mRNA-2752 / Moderna - LARVOL DELTA

Immunotherapy in High-risk Ductal Carcinoma in Situ (DCIS) (clinicaltrials.gov) - P1 | N=42 | Active, not recruiting | Sponsor: Laura Esserman | Trial primary completion date: Mar 2025 ➔ Mar 2026 | Recruiting ➔ Active, not recruiting | N=68 ➔ 42 | Trial completion date: Mar 2025 ➔ Mar 2026

Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • Oncology • Solid Tumor • HER-2

Intratumoral Injection of mRNA-2752 and Pembrolizumab for High-Risk Ductal Carcinoma In Situ: A Phase 1 Nonrandomized Clinical Trial. (PubMed, JAMA Oncol) - P1 | "These findings warrant additional investigation, and studies are ongoing. ClinicalTrials.gov Identifier: NCT02872025."

Clinical • Journal • P1 data • Dermatology • Immunology • Oncology • Urticaria • HER-2 • TNFSF4

Immunotherapy in High-risk Ductal Carcinoma in Situ (DCIS) (clinicaltrials.gov) - P1 | N=68 | Recruiting | Sponsor: Laura Esserman | Trial completion date: Mar 2024 ➔ Mar 2025 | Trial primary completion date: Mar 2024 ➔ Mar 2025

Trial completion date • Trial primary completion date • Oncology • Solid Tumor • HER-2

Dose Escalation Study of mRNA-2752 for Intratumoral Injection to Participants in Advanced Malignancies (clinicaltrials.gov) - P1 | N=134 | Active, not recruiting | Sponsor: ModernaTX, Inc. | Trial completion date: Apr 2025 ➔ Mar 2026 | Trial primary completion date: May 2024 ➔ Mar 2026

Checkpoint block • Checkpoint inhibition • Combination therapy • Lipid Nanoparticle • Metastases • Trial completion date • Trial primary completion date • Breast Cancer • Cutaneous Melanoma • Genito-urinary Cancer • Head and Neck Cancer • Hematological Malignancies • Lung Cancer • Lymphoma • Melanoma • Non Small Cell Lung Cancer • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • Urothelial Cancer • BRAF • PD-L1

Intratumoral (ITu) delivery of mRNA-2752 encoding human OX40L/IL-23/IL-36γ in combination with durvalumab induces an immunostimulatory effect within the tumor microenvironment (TME) of patients with advanced solid tumors (AACR 2024) - P1 | "RNA-Seq transcriptome analysis showed increases in the immune inflamed gene signatures related to antitumor activity in 24/43 (56%) pts post-treatment, and the pre-existing immune inflamed phenotype within the TME was associated with clinical benefit.Conclusions mRNA-2752 ITu injection induced a systemic immunomodulatory effect by elevating effector cytokines. This was associated with pharmacodynamic changes within the TME, including increases in T cell abundance and proliferation, and upregulation of immune gene signatures that correlate with antitumor response."

Biomarker • Clinical • Combination therapy • IO biomarker • Metastases • Tumor microenvironment • Oncology • Solid Tumor • CCL21 • CCR7 • CD69 • CD8 • GZMB • IFNG • IL23A • ITGAE • PRF1 • TCF7 • TNFSF4

Dose Escalation Study of mRNA-2752 for Intratumoral Injection to Participants in Advanced Malignancies (clinicaltrials.gov) - P1 | N=134 | Active, not recruiting | Sponsor: ModernaTX, Inc. | Recruiting ➔ Active, not recruiting | N=264 ➔ 134

Enrollment change • Enrollment closed • Breast Cancer • Cutaneous Melanoma • Genito-urinary Cancer • Head and Neck Cancer • Hematological Malignancies • Lung Cancer • Lymphoma • Melanoma • Non Small Cell Lung Cancer • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • Urothelial Cancer • BRAF • PD-L1

Immunotherapy in High-risk Ductal Carcinoma in Situ (DCIS) (clinicaltrials.gov) - P1 | N=68 | Recruiting | Sponsor: Laura Esserman | N=48 ➔ 68

Enrollment change • Oncology • HER-2

Safety and Preliminary Efficacy of mRNA-2752, a Lipid Nanoparticle Encapsulating mRNAs Encoding Human OX40L/IL-23/IL-36γ for Intratumoral (ITu) Injection, and durvalumab (IV) in TNBC, HNSCC, and Melanoma (SITC 2022) - "Biomarker analyses indicate mRNA-2752 drives cytokine responses. Consistent with the expected mechanism of action, a productive and sustained inflammatory response is observed in the TME in response to treatment, including signatures of increased innate and adaptive immune cell abundance and effector response."

Clinical • IO biomarker • Head and Neck Cancer • Melanoma • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • CD8 • IFNG • IL23A • TNFA

Harnessing the tumor immune microenvironment to control high-risk ductal carcinoma in situ: A phase I clinical trial of intralesional pembrolizumab and mRNA 2752 combination therapy (SABCS 2021) - "mRNA 2752 is a lipid nanoparticle encoding the cytokines IL-23, IL-36γ, and OX-40L that has been found to potentiate the efficacy of the PD-L1 inhibitor durvalumab in a prior phase I trial. A single injection of combination intralesional pembrolizumab-mRNA 2752 generated a clinically significant inflammatory reaction at the site of injection and systemically; however, this was not found to result in a significant decrease in the size of the DCIS lesion on breast MRI nor a significant increase in T cells at the injection site by the time of surgical resection. The use of oral methylprednisolone one week after the injection may have reduced T cell recruitment and activation."

Clinical • Combination therapy • P1 data • Breast Cancer • Oncology • CASP3 • HER-2 • MRI

Dose Escalation Study of mRNA-2752 for Intratumoral Injection to Participants in Advanced Malignancies (clinicaltrials.gov) - P1 | N=264 | Recruiting | Sponsor: ModernaTX, Inc. | Trial completion date: Jan 2023 ➔ Apr 2025 | Trial primary completion date: Jan 2023 ➔ May 2024

Checkpoint block • Checkpoint inhibition • Combination therapy • Metastases • Trial completion date • Trial primary completion date • Breast Cancer • Cutaneous Melanoma • Genito-urinary Cancer • Head and Neck Cancer • Hematological Malignancies • Immune Modulation • Inflammation • Lung Cancer • Lymphoma • Melanoma • Non Small Cell Lung Cancer • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • Urothelial Cancer • BRAF • PD-L1

Intralesional injection of anti-PD-1 (pembrolizumab) and OX40L/IL-23/IL-36 mRNAs (mRNA-2752) results in regression of DCIS characterized by lymphocytic infiltrates (SABCS 2022) - "The combination of intralesional pembro and mRNA-2752 demonstrated modulation of the tumor immune microenvironment and robust antitumor activity in high-risk DCIS (typically HR- or HER2+) with existing T cell infiltrates. This is an ongoing study; the optimal Phase 2 dose for the combination will be based on the totality of evolving safety and translational data."

Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Negative Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CD8 • HER-2 • IL23A • PD-L1

[VIRTUAL] A phase I study of mRNA-2752, a lipid nanoparticle encapsulating mRNAs encoding human OX40L, IL-23, and IL-36γ, for intratumoral (iTu) injection alone and in combination with durvalumab. (ASCO 2020) - P1 | "iTu mRNA-2752 given as monotherapy and in combination with durva is tolerable at all dose levels studied, and administration can be associated with tumor shrinkage. Analyses of tumor and plasma biomarkers suggest a sustained immunomodulatory effect of treatment that includes elevated IFN-γ, TNF-α, and PD-L1 levels. These data support the ongoing testing of the mRNA-2752/durva combination in the dose escalation part of the study."

Combination therapy • IO biomarker • P1 data • Bladder Cancer • Genito-urinary Cancer • Hematological Disorders • Hematological Malignancies • Immune Modulation • Inflammation • Oncology • Urothelial Cancer • IFNG • IL6

Phase 1 study of mRNA-2752, a lipid nanoparticle encapsulating mRNAs encoding human OX40L/IL-23/IL-36γ, for intratumoral (ITu) injection +/- durvalumab in advanced solid tumors and lymphoma (SITC 2021) - P1 | "PK/PD modeling supports QW dosing which is being explored in cutaneous melanoma in the neoadjuvant setting. Trial Registration NCT03739931"

IO biomarker • P1 data • Bladder Cancer • Cutaneous Melanoma • Diffuse Large B Cell Lymphoma • Genito-urinary Cancer • Hematological Malignancies • Lung Cancer • Lymphoma • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • Urothelial Cancer • IFNG • IL22 • IL6 • TNFA

Pembrolizumab in High-risk Ductal Carcinoma in Situ (DCIS) (clinicaltrials.gov) - P1 | N=48 | Recruiting | Sponsor: Laura Esserman | Trial completion date: Jun 2023 ➔ Mar 2024 | Trial primary completion date: Jun 2023 ➔ Mar 2024

Trial completion date • Trial primary completion date • Oncology • HER-2

Pembrolizumab in High-risk Ductal Carcinoma in Situ (DCIS) (clinicaltrials.gov) - P1 | N=48 | Recruiting | Sponsor: Laura Esserman | Trial completion date: Dec 2021 ➔ Jun 2023 | Trial primary completion date: Sep 2021 ➔ Jun 2023

Trial completion date • Trial primary completion date • Oncology • HER-2

Moderna Announces Presentation of Interim Data from Phase 1 Study of mRNA Triplet Program at 2021 SITC Annual Meeting (Businesswire) - P1, N=264; NCT03739931; Sponsor: ModernaTX, Inc.; "Moderna...announced interim data from an ongoing Phase 1 clinical study of mRNA-2752 (Triplet) in patients with accessible solid tumors and lymphomas. The data showed that the Company’s mRNA Triplet program given in combination with AstraZeneca’s durvalumab (IMFINZI®) was tolerated at all dose levels tested and elicited evidence of anti-tumor activity....Durable PRs seen in a PD-L1-low squamous-cell bladder cancer patient, and a Diffuse large B-cell lymphoma (DLBCL) after progression on CAR-T. Treatment response of the injected lesion was seen in a melanoma patient progressed on pembrolizumab and T-VEC."

P1 data • Bladder Cancer • Diffuse Large B Cell Lymphoma • Genito-urinary Cancer • Hematological Malignancies • Lymphoma • Melanoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • Urothelial Cancer

Moderna Reports Third Quarter Fiscal Year 2021 Financial Results and Provides Business Updates (Businesswire) - "Phase 2 randomized, placebo-controlled study of personalized cancer vaccine (PCV) (mRNA-4157) in combination with Merck’s pembrolizumab (KEYTRUDA®), compared to pembrolizumab alone, for the adjuvant treatment of high-risk resected melanoma is fully enrolled; data readout expected in the fourth quarter of 2022....OX40L/IL-23/IL-36γ (Triplet) (mRNA-2752): The Phase 1 trial evaluating mRNA-2752 as a single agent and in combination with durvalumab in patients with advanced solid tumor malignancies and lymphoma is fully enrolled. Enrollment in additional cohorts is ongoing...IL-12 (MEDI1191): The Phase 1 open-label, multi-center study of intratumoral injections of MEDI1191 alone and in combination with durvalumab in patients with advanced solid tumors, led by AstraZeneca, is ongoing."

Enrollment status • P2 data • Trial status • Hematological Malignancies • Lymphoma • Melanoma • Oncology • Solid Tumor

Dose Escalation Study of mRNA-2752 for Intratumoral Injection to Participants in Advanced Malignancies (clinicaltrials.gov) - P1; N=264; Recruiting; Sponsor: ModernaTX, Inc.; N=126 ➔ 264; Trial completion date: Jul 2021 ➔ Jan 2023; Trial primary completion date: Jul 2021 ➔ Jan 2023

Checkpoint inhibition • Clinical • Combination therapy • Enrollment change • Trial completion date • Trial primary completion date • Breast Cancer • Cutaneous Melanoma • Follicular Lymphoma • Genito-urinary Cancer • Head and Neck Cancer • Hematological Malignancies • Immune Modulation • Inflammation • Lung Cancer • Lymphoma • Melanoma • Non Small Cell Lung Cancer • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • Urothelial Cancer • BRAF

A Phase I, 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 (AACR 2019) - P1; "The study consists of 3 dose escalation and dose confirmation parts on 3 treatment arms: mRNA-2752 monotherapy, mRNA-2752 in combination with Durvalumab, and mRNA-2752 in combination with Tremelimumab. The study is open and enrolling. NCT03739931."

Checkpoint inhibition • Clinical • Combination therapy • IO Biomarker • PD(L)-1 Biomarker

Moderna Reports Second Quarter Fiscal Year 2021 Financial Results and Provides Business Updates (Businesswire) - “Discontinued further development of mRNA-2416, our standalone OX40L candidate; focus shifted to the development of mRNA-2752, which comprises mRNAs for OX40L plus two cytokines, IL23 + IL36γ.”

Clinical • Discontinued • Oncology

Sarah Cannon to present latest cancer research insights at ASCO20 Virtual Meeting (Businesswire) - "Sarah Cannon announced that it will present its latest cancer research insights at the American Society of Clinical Oncology’s (ASCO®) Annual Meeting being held virtually May 29 – 31, 2020. This year, Sarah Cannon’s drug development and research expertise is featured through more than 110 abstracts and presentations, including data from more than 50 phase 1 studies....Jesus Berdeja, MD...is the discussant on the plenary session focused on 'Carfilzomib, Lenalidomide, and Dexamethasone Versus Bortezomib, Lenalidomide, and Dexamethasone for Initial Therapy of Newly Diagnosed Multiple Myeloma' on Sunday, May 31 from 12-2:30 PM CT. Dr. Berdeja will also highlight data in an oral presentation on 'Update of CARTITUDE-1: A Phase Ib/II Study of JNJ-4528, a B-Cell Maturation Antigen-Directed CAR-T-Cell Therapy, in Relapsed/Refractory Multiple Myeloma.' (Abstract 8505)."

Clinical data • Breast Cancer • Diffuse Large B Cell Lymphoma • Genito-urinary Cancer • Gynecologic Cancers • Hematological Malignancies • Indolent Lymphoma • Lung Cancer • Multiple Myeloma • Non Small Cell Lung Cancer • Non-Hodgkin’s Lymphoma • Oncology • Ovarian Cancer • Prostate Cancer • Rectal Cancer • Small Cell Lung Cancer • Solid Tumor

Dose Escalation Study of mRNA-2752 for Intratumoral Injection to Participants With Advanced Malignancies (clinicaltrials.gov) - P1; N=126; Recruiting; Sponsor: ModernaTX, Inc.; Trial primary completion date: Jun 2020 ➔ Jul 2021

Checkpoint inhibition • Clinical • Combination therapy • Trial primary completion date • Breast Cancer • Follicular Lymphoma • Genito-urinary Cancer • Head and Neck Cancer • Hematological Malignancies • Immune Modulation • Inflammation • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • Urothelial Cancer

Novel Targets for the Treatment of Bladder Cancer (PracticeUpdate) - "Dr. Gupta: The androgen receptor is a compelling target because there is a lot of preclinical evidence that it is upregulated in bladder cancer. Targeting the androgen receptor, with androgen deprivation therapy or antiandrogen therapies, reduces the tumor volume and tumor growth in preclinical models....Another novel agent that we are very interested in is mRNA-2752, which is a lipid nanoparticle encapsulating mRNA encoding human OX40 Ligand....Now the study is focusing as a dose expansion cohort in bladder cancer because there is some preliminary activity that it works well, and this is now going to be in combination with the checkpoint inhibitor durvalumab. That is another novel exciting target to look at beyond the traditional immunotherapies that we have been using."

Interview • Video

Dose Escalation Study of mRNA-2752 for Intratumoral Injection to Patients With Advanced Malignancies (clinicaltrials.gov) - P1; N=126; Recruiting; Sponsor: ModernaTX, Inc.; Trial completion date: Nov 2021 ➔ Jul 2021

Checkpoint inhibition • Clinical • Combination therapy • PD(L)-1 Biomarker • Trial completion date

Newly published pre-clinical data show intratumoral injections of messenger RNA encoding three immune modulators stimulate durable anti-cancer responses in treated and distal tumors (Businesswire) - “Moderna, Inc…announced the publication of pre-clinical data that shows the therapeutic potential of mRNA-2752…The study showed that in a MC38-R mouse cancer model that is considered immunosuppressive and found to be unresponsive to checkpoint inhibitor immunotherapy…Moderna has advanced mRNA-2752 into a Phase 1 study…is evaluating the safety and tolerability of mRNA-2752 as a monotherapy or in combination with either AstraZeneca’s durvalumab (anti-PD-L1 antibody) or tremelimumab (anti-CTLA-4 antibody) and will assess anti-tumor activity, protein expression in tumors and pharmacokinetics and exploratory endpoints that include assessment of immunological response.”

Clinical protocol • Preclinical