Study of Avelumab-M3814 Combinations

Solid Tumors Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03724890
• Other study ID #: MS201964_0001
• Status: Completed
• Phase: Phase 1
• Start date: November 27, 2018
• Est. completion date: August 17, 2022

Study information

• Verified date: November 2022
• Source: EMD Serono
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 57
• Est. completion date: August 17, 2022
• Est. primary completion date: September 1, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Neoplasms
• Oncology
• Solid Tumors

Intervention

Drug:
• M3814
Participants will receive M3814 twice daily (BID) continuously starting from Day 1 until progressive disease (PD) or unacceptable toxicity.
• M3814
Participants will receive M3814 concomitantly with RT once (QD) daily starting Day 1 for 5 days per week for 2 weeks in total.
• 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.

Locations

Country	Name	City	State
United States	The University of Chicago Medical Center	Chicago	Illinois
United States	UC Health Clinical Trials Office (10702)	Cincinnati	Ohio
United States	Greenville Hospital System University Medical Center (ITOR)	Greenville	South Carolina
United States	Mount Sinai - PRIME (10707)	Lake Success	New York
United States	Vanderbilt-Ingram Cancer Center (8867)	Nashville	Tennessee
United States	University of Oklahoma Health Sciences Center - Stephenson Cancer Center	Oklahoma City	Oklahoma
United States	University of Pittsburgh Medical Center Health System	Pittsburgh	Pennsylvania
United States	H. Lee Moffitt Cancer Center and Research Institute, Inc	Tampa	Florida

Sponsors (2)

Lead Sponsor	Collaborator
EMD Serono Research & Development Institute, Inc.	Merck KGaA, Darmstadt, Germany

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Part A: Occurrence of Dose-limiting Toxicities (DLTs)		From first study intervention to planned final assessment at 3 weeks
Primary	Part B: Occurrence of Dose-limiting Toxicities (DLTs)		From first study intervention to planned final assessment at 4 weeks
Primary	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
Primary	Part FE: Maximum Observed Drug Concentration (Cmax) of M3814		Pre-dose up to end of treatment at 268 days
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Part A and B: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-8) 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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Part A and B: Terminal Elimination Rate Constant (?z) 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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Part A, B and FE: Overall Survival		From the first study intervention to planned final assessment at 508 days
Secondary	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

External Links

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