Dose Escalation Study of mRNA-2752 for Intratumoral Injection to Participants in Advanced Malignancies

A Phase 1, Open-Label, Multicenter, Dose Escalation Study of mRNA-2752, a Lipid Nanoparticle Encapsulating mRNAs Encoding Human OX40L, IL-23, and IL-36γ, for Intratumoral Injection Alone and in Combination With Immune Checkpoint Blockade

The clinical study will assess the safety and tolerability of escalating intratumoral doses of mRNA-2752 in participants with relapsed/refractory solid tumor malignancies or lymphoma.

Study Overview

• Status: Completed
• Conditions: Dose Escalation: Relapsed/Refractory Solid Tumor Malignancies or Lymphoma; Dose Expansion: Triple Negative Breast Cancer, HNSCC, Non-Hodgkins, Urothelial Cancer, Immune Checkpoint Refractory Melanoma, and NSCLC Lymphoma
• Intervention / Treatment: Biological: mRNA-2752; Biological: Durvalumab

Detailed Description

This is a Phase 1, open-label, multicenter, dose-escalation study of intratumoral injections of mRNA-2752 alone and in combination with intravenously administered immune checkpoint blockade therapy in participants with histologically confirmed advanced or metastatic solid tumor malignancies or lymphoma. The study consists of Dose Escalation and Dose Confirmation Parts, which will occur in Arm A and Arm B, followed by a Dose Expansion Part, which will occur in Arm B, and a Dose Exploration in Arm C as a neoadjuvant therapy for cutaneous melanoma.

Participants in Arm A and in Arm B will be enrolled into the Dose Escalation Part and the doses of mRNA-2752 will be administered in a dose escalation regimen until a maximum tolerated dose (MTD) or a recommended dose for expansion (RDE) is identified. When the MTD/RDE is identified, participants with solid tumors or lymphoma with visceral lesions may be enrolled into the Dose Confirmation Part to confirm that the dose is also appropriate for this subgroup.

• Study Type: Interventional
• Enrollment (Actual): 134
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • Melbourne, Australia, 3004
    • Alfred Health
  • Westmead, Australia, 2145
    • Westmead Hospital
  • Wollstonecraft, Australia
    • Melanoma Institute of Australia
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • One Clinical Research Perth
• Israel
  • Haifa, Israel, 3109601
    • Rambam Medical Center
  • Petah Tikva, Israel, 4941492
    • Rabin Medical Center
  • Ramat Gan, Israel, 5224213
    • Chaim Sheba Medical Center
  • Tel Aviv-Yafo, Israel, 6423906
    • Tel Aviv Sourasky Medical Center
• United States
  • California
    • San Francisco, California, United States, 94143
      • UCSF Helen Diller Family Comprehensive Cancer Center
    • Santa Monica, California, United States, 90404
      • Providence St. John's Health Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Denver
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale Cancer Center
  • Florida
    • Sarasota, Florida, United States, 34232
      • Sarah Cannon Research Institute at Florida Cancer Specialists
  • Illinois
    • Chicago, Illinois, United States, 60637
      • The University of Chicago Medicine
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02215
      • Cancer Center at Beth Israel Deaconess Medical Center
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
  • New York
    • New York, New York, United States, 10029
      • Icahn School of Medicine at Mount Sinai
    • New York, New York, United States, 10016
      • NYU Langone Medical Center
    • Rochester, New York, United States, 14642
      • James P. Wilmot Cancer Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • The Cleveland Clinic Foundation
  • Oregon
    • Portland, Oregon, United States, 97239-3011
      • Oregon Health and Science University
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Written informed consent prior to completing any study-specific procedure
• Histologically confirmed advanced or metastatic disease with at least 1 measurable lesion as determined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or Cheson 2016 criteria

• Dose Escalation/Confirmation:

  o Has disease progression after adequate standard of care therapies for metastatic disease that are known to confer clinical benefit, is intolerant to treatment, or refuses standard treatment (no limit to prior lines of therapy)

• Dose Expansion:

  • Group 1 Triple negative breast cancer: Must have objective evidence of disease progression during or following at least one prior line of therapy for metastatic or locally advanced disease. Enrollment to Stage 3 of this cohort will include participants who have previously progressed on prior immune checkpoint blockade or participants with programmed death-ligand 1 (PD-L1) negative tumor based on archival tissue (if available).
  • Group 2 Head and neck squamous cell carcinoma: Must have objective evidence of disease progression during or following platinum-containing chemotherapy as well as a PD-1/L1 therapy
  • Group 3 Non-Hodgkin's lymphoma: Must have objective evidence of disease progression and have received 2 or more prior lines of therapy. Participants with large B-cell lymphoma must have received prior anthracycline containing chemotherapy.
  • Group 4 Urothelial cancer, first line: Must be cisplatin ineligible and PD-L1 negative
  • Group 5 Urothelial cancer: Must have objective evidence of disease progression during or following platinum-containing chemotherapy
  • Group 6 Cutaneous melanoma: Must be refractory to immune checkpoint blockade in the primary or secondary acquired resistance setting.
  • Group 7 Non-small cell lung cancer, primary refractory or secondary acquired resistance to immune checkpoint blockade.

• Dose Exploration:

  o Newly diagnosed resectable, BRAF wild-type, Stage IIIB/C/D and Stage IV cutaneous melanoma with clinically evident lymph node involvement in the neoadjuvant setting.

• Has a tumor lesion amenable to biopsy and must be willing to provide the baseline and on-treatment tumor biopsy samples if medically feasible. For participants with only 1 lesion amenable to injection, biopsy, and RECIST assessment, that lesion must be ≥2 centimeters (cm)
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤1, with no deterioration over the previous 2 weeks prior to baseline or day of first dosing.
• Has a body weight of >30 kilograms (kg)
• Adequate hematological and biological function
• Has evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal participants
• Treatment Arm B and Arm C: Clinical euthyroid status. Participants with clinically stable hypothyroidism, on adequate thyroid supplementation, are permitted on study.

Exclusion Criteria:

• Has received prior systemic anticancer therapy including investigational agents within 5 half-lives or 28 days of the start of study treatment, whichever is shorter. Participants enrolled to Arm C may not have received any previous anti-cancer therapy, immune therapy, radiotherapy, or investigational agents.
• Has received prior radiotherapy within 14 days before the first dose of study treatment. Participants enrolled to Arm C may not have had prior anticancer therapy including radiotherapy.
• Has received a live vaccine within 30 days before the first dose of study treatment
• Has current or prior use of immunosuppressive medication within 14 days before the first dose of study treatment
• Have major surgical procedures within 28 days or non-study-related minor procedures within 7 days before the first dose of study treatment.
• Requires active systemic anticoagulation at the time of intratumoral injection or biopsy
• Active central nervous system tumors or metastases

• Any unresolved toxicity National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and protocol defined laboratory values

  • Participants with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Medical Monitor.
  • Participants with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the Medical Monitor.
• Any active or prior documented autoimmune or inflammatory disorders
• History of primary immunodeficiency, allogenic solid organ transplantation, or tuberculosis
• Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice), hepatitis B (known positive HBV surface antigen [HBsAg] result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Participants with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Participants positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA).
• Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease (ILD), serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs, or compromise the ability of the participant to give written informed consent
• Has active GI bleeding or hemoptysis or history of bleeding disorder
• Is a female participant who is pregnant or breastfeeding or male or female participant of reproductive potential who are not willing to employ effective birth control from screening to 120 days after the last dose of study treatment

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A: mRNA-2752; Participants will be administered mRNA-2752 at an applicable dose as monotherapy.	Biological: mRNA-2752; Solution for intratumoral injection
Experimental: Arm B: mRNA-2752 + Durvalumab; Participants will be administered mRNA-2752 at an applicable dose in combination with durvalumab.	Biological: mRNA-2752; Solution for intratumoral injection; Biological: Durvalumab; Solution for infusion after dilution
Experimental: Arm C: mRNA-2752 Alone or mRNA-2752 + Durvalumab; Participants will be administered mRNA-2752 at an applicable dose as monotherapy or in combination with durvalumab.	Biological: mRNA-2752; Solution for intratumoral injection; Biological: Durvalumab; Solution for infusion after dilution

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Number of Participants with Dose Limiting Toxicities (DLTs)	Up to Day 28
Arm B: Overall Response Rate (ORR): Percentage of Participants with Tumor Response (Partial or Complete) Based on Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) in Cutaneous Melanoma	Up to 2 years
Number of Participants with Adverse Events (AEs)	Up to 27 months

Secondary Outcome Measures

Outcome Measure	Time Frame
ORR: Percentage of Participants with Tumor Response (Partial or Complete) Based on RECIST v1.1 and modified RECIST (iRECIST), and Cheson and Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC) for Participants With Lymphoma	Up to 2 years
Pharmacokinetics: Maximum Observed Concentration (Cmax)	Predose, immediately after injection, and 15 minutes up to 168 hours postdose

Collaborators and Investigators

• Sponsor: ModernaTX, Inc.
• Collaborators: AstraZeneca

Publications and helpful links

General Publications

• Srikrishna D, Sachsenmeier K. We need to bring R0 < 1 to treat cancer too. Genome Med. 2021 Jul 26;13(1):120. doi: 10.1186/s13073-021-00940-9.

Study record dates

Study Major Dates

• Study Start (Actual): November 27, 2018
• Primary Completion (Actual): August 1, 2025
• Study Completion (Actual): August 1, 2025

Study Registration Dates

• First Submitted: November 8, 2018
• First Submitted That Met QC Criteria: November 9, 2018
• First Posted (Actual): November 14, 2018

Study Record Updates

• Last Update Posted (Estimated): August 15, 2025
• Last Update Submitted That Met QC Criteria: August 14, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Keywords: Intratumoral injection; IL-23; OX40L; mRNA-2752; IL-36γ
• Additional Relevant MeSH Terms: Neoplasms by Site; Immune System Diseases; Neoplasms by Histologic Type; Skin Diseases; Breast Diseases; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Breast Neoplasms; Neoplasms; Lymphoma; Triple Negative Breast Neoplasms; Antineoplastic Agents, Immunological; Antineoplastic Agents; Durvalumab
• Other Study ID Numbers: mRNA-2752-P101; 2022-001597-55 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No