Study of Avelumab-M3814 Combinations

Study Overview
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Brief Summary
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The main purpose of the study is to evaluate a safe, tolerable recommended Phase II dose (RP2D) and/or the maximum tolerated dose (MTD) of M3814 when given in combination with avelumab with and without radiotherapy in participants with selected advanced solid tumors.

Official Title
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A Multicenter, Open-Label, Dose Escalation Phase I Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of the DNA-PK Inhibitor M3814 in Combination With Avelumab With and Without Palliative Radiotherapy in Participants With Selected Advanced Solid Tumors

Conditions
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Oncology, Solid Tumors

Intervention / Treatment
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* Drug: M3814
* Drug: M3814
* Drug: Avelumab
* Radiation: Radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Part A and Part FE (M3814 + avelumab): Participants must have histologically or cytologically proven advanced or metastatic solid tumors for which no standard therapy exists, standard therapy has failed, or participants are intolerant to or have rejected established therapy known to provide clinical benefit for their condition Part B (M3814 + Radiotherapy [RT] + avelumab): histologically or cytologically proven advanced or metastatic solid tumors for which no standard therapy exists, standard therapy has failed, or participants are intolerant to or have rejected established therapy known to provide benefit for their condition and are amenable to receive RT Part A, B and FE: Measurable or evaluable disease according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v 1.1) Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 1 at study entry Part A, B and FE: Female participants of childbearing potential should be willing to use a highly effective contraceptive method Part A, B and FE: Male participants should agree to refrain from donating sperm plus, either: abstain from any activity that allows for exposure to ejaculate Use an adequate method of contraception starting with the first dose of study therapy through 90 days after the last dose of study therapy Part A, B and FE: Be willing to provide informed consent for the trial Other protocol defined inclusion criteria could apply Exclusion Criteria: Participants who have received prior chemotherapy, hormonal anticancer therapy with the exception of luteinizing hormone-releasing hormone analogs, biologic therapy, or any other anticancer therapy within 28 days of the first dose of study treatments (6 weeks for nitrosoureas or mitomycin C) Participants who have undergone major surgery for any reason, except diagnostic biopsy, within 4 weeks of the study intervention and/or has not fully recovered from the surgery within 4 weeks of the study intervention Participants with evidence of active or history of autoimmune disease that might deteriorate when receiving an immune-stimulatory agent Participants with brain metastases, except those meeting the following criteria: a) brain metastases that have been treated locally and are clinically stable for greater than or equal to (>=) 4 weeks prior to randomization b) no ongoing neurological symptoms that are related to the brain localization of the disease (sequelae that are a consequence of the treatment of the brain metastases are acceptable) c) participants must be either off steroids or on a stable or decreasing dose of less than (<) 10 milligrams (mg) daily prednisone (or equivalent) Participants with severe acute or chronic medical conditions including immune colitis, inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year), psychiatric or substance abuse disorders; or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study intervention administration or may interfere with the interpretation of study results Participants requiring systemic immunosuppressive agents (such as steroids) for any reason who cannot be tapered off these drugs before start of study intervention, with the following exceptions: a) participants with adrenal insufficiency, may continue corticosteroids at physiologic replacement dose, equivalent to less than or equal to (<=) 10 mg prednisone daily b) participants requiring steroids through a route known to result in a minimal systemic exposure (topical, intranasal, intra-ocular, or inhalation) is permitted c) participants with previous or ongoing administration of systemic steroids for the management of an acute allergic phenomenon planned to be completed in 14 days, or that the dose after 14 days will be equivalent to <= 10 mg prednisone daily Participants with a history of human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome, Hepatitis B virus or Hepatitis C and with history of infection must have a polymerase chain reaction (PCR) documentation that infection is cleared Participants who have received a live vaccine within 30 days prior to the first dose of trial treatment Participants with known prior severe hypersensitivity to any of the investigational products or any component in its formulations Participants with evidence of additional malignancy within the last 5 years unless a complete remission without further recurrence was achieved at least 2 years prior to study entry and participants were deemed to have been cured with no additional therapy required or anticipated to be required. Participants with treated nonmelanoma skin cancers, carcinoma in situ of skin, bladder, cervix, colon/rectum, breast, or prostate may participate Participants pretreated with immunotherapy who have, any history of dose limiting toxicities (DLTs) with prior immunotherapy agents, including Grade 3/4 immune-related adverse events (irAEs); irreversible irAEs; Grade greater than or equals to (>=) 3 irAEs that did not respond to steroid rescue; or neurologic irAE with significant clinical sequelae Participants with irAE requiring hormone replacement therapy (e.g., thyroxine, insulin, or physiologic dose of corticosteroid replacement therapy for adrenal or pituitary insufficiency) may participate as long as the endocrinopathy is well controlled and the participant is not otherwise symptomatic from hormone insufficiency Physiologic corticosteroid dose is defined as <= 10 mg daily of prednisone or equivalent for Part B only: Participants who have confirmed esophagitis and in whom radiation planning target volume will include any portion of the esophagus, the participant is not eligible unless an esophageal endoscopy rules out the presence of esophagitis Participants in whom more than 10 percent (%) of the total esophagus volume might receive more than 15 gray (Gy) (50% of the prescribed radiotherapy [RT] dose) Participants who have had previous radiotherapy to the same region as intended to be irradiated in this study within the past 12 months Participants who have had extensive previous radiotherapy on >= 30% of bone marrow reserve or prior bone marrow/stem cell transplantation within 5 years before study start If participant hepatic metastatic lesion is selected to be irradiated: - the non-tumor liver volume < 700 milli liters (mL); - Child-Pugh score >= 8 Other protocol defined exclusion criteria could apply

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: M3814 + Avelumab<br> | Drug: M3814<br>* Participants will receive M3814 twice daily (BID) continuously starting from Day 1 until progressive disease (PD) or unacceptable toxicity.<br>* Other names: MSC2490484A;Drug: Avelumab<br>* Participants will receive avelumab once every 2 weeks (Q2W) starting from Day 1 until PD or unacceptable toxicity.<br>|
| Experimental: Part B: M3814 + Avelumab + Radiotherapy (RT)<br> | Drug: M3814<br>* Participants will receive M3814 concomitantly with RT once (QD) daily starting Day 1 for 5 days per week for 2 weeks in total.<br>* Other names: MSC2490484A;Drug: Avelumab<br>* Participants will receive avelumab once every 2 weeks (Q2W) starting from Day 1 until PD or unacceptable toxicity.<br>Radiation: Radiotherapy<br>* Participants will receive radiotherapy at the dose of 3 grays (Gy) per day starting Day 1 for 5 days per week for 2 weeks.<br>|
| Experimental: Part FE: M3814 + Avelumab (fasted/fed state)<br> | Drug: M3814<br>* Participants will receive M3814 twice daily (BID) continuously starting from Day 1 until progressive disease (PD) or unacceptable toxicity.<br>* Other names: MSC2490484A;Drug: Avelumab<br>* Participants will receive avelumab once every 2 weeks (Q2W) starting from Day 1 until PD or unacceptable toxicity.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Occurrence of Dose-limiting Toxicities (DLTs) |  | From first study intervention to planned final assessment at 3 weeks | 
| Part B: Occurrence of Dose-limiting Toxicities (DLTs) |  | From first study intervention to planned final assessment at 4 weeks | 
| Part FE: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUC0-t) of M3814 |  | Pre-dose up to end of treatment at 268 days | 
| Part FE: Maximum Observed Drug Concentration (Cmax) of M3814 |  | Pre-dose up to end of treatment at 268 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A, B and FE: Occurrence of Treatment-emergent Adverse Events (TEAEs) and Treatment-related AEs According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) and Serious Adverse Events |  | From the first study intervention to planned final assessment at 508 days | 
| Part A, B and FE: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters, Vital Signs, Physical Examination, Electrocardiogram (ECG) Findings | Number of participants with clinically significant abnormalities will be reported. | From the first study intervention to planned final assessment at 508 days | 
| Part A, B and FE: Number of Participants With Status Assessed on Eastern Cooperative Oncology Group Performance Status (ECOG PS) |  | From the first study intervention to planned final assessment at 508 days | 
| Part A and B: Maximum Observed Drug Concentration (Cmax) of Avelumab |  | Part A: Pre-dose up to end of treatment at 299 days; Part B: Pre-dose up to end of treatment at 451 days | 
| Part A and B: Minimum Observed Drug Concentration (Cmin) of Avelumab |  | Part A: Pre-dose up to end of treatment at 299 days; Part B: Pre-dose up to end of treatment at 451 days | 
| Part A and B: Accumulation Ratio for Cmax [Racc(Cmax)] of Avelumab |  | Part A: Pre-dose up to end of treatment at 299 days; Part B: Pre-dose up to end of treatment at 451 days | 
| Part A and B: Accumulation Ratio for AUC [Racc (AUC)] of Avelumab |  | Part A: Pre-dose up to end of treatment at 299 days; Part B: Pre-dose up to end of treatment at 451 days | 
| Part A and B: Apparent Terminal Half-life (t1/2) of Avelumab |  | Part A: Pre-dose up to end of treatment at 299 days; Part B: Pre-dose up to end of treatment at 451 days | 
| Part A and B: Maximum Observed Drug Concentration (Cmax) of M3814 |  | Part A: Pre-dose up to end of treatment at 268 days; Part B: Pre-dose up to end of treatment at 343 days | 
| Part A and B: Time to Reach the Maximum Plasma Concentration (tmax) of M3814 |  | Part A: Pre-dose up to end of treatment at 268 days; Part B: Pre-dose up to end of treatment at 343 days | 
| Part A and B: Minimum Observed Drug Concentration (Cmin) of M3814 |  | Part A: Pre-dose up to end of treatment at 268 days; Part B: Pre-dose up to end of treatment at 343 days | 
| Part A and B: Average Plasma Concentration of M3814 Observed Post-dose (Cavg) |  | Part A: Pre-dose up to end of treatment at 268 days; Part B: Pre-dose up to end of treatment at 343 days | 
| Part A and B: Fluctuation Index of M3814 |  | Part A: Pre-dose up to end of treatment at 268 days; Part B: Pre-dose up to end of treatment at 343 days | 
| Part A and B: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUC0-t) of M3814 |  | Part A: Pre-dose up to end of treatment at 268 days; Part B: Pre-dose up to end of treatment at 343 days | 
| Part A and B: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-∞) of M3814 |  | Part A: Pre-dose up to end of treatment at 268 days; Part B: Pre-dose up to end of treatment at 343 days | 
| Part A and B: Accumulation ratio for Cmax [Racc(Cmax)] of M3814 |  | Part A: Pre-dose up to end of treatment at 268 days; Part B: Pre-dose up to end of treatment at 343 days | 
| Part A: Accumulation ratio for AUC [Racc(Auc)] of M3814 |  | Part A: Pre-dose up to end of treatment at 268 days; Part B: Pre-dose up to end of treatment at 343 days | 
| Part A: Apparent Terminal Half-life (t1/2) of M3814 |  | Part A: Pre-dose up to end of treatment at 268 days; Part B: Pre-dose up to end of treatment at 343 days | 
| Part A and B: Apparent Volume of Distribution During Terminal Phase (Vz/f) of M3814 |  | Part A: Pre-dose up to end of treatment at 268 days; Part B: Pre-dose up to end of treatment at 343 days | 
| Part A and B: Apparent Clearance (CL/f) of M3814 |  | Part A: Pre-dose up to end of treatment at 268 days; Part B: Pre-dose up to end of treatment at 343 days | 
| Part A and B: Terminal Elimination Rate Constant (λz) of M3814 |  | Part A: Pre-dose up to end of treatment at 268 days; Part B: Pre-dose up to end of treatment at 343 days | 
| Part A, B and FE: Number of Participants With Positive Antidrug Antibody (ADA) Assay |  | Part A and FE: From the first study intervention to planned final assessment at 299 days; Part B: From the first study intervention to planned final Part B assessment at 451 days | 
| Part A, B and FE: Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v 1.1) |  | From the first study intervention to planned final assessment at 508 days | 
| Part A, B and FE: Duration of Response (DOR) as Assessed by the Investigators According to RECIST v 1.1 |  | From the first study intervention to planned final assessment at 508 days | 
| Part A, B and FE: Progression-free Survival (PFS) Time According to RECIST v 1.1 Assessed by Investigator |  | Part A and FE: From baseline to planned final assessment at 305 days; Part B: From baseline to planned final assessment at 473 days | 
| Part A, B and FE: Tumor size Based on Investigator Assessment According to RECIST v 1.1 |  | From the first study intervention to planned final assessment at 508 days | 
| Part A, B and FE: Overall Survival |  | From the first study intervention to planned final assessment at 508 days | 
| Part B: Number of Participants with Radiotherapy (RT)-induced Toxicity According to NCI-CTCAE v 5.0 |  | From the first study intervention to planned final assessment at 508 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Palliative Radiotherapy, Advanced solid tumors, M3814, Avelumab