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Study of M3814 in Combination With Capecitabine and Radiotherapy in Rectal Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03770689
Recruitment Status : Recruiting
First Posted : December 10, 2018
Last Update Posted : October 20, 2020
Sponsor:
Collaborator:
Merck KGaA, Darmstadt, Germany
Information provided by (Responsible Party):
EMD Serono ( EMD Serono Research & Development Institute, Inc. )

Brief Summary:
The main purpose of the study is to define maximum tolerated dose (MTD), recommended Phase II dose (RP2D) of M3814 in combination with capecitabine and radiotherapy (RT) in Phase Ib and to evaluate the efficacy of M3814 in terms of Pathological Clinical Response (pCR)/Clinical Complete Response (cCR) when administered in combination with capecitabine and RT versus placebo, capecitabine, and RT in Phase II.

Condition or disease Intervention/treatment Phase
Locally Advanced Rectal Cancer Drug: Phase Ib: M3814 Drug: Capecitabine Radiation: Radiotherapy (RT) Drug: Phase II: M3814 Drug: Phase II: Placebo Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 160 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Multicenter Study With an Open-label Phase Ib Part Followed by a Randomized, Placebo-controlled, Double-blind, Phase II Part to Evaluate Efficacy, Safety, Tolerability, and Pharmacokinetics of the DNA-PK Inhibitor M3814 in Combination With Capecitabine and Radiotherapy in Participants With Locally Advanced Rectal Cancer
Actual Study Start Date : March 20, 2019
Estimated Primary Completion Date : July 31, 2021
Estimated Study Completion Date : July 31, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Phase Ib: M3814 + Capecitabine + RT Drug: Phase Ib: M3814
Participants will receive M3814 at an escalated dose starting from 50 mg once daily 5 days per week in first cohort up to week 6 and for the next cohorts M3814 dose will be determined by the Safety Monitoring Committee (SMC) guided by a Bayesian 2-parameter logistic regression model with overdose control.
Other Names:
  • Peposertib
  • MSC2490484A

Drug: Capecitabine
Participants will receive capecitabine at a dose of 825 milligram per square meter (mg/m^2) twice daily 5 days per week in Phase Ib and Phase II up to week 6.

Radiation: Radiotherapy (RT)
Participants will receive RT of approximately 50 Gray (Gy) to the tumor area and 45 Gy to the electively irradiated tissues in 25 to 28 fractions (corresponding to 5 to 5.5 weeks) Phase Ib and Phase II.

Experimental: Phase II: M3814 + capecitabine + RT Drug: Capecitabine
Participants will receive capecitabine at a dose of 825 milligram per square meter (mg/m^2) twice daily 5 days per week in Phase Ib and Phase II up to week 6.

Radiation: Radiotherapy (RT)
Participants will receive RT of approximately 50 Gray (Gy) to the tumor area and 45 Gy to the electively irradiated tissues in 25 to 28 fractions (corresponding to 5 to 5.5 weeks) Phase Ib and Phase II.

Drug: Phase II: M3814
Participants will receive M3814 50 mg or matching placebo at the RP2D once daily 5 days per week up to week 6.
Other Names:
  • Peposertib
  • MSC2490484A

Placebo Comparator: Phase II: Placebo + capecitabine + RT Drug: Capecitabine
Participants will receive capecitabine at a dose of 825 milligram per square meter (mg/m^2) twice daily 5 days per week in Phase Ib and Phase II up to week 6.

Radiation: Radiotherapy (RT)
Participants will receive RT of approximately 50 Gray (Gy) to the tumor area and 45 Gy to the electively irradiated tissues in 25 to 28 fractions (corresponding to 5 to 5.5 weeks) Phase Ib and Phase II.

Drug: Phase II: Placebo
Participants will receive Placebo matched to M3814 for 5 days per week up to week 6.




Primary Outcome Measures :
  1. Phase Ib: Number of Participants Experiencing a Dose Limiting Toxicity (DLT) [ Time Frame: Time from first dose of study drug to end of chemo radiotherapy with a final assessment at 4 weeks post-surgery ]
  2. Phase II: Proportion of Participants With Pathological Complete Response (pCR) and Clinical Complete Response (cCR) [ Time Frame: Post-surgery at Day 119 (pCR); 2 weeks prior-surgery (cCR) ]

Secondary Outcome Measures :
  1. Phase Ib and II: Occurrence of Treatment-related Adverse Events (TEAEs) According to National Cancer Institute Common Terminology Criteria of Adverse Events (NCI-CTCAE) version 5.0 [ Time Frame: Time from first dose of study drug to final assessment at 5 years for each phase ]
  2. Phase Ib and II: Number of Participants With Abnormalities (Grade Greater than or equals to (≥) 3) in Laboratory Test Values [ Time Frame: Time from first study drug to final assessment at 5 years for each phase ]
  3. Phase Ib and II: Number of Participants With Markedly Abnormal Vital Sign Measurements [ Time Frame: Time from first dose of study drug to final assessment at 5 years for each phase ]
  4. Phase Ib and II: Number of Participants With Clinically Significant Abnormal Electrocardiogram (ECG) Findings [ Time Frame: Time from first dose of study drug to final assessment at 5 years for each phase ]
  5. Phase Ib: Overall Survival [ Time Frame: Time from first dose of study drug to final assessment at 5 years ]
  6. Phase Ib: Disease-free Survival [ Time Frame: Time from first study drug to final assessment at 5 years ]
  7. Phase Ib: Best Overall Response Assessed by Investigator [ Time Frame: Time from first dose of study drug until surgery at Day 119 ]
  8. Phase Ib and II: Time from Surgery to Local Recurrence and Distant Metastasis [ Time Frame: Time from surgery to final assessment at 5 years for each phase ]
  9. Phase Ib: Maximum Observed Drug Concentration (Cmax) of M3814 [ Time Frame: Pre-dose, 1, 2, 3 and 4 hour post-dose on Fraction Day (FD1) and Fraction Day 9 ]
  10. Phase Ib: Area Under the Plasma Concentration-time Curve From Time Zero to Last Sampling Time (tlast) (AUC0-t) of M3814 [ Time Frame: Pre-dose, 1, 2, 3 and 4 hour post-dose on Fraction Day 1 and Fraction Day 9 ]
  11. Phase Ib: Time to Reach Maximum Plasma Concentration (tmax) of M3814 [ Time Frame: Pre-dose, 1, 2, 3 and 4 hour post-dose on Fraction Day 1 and Fraction Day 9 ]
  12. Phase Ib and II: Total Body Clearance of Drug From Plasma Following Oral Administration (CL/f) of M3814 [ Time Frame: Pre-dose, 1, 2, 3 and 4 hour post-dose on Fraction Day 1 and Fraction Day 9 for each phase for each phase ]
  13. Phase Ib and II: Apparent Volume of Distribution (Vz/f) of M3814 [ Time Frame: Pre-dose, 1, 2, 3 and 4 hour post-dose on Fraction Day 1 and Fraction Day 9 for each phase ]
  14. Phase Ib: Apparent Terminal Half-life (t1/2) of M3814 [ Time Frame: Pre-dose, 1, 2, 3 and 4 hour post-dose on Fraction Day 1 and Fraction Day 9 ]
  15. Phase II: Overall Survival [ Time Frame: Time from randomization to final assessment at 5 years ]
  16. Phase II: Best Overall Response Assessed by Investigator [ Time Frame: Time from randomization until Day 119 ]
  17. Phase II: Neoadjuvant Rectal Score [ Time Frame: Post-surgery at Day 119 ]
  18. Phase II: Proportion of Participants With/Without Surgical Intervention [ Time Frame: Time from randomization to final assessment at 5 years ]
  19. Phase II: Number of Participants With R0 Resection (No Residual Tumor) [ Time Frame: Post-surgery at Day 119 ]
  20. Phase II: Quality of Life (QoL) Measured Using European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) [ Time Frame: Time from randomization to assessment at 2 years ]
  21. Phase II: Quality of Life (QoL) Measured Using European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Colorectal Cancer (EORTC-CR29) [ Time Frame: Time from randomization to assessment at 2 years ]
  22. Phase II: Quality of Life (QoL) Measured Using EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) [ Time Frame: Time from randomization to assessment at 2 years ]
  23. Phase Ib and II: Proportion of Participants With Pathological Complete Response (pCR) [ Time Frame: Post-surgery at Day 119 ]
  24. Phase Ib: Proportion of Participants With Clinical Complete Response (cCR) [ Time Frame: Time from first study drug until 1 to 2 weeks prior to surgery ]
  25. Phase II: Proportion of Participants With Clinical Complete Response (cCR) [ Time Frame: Time from randomization until surgery at Day 119 ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Participants who have an Eastern Cooperative Oncology Group Performance Status less than or equals to (≤) 1
  • Participants who have histologically confirmed and localized resectable rectal cancer (Stage III).
  • Participants who received induction chemotherapy are allowed to be enrolled to this study except this induction is resulting in complete response.
  • Participants who have lower edge of the tumor located in rectum
  • Adequate hematological, hepatic and renal function as defined in the protocol
  • Male participants if they agree to the following during the study intervention period and for at least 12 weeks after the last dose of study intervention
  • Female participants are eligible if not pregnant or breastfeeding
  • Other protocol defined inclusion criteria could apply

Exclusion Criteria:

  • Participants with history of any other significant medical disease or psychiatric conditions that might in the assessment of the Investigator preclude safe participation in the study
  • Participants with history of difficulty swallowing, malabsorption, or other chronic gastrointestinal disease or conditions that may hamper compliance and/or absorption of the study intervention
  • Unstable cardiovascular function within 6 months prior to enrollment
  • Hypertension uncontrolled by medication (ie, systolic blood pressure >= 150 millimeter of mercury (mmHg) and diastolic blood pressure >= 90 mmHg)
  • Participants with history of other malignant disease within the past 5 years, other than successfully treated basal carcinoma of the skin or carcinoma in situ of the cervix
  • Participants with known human immunodeficiency virus positivity, known active hepatitis (for example, hepatitis B virus or hepatitis C virus), current alcohol abuse, or cirrhosis
  • Participants with ongoing active infection other than human immunodeficiency virus, hepatitis B virus, or hepatitis C virus, or treatment with a live attenuated vaccine within 4 weeks of dosing
  • Participants with concomitant use of H2-blocker or proton pump inhibitors (PPIs) (or unable to stop at least 5 days prior to the first treatment). Note that calcium carbonate is acceptable
  • Participation in any interventional clinical study within 28 days prior to Screening or during participation in this study
  • Other protocol defined exclusion criteria could apply.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03770689


Contacts
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Contact: US Medical Information 888-275-7376 eMediUSA@emdserono.com
Contact: Communication Center +49 6151 72 5200 service@emdgroup.com

Locations
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United States, Colorado
University of Colorado Cancer Center Recruiting
Aurora, Colorado, United States, 80045
Principal Investigator: Karyn Goodman         
United States, Connecticut
Yale University - Pediatric Respiratory Medicine Recruiting
New Haven, Connecticut, United States, 06520
Contact       michael.cecchini@yale.edu   
Principal Investigator: Michael Cecchini         
United States, New York
Montefiore Medical Center Recruiting
Bronx, New York, United States, 10461
Principal Investigator: Sanjay Goel         
Northwell Health, Inc Recruiting
Great Neck, New York, United States, 10042
Principal Investigator: Tony Philip         
Memorial Sloan-Kettering Cancer Center (MSKCC) - New York Recruiting
New York, New York, United States, 10065
Principal Investigator: Paul Romesser         
United States, Ohio
Ohio State University Clinical Trials Management Office - Ohio State CTMO Parent Recruiting
Columbus, Ohio, United States, 43210
Principal Investigator: Eric Miller         
University of Toledo Medical Center - Hematology/Oncology Recruiting
Toledo, Ohio, United States, 43614
Principal Investigator: John Nemunaitis         
United States, South Carolina
Med. Univ. of South Carolina Recruiting
Charleston, South Carolina, United States, 29425
Principal Investigator: Carolyn Britten         
Greenville Hospital System University Medical Center (ITOR) Recruiting
Greenville, South Carolina, United States, 29605
Principal Investigator: Ki Y Chung         
United States, Texas
The University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Principal Investigator: Emma Holliday         
Spain
Hospital Universitari Vall d'Hebron - Dept of Oncology Recruiting
Barcelona, Spain
Principal Investigator: Jaume Capdevila Castillon         
Hospital Universitario 12 de Octubre - Servicio de Oncologia Recruiting
Madrid, Spain
Principal Investigator: Rocio G Garcia Carbonero         
Hospital Regional Universitario de Malaga Recruiting
Málaga, Spain
Principal Investigator: Silvia Gil Calle         
Hospital Clinico Universitario de Valencia - Servicio de Hematologia y Oncologia Medica Recruiting
Valencia, Spain
Principal Investigator: Susana Rosello Keranen         
Sponsors and Collaborators
EMD Serono Research & Development Institute, Inc.
Merck KGaA, Darmstadt, Germany
Investigators
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Study Director: Medical Responsible Merck KGaA, Darmstadt, Germany
Additional Information:
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Responsible Party: EMD Serono Research & Development Institute, Inc.
ClinicalTrials.gov Identifier: NCT03770689    
Other Study ID Numbers: MS100036_0020
2018-002275-18 ( EudraCT Number )
First Posted: December 10, 2018    Key Record Dates
Last Update Posted: October 20, 2020
Last Verified: October 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: EMD Serono, Inc. is committed to sharing patient-level data and supporting documentation from applicable studies according to company policies. Further information on data sharing and how to request data can be found on our website https://www.emdgroup.com/en/research/our-approach-to-research-and-development/healthcare/clinical-trials/commitment-responsible-data-sharing.html

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by EMD Serono ( EMD Serono Research & Development Institute, Inc. ):
DNA-PK inhibitor
M3814
capecitabine
Additional relevant MeSH terms:
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Rectal Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Intestinal Diseases
Rectal Diseases
Capecitabine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents