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

Phase 1

Terminated

Conditions: Relapsed/Refractory Solid Tumor Malignancies or Lymphoma
Ovarian Cancer

Interventions: Biological: mRNA-2416
Biological: Durvalumab

Registration Number: NCT03323398

Lead Sponsor: ModernaTX, Inc.

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.

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 79

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm A: mRNA-2416 Alone	mRNA-2416	Participants will be administered mRNA-2416 through an intratumoral injection at the applicable dose on Days 1 and 15 for six 28-day cycles.
Arm B: mRNA-2416 in Combination with Durvalumab	mRNA-2416	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.
Arm B: mRNA-2416 in Combination with Durvalumab	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.

Primary Outcome Measures

Name	Time	Method
Number of Participants Who Experienced Dose Limiting Toxicities (DLTs)	Days 1-28 (Cycle 1)	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.
Number of Participants With a Treatment-Emergent AEs (TEAE) or a Serious AE	Day 1 up to 90 days after the last dose of study treatment (maximum exposure=26.3 weeks)	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.
Objective Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1	Day 1 through 6 months after the last dose of study treatment, or until disease progression, whichever occurred first (maximum exposure=26.3 weeks)	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.

Secondary Outcome Measures

Name	Time	Method
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)	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.
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	Data are presented for number of participants with anti-OX40L antibodies. OX40L is the protein translated by the drug product.
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)	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.

Trial Locations

Locations (9): 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
University of Colorado Hospital
🇺🇸Aurora, Colorado, United States