimens administered for metastatic disease.
• Completion of all previous therapy (including surgery, radiotherapy, chemotherapy, immunotherapy, or investigational therapy) for the treatment of cancer ?3 weeks before the start of study therapy.
• Part 2 only: Presence of radiographically measurable disease (defined as the presence of ?1 lesion that measures ?10 mm [?15 mm for lymph nodes]). Measurable disease that was previously radiated is only permitted if progressing.
• Agrees to undergo a pretreatment and a post-treatment biopsy.
• Microsatellite stable disease determined by IHC and/or polymerase chain reaction (PCR).
• Adequate bone marrow function
• Adequate hepatic function
• Adequate renal function
• Normal coagulation profile
• Negative antiviral serology
• Female subjects of childbearing potential must not be pregnant or breastfeeding
• Willingness to use protocol-recommended methods of contraception or to abstain from heterosexual intercourse from start of therapy until at lest 30 days after the last dose of study therapy
• Life expectancy of ?3 months.

Exclusion Criteria:

• History of another malignancy except for adequately treated local basal cell or squamous cell carcinoma of the skin; in situ cervical or breast carcinoma; adequately treated, papillary, noninvasive bladder cancer; other adequately treated Stage 1 or 2 cancers currently in complete remission, or any other cancer that has been in complete remission for ?2 years.
• Known symptomatic brain metastases requiring ?10 mg/day of prednisolone (or its equivalent).
• Significant cardiovascular disease.
• Significant screening ECG abnormalities.
• Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent.
• Known history of colitis, inflammatory bowel disease, pneumonitis, or pulmonary fibrosis.
• Ongoing risk for bleeding due to active peptic ulcer disease or bleeding diathesis.
• Evidence of an ongoing systemic bacterial, fungal, or viral infection.
• Any condition that may impact the subject's ability to swallow oral medications.
• Major surgery within 4 weeks before the start of study therapy.
• Prior solid organ or bone marrow progenitor cell transplantation.
• Prior therapy with any known inhibitor of MNK-1 or MNK-2.
• Prior therapy with any of the following: PD-1, PD-L1, CTLA4 antibody, or any other drug targeting T cell checkpoint pathways.
• Prior high dose chemotherapy requiring stem cell rescue.
• Intolerance to or prior severe (?Grade 3) allergic or anaphylactic reaction to infused antibodies or infused therapeutic proteins.
• Vaccination within 4 weeks of the first dose of avelumab and while on study.
• Ongoing immunosuppressive therapy.
• Use of a strong inhibitor or inducer of cytochrome P450 3A4 (CYP3A4) within 7 days prior to the start of study therapy or expected requirement for use of a strong CYP3A4 inhibitor or inducer during study therapy.
• Previously received investigational product in a clinical trial within 30 days or within 5 elimination half lives (whichever is longer) prior to the start of study therapy, or is planning to take part in another clinical trial while participating in this study.
• Has any illness, medical condition, organ system dysfunction, or social situation, including mental illness or substance abuse, deemed by the Investigator to be likely to interfere with a subject's ability to sign informed consent, adversely affect the subject's ability to cooperate and participate in the study, or compromise the interpretation of study results

• Merck KGaA, Darmstadt, Germany
• Pfizer