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 (KEYNOTE-603)

• ClinicalTrials.gov Identifier: NCT03313778
• Recruitment Status: Recruiting
• First Posted: October 18, 2017
• Last Update Posted: March 30, 2020
• Sponsor: ModernaTX, Inc.
• Collaborator: Merck Sharp & Dohme Corp.
• Information provided by (Responsible Party): ModernaTX, Inc.

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Solid Tumors	Biological: mRNA-4157; Biological: Pembrolizumab	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 90 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: August 14, 2017
• Estimated Primary Completion Date: December 2020
• Estimated Study Completion Date: June 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Part A: Dose Escalation; mRNA-4157	Biological: mRNA-4157; Personalized cancer vaccine
Experimental: Part B: Dose Escalation; mRNA-4157 + pembrolizumab	Biological: mRNA-4157; Personalized cancer vaccine; Biological: Pembrolizumab; intravenous infusion
Experimental: Part B: Dose Expansion; mRNA-4157 + pembrolizumab	Biological: mRNA-4157; Personalized cancer vaccine; Biological: Pembrolizumab; intravenous infusion
Experimental: Part B, C, and D: Dose Expansion; mRNA-4157 + pembrolizumab	Biological: mRNA-4157; Personalized cancer vaccine; Biological: Pembrolizumab; intravenous infusion

Outcome Measures

Primary Outcome Measures :

1. Percentage of subjects with dose limiting toxicities [ Time Frame: Parts A and B dose escalation Days 1-21 ]
2. Percentage of subjects with adverse events [ Time Frame: Part A: baseline through 100 days after last mRNA-4157 dose; Parts B, C, and D: baseline through 90 days after last pembrolizumab dose ]

Secondary Outcome Measures :

1. Percentage change from baseline of biomarker levels in tumors [ Time Frame: Baseline through Day 50 ]
2. Antigen-specific T-cell responses in peripheral blood [ Time Frame: Baseline through 100 days after last mRNA-4157 dose ]
3. 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 ]
4. 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 ]
5. 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 ]
6. 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 ]
7. 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 ]
8. 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 ]
9. Parts B, C, and D: Serum concentration of pembrolizumab [ Time Frame: Pre-infusion until 30 days post last dose of pembrolizumab ]
10. 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 ]

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:

• 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.

Contacts and Locations

Contacts

Contact: Moderna Clinical Trials; 855-663-6762; clinicaltrials@modernatx.com

Locations

United States, Arizona

University of Arizona; Recruiting

Tucson, Arizona, United States, 85721

Contact 520-694-9057

United States, Florida

Florida Cancer Specialists; Recruiting

Sarasota, Florida, United States, 34232

Contact 352-339-7000

United States, Massachusetts

Massachusetts General Hospital; Recruiting

Boston, Massachusetts, United States, 02114

Contact 877-726-5130

United States, New Jersey

John Theurer Cancer Center; Recruiting

Hackensack, New Jersey, United States, 07601

Contact 551-996-5855

United States, New York

NYU Langone; Recruiting

New York, New York, United States, 10016

Contact 212-263-4432

United States, North Carolina

Duke Cancer Institute; Recruiting

Durham, North Carolina, United States, 27710

Contact 888-275-3853

United States, Tennessee

Sarah Cannon Research Institute, Tennessee Oncology; Recruiting

Nashville, Tennessee, United States, 37203

Contact 615-514-2401

Sponsors and Collaborators

ModernaTX, Inc.

Merck Sharp & Dohme Corp.

More Information

• Responsible Party: ModernaTX, Inc.
• ClinicalTrials.gov Identifier: NCT03313778
• Other Study ID Numbers: mRNA-4157-P101
• First Posted: October 18, 2017
• Last Update Posted: March 30, 2020
• Last Verified: March 2020

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-4157; Personalized cancer vaccine; PCV; pembrolizumab; Moderna

Additional relevant MeSH terms:

Neoplasms; Pembrolizumab; Antineoplastic Agents, Immunological; Antineoplastic Agents