Clinical Trial 21220

• Overview

  Study 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

  Summary:

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

  Objective:

  Primary Objectives: For Part A To determine the safety and tolerability of mRNA-4157 monotherapy in subjects with resected solid tumors. For Parts B, C and D To determine the safety, tolerability, and RP2D of mRNA-4157 administered in combination with pembrolizumab. Secondary Objectives: For Part A apheresis expansion cohort To assess the immunogenicity of mRNA-4157 from apheresis samples in subjects with resected solid tumors. For Part B biopsy expansion cohort To assess modulation of relevant biomarkers in tumors by mRNA- 4157 in combination with pembrolizumab. For Part C HNSCC cohort: To characterize preliminary antitumor activity of mRNA4157 in combination with pembrolizumab. For Part D To assess the immunogenicity of mRNA-4157 and pembrolizumab from apheresis samples in subjects with resected cutaneous melanoma.

• Treatments

  Therapies:

  Chemotherapy (NOS); Immunotherapy; Therapy (NOS)

  Medications:

  Pembrolizumab (Keytruda); mRNA-4157 ()

• 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: Participants must have one of the histologically-confirmed solid malignancies listed below, must be clinically disease-free at study entry (that is, participants in the adjuvant setting). Participants 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 participant's medical record.
  • Part B: Participants must have one of the histologically- or cytologically-confirmed unresectable (locally advanced or metastatic) solid malignancies listed below, have measurable disease at study entry defined by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1., and be considered suitable for treatment with pembrolizumab; in this study pembrolizumab will be considered an investigational study drug.
  • Participants with any of the following solid malignancies:
  • a. Non-small cell lung cancer (participants in Part B must either lack epidermal growth factor receptor (EGFR) sensitizing mutation or anaplastic lymphoma kinase (ALK) translocation per local test results or must have progressed on approved standard of care treatment for EGFR or ALK positive non-small cell lung cancer [NSCLC]) b. Small cell lung cancer c. Melanoma d. Bladder urothelial carcinoma e. Human papillomavirus-negative head and neck squamous cell carcinoma (HPV-ve HNSCC) f. Any solid malignancy known to be microsatellite instable (MSI) high/mismatch repair (MMR) deficient g. Any solid malignancy known to have a high tumor mutational load/burden
  • Part C: Participants must have one of the histologically- or cytologically confirmed unresectable (locally advanced or metastatic) solid malignancies listed below, must not have received prior anti-programmed cell death protein 1 (PD-1)/programmed death -ligand 1 (PD-L1) therapy, and must have measurable disease at study entry defined by RECIST 1.1.
  • Microsatellite stable (MSS)-CRC; or HPV-ve metastatic or recurrent HPV-ve HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx; or Bladder urothelial carcinoma
  • Part D: Participants must have completed resected adjuvant melanoma and must be clinically disease-free at study entry. Participants 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 participant's medical record.
  • Parts A and D: Participants must have a formalin-fixed paraffin embedded (FFPE) tumor sample available (for example, from their prior surgery) that is suitable for the next generation sequencing (NGS) required for this study.
  • Parts B and C: Participants must have at least 1 lesion amenable to the mandatory fresh tumor biopsy at study entry and provide a biopsy suitable for the next generation sequencing (NGS) required for this study.
  • Additional criteria will apply

• Exclusion Criteria

  • Treatment with any of the following:
  • 1. Any investigational agents, anti-cancer monoclonal antibody, anti-cancer therapeutic vaccine, immunostimulant (for example, 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 granulocyte colony stimulating factor [G-CSF], granulocyte/macrophage colony stimulating factor [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 participants in Parts A, B, and D of this study, but only participants 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 participation for the full duration of the study, or is not in the best interest of the participant 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
  • Participants with a history of interstitial lung disease
  • An active infection requiring systemic therapy
  • A known history of human immunodeficiency virus (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
  • Participants 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.

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