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Study of Avelumab-M3814 Combinations

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03724890
Recruitment Status : Recruiting
First Posted : October 30, 2018
Last Update Posted : October 5, 2020
Sponsor:
Collaborator:
Merck KGaA, Darmstadt, Germany
Information provided by (Responsible Party):
EMD Serono ( EMD Serono Research & Development Institute, Inc. )

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Oncology Solid Tumors Drug: M3814 Drug: Avelumab Radiation: Radiotherapy Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 47 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : November 27, 2018
Estimated Primary Completion Date : April 13, 2021
Estimated Study Completion Date : April 30, 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Avelumab

Arm Intervention/treatment
Experimental: Part A: M3814 + Avelumab Drug: M3814
Participants will receive M3814 twice daily (BID) continuously starting from Day 1 until progressive disease (PD) or unacceptable toxicity.
Other Names:
  • Peposertib
  • MSC2490484A

Drug: Avelumab
Participants will receive avelumab once every 2 weeks (Q2W) starting from Day 1 until PD or unacceptable toxicity.

Experimental: Part B: M3814 + Avelumab + Radiotherapy (RT) Drug: M3814
Participants will receive M3814 concomitantly with RT once (QD) daily starting Day 1 for 5 days per week for 2 weeks in total.
Other Names:
  • Peposertib
  • MSC2490484A

Drug: Avelumab
Participants will receive avelumab once every 2 weeks (Q2W) starting from Day 1 until PD or unacceptable toxicity.

Radiation: Radiotherapy
Participants will receive radiotherapy at the dose of 3 grays (Gy) per day starting Day 1 for 5 days per week for 2 weeks.

Experimental: Part FE: M3814 + Avelumab (fasted/fed state) Drug: M3814
Participants will receive M3814 twice daily (BID) continuously starting from Day 1 until progressive disease (PD) or unacceptable toxicity.
Other Names:
  • Peposertib
  • MSC2490484A

Drug: Avelumab
Participants will receive avelumab once every 2 weeks (Q2W) starting from Day 1 until PD or unacceptable toxicity.




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

Secondary Outcome Measures :
  1. 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 [ Time Frame: From the first study intervention to planned final assessment at 508 days ]
  2. Part A, B and FE: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters, Vital Signs, Physical Examination, Electrocardiogram (ECG) Findings [ Time Frame: From the first study intervention to planned final assessment at 508 days ]
    Number of participants with clinically significant abnormalities will be reported.

  3. Part A, B and FE: Number of Participants With Status Assessed on Eastern Cooperative Oncology Group Performance Status (ECOG PS) [ Time Frame: From the first study intervention to planned final assessment at 508 days ]
  4. Part A and B: Maximum Observed Drug Concentration (Cmax) of Avelumab [ Time Frame: Part A: Pre-dose up to end of treatment at 299 days; Part B: Pre-dose up to end of treatment at 451 days ]
  5. Part A and B: Minimum Observed Drug Concentration (Cmin) of Avelumab [ Time Frame: Part A: Pre-dose up to end of treatment at 299 days; Part B: Pre-dose up to end of treatment at 451 days ]
  6. Part A and B: Accumulation Ratio for Cmax [Racc(Cmax)] of Avelumab [ Time Frame: Part A: Pre-dose up to end of treatment at 299 days; Part B: Pre-dose up to end of treatment at 451 days ]
  7. Part A and B: Accumulation Ratio for AUC [Racc (AUC)] of Avelumab [ Time Frame: Part A: Pre-dose up to end of treatment at 299 days; Part B: Pre-dose up to end of treatment at 451 days ]
  8. Part A and B: Apparent Terminal Half-life (t1/2) of Avelumab [ Time Frame: Part A: Pre-dose up to end of treatment at 299 days; Part B: Pre-dose up to end of treatment at 451 days ]
  9. Part A and B: Maximum Observed Drug Concentration (Cmax) of M3814 [ Time Frame: Part A: Pre-dose up to end of treatment at 268 days; Part B: Pre-dose up to end of treatment at 343 days ]
  10. Part A and B: Time to Reach the Maximum Plasma Concentration (tmax) of M3814 [ Time Frame: Part A: Pre-dose up to end of treatment at 268 days; Part B: Pre-dose up to end of treatment at 343 days ]
  11. Part A and B: Minimum Observed Drug Concentration (Cmin) of M3814 [ Time Frame: Part A: Pre-dose up to end of treatment at 268 days; Part B: Pre-dose up to end of treatment at 343 days ]
  12. Part A and B: Average Plasma Concentration of M3814 Observed Post-dose (Cavg) [ Time Frame: Part A: Pre-dose up to end of treatment at 268 days; Part B: Pre-dose up to end of treatment at 343 days ]
  13. Part A and B: Fluctuation Index of M3814 [ Time Frame: Part A: Pre-dose up to end of treatment at 268 days; Part B: Pre-dose up to end of treatment at 343 days ]
  14. Part A and B: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUC0-t) of M3814 [ Time Frame: Part A: Pre-dose up to end of treatment at 268 days; Part B: Pre-dose up to end of treatment at 343 days ]
  15. Part A and B: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-∞) of M3814 [ Time Frame: Part A: Pre-dose up to end of treatment at 268 days; Part B: Pre-dose up to end of treatment at 343 days ]
  16. Part A and B: Accumulation ratio for Cmax [Racc(Cmax)] of M3814 [ Time Frame: Part A: Pre-dose up to end of treatment at 268 days; Part B: Pre-dose up to end of treatment at 343 days ]
  17. Part A: Accumulation ratio for AUC [Racc(Auc)] of M3814 [ Time Frame: Part A: Pre-dose up to end of treatment at 268 days; Part B: Pre-dose up to end of treatment at 343 days ]
  18. Part A: Apparent Terminal Half-life (t1/2) of M3814 [ Time Frame: Part A: Pre-dose up to end of treatment at 268 days; Part B: Pre-dose up to end of treatment at 343 days ]
  19. Part A and B: Apparent Volume of Distribution During Terminal Phase (Vz/f) of M3814 [ Time Frame: Part A: Pre-dose up to end of treatment at 268 days; Part B: Pre-dose up to end of treatment at 343 days ]
  20. Part A and B: Apparent Clearance (CL/f) of M3814 [ Time Frame: Part A: Pre-dose up to end of treatment at 268 days; Part B: Pre-dose up to end of treatment at 343 days ]
  21. Part A and B: Terminal Elimination Rate Constant (λz) of M3814 [ Time Frame: Part A: Pre-dose up to end of treatment at 268 days; Part B: Pre-dose up to end of treatment at 343 days ]
  22. Part A, B and FE: Number of Participants With Positive Antidrug Antibody (ADA) Assay [ Time Frame: 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 ]
  23. 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) [ Time Frame: From the first study intervention to planned final assessment at 508 days ]
  24. Part A, B and FE: Duration of Response (DOR) as Assessed by the Investigators According to RECIST v 1.1 [ Time Frame: From the first study intervention to planned final assessment at 508 days ]
  25. Part A, B and FE: Progression-free Survival (PFS) Time According to RECIST v 1.1 Assessed by Investigator [ Time Frame: Part A and FE: From baseline to planned final assessment at 305 days; Part B: From baseline to planned final assessment at 473 days ]
  26. Part A, B and FE: Tumor size Based on Investigator Assessment According to RECIST v 1.1 [ Time Frame: From the first study intervention to planned final assessment at 508 days ]
  27. Part A, B and FE: Overall Survival [ Time Frame: From the first study intervention to planned final assessment at 508 days ]
  28. Part B: Number of Participants with Radiotherapy (RT)-induced Toxicity According to NCI-CTCAE v 5.0 [ Time Frame: From the first study intervention to planned final assessment at 508 days ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03724890


Contacts
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Contact: US Medical Information 888-275-7376 eMediUSA@emdserono.com
Contact: Communication Center +49 6151 72 ext 5200 service@emdgroup.com

Locations
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United States, California
Marin Cancer Care, Inc. - Pharmatech Oncology, Inc. Recruiting
Greenbrae, California, United States, 94904
Contact       peisenberg@marincancercare.com   
Principal Investigator: Peter D Eisenberg         
United States, Florida
H. Lee Moffitt Cancer Center and Research Institute, Inc Recruiting
Tampa, Florida, United States, 33612
United States, Illinois
The University of Chicago Medical Center Recruiting
Chicago, Illinois, United States, 60637
United States, New York
Mount Sinai - PRIME (10707) Recruiting
Lake Success, New York, United States, 11041
United States, Ohio
UC Health Clinical Trials Office (10702) Recruiting
Cincinnati, Ohio, United States, 45267-0502
Contact       morri2j7@ucmail.uc.edu   
Principal Investigator: John C Morris         
United States, Oklahoma
University of Oklahoma Health Sciences Center - Stephenson Cancer Center Recruiting
Oklahoma City, Oklahoma, United States, 73104
United States, Pennsylvania
University of Pittsburgh Medical Center Health System Recruiting
Pittsburgh, Pennsylvania, United States, 15213
Contact       jluke@medicine.bsd.uchicago.edu   
Principal Investigator: Jason J Luke         
United States, South Carolina
Greenville Hospital System University Medical Center (ITOR) Recruiting
Greenville, South Carolina, United States, 29605
Contact       william.edenfield@prismahealth.org   
Principal Investigator: William J Edenfield         
United States, Tennessee
Tennessee Oncology, PLLC Recruiting
Nashville, Tennessee, United States, 37205
Vanderbilt-Ingram Cancer Center (8867) Recruiting
Nashville, Tennessee, United States, 37212
Contact       wade.iams@vumc.org   
Principal Investigator: Wade Iams         
Sponsors and Collaborators
EMD Serono Research & Development Institute, Inc.
Merck KGaA, Darmstadt, Germany
Investigators
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Study Director: Medical Responsible Merck KGaA, Darmstadt, Germany
Additional Information:
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Responsible Party: EMD Serono Research & Development Institute, Inc.
ClinicalTrials.gov Identifier: NCT03724890    
Other Study ID Numbers: MS201964_0001
First Posted: October 30, 2018    Key Record Dates
Last Update Posted: October 5, 2020
Last Verified: September 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by EMD Serono ( EMD Serono Research & Development Institute, Inc. ):
Palliative Radiotherapy
Advanced solid tumors
M3814
Avelumab
Additional relevant MeSH terms:
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Neoplasms