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

• ClinicalTrials.gov Identifier: NCT03323398
• Recruitment Status: Terminated
• First Posted: October 27, 2017
• Last Update Posted: July 11, 2022
• Sponsor: ModernaTX, Inc.
• Information provided by (Responsible Party): ModernaTX, Inc.

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Relapsed/Refractory Solid Tumor Malignancies or Lymphoma; Ovarian Cancer	Biological: mRNA-2416; Biological: Durvalumab	Phase 1; Phase 2

Detailed Description:

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 79 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1/2, Open-Label, Multicenter, Dose Escalation and Efficacy Study of mRNA-2416, a Lipid Nanoparticle Encapsulated mRNA Encoding Human OX40L, for Intratumoral Injection Alone or in Combination With Durvalumab for Patients With Advanced Malignancies
• Actual Study Start Date: August 15, 2017
• Actual Primary Completion Date: August 18, 2021
• Actual Study Completion Date: August 18, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm A: mRNA-2416 Alone; 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; mRNA encoding human OX40L
Experimental: Arm B: mRNA-2416 in Combination with Durvalumab; 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; mRNA encoding human OX40L; Biological: Durvalumab; PD-L1 inhibitor

Outcome Measures

Primary Outcome Measures :

1. Percentage of Participants Who Experienced Dose Limiting Toxicities (DLTs) [ Time Frame: Days 1-28 (Cycle 1) ]
2. Number of Participants with Adverse Events (AEs) and Serious AEs as Defined by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 [ Time Frame: Day 1 up to 90 days after the last dose of study treatment (duration of study treatment is up to 168 days) ]
3. Objective Response Rate (ORR) Based on RECIST v1.1 [ Time Frame: Day 1 through 6 months after the last dose of study treatment (duration of study treatment is up to 168 days), or until disease progression, whichever occurs first ]

Secondary Outcome Measures :

1. Percentage of Participants with Anti-OX40L Antibodies [ Time Frame: Predose on Day 1 and Day 15 of Cycle 1; predose on Day 1 of Cycles 2 and 3; predose on Day 15 of Cycle 3; predose on Day 1 of Cycles 4, 5, and 6; and End of Treatment (duration of study treatment is up to 168 days) ]
2. Maximum Observed Serum Concentration (Cmax) of mRNA-2416 Alone or in Combination with Durvalumab [ Time Frame: Predose on Day 1 of Cycle 1; 3, 6, 24, and 168 hours postdose on Day 1 of Cycle 1; and Predose on Day 1 of Cycle 2 (each cycle=28 days) ]
3. Area Under the Serum Concentration-Time Curve (AUC) of mRNA-2416 Alone or in Combination with Durvalumab [ Time Frame: Predose on Day 1 of Cycle 1; 3, 6, 24, and 168 hours postdose on Day 1 of Cycle 1; and Predose on Day 1 of Cycle 2 (each cycle=28 days) ]
4. Duration of Response Based on RECIST v1.1 [ Time Frame: Baseline through 6 months after last mRNA-2416 monotherapy dose ]
5. Disease Control Rate in Participants with Ovarian Cancer (RECIST v1.1) [ Time Frame: Baseline through 6 months after last dose of study treatment (duration of study treatment is up to 168 days) ]

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• 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.
• Male and female participants must agree to use a highly reliable method of birth control.
• Must have life expectancy of at least 12 weeks
• Body weight >30 kilograms (kg)

Exclusion Criteria:

• 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

• Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria

  • 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:

  • Medically uncontrolled hypertension
  • New York Heart Association Class III or IV cardiac disease
  • Myocardial infarction within prior 6 months
  • Unstable angina
  • Unstable arrhythmias or mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 milliseconds (ms) calculated from 3 electrocardiograms (ECGs) (within 15 minutes at 5 minutes apart)

• History of another primary malignancy except for:

  • Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of IP and of low potential risk for recurrence
  • Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
  • Adequately treated carcinoma in situ without evidence of disease
• Females who are pregnant or breastfeeding
• Any other unstable or clinically significant concurrent medical condition (for example, substance abuse, psychiatric illness/social situations, uncontrolled intercurrent illness including active infection, arterial thrombosis, symptomatic pulmonary embolism, active interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea) that would, in the opinion of the investigator, jeopardize the safety of a participant, impact their expected survival through the end of the study participation, and/or impact their ability to give written informed consent or comply with the protocol

• For participants who have received prior anti-programmed death 1 (PD-1) or anti-programmed death ligand 1 (PD-L1) therapy, a participant must not have experienced any of the following:

  • Must not have experienced a toxicity that led to permanent discontinuation of prior immunotherapy.
  • All AEs while receiving prior immunotherapy must have completely resolved or resolved to baseline prior to screening for this study.
• Must not have experienced a Grade ≥3 immune related AE or an immune related neurologic or ocular AE of any grade while receiving prior immunotherapy. Note: Participants with endocrine AEs of Grade ≤2 are permitted to enroll if they are stable while maintained on appropriate replacement therapy and are asymptomatic.
• Must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE, not have experienced recurrence of an AE if re-challenged, and not currently require maintenance doses of >10 milligrams (mg) prednisone or equivalent per day.
• Has an 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 RNA.
• Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
• Has a history of leptomeningeal carcinomatosis.
• Has involvement in the planning and/or conduct of the study.
• Must not plan to donate blood or blood components while participating in this study and through 90 days after the last dose of study treatment

Contacts and Locations

Locations

United States, Colorado

University of Colorado Hospital

Aurora, Colorado, United States, 80045

United States, Connecticut

Smilow Cancer Hospital

New Haven, Connecticut, United States, 06520

United States, Indiana

Northwestern Memorial Hospital

Indianapolis, Indiana, United States, 46202

United States, Massachusetts

Massachusetts General Hospital

Boston, Massachusetts, United States, 02114

Dana Farber Cancer Institute

Boston, Massachusetts, United States, 02215

United States, Minnesota

University of Minnesota Medical Center

Minneapolis, Minnesota, United States, 55455

United States, Oklahoma

University of Oklahoma Peggy and Charles Stephenson Cancer Center

Oklahoma City, Oklahoma, United States, 73104

United States, Rhode Island

Women & Infants Hospital

Providence, Rhode Island, United States, 02905

United States, Tennessee

Sarah Cannon Research Institute

Nashville, Tennessee, United States, 37203

Sponsors and Collaborators

ModernaTX, Inc.

More Information

• Responsible Party: ModernaTX, Inc.
• ClinicalTrials.gov Identifier: NCT03323398
• Other Study ID Numbers: mRNA-2416-P101
• First Posted: October 27, 2017
• Last Update Posted: July 11, 2022
• Last Verified: July 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by ModernaTX, Inc.:

mRNA-2416; OX40 ligand; OX40L; Moderna

Additional relevant MeSH terms:

Neoplasms; Durvalumab; Antineoplastic Agents, Immunological; Antineoplastic Agents