A Molecularly Driven Phase 1b Dose Escalation and Dose Expansion Study of the DNA-PK Inhibitor Peposertib (M3814) in Combination With the ATR Inhibitor M1774
Overview
- Phase
- Phase 1
- Status
- Recruiting
- Enrollment
- 66
- Locations
- 10
- Primary Endpoint
- Incidence of adverse events
Overview
Brief Summary
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.
Detailed Description
PRIMARY OBJECTIVES:
I. To determine the safety and tolerability of peposertib (M3814) in combination with tuvusertib (M1774). (DOSE ESCALATION AND EXPANSION COHORT) II. To determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of the combination of peposertib (M3814) and tuvusertib (M1774). (DOSE ESCALATION COHORT)
SECONDARY OBJECTIVES:
I. To observe and record anti-tumor activity. II. To determine the pharmacokinetic (PK) profiles of peposertib (M3814) and tuvusertib (M1774) when administered in combination.
EXPLORATORY OBJECTIVES:
I. To explore correlations between pharmacodynamic (PD) and predictive biomarkers (gammaH2AX, phospho-KAP1 and phospho-RPA) with clinical outcomes.
II. To explore correlations between baseline genomic alterations of ataxia-telangiectasia mutated (ATM) or markers of replicative stress, ATM expression by immunohistochemistry (IHC), RAD5' foci formation with clinical outcomes.
III. To determine metrics of anticancer activity including the objective response rate (ORR) and progression-free survival (PFS).
OUTLINE: This a dose-escalation study of peposertib and tuvusertib, followed by a dose-expansion study.
Patients receive peposertib orally (PO) once (QD) or twice (BID) daily on days 2-14 of cycle 1 and days 1-14 of subsequent cycles in combination with tuvusertib PO QD or BID daily on days 1-14 of each cycle. Cycles repeat every 28 days in the absence of disease progression, pregnancy, non-compliance, unacceptable toxicity, termination of the study or the study drug is no longer available. Patients also undergo tumor biopsy, blood sample collection, positron emission tomography (PET), computed tomography (CT), and magnetic resonance imaging (MRI) throughout the study.
After completion of study treatment, patients are followed up for a minimum of 30 days after removal from treatment or until initiating a new anticancer therapy or until death, whichever occurs first.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •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.
- •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 of inactivating ATM mutations, MYC amplification, mutation of FBXW7, CCNE1 amplification, SWI/SNF member mutation (ARID1A, PBRM1, SMARCA4, ARID2, ARID1b, SMARCB1, SMARCA2, SS18), and 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.
- •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.
- •Life expectancy \> 3 months.
- •Eastern cooperative oncology group (ECOG) performance status =\< 2 (Karnofsky \>= 60%).
- •Measurable disease by response evaluation criteria in solid tumors (RECIST) 1.1 (RECIST) 1.1 non-measurable disease permitted for the dose escalation portion).
- •Hemoglobin \>= 9 g/dL.
- •Absolute neutrophil count \>= 1,500/mcL.
- •Platelets \>= 1000,000/mcL.
Exclusion Criteria
- •Patients who have received immunotherapy within 21 days of Cycle 1 Day
- •Patients who have received therapeutic radiation therapy within 21 days, or palliative radiation therapy within 7 days, of Cycle 1 Day
- •Patients who have undergone major surgery within 21 days of Cycle 1 Day
- •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
- •Patients who are receiving any other investigational agents.
- •Patients with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate central nervous system (CNS) specific treatment is not required and is unlikely to be required during the first cycle of therapy.
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to peposertib (M3814) and tuvusertib (M1774).
- •Patients who cannot discontinue concomitant medications or herbal supplements that are strong inhibitors or strong inducers of cytochrome P450 (CYP) isoenzymes, CYP1A2, CYP3A4/5, CYP2C19, and CYP2C
- •Concomitant use of substrates hMATE1, hMATE2, and CYP3A4/5 substrates with a narrow therapeutic index are also excluded. Opioids may interact with these enzymes; use of opioids while on study is allowed but should be closely monitored. Concomitant administration of sensitive substrates of P-gp, BCRP, OCT1, OATP1B1, and OATP1B3 should be avoided (if the use is unavoidable, carefully monitor patients for signs of increased toxicity). Patients may confer with the study doctor to determine if alternative medications can be used. The following categories of medications and herbal supplements must be discontinued for at least the specified period of time before the patient can be treated:
- •Strong inducers of CYP1A2, CYP3A4/5, CYP2C19, and CYP2C9: \>= 3 weeks prior to study treatment.
Arms & Interventions
Treatment (peposertib, tuvusertib)
Patients receive peposertib PO QD or BID daily on days 2-14 of cycle 1 and days 1-14 of subsequent cycles in combination with tuvusertib PO QD or BID daily on days 1-14 of each cycle. Cycles repeat every 28 days in the absence of disease progression, pregnancy, non-compliance, unacceptable toxicity, termination of the study or the study drug is no longer available. Patients also undergo tumor biopsy, blood sample collection, PET, CT, and MRI throughout the study.
Intervention: Biopsy Procedure (Procedure)
Treatment (peposertib, tuvusertib)
Patients receive peposertib PO QD or BID daily on days 2-14 of cycle 1 and days 1-14 of subsequent cycles in combination with tuvusertib PO QD or BID daily on days 1-14 of each cycle. Cycles repeat every 28 days in the absence of disease progression, pregnancy, non-compliance, unacceptable toxicity, termination of the study or the study drug is no longer available. Patients also undergo tumor biopsy, blood sample collection, PET, CT, and MRI throughout the study.
Intervention: Biospecimen Collection (Procedure)
Treatment (peposertib, tuvusertib)
Patients receive peposertib PO QD or BID daily on days 2-14 of cycle 1 and days 1-14 of subsequent cycles in combination with tuvusertib PO QD or BID daily on days 1-14 of each cycle. Cycles repeat every 28 days in the absence of disease progression, pregnancy, non-compliance, unacceptable toxicity, termination of the study or the study drug is no longer available. Patients also undergo tumor biopsy, blood sample collection, PET, CT, and MRI throughout the study.
Intervention: Computed Tomography (Procedure)
Treatment (peposertib, tuvusertib)
Patients receive peposertib PO QD or BID daily on days 2-14 of cycle 1 and days 1-14 of subsequent cycles in combination with tuvusertib PO QD or BID daily on days 1-14 of each cycle. Cycles repeat every 28 days in the absence of disease progression, pregnancy, non-compliance, unacceptable toxicity, termination of the study or the study drug is no longer available. Patients also undergo tumor biopsy, blood sample collection, PET, CT, and MRI throughout the study.
Intervention: Magnetic Resonance Imaging (Procedure)
Treatment (peposertib, tuvusertib)
Patients receive peposertib PO QD or BID daily on days 2-14 of cycle 1 and days 1-14 of subsequent cycles in combination with tuvusertib PO QD or BID daily on days 1-14 of each cycle. Cycles repeat every 28 days in the absence of disease progression, pregnancy, non-compliance, unacceptable toxicity, termination of the study or the study drug is no longer available. Patients also undergo tumor biopsy, blood sample collection, PET, CT, and MRI throughout the study.
Intervention: Peposertib (Drug)
Treatment (peposertib, tuvusertib)
Patients receive peposertib PO QD or BID daily on days 2-14 of cycle 1 and days 1-14 of subsequent cycles in combination with tuvusertib PO QD or BID daily on days 1-14 of each cycle. Cycles repeat every 28 days in the absence of disease progression, pregnancy, non-compliance, unacceptable toxicity, termination of the study or the study drug is no longer available. Patients also undergo tumor biopsy, blood sample collection, PET, CT, and MRI throughout the study.
Intervention: Positron Emission Tomography (Procedure)
Treatment (peposertib, tuvusertib)
Patients receive peposertib PO QD or BID daily on days 2-14 of cycle 1 and days 1-14 of subsequent cycles in combination with tuvusertib PO QD or BID daily on days 1-14 of each cycle. Cycles repeat every 28 days in the absence of disease progression, pregnancy, non-compliance, unacceptable toxicity, termination of the study or the study drug is no longer available. Patients also undergo tumor biopsy, blood sample collection, PET, CT, and MRI throughout the study.
Intervention: Tuvusertib (Drug)
Outcomes
Primary Outcomes
Incidence of adverse events
Time Frame: Up to week 12
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.
Incidence of dose limiting toxicity
Time Frame: Up to 28 days
Secondary Outcomes
- Pharmacokinetic (PK) analysis(Pre, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 hour (h) post dose on cycle (C)1 day (D)1, pre, 0.5, 1, 1.5, 2, 3, 4, 6, and 8 h post dose on C1D10 (dose-escalation); pre, 0.5, 1,1.5, 2, and 3 h post dose on C1D1 and C1D10 (dose-expansion))
- Pharmacokinetic (PK) analysis(Pre, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 hour (h) post dose on cycle (C)1 day (D)1, pre, 0.5, 1, 1.5, 2, 3, 4, 6, and 8 h post dose on C1D10 (dose-escalation); pre, 0.5, 1,1.5, 2, and 3 h post dose on C1D1 and C1D10 (dose-expansion))