An Open-label, Multicenter Trial of the Safety, Tolerability, and Pharmacokinetic/Pharmacodynamic Profile of M1774 in Participants With Metastatic or Locally Advanced Unresectable Solid Tumors (DDRiver Solid Tumors 301)

Study Identifier:
MS201924_0001
CT.gov Identifier:
NCT04170153
EudraCT Identifier:
2019-002203-18
EU Trial (CTIS) Number:
2024-515848-23-00
Study Contact Information:
(210) 593-5651 or [email protected]
Study Complete

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Study Summary

To establish the safety, tolerability and Pharmacokinetic/Pharmacodynamic (PK/PD) profile (with and without food) and early signs of efficacy of M1774 as monotherapy and in combination with the poly (ADP-ribose) polymerase (PARP) inhibitor niraparib.

To evaluate the safety and tolerability, maximum tolerated dose, recommended dose for expansion (RDE) and pharmacokinetics (PK) of M1774 (part A1),

the effect of food on M1774 PK (part A2), and the efficacy of M1774 in patients with tumors harboring selected mutations (part A3).

An additional objective is to assess the pharmacodynamics of M1774 by measuring relative changes in baseline p-CHK1 and gamma-H2AX expression in paired tumor biopsies and serial blood samples.

To establish the safety, tolerability, and PK profile (fasting and non-fasting) of M1774.

To report tuvusertib pharmacokinetics, changes in levels of ɣ-H2AX (a pharmacodynamic biomarker of ATR inhibition) and immunocyte subsets, and a retrospective analysis of molecular response (MR).

MR was defined as >50% reduction in circulating tumor DNA (ctDNA), according to changes from baseline in somatic single nucleotide variant (SNV) allele frequencies or tumor-specific DNA-methylation levels.

Medical Condition
The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.
Solid Tumor
Phase
The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
Phase I
Sex
Female & Male
Age
18+ years
Study Drug
Drug: Experimental: Part A1: Monotherapy Dose Escalation
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Drug: Experimental: Part A2 - Preliminary Food Effect Assessment
Drug: Experimental: Part A3 - Monotherapy Expansion
Drug: Experimental: Part B1: Combination Therapy Dose Finding
Drug: B1b: Participants with baseline body weight greater than or equal to (>=) 77 kg and or platelets >= 150,000 mm^3 will receive Niraparib once daily combined with different doses of M1774 and schedule determined as recommended dose for expansion (RDE) in Part B1a.
Drug: Experimental: Part A4: Japan Dose Confirmation Monotherapy
Drug: Experimental: Part A5: China Dose Confirmation Monotherapy
Drug: In the dose escalation phase (part A1 [open]), 18-24 patients are due to receive M1774 at a starting dose of 5 mg once daily. The preliminary food assessment (part A2) will follow a randomized two-sequence two-period crossover design in which < or = 12 patients will be randomized (1: 1) to receive a single dose of M1774 on Day -7 at the RDE (determined in part A1) in either a fed or fasted condition. After the food assessment, patients will subsequently receive M1774 according to the part A1 dosing schedule.
Drug: [Part A4]M1774 will be administered at a dose and schedule determined as recommended dose for expansion (RDE) in Part A1.
Drug: Patients received 5 mg to 270 mg QD along with BID and intermittent regimens in 21-day cycles.
Drug: Tuvusertib was administered at the global RDE (180 mg once daily, 2 weeks on/1 week off) in a cohort of Japanese Patients
Drug: ASCO 2024
Drug: ESMO 2024:
Study Status
Indicates the current recruitment status or the expanded access status
Study Complete

Requirements information
Inclusion criteria
  • Participants with locally advanced or metastatic disease that is refractory to standard therapy or for which no standard therapy is judged appropriate by the Investigator which may convey clinical benefit
  • Eastern Cooperative Oncology Group (ECOG) Performance Status less than or equal to (<=) 1
  • Participants with clinically controlled brain metastases, which is defined as individuals with central nervous system metastases that have been treated for, are asymptomatic, and have discontinued steroids (for the treatment of brain metastases) for greater than (>) 28 days may be enrolled
  • Participants with meningeal carcinomatosis are excluded
  • In Part A3, measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
  • Part A3: Participants with presence of loss of function mutations in the genes for ARID1A, ATRX and /or DAXX and ATM
  • Contraceptive use by males or females will be consistent with local regulations on contraception methods for those participating in clinical studies
  • Adequate hematological, hepatic, and renal function as defined in the protocol
  • Female participants are not pregnant or breastfeeding
  • Part B1:
  • Subpart B1a: Participants with Baseline Body weight < 77 kg or platelets <150,000 cubic per millimeter (mm^3) Subpart B1b: Participants with Baseline Body weight >= 77 kg and platelets >=150,000 mm^3 will be included
  • - Other protocol defined inclusion criteria could apply
  • Part A3 only: Participants whose tumor has at least 1 of the following molecular defects:
  • -Cohort 1: loss of function mutations in the gene for ARID1A
  • -Cohort 2: loss of function mutations in the genes for ATRX and/or DAXX
  • -Cohort 3: loss of function mutation in the gene for ATM.
  • -Part A4 only: participants who are resident in Japan and self-report Japanese ethnicity
  • -Part A3 only: measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1.
  • -Adequate hematologic function
  • -Adequate hepatic function
  • -Adequate renal function
  • Age: ≥18 years old (or >18 years old according to the national legal age) when signing the informed consent form.
  • 2 Subject type and disease characteristics: Patients who are refractory to standard therapy or who in the investigator's opinion are not suitable for standard therapy (i.e., those who have exhausted all standard treatment options according to international guidelines) tester).
  • 3 Subjects who settled in China and self-reported as Chinese ethnicity.
  • 4 Eastern Cooperative Oncology Group (ECOG) performance status score ≤ 1 point.
  • 5 Clinically controlled brain metastases, defined as patients with treated CNS metastases who are asymptomatic and have discontinued steroid therapy for brain metastases for >28 days. Patients with meningeal metastases will be excluded.
  • 6 Have adequate hematological function, as shown by: platelet count ≥ 100,000/mm3. Hemoglobin ≥ 9.0 g/dL. Absolute neutrophil count ≥1.500 μL and no growth factor treatment within the previous 14 days.
  • 7 Adequate liver function, defined as: total bilirubin level ≤1.5 x upper limit of normal (ULN; if total bilirubin >1.5 x ULN in Gilbert's syndrome), aspartate aminotransferase (AST) ≤3 x ULN, alanine aminotransferase (ALT) ≤3×ULN or ≤5×ULN with liver metastasis.
  • 8 Adequate renal function, defined as: serum creatinine ≤ 1.5 x ULN. If serum creatinine is >1.5×ULN, creatinine clearance calculated by the Cockcroft-Gault formula or measured by 24-hour urine collection is required to be ≥50 mL/min. The Cockcroft-Gault formula is: Glomerular filtration rate [mL/min] = {(140 - age) x body weight/(72 x serum creatinine [mg/dL])} x 0.85 (if female).
  • 9 male or female.
  • 10 The contraceptive measures used by men or women should comply with local regulations on the local contraceptive law of clinical research subjects (see Protocol Appendix 14 for specific requirements in Japan). Male subjects: agree to take the following measures during the study drug period and for at least 3 months after the last dose of the study drug: Avoid sperm donation. Plus: Avoid any activity that could expose you to ejaculation. Or, use a male condom: When having sexual intercourse with women of childbearing potential (WOCBP), it is recommended to use a high-efficiency contraceptive method with an annual failure rate of <1% (see Appendix 5), and the condom may break or leak. During the study, male subjects had to use condoms when having sex with pregnant female partners. Female subjects: not pregnant or breastfeeding and meet at least one of the following conditions: non-WOCBP. Alternatively, as described in Appendix 5, WOCBPs should use a highly effective method of contraception (i.e., <1% annual failure rate), preferably with low user dependence, during the following periods: Before the first dose of study drug, if using hormonal contraceptives: Has completed ≥ 1 4-week course of oral contraceptives and has menstruated or started to menstruate. Or, have used long-acting contraceptives or long-term oral contraceptives for at least 28 days with a documented negative pregnancy test (using a high-sensitivity assay). Study drug administration period: At least 6 months after the study drug administration period (ie, after the last administration), and agree not to donate eggs (eggs, oocytes) for reproduction during this period. The investigator assessed the effectiveness of contraceptive methods associated with the first dose of study drug. Negative serum pregnancy test within 24 hours prior to first dose of study drug as required by local regulations. Women should not breastfeed for at least 1 month during and after the study period (i.e. after the last dose of the study drug). Additional pregnancy testing requirements during and after the study drug dosing period are described in Section 8.2.4. Medical history, menstrual history, and recent sexual behavior were reviewed by the investigator to reduce the risk of women with undetected pregnancies early in the enrollment process.
  • 11 Obtaining Informed Consent Form: Able to sign the Informed Consent Form (ICF) described in Appendix 4, including following the requirements and restrictions outlined in the ICF and this protocol.
Exclusion criteria
  • Participants with major surgery (as deemed by the Investigator) for any reason, except diagnostic biopsy, within 4 weeks of the study intervention and/or if the participant has not fully recovered from the surgery within 4 weeks of the study intervention
  • Presence of toxicities due to prior anticancer therapies (example, radiotherapy, chemotherapy, immunotherapies, et cetera [etc]) that do not recover to <= Grade 1 with the exception of toxicities that do not pose a safety risk to the participant in the judgment of the Investigator (example: ongoing Grade 2 alopecia)
  • Part B1 only: Uncontrolled arterial hypertension which is systolic blood pressure >140 millimeter of mercury (mmHg); Diastolic blood pressure >90mmHg
  • Unstable angina, myocardial infarction, congestive heart failure >= II or a coronary revascularization procedure within 180 days of study entry. Calculated QTc average (using the Fridericia correction calculation) of > 450 msec for males and > 470 msec for females that does not resolve with correction of electrolyte abnormalities
  • Participants with active and/or uncontrolled infection. The following exceptions apply:
  • Participants with human immunodeficiency virus (HIV) infection are eligible if they are on effective antiretroviral therapy with undetectable viral load within 6 months, provided there is no expected drug-drug interaction
  • Participants with evidence of chronic hepatitis B virus (HBV) infection are eligible if the HBV viral load is undetectable on suppressive therapy (if indicated), and if they have alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin levels < upper limit of normal (ULN), and provided there is no expected drug-drug interaction
  • Participants with a history of hepatitis C virus (HCV) infection are eligible if they have been treated and cured. For participants with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load, and if they have ALT, AST, and total bilirubin levels < ULN
  • Treatment with live or live attenuated vaccine within 30 days of dosing (non-replicating vector vaccines are permitted)
  • Part B1 only: participants diagnosed with hereditary diseases characterized by genetic defects of DNA repair mechanisms, including ataxia telangiectasia, Nijmegen breakage syndrome, Werner syndrome, Bloom Syndrome, Fanconi anemia, xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy
  • Any other clinical condition, uncontrolled concurrent illness, or other situation which in the Investigator's opinion would not make the participant a good candidate for the clinical study including or may potentially impact the absorption of M1774, such as (but not limiting to) significant small bowel resection or gastric surgery and exocrine pancreatic insufficiency requiring pancreatic enzyme replacement therapy
  • Prohibited concomitant medication, as per Protocol
  • Another investigational drug within 28 days or 5 half-lives, whichever is shorter, prior to start of administration of study intervention
  • Prior use of Ataxia telangiectasia mutated and Rad3-related (ATR) inhibitor and/or Checkpoint kinase 1 (CHK1) inhibitor
  • Participants who cannot comply with restrictions for medications or food
  • Part B1 only: Participants with a known history of acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS), and prostate cancer
  • Other protocol defined exclusion criteria could apply
  • Participants with major surgery (as deemed by the Investigator) for any reason, except diagnostic biopsy, within 4 weeks of the study intervention and/or if the participant has not fully recovered from the surgery within 4 weeks of the study intervention
  • Presence of toxicities due to prior anticancer therapies (example, radiotherapy, chemotherapy, immunotherapies, et cetera [etc]) that do not recover to <= Grade 1 with the exception of toxicities that do not pose a safety risk to the participant in the judgment of the Investigator (example: ongoing Grade 2 alopecia)
  • Uncontrolled arterial hypertension which is systolic blood pressure >140 millimeter of mercury (mmHg); Diastolic blood pressure >90mmHg;
  • Unstable angina, myocardial infarction, congestive heart failure >= II) or a coronary revascularization procedure within 180 days of study entry. Calculated QTc average (using the Fridericia correction calculation) of > 450 msec for males and > 470 msec for females that does not resolve with correction of electrolyte abnormalities
  • Participants with active and/or uncontrolled infection. The following exceptions apply:
  • Participants with human immunodeficiency virus (HIV) infection are eligible if they are on effective antiretroviral therapy with undetectable viral load within 6 months, provided there is no expected drug-drug interaction.
  • Participants with evidence of chronic hepatitis B virus (HBV) infection are eligible if the HBV viral load is undetectable on suppressive therapy (if indicated), and if they have alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin levels < upper limit of normal (ULN), and provided there is no expected drug-drug interaction.
  • Participants with a history of hepatitis C virus (HCV) infection are eligible if they have been treated and cured. For participants with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load, and if they have ALT, AST, and total bilirubin levels < ULN.
  • Treatment with live or live attenuated vaccine within 30 days of dosing (non-replicating vector vaccines are permitted)
  • Part B1 only: participants diagnosed with hereditary diseases characterized by genetic defects of DNA repair mechanisms, including ataxia telangiectasia, Nijmegen breakage syndrome, Werner syndrome, Bloom Syndrome, Fanconi anemia, xeroderma pigmentosae, Cockayne syndrome, and trichothiodystrophy
  • Any other clinical condition, uncontrolled concurrent illness, or other situation which in the Investigator's opinion would not make the participant a good candidate for the clinical study including or may potentially impact the absorption of M1774, such as (but not limiting to) significant small bowel resection or gastric surgery and exocrine pancreatic insufficiency requiring pancreatic enzyme replacement therapy
  • Prohibited concomitant medication, as per Protocol
  • Another investigational drug within 28 days or 5 half-lives, whichever is shorter, prior to start of administration of study intervention
  • Prior use of Ataxia telangiectasia mutated and Rad3-related (ATR) inhibitor and/or Checkpoint kinase 1 (CHK1) inhibitor
  • Participants who cannot comply with restrictions for medications or food. Part B1 only: Participants with a known history of acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS), prostate cancer, and uncontrolled arterial hypertension
  • Other protocol defined exclusion criteria could apply

Clinical Study Information for Healthcare Providers

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Study Locations

Location
Investigator
Status
Condition(s) Treated at Site
Location
START Madrid, Spain (CIOCC)
Madrid, Spain, 28050
Investigator
Irene Moreno
Status
Terminated/Withdrawn
Condition(s) Treated at Site
Solid Tumor