Study of Oral MRT-2359 in Selected Cancer Patients

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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NSCLC, SCLC, High Grade Neuroendocrine Cancer, DLBCL, L-MYC and N-MYC Amplified Solid Tumors, NSCLC With High or Low L-MYC or N-MYC Expression

Intervention / Treatment
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* Drug: Oral MRT-2359
* Drug: Oral MRT-2359
* Drug: Oral MRT-2359
* Drug: Oral MRT-2359


Participation Criteria
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Eligibility Criteria
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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 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 Dose Escalation<br>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<br>* Orally administered tablets of MRT-2359.<br>|
| Experimental: Phase 2 Expansion - NSCLC<br>Patients with NSCLC with high or low L-MYC or N-MYC expression | Drug: Oral MRT-2359<br>* Orally administered tablets of MRT-2359.<br>|
| Experimental: Phase 2 Expansion - SCLC<br>Patients with SCLC | Drug: Oral MRT-2359<br>* Orally administered tablets of MRT-2359.<br>|
| Experimental: Phase 2 Expansion - L-MYC or N-MYC amplified solid tumors<br>Patients with L-MYC or N-MYC amplified solid tumors | Drug: Oral MRT-2359<br>* Orally administered tablets of MRT-2359.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 | Measure Description | 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), DCR, PFS, and OS |  | 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, AUC0-inf, mean residence time, accumulation ratio, etc. |  | 28 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Small Cell Lung Cancer, Non-Small Cell Lung Cancer, L-MYC Amplification, N-MYC Amplification, L-MYC expression, N-MYC expression, High-grade neuroendocrine, Diffuse Large B-Cell Lymphoma, Molecular glue degrader, Anti-tumor, GSPT1