Clinical Trials /

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

NCT03323398

Description:

This clinical study will assess the safety and tolerability of escalating intratumoral doses of mRNA-2416 alone and in combination with intravenously administered flat doses of durvalumab in patients 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

Related Conditions:
  • Fallopian Tube Carcinoma
  • Lymphoma
  • Malignant Solid Tumor
  • Ovarian Carcinoma
  • Primary Peritoneal Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Dose Escalation and Efficacy Study of mRNA 2416 for Intratumoral Injection Alone and in Combination With Durvalumab for Patients With Advanced Malignancies
  • 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

Clinical Trial IDs

  • ORG STUDY ID: mRNA-2416-P101
  • NCT ID: NCT03323398

Conditions

  • Relapsed/Refractory Solid Tumor Malignancies or Lymphoma
  • Ovarian Cancer

Interventions

DrugSynonymsArms
mRNA-2416Arm A: mRNA-2416 alone
DurvalumabArm B: mRNA-2416 in combination with durvalumab

Purpose

This clinical study will assess the safety and tolerability of escalating intratumoral doses of mRNA-2416 alone and in combination with intravenously administered flat doses of durvalumab in patients 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

Detailed Description

      This is a first-in-human, Phase 1, 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 patients 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 in patients with ovarian cancer at the MTD/RDE as determined by the Dose
      Escalation period. Once the expected 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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A: mRNA-2416 aloneExperimentalmRNA-2416 escalating dose levels; expansion cohort
  • mRNA-2416
Arm B: mRNA-2416 in combination with durvalumabExperimentalmRNA-2416 in combination with durvalumab escalating dose levels; expansion cohort
  • mRNA-2416
  • Durvalumab

Eligibility 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. Patients must have received at least 2 prior lines
             of therapy. Patients with known BRCA mutation positive must have been treated with and
             progressed on at least 1 prior PARPi (poly(ADP-ribose) polymerase inhibitor)

          -  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). Patients must have a tumor lesion amenable to biopsy
                  and consent to a pre-treatment and an on-treatment biopsy. For patients with only
                  one lesion amenable to injection, biopsy, and RECIST assessment, the lesion must
                  be ≥ 2 cm

               -  Biopsy Cohort Enrichment: Patients 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

          -  Patients must have measurable disease as determined by RECIST v1.1 (solid tumors) or
             Cheson 2014 criteria (lymphomas).

             - Dose Expansion: Patients 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 patients of childbearing potential must have a negative serum pregnancy test
             during screening.

          -  Male and female patients must agree to use a highly reliable method of birth control.

          -  Must have life expectancy of at least 12 weeks

          -  Body weight > 30 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

               -  Patients with Grade ≥ 2 neuropathy will be evaluated on a case-by-case basis
                  after consultation with the Study Physician

               -  Patients 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 [eg, colitis or Crohn's disease], diverticulitis [with the
             exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or
             Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid
             arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this
             criterion:

               -  Patients with vitiligo or alopecia

               -  Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone
                  replacement

               -  Patients with any chronic skin condition that does not require systemic therapy

               -  Patients without active disease in the last 5 years may be included but only
                  after consultation with the Moderna medical monitor

               -  Patients 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: Patients, 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 ms calculated from 3 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 (eg,
             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, etc.) that would, in the opinion of the
             investigator, jeopardize the safety of a patient, 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 patients who have received prior anti-PD-1 or anti PD-L1 therapy, a patient 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:
             Patients 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 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). Patients with a past or resolved HBV infection (defined as the presence
             of hepatitis B core antibody [anti HBc] and absence of HBsAg) are eligible. Patients
             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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Percentage of subjects with dose limiting toxicities (DLTs) with mRNA-2416 alone
Time Frame:Days 1-28
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Percentage of subjects with anti-OX40L antibodies
Time Frame:Pre-dose through 14 days after last dose of study treatment
Safety Issue:
Description:
Measure:Maximum Observed Serum Concentration (Cmax) of mRNA-2416
Time Frame:Pre-dose through 29 days after initial mRNA-2416 dose
Safety Issue:
Description:
Measure:Maximum Observed Serum Concentration (Cmax) of mRNA-2416 alone
Time Frame:Pre-dose through 29 days after initial dose of study treatment
Safety Issue:
Description:
Measure:Area under the serum concentration-time curve (AUC) of mRNA-2416 alone
Time Frame:Pre-dose through 29 days after initial dose of study treatment
Safety Issue:
Description:
Measure:Area under the serum concentration-time curve (AUC) of mRNA-2416 in combination with durvalumab
Time Frame:Pre-dose through 29 days after initial dose of study treatment
Safety Issue:
Description:
Measure:In Phase I only: ORR based on RECIST v1.1 or Cheson 2014 criteria (lymphomas)
Time Frame:Baseline through 6 months after last mRNA-2416 monotherapy dose
Safety Issue:
Description:
Measure:In Phase I only: duration of response based on RECIST v1.1 or Cheson 2014 criteria (lymphomas)
Time Frame:Baseline through 6 months after last mRNA-2416 monotherapy dose
Safety Issue:
Description:
Measure:In Phase I only: progression-free survival based on RECIST v1.1 or Cheson 2014 criteria (lymphomas)
Time Frame:Baseline through 6 months after last mRNA-2416 monotherapy dose
Safety Issue:
Description:
Measure:Disease control rate in patients with ovarian cancer (RECIST v1.1)
Time Frame:Baseline through 6 months after last mRNA-2416 dose
Safety Issue:
Description:
Measure:In Phase II: disease control rate in patients with ovarian cancer (RECIST v1.1)
Time Frame:Baseline through 6 months after last dose of study treatment
Safety Issue:
Description:
Measure:In Phase II: duration of response in patients with ovarian cancer (RECIST v1.1)
Time Frame:Baseline through 6 months after last dose of study treatment
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:ModernaTX, Inc.

Trial Keywords

  • mRNA-2416
  • OX40 ligand
  • OX40L
  • Moderna

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