Clinical trial NCT03225105: M3541 in Combination With Radiotherapy in 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Solid Tumors
Keywords: Solid Tumors
M3541
Palliative radiotherapy
Adenosine triphosphate-competitive inhibitor
Lead sponsor: EMD Serono
Sponsor class: INDUSTRY
Collaborators: name: Merck KGaA, Darmstadt, Germany
First posted: 2017-07-21
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Subsequent cohorts of patients treated at different dose levels.
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion Criteria:

* 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)
* 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 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).
* Other protocol defined exclusion criteria could apply

Primary outcomes:
measure: M3541 50 mg + 100 mg + 200 mg + RT: Number of Participants With Dose Limiting Toxicities (DLTs)
timeFrame: Baseline up to 5 weeks (including 2 weeks of treatment and 3 weeks of follow-up period)
measure: M3541 300 mg + RT: Number of Participants With Dose Limiting Toxicities (DLTs)
timeFrame: Baseline up to 4 weeks (including 2 weeks of treatment and 2 weeks of the follow-up period)
Secondary outcomes:
measure: 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)
timeFrame: Baseline up to 749 days
measure: Number of Participants With Grade 3 or Higher Laboratory Abnormalities Based on National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE)
timeFrame: Baseline up to Day 44
measure: Number of Participants With Abnormalities in Vital Signs
timeFrame: Baseline up to 379 days
measure: Number of Participants With Abnormalities in Physical Examination Reported as Adverse Events (AEs)
timeFrame: Baseline up to 379 days
measure: Number of Participants With Abnormal Change From Baseline in Electrocardiogram (ECG)
timeFrame: Baseline up to 15 days
measure: Number of Participants With Best Overall Response (BOR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
timeFrame: Time from randomization to 964 days
measure: Progression-Free Survival (PFS) Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Investigator
timeFrame: From first dose of study drug to disease progression or death from any cause, assessed up to 964 days
measure: Maximum Observed Plasma Concentration (Cmax) of M3541
timeFrame: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
measure: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M3541
timeFrame: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
measure: Time to Reach Maximum Observed Plasma Concentration (Tmax) of M3541
timeFrame: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
measure: Apparent Terminal Half-Life (t1/2) of M3541
timeFrame: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
measure: Area Under Plasma Concentration-Time Curve From Time Zero to the Last Quantifiable Sampling Time Point (AUC[0-last]) of M3541
timeFrame: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
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
timeFrame: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
measure: Area Under the Concentration-Time Curve From Time Zero to 6 Hour Postdose (AUC[0-6h]) of M3541
timeFrame: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
measure: Area Under Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC[0-inf]) of M3541
timeFrame: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
measure: Dose Normalized Area Under Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC[0-inf]/Dose) of M3541
timeFrame: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
measure: Oral Clearance (CL/F) of M3541
timeFrame: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
measure: Oral Clearance at Steady-State (CLss/F) of M3541
timeFrame: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
measure: Apparent Volume of Distribution During Terminal Phase (Vz/F) of M3541
timeFrame: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
measure: Apparent Volume of Distribution at Steady-State (Vss/F) of M3541
timeFrame: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
measure: Accumulation Ratio for Area Under Plasma Concentration-Time Curve From Time Zero to 6 Hour (Racc[AUC0-6]) of M3541
timeFrame: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
measure: Accumulation Ratio for Maximum Observed Plasma Concentration (Racc[Cmax])
timeFrame: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
measure: Pre-dose Plasma Concentration (Ctrough) of M3541
timeFrame: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
measure: Minimum Observed Plasma Concentration (Cmin) of M3541
timeFrame: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
measure: Average Plasma Concentration (Cavg) of M3541
timeFrame: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
Other outcomes:
Locations:
city: Indianapolis
country: United States
facility: IU Simon Cancer Center
state: Indiana
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt-Ingram Cancer Center
state: Tennessee
Study officials:
affiliation: EMD Serono Inc., a business of Merck KGaA, Darmstadt, Germany
name: Medical Responsible
role: STUDY_DIRECTOR
References:
citation: 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.