Clinical trial NCT02516813: Phase 1 Trial of MSC2490484A, an Inhibitor of a DNA-dependent Protein Kinase, in Combination With Radiotherapy
Official title: An Open Label, Phase Ia/Ib Trial of the DNA-PK Inhibitor MSC2490484A in Combination With Radiotherapy in Patients With Advanced Solid Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Advanced Solid Tumors
Keywords: M3814
Advanced solid tumors
DNA-PK Inhibitor
Radiotherapy
Chemotherapy
Lead sponsor: EMD Serono
Sponsor class: INDUSTRY
Collaborators: name: Merck KGaA, Darmstadt, Germany
First posted: 2015-08-06
Enrollment: 52
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).


Eligibility criteria: 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.

Primary outcomes:
measure: 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)
timeFrame: Time from first dose of study treatment up to 5 weeks
measure: 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)
timeFrame: Time from first dose of study treatment up to 12 weeks
Secondary outcomes:
measure: 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)
timeFrame: Time from first dose of study treatment up to long term safety follow-up period (Up to approximately 1 year)
measure: 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)
timeFrame: Time from first dose of study treatment up to long term safety follow-up period (Up to approximately 1 year)
measure: 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)
timeFrame: Time from first dose of study treatment up to long term safety follow-up period (Up to approximately 1 year)
measure: Phase 1a (Arm A and Arm B): Number of Participants With Markedly Abnormal Vital Sign Measurements
timeFrame: Time from first dose of study treatment up to long term safety follow-up period (Up to approximately 1 year)
measure: Phase 1a (Arm A and Arm B): Number of Participants With Shifts From Normal Baseline to Abnormal Post-baseline in Electrocardiogram (ECG)
timeFrame: Time from first dose of study treatment up to long term safety follow-up period (Up to approximately 1 year)
measure: 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
timeFrame: Time from first dose of study treatment up to long term safety follow-up period (Up to approximately 1 year)
measure: 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
timeFrame: Time from first dose of study treatment up to long term safety follow-up period (Up to approximately 1 year)
measure: 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
timeFrame: Time from first dose of study treatment up to long term safety follow-up period (Up to approximately 1 year)
measure: Phase 1a (Arm A and Arm B): Maximum Plasma Concentration (Cmax) of M3814 After Single Dose
timeFrame: Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 1 and Fraction Day 6
measure: Phase 1a (Arm A and Arm B): Time to Reach Maximum Plasma Concentration (Tmax) of M3814 After Single Dose
timeFrame: Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 1 and Fraction Day 6
measure: 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
timeFrame: Pre-dose, 0.5, 1, 2, 4, 6 and 24 hours post-dose on Fraction Day 1 and Fraction Day 6
measure: 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
timeFrame: Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 1 and Fraction Day 6
measure: Phase 1a (Arm A and Arm B): Apparent Terminal Half Life (t1/2) of M3814 After Single Dose
timeFrame: Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 1 and Fraction Day 6
measure: Phase 1a (Arm A and Arm B): Total Body Clearance Following Oral Administration (CL/f) of M3814 After Single Dose
timeFrame: Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 1 and Fraction Day 6
measure: Phase 1a (Arm A and Arm B): Apparent Volume of Distribution (Vz/f) of M3814 After Single Dose
timeFrame: Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 1 and Fraction Day 6
measure: Phase 1a (Arm A and Arm B): Maximum Plasma Concentration (Cmax) of M3814 After Multiple Dose
timeFrame: Pre-dose, 0.5, 1, 2 and 4 hours post-dose on Fraction Day 10
measure: Phase 1a (Arm A and Arm B): Time to Reach Maximum Plasma Concentration (Tmax) of M3814 After Multiple Dose
timeFrame: Pre-dose, 0.5, 1, 2 and 4 hours post-dose on Fraction Day 10
measure: Phase 1a (Arm A and Arm B): Area Under the Plasma Concentration-time Curve Over the Dosing Interval (AUCtau) of M3814 After Multiple Dosing
timeFrame: Pre-dose, 0.5, 1, 2 and 4 hours post-dose on Fraction Day 10
measure: 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
timeFrame: Pre-dose, 0.5, 1, 2 and 4 hours post-dose on Fraction Day 10
measure: Phase 1a (Arm A and Arm B): Apparent Terminal Half Life (t1/2) of M3814 After Multiple Dose
timeFrame: Pre-dose, 0.5, 1, 2 and 4 hours post-dose on Fraction Day 10
measure: Phase 1a (Arm A and Arm B): Oral Clearance in Plasma at Steady State (CLss/f) of M3814 After Multiple Dose
timeFrame: Pre-dose, 0.5, 1, 2 and 4 hours post-dose on Fraction Day 10
measure: Phase 1a (Arm A and Arm B): Apparent Volume of Distribution at Steady-State (Vss/f) of M3814 After Multiple Dose
timeFrame: Pre-dose, 0.5, 1, 2 and 4 hours post-dose on Fraction Day 10
measure: 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
timeFrame: Pre-dose, 0.5, 1, 2, 4 and 24 hours post-dose on Fraction Day 1 and Fraction Day 10
measure: Phase 1a (Arm A and Arm B): Accumulation Ratio of Cmax (Racc (Cmax) of M3814 After Multiple Dose
timeFrame: Pre-dose, 0.5, 1, 2 and 4 hours post-dose on Fraction Day 1 and Fraction Day 10
measure: Ancillary cPoP: Maximum Observed Plasma Concentration (Cmax) of M3814
timeFrame: Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 2
measure: Ancillary cPoP: Time to Reach Maximum Plasma Concentration (Tmax) of M3814
timeFrame: Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 2
measure: Ancillary cPoP: Area Under the Plasma Concentration-time Curve From Time Zero to 4 Hours (AUC0-4) of M3814
timeFrame: Pre-dose, 0.5, 1, 2 and 4 hours post-dose on Fraction Day 2
measure: Ancillary cPoP: Area Under the Plasma Concentration-time Curve From Time Zero to Last Sampling Time (Tlast) (AUC0-t) of M3814
timeFrame: Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 2
measure: Ancillary cPoP: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M3814
timeFrame: Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 2
measure: Ancillary cPoP: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to 4 Hours (AUC0-4)/Dose of M3814
timeFrame: Pre-dose, 0.5, 1, 2 and 4 hours post-dose on Fraction Day 2
measure: Ancillary cPoP: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M3814
timeFrame: Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 2
Other outcomes:
Locations:
city: Fresno
country: United States
facility: Research site
state: California
city: Fort Lauderdale
country: United States
facility: Holy Cross Hospital Inc.
state: Florida
city: Miami
country: United States
facility: University of Miami Miller School of Medicine
state: Florida
city: Billings
country: United States
facility: Research site
state: Montana
city: Bronx
country: United States
facility: Montefiore Medical Center PRIME
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Philadelphia
country: United States
facility: Thomas Jefferson University Hospital
state: Pennsylvania
city: Houston
country: United States
facility: Research site
state: Texas
city: Tacoma
country: United States
facility: Research site
state: Washington
city: Leuven
country: Belgium
facility: Research site
city: Copenhagen
country: Denmark
facility: Rigshospitalet - PARENT
city: Herlev
country: Denmark
facility: Herlev Hospital - PARENT
city: Freiburg
country: Germany
facility: Research site
state: Baden Wuerttemberg
city: Berlin
country: Germany
facility: Charite Research Organisation GmbH - Phase - I Unit of Hematology and Oncology
city: Dresden
country: Germany
facility: Universitaetsklinikum Carl Gustav Carus TU Dresden
city: Essen
country: Germany
facility: Universitaetsklinikum Essen - Westdeutsches Tumorzentrum
city: Heidelberg
country: Germany
facility: Universitaetsklinikum Heidelberg - RadioOnkologie und Strahlentherapie
city: Kiel
country: Germany
facility: Universitaetsklinikum Schleswig-Holstein - Campus Kiel - Klinik für diagnostische Radiologie
city: Mainz
country: Germany
facility: Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz - Klinik und Poliklinik fuer Radiologie
city: Mannheim
country: Germany
facility: Klinikum Mannheim GmbH Universitaetsklinikum - Parent
city: Tuebingen
country: Germany
facility: Universitaetsklinikum Tuebingen - Medizinische Klinik I
city: Amsterdam
country: Netherlands
facility: Research site
city: Amsterdam
country: Netherlands
facility: Antoni van Leeuwenhoek Ziekenhuis
city: Oslo
country: Norway
facility: Research site
city: Solna
country: Sweden
facility: Karolinska universitetssjukhuset - Solna - Radiumhemmet (onkologi)
city: Zuerich
country: Switzerland
facility: Universitaetsspital Zuerich - Parent
Study officials:
affiliation: Merck KGaA, Darmstadt, Germany
name: Medical Responsible
role: STUDY_DIRECTOR
References: