M3541 in Combination With Radiotherapy in Solid Tumors

NCT03225105 | Terminated Phase 1 Results DMC FDA Drug

• 1 other identifier: MS200770_0001
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 5

Brief Summary

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

Conditions

Solid Tumors

Keywords

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

Outcome Measures

Primary Outcomes (2)

• M3541 50 mg + 100 mg + 200 mg + RT: Number of Participants With Dose Limiting Toxicities (DLTs)

  DLT is classified per the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and defined as any of the following events occurring after first dose of study intervention and judged not to be related to underlying disease or any previous or concomitant medication. Grade (Gr) \>=3 non-hematologic toxicity with exception of Nausea, vomiting and diarrhea lasting =\<3 days in once per FD; Worsening of preexisting tumor pain associated with tumor lesions for which participant was irradiated in context of this study; Evidence of treatment-related hepatocellular injury for \>3 days in the once per FD; Any occurrence of Hy's law; Gr 4 neutropenia lasting for \>5 days, Gr 4 thrombocytopenia or Gr 4 anemia that was unexplained by underlying disease; Any toxicity related to study treatment that caused participant to interrupt treatment for not to be able to be treated within 24 hours of the scheduled treatment time.

  Baseline up to 5 weeks (including 2 weeks of treatment and 3 weeks of follow-up period)

• M3541 300 mg + RT: Number of Participants With Dose Limiting Toxicities (DLTs)

  DLT is classified per the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and defined as any of the following events occurring after first dose of study intervention and judged not to be related to underlying disease or any previous or concomitant medication. Grade (Gr) \>=3 non-hematologic toxicity with exception of Nausea, vomiting and diarrhea lasting =\<3 days in once per FD; Worsening of preexisting tumor pain associated with tumor lesions for which participant was irradiated in context of this study; Evidence of treatment-related hepatocellular injury for \>3 days in the once per FD; Any occurrence of Hy's law; Gr 4 neutropenia lasting for \>5 days, Gr 4 thrombocytopenia or Gr 4 anemia that was unexplained by underlying disease; Any toxicity related to study treatment that caused participant to interrupt treatment for not to be able to be treated within 24 hours of the scheduled treatment time.

  Baseline up to 4 weeks (including 2 weeks of treatment and 2 weeks of the follow-up period)

Secondary Outcomes (25)

• Number of Participants With Treatment Emergent Adverse Events (TEAEs), Grade >=3 Adverse Events (AEs), Serious TEAEs and Deaths According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, Version 4.03 (CTCAE V4.03)

  Baseline up to 749 days

• Number of Participants With Grade 3 or Higher Laboratory Abnormalities Based on National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE)

  Baseline up to Day 44

• Number of Participants With Abnormalities in Vital Signs

  Baseline up to 379 days

• Number of Participants With Abnormalities in Physical Examination Reported as Adverse Events (AEs)

  Baseline up to 379 days

• Number of Participants With Abnormal Change From Baseline in Electrocardiogram (ECG)

  Baseline up to 15 days

Study Arms (4)

M3541 50 mg + RT

EXPERIMENTAL

Participants received 50 milligrams (mg) M3541 orally once per fraction day (FD) in combination with palliative radiotherapy (RT) administered in fraction of 30 Gray (Gy) given in 10 fractions of 3 Gy/FD on FD 1 to FD 10, for 2 consecutive calendar weeks (ie, Monday through Friday, with the intervening Saturday and Sunday as M3541 / RT holidays).

Drug: M3541; Radiation: Palliative Radiotherapy (RT)

M3541 100 mg + RT

EXPERIMENTAL

Participants received 100 mg M3541 orally once per FD in combination with palliative RT administered in fraction of 30 Gray (Gy) given in 10 fractions of 3 Gy/FD on FD 1 to FD 10 for 2 consecutive calendar weeks (ie, Monday through Friday, with the intervening Saturday and Sunday as M3541 / RT holidays).

Drug: M3541; Radiation: Palliative Radiotherapy (RT)

M3541 200 mg + RT

EXPERIMENTAL

Participants received 200 mg M3541 orally once per FD in combination with palliative RT administered in fraction of 30 Gray (Gy) given in 10 fractions of 3 Gy/FD on FD 1 to FD 10 for 2 consecutive calendar weeks (ie, Monday through Friday, with the intervening Saturday and Sunday as M3541 / RT holidays).

Drug: M3541; Radiation: Palliative Radiotherapy (RT)

M3541 300 mg + RT

EXPERIMENTAL

Participants received 300 mg M3541 orally once per FD in combination with palliative RT administered in fraction of 30 Gray (Gy) given in 10 fractions of 3 Gy/FD on FD 1 to FD 10 for 2 consecutive calendar weeks (ie, Monday through Friday, with the intervening Saturday and Sunday as M3541 / RT holidays).

Drug: M3541; Radiation: Palliative Radiotherapy (RT)

Interventions

M3541 DRUG

Participants received M3541 orally once per fraction day (FD) for two consecutive calendar weeks (that is, Monday through Friday, with Saturday and Sunday as M3541 holidays).

M3541 100 mg + RT; M3541 200 mg + RT; M3541 300 mg + RT; M3541 50 mg + RT

Palliative Radiotherapy (RT) RADIATION

Participants received 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 Friday, with Saturday and Sunday as RT holidays).

M3541 100 mg + RT; M3541 200 mg + RT; M3541 300 mg + RT; M3541 50 mg + RT

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants 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; participants 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 participant is male or a female of childbearing potential (female partners of childbearing potential of male participants must also agree to use highly effective contraception)

You may not qualify if:

• 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 Common Terminology Criteria for Adverse Events (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
• Participants 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. Participants 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. Participants 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
• Participants 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).

Sponsors & Collaborators

• EMD Serono Research & Development Institute, Inc.: lead
• Merck KGaA, Darmstadt, Germany: collaborator

Study Sites (5)

IU Simon Cancer Center

Indianapolis, Indiana, 46202, United States

Location

Washington University

St Louis, Missouri, 63110, United States

Location

Hackensack University Medical Center

Hackensack, New Jersey, 07601, United States

Location

Fox Chase Cancer Center

Philadelphia, Pennsylvania, 19111, United States

Location

Vanderbilt-Ingram Cancer Center

Nashville, Tennessee, 37212, United States

Location

Related Publications (1)

• Waqar SN, Robinson C, Olszanski AJ, Spira A, Hackmaster M, Lucas L, Sponton L, Jin H, Hering U, Cronier D, Grinberg M, Seithel-Keuth A, Diaz-Padilla I, Berlin J. Phase I trial of ATM inhibitor M3541 in combination with palliative radiotherapy in patients with solid tumors. Invest New Drugs. 2022 Jun;40(3):596-605. doi: 10.1007/s10637-022-01216-8. Epub 2022 Feb 12.

  PMID: 35150356 DERIVED

Related Links

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

Limitations and Caveats

The study was terminated early per sponsor decision to halt further development of M3541 due to pharmaceutical and PK/pharmacodynamics properties that precluded further clinical development.

Results Point of Contact

• Title: Communication Center
• Organization: Merck KGaA, Darmstadt, Germany

service@emdgroup.com

+49-6151-72-5200

Study Officials

• Medical Responsible

  EMD Serono Inc., a business of Merck KGaA, Darmstadt, Germany

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Subsequent cohorts of patients treated at different dose levels.

Study Record Dates

• First Submitted: July 19, 2017
• First Posted: July 21, 2017
• Study Start: September 6, 2017
• Primary Completion: September 2, 2019
• Study Completion: April 27, 2020
• Last Updated: November 22, 2023
• Results First Posted: November 22, 2023

Record last verified: 2023-01

Locations

US (5)