A Study of mRNA-5671/V941 as Monotherapy and in Combination With Pembrolizumab (V941-001)

Study Overview
=================
Brief Summary
-----------------
This study will determine the safety and tolerability and establish a preliminary recommended Phase 2 dose of V941(mRNA-5671/V941) as a monotherapy and in combination with pembrolizumab infusion.

Official Title
-----------------
A Phase 1, Open-Label, Multicenter Study to Assess the Safety and Tolerability of mRNA-5671/V941 as a Monotherapy and in Combination With Pembrolizumab in Participants With KRAS Mutant Advanced or Metastatic Non-Small Cell Lung Cancer, Colorectal Cancer or Pancreatic Adenocarcinoma

Conditions
-----------------
Neoplasms, Carcinoma, Non-Small-Cell Lung, Pancreatic Neoplasms, Colorectal Neoplasms

Intervention / Treatment
-----------------
* Biological: V941
* Biological: Pembrolizumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Part 2 Only - Has a histologically confirmed advanced or metastatic non-small cell lung cancer (NSCLC), non-mismatch repair deficient/microsatellite instability-high tumors colorectal cancers (non-MSI-H CRC), or pancreatic adenocarcinoma, and confirmed HLA types HLA-A11:01 and/or HLA C08:02 (and/or potentially other additional HLA types to be specified). NSCLC: Participants must have been tested for mutations affecting EGFR and/or anaplastic lymphoma kinase (ALK). Participants with ALK or epidermal growth factor receptor (EGFR)-positive NSCLC must have had recurrent or progressive disease (PD) after treatment with the corresponding inhibitor and current standard of care, in any sequence. Non-MSI-H CRC: Participant tumors must have been locally tested for MSI and have been found to be non-MSI-H. All Has a histologically confirmed advanced or metastatic KRAS 4MUT+ (G12D, G12V, G13D or G12C) (4 prevalent KRAS mutant antigens in solid tumors) solid tumor identified by local laboratory testing, and who have received, or been intolerant to, or ineligible for all treatment known to confer clinical benefit. A male participant must agree to use study-approved contraception during the treatment period and for at least 120 days after the last dose of study intervention and refrain from donating sperm during this period. A female participant was not be pregnant, not breastfeeding, and at not be a woman of childbearing potential (WOCBP) OR if a WOCBP, agrees to follow study-approved contraceptive guidance during treatment period and for at least 120 days after the last dose of study intervention. Have measurable disease per RECIST 1.1 as assessed by the local site investigator/radiology. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions. For Part 1 only: Cutaneous lesions can be considered in addition to imaging, but measurable disease should be defined by radiologic assessment. Have an evaluable archival tumor sample to submit for analysis. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Have adequate organ function Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale. Exclusion Criteria: A WOCBP who has a positive urine pregnancy test within 72 hours prior to randomization or treatment allocation Has an active infection requiring therapy. Has a history of interstitial lung disease. Has an active autoimmune disease that has required systemic treatment in the past 2 years (ie, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs) except vitiligo or resolved childhood asthma/atopy. Has not fully recovered from any effects of major surgery or has evidence of detectable infection. Surgeries that required general anesthesia must be completed at least 2 weeks before first study treatment administration. Surgery requiring regional/epidural anesthesia must be completed at least 72 hours before first study treatment administration and participants should be recovered. Has had chemotherapy, definitive radiation, or biological cancer therapy within 4 weeks (2 weeks for palliative radiation) prior to the first dose of study therapy, non-cytotoxic small molecule therapeutics within 5 half-lives (or 2 weeks, whichever is longer) prior to the first dose of study treatment, or has not recovered to Common Toxicity Criteria for Adverse Events (CTCAE) Grade 1 or better from any adverse events that were due to cancer therapeutics administered more than 4 weeks earlier (this includes participants with previous immunomodulatory therapy with residual immune-related adverse events). Has received a live-virus vaccine within 30 days of planned treatment start. Seasonal flu vaccines that do not contain live virus are permitted. Has received hematopoietic colony-stimulating growth factors (eg, granulocyte-colony stimulating factor, granulocyte-macrophage-colony stimulating factor, macrophage colony stimulating factor) within 2 weeks prior to the first dose of study intervention. Discontinued from therapy with an anti-programmed cell death protein 1 (anti-PD-1), anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (TCR; eg, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), CD137 (4-1BB, Tumor necrosis factor-receptor superfamily 9 [TNFSF9]), and OX 40 (TNFRSF4), due to a Grade 3 or higher immune-related adverse event (irAE). Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 28 days prior to the first dose of study intervention. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study drug. Has a known additional malignancy that is progressing or has required active treatment within the past 2 years. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV ribonucleic acid (RNA) [qualitative] is detected) infection. Has a known history of HIV. Has a known psychiatric or substance abuse disorder that would interfere with cooperating with the requirements of the study. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study intervention. Has had an allogenic tissue/solid organ transplant.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: V941 Monotherapy<br>V941(mRNA-5671/V941) administered intramuscularly (IM) once every 3 weeks (Q3W) for 9 3-week cycles | Biological: V941<br>* V941 administered IM, Q3W for 9 3-week cycles<br>* Other names: mRNA-5671/V941;|
| Experimental: V941 + Pembrolizumab<br>V941(mRNA-5671/V941) administered IM Q3W for 9 cycles and pembrolizumab 200 mg, intravenous (IV) for 35 3-week cycles | Biological: V941<br>* V941 administered IM, Q3W for 9 3-week cycles<br>* Other names: mRNA-5671/V941;Biological: Pembrolizumab<br>* Pembrolizumab 200 mg, IV for 35 3-week cycles<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-Limiting Toxicities (DLTs) | The following toxicities graded for severity using NCI Common Terminology for Adverse Events (CTCAE), Version 4.0 will be considered a DLT if judged by the investigator to be possibly related to study investigational products: 1) Grade 4 nonhematologic toxicity (ie. not a laboratory finding). 2) Grade 4 hematologic toxicity lasting ≥ 7 days, except thrombocytopenia: 3) Grade 4 thrombocytopenia of any duration 4) Grade 3 thrombocytopenia associated with clinically significant bleeding 5) Any nonhematologic AE ≥ Grade 3 in severity, with some exceptions 6) Any Grade 3 or Grade 4 nonhematologic laboratory value that meets one of the study criteria 7) Febrile neutropenia Grade 3 or Grade 4 8) Prolonged delay (> 2 weeks) in initiating Cycle 2 due to treatment-related toxicity. 9) Any treatment-related toxicity that causes the participant to discontinue treatment during Cycle 1. 10) Grade 5 toxicity 11) Any other clinically significant toxicity judged to be a DLT by the investigator. | Cycle 1 (Up to 21 days) | 
| Number of Participants Who Experienced an Adverse Event (AE) | An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. The number of participants who experienced an AE will be reported. | Up to approximately 25 months | 
| Number of Participants Who Discontinued Study Treatment Due to an AE | An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. The number of participants who discontinued study treatment due to an AE will be reported. | Up to approximately 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | ORR is assessed by the investigator based on Response Rate Assessed by Modified Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) and RECIST for immune-based therapeutics (iRECIST) following administration of V941 in combination with pembrolizumab. Objective response is a confirmed complete response (CR) or partial response (PR). | Up to approximately 24 months | 
| Mutant KRAS Specific T cells | Presence of and changes in the quantity of mutant KRAS specific T cells in the blood. | Up to approximately 24 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
cancer, solid tumors, therapeutic vaccine, Pembrolizumab, PD1, PD-1, PDL1, PD-L1, KRAS, mRNA