Clinical Trials /

Study of Avelumab-M3814 Combinations

NCT03724890

Description:

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.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: 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

Clinical Trial IDs

  • ORG STUDY ID: MS201964_0001
  • NCT ID: NCT03724890

Conditions

  • Oncology
  • Solid Tumors

Interventions

DrugSynonymsArms
M3814Part A: M3814 + Avelumab
M3814Part B: M3814 + Avelumab + Radiotherapy (RT)
AvelumabPart A: M3814 + Avelumab

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Part A: M3814 + AvelumabExperimental
  • M3814
  • Avelumab
Part B: M3814 + Avelumab + Radiotherapy (RT)Experimental
  • M3814
  • Avelumab

Eligibility Criteria

        Inclusion Criteria:

          -  Part A (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 with primary tumors or metastatic tumor lesions in
             the lung 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 to the tumor in the lung

          -  Part A and B: Measurable or evaluable disease according to RECIST v 1.1

          -  Part A and B: Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to
             1 at study entry Demonstrate adequate organ function including bone marrow, liver and
             kidney based on blood tests within 28 days of first dose of study therapy)/ Have
             provided tissue from an archival tissue sample or newly obtained tissue sample

          -  Part A and B: Female participants of childbearing potential should be willing to use a
             highly effective contraceptive method or be surgically sterile, or abstain from
             heterosexual activity for the course of the study through 90 days after the last dose
             of study medication

          -  Part A and B: Male participants should agree to refrain from donating sperm and 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 and B: 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 4 weeks prior to 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 have 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 evidence of active central nervous system (CNS) metastases.
             Participants with previously treated brain metastases may participate provided the
             brain metastases are stable for at least 4 weeks prior to the first dose of study
             treatments and they are either off steroids or on a stable or decreasing dose of less
             than (<) 10 milligram (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 laboratory abnormalities that might confound trial results, interfere
             with the patient's participation or is not in the best interest of the participant

          -  Participants requiring systemic immunosuppressive treatment (such as steroids) for any
             reason who cannot be tapered off these drugs before start of study treatment.
             Participants with adrenal insufficiency, may continue corticosteroids at physiologic
             replacement dose, patients requiring steroids through a route known to result in a
             minimal systemic exposure (topical, intranasal, intra-ocular, or inhalation) or
             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 less than or equals to (<=) 10 mg
             prednisone daily may participate

          -  Participants with a history of human immunodeficiency virus (HIV), HIV 1/2 antibodies
             or known acquired immunodeficiency syndrome, Hepatitis B or Hepatitis C

          -  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 patients were deemed to have been cured with no additional therapy
             required or anticipated to be required. Patients 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 toxicities 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

          -  Participants who are pregnant / breastfeeding or expecting to conceive within the
             duration of the trial, starting with the screening visit through 90 days after the
             last dose

          -  for Part B only:

          -  Participants who have confirmed esophagitis and in whom radiation planning target
             volume will include any portion of the esophagus

          -  Participants in whom more than 10 percent (%) of the total esophagus might receive
             more than 15 Gy (50% of the prescribed 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

          -  Other protocol defined exclusion criteria could apply
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Part A: Occurrence of Dose-limiting Toxicities (DLTs)
Time Frame:From first study intervention to planned final assessment at 3 weeks
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Part A and B: 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
Safety Issue:
Description:
Measure:Part A and B: 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
Safety Issue:
Description:Number of participants with clinically significant abnormalities will be reported.
Measure:Part A and B: 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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure:Part A and B: Number of Participants With Positive Antidrug Antibody (ADA) Assay
Time Frame:Part A: 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
Safety Issue:
Description:
Measure:Part A and B: 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
Safety Issue:
Description:
Measure:Part A and B: 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
Safety Issue:
Description:
Measure:Part A and B: Progression-free Survival (PFS) Time According to RECIST v 1.1 Assessed by Investigator
Time Frame:Part A: From baseline to planned final assessment at 305 days; Part B: From baseline to planned final assessment at 473 days
Safety Issue:
Description:
Measure:Part A and B: 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
Safety Issue:
Description:
Measure:Part A and B: Overall Survival
Time Frame:From the first study intervention to planned final assessment at 508 days
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:EMD Serono Research & Development Institute, Inc.

Trial Keywords

  • Palliative Radiotherapy
  • Advanced solid tumors
  • M3814
  • Avelumab

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