This phase I trial tests the safety, side effects and best dose of peposertib (M3814) in combination with tuvusertib (M1774) in treating patients with solid tumors that have spread to other places in the body (advanced). Peposertib and tuvusertib stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Patients must have histologically confirmed solid malignancy that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective, or if the treating investigator deems the study appropriate.
For the dose escalation and dose expansion phases, patients must have genomic (tumor next-generation sequencing [NGS], circulating tumor deoxyribonucleic acid [ctDNA], fluorescence in situ hybridization [FISH], etc.) or immunohistochemical evidence (e.g., loss of expression) of inactivating ATM mutations, MYC amplification, mutation of FBXW7, CCNE1 amplification, SWI/SNF member mutation (ARID1A, PBRM1, SMARCA4, ARID2, ARID1b, SMARCB1, SMARCA2, SS18) and mutation or loss of expression of ATRX/DAXX. Mutations may be germline or somatic. All mutations/alterations must be approved by the overall principal investigator (PI). Other SWI/SNF mutations may be considered after discussion with the overall PI.
Progression on at least one prior standard therapy (if no standard therapy exists, the patient may be allowed if the treating investigator deems appropriate).
Age >= 18 years. Because no dosing or adverse event data are currently available on the use of peposertib (M3814) in combination with tuvusertib (M1774) in patients < 18 years of age, children are excluded from this study.
Patients who have received immunotherapy within 21 days of Cycle 1 Day 1.
Patients who have received therapeutic radiation therapy within 21 days, or palliative radiation therapy within 7 days, of Cycle 1 Day 1.
Patients who have undergone major surgery within 21 days of Cycle 1 Day 1.
Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > Grade 1) with the exception of alopecia, controlled endocrine toxicity (e.g., hypothyroidism), and cutaneous toxicity which will be permitted at Grade 2.
Single group
Biopsy Procedure
Procedure/SurgeryUndergo tissue biopsy
Biospecimen Collection
Procedure/SurgeryUndergo blood sample collection
Computed Tomography
Procedure/SurgeryUndergo CT
Magnetic Resonance Imaging
Procedure/SurgeryUndergo MRI
Peposertib
DrugGiven PO
Positron Emission Tomography
Procedure/SurgeryUndergo PET
Tuvusertib
DrugGiven PO
Incidence of dose limiting toxicity
Incidence of adverse events
Descriptive statistics will be used for safety in the Phase 1b escalation study. Patients will be included in this analysis if they receive at least one dose of any study treatment. For toxicity reporting, all adverse events will be graded and analyzed using Common Terminology Criteria for Adverse Events (CTCAE). Type of adverse events, intensity (grading), and attribution will be provided in a listing. All adverse events resulting in discontinuation, dose modification, and/or dosing interruption, and/or treatment delay of drug will also be summarized. Laboratory test results will be classified according to CTCAE.
Pharmacokinetic (PK) analysis
Peposertib (M3814) and tuvusertib (M1774) concentrations in these samples will be quantitatively measured using a liquid chromatography/tandem mass spectrometric method. The individual PK parameters will be derived: maximum concentration (Cmax), time to maximum concentration (Tmax), are under the curve (AUC), half life (T1/2), apparent oral clearance (Cl/F), and apparent volume of distribution in steady state (Vss/F) using non-compartmental methods with the software WinNonlin, as feasible. Advanced population PK methods may be employed to assess the link between drug exposure and biological effects and efficacy. The PK variables will be tabulated and descriptive statistics (e.g., geometric means and coefficients of variation) calculated for each dose level. PK parameters (e.g., T1/2, Cmax, Cl, and AUC) will be compared across dose level using nonparametric statistical testing techniques.
Pharmacodynamics (PD)
Will be assessed using the changes in gammaH2AX, phosphorylated biomarkers (e.g., NBS1, RPA, KAP1), and gene expression by ribonucleic acid sequencing before and on treatment. Correlation between mutation status and immunohistochemistry results with ATM will be descriptive as well.
Overall response rate (ORR)
In the phase 1b expansion, the ORR will be estimated by the proportion of patients who achieve complete or partial response as their best response to treatment. ORR will be accompanied by a 95% confidence interval estimated using exact binomial methods.
Progression free survival (PFS)
The time to event endpoint PFS will be estimated with the Kaplan Meier methodology. Median and event-free rate at selected time points will be provided with 95% confidence interval.
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