A Phase 1 Open-Label Multicenter Study to Assess the Safety Tolerability and Immunogenicity of mRNA-4157 Alone or in Combination in Participants with Solid Tumors
Brief description of study
This is a 2-part, open-label, Phase 1, multicenter dose-escalation, FIH study of mRNA-4157 monotherapy in subjects with resected solid tumors (Part A) who are in the adjuvant setting (i.e.,status post-resection, including: those who have completed standard of care or have refused standardof care adjuvant therapy) and of mRNA-4157 in combination with pembrolizumab in subjects withunresectable (locally advanced or metastatic) solid tumors (Part B).Part A: an mTPI dose-escalation design will be used. Eligible subjects will each receive a fixed doseof 0.04 mg, 0.13 mg, or 0.39 mg of mRNA-4157 administered via an IM injection on Day 1 of each21-day cycle. Study Day 1 is the day corresponding to the first injection of mRNA-4157 (C1D1).Dosing will be staggered by 1 week between the first and next subject in the first cohort for safetymonitoring purposes. Subjects who do not have a dose limiting toxicity (DLT) following the first 21-day cycle of mRNA-4157 may continue to receive mRNA-4157 on Day 1 of subsequent 21-daycycles, for a maximum of 4 cycles. Intermediate doses may be implemented if determined necessaryby the SRC (Section 3.1.2).After the first 3 subjects have completed the DLT observation period, the safety and tolerability datawill be reviewed by the mRNA-4157 SRC and the decision will be made to dose-escalate, continueenrolling at that dose level (expansion), dose de-escalate, or stop dosing due to unacceptable toxicityon the basis of the dose escalation guidelines described in Section 3.1.2. The rules described inSection 3.1.2 will be used to determine further enrollment at the current dose level. Subjects will beassigned to a dosing cohort based on the order of dose escalation and where cohort slots are open.Part B: The Dose Escalation Phase of Part B will begin after the first dose level from Part A iscleared by the SRC. Thereafter, Parts A and B will run concurrently. An interactive voice responsesystem or similar system will be used to allocate eligible subjects to each cohort in both Part A and Bof the study; note that because the subject population is different for Parts A and B, individualsubjects can only participate in the Part of the study they are eligible for.Dose escalation of mRNA-4157 in Part B will be conducted using the mTPI design in a similarmanner to Part A (with a fixed dose of pembrolizumab for all subjects in Part B).Each subject will receive a maximum of 4 cycles of mRNA-4157, and subjects in Part B maycontinue pembrolizumab until progression, unacceptable toxicity, or up to 35 cycles (2 years oftreatment), whichever is sooner (Section 5.3)After completion of the Part B Escalation Phase, the Part B Expansion Phase may then enroll up to30 additional subjects per dose level, at 1 or 2 doses (as determined by the SRC), at and/or below thecombination RP2D (i.e., a maximum of 60 subjects in the Expansion Phase if 2 dose levels arestudied). If 2 dose levels are studied in the Expansion Phase, subjects will be randomly allocated toeach dose level. Of these Expansion Phase subjects, at least one sub-cohort of 10 subjects may beincluded in order to obtain a mandatory on-treatment tumor biopsy to assess the biological activity ofmRNA-4157 in combination with pembrolizumab in tumors. The first 10 subjects who consent tomandatory on-treatment biopsies will be placed into a biopsy sub-cohort if such a cohort is open(otherwise on-treatment biopsies are optional in the Expansion Phase). If 2 dose levels are studied inthe Part B Expansion Phase, then 2 biopsy sub-cohorts may be included, 1 at each dose level.The same stopping rule as the dose Escalation Phase will also be applied in the Expansion Phase,such that if the rate of AEs meeting DLT criteria at the RP2D (or any lower dose used in theExpansion Phase) is 30% or higher, then recruitment at that dose level will be stopped. A thorough and in-depth review of all the study data would be performed, and the SRC may consider expansionof a lower dose level.There will be no Part A Expansion Phase for subjects in the adjuvant setting.
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