An Open Label, Multicenter, Phase 1 Study to Evaluate the Safety, Tolerability, and Pharmacokinetic/Pharmacodynamic Profile of the PARP1 Inhibitor M9466 Alone or in Combination in Participants With Advanced Solid Tumors
Overview
- Phase
- Phase 1
- Intervention
- M9466
- Conditions
- Advanced Solid Tumor
- Sponsor
- EMD Serono Research & Development Institute, Inc.
- Enrollment
- 141
- Locations
- 22
- Primary Endpoint
- Module 1 Part A1 and Part A2: Number of Participants With Treatment-Emergent Adverse Events (TEAE), and Treatment-related AEs (TRAEs)
- Status
- Active, not recruiting
- Last Updated
- last month
Overview
Brief Summary
The purpose of this study is to evaluate the safety, tolerability, pharmacokinetic, pharmacodynamic profile of M9466 with and without tuvusertib or an ARPi and early signs of clinical activity of M9466 with tuvusertib in participants with advanced solid tumors. Study details include: Study/Treatment Duration: Participants will be treated until disease progression, death, discontinuation, or End of Study. Visit Frequency: Every week in the first 2 cycles, followed by every 3 weeks in the subsequent cycles. An End of Treatment Visit and Safety Follow-up/Discontinuation Visit are scheduled after the treatment period.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Module 1 Part A and Module 2 Part A1: Locally advanced or metastatic disease that is refractory to standard therapy or for which no standard therapy is judged appropriate by the Investigator
- •Module 1 Part A2: Histologically or pathologically confirmed advanced or metastatic CRPC or EOC
- •Eastern Cooperative Oncology Group Performance Status less than or equal to (\<=) 1
- •Life expectancy of more than 6 months
- •Have adequate hematologic function
- •Participants who received chemotherapy, extensive radiotherapy, biological therapy (e.g. antibodies) or investigational agents will have a washout period of 4 weeks (6 weeks for nitrosourea, mitomycin-C) or 5 half-lives whichever is shorter, prior to starting study intervention with M9466 (± tuvusertib)
- •Module 3 Part A1:
- •Histologically or pathologically confirmed diagnosis of prostate cancer
- •Metastatic disease documented by positive bone scan or metastatic lesions on CT or MRI
- •Participants with Metastatic Castration-Resistant Prostate Cancer (mCRPC) or metastatic hormone-sensitive prostate cancer (mHSPC) are allowed. For mCRPC, serum testosterone levels ≤ 50 /dL (≤ 1.75 nmol/L).
Exclusion Criteria
- •Persistence of Adverse Events related to any prior treatments that have not recovered to Grade less than 1 by NCI Common Terminology Criteria for Adverse Events- v5.0 unless AEs are clinically nonsignificant and/or stable on supportive therapy in the opinion of the Investigator (e.g. neuropathy or alopecia)
- •Participant has a history of additional malignancy within 5 years before the date of enrollment other than disease under study (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, benign prostate neoplasm/hypertropia, 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)
- •Participants with known brain metastases, except if clinically controlled, which is defined as individuals with Central Nervous System (CNS) tumors that have been treated, are asymptomatic and who have discontinued steroids (for the treatment of CNS tumors) for more than 28 days
- •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 (including exocrine pancreatic insufficiency requiring pancreatic enzyme replacement therapy), and/or other situations that may preclude adequate absorption of oral medications
- •Cerebrovascular accident or stroke
- •Module 3 only:
- •Current evidence of any of the following:
- •Any medical condition that would make prednisone (or equivalent) use contraindicated.
- •Any chronic medical condition requiring a higher dose of corticosteroid than 10 mg prednisone (or equivalent) once daily.
- •History of uncontrolled pituitary or adrenal dysfunction
Arms & Interventions
M9466 plus Tuvusertib
Intervention: M9466
M9466 plus Tuvusertib
Intervention: Tuvusertib
M9466 Monotherapy
Intervention: M9466
M9466 with AA-P(abiraterone acetate and prednisone or prednisolone)
Intervention: M9466
M9466 with AA-P(abiraterone acetate and prednisone or prednisolone)
Intervention: Abiraterone acetate
M9466 with AA-P(abiraterone acetate and prednisone or prednisolone)
Intervention: Prednisone/Prednisolone
Outcomes
Primary Outcomes
Module 1 Part A1 and Part A2: Number of Participants With Treatment-Emergent Adverse Events (TEAE), and Treatment-related AEs (TRAEs)
Time Frame: Time from first treatment up to 30 days after end of study intervention (approximately assessed up to 20 months)
Module 1 Part A1 and Part A2: Number of Participants with Dose Limiting Toxicity (DLT)-like events
Time Frame: Day 1 up to Day 21 of Cycle 1 (each cycle is of 21 days)
Module 2 Part A1: Pharmacokinetic (PK) Plasma Concentrations of M9466
Time Frame: Cycle 1 Day 1 (C1D1), C1D8 and C1D15
Module 2 Part A2: Number of Participants With Treatment-Emergent Adverse Events (TEAE), and Treatment-related AEs (TRAEs)
Time Frame: Time from first treatment up to 30 days after end of study intervention (approximately assessed up to 20 months)
Module 3 Part A1: Number of Participants With Treatment-Emergent Adverse Events (TEAE), and Treatment-related AEs
Time Frame: Time from first treatment up to 30 days after end of study intervention
Module 3 Part A1: Number of Participants with Dose Limiting Toxicity (DLT)-like Events
Time Frame: Day 1 up to Day 21 of Cycle 1(each cycle is of 21 days)
Secondary Outcomes
- Module 1 Part A1 and Part A2, Module 2 Part A1 and A2 and Module 3 Part A1: Pharmacokinetic (PK) Plasma Concentrations of M9466 and Tuvusertib(Module 1 Part A1: C1D1 and C1D5 or C1D6; Module 1 Part A2: C1D1, C1D2, C1D3 or C1D4 and C1D8; Module 2 Part A1: C1D1, C1D8 and C1D15; Module 2 Part A2: C1D1, C1D2 and C1D8, C1D22 and C2D1; Module 2 Part A1: C1D1 and C1D8)
- Module 1 Part A1 and Part A2, Module 2 Part A2: Objective Response (OR) According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (or PCWG3 for prostate cancer) as Assessed by Investigator(Time from first treatment to planned assessment at 12 months)
- Module 1 Part A1 and Part A2; Module 2 Part A1 : Effect of M9466 in combination with tuvusertib on QTc interval as determined by Digital ECGs(Time from first treatment to planned assessment at 12 months)
- Module 2 Part A1: Number of Participants With Treatment-Emergent Adverse Events (TEAE), and Treatment-Related AEs(Time from first treatment up to 30 days after end of study intervention (approximately assessed up to 20 months))
- Module 2 Part A1 and Part A2: Relative Changes in Pharmacodynamics Markers in Paired Tumor Biopsies(Day 1, Day 8 and Day 15)