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M3541 in Combination With Radiotherapy in Subjects With Solid Tumors

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ClinicalTrials.gov Identifier: NCT03225105
Recruitment Status : Completed
First Posted : July 21, 2017
Last Update Posted : September 14, 2020
Sponsor:
Collaborator:
Merck KGaA, Darmstadt, Germany
Information provided by (Responsible Party):
EMD Serono ( EMD Serono Research & Development Institute, Inc. )

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Solid Tumors Drug: M3541 Radiation: Palliative Radiotherapy (RT) Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 15 participants
Allocation: N/A
Intervention Model: Sequential Assignment
Intervention Model Description: Subsequent cohorts of patients treated at different dose levels.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I, Open-label, Uncontrolled, Multicenter, Dose-escalation Study of M3541 in Combination With Palliative Radiotherapy in Subjects With Solid Tumors
Actual Study Start Date : September 6, 2017
Actual Primary Completion Date : September 2, 2019
Actual Study Completion Date : April 27, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Palliative Care

Arm Intervention/treatment
Experimental: M3541 + Palliative Radiotherapy (RT) Drug: M3541
Subjects will receive M3541 orally in combination with fractionated palliative RT for two consecutive calendar weeks (that is, Monday through Sunday, with Saturday and Sunday as M3541 / RT holidays).

Radiation: Palliative Radiotherapy (RT)
Subjects will receive RT dose of 30 Gray (Gy) given in 10 fractions (3 Gy given per fraction day) administered over two consecutive calendar weeks (that is, Monday through Sunday, with Saturday and Sunday as M3541 / RT holidays).




Primary Outcome Measures :
  1. Occurrence of Dose-limiting Toxicities (DLTs) [ Time Frame: Baseline up to 5 weeks ]

Secondary Outcome Measures :
  1. 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 ]
  2. Number of Subjects With Clinically Significant Laboratory Abnormalities [ Time Frame: Baseline up to Day 44 ]
  3. Number of Subjects With Clinically Significant Abnormalities in Vital Signs and Physical Examination Findings [ Time Frame: Baseline up to 32 months ]
  4. Number of Subjects With Clinically Significant Electrocardiogram (ECG) Abnormalities [ Time Frame: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6, 8, 12 hours post-dose on Fraction Day [FD] 1; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6, 72, 240 hours post-dose on FD 9; pre-dose and 2.25 hours post-dose on FD 2, FD 3, FD 4, FD 5, and FD 6 ]
  5. 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 ]
  6. 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 ]
  7. Maximum Observed Plasma Concentration (Cmax) of M3541 [ Time Frame: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6, 8, 12 hours post-dose on FD 1; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6, 72, 240 hours post-dose on FD 9; pre-dose and 2.25 hours post-dose on FD 2, FD 3, FD 4, FD 5, and FD 6 ]
  8. Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M3541 [ Time Frame: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6, 8, 12 hours post-dose on FD 1; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6, 72, 240 hours post-dose on FD 9 ]
  9. Time to Reach Maximum Observed Plasma Concentration (Tmax) of M3541 [ Time Frame: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6, 8, 12 hours post-dose on FD 1; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6, 72, 240 hours post-dose on FD 9 ]
  10. Apparent Terminal Half-Life (t1/2) of M3541 [ Time Frame: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6, 8, 12 hours post-dose on FD 1; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6, 72, 240 hours post-dose on FD 9 ]
  11. 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, 8, 12 hours post-dose on FD 1; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6, 72, 240 hours post-dose on FD 9 ]
  12. 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, 8, 12 hours post-dose on FD 1; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6, 72, 240 hours post-dose on FD 9 ]
  13. 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 ]
  14. 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 ]
  15. 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 ]
  16. 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 ]
  17. Oral Clearance at Steady-State (CLss/F) of M3541 [ Time Frame: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6, 72, 240 hours post-dose on FD 9 ]
  18. 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 ]
  19. Apparent Volume of Distribution at Steady-State (Vss/F) of M3541 [ Time Frame: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6, 72, 240 hours post-dose on FD 9 ]
  20. Accumulation Ratio for Area Under the Concentration-Time Curve (Racc[AUC]) [ Time Frame: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6, 72, 240 hours post-dose on FD 9 ]
  21. Accumulation Ratio for Maximum Concentration (Racc[Cmax]) [ Time Frame: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6, 72, 240 hours post-dose on FD 9 ]
  22. Predose Plasma Concentration (Ctrough) of M3541 [ Time Frame: pre-dose on FD 2, FD 3, FD, 4, FD 5, and FD 6 ]
  23. Minimum Observed Plasma Concentration (Cmin) of M3541 [ Time Frame: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6, 72, 240 hours post-dose on FD 9 ]
  24. Average Plasma Concentration (Cavg) of M3541 [ Time Frame: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6, 72, 240 hours post-dose on FD 9 ]


Information from the National Library of Medicine

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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:

  • 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).
  • 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): NCT03225105


Locations
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United States, Indiana
IU Simon Cancer Center
Indianapolis, Indiana, United States, 46202
United States, Missouri
Washington University
Saint Louis, Missouri, United States, 63110
United States, New Jersey
Hackensack University Medical Center
Hackensack, New Jersey, United States, 07601
United States, Pennsylvania
Fox Chase Cancer Center
Philadelphia, Pennsylvania, United States, 19111
United States, Tennessee
Vanderbilt-Ingram Cancer Center
Nashville, Tennessee, United States, 37212
Sponsors and Collaborators
EMD Serono Research & Development Institute, Inc.
Merck KGaA, Darmstadt, Germany
Investigators
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Study Director: Medical Responsible EMD Serono Inc., a business of Merck KGaA, Darmstadt, Germany
Additional Information:
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Responsible Party: EMD Serono Research & Development Institute, Inc.
ClinicalTrials.gov Identifier: NCT03225105    
Other Study ID Numbers: MS200770_0001
First Posted: July 21, 2017    Key Record Dates
Last Update Posted: September 14, 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. ):
Solid Tumors
M3541
Palliative radiotherapy
Adenosine triphosphate-competitive inhibitor
Additional relevant MeSH terms:
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Neoplasms