An Open-label, Multicenter Phase Ib Study of the Safety, Tolerability, and Pharmacokinetic/Pharmacodynamic Profile of the ATR Inhibitor Tuvusertib (M1774) in Combination With DNA Damage Response Inhibitors or Immune Checkpoint Inhibitors in Patients With Metastatic or Locally Advanced Unresectable Solid Tumors (DDRiver Solid Tumors 320)
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Study Summary
To establish the safety, tolerability, Pharmacokinetic/Pharmacodynamic (PK/PD) profile, maximum tolerated dose (MTD) combinations (if observed) and recommended dose for expansion (RDE) combination for M1774 in combination with Drug A (DNA Damage Response Inhibitor - in Part A1) and in combination with Drug B (Immune Checkpoint Inhibitor - in Part B1) in patients with metastatic or locally advanced unresectable solid tumors who are intolerant or have no standard therapy available.
To investigate safety, tolerability, PK and PD of tuvusertib + lartesertib in pts with advanced solid tumors refractory to standard therapy.
PK samples were analyzed by a validated LC/MS method, and PD via γ-H2AX in ex vivo-stimulated CD45+ fraction by flow cytometry.
PD analysis comprised γ-H2AX in serial blood samples, stimulated ex vivowith 4-NQO, bleomycin, or controls. Flow cytometry was used to measure target inhibition via γ-H2AX modulation in the CD45+ lymphocytes fraction
To explore the effect of tuvusertib + lartesertib on the immunophenotype (myeloid-derived suppressor cells, T and B lymphocytes, monocytes, and natural killer cells subsets) in serial blood samples. Pharmacokinetic samples were analyzed by a validated bioanalytical liquid chromatography/mass spectrometry method
- Parts A1, A1.1, A1.2, A2, A3, and A2/3: Participants with metastatic or locally advanced unresectable solid tumors refractory to standard therapy or for which no standard therapy is judged appropriate by the Investigator, which may convey clinical benefit, or who cannot tolerate standard of care treatment
- Parts A1.1 and A1.2: Triple negative breast cancer, epithelial ovarian cancer, castrate resistant prostate cancer, urothelial cancer, endometrial cancer, and colorectal cancer independent of mutation status.
- Part A2: Participants with advanced prostate cancer whose tumor carries a genetic loss of function (LoF) mutation(s) in the gene ataxia telangiectasia mutated (ATM). No more than 3 prior lines of therapy for castrate resistant disease. Prior therapy must have included a taxane and a novel antiandrogen (example [e.g.] enzalutamide).
- Part A3: Participants with advanced endometrial cancer whose tumor carries a genetic LoF mutation(s) in the gene AT-rich interaction domain 1A (ARID1A). Prior therapy must have included a platinum agent. Prior therapy must also have included a checkpoint inhibitor if the participant has mismatch repair (MMR)-deficient endometrial cancer. Note for Parts A2/A3: Participants with ATM LoF mutated prostate cancer and ARID1A LoF mutated endometrial cancer should be prioritized to the respective expansion arms instead of being enrolled in Part A1.1. The presence of ATM and ARID1A LoF mutations will be determined according to historic data collected prior to prescreening, generated by an assay with appropriate regulatory status, in either tumor or liquid biopsy. The Sponsor will confirm that mutations certified by historic data fulfil this definition.
- Participants with eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, with estimated life expectancy of at least 3 months
- Adequate hematological, hepatic, and renal function as defined in the protocol
- Other protocol defined inclusion criteria could apply
- Participants with any condition, including any uncontrolled disease state other than with metastatic or locally advanced unresectable solid tumors, that in the Investigator's opinion constitutes an inappropriate risk or a contraindication for participation in the study or that could interfere with the study objectives, conduct, or evaluation
- Participants with a known additional malignancy that is progressing and/or requires active treatment
- Participants with carcinomatous meningitis are excluded regardless of clinical stability
- Participants with serious gastrointestinal bleeding within 3 months, refractory nausea and vomiting, uncontrolled diarrhea, known malabsorption, significant small bowel resection or gastric bypass surgery, use of feeding tubes, other chronic gastrointestinal disease, and/or other situations that may preclude adequate absorption of oral medications
- Participants with organ transplantation, including allogeneic stem cell transplant
- Other protocol defined exclusion criteria could apply
Clinical Study Information for Healthcare Providers
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