Study of Oral MRT-2359 in Selected Cancer Patients

A Phase 1/2 Study of Oral MRT-2359 in Patients With MYC-Driven and Other Selected Solid Tumors Including Lung Cancer and Diffuse B-Cell Lymphoma

This Phase 1/2, open-label, multicenter study is conducted in patients with previously treated selected solid tumors, including non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), high-grade neuroendocrine cancer of any primary site, diffuse large B-cell lymphoma (DLBCL), and tumors with L-MYC or N-MYC amplification. Patients receive escalating doses of a GSPT1 molecular glue degrader MRT-2359 to determine safety, tolerability, maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of MRT-2359. Once the MTD and/or RP2D is identified, additional patients enroll to Phase 2 study, which includes molecular biomarkers stratification or selection, namely expression or amplification of L-MYC and N-MYC genes, hormone receptor positive (HR)-positive, human epidermal growth factor 2 (HER2)-negative breast cancer and prostate cancer.

Study Overview

• Status: Active, not recruiting
• Conditions: NSCLC; Prostate Cancer; SCLC; DLBCL; High Grade Neuroendocrine Cancer; L-MYC and N-MYC Amplified Solid Tumors; NSCLC With High or Low L-MYC or N-MYC Expression; HR-positive, HER2-negative Breast Cancer
• Intervention / Treatment: Drug: Oral MRT-2359; Drug: Oral MRT-2359; Drug: Oral MRT-2359

Detailed Description

This Phase 1/2, open-label, multicenter, dose escalation and expansion study to assess the safety, tolerability, pharmacokinetic (PK), pharmacodynamic (PD), and preliminary clinical activity of MRT-2359 in patients with previously treated selected solid tumors, including lung cancer (NSCLC and SCLC), high-grade neuroendocrine cancer of any primary site, and DLBCL.

• The primary aim of Phase 1 part is safety, tolerability, MTD and/or RP2D of MRT-2359.
• The primary aim of Phase 2 part is assessment of preliminary anti-tumor activity of MRT-2359.

• Study Type: Interventional
• Enrollment (Estimated): 174
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85258
      • Honor Health Research Institute
  • California
    • San Diego, California, United States, 92037
      • University of California San Diego
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale University
  • Kansas
    • Lawrence, Kansas, United States, 66044
      • University of Kansas Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Cancer Institute
    • Grand Rapids, Michigan, United States, 49546
      • South Texas Accelerated Research Therapeutics (START) Midwest
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Washington University
  • New York
    • New York, New York, United States, 10021
      • Memorial Sloan Kettering Cancer Center
    • New York, New York, United States, 10032
      • Columbia University Irving Medical Centre
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute
  • Texas
    • Dallas, Texas, United States, 75251
      • Mary Crowley Cancer Research
    • Houston, Texas, United States, 77030-4009
      • MD Anderson Cancer Center
    • San Antonio, Texas, United States, 78229
      • South Texas Accelerated Research Therapeutics (START)
  • Utah
    • West Valley City, Utah, United States, 84119
      • South Texas Accelerated Research Therapeutics (START) Mountain Region
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Virginia Cancer Specialists Research Institute
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutchinson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Phase 1 enrollment population:

• NSCLC
• SCLC
• High-grade neuroendocrine cancer of any primary site
• Any solid tumors with L-MYC or N-MYC amplification
• DLBCL

Phase 2 enrollment population:

• Any solid tumors with L-MYC or N-MYC amplification
• NSCLC with high or low L-MYC or N-MYC expression status (testing will be provided) or SCLC
• HR-positive, HER2-negative breast cancer - MRT-2359 in combination with fulvestrant
• Non-neuroendocrine prostate cancer - MRT-2359 in combination with enzalutamide

Phase 1 and Phase 2 Inclusion Criteria:

• Have a selected advanced solid tumor or DLBCL (listed above) for which there are no further standard therapeutic options available
• Be age ≥ 18 years and willing to voluntarily complete the informed consent process
• A predicted life expectancy of ≥ 3 months and an ECOG performance status ≤ 2
• Have measurable disease by RECIST 1.1 (Eisenhauer et al., 2009) in case of solid tumors or Revised Response Criteria for Malignant Lymphoma (Phase 1 only) (Cheson et al., 2014) in case of DLBCL
• Have adequate organ function defined by the selected laboratory parameters
• If female of childbearing potential, avoid becoming pregnant and agree to use acceptable methods of contraception after informed consent, throughout the study, and for 90 days after the last dose of MRT-2359
• Male of reproductive potential must use an approved methods of contraception from informed consent until 90 days after study discharge

Exclusion Criteria:

• Have received prior chemotherapy, definitive radiation, biological cancer therapy or any investigational agent within 21 days before the first dose of study treatment, or have any AEs that have failed to recover to baseline. In patients with prostate cancer, continuance of systemic therapies to maintain castration levels of testosterone is allowed. Pre-menopausal patients with hormone-dependent breast cancer can continue on therapies used for suppression of ovarian function.
• Have received bisphosphonates or denosumab within 14 days before the first administration of the study drug unless they were given for acute hypercalcemia
• Inability to swallow oral medication
• Have received prior therapy with a GSPT1 degrader that was discontinued due to an AE
• Have received prior auto-HCT and not fully recovered from effects of the last transplant
• Have received prior allogeneic hematopoietic stem cell transplantation within past 6 months and/or have symptoms of graft-versus-host disease. Patients requiring minimal intervention such as topical steroids are eligible
• Have received a live vaccine within 90 days before the first dose of study treatment
• COVID-19 immunization within 14 days of receiving the first dose of MRT-2359
• Current use of chronic systemic steroid therapy in excess of replacement doses (prednisone ≤ 10 mg/day is acceptable)
• Have clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal absorption of the study drug
• Have a history of a second malignancy, unless controlled not requiring therapy
• Have clinically active central nervous system involvement and/or carcinomatous meningitis. Patients with treated and stable brain metastases (not progressing for at least 4 weeks prior to enrollment) not requiring steroids are eligible
• Have a confirmed history of (non-infectious) pneumonitis that required steroids
• Have known human immunodeficiency virus (HIV) unless the patient is on antiviral therapy with undetectable HIV RNA levels
• Have known hepatitis B or C infection(s) unless treated with undetectable hepatitis B DNA or hepatitis C RNA levels
• Clinically significant cardiac disease
• Be pregnant or breastfeeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 1 Dose Escalation; Patients with NSCLC, SCLC, high-grade neuroendocrine cancer of any primary site, any solid tumors with L-MYC or N-MYC amplification, or DLBCL	Drug: Oral MRT-2359; Orally administered tablets of MRT-2359.; Drug: Oral MRT-2359; Orally administered tablets of MRT-2359 in conjunction with intramuscular administration of fulvestrant.; Drug: Oral MRT-2359; Orally administered tablets of MRT-2359 in conjunction with orally administered enzalutamide.
Experimental: Phase 2 Expansion - L-MYC or N-MYC amplified solid tumors; Patients with L-MYC or N-MYC amplified solid tumors	Drug: Oral MRT-2359; Orally administered tablets of MRT-2359.; Drug: Oral MRT-2359; Orally administered tablets of MRT-2359 in conjunction with intramuscular administration of fulvestrant.; Drug: Oral MRT-2359; Orally administered tablets of MRT-2359 in conjunction with orally administered enzalutamide.
Experimental: Phase 2 Expansion - NSCLC; Patients with NSCLC with high or low L-MYC or N-MYC expression	Drug: Oral MRT-2359; Orally administered tablets of MRT-2359.; Drug: Oral MRT-2359; Orally administered tablets of MRT-2359 in conjunction with intramuscular administration of fulvestrant.; Drug: Oral MRT-2359; Orally administered tablets of MRT-2359 in conjunction with orally administered enzalutamide.
Experimental: Phase 2 Expansion - SCLC; Patients with SCLC	Drug: Oral MRT-2359; Orally administered tablets of MRT-2359.; Drug: Oral MRT-2359; Orally administered tablets of MRT-2359 in conjunction with intramuscular administration of fulvestrant.; Drug: Oral MRT-2359; Orally administered tablets of MRT-2359 in conjunction with orally administered enzalutamide.
Experimental: Phase 2 Expansion - HR-positive, HER2-negative breast cancer; Patients with HR-positive, HER2-negative breast cancer in combination with fulvestrant	Drug: Oral MRT-2359; Orally administered tablets of MRT-2359.; Drug: Oral MRT-2359; Orally administered tablets of MRT-2359 in conjunction with intramuscular administration of fulvestrant.; Drug: Oral MRT-2359; Orally administered tablets of MRT-2359 in conjunction with orally administered enzalutamide.
Experimental: Phase 2 Expansion - Prostate Cancer; Patients with prostate cancer in combination with enzalutamide	Drug: Oral MRT-2359; Orally administered tablets of MRT-2359.; Drug: Oral MRT-2359; Orally administered tablets of MRT-2359 in conjunction with intramuscular administration of fulvestrant.; Drug: Oral MRT-2359; Orally administered tablets of MRT-2359 in conjunction with orally administered enzalutamide.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Phase 1 Evaluates safety and tolerability of MRT-2359 over a 28-day cycle by the occurrence and frequency of dose limiting toxicities (DLTs) for determination of the MTD and/or RP2D	28 days
Phase 2 Evaluates preliminary anti-tumor activity of MRT-2359 by overall response rate (ORR) as determined by RECIST 1.1	56 days (up to approximately 24 months from screening to end of study participation

Secondary Outcome Measures

Outcome Measure	Time Frame
Phase 1 safety and tolerability of MRT-2359 (orally over a 28-day cycle) by the nature, incidence, and severity of all treatment-emergent adverse events (TEAEs), including treatment-related TEAEs and serious adverse events (SAEs)	18 months
Phase 1 preliminary anti-tumor activity: ORR (RECIST 1.1/Revised Response Criteria for Malignant Lymphoma),duration of response for complete response(CR)/partial response(PR), disease control rate, progression-free survival, overall survival	18 months
Phase 1 Dose Escalation characterizes the PK profile of MRT-2359 by standard primary PK parameters including, but not limited to, AUC, Cmax, tmax, and t1/2	28 days
Phase 1 Dose Escalation evaluates the effect of a high-fat meal on the relative bioavailability of MRT-2359 by standard primary PK parameters including, but not limited to, AUC and Cmax	7 days
Phase 2 Dose Expansion evaluates the safety and tolerability of MRT-2359 administered orally over a 28-day cycle by the nature, incidence, and severity of all TEAEs, including treatment-related TEAEs and SAEs according to the NCI CTCAE, version 5.0	24 months
Phase 2 Dose Expansion evaluates additional measures of the preliminary anti-tumor activity of MRT-2359 such as DoR (in patients with the best overall response of CR or PR)	24 months
Phase 2 Dose Expansion further characterizes the PK profile of MRT-2359 by evaluating MRT-2359 plasma concentration to establish PK parameters including, but not limited to, Cmax, tmax, AUC0-t, AUC0inf, mean residence time, accumulation ratio, etc.	28 days
Phase 2 Dose Expansion evaluates additional measures of the preliminary anti-tumor activity of MRT-2359 such as DCR	24 months
Phase 2 Dose Expansion evaluates additional measures of the preliminary anti-tumor activity of MRT-2359 such as PFS	24 months
Phase 2 Dose Expansion evaluates additional measures of the preliminary anti-tumor activity of MRT-2359 such as OS	24 months
Phase 2 Dose Expansion evaluates additional measures of the preliminary anti-tumor activity of MRT-2359 such as PSA response	24 months

Collaborators and Investigators

• Sponsor: Monte Rosa Therapeutics, Inc

Study record dates

Study Major Dates

• Study Start (Actual): October 12, 2022
• Primary Completion (Estimated): May 1, 2026
• Study Completion (Estimated): November 1, 2027

Study Registration Dates

• First Submitted: September 16, 2022
• First Submitted That Met QC Criteria: September 16, 2022
• First Posted (Actual): September 19, 2022

Study Record Updates

• Last Update Posted (Actual): March 3, 2026
• Last Update Submitted That Met QC Criteria: February 27, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Breast Cancer; Non-Small Cell Lung Cancer; Prostate Cancer; Small Cell Lung Cancer; Diffuse Large B-Cell Lymphoma; HER2-negative; Anti-tumor; HR-positive; GSPT1; L-MYC Amplification; N-MYC Amplification; L-MYC expression; N-MYC expression; High-grade neuroendocrine; Molecular glue degrader
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Prostatic Diseases; Male Urogenital Diseases; Immune System Diseases; Respiratory Tract Diseases; Neoplasms by Histologic Type; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Skin Diseases; Breast Diseases; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma, B-Cell; Lymphoma; Carcinoma, Bronchogenic; Bronchial Neoplasms; Skin and Connective Tissue Diseases; Hemic and Lymphatic Diseases; Prostatic Neoplasms; Breast Neoplasms; Lymphoma, Large B-Cell, Diffuse; Carcinoma, Non-Small-Cell Lung; Small Cell Lung Carcinoma
• Other Study ID Numbers: MRT-2359-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No