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

Study Overview
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Brief Summary
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This is a Phase 2, open-label, 2-part, multicenter study in subjects with MSS relapsed/refractory colorectal cancer. The primary objective of Part 1 is to evaluate the safety and tolerability of escalating doses of eFT508 in combination with a fixed dose of avelumab to determine the maximum tolerated dose (MTD) of eFT508 and to select a recommended dose for Part 2. The primary objective of Part 2 is to evaluate antitumor activity of eFT508 at the recommended dose in combination with avelumab or eFT508 monotherapy. Parts 1 and 2 will also evaluate pharmacokinetics (PK) and pharmacodynamics.

Official Title
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A Phase 2, Open-Label, Randomized, Non-Comparative Study With Preliminary Dose Finding to Evaluate eFT508 Monotherapy or eFT508 in Combination With Avelumab in Subjects With Microsatellite Stable Relapsed or Refractory Colorectal Cancer

Conditions
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Microsatellite Stable Relapsed or Refractory Colorectal Cancer

Intervention / Treatment
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* Drug: eFT508
* Drug: Avelumab


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: In Part 1, subjects will receive eFT508 in combination with a fixed dose of avelumab. Once the recommended dose of eFT508 in combination with avelumab is determined in Part 1, enrollment in Part 2 will begin. Subjects will be randomized in approximately a 2:1 ratio to receive eFT508 in combination with avelumab or eFT508 monotherapy.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: eFT508 plus avelumab dose finding Arm<br>subjects will receive eFT508 in combination with a fixed dose of avelumab | Drug: eFT508<br>* eFT508 will be taken orally (PO) twice a day (bid).<br>Drug: Avelumab<br>* Avelumab 10 mg/kg will be administered intravenously (IV) on Day 1 and once every 2 weeks (q2wk) thereafter<br>|
| Experimental: Part 2: eFT508 plus avelumab<br>subjects will receive eFT508 in combination with a fixed dose of avelumab | Drug: eFT508<br>* eFT508 will be taken orally (PO) twice a day (bid).<br>Drug: Avelumab<br>* Avelumab 10 mg/kg will be administered intravenously (IV) on Day 1 and once every 2 weeks (q2wk) thereafter<br>|
| Experimental: Part 2: eFT508 alone<br>subjects will receive eFT508 alone | Drug: eFT508<br>* eFT508 will be taken orally (PO) twice a day (bid).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Proportion of subjects with a dose limiting toxicity (DLT) during the first treatment cycle |  | 28 days | 
| Part 2: Overall Response Rate | the proportion of subjects whose best overall response is a complete or partial response | 8-16 weeks |