Clinical Trials /

Safety, Tolerability, and Immunogenicity of mRNA-4157 Alone in Subjects With Resected Solid Tumors and in Combination With Pembrolizumab in Subjects With Unresectable Solid Tumors

NCT03313778

Description:

The purpose of this study is to assess the safety, tolerability and immunogenicity of mRNA-4157 alone in subjects with resected solid tumors, and in combination with pembrolizumab in subjects with unresectable solid tumors.

Related Conditions:
  • Bladder Carcinoma
  • Bladder Urothelial Carcinoma
  • Colorectal Carcinoma
  • Endometrial Carcinoma
  • Esophageal Adenocarcinoma
  • Gastric Adenocarcinoma
  • Malignant Solid Tumor
  • Melanoma
  • Non-Small Cell Lung Carcinoma
  • Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Safety, Tolerability, and Immunogenicity of mRNA-4157 Alone in Subjects With Resected Solid Tumors and in Combination With Pembrolizumab in Subjects With Unresectable Solid Tumors
  • Official Title: A Phase 1, Open-Label, Multicenter Study to Assess the Safety, Tolerability, and Immunogenicity of mRNA-4157 Alone in Subjects With Resected Solid Tumors and in Combination With Pembrolizumab in Subjects With Unresectable Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: mRNA-4157-P101
  • NCT ID: NCT03313778

Conditions

  • Solid Tumors

Interventions

DrugSynonymsArms
mRNA-4157Part A: Dose Escalation
PembrolizumabPart B: Dose Escalation

Purpose

The purpose of this study is to assess the safety, tolerability and immunogenicity of mRNA-4157 alone in subjects with resected solid tumors, and in combination with pembrolizumab in subjects with unresectable solid tumors.

Trial Arms

NameTypeDescriptionInterventions
Part A: Dose EscalationExperimentalmRNA-4157
  • mRNA-4157
Part B: Dose EscalationExperimentalmRNA-4157 + pembrolizumab
  • mRNA-4157
  • Pembrolizumab
Part B: Dose ExpansionExperimentalmRNA-4157 + pembrolizumab
  • mRNA-4157
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          -  Male or female, ≥ 18 years old with the ability to understand and provide signed and
             witnessed informed consent, and agree to comply with protocol requirements

          -  Part A: Subjects must have one of the histologically-confirmed solid malignancies
             listed below, must be clinically disease-free at study entry (i.e., subjects in the
             adjuvant setting). Subjects will be permitted to complete any standard of care
             adjuvant therapy prior to study entry, and those not eligible for any standard of care
             adjuvant treatment, or who decline such treatment, are permitted to consent to this
             study, as long as all treatment options have been transparently disclosed and
             documented in the Subject's medical record

          -  Part B: Subjects must have one of the histologically- or cytologically-confirmed
             unresectable (locally advanced or metastatic) solid malignancies listed below, AND
             have measurable disease at study entry defined by RECIST 1.1. AND be considered
             suitable for treatment with pembrolizumab; in this study pembrolizumab will be
             considered an investigational study drug.

        Subjects with any of the following solid malignancies:

        a. Non-small cell lung cancer (subjects in Part B must either lack EGFR sensitizing
        mutation or ALK translocation per local test results, or must have progressed on approved
        standard of care treatment for EGFR or ALK positive NSCLC) b. Small cell lung cancer c.
        Melanoma d. Bladder urothelial carcinoma e. Human papillomavirus-negative HNSCC f. Any
        solid malignancy known to be MSI high/MMR deficient per local test results, including but
        not limited to: CRC, stomach adenocarcinoma, esophageal adenocarcinoma and endometrial
        cancer

          -  Part C: Subjects must have one of the histologically‑ or cytologically confirmed
             unresectable (locally advanced or metastatic) solid malignancies listed below, AND
             must not have received prior anti‑PD‑1/PD-L1 therapy, AND must have measurable disease
             at study entry defined by RECIST 1.1

               1. MSS-CRC

               2. HPV negative metastatic or recurrent HNSCC of the oral cavity, oropharynx,
                  hypopharynx, or larynx

               3. Bladder urothelial carcinoma

          -  Part D: Subject must have completed resected adjuvant melanoma and must be clinically
             disease-free at study entry (i.e., subjects in the adjuvant setting). Subjects will be
             permitted to complete any standard of care adjuvant therapy prior to study entry, and
             those not eligible for any standard of care adjuvant treatment, or who decline such
             treatment, are permitted to consent to this study, as long as all treatment options
             have been transparently disclosed and documented in the subject's medical record

          -  Parts A and D: subjects must have a FFPE tumor sample available (e.g., from their
             prior surgery) that is suitable for the next generation sequencing (NGS) required for
             this study.

          -  Parts B and C: subjects must have at least 1 lesion amenable to the mandatory fresh
             tumor biopsy at study entry and provide a biopsy suitable for the NGS required for
             this study. An existing (archival) FFPE tumor sample may instead be used for NGS after
             discussing with medical monitor

          -  Subjects must have resolution of toxic effect(s) from prior therapy to Grade 1 or
             less. Subjects with ≤ Grade 2 neuropathy or alopecia are an exception to this
             criterion. If a subject received major surgery or radiation therapy of > 30 Gy, they
             must have recovered from the toxicity and/or complications from the intervention to
             Grade 1 or less

          -  Subject is willing to use an adequate method of contraception for the course of the
             study through 120 days after the last dose of study drug (male and female participants
             of childbearing potential)

          -  Subjects with PS of 0 or 1 on the ECOG Performance Scale

          -  Life expectancy > 12 weeks at Screening

          -  Subjects with adequate organ and marrow function

          -  Parts A and D: Subject must consent to required apheresis procedure and meet
             additional inclusion criteria per local institutional apheresis procedure

        Exclusion Criteria:

          -  Treatment with any of the following:

               1. Any investigational agents, anti-cancer monoclonal antibody, anti-cancer
                  therapeutic vaccine, immunostimulant (e.g. IL-2) or study drugs from a previous
                  clinical study within 4 weeks of the first dose of mRNA-4157 or pembrolizumab
                  (note only a 2 week wash out is required from prior pembrolizumab treatment)

               2. Any chemotherapy, targeted small molecule therapy, or radiation therapy within 2
                  weeks of the first dose of mRNA-4157 or pembrolizumab

               3. Live-virus vaccination within 30 days of the first dose of mRNA-4157 or
                  pembrolizumab. Seasonal flu vaccines that do not contain live virus are permitted

               4. Any systemic steroid therapy or other form of immunosuppressive therapy within 7
                  days of the first dose of mRNA-4157 or pembrolizumab

               5. Transfusion of blood products (including platelets or red blood cells[RBCs]) or
                  administration of colony stimulating factors (including G-CSF, GM-CSF or
                  recombinant erythropoietin) within 1 week of the NGS blood sample during
                  screening, and 4 weeks of the first dose of mRNA-4157 or pembrolizumab

          -  Prior PD-1/PD-L1 treatment is permitted for subjects in Parts A, B and D of this
             study, but only subjects who have progressed on their prior PD-1/PD-L1 treatment
             without a partial or complete response, and without discontinuing for drug-related
             toxicity are eligible

          -  Active central nervous system metastases and/or carcinomatous meningitis

          -  Active autoimmune disease that has required systemic treatment in past 2 years

          -  Has a history of (noninfectious) pneumonitis that required steroids or has current
             pneumonitis

          -  Has a diagnosis of immunodeficiency

          -  Any clinically-significant cardiac disease defined as New York Heart Association class
             III or IV within the past 6 months of Screening, unless, in the opinion of the
             Investigator, the disease is well-controlled

          -  A history or current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the study, interfere with the subject's
             participation for the full duration of the study, or is not in the best interest of
             the subject to participate, in the opinion of the treating Investigator

          -  Known psychiatric or substance abuse disorders that would interfere with cooperation
             with the requirements of the trial

          -  Previously identified hypersensitivity to components of the formulations used in this
             study

          -  Had a solid organ or allogeneic bone marrow transplant

          -  Subjects with a history of interstitial lung disease

          -  An active infection requiring systemic therapy

          -  A known history of HIV

          -  Known active Hepatitis B or Hepatitis C

          -  Known additional malignancy that is progressing or requires active treatment.
             Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
             skin that has undergone curative therapy or in situ cervical cancer

          -  Subjects participating in apheresis; mandatory in the Part A apheresis expansion phase
             cohort and Part D (optional for other study parts), must not meet any of the exclusion
             criteria on any day when apheresis is performed, either protocol specific apheresis
             criteria, or per local institutional apheresis protocol.
      
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
Time Frame:Parts A and B dose escalation Days 1-21
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Percentage change from baseline of biomarker levels in tumors
Time Frame:Baseline through Day 50
Safety Issue:
Description:
Measure:Antigen-specific T-cell responses in peripheral blood
Time Frame:Baseline through 100 days after last mRNA-4157 dose
Safety Issue:
Description:
Measure:Parts A and D: Relapse free survival (RFS): time between the date of first dose of mRNA-4157 and either radiological disease relapse, clinical/symptomatic disease relapse as assessed by the Investigator or death (whichever is sooner)
Time Frame:Baseline through 2 years after first mRNA-4157 dose
Safety Issue:
Description:
Measure:Parts B and C: Overall Response Rate (ORR): Percentage of patients with tumor response (partial or complete)
Time Frame:Baseline through 30 days after the last dose of pembrolizumab
Safety Issue:
Description:
Measure:Parts B and C: Duration of Response (DoR): time from first tumor response (partial or complete) until either radiological disease progression, clinical/symptomatic disease progression or death (whichever is sooner)
Time Frame:Baseline through 30 days after the last dose of pembrolizumab
Safety Issue:
Description:
Measure:Parts B and C: Progression free survival (PFS): time between the date of first dose of pembrolizumab and the date of either radiological disease progression, clinical/symptomatic disease progression or death (whichever is sooner)
Time Frame:Baseline through 30 days after the last dose of pembrolizumab
Safety Issue:
Description:
Measure:Parts B and C: Overall survival (OS): time between the date of the first dose of study drug and the date of death due to any cause
Time Frame:Baseline through 30 days after the last dose of pembrolizumab
Safety Issue:
Description:
Measure:Parts A, B, C, and D: Percent change in blood borne biomarkers (for example ctDNA and circulating cytokines) and potential correlation to clinical outcome
Time Frame:Baseline through 30 days after the last dose of pembrolizumab
Safety Issue:
Description:
Measure:Parts B, C, and D: Serum concentration of pembrolizumab
Time Frame:Pre-infusion until 30 days post last dose of pembrolizumab
Safety Issue:
Description:
Measure:Parts B, C, and D: Percentage of patients with anti-drug-antibodies (ADA's) to pembrolizumab
Time Frame:Pre-infusion until 30 days post last dose of pembrolizumab
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Moderna Therapeutics

Trial Keywords

  • mRNA-4157
  • Personalized cancer vaccine
  • PCV
  • pembrolizumab

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