Dose Escalation and Efficacy Study of mRNA-2416 for Intratumoral Injection Alone and in Combination With Durvalumab for Participants With Advanced Malignancies

NCT03323398 | Terminated Phase 1 Results DMC FDA Drug

• 1 other identifier: mRNA-2416-P101
• Study Type: interventional
• Target: 79
• Locations: 1 country
• Sites: 9

Brief Summary

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.

Conditions

Relapsed/Refractory Solid Tumor Malignancies or Lymphoma; Ovarian Cancer

Keywords

mRNA-2416; OX40 ligand; OX40L; Moderna

Outcome Measures

Primary Outcomes (3)

• 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.

  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.

  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.

  Day 1 through 6 months after the last dose of study treatment, or until disease progression, whichever occurred first (maximum exposure=26.3 weeks)

Secondary Outcomes (3)

• Duration of Response in Participants With Ovarian Cancer (RECIST Version 1.1)

  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)

  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

  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

Study Arms (2)

Arm A: mRNA-2416 Alone

EXPERIMENTAL

Participants will be administered mRNA-2416 through an intratumoral injection at the applicable dose on Days 1 and 15 for six 28-day cycles.

Biological: mRNA-2416

Arm B: mRNA-2416 in Combination with Durvalumab

EXPERIMENTAL

Participants will be administered mRNA-2416 through an intratumoral injection at the applicable dose on Days 1 and 15 of Cycle 1 and on Day 1 of Cycles 2 through 6 in combination with durvalumab through an intravenous infusion at a fixed dose on Day 1 of Cycles 1 through 6. The duration for each cycle is 28 days.

Biological: mRNA-2416; Biological: Durvalumab

Interventions

mRNA-2416 BIOLOGICAL

mRNA encoding human OX40L

Arm A: mRNA-2416 Alone; Arm B: mRNA-2416 in Combination with Durvalumab

Durvalumab BIOLOGICAL

PD-L1 inhibitor

Arm B: mRNA-2416 in Combination with Durvalumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent prior to completing any study-specific procedure
• Dose Escalation and Dose Confirmation Periods: Histologically- or cytologically-confirmed advanced/metastatic solid tumor or lymphoma by pathology report and who has received, or been intolerant to, all approved therapies
• Dose Expansion Period: Histologically or cytologically confirmed diagnosis of: epithelial cancer of the ovary, fallopian tube, or peritoneum which is platinum resistant or platinum refractory. Participants must have received at least 2 prior lines of therapy. Participants with known Breast Cancer gene 1 (BRCA) mutation positive must have been treated with and progressed on at least 1 prior poly\[ADP-ribose\] polymerase inhibitor (PARPi)
• Lesions for intratumoral injection and biopsies:
• Dose Escalation: A minimum of one lesion that is easily accessible for injection where easily accessible is defined as a cutaneous or subcutaneous mass that is palpable and/or visualizable by ultrasound
• Dose Confirmation: A minimum of one visceral lesion injectable with ultrasound or computer tomography (CT) guidance and that is not encasing or abutting major vascular structures or are in a location that are considered high risk for AEs by the enrolling physician
• Dose Expansion: A minimum of one lesion amenable to injection (either non-visceral or visceral). Participants must have a tumor lesion amenable to biopsy and consent to a pre-treatment and an on-treatment biopsy. For participants with only one lesion amenable to injection, biopsy, and RECIST assessment, the lesion must be ≥2 centimeters (cm)
• Biopsy Cohort Enrichment: Participants must have a tumor lesion amenable to biopsy and consent to a pre-treatment and an on-treatment biopsy
• All lesion(s) targeted for the initial injection must be ≥0.5 cm on longest diameter, be at least 5 mm thick, and have distinct borders based on exam or imaging, not close to critical structures such as major vessels, nerves, or airways
• Participants must have measurable disease as determined by RECIST v1.1 (solid tumors) or Cheson 2014 criteria (lymphomas).
• \- Dose Expansion: Participants must have at least 1 measurable lesion per RECIST v1.1 which has not been previously irradiated
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤1
• Adequate hematological and biological function
• Adequate thyroid function: Thyroid-stimulating hormone within normal range.
• Female participants of childbearing potential must have a negative serum pregnancy test during screening.

You may not qualify if:

• Active central nervous system tumors or metastases
• Treatment with chemotherapy, radiation (local radiation for palliative care is permitted), hormonal anti-cancer treatment, or biologic therapy \<14 days prior to the first day of study treatment (Cycle 1 Day 1 \[C1D1\]). Treatment with any other investigational agent or treatment with any anti-cancer monoclonal antibody, immunostimulant, or vaccine \<28 days prior to C1D1
• Participants with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician
• Participants with irreversible toxicity not reasonably expected to be exacerbated by the treatment with durvalumab may be included only after consultation with the Study Physician
• Has active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[for example, colitis or Crohn's disease\], diverticulitis \[with the exception of diverticulosis\], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome \[for example, granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis\]). The following are exceptions to this criterion:
• Participants with vitiligo or alopecia
• Participants with hypothyroidism (for example, following Hashimoto syndrome) stable on hormone replacement
• Participants with any chronic skin condition that does not require systemic therapy
• Participants without active disease in the last 5 years may be included but only after consultation with the Moderna medical monitor
• Participants with celiac disease controlled by diet alone
• Has a history of primary immunodeficiency, allogenic solid organ transplantation, or tuberculosis
• Receipt of live attenuated vaccine within 30 days prior to the first dose of study treatment. Note: Participants, if enrolled, should not receive live vaccine whilst receiving study treatment and up to 30 days after the last dose of study treatment.
• History of human immunodeficiency virus infection
• Active/chronic hepatitis B or C
• Any of the following cardiac abnormalities:

Sponsors & Collaborators

• ModernaTX, Inc.: lead

Study Sites (9)

University of Colorado Hospital

Aurora, Colorado, 80045, United States

Location

Smilow Cancer Hospital

New Haven, Connecticut, 06520, United States

Location

Northwestern Memorial Hospital

Indianapolis, Indiana, 46202, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

University of Minnesota Medical Center

Minneapolis, Minnesota, 55455, United States

Location

University of Oklahoma Peggy and Charles Stephenson Cancer Center

Oklahoma City, Oklahoma, 73104, United States

Location

Women & Infants Hospital

Providence, Rhode Island, 02905, United States

Location

Sarah Cannon Research Institute

Nashville, Tennessee, 37203, United States

Location

MeSH Terms

Conditions

Recurrence; Lymphoma; Ovarian Neoplasms

Interventions

durvalumab

Condition Hierarchy (Ancestors)

Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Endocrine Gland Neoplasms; Neoplasms by Site; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Genital Diseases; Endocrine System Diseases; Gonadal Disorders

Limitations and Caveats

This study was halted prematurely because the efficacy endpoints were not met for either treatment arm.

Results Point of Contact

• Title: Moderna Clinical Trials Support Center
• Organization: ModernaTX, Inc.

clinicaltrials@modernatx.com

1-877-777-7187

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 23, 2017
• First Posted: October 27, 2017
• Study Start: August 15, 2017
• Primary Completion: August 18, 2021
• Study Completion: August 18, 2021
• Last Updated: July 31, 2024
• Results First Posted: July 31, 2024

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (9)