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Clinical Trials/NCT03724890
NCT03724890
Completed
Phase 1

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

EMD Serono Research & Development Institute, Inc.8 sites in 1 country57 target enrollmentStarted: November 27, 2018Last updated:
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ConditionsOncologySolid Tumors
InterventionsRadiotherapyM3814Avelumab
DrugsM3814Avelumab

Overview

Phase
Phase 1
Status
Completed
Enrollment
57
Locations
8
Primary Endpoint
Part FE: Maximum Observed Plasma Concentration (Cmax) of M3814
OverviewStudy DesignEligibility CriteriaArms & InterventionsOutcomesInvestigatorsSitesRecords & IdentifiersSimilar Trials

Overview

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.

Study Design

Study Type
Interventional
Allocation
Non Randomized
Intervention Model
Parallel
Primary Purpose
Treatment
Masking
None

Eligibility Criteria

Ages
18 Years to — (Adult, Older Adult)
Sex
All
Accepts Healthy Volunteers
No

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

Arms & Interventions

Part B: M3814 + Avelumab + Radiotherapy (RT)

Experimental

Intervention: Radiotherapy (Radiation)

Part B: M3814 + Avelumab + Radiotherapy (RT)

Experimental

Intervention: M3814 (Drug)

Part A: M3814 + Avelumab

Experimental

Intervention: M3814 (Drug)

Part A: M3814 + Avelumab

Experimental

Intervention: Avelumab (Drug)

Part B: M3814 + Avelumab + Radiotherapy (RT)

Experimental

Intervention: Avelumab (Drug)

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

Experimental

Intervention: M3814 (Drug)

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

Experimental

Intervention: Avelumab (Drug)

Outcomes

Primary Outcomes

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

Time Frame: 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

Cmax was obtained directly from the concentration versus time curve.

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

Time Frame: Day 1 up to Day 21

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.

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

Time Frame: Day 1 up to Day 28

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.

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

Time Frame: 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

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

Secondary Outcomes

  • Part A: Average Plasma Concentration of M3814 Observed Post-dose (Cavg)(Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 1)
  • Part B: Average Plasma Concentration of M3814 Observed Post-dose (Cavg)(Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1)
  • Part A: Fluctuation Index of M3814(Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 1)
  • Part B: Fluctuation Index of M3814(Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1)
  • Part B: Accumulation Ratio of AUC [Racc (AUC 0-24)] of M3814(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)
  • Part B: Accumulation Ratio of Cmax [Racc(Cmax)] of M3814(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)
  • Part A: Accumulation Ratio of AUC [Racc (AUC 0-12)] of M3814(Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Days 1 and 15)
  • 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 A: Number of Participants With Clinically Meaningful Change From Baseline in Electrocardiogram (ECG)(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))
  • Part FE: 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 404 Days))
  • Part B: Number of Participants With Clinically Meaningful Change From Baseline in Electrocardiogram (ECG)(Time from first study intervention up to long term safety follow-up period (Up to 513 Days))
  • Part FE: Number of Participants With Clinically Meaningful Change From Baseline in Electrocardiogram (ECG)(Time from first study intervention up to long term safety follow-up period (Up to 404 Days))
  • Part A: Number of Participants With Clinically Meaningful Change From Baseline in Vital Signs(Time from first study intervention up to long term safety follow-up period (Up to 516 days))
  • Part B: Number of Participants With Clinically Meaningful Change From Baseline in Vital Signs(Time from first study intervention up to long term safety follow-up period (Up to 513 Days))
  • Part FE: Number of Participants With Clinically Meaningful Change From Baseline in Vital Signs(Time from first study intervention up to long term safety follow-up period (Up to 404 Days))
  • Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score(Time from first study intervention up to long term safety follow-up period (Up to 516 days))
  • Part A: Accumulation Ratio of Maximum Observed Drug Concentration [Racc(Cmax)] of M3814(Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Days 1 and 15)
  • Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score(Time from first study intervention up to long term safety follow-up period (Up to 513 Days))
  • Part FE: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score(Time from first study intervention up to long term safety follow-up period (Up to 404 Days))
  • Part A: Single Dose: Maximum Observed Plasma Concentration (Cmax) of M3814(Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 1)
  • Part A: Multiple Dose: Maximum Observed Plasma Concentration (Cmax) of M3814(Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 15)
  • Part B: Single Dose: Maximum Observed Drug Concentration (Cmax) of M3814(Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1)
  • Part B: Multiple Dose: Maximum Observed Drug Concentration (Cmax) of M3814(Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 10)
  • Part A: Single Dose: Time to Reach the Maximum Plasma Concentration (Tmax) of M3814(Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 15)
  • Part A: Multiple Dose: Time to Reach the Maximum Plasma Concentration (Tmax) of M3814(Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 15)
  • Part B: Single Dose: Time to Reach the Maximum Plasma Concentration (Tmax) of M3814(Pre-dose, 2, 4 and 6 hours post-dose on Day 10)
  • Part B: Multiple Dose: Time to Reach the Maximum Plasma Concentration (Tmax) of M3814(Pre-dose, 2, 4 and 6 hours post-dose on Day 10)
  • Part A: Minimum Observed Drug Concentration (Cmin) of M3814(Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 1)
  • Part B: Minimum Observed Drug Concentration (Cmin) of M3814(Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1)
  • Part A: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUC0-t) of M3814(Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 1)
  • Part B: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUC0-t) of M3814(Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1)
  • Part A: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M3814(Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 1)
  • Part B: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M3814(Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1)
  • Part A: Single Dose: Apparent Terminal Half-life (t1/2) of M3814(Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 15)
  • Part A: Multiple Doses: Apparent Terminal Half-life (t1/2) of M3814(Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 15)
  • Part B: Single Dose: Apparent Terminal Half-life (t1/2) of M3814(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)
  • Part B: Multiple Dose: Apparent Terminal Half-life (t1/2) of M3814(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)
  • Part A: Apparent Volume of Distribution During Terminal Phase (Vz/f) of M3814(Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 1)
  • Part B: Apparent Volume of Distribution During Terminal Phase (Vz/f) of M3814(Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1)
  • Part A: Apparent Clearance (CL/f) of M3814(Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 1)
  • Part B: Apparent Clearance (CL/f) of M3814(Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1)
  • Part A: Terminal Elimination Rate Constant (Lambda z) of M3814(Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 1)
  • Part B: Terminal Elimination Rate Constant (Lambda z) of M3814(Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1)
  • Part A: Number of Participants With Positive Antidrug Antibody (ADA)(Time from first study intervention up to long term safety follow-up period (Up to 516 Days))
  • Part B: Number of Participants With Positive Antidrug Antibody (ADA)(Time from first study intervention up to long term safety follow-up period (Up to 513 Days))
  • Part FE: Number of Participants With Positive Antidrug Antibody (ADA)(Part FE: From the first study intervention to 508 days)
  • 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)(Time from first study intervention up to long term safety follow-up period (Up to 516 Days))
  • 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)(Time from first study intervention up to long term safety follow-up period (Up to 513 Days))
  • 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)(Time from first study intervention up to long term safety follow-up period (Up to 404 Days))
  • Part A: Duration of Response (DoR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Investigator(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)
  • Part B: Duration of Response (DoR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Investigator(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)
  • Part FE: Duration of Response (DoR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Investigator(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)
  • Part A: Progression-free Survival (PFS) Time According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) Assessed by Investigator(Time from first study intervention up to long term safety follow-up period (Up to 516 Days))
  • Part B: Progression-free Survival (PFS) Time According to RECIST v 1.1 Assessed by Investigator(Time from first study intervention up to long term safety follow-up period (Up to 513 Days))
  • Part FE: Progression-free Survival (PFS) Time According to RECIST v 1.1 Assessed by Investigator(Time from first study intervention up to long term safety follow-up period (Up to 404 Days))
  • Part A: Overall Survival(Time from first study intervention up to long term safety follow-up period (Up to 1359 Days))
  • Part B: Overall Survival(Time from first study intervention up to long term safety follow-up period (Up to 1359 Days))
  • Part FE: Overall Survival(Time from first study intervention up to long term safety follow-up period (Up to 1359 Days))
  • Part A: Best Percent Change From Baseline in Tumor Size According to RECIST v 1.1(Time from first study intervention up to long term safety follow-up period (Up to 516 Days))
  • Part B: Best Percent Change From Baseline in Tumor Size According to RECIST v 1.1(Time from first study intervention up to long term safety follow-up period (Up to 513 Days))
  • Part FE: Best Percent Change From Baseline in Tumor Size According to RECIST v 1.1(Time from first study intervention up to long term safety follow-up period (Up to 404 Days))
  • Part B: Number of Participants With Radiotherapy (RT)-Induced Toxicity According to NCI-CTCAE v 5.0(Time from first study intervention up to long term safety follow-up period (Up to 512.4 Days))

Investigators

Sponsor Class
Industry
Responsible Party
Sponsor

Study Sites (8)

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