This clinical study will assess the safety and tolerability of escalating doses of mRNA-2416 alone and in combination with administered fixed doses of durvalumab in participants with relapsed/refractory solid tumor malignancies or lymphoma, as well as the objective response rate (ORR) of mRNA-2416 alone or in combination with durvalumab in ovarian cancer based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. The applicable dose of mRNA-2416 will be injected directly into the participant's tumor (intratumoral) and the applicable dose of durvalumab will be administered intravenously.
This is a first-in-human, Phase 1/2, open-label, multicenter, dose escalation and efficacy study designed to determine the safety and tolerability of repeated intratumoral injections of mRNA-2416 alone (Arm A) and in combination with intravenously administered durvalumab (Arm B) in participants with advanced relapsed/refractory solid tumor malignancies or lymphoma and to assess the ORR of mRNA-2416 alone and in combination with durvalumab in ovarian cancer based on RECIST v1.1. The study includes 2 treatment arms (mRNA-2416 monotherapy \[Arm A\],and mRNA-2416 + durvalumab \[Arm B\]), each arm of the study consists of a Dose Escalation period in non-visceral lesions followed by a Dose Confirmation period in visceral lesions and an Expansion period (Arm B only) in participants with ovarian cancer at the MTD/RDE as determined by the Dose Escalation period. Once the expected maximum tolerated dose/recommended dose for expansion (MTD/RDE) has been cleared in Dose Escalation for Arm A, Dose Escalation for Arm B will begin with mRNA-2416 at 1 dose level lower than the Arm A MTD/RDE. Following completion of 6 cycles of mRNA-2416 + durvalumab (Arm B), participants may continue with durvalumab alone until disease progression, unacceptable toxicity, or 24 months of treatment (total), whichever is sooner.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
79
mRNA encoding human OX40L
PD-L1 inhibitor
University of Colorado Hospital
Aurora, Colorado, United States
Smilow Cancer Hospital
New Haven, Connecticut, United States
Northwestern Memorial Hospital
Indianapolis, Indiana, United States
Massachusetts General Hospital
Boston, Massachusetts, United States
Dana Farber Cancer Institute
Boston, Massachusetts, United States
University of Minnesota Medical Center
Minneapolis, Minnesota, United States
University of Oklahoma Peggy and Charles Stephenson Cancer Center
Oklahoma City, Oklahoma, United States
Women & Infants Hospital
Providence, Rhode Island, United States
Sarah Cannon Research Institute
Nashville, Tennessee, United States
Number of Participants Who Experienced Dose Limiting Toxicities (DLTs)
DLTs: assessed by Investigator as unrelated to disease, disease progression, intercurrent illness, or concomitant medications; at least possibly related to study drug; and occurred within first 28 days of the study. DLTs in Arm A participants: Grade (Gr)3 adverse events (AEs) (except Gr3 thrombocytopenia lasting \<7 days/Gr3 neutropenia without fever or lasting \<7 days) and any Gr4/5 toxicity. DLTs (criteria assessed by Investigator) participants in Arm B: diarrhea/colitis; pneumonitis; hepatitis; rash; peripheral neuromotor syndromes; myocarditis; myositis/polymyositis; endocrinopathies involving thyroid, pituitary glands, or adrenal insufficiency; type I diabetes mellitus; nephritis; elevated amylase/lipase pancreatitis; all other immunemediated/nonimmunemediated AEs; infusion-related reactions; any Gr≥3 immune/nonimmune AE except vitiligo/alopecia; neutropenia Gr≥3 with fever/Gr4 lasting \>7 days; Gr≥3 thrombocytopenia and significant bleeding; Gr4 thrombocytopenia; and Gr4 anemia.
Time frame: Days 1-28 (Cycle 1)
Number of Participants With a Treatment-Emergent AEs (TEAE) or a Serious AE
An AE is any adverse experience in a participant administered a study drug, whether or not it is considered drug related, that occurred during study participation. This would include any side effect, injury, toxicity, sensitivity reaction, intercurrent illness, or sudden death. Conditions that started before study entry were reported as an AE if the frequency, intensity, or character of the condition worsened during the study. A TEAE was defined as any AE that newly appeared, increased in frequency, or worsened in severity following initiation of study drug. A serious AE (SAE) was defined as any AE that resulted in death, is life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in disability/permanent damage, was a congenital anomaly/birth defect, or was an important medical event. A summary of SAEs and all nonserious AEs ("Other"), regardless of causality, is located in the Reported "Adverse Events" section.
Time frame: Day 1 up to 90 days after the last dose of study treatment (maximum exposure=26.3 weeks)
Objective Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
ORR was defined as the percentage of participants in the Activity Evaluable Set with best overall response of Partial Response (PR) or better, where the denominator was the number of participants with solid tumor. Solid tumor response was assessed by Investigators based on RECIST version 1.1 (complete response \[CR\], PR, stable disease \[SD\], progressive disease \[PD\], or not evaluable), and based on Immune-related Response Criteria (irRC) (immune-related CR, immune-related PR, immune-related SD, immune-related PD, or not evaluable). The 95% confidence interval (CI) was based on the Clopper-Pearson exact test.
Time frame: Day 1 through 6 months after the last dose of study treatment, or until disease progression, whichever occurred first (maximum exposure=26.3 weeks)
Duration of Response in Participants With Ovarian Cancer (RECIST Version 1.1)
Duration of response was defined as the time from first response (PR or better, as assessed by Investigators based on RECIST version 1.1) to first occurrence of a disease progression. Participants who never achieved a response were excluded from this analysis. DOR (days) = date of event/censoring - date of first response + 1. Duration of response could only be calculated if more than 1 participant had a PR. Since only 1 participant had a PR, the duration of response could not be calculated.
Time frame: Day 1 through 6 months after last dose of study treatment, or until disease progression, whichever occurred first (maximum exposure=26.3 weeks)
Disease Control Rate in Participants With Ovarian Cancer (RECIST Version 1.1)
Disease control rate (DCR) was defined as the percentage of participants in the Activity Evaluable Set with best overall response of PR or better, or SD ≥55 days (from the first dose date to the last SD assessment, and without PD between), where the denominator is the number of participants with solid tumor. Solid tumor response was assessed by investigators based on RECIST version 1.1 (CR, PR, SD, PD, or not evaluable), and based on irRC (immune-related CR, immune-related PR, immune-related SD, immune-related PD, or not evaluable). The 95% CI was based on the Clopper-Pearson exact test.
Time frame: Day 1 through 6 months after last dose of study treatment, or until disease progression, whichever occurred first (maximum exposure=26.3 weeks)
Number of Participants With Anti-OX40L Antibodies
Data are presented for number of participants with anti-OX40L antibodies. OX40L is the protein translated by the drug product.
Time frame: Cycle (C) 1 Day (D) 1, C1D15, C2D1, C3D1, C3D15, C4D1, C5D1, C6D1, C6D15, End of Treatment (maximum exposure=26.3 weeks); Cycle =28 days
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