M3541 in Combination With Radiotherapy in Solid Tumors

Study Overview
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Brief Summary
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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.

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

Conditions
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Solid Tumors

Intervention / Treatment
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* Drug: M3541
* Radiation: Palliative Radiotherapy (RT)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Subsequent cohorts of patients treated at different dose levels.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: M3541 50 mg + RT<br>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<br>* 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).<br>Radiation: Palliative Radiotherapy (RT)<br>* 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).<br>|
| Experimental: M3541 100 mg + RT<br>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<br>* 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).<br>Radiation: Palliative Radiotherapy (RT)<br>* 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).<br>|
| Experimental: M3541 200 mg + RT<br>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<br>* 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).<br>Radiation: Palliative Radiotherapy (RT)<br>* 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).<br>|
| Experimental: M3541 300 mg + RT<br>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<br>* 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).<br>Radiation: Palliative Radiotherapy (RT)<br>* 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).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | An AE was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. A serious AE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs are events with start date on or after the date of first dose of study treatment and up to and including 30 days after the last dose of study treatment, or events with start date prior to the date of first dose of study treatment, and worsened in severity or become serious during treatment. TEAEs include both Serious TEAEs and non-serious TEAEs. | 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) | The laboratory assessment included measurements hematology and biochemistry parameters. It had been graded according to NCI-CTCAE version 4.03 into Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (Life-threatening) and Grade 5 = death. Participants with grade 3 or higher were reported. | Baseline up to Day 44 | 
| Number of Participants With Abnormalities in Vital Signs | Vital signs assessment included blood pressure, pulse rate, body temperature, respiratory rate, and body weight. Notably abnormal vital signs were: Blood pressure: systolic blood pressure >= 140 millimeter of mercury (mmHg) & diastolic blood pressure >=90 mmHg on treatment; Pulse rate >100 beats/min; Body temperature >= 38 degree Celsius (°C) on treatment; Respiratory rate >= 20 breaths/min; Weight (kilogram) > +/-20% from baseline. Number of Participants with abnormalities in vital signs were reported. | Baseline up to 379 days | 
| Number of Participants With Abnormalities in Physical Examination Reported as Adverse Events (AEs) | Number of participants with any clinically significant abnormalities in physical examination reported as adverse events with National Cancer Institute Common Terminology Criteria (NCI-CTC) Grade >=3 were presented. | Baseline up to 379 days | 
| Number of Participants With Abnormal Change From Baseline in Electrocardiogram (ECG) | The 12-lead ECG was recorded after the participant was in semi-supine position for at least 5 minutes. The ECG was obtained using a Holter recorder. Number of Participants with abnormal change from baseline in ECG were reported. | Baseline up to 15 days | 
| Number of Participants With Best Overall Response (BOR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | BOR was determined according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). BOR is defined as the best response of any of the complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) recorded from the date of randomization until disease progression or recurrence (taking the smallest measurement recorded since the start of treatment as reference). CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. SD=Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD is defined as at least a 20 percent (%) increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. | Time from randomization to 964 days | 
| Progression-Free Survival (PFS) Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Investigator | PFS is defined as the time (in months) from first administration of M3541 until the first date of progressive disease (PD) or death due to any cause. PFS was assessed as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). PD was defined as at least a 20% increase in the sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions and unequivocal progression of non-target lesions. Participants with neither disease progression nor death were censored at the last date of the last tumor assessment that confirmed that their disease had not progressed. Participant wise data reported for this outcome measure. | From first dose of study drug to disease progression or death from any cause, assessed up to 964 days | 
| Maximum Observed Plasma Concentration (Cmax) of M3541 | Cmax was obtained directly from the plasma concentration versus time curve. | 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 | 
| Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M3541 | Dose normalized was calculated as Cmax obtained directly from the concentration versus time curve divided by dose. | 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 | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of M3541 | Time to reach the maximum plasma concentration (Tmax) was obtained directly from the concentration versus time curve. | 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 | 
| Apparent Terminal Half-Life (t1/2) of M3541 | Apparent terminal half-life was defined as the time required for the plasma concentration of drug to decrease 50 percent in the final stage of its elimination. | 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 | 
| Area Under Plasma Concentration-Time Curve From Time Zero to the Last Quantifiable Sampling Time Point (AUC[0-last]) of M3541 | AUC(0-last) is defined as the area under the concentration-time curve from dosing (time 0) to the time of the last measured concentration. AUC(0-last) will be estimated using the Linear Up Log Down calculation method. | 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 | 
| Dose Normalized Area Under the Concentration-Time Curve From Time Zero to the Last Quantifiable Sampling Time Point (AUC[0-last]/Dose) of M3541 | The Dose normalized AUC from time zero to the last sampling time (0-last) at which the concentration is at or above the lower limit of quantification. Normalized using the actual dose, using the formula AUC0-last/Dose. | 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 | 
| Area Under the Concentration-Time Curve From Time Zero to 6 Hour Postdose (AUC[0-6h]) of M3541 | Area under the drug concentration-time curve from 0 to 6 hour post dosing for M3541. AUC0-6 was calculated according to the mixed log-linear trapezoidal rule. | 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 | 
| Area Under Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC[0-inf]) of M3541 | AUC0-inf is the area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time. | 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 | 
| Dose Normalized Area Under Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC[0-inf]/Dose) of M3541 | Dose normalized was calculated as area under the plasma concentration-time curve from time zero to 8 h postdose divided by dose. | 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 | 
| Oral Clearance (CL/F) of M3541 | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. CL/f = Dose /AUC0-inf. Predicted AUC0-inf should be used. | 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 | 
| Oral Clearance at Steady-State (CLss/F) of M3541 | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. | 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 | 
| Apparent Volume of Distribution During Terminal Phase (Vz/F) of M3541 | The Vz/f was defined as the theoretical volume in which the total amount of required to uniformly distribute to produce the desired plasma concentration. Apparent volume of distribution after oral dose (Vz/F) was influenced by the fraction absorbed. The Vz/f was calculated by dividing the dose with area under the concentration time curve from time zero to infinity multiplied with terminal elimination rate constant Lambda(z). Vz/f=Dose/AUC(0-inf)* Lambda(z). | 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 | 
| Apparent Volume of Distribution at Steady-State (Vss/F) of M3541 | Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vss/f after oral dose was influenced by the fraction absorbed. | 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 | 
| Accumulation Ratio for Area Under Plasma Concentration-Time Curve From Time Zero to 6 Hour (Racc[AUC0-6]) of M3541 | The accumulation ratio to assess the increase in exposure via AUC0-6h. Racc(AUC0-6h)= (AUC0-6h after multiple dose) / (AUC0-6h after single dose). | 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 | 
| Accumulation Ratio for Maximum Observed Plasma Concentration (Racc[Cmax]) | The accumulation ratio is to assess the increase in maximum concentration with multiple dosing. Racc(Cmax) = (Cmax after multiple dose)/ (Cmax after single dose). | 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 | 
| Pre-dose Plasma Concentration (Ctrough) of M3541 | Ctrough is the concentration prior to study drug administration. | 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 | 
| Minimum Observed Plasma Concentration (Cmin) of M3541 | Cmin is minimum observed plasma concentration obtained directly from the concentration versus time curve. | 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 | 
| Average Plasma Concentration (Cavg) of M3541 | Cavg was defined as average plasma concentration. | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Solid Tumors, M3541, Palliative radiotherapy, Adenosine triphosphate-competitive inhibitor