Clinical trial NCT03724890: Study of Avelumab-M3814 Combinations
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Oncology
Solid Tumors
Keywords: Palliative Radiotherapy
Advanced solid tumors
M3814
Avelumab
Lead sponsor: EMD Serono
Sponsor class: INDUSTRY
Collaborators: name: Merck KGaA, Darmstadt, Germany
First posted: 2018-10-30
Enrollment: 57
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The main purpose of the study was 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.


Eligibility criteria: Inclusion Criteria:

* Part A and Part FE (M3814 + avelumab): Participants had 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 had 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 had 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 had 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 had 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 had 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

Primary outcomes:
measure: Part A: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) Assessed Using National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Version 5.0
timeFrame: Day 1 up to Day 21
measure: Part B: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) Assessed Using National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Version 5.0
timeFrame: Day 1 up to Day 28
measure: Part Food Effect (FE): Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to 6 Hour (AUC0-6hour) of M3814
timeFrame: Pre-dose, 1, 2, 4 and 6 hours post-dose on Day 1; Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 15; Pre-dose, 2, 4 and 6 hours post-dose on Day 22
measure: Part FE: Maximum Observed Plasma Concentration (Cmax) of M3814
timeFrame: Pre-dose, 1, 2, 4 and 6 hours post-dose on Day 1; Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 15; Pre-dose, 2, 4 and 6 hours post-dose on Day 22
Secondary outcomes:
measure: Part A: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-related TEAEs and Serious TEAEs According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0
timeFrame: Time from first study intervention up to long term safety follow-up period (Up to 516 days)
measure: Part B: Number of Participants With Treatment-Emergent Adverse Events, Treatment-related TEAEs and Serious TEAEs According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0
timeFrame: Time from first study intervention up to long term safety follow-up period (Up to 513 Days)
measure: Part FE: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-related TEAEs and Serious TEAEs According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0
timeFrame: Time from first study intervention up to long term safety follow-up period (Up to 404 Days)
measure: Part A: Number of Participants With Abnormalities Grade Greater Than or Equals to (>=) 3 in Laboratory Test Values
timeFrame: Time from first study intervention up to long term safety follow-up period (Up to 516 days)
measure: Part B: Number of Participants With Abnormalities Grade Greater Than or Equals to (>=) 3 in Laboratory Test Values
timeFrame: Time from first study intervention up to long term safety follow-up period (Up to 513 Days)
measure: Part FE: Number of Participants With Abnormalities Grade Greater Than or Equals to (>=) 3 in Laboratory Test Values
timeFrame: Time from first study intervention up to long term safety follow-up period (Up to 404 Days)
measure: Part A: Number of Participants With Clinically Meaningful Change From Baseline in Electrocardiogram (ECG)
timeFrame: Time from first study intervention up to long term safety follow-up period (Up to 516 days)
measure: Part B: Number of Participants With Clinically Meaningful Change From Baseline in Electrocardiogram (ECG)
timeFrame: Time from first study intervention up to long term safety follow-up period (Up to 513 Days)
measure: Part FE: Number of Participants With Clinically Meaningful Change From Baseline in Electrocardiogram (ECG)
timeFrame: Time from first study intervention up to long term safety follow-up period (Up to 404 Days)
measure: Part A: Number of Participants With Clinically Meaningful Change From Baseline in Vital Signs
timeFrame: Time from first study intervention up to long term safety follow-up period (Up to 516 days)
measure: Part B: Number of Participants With Clinically Meaningful Change From Baseline in Vital Signs
timeFrame: Time from first study intervention up to long term safety follow-up period (Up to 513 Days)
measure: Part FE: Number of Participants With Clinically Meaningful Change From Baseline in Vital Signs
timeFrame: Time from first study intervention up to long term safety follow-up period (Up to 404 Days)
measure: Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score
timeFrame: Time from first study intervention up to long term safety follow-up period (Up to 516 days)
measure: Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score
timeFrame: Time from first study intervention up to long term safety follow-up period (Up to 513 Days)
measure: Part FE: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score
timeFrame: Time from first study intervention up to long term safety follow-up period (Up to 404 Days)
measure: Part A: Single Dose: Maximum Observed Plasma Concentration (Cmax) of M3814
timeFrame: Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 1
measure: Part A: Multiple Dose: Maximum Observed Plasma Concentration (Cmax) of M3814
timeFrame: Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 15
measure: Part B: Single Dose: Maximum Observed Drug Concentration (Cmax) of M3814
timeFrame: Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1
measure: Part B: Multiple Dose: Maximum Observed Drug Concentration (Cmax) of M3814
timeFrame: Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 10
measure: Part A: Single Dose: Time to Reach the Maximum Plasma Concentration (Tmax) of M3814
timeFrame: Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 15
measure: Part A: Multiple Dose: Time to Reach the Maximum Plasma Concentration (Tmax) of M3814
timeFrame: Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 15
measure: Part B: Single Dose: Time to Reach the Maximum Plasma Concentration (Tmax) of M3814
timeFrame: Pre-dose, 2, 4 and 6 hours post-dose on Day 10
measure: Part B: Multiple Dose: Time to Reach the Maximum Plasma Concentration (Tmax) of M3814
timeFrame: Pre-dose, 2, 4 and 6 hours post-dose on Day 10
measure: Part A: Minimum Observed Drug Concentration (Cmin) of M3814
timeFrame: Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 1
measure: Part B: Minimum Observed Drug Concentration (Cmin) of M3814
timeFrame: Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1
measure: Part A: Average Plasma Concentration of M3814 Observed Post-dose (Cavg)
timeFrame: Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 1
measure: Part B: Average Plasma Concentration of M3814 Observed Post-dose (Cavg)
timeFrame: Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1
measure: Part A: Fluctuation Index of M3814
timeFrame: Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 1
measure: Part B: Fluctuation Index of M3814
timeFrame: Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1
measure: Part A: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUC0-t) of M3814
timeFrame: Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 1
measure: Part B: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUC0-t) of M3814
timeFrame: Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1
measure: Part A: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M3814
timeFrame: Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 1
measure: Part B: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M3814
timeFrame: Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1
measure: Part A: Accumulation Ratio of Maximum Observed Drug Concentration [Racc(Cmax)] of M3814
timeFrame: Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Days 1 and 15
measure: Part B: Accumulation Ratio of Cmax [Racc(Cmax)] of M3814
timeFrame: Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1;Pre-dose, 2, 4 and 6 hours post-dose on Day 10
measure: Part A: Accumulation Ratio of AUC [Racc (AUC 0-12)] of M3814
timeFrame: Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Days 1 and 15
measure: Part B: Accumulation Ratio of AUC [Racc (AUC 0-24)] of M3814
timeFrame: Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1; Pre-dose, 2, 4 and 6 hours post-dose on Day 10
measure: Part A: Single Dose: Apparent Terminal Half-life (t1/2) of M3814
timeFrame: Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 15
measure: Part A: Multiple Doses: Apparent Terminal Half-life (t1/2) of M3814
timeFrame: Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 15
measure: Part B: Single Dose: Apparent Terminal Half-life (t1/2) of M3814
timeFrame: Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1;Pre-dose, 2, 4 and 6 hours post-dose on Day 10
measure: Part B: Multiple Dose: Apparent Terminal Half-life (t1/2) of M3814
timeFrame: Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1;Pre-dose, 2, 4 and 6 hours post-dose on Day 10
measure: Part A: Apparent Volume of Distribution During Terminal Phase (Vz/f) of M3814
timeFrame: Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 1
measure: Part B: Apparent Volume of Distribution During Terminal Phase (Vz/f) of M3814
timeFrame: Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1
measure: Part A: Apparent Clearance (CL/f) of M3814
timeFrame: Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 1
measure: Part B: Apparent Clearance (CL/f) of M3814
timeFrame: Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1
measure: Part A: Terminal Elimination Rate Constant (Lambda z) of M3814
timeFrame: Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 1
measure: Part B: Terminal Elimination Rate Constant (Lambda z) of M3814
timeFrame: Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1
measure: Part A: Number of Participants With Positive Antidrug Antibody (ADA)
timeFrame: Time from first study intervention up to long term safety follow-up period (Up to 516 Days)
measure: Part B: Number of Participants With Positive Antidrug Antibody (ADA)
timeFrame: Time from first study intervention up to long term safety follow-up period (Up to 513 Days)
measure: Part FE: Number of Participants With Positive Antidrug Antibody (ADA)
timeFrame: Part FE: From the first study intervention to 508 days
measure: Part A: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
timeFrame: Time from first study intervention up to long term safety follow-up period (Up to 516 Days)
measure: Part B: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
timeFrame: Time from first study intervention up to long term safety follow-up period (Up to 513 Days)
measure: Part FE: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
timeFrame: Time from first study intervention up to long term safety follow-up period (Up to 404 Days)
measure: Part A: Duration of Response (DoR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Investigator
timeFrame: Time from first documentation of objective response until date of first documentation of PD or death due to any cause, whichever occurred first, assessed up to 516 Days
measure: Part B: Duration of Response (DoR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Investigator
timeFrame: Time from first documentation of objective response until date of first documentation of PD or death due to any cause, whichever occurred first, assessed up to 513 Days
measure: Part FE: Duration of Response (DoR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Investigator
timeFrame: Time from first documentation of objective response until date of first documentation of PD or death due to any cause, whichever occurred first, assessed up to 44 Weeks
measure: Part A: Progression-free Survival (PFS) Time According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) Assessed by Investigator
timeFrame: Time from first study intervention up to long term safety follow-up period (Up to 516 Days)
measure: Part B: Progression-free Survival (PFS) Time According to RECIST v 1.1 Assessed by Investigator
timeFrame: Time from first study intervention up to long term safety follow-up period (Up to 513 Days)
measure: Part FE: Progression-free Survival (PFS) Time According to RECIST v 1.1 Assessed by Investigator
timeFrame: Time from first study intervention up to long term safety follow-up period (Up to 404 Days)
measure: Part A: Overall Survival
timeFrame: Time from first study intervention up to long term safety follow-up period (Up to 1359 Days)
measure: Part B: Overall Survival
timeFrame: Time from first study intervention up to long term safety follow-up period (Up to 1359 Days)
measure: Part FE: Overall Survival
timeFrame: Time from first study intervention up to long term safety follow-up period (Up to 1359 Days)
measure: Part A: Best Percent Change From Baseline in Tumor Size According to RECIST v 1.1
timeFrame: Time from first study intervention up to long term safety follow-up period (Up to 516 Days)
measure: Part B: Best Percent Change From Baseline in Tumor Size According to RECIST v 1.1
timeFrame: Time from first study intervention up to long term safety follow-up period (Up to 513 Days)
measure: Part FE: Best Percent Change From Baseline in Tumor Size According to RECIST v 1.1
timeFrame: Time from first study intervention up to long term safety follow-up period (Up to 404 Days)
measure: Part B: Number of Participants With Radiotherapy (RT)-Induced Toxicity According to NCI-CTCAE v 5.0
timeFrame: Time from first study intervention up to long term safety follow-up period (Up to 512.4 Days)
Other outcomes:
Locations:
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center and Research Institute, Inc
state: Florida
city: Chicago
country: United States
facility: The University of Chicago Medical Center
state: Illinois
city: Lake Success
country: United States
facility: Mount Sinai - PRIME (10707)
state: New York
city: Cincinnati
country: United States
facility: UC Health Clinical Trials Office (10702)
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center - Stephenson Cancer Center
state: Oklahoma
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center Health System
state: Pennsylvania
city: Greenville
country: United States
facility: Greenville Hospital System University Medical Center (ITOR)
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt-Ingram Cancer Center (8867)
state: Tennessee
Study officials:
affiliation: Merck KGaA, Darmstadt, Germany
name: Medical Responsible
role: STUDY_DIRECTOR
References:
citation: Perez B, Aljumaily R, Marron TU, Shafique MR, Burris H, Iams WT, Chmura SJ, Luke JJ, Edenfield W, Sohal D, Liao X, Boesler C, Machl A, Seebeck J, Becker A, Guenther B, Rodriguez-Gutierrez A, Antonia SJ. Phase I study of peposertib and avelumab with or without palliative radiotherapy in patients with advanced solid tumors. ESMO Open. 2024 Feb;9(2):102217. doi: 10.1016/j.esmoop.2023.102217. Epub 2024 Feb 5.