Phase 1 Trial of MSC2490484A, an Inhibitor of a DNA-dependent Protein Kinase, in Combination With Radiotherapy

Phase 1

Completed

Conditions: Advanced Solid Tumors

Interventions: Drug: M3814 100 mg
Drug: M3814 200 mg
Drug: M3814 300 mg
Drug: M3814 400 mg
Drug: M3814 50 mg
Radiation: Fractionated RT
Drug: Cisplatin

Registration Number: NCT02516813

Lead Sponsor: EMD Serono Research & Development Institute, Inc.

Brief Summary: M3814 was an investigational drug that is being evaluated for the treatment of participants with locally advanced tumors. The main purposes of this study was to determine the safety, the tolerability and the efficacy of M3814 in combination with radiotherapy and in combination with chemoradiotherapy (Radiotherapy + cisplatin).

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 52

Inclusion Criteria

Phase Ia part: advanced solid tumors or metastases including lymphoma localized in the head and neck region or thorax with an indication for fractionated palliative RT (Arm A); or treatment-naïve SCCHN eligible for fractionated curatively intended RT with concurrent cisplatin (Arm B)
Phase Ib part: treatment-naïve Stage III A/B NSCLC not eligible for surgical resection or concurrent chemoradiation (Arm A expansion cohort) or treatment-naïve SCCHN eligible for fractionated curatively intended RT with concurrent cisplatin (Arm B expansion cohort)
Ancillary cPoP Part: any tumor with at least 2 (sub)cutaneous tumor/metastases at least 2 cm apart which are RT naïve with an indication for high dose palliative RT
Availability of archival tumor material, either as a block or slides (Phase Ia and Ib). If no archival material is available then a fresh biopsy should be taken
Willing to have tumor biopsies collected in Ancillary cPoP
Measurable or evaluable disease by RECIST v1.1 (not required for ancillary cPoP part of the study)
Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 1
Life expectancy of ≥ 3 months (Phase Ia, Arm A) or ≥ 6 months (Phase Ia, Arm B and Phase Ib)
Female subjects of childbearing potential and male subjects with female partners of childbearing potential must be willing to avoid pregnancy.

Exclusion Criteria

Chemotherapy, immunotherapy, hormonal therapy, biologic therapy, or any other anticancer therapy or investigational medicinal product (IMP) within 28 days of first trial drug intake for Phase Ia subjects, and any prior therapy for Phase Ib subjects. For subjects with rapidly growing tumors localized in the head and neck region or thorax where the treating physician cannot wait for 28 days, inclusion may take place if there is no residual toxicity from previous treatment (maximum CTCAE Grade 1)
Prior RT to the same region within 12 months (Phase Ia, Arm A; subjects with tumors localized in the head and neck region or thorax) or at any time previously (Phase Ia, Arm B; treatment-naïve subjects with SCCHN and Phase Ib; treatment-naïve subjects with Stage III A/B NSCLC or SCCHN)
Extensive prior RT on ≥30% of bone marrow reserve as judged by the investigator or prior bone marrow/stem cell transplantation within 5 years before trial start.
Poor vital organ functions defined as:
- Bone marrow impairment as evidenced by hemoglobin <10.0 g/dL, neutrophil count <1.0 × 109/L, platelets <100 × 109/L
- Renal impairment as evidenced by serum creatinine >1.5 × upper limit of normal (ULN)
- Liver function abnormality as defined by total bilirubin >1.5 × ULN or aspartate aminotransferase (AST)/alanine aminotransferase (ALT) >2.5 × ULN (except for subjects with liver involvement, who can have AST/ALT >5 × ULN)
History of difficulty swallowing, malabsorption or other chronic gastrointestinal disease or conditions that may hamper compliance and/or absorption of the IMP, use of percutaneous endoscopic gastrostomy (PEG) tubes
Significant cardiac conduction abnormalities, including a history of long QTc syndrome and/or pacemaker, or impaired cardiovascular function such as New York Heart Association classification score >2.
Subjects currently receiving (or unable to stop using prior to receiving the first dose of trial drug) medications or herbal supplements known to be potent inhibitors of cytochrome P450 (CYP)3A or CYP2C19 (must stop at least 1 week prior), potent inducers of CYP3A or CYP2C19 (must stop at least 3 weeks prior), or drugs mainly metabolized by CYP3A with a narrow therapeutic index (must stop at least one day prior).
Subjects currently receiving H2-blocker or proton pump inhibitors (or unable to stop at least 5 days prior to the first treatment).
If the planned radiation field includes any part of the esophagus and the subject has symptoms of ongoing esophagitis, the subject is not eligible, unless an esophageal endoscopy rules out the presence of esophagitis
Subjects where more than 10% of the total esophagus volume receives more than 50% of the prescribed RT dose

Main exclusion criteria for Ancillary Clinical Proof-of-Principle Part:

History of difficulty swallowing, malabsorption or other chronic gastrointestinal disease or conditions that may hamper compliance and/or absorption of the IMP
History of any other significant medical disease such as major gastric or small bowel surgery, recent drainage of significant volumes of ascites or pleural effusion (as per Investigator's judgement) or a psychiatric condition that might impair the subject's well-being or preclude full participation in the trial
Subjects currently receiving (or unable to stop using prior to receiving the first dose of study drug) medications or herbal supplements known to be potent inhibitors of CYP3A or CYP2C19 must stop at least 1 week prior to taking MSC2490484A. Subjects receiving potent inducers of CYP3A or CYP2C19 must stop at least 3 weeks prior to taking MSC2490484A. Those receiving drugs mainly metabolized by CYP3A with a narrow therapeutic index as judged by the Investigator (and after optional consultation with the Sponsor) must stop at least one day prior to taking MSC2490484A.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Phase 1a (Arm A): M3814 Capsule (100 mg) + RT	M3814 100 mg	Participants with locally advanced disease (any tumor or metastases including lymphomas) localized in the head and neck region or thorax that was not amenable to surgical therapy, or with standard systemic therapy with an indication for palliative radiotherapy (RT) received 100 milligrams (mg) of M3814 as capsule orally once daily on fraction day (FD) 6 in combination with RT (3 Gray \[Gy\] x 10, 5 fractions per week \[F/W\]).
Phase 1a (Arm A): M3814 Capsule (100 mg) + RT	Fractionated RT	Participants with locally advanced disease (any tumor or metastases including lymphomas) localized in the head and neck region or thorax that was not amenable to surgical therapy, or with standard systemic therapy with an indication for palliative radiotherapy (RT) received 100 milligrams (mg) of M3814 as capsule orally once daily on fraction day (FD) 6 in combination with RT (3 Gray \[Gy\] x 10, 5 fractions per week \[F/W\]).
Phase 1a (Arm A): M3814 Capsule (200 mg) + RT	M3814 200 mg	Participants with locally advanced disease (any tumor or metastases including lymphomas) localized in the head and neck region or thorax that was not amenable to surgical therapy, or with standard systemic therapy with an indication for palliative RT received 200 mg of M3814 as capsule orally once daily on FD 6 in combination with RT (3 \[Gy\] x 10, 5 F/W).
Phase 1a (Arm A): M3814 Capsule (200 mg) + RT	Fractionated RT	Participants with locally advanced disease (any tumor or metastases including lymphomas) localized in the head and neck region or thorax that was not amenable to surgical therapy, or with standard systemic therapy with an indication for palliative RT received 200 mg of M3814 as capsule orally once daily on FD 6 in combination with RT (3 \[Gy\] x 10, 5 F/W).
Phase 1a (Arm A): M3814 Capsule (300 mg) + RT	M3814 300 mg	Participants with locally advanced disease (any tumor or metastases including lymphomas) localized in the head and neck region or thorax that was not amenable to surgical therapy, or with standard systemic therapy with an indication for palliative RT received 300 mg of M3814 as capsule orally once daily on FD 6 in combination with RT (3 \[Gy\] x 10, 5 F/W).
Phase 1a (Arm A): M3814 Capsule (300 mg) + RT	Fractionated RT	Participants with locally advanced disease (any tumor or metastases including lymphomas) localized in the head and neck region or thorax that was not amenable to surgical therapy, or with standard systemic therapy with an indication for palliative RT received 300 mg of M3814 as capsule orally once daily on FD 6 in combination with RT (3 \[Gy\] x 10, 5 F/W).
Phase 1a (Arm A): M3814 Capsule (400 mg) + RT	M3814 400 mg	Participants with locally advanced disease (any tumor or metastases including lymphomas) localized in the head and neck region or thorax that was not amenable to surgical therapy, or with standard systemic therapy with an indication for palliative RT received 400 mg of M3814 as capsule orally once daily on FD 6 in combination with RT (3 \[Gy\] x 10, 5 F/W).
Phase 1a (Arm A): M3814 Capsule (400 mg) + RT	Fractionated RT	Participants with locally advanced disease (any tumor or metastases including lymphomas) localized in the head and neck region or thorax that was not amenable to surgical therapy, or with standard systemic therapy with an indication for palliative RT received 400 mg of M3814 as capsule orally once daily on FD 6 in combination with RT (3 \[Gy\] x 10, 5 F/W).
Phase 1a (Arm A): M3814 Tablet (100 mg) + RT	M3814 100 mg	Participants with locally advanced disease (any tumor or metastases including lymphomas) localized in the head and neck region or thorax that was not amenable to surgical therapy, or with standard systemic therapy with an indication for palliative RT received 100 mg of M3814 as tablet orally once daily for 2 consecutive weeks in combination with RT (3 Gy x 10, 5 F/W).
Phase 1a (Arm A): M3814 Tablet (100 mg) + RT	Fractionated RT	Participants with locally advanced disease (any tumor or metastases including lymphomas) localized in the head and neck region or thorax that was not amenable to surgical therapy, or with standard systemic therapy with an indication for palliative RT received 100 mg of M3814 as tablet orally once daily for 2 consecutive weeks in combination with RT (3 Gy x 10, 5 F/W).
Phase 1a (Arm A): M3814 Tablet (200 mg) + RT	M3814 200 mg	Participants with locally advanced disease (any tumor or metastases including lymphomas) localized in the head and neck region or thorax that was not amenable to surgical therapy, or with standard systemic therapy with an indication for palliative RT received 200 mg of M3814 as tablet orally once daily for 2 consecutive weeks in combination with RT (3 Gy x 10, 5 F/W).
Phase 1a (Arm A): M3814 Tablet (200 mg) + RT	Fractionated RT	Participants with locally advanced disease (any tumor or metastases including lymphomas) localized in the head and neck region or thorax that was not amenable to surgical therapy, or with standard systemic therapy with an indication for palliative RT received 200 mg of M3814 as tablet orally once daily for 2 consecutive weeks in combination with RT (3 Gy x 10, 5 F/W).
Phase 1a (Arm A): M3814 Tablet (300 mg) + RT	M3814 300 mg	Participants with locally advanced disease (any tumor or metastases including lymphomas) localized in the head and neck region or thorax that was not amenable to surgical therapy, or with standard systemic therapy with an indication for palliative RT received 300 mg of M3814 as tablet orally once daily for 2 consecutive weeks in combination with RT (3 Gy x 10, 5 F/W).
Phase 1a (Arm A): M3814 Tablet (300 mg) + RT	Fractionated RT	Participants with locally advanced disease (any tumor or metastases including lymphomas) localized in the head and neck region or thorax that was not amenable to surgical therapy, or with standard systemic therapy with an indication for palliative RT received 300 mg of M3814 as tablet orally once daily for 2 consecutive weeks in combination with RT (3 Gy x 10, 5 F/W).
Phase 1a (Arm B): M3814 Capsule (50 mg) + CRT	M3814 50 mg	Participants with local/locally advanced squamous cell carcinoma of the head and neck (SCCHN) received 50 mg of M3814 as capsule orally once daily on FD 6 in combination with fractionated RT (2 Gy x 33 to 35 fractions; 5 F/W) and Cisplatin twice at a dose of 100 milligrams per square meter (mg/m\^2) or weekly at a dose of 40 (mg/m\^2).
Phase 1a (Arm B): M3814 Capsule (50 mg) + CRT	Fractionated RT	Participants with local/locally advanced squamous cell carcinoma of the head and neck (SCCHN) received 50 mg of M3814 as capsule orally once daily on FD 6 in combination with fractionated RT (2 Gy x 33 to 35 fractions; 5 F/W) and Cisplatin twice at a dose of 100 milligrams per square meter (mg/m\^2) or weekly at a dose of 40 (mg/m\^2).
Phase 1a (Arm B): M3814 Capsule (50 mg) + CRT	Cisplatin	Participants with local/locally advanced squamous cell carcinoma of the head and neck (SCCHN) received 50 mg of M3814 as capsule orally once daily on FD 6 in combination with fractionated RT (2 Gy x 33 to 35 fractions; 5 F/W) and Cisplatin twice at a dose of 100 milligrams per square meter (mg/m\^2) or weekly at a dose of 40 (mg/m\^2).
Phase 1a (Arm B): M3814 Tablet (100 mg) + CRT	Fractionated RT	Participants with squamous cell carcinoma of the head and neck (SCCHN) received 100 mg of M3814 as tablet orally once daily for 7 consecutive weeks in combination with fractionated RT (2 Gy X 33 to 35 fractions; 5 F/W) and Cisplatin twice at a dose of 100 mg/m\^2 or weekly at a dose of 40 (mg/m\^2).
Phase 1a (Arm B): M3814 Tablet (100 mg) + CRT	Cisplatin	Participants with squamous cell carcinoma of the head and neck (SCCHN) received 100 mg of M3814 as tablet orally once daily for 7 consecutive weeks in combination with fractionated RT (2 Gy X 33 to 35 fractions; 5 F/W) and Cisplatin twice at a dose of 100 mg/m\^2 or weekly at a dose of 40 (mg/m\^2).
Ancillary cPoP: M3814 Capsule (100 mg) + RT	M3814 100 mg	Participants with at least 2 (sub)cutaneous tumor/metastases of any type (at least 2 centimeters \[cm\] apart) with an indication for single high dose-palliative RT were included and received single oral dose of M3814 capsule at a dose of 100 mg on Day 2, prior 1.5 hours start of RT and a single high dose of RT (10-25 Gy) on Lesion 1 on Day 1 and on Lesion 2 on Day 2.
Ancillary cPoP: M3814 Capsule (100 mg) + RT	Fractionated RT	Participants with at least 2 (sub)cutaneous tumor/metastases of any type (at least 2 centimeters \[cm\] apart) with an indication for single high dose-palliative RT were included and received single oral dose of M3814 capsule at a dose of 100 mg on Day 2, prior 1.5 hours start of RT and a single high dose of RT (10-25 Gy) on Lesion 1 on Day 1 and on Lesion 2 on Day 2.
Ancillary cPOP: M3814 Capsule (200 mg) + RT	M3814 200 mg	Participants with at least 2 (sub)cutaneous tumor/metastases of any type (at least 2 cm apart) with an indication for single high dose-palliative RT were included and received single oral dose of M3814 capsule at a dose of 200 mg on Day 2, prior 1.5 hours start of RT and a single high dose of RT (10-25 Gy) on Lesion 1 on Day 1 and on Lesion 2 on Day 2.
Ancillary cPOP: M3814 Capsule (200 mg) + RT	Fractionated RT	Participants with at least 2 (sub)cutaneous tumor/metastases of any type (at least 2 cm apart) with an indication for single high dose-palliative RT were included and received single oral dose of M3814 capsule at a dose of 200 mg on Day 2, prior 1.5 hours start of RT and a single high dose of RT (10-25 Gy) on Lesion 1 on Day 1 and on Lesion 2 on Day 2.
Ancillary cPOP: M3814 Capsule (400 mg) + RT	M3814 400 mg	Participants with at least 2 (sub)cutaneous tumor/metastases of any type (at least 2 cm apart) with an indication for single high dose-palliative RT were included and received single oral dose of M3814 capsule at a dose of 400 mg on Day 2, prior 1.5 hours start of RT and a single high dose of RT (10-25 Gy) on Lesion 1 on Day 1 and on Lesion 2 on Day 2
Ancillary cPOP: M3814 Capsule (400 mg) + RT	Fractionated RT	Participants with at least 2 (sub)cutaneous tumor/metastases of any type (at least 2 cm apart) with an indication for single high dose-palliative RT were included and received single oral dose of M3814 capsule at a dose of 400 mg on Day 2, prior 1.5 hours start of RT and a single high dose of RT (10-25 Gy) on Lesion 1 on Day 1 and on Lesion 2 on Day 2

Primary Outcome Measures

Name	Time	Method
Phase 1a (Arm A): Number of Participants Who Experienced at Least One Dose-limiting Toxicity (DLT) According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)	Time from first dose of study treatment up to 5 weeks	DLT: any Grade (Gr) greater than or equal to (\>=) 3 nonhematologic adverse event (AE)/any Gr\>=4 hematologic AE that is related to any of study treatments and occurs during the DLT period of 5 weeks (Phase Ia, Arm A) after the first dose of M3814. Following are considered as DLTs: Gr3 thrombocytopenia with medically concerning bleeding; Febrile neutropenia; Any toxicity/study treatment-related adverse event (TEAE) that, in opinion of Safety Monitoring Committee (SMC), is of potential clinical significance such that further dose escalation would expose participants to unacceptable risk; Any toxicity related to study treatments that causes participant to receive less than 80 percent (%) of the planned RT dose; Evidence of study treatment-related hepatocellular injury for \> 3 days.
Phase 1a (Arm B): Number of Participants Who Experienced at Least One Dose-limiting Toxicity (DLT) According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)	Time from first dose of study treatment up to 12 weeks	DLT: any Grade (Gr) greater than or equal to (\>=) 3 nonhematologic AE/any Gr\>=4 hematologic AE that is related to any of study treatments and occurs during the DLT period of 12 weeks (Phase Ia, Arm B) after the first dose of M3814. Following are considered as DLTs: Gr3 thrombocytopenia with medically concerning bleeding; Febrile neutropenia; Any toxicity/study treatment-related adverse event (TEAE) that, in opinion of Safety Monitoring Committee (SMC), is of potential clinical significance such that further dose escalation would expose participants to unacceptable risk; Any toxicity related to study treatments that causes participant to receive less than 80 percent (%) of the planned RT dose; Any toxicity related to study treatments leading to an interruption of RT longer than 1 week in Arm B; Evidence of study treatment-related hepatocellular injury for \> 3 days.

Secondary Outcome Measures

Name	Time	Method
Phase 1a (Arm A and Arm B): Number of Participants With Grade Greater Than or Equal to (>=) 3 Treatment-Emergent Adverse Events (TEAEs) According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)	Time from first dose of study treatment up to long term safety follow-up period (Up to approximately 1 year)	Adverse Event (AE) was defined any untoward medical occurrence in a participant administered with a study drug, which does not necessarily have a causal relationship with this treatment. Serious AE was defined AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAEs: TEAEs was defined as events with onset date or worsening during the on-treatment period. TEAEs included serious AEs and non-serious AEs. As per NCI-CTCAE v4.03, Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening; Grade 5: Death. Number of participants with Grade \>=3 TEAEs were reported.
Phase 1a (Arm A and Arm B): Number of Participants With Shifts From Baseline to Worst Post-Baseline Grade in Hematology Parameters According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTC v4.03)	Time from first dose of study treatment up to long term safety follow-up period (Up to approximately 1 year)	Number of participants with shifts from Baseline values (Grade 0/1/2) to worst post-baseline values (Grade 1/2/3/4) were reported as per NCI-CTCAE, v4.03 graded from Grade 1 to 5. Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening; Grade 5: Death. Shifts in hematology parameter (hemoglobin low, leukocytes low, lymphocytes low, neutrophil count decreased, and platelet count decreased) were reported.
Phase 1a (Arm A and Arm B): Total Body Clearance Following Oral Administration (CL/f) of M3814 After Single Dose	Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 1 and Fraction Day 6	The apparent total body clearance of study intervention following extravascular administration on FD1, taking into account the fraction of dose absorbed. CL/f = Dose oral (p.o.)/AUC0-inf. The predicted AUC0-inf should be used.
Phase 1a (Arm A and Arm B): Number of Participants With Shifts From Baseline to Worst Post-Baseline Grade in Biochemistry Parameters According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)	Time from first dose of study treatment up to long term safety follow-up period (Up to approximately 1 year)	Number of participants with shifts from Baseline values (Grade 0/1/2) to worst post-baseline values (Grade 1/2/3/4) were reported as per NCI-CTCAE, v4.03 graded from Grade 1 to 5. Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening; Grade 5: Death. Shifts in biochemistry parameter (phosphate low, potassium low, sodium low, alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, blood bilirubin increased, glucose high, glucose low, albumin low and creatinine increased) were reported.
Phase 1a (Arm A and Arm B): Number of Participants With Markedly Abnormal Vital Sign Measurements	Time from first dose of study treatment up to long term safety follow-up period (Up to approximately 1 year)	Vital sign assessments included assessments of heart rate, blood pressure, body weight and body temperature. Abnormal vital sign measurement was decided by Investigator. Number of participants with markedly abnormal vital sign measurements were reported.
Phase 1a (Arm A and Arm B): Number of Participants With Shifts From Normal Baseline to Abnormal Post-baseline in Electrocardiogram (ECG)	Time from first dose of study treatment up to long term safety follow-up period (Up to approximately 1 year)	Electrocardiograms (ECG) was obtained after the participant has been in a supine position for at least 5 minutes. ECG parameters included heart rate, atrial ventricular conduction, QR and QT intervals (including QTcF), and possible arrhythmias. Any ECG finding that was judged by the investigator as a abnormal (worsening) compared with a baseline value was considered an adverse event. Number of participants with shifts from normal baseline values to abnormal post-baseline values in ECG were reported.
Phase 1a (Arm A and Arm B): Number of Participants With Confirmed Best Overall Response (BOR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Investigator	Time from first dose of study treatment up to long term safety follow-up period (Up to approximately 1 year)	Confirmed BOR was defined as best response of any of complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) recorded from date of randomization until disease progression. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) 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: defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. CR or PR must be confirmed by a subsequent tumor assessment, at least 4 weeks after initial documentation of CR or PR.
Phase 1a (Arm A and Arm B): Number of Participants With Unconfirmed Best Overall Response (BOR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Investigator	Time from first dose of study treatment up to long term safety follow-up period (Up to approximately 1 year)	Unconfirmed BOR was defined as unconfirmed best response of any of complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) recorded from date of randomization until disease progression. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) 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: defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.
Phase 1a (Arm A and Arm B): Median Percent Change From Baseline in Tumor Size Measurement According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Investigator	Time from first dose of study treatment up to long term safety follow-up period (Up to approximately 1 year)	The tumor size was defined as the sum of the longest diameters for the target lesions. The sum of lesion diameters was calculated using RECIST v1.1 and was assessed by Investigator.
Phase 1a (Arm A and Arm B): Maximum Plasma Concentration (Cmax) of M3814 After Single Dose	Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 1 and Fraction Day 6	Cmax was taken directly from the observed concentration-time curve.
Phase 1a (Arm A and Arm B): Time to Reach Maximum Plasma Concentration (Tmax) of M3814 After Single Dose	Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 1 and Fraction Day 6	tmax was obtained directly from the concentration versus time curve.
Phase 1a (Arm A and Arm B): Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) of M3814 After Single Dose	Pre-dose, 0.5, 1, 2, 4, 6 and 24 hours post-dose on Fraction Day 1 and Fraction Day 6	AUC0-24 of M3814 was defined as the area under the concentration time curve from time 0 to 24 hours post-dose.
Phase 1a (Arm A and Arm B): Area Under the Plasma Concentration-Time From Time Zero Extrapolated to Infinity (AUC0-inf) of M3814 After Single Dose	Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 1 and Fraction Day 6	The AUC from time zero (dosing time) extrapolated to infinity, based on the predicted value for the concentration at tlast, as estimated using the linear regression from the determination of the terminal first order (elimination) rate constant (lambda z). AUC0-inf = AUC0-t plus Clast pred/lambda z. Lambda z was terminal elimination rate constant determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve.
Phase 1a (Arm A and Arm B): Apparent Terminal Half Life (t1/2) of M3814 After Single Dose	Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 1 and Fraction Day 6	t1/2 was the time measured for the concentration to decrease by one half. t1/2 was calculated by natural log 2 divided by Lambda z.
Phase 1a (Arm A and Arm B): Apparent Volume of Distribution (Vz/f) of M3814 After Single Dose	Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 1 and Fraction Day 6	Apparent volume of distribution during the terminal phase following extravascular administration for M8891 was calculated. Vz/f = Dose/(AUC0-infinity multiply by Lambda z) following single dose. The AUC from time zero (dosing time) extrapolated to infinity, based on the predicted value for the concentration at tlast, as estimated using the linear regression from lambda z determination. AUC(0- inf)=AUC0-t plus Clastpred/lambda z where Clastpred was last predicted concentration. Lambda Z was terminal elimination rate constant determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve.
Phase 1a (Arm A and Arm B): Maximum Plasma Concentration (Cmax) of M3814 After Multiple Dose	Pre-dose, 0.5, 1, 2 and 4 hours post-dose on Fraction Day 10	Cmax was taken directly from the observed concentration-time curve.
Phase 1a (Arm A and Arm B): Time to Reach Maximum Plasma Concentration (Tmax) of M3814 After Multiple Dose	Pre-dose, 0.5, 1, 2 and 4 hours post-dose on Fraction Day 10	tmax was obtained directly from the concentration versus time curve.
Phase 1a (Arm A and Arm B): Area Under the Plasma Concentration-time Curve Over the Dosing Interval (AUCtau) of M3814 After Multiple Dosing	Pre-dose, 0.5, 1, 2 and 4 hours post-dose on Fraction Day 10	AUCtau was defined as area under the plasma concentration-time curve from time zero to the end of the dosing interval (tau). AUCtau was calculated using the mixed log linear trapezoidal rule.
Phase 1a (Arm A and Arm B): Area Under the Plasma Concentration-Time From Time Zero Extrapolated to Infinity (AUC0-inf) of M3814 After Multiple Dose	Pre-dose, 0.5, 1, 2 and 4 hours post-dose on Fraction Day 10	The AUC from time zero (dosing time) extrapolated to infinity, based on the predicted value for the concentration at tlast, as estimated using the linear regression from the determination of the terminal first order (elimination) rate constant (lambda z). AUC0-inf = AUC0-t plus Clast pred/lambda z. Lambda z was terminal elimination rate constant determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve.
Phase 1a (Arm A and Arm B): Apparent Terminal Half Life (t1/2) of M3814 After Multiple Dose	Pre-dose, 0.5, 1, 2 and 4 hours post-dose on Fraction Day 10	t1/2 was the time measured for the concentration to decrease by one half. t1/2 was calculated by natural log 2 divided by Lambda z.
Phase 1a (Arm A and Arm B): Oral Clearance in Plasma at Steady State (CLss/f) of M3814 After Multiple Dose	Pre-dose, 0.5, 1, 2 and 4 hours post-dose on Fraction Day 10	Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes.
Phase 1a (Arm A and Arm B): Apparent Volume of Distribution at Steady-State (Vss/f) of M3814 After Multiple Dose	Pre-dose, 0.5, 1, 2 and 4 hours post-dose on Fraction Day 10	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.
Phase 1a (Arm A and Arm B): Accumulation Ratio of Area Under the Concentration-Time Curve (AUC) [Racc(AUC0-24)] of M3814 After Multiple Dose	Pre-dose, 0.5, 1, 2, 4 and 24 hours post-dose on Fraction Day 1 and Fraction Day 10	Accumulation ratio for AUC was calculated as AUC, after dosing on fraction Day 10 divided by AUC, after dosing on fraction Day 1 of cycle 1.
Phase 1a (Arm A and Arm B): Accumulation Ratio of Cmax (Racc (Cmax) of M3814 After Multiple Dose	Pre-dose, 0.5, 1, 2 and 4 hours post-dose on Fraction Day 1 and Fraction Day 10	Accumulation ratio for Cmax was calculated as Cmax, after dosing on fraction Day 10 divided by Cmax, after dosing on fraction Day 1 of cycle 1.
Ancillary cPoP: Maximum Observed Plasma Concentration (Cmax) of M3814	Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 2	Cmax was taken directly from the observed concentration-time curve.
Ancillary cPoP: Time to Reach Maximum Plasma Concentration (Tmax) of M3814	Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 2	tmax was obtained directly from the concentration versus time curve.
Ancillary cPoP: Area Under the Plasma Concentration-time Curve From Time Zero to 4 Hours (AUC0-4) of M3814	Pre-dose, 0.5, 1, 2 and 4 hours post-dose on Fraction Day 2	AUC0-4hr is the area under the plasma concentration-time curve from time 0 to 4 hours post-dose. This is a measure of the average amount of study drug M3814 in the blood plasma over a period of 4 hours after the dose.
Ancillary cPoP: Area Under the Plasma Concentration-time Curve From Time Zero to Last Sampling Time (Tlast) (AUC0-t) of M3814	Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 2	Area under the plasma concentration vs time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ). AUC0-t was to be calculated according to the mixed log-linear trapezoidal rule.
Ancillary cPoP: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M3814	Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 2	AUC0-t/Dose was defined as AUC from time of dosing to the time of the last measurable concentration divided by dose.
Ancillary cPoP: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to 4 Hours (AUC0-4)/Dose of M3814	Pre-dose, 0.5, 1, 2 and 4 hours post-dose on Fraction Day 2	AUC0-4/Dose was defined as AUC from time of dosing to the time zero to 4 hours divided by dose.
Ancillary cPoP: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M3814	Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 2	Cmax/Dose was calculated as maximum observed plasma concentration obtained directly from the concentration versus time curve divided by dose. Cmax/dose was measured in nanogram per milliliter per milligram (ng/mL/mg).

Trial Locations

Locations (19): Research site
🇳🇴
Oslo, Norway
Universitaetsklinikum Schleswig-Holstein - Campus Kiel - Klinik für diagnostische Radiologie
🇩🇪
Kiel, Germany
University of Miami Miller School of Medicine
🇺🇸
Miami, Florida, United States
Universitaetsklinikum Carl Gustav Carus TU Dresden
🇩🇪
Dresden, Germany
Holy Cross Hospital Inc.
🇺🇸
Fort Lauderdale, Florida, United States
Montefiore Medical Center PRIME
🇺🇸
Bronx, New York, United States
Memorial Sloan Kettering Cancer Center
🇺🇸
New York, New York, United States
Rigshospitalet - PARENT
🇩🇰
Copenhagen, Denmark
Universitaetsklinikum Essen - Westdeutsches Tumorzentrum
🇩🇪
Essen, Germany
Universitaetsklinikum Heidelberg - RadioOnkologie und Strahlentherapie
🇩🇪
Heidelberg, Germany
Herlev Hospital - PARENT
🇩🇰
Herlev, Denmark
Charite Research Organisation GmbH - Phase - I Unit of Hematology and Oncology
🇩🇪
Berlin, Germany
Klinikum Mannheim GmbH Universitaetsklinikum - Parent
🇩🇪
Mannheim, Germany
Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz - Klinik und Poliklinik fuer Radiologie
🇩🇪
Mainz, Germany
Antoni van Leeuwenhoek Ziekenhuis
🇳🇱
Amsterdam, Netherlands
Universitaetsklinikum Tuebingen - Medizinische Klinik I
🇩🇪
Tuebingen, Germany
Karolinska universitetssjukhuset - Solna - Radiumhemmet (onkologi)
🇸🇪
Solna, Sweden
Universitaetsspital Zuerich - Parent
🇨🇭
Zuerich, Switzerland
Thomas Jefferson University Hospital
🇺🇸
Philadelphia, Pennsylvania, United States