Clinical trial NCT03225105
Conditions: Solid Tumors
Keywords: Solid Tumors M3541 Palliative radiotherapy Adenosine triphosphate-competitive inhibitor
Sponsor: EMD Serono Research & Development Institute, Inc.
Start date: 2017-09-06; Completion date: 2020-04-27
Enrollment: 15 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

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.

Detailed description:

Arms: arm 1: 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). arm 2: 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). arm 3: 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). arm 4: 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).
Interventions: intervention 1: M3541 intervention 2: Palliative Radiotherapy (RT)
Intervention descriptions: intervention 1: 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). intervention 2: 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).

Protocol documents:
Prot_000.pdf: 
















































































M3541 
M3541 in Combination With Radiotherapy in Solid Tumors
MS200770-0001
41/143
Details of structures and associated procedures will be defined in a separate Manual of Operations, 
which will be prepared under the supervision of the Clinical Trial Leader.
The study will appear in ClinicalTrials.gov and all other required registries.
2.3
Safety Monitoring Committee
A Safety Monitoring Committee (SMC) will serve as both a safety monitoring and 
decision-making body. The SMC is responsible for dose-escalation / de-escalation decisions (such 
as adding new cohorts at different previously non-explored dose level or modifying dose 
schedules) and may decide to enroll additional subjects at a previously explored dose level and / or 
schedule, which will be considered a new cohort at that dose level. While changing the schedule, 
the SMC will ensure to change appropriately (or not) the ECG assessments and PK sampling times. 
The SMC may recommend to stop the study based on the observed safety profile. The decisions
of the SMC will be guided by the results of the Bayesian regression model with overdose control 
(see Section 5.1). The recommendation according to the Bayesian regression model is not binding 
and the final decision is to be made by the SMC.
The specific working procedures will be described in an SMC charter, which will be established 
prior to the start of recruitment.
3
Background Information
Many patients with cancer are administered treatments which generate DNA damage, such as 
radiotherapy (RT) (ionizing radiation) and certain chemotherapeutic drugs. DNA strand breaks are 
difficult to repair, especially highly genotoxic double-strand breaks (DSB) and if left unrepaired, 
may lead to cell cycle arrest, cell death, or senescence. Double-strand breaks in DNA are remedied 
by 2 major distinct mechanisms; the homologous recombination repair and the nonhomologous 
end joining pathway. 
Ataxia-telangiectasia mutated (ATM) is a ubiquitously expressed serine / threonine protein kinase 
primarily activated by DSBs. It phosphorylates a network of key proteins (eg, H2AX, CHK2, p53, 
KAP1). Beside DSB repair, ATM affects the DNA damage checkpoint and thereby controls cell 
cycle arrest, and irreversible physiological responses such as senescence or cell death. In addition, 
ATM is part of other signaling networks, including cell metabolism and growth, oxidative stress, 
and chromatin remodeling, all of which are able to affect cancer progression. The inhibition of 
ATM kinase results in a synergistic enhancement of DNA DSB-inducing treatment modalities, 
such as RT, certain chemotherapeutic drugs, and the combination of both, chemoradiotherapy.
3.1
M3541
M3541 is a highly potent, and selective adenosine triphosphate-competitive inhibitor of the ATM 
kinase. As a result of the mechanism of action, M3541 enhances the therapeutic effect of DNA 
DSB-inducing treatment modalities. In vivo, M3541 has been shown to improve the antitumor 
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SAP_001.pdf: