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

NCT02516813 | Completed Phase 1 Results DMC

• 2 other identifiers: 100036-0022015-000673-12
• Study Type: interventional
• Target: 52
• Locations: 8 countries
• Sites: 26

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).

Conditions

Advanced Solid Tumors

Keywords

M3814; Advanced solid tumors; DNA-PK Inhibitor; Radiotherapy; Chemotherapy

Outcome Measures

Primary Outcomes (2)

• 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)

  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.

  Time from first dose of study treatment up to 5 weeks

• 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)

  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.

  Time from first dose of study treatment up to 12 weeks

Secondary Outcomes (31)

• 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)

• 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)

• 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)

• 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)

• 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)

Study Arms (12)

Phase 1a (Arm A): M3814 Capsule (100 mg) + RT

EXPERIMENTAL

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 \[F/W\]).

Drug: M3814 100 mg; Radiation: Fractionated RT

Phase 1a (Arm A): M3814 Capsule (200 mg) + RT

EXPERIMENTAL

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).

Drug: M3814 200 mg; Radiation: Fractionated RT

Phase 1a (Arm A): M3814 Capsule (300 mg) + RT

EXPERIMENTAL

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).

Drug: M3814 300 mg; Radiation: Fractionated RT

Phase 1a (Arm A): M3814 Capsule (400 mg) + RT

EXPERIMENTAL

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).

Drug: M3814 400 mg; Radiation: Fractionated RT

Phase 1a (Arm A): M3814 Tablet (100 mg) + RT

EXPERIMENTAL

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).

Drug: M3814 100 mg; Radiation: Fractionated RT

Phase 1a (Arm A): M3814 Tablet (200 mg) + RT

EXPERIMENTAL

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).

Drug: M3814 200 mg; Radiation: Fractionated RT

Phase 1a (Arm A): M3814 Tablet (300 mg) + RT

EXPERIMENTAL

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).

Drug: M3814 300 mg; Radiation: Fractionated RT

Phase 1a (Arm B): M3814 Capsule (50 mg) + CRT

EXPERIMENTAL

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).

Drug: M3814 50 mg; Radiation: Fractionated RT; Drug: Cisplatin

Phase 1a (Arm B): M3814 Tablet (100 mg) + CRT

EXPERIMENTAL

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).

Radiation: Fractionated RT; Drug: Cisplatin

Ancillary cPoP: M3814 Capsule (100 mg) + RT

EXPERIMENTAL

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.

Drug: M3814 100 mg; Radiation: Fractionated RT

Ancillary cPOP: M3814 Capsule (200 mg) + RT

EXPERIMENTAL

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.

Drug: M3814 200 mg; Radiation: Fractionated RT

Ancillary cPOP: M3814 Capsule (400 mg) + RT

EXPERIMENTAL

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

Drug: M3814 400 mg; Radiation: Fractionated RT

Interventions

M3814 100 mg DRUG

Participants received 100 mg of M3814 as capsule or tablet orally once daily.

Also known as: Peposertib, MSC2490484A

Ancillary cPoP: M3814 Capsule (100 mg) + RT; Phase 1a (Arm A): M3814 Capsule (100 mg) + RT; Phase 1a (Arm A): M3814 Tablet (100 mg) + RT

M3814 200 mg DRUG

Participants received 200 mg of M3814 as capsule or tablet orally once daily.

Also known as: Peposertib, MSC2490484

Ancillary cPOP: M3814 Capsule (200 mg) + RT; Phase 1a (Arm A): M3814 Capsule (200 mg) + RT; Phase 1a (Arm A): M3814 Tablet (200 mg) + RT

M3814 300 mg DRUG

Participants received 300 mg of M3814 as capsule or tablet orally once daily.

Also known as: Peposertib, MSC2490484

Phase 1a (Arm A): M3814 Capsule (300 mg) + RT; Phase 1a (Arm A): M3814 Tablet (300 mg) + RT

M3814 400 mg DRUG

Participants received 400 mg of M3814 as capsule or tablet orally once daily.

Also known as: Peposertib, MSC2490484

Ancillary cPOP: M3814 Capsule (400 mg) + RT; Phase 1a (Arm A): M3814 Capsule (400 mg) + RT

M3814 50 mg DRUG

Participants received 100 mg of M3814 as capsule orally once daily.

Also known as: Peposertib, MSC2490484

Phase 1a (Arm B): M3814 Capsule (50 mg) + CRT

Fractionated RT RADIATION

Participants received fractionated palliative RT (3 Gray \[Gy\] \* 10 in Arm A and 2 Gy \* 33 to 35, 5 fractions per week \[F/W\]) in Arm B and received a single high dose of RT (10-25 Gy) capsule on Day 1 given on Lesion 1 and a single high dose of RT (10-25 Gy) on Day 2 given on Lesion 2 in ancillary CPoP part.

Ancillary cPOP: M3814 Capsule (200 mg) + RT; Ancillary cPOP: M3814 Capsule (400 mg) + RT; Ancillary cPoP: M3814 Capsule (100 mg) + RT; Phase 1a (Arm A): M3814 Capsule (100 mg) + RT; Phase 1a (Arm A): M3814 Capsule (200 mg) + RT; Phase 1a (Arm A): M3814 Capsule (300 mg) + RT; Phase 1a (Arm A): M3814 Capsule (400 mg) + RT; Phase 1a (Arm A): M3814 Tablet (100 mg) + RT; Phase 1a (Arm A): M3814 Tablet (200 mg) + RT; Phase 1a (Arm A): M3814 Tablet (300 mg) + RT; Phase 1a (Arm B): M3814 Capsule (50 mg) + CRT; Phase 1a (Arm B): M3814 Tablet (100 mg) + CRT

Cisplatin DRUG

Participants received 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 Capsule (50 mg) + CRT; Phase 1a (Arm B): M3814 Tablet (100 mg) + CRT

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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
• 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.

Sponsors & Collaborators

• EMD Serono Research & Development Institute, Inc.: lead
• Merck KGaA, Darmstadt, Germany: collaborator

Study Sites (26)

Research site

Fresno, California, 93720, United States

Location

Holy Cross Hospital Inc.

Fort Lauderdale, Florida, 33308, United States

Location

University of Miami Miller School of Medicine

Miami, Florida, 33136, United States

Location

Research site

Billings, Montana, 59101, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Montefiore Medical Center PRIME

The Bronx, New York, 10461, United States

Location

Thomas Jefferson University Hospital

Philadelphia, Pennsylvania, 19107, United States

Location

Research site

Houston, Texas, 77030, United States

Location

Research site

Tacoma, Washington, 98405, United States

Location

Research site

Leuven, Belgium

Location

Rigshospitalet - PARENT

Copenhagen, Denmark

Location

Herlev Hospital - PARENT

Herlev, Denmark

Location

Research site

Freiburg im Breisgau, Baden-Wurttemberg, 79106, Germany

Location

Charite Research Organisation GmbH - Phase - I Unit of Hematology and Oncology

Berlin, Germany

Location

Universitaetsklinikum Carl Gustav Carus TU Dresden

Dresden, Germany

Location

Universitaetsklinikum Essen - Westdeutsches Tumorzentrum

Essen, Germany

Location

Universitaetsklinikum Heidelberg - RadioOnkologie und Strahlentherapie

Heidelberg, Germany

Location

Universitaetsklinikum Schleswig-Holstein - Campus Kiel - Klinik für diagnostische Radiologie

Kiel, Germany

Location

Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz - Klinik und Poliklinik fuer Radiologie

Mainz, Germany

Location

Klinikum Mannheim GmbH Universitaetsklinikum - Parent

Mannheim, Germany

Location

Universitaetsklinikum Tuebingen - Medizinische Klinik I

Tübingen, Germany

Location

Research site

Amsterdam, 1066 CX, Netherlands

Location

Antoni van Leeuwenhoek Ziekenhuis

Amsterdam, Netherlands

Location

Research site

Oslo, Norway

Location

Karolinska universitetssjukhuset - Solna - Radiumhemmet (onkologi)

Solna, Sweden

Location

Universitaetsspital Zuerich - Parent

Zurich, Switzerland

Location

Related Links

• Trial Awareness and Transparency website
• US Medical Information website, Medical Resources

MeSH Terms

Interventions

peposertib; Cisplatin

Intervention Hierarchy (Ancestors)

Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds

Results Point of Contact

• Title: Communication Center
• Organization: Merck KGaA, Darmstadt, Germany

service@emdgroup.com

+49-6151-72-5200

Study Officials

• Medical Responsible

  Merck KGaA, Darmstadt, Germany

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 4, 2015
• First Posted: August 6, 2015
• Study Start: September 15, 2015
• Primary Completion: March 26, 2021
• Study Completion: November 19, 2021
• Last Updated: October 15, 2024
• Results First Posted: October 15, 2024

Record last verified: 2024-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (9); DE (9); NL (2); BE (1); CH (1); SE (1); DK (2); NO (1)