Clinical Trials /

M3541 in Combination With Radiotherapy in Subjects With Solid Tumors

NCT03225105

Description:

This dose-escalation study will evaluate the safety, tolerability, pharmacokinetic (PK), pharmacodynamic, and explore antitumor activity of M3541 in combination with fractionated palliative radiotherapy (RT) in subjects with solid tumors with malignant lesions in the thorax, abdominal cavity, head and neck region, or extremities likely to benefit from palliative RT.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: M3541 in Combination With Radiotherapy in Subjects With Solid Tumors
  • Official Title: A Phase I, Open-label, Uncontrolled, Multicenter, Dose-escalation Study of M3541 in Combination With Palliative Radiotherapy in Subjects With Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: MS200770_0001
  • NCT ID: NCT03225105

Conditions

  • Solid Tumors

Interventions

DrugSynonymsArms
M3541M3541 + Palliative Radiotherapy (RT)

Purpose

This dose-escalation study will evaluate the safety, tolerability, pharmacokinetic (PK), pharmacodynamic, and signs of clinical efficacy of M3541 in combination with fractionated palliative radiotherapy (RT) in subjects with solid tumors with malignant lesions in the thorax, abdominal cavity, head and neck region, or extremities likely to benefit from palliative RT.

Trial Arms

NameTypeDescriptionInterventions
M3541 + Palliative Radiotherapy (RT)Experimental
  • M3541

Eligibility Criteria

        Inclusion Criteria:

          -  Subjects must have solid tumors with malignant lesions in the thorax, abdominal
             cavity, head and neck region, or extremities (any histology) likely to benefit from
             palliative radiotherapy; subjects requiring palliative RT for lesions in the spine or
             lesions adjacent to the spinal cord are excluded from this study

          -  Eastern Cooperative Oncology Group performance status (ECOG PS) =< 2

          -  Life expectancy >= 3 months

          -  Adequate hematologic, hepatic, and renal function

          -  Agree to use highly effective contraception (that is, methods with a failure rate of
             less than 1 percent per year) if the subject is male or a female of childbearing
             potential (female partners of childbearing potential of male subjects must also agree
             to use highly effective contraception)

          -  Other protocol defined inclusion criteria could apply

        Exclusion Criteria:

          -  Use of other anticancer therapy within 15 days before the first dose of M3541
             administration and should not be within the "at risk follow-up period" for that
             specific anticancer therapy. The use of any investigational agent is not allowed
             within 28 days before the first dose of M3541

          -  Residual toxicity due to previous anticancer therapy with no return to baseline or =<
             Grade 1 (except alopecia) according to CTCAE V4.03

          -  Extensive prior RT on more than 30 percent of bone marrow reserves (by Investigator
             judgment), or prior bone marrow/stem cell transplantation within 5 years before study
             start

          -  Prior RT to the same region that would be irradiated in this study

          -  Subjects at increased risk for radiation toxicities, such as known collagen vascular
             disease (example, scleroderma, Sjogren's disease, etc) or other inherited radiation
             hypersensitivity syndromes (example, Gorlin syndrome, Fanconi anemia,
             ataxia-telangiectasia, etc.)

          -  Surgical intervention within 28 days prior to the first dose of M3541 administration

          -  Known central nervous system metastases causing clinical symptoms or metastases that
             require therapeutic intervention. Subjects with a history of treated central nervous
             system (CNS) metastases (by surgery or radiation therapy) are not eligible unless they
             have fully recovered from treatment, demonstrated no progression for at least 2
             months, and do not require continued steroid therapy. Subjects with CNS metastases
             incidentally detected during Screening that do not cause clinical symptoms and for
             which standard of care suggests no therapeutic intervention is indicated, should be
             discussed with the Sponsor Medical Responsible

          -  Active difficulty swallowing, malabsorption or other chronic gastrointestinal disease
             or conditions (including pancreas deficiency requiring Creon therapy) that may hamper
             compliance and/or absorption of M3541

          -  Subjects currently receiving or unable to stop using medications or herbal supplements
             known to be potent inhibitors of cytochrome P450 (CYP) 3A and / or P-glycoprotein
             (P-gp) (CYP and / P-gp must stop at least 1 week before treatment with M3541) or
             potent inducers of CYP3A or P-gp (must stop at least 3 weeks before treatment with
             M3541) or drugs mainly metabolized by CYP3A with a narrow therapeutic index (must stop
             at least 1 day prior). However, the inclusion of these subjects, who in the opinion of
             the Investigator may benefit from treatment with M3541, must be approved by the
             Sponsor

          -  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:Occurrence of Dose-limiting Toxicities (DLTs)
Time Frame:Baseline up to 5 weeks
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Occurrence of Treatment Emergent Adverse Events (TEAEs), Grade >=3 AEs, Serious AEs and Deaths According to Common Terminology Criteria of Adverse Events (CTCAE) version 4.03
Time Frame:Baseline up to 32 months
Safety Issue:
Description:
Measure:Number of Subjects With Clinically Significant Laboratory Abnormalities
Time Frame:Baseline up to Day 44
Safety Issue:
Description:
Measure:Number of Subjects With Clinically Significant Abnormalities in Vital Signs and Physical Examination Findings
Time Frame:Baseline up to 32 months
Safety Issue:
Description:
Measure:Number of Subjects With Clinically Significant Electrocardiogram (ECG) Abnormalities
Time Frame:Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day [FD] 1 and FD 9; 8 , 12 hours post-dose on FD 1; pre-dose and 2.25 hours post-dose on FD 2, FD 3, FD 4, FD 5, and FD 6
Safety Issue:
Description:
Measure:Best Overall Response (BOR) as Assessed by Investigator
Time Frame:Baseline, every 6 weeks (starting on Post-treatment Day 42) for the first 6 months, then every 12 weeks thereafter until disease progression, assessed up to 1 year
Safety Issue:
Description:
Measure:Progression Free Survival (PFS) as Assessed by Investigator
Time Frame:From first dose of study drug to disease progression onset of other anticancer therapy, or death from any cause, assessed up to 1 year
Safety Issue:
Description:
Measure:Maximum Observed Plasma Concentration (Cmax) of M3541
Time Frame:Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on FD 1 and FD 9; 8, 12 hours post-dose on FD 1; pre-dose and 2.25 hours post-dose on FD 2, FD 3, FD 4, FD 5, and FD 6
Safety Issue:
Description:
Measure:Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M3541
Time Frame:Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on FD 1 and FD 9; 8, 12 hours post-dose on FD 1
Safety Issue:
Description:
Measure:Time to Reach Maximum Observed Plasma Concentration (Tmax) of M3541
Time Frame:Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on FD 1 and FD 9; 8, 12 hours post-dose on FD 1
Safety Issue:
Description:
Measure:Apparent Terminal Half-Life (t1/2) of M3541
Time Frame:Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on FD 1 and FD 9; 8, 12 hours post-dose on FD 1
Safety Issue:
Description:
Measure:Area Under the Concentration-Time Curve From Time Zero to the Last Quantifiable Sampling Time Point (AUC[0-last]) of M3541
Time Frame:Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on FD 1 and FD 9; 8, 12 hours post-dose on FD 1
Safety Issue:
Description:
Measure:Dose Normalized Area Under the Concentration-Time Curve From Time Zero to the Last Quantifiable Sampling Time Point (AUC[0-last]/dose) of M3541
Time Frame:Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on FD 1 and FD 9; 8, 12 hours post-dose on FD 1
Safety Issue:
Description:
Measure:Area Under the Concentration-Time Curve From Time Zero to 6 Hour Postdose (AUC[0-6h]) of M3541
Time Frame:Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4 and 6 hours post-dose on FD 1
Safety Issue:
Description:
Measure:Area Under the Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC[0-inf]) of M3541
Time Frame:Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6, 8 and 12 hours post-dose on FD 1
Safety Issue:
Description:
Measure:Dose Normalized Area Under the Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC[0-inf]/dose) of M3541
Time Frame:Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6, 8 and 12 hours post-dose on FD 1
Safety Issue:
Description:
Measure:Oral Clearance (CL/F) of M3541
Time Frame:Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6, 8 and 12 hours post-dose on FD 1
Safety Issue:
Description:
Measure:Oral Clearance at Steady-State (CLss/F) of M3541
Time Frame:Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4 and 6 hours post-dose on FD 9
Safety Issue:
Description:
Measure:Apparent Volume of Distribution During Terminal Phase (Vz/F) of M3541
Time Frame:Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6, 8 and 12 hours post-dose on FD 1
Safety Issue:
Description:
Measure:Apparent Volume of Distribution at Steady-State (Vss/F) of M3541
Time Frame:Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4 and 6 hours post-dose on FD 9
Safety Issue:
Description:
Measure:Accumulation Ratio for Area Under the Concentration-Time Curve (Racc[AUC])
Time Frame:Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4 and 6 hours post-dose on FD 9
Safety Issue:
Description:
Measure:Accumulation Ratio for Maximum Concentration (Racc[Cmax])
Time Frame:Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4 and 6 hours post-dose on FD 9
Safety Issue:
Description:
Measure:Predose Plasma Concentration (Ctrough) of M3541
Time Frame:pre-dose on FD 2, FD 3, FD, 4, FD 5, and FD 6
Safety Issue:
Description:
Measure:Minimum Observed Plasma Concentration (Cmin) of M3541
Time Frame:Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4 and 6 hours post-dose on FD 9
Safety Issue:
Description:
Measure:Average Plasma Concentration (Cavg) of M3541
Time Frame:Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4 and 6 hours post-dose on FD 9
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:EMD Serono Research & Development Institute, Inc.

Trial Keywords

  • Solid Tumors
  • M3541
  • Palliative radiotherapy
  • Adenosine triphosphate-competitive inhibitor

Last Updated

February 8, 2018