An open-label, multicenter, Phase 1b/2a study to evaluate efficacy, safety, tolerability, and pharmacokinetics of the ATR inhibitor Tuvusertib (M1774) in combination with cemiplimab in participants with non-squamous non-small cell lung cancer that has progressed on prior anti-PD-(L)1 and platinum-based therapies (DDRiver NSCLC 322)
- Trial ID
- 2022-502010-85-00
- Protocol
- MS201924_0022
- Sponsor
- Merck Healthcare KGaA
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** in terms of objective response (OR), as well as the **safety** and **tolerability** of the ATR inhibitor Tuvusertib in combination with cemiplimab in participants with non-squamous non-small cell lung cancer (NSCLC) that has progressed following prior anti-PD-(L)1 and platinum-based therapies. This assessment is crucial for determining the optimal dosing regimen for the subsequent Phase 2a part of the study, thereby potentially improving therapeutic strategies for this patient population.
Secondary objectives include:
- Phase 1b: Assessing efficacy in terms of duration of response (DoR), progression-free survival (PFS), and overall survival (OS) with Tuvusertib in combination with cemiplimab, both with and without subsequent anticancer therapy.
- Phase 2a: Evaluating efficacy in terms of DoR, PFS, and OS with Tuvusertib in combination with cemiplimab, irrespective of subsequent anticancer therapy, and assessing the safety and tolerability of the combination.
Participants
The clinical trial involves a total of **85 participants** diagnosed with **Non-Squamous Non-Small Cell Lung Cancer**. The study population includes both male and female subjects who are **18 years of age or older**. Participants were selected based on specific criteria, including a histologically or cytologically confirmed diagnosis of the disease and documented disease progression during or after certain systemic therapies. The trial includes individuals with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants must have adequate hematological, hepatic, and renal function. The trial population is not limited by gender, and both male and female subjects are included. The study also considers vulnerable populations. Lifestyle factors such as diet and physical activity are not specified in the available data. Key inclusion criteria include measurable disease per RECIST v1.1 and the availability of archival FFPE tumor tissue or tumor genomic profiling. The trial does not specify any exclusion criteria in the provided data.
Plans and Procedures
The clinical trial is designed as an open-label, multicenter, Phase 1b/2a study to evaluate the efficacy, safety, tolerability, and pharmacokinetics of the ATR inhibitor **Tuvusertib** (M1774) in combination with **cemiplimab** in participants with non-squamous non-small cell lung cancer (NSCLC) that has progressed on prior anti-PD-(L)1 and platinum-based therapies. The trial employs a randomized, controlled methodology, with the primary objective of assessing the objective response (OR) and safety profile of the combination therapy. The trial is expected to conclude by October 2025, with recruitment starting in October 2023.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis, and previous treatment history. The screening will ensure participants have measurable disease per RECIST v1.1 and adequate organ function. Following the screening, participants will be enrolled in the trial and will attend regular follow-up visits to monitor treatment response and adverse events. The end-of-study visit will occur after the completion of the treatment regimen or upon early termination.
The expected length of participant involvement in the trial is contingent upon the progression of the disease and the individual's response to the treatment. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. The trial aims to provide comprehensive data on the duration of response, progression-free survival, and overall survival, contributing to the selection of an optimal dosing regimen for future studies.
Treatment
The clinical trial involves the administration of the experimental medication **M1774**, which is a small chemical molecule formulated as a hard capsule. The active substance in M1774 is **2-amino-6-fluoro-N-(5-fluoro-4-(1-methyl-1H-imidazol-5-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide**. This compound is administered orally. The pharmaceutical form of M1774 is consistent across all participants, ensuring uniformity in the delivery method. The dosing schedule and frequency of administration are determined based on the study protocol, with compliance monitored through standard clinical trial procedures. M1774 is not a pediatric formulation and is not classified as an orphan drug.
In addition to M1774, the trial includes the administration of **LIBTAYO 350 mg concentrate for solution for infusion**, which contains the active substance **cemiplimab**. Cemiplimab is a protein-based therapeutic agent, specifically categorized under the ATC code L01XC33. LIBTAYO is administered as a solution for infusion, with the route of administration being intravenous. The dosing regimen for LIBTAYO is designed to complement the administration of M1774, and participant compliance is monitored through infusion records and clinical assessments. LIBTAYO is not a pediatric formulation and is not designated as an orphan drug. The combination of M1774 and LIBTAYO aims to evaluate the efficacy, safety, and tolerability in participants with non-squamous non-small cell lung cancer that has progressed on prior anti-PD-(L)1 and platinum-based therapies.
Efficacy
The efficacy of the clinical trial will be assessed through several primary and secondary endpoints. The primary endpoints include the **Confirmed Overall Response (OR)** according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, as assessed by the investigator, and the number of participants with adverse events (AEs) and treatment-related AEs during Phase 1b. Secondary endpoints encompass the **Duration of Response (DoR)**, **Progression-Free Survival (PFS)**, and **Overall Survival (OS)**, all evaluated according to RECIST 1.1 by the investigator. Additionally, the number of participants with AEs and treatment-related AEs will be recorded in Phase 2a.
The trial will utilize the Guardant360 CDx v2 device, a central liquid biopsy assay, to analyze tumor molecular alterations. This tool will be instrumental in the central liquid biopsy analysis required for the Phase 2a part of the study. The efficacy assessments will be conducted at various timepoints throughout the trial, although specific timepoints are not detailed in the provided data. The trial aims to evaluate the efficacy of the ATR inhibitor Tuvusertib (M1774) in combination with cemiplimab in participants with non-squamous non-small cell lung cancer (nsqNSCLC) that has progressed on prior anti-PD-(L)1 and platinum-based therapies.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Are ≥ 18 years of age at the time of signing the informed consent
- Are diagnosed with nsqNSCLC histologically or cytologically confirmed
- Radiologically confirmed/documented disease progression during or after the following systemic therapies (all required): •a. At most, 1 line of anti-PD-(L)1 therapy for locally advanced or metastatic disease. Note 1: Rechallenge with the same anti-PD-(L)1 for disease considered sensitive to anti-PD-(L)1 therapy (e.g. after a treatment break) is considered 1 line. Note 2: this includes (neo)adjuvant anti-PD-(L)1 therapy for locally advanced disease, provided disease progression occurs within 16 weeks of the last dose of anti-PD-(L)1 therapy. •b. Platinum-based therapy for locally advanced or metastatic disease, given in combination or sequentially with anti-PD-(L)1 therapy. Participants who received (neo)adjuvant platinum-based therapy meet this criterion if disease progression occurred within 6 months from the last dose that the participant received that therapy. No additional cytotoxic therapies after progression on platinum-based therapy are allowed •c. Prior best overall response of stable disease or better with anti-PD-(L)1 therapy •d. Disease progression must have occurred while the participant has been receiving anti-PD-(L)1 therapy or within 16 weeks of the last dose of anti-PD-(L)1 therapy
- Measurable disease per RECIST v1.1, as assessed by the Investigator
- ECOG PS 0 or 1
- Adequate hematological, hepatic and renal function as defined in the protocol.
- Archival FFPE tumor tissue is available or tumor genomic profiling with a NGS based test performed in a certified laboratory and PD-L1 status as determined by an assay of appropriate regulatory status are required.
- Phase 2a part only: central liquid biopsy analysis of tumor molecular alterations with an assay with appropriate regulatory status. Participants will be allocated to Stratum A, B and C as defined in the protocol.
- Other protocol defined inclusion criteria could apply
Exclusion Criteria
- Participants with tumors harboring actionable EGFR or ALK genomic aberrations. Participants with tumors with other actionable aberrations are eligible and allowed to have received up to 1 line of available targeted therapy
- History of additional malignancy within 3 years before the date of enrollment. Exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy that in the opinion of the Investigator, with concurrence of the Sponsor’s Medical Monitor, is considered cured with minimal risk of recurrence within 3 years
- Known brain metastases, unless clinically stable
- history of (noninfectious) pneumonitis that required systemic corticosteroids or current pneumonitis/interstitial lung disease
- Other protocol defined inclusion criteria could apply.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 31 Oct 2023 | 32 |
 France | Not Recruiting | 31 Oct 2023 | 33 |
 Germany | Not Recruiting | 31 Oct 2023 | 16 |
 Italy | Not Recruiting | 31 Oct 2023 | 30 |
 Spain | Not Recruiting | 31 Oct 2023 | 59 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
LIBTAYO 350 mg concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | SOLUTION FOR INFUSION | — | — | PRD7478447 |
M1774 | Test | CAPSULE, HARD | ORAL | — | — | PRD8913564 |
M1774 | Test | CAPSULE, HARD | ORAL | — | — | PRD9533555 |
M1774 | Test | CAPSULE, HARD | ORAL | — | — | PRD8913563 |