Study of Avelumab-M3814 Combinations

NCT03724890 | Completed Phase 1 Results FDA Drug

• 1 other identifier: MS201964_0001
• Study Type: interventional
• Target: 57
• Locations: 1 country
• Sites: 8

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.

Conditions

Oncology; Solid Tumors

Keywords

Palliative Radiotherapy; Advanced solid tumors; M3814; Avelumab

Outcome Measures

Primary Outcomes (4)

• 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

  A DLT was defined as any Grade more than or equal to \>= 3 nonhematologic Adverse Event(AE) or any Grade\>= 4 hematologic,, occurring during the DLT period that is related to any of the study interventions. In addition, a DLT is considered: Grade 3 thrombocytopenia with medically concerning bleeding, Any febrile neutropenia. A study intervention-related Treatment emergent Adverse Event(TEAE) is of potential clinical significance such that further dose escalation would expose participants to unacceptable risk. Any toxicity related to study intervention that causes the participant to receive less than 80% of M3814 during DLT period, evidence of study treatment-related hepatocellular injury for more than 3 days, such as\> 5-fold elevations above the Upper Limits of Normal (ULN) of Alanine Aminotransferase (ALT) or Aspartate Aminotransferase(AST) with or without elevation of serum total bilirubin to \> 2 × ULN. Number of Participants with DLT Grade \>= 3 were reported.

  Day 1 up to Day 21

• 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

  A DLT was defined as any Grade more than or equal to \>= 3 nonhematologic Adverse Event(AE) or any Grade\>= 4 hematologic,, occurring during the DLT period that is related to any of the study interventions. In addition, a DLT is considered: Grade 3 thrombocytopenia with medically concerning bleeding, Any febrile neutropenia. A study intervention-related Treatment emergent Adverse Event(TEAE) is of potential clinical significance such that further dose escalation would expose participants to unacceptable risk. Any toxicity related to study intervention that causes the participant to receive less than 80% of M3814 during DLT period, evidence of study treatment-related hepatocellular injury for more than 3 days, such as\> 5-fold elevations above the Upper Limits of Normal (ULN) of Alanine Aminotransferase (ALT) or Aspartate Aminotransferase(AST) with or without elevation of serum total bilirubin to \> 2 × ULN. Number of Participants with DLT Grade \>= 3 were reported.

  Day 1 up to Day 28

• Part Food Effect (FE): Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to 6 Hour (AUC0-6hour) of M3814

  Area under the plasma concentration versus time curve from time zero to 6 hours post dosing for M3814 was reported.

  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

• Part FE: Maximum Observed Plasma Concentration (Cmax) of M3814

  Cmax was obtained directly from the concentration versus time curve.

  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 (66)

• 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

  Time from first study intervention up to long term safety follow-up period (Up to 516 days)

• 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

  Time from first study intervention up to long term safety follow-up period (Up to 513 Days)

• 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

  Time from first study intervention up to long term safety follow-up period (Up to 404 Days)

• Part A: Number of Participants With Abnormalities Grade Greater Than or Equals to (>=) 3 in Laboratory Test Values

  Time from first study intervention up to long term safety follow-up period (Up to 516 days)

• Part B: Number of Participants With Abnormalities Grade Greater Than or Equals to (>=) 3 in Laboratory Test Values

  Time from first study intervention up to long term safety follow-up period (Up to 513 Days)

Study Arms (3)

Part A: M3814 + Avelumab

EXPERIMENTAL

Drug: M3814; Drug: Avelumab

Part B: M3814 + Avelumab + Radiotherapy (RT)

EXPERIMENTAL

Drug: M3814; Drug: Avelumab; Radiation: Radiotherapy

Part FE: M3814 + Avelumab (fasted/fed state)

EXPERIMENTAL

Drug: M3814; Drug: Avelumab

Interventions

M3814 DRUG

Participants received M3814 twice daily (BID) continuously starting from Day 1 until progressive disease (PD) or unacceptable toxicity.

Also known as: Peposertib, MSC2490484A

Part A: M3814 + Avelumab; Part FE: M3814 + Avelumab (fasted/fed state)

Avelumab DRUG

Participants received avelumab once every 2 weeks (Q2W) starting from Day 1 until PD or unacceptable toxicity.

Part A: M3814 + Avelumab; Part B: M3814 + Avelumab + Radiotherapy (RT); Part FE: M3814 + Avelumab (fasted/fed state)

Radiotherapy RADIATION

Participants received radiotherapy at the dose of 3 grays (Gy) per day starting Day 1 for 5 days per week for 2 weeks.

Part B: M3814 + Avelumab + Radiotherapy (RT)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• EMD Serono Research & Development Institute, Inc.: lead
• Merck KGaA, Darmstadt, Germany: collaborator

Study Sites (8)

H. Lee Moffitt Cancer Center and Research Institute, Inc

Tampa, Florida, 33612, United States

Location

The University of Chicago Medical Center

Chicago, Illinois, 60637, United States

Location

Mount Sinai - PRIME (10707)

Lake Success, New York, 11041, United States

Location

UC Health Clinical Trials Office (10702)

Cincinnati, Ohio, 45267-0502, United States

Location

University of Oklahoma Health Sciences Center - Stephenson Cancer Center

Oklahoma City, Oklahoma, 73104, United States

Location

University of Pittsburgh Medical Center Health System

Pittsburgh, Pennsylvania, 15213, United States

Location

Greenville Hospital System University Medical Center (ITOR)

Greenville, South Carolina, 29605, United States

Location

Vanderbilt-Ingram Cancer Center (8867)

Nashville, Tennessee, 37212, United States

Location

Related Publications (1)

• 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.

  PMID: 38320431 BACKGROUND

Related Links

• Trial Awareness and Transparency website
• US Medical Information website, Medical Resources

MeSH Terms

Conditions

Neoplasms

Interventions

peposertib; avelumab; Radiotherapy

Intervention Hierarchy (Ancestors)

Therapeutics

Limitations and Caveats

Data collection and analysis of Pharmacokinetics and Immunogenicity for Avelumab were omitted and not conducted due to business reason. PK parameters for avelumab were planned but the decision was made to only list and summarize with descriptive statistics avelumab concentrations.

Results Point of Contact

• Title: Communication Center
• Organization: Merck KGaA, Darmstadt, Germany

service@emdgroup.com

+49-6151-72-5200

Study Officials

• Medical Responsible

  Merck KGaA, Darmstadt, Germany

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 29, 2018
• First Posted: October 30, 2018
• Study Start: November 27, 2018
• Primary Completion: September 1, 2021
• Study Completion: August 17, 2022
• Last Updated: April 10, 2025
• Results First Posted: April 10, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (8)