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Trial record 10 of 14 for:    M3814

Study of Peposertib in Combination With Capecitabine and RT 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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03770689
Recruitment Status : Completed
First Posted : December 10, 2018
Results First Posted : July 7, 2022
Last Update Posted : July 7, 2022
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 was to define maximum tolerated dose (MTD), recommended Phase II dose (RP2D) safety and tolerability of Peposertib in combination with capecitabine and radiotherapy (RT).

Condition or disease Intervention/treatment Phase
Locally Advanced Rectal Cancer Drug: Peposertib 50 mg Drug: Peposertib 100 mg Drug: Peposertib 150 mg Drug: Peposertib 250 mg Drug: Capecitabine Radiation: Radiotherapy (RT) Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 19 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
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 Peposertib (M3814) in Combination With Capecitabine and RT in Participants With Locally Advanced Rectal Cancer
Actual Study Start Date : March 20, 2019
Actual Primary Completion Date : June 21, 2021
Actual Study Completion Date : February 21, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Peposertib 50 mg + RT + Capecitabine
Participants received peposertib 50 milligram (mg) once daily in combination with capecitabine 825 milligram per square meter (mg/m^2) twice daily 5 days per week and radiotherapy (RT) of 50 to 50.4 Gray (Gy) to the tumor area and 45 Gy to the electively irradiated tissues in 25 to 28 fractions up to 5.5 weeks treatment period.
Drug: Peposertib 50 mg
Participants received peposertib 50 milligram (mg) once daily 5 days per week up to 5.5 weeks.
Other Names:
  • M3814
  • MSC2490484A

Drug: Capecitabine
Participants received capecitabine at a dose of 825 milligram per square meter (mg/m^2) twice daily 5 days per week up to 5.5 weeks.

Radiation: Radiotherapy (RT)
Participants received RT 50 to 50.4 Gray (Gy) to the tumor area and 45 Gy to the electively irradiated tissues in 25 to 28 fractions up to 5.5 weeks.

Experimental: Peposertib 100 mg + RT + Capecitabine
Participants received peposertib 100 mg once daily in combination with capecitabine 825 mg/m^2 twice daily 5 days per week and RT of 50 to 50.4 Gy to the tumor area and 45 Gy to the electively irradiated tissues in 25 to 28 fractions up to 5.5 weeks treatment period.
Drug: Peposertib 100 mg
Participants received peposertib 100 mg once daily 5 days per week up to 5.5 weeks.

Drug: Capecitabine
Participants received capecitabine at a dose of 825 milligram per square meter (mg/m^2) twice daily 5 days per week up to 5.5 weeks.

Radiation: Radiotherapy (RT)
Participants received RT 50 to 50.4 Gray (Gy) to the tumor area and 45 Gy to the electively irradiated tissues in 25 to 28 fractions up to 5.5 weeks.

Experimental: Peposertib 150 mg + RT + Capecitabine
Participants received peposertib 150 mg once daily in combination with capecitabine 825 mg/m^2 twice daily 5 days per week and RT of 50 to 50.4 Gy to the tumor area and 45 Gy to the electively irradiated tissues in 25 to 28 fractions up to 5.5 weeks treatment period.
Drug: Peposertib 150 mg
Participants received peposertib 150 mg once daily 5 days per week up to 5.5 weeks.

Drug: Capecitabine
Participants received capecitabine at a dose of 825 milligram per square meter (mg/m^2) twice daily 5 days per week up to 5.5 weeks.

Radiation: Radiotherapy (RT)
Participants received RT 50 to 50.4 Gray (Gy) to the tumor area and 45 Gy to the electively irradiated tissues in 25 to 28 fractions up to 5.5 weeks.

Experimental: Peposertib 250 mg + RT + Capecitabine
Participants received peposertib 250 mg once daily in combination with capecitabine 825 mg/m^2 twice daily 5 days per week and RT of 50 to 50.4 Gy to the tumor area and 45 Gy to the electively irradiated tissues in 25 to 28 fractions up to 5.5 weeks treatment period.
Drug: Peposertib 250 mg
Participants received peposertib 250 mg once daily 5 days per week up to 5.5 weeks.

Drug: Capecitabine
Participants received capecitabine at a dose of 825 milligram per square meter (mg/m^2) twice daily 5 days per week up to 5.5 weeks.

Radiation: Radiotherapy (RT)
Participants received RT 50 to 50.4 Gray (Gy) to the tumor area and 45 Gy to the electively irradiated tissues in 25 to 28 fractions up to 5.5 weeks.




Primary Outcome Measures :
  1. Number of Participants Who Experienced Dose Limiting Toxicity (DLT) Confirmed by Safety Monitoring Committee (SMC) [ Time Frame: Time from first study intervention up to 19 weeks (including 5.5 weeks of treatment and 13.5 weeks of short term safety follow-up period) ]
    DLT is defined as any of following treatment emergent adverse events (TEAEs) considered possibly related to study treatment by Investigator and/or Sponsor up to completion of assigned chemoradiotherapy treatment. DLT were based on SMC: Adverse drug reaction that, in the opinion of SMC, is of potential clinical significance such that further dose escalation would expose participants to unacceptable risk; Any occurrence of drug-induced liver injury meeting the Hy's law criteria; Any Grade 3 toxicity excluding diarrhea, neutropenia lasting for ≤ 5 days, nausea & vomiting, Grade 3 thrombocytopenia without bleeding; Grade ≥ 4 AEs at least possibly related to study drug, irrespective of duration, excluding: Isolated Grade 4 lymphocytopenia without clinical symptoms; Neutropenia lasting for ≤ 5 days and not associated with fever; Any toxicity related to study drug that causes participant to receive > 80% of planned peposertib, capecitabine or RT dose.


Secondary Outcome Measures :
  1. Number of Participants Wtih Treatment Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs According to National Cancer Institute Common Terminology Criteria of Adverse Events (NCI-CTCAE) Version 5.0 [ Time Frame: Time from first study intervention up to long term safety follow-up period (Up to approximately 1 year) ]
    Adverse event (AE) is any untoward medical occurrence in participant administered pharmaceutical product, regardless of causal relationship with this treatment. Therefore, an AE can be any unfavorable & unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, regardless if it is considered related to medicinal product. Serious AE: 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. TEAE: AE with onset after start of treatment or with onset date before the treatment start date but worsening after treatment start date. TEAEs included both serious and non-serious TEAEs. Treatment-related TEAEs: reasonably related to study intervention. Number of participants with TEAEs and treatment related TEAEs were reported.

  2. Number of Participants With Abnormalities [Grade Greater Than or Equals to (>=) 3] in Laboratory Test Values [ Time Frame: Time from first study intervention up to long term safety follow-up period (Up to approximately 1 year) ]
    The laboratory measurements included hematology and biochemistry values were graded with National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 toxicity grades (where Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening and Grade 5 = death). Number of participants with abnormalities Grade >= 3 in laboratory test values were reported.

  3. Number of Participants With Markedly Abnormal Vital Sign Measurements [ Time Frame: Time from first study intervention up to long term safety follow-up period (Up to approximately 1 year) ]
    Vital sign assessments included assessments of heart rate, diastolic blood pressure, systolic blood pressure, respiratory rate and temperature. Number of participants with markedly abnormal vital sign measurements were reported.

  4. Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Findings [ Time Frame: Time from first study intervention up to long term safety follow-up period (Up to approximately 1 year) ]
    Electrocardiograms (ECG) was obtained after the participant has been in a semi-supine position for at least 5 min. ECG parameters included heart rate, PQ/PR duration, QRS and QT duration, QT Interval. Clinical significance was determined by the investigator. Number of participants with clinically significant abnormalities in 12-lead ECG were reported.

  5. Percentage of Participants With Composite Pathological Complete Response (pCR)/ Clinical Complete Response (cCR) [ Time Frame: At Week 15 ]
    pCR: It is defined as absence of viable tumor cells in the primary tumor and lymph nodes. Participants considered to have a pCR if they undergo surgery and no residual cancer is found on histological examination of removed specimen. cCR: Participants are considered to have a cCR if: 1) Absence of any residual tumor in primary site and draining lymph nodes on imaging with magnetic resonance imaging; 2) No visible lesion at endoscopy except a flat scar, telangiectasia, and/or whitening of mucosa; 3) Absence of any palpable tumor or irregularity on digital rectal examination (DRE) and endoscopic ultrasonography (EUS); 4) If a biopsy is taken, it must be negative. Participants are considered as responders to composite endpoint pCR/cCR if participant had surgery and had pCR; participant did not undergo surgery but had cCR. Number of participants with composite pathological complete response (pCR)/ clinical complete response (cCR) were reported.

  6. Disease-free Survival [ Time Frame: Time from first study intervention up to approximately 24 months ]
    Disease-free Survival time, defined as the time from first treatment day to the date of the first documentation of objective progressive disease or death due to any cause, whichever occurs first. Median disease-free survival time was estimated according to Kaplan-Meier method.

  7. Percentage of Participants With Pathological Complete Response (pCR) [ Time Frame: At Week 15 ]
    pCR is defined as the absence of viable tumor cells in the primary tumor and lymph nodes. Participants are considered to have a pCR if they undergo surgery and no residual cancer is found on histological examination of the removed specimen.

  8. Percentage of Participants With Clinical Complete Response (cCR) [ Time Frame: At Week 15 ]
    cCR: It is defined as participants considered to have a cCR if: 1) Absence of any residual tumor in the primary site and draining lymph nodes on imaging with magnetic resonance; 2) No visible lesion at endoscopy except a flat scar, telangiectasia, and/or whitening of the mucosa; 3) Absence of any palpable tumor or irregularity on digital rectal examination (DRE) and endoscopic ultrasonography (EUS); 4) If a biopsy is taken, it must be negative.

  9. Time From Surgery to Local Recurrence [ Time Frame: Time from surgery up to approximately 1 year ]
    Time from surgery to local recurrence defined as time from day of surgery to the date of the first documentation of progression of disease, flagged as local recurrence. Median time from surgery to local recurrence was estimated according to Kaplan-Meier method.

  10. Time From Surgery to Distant Metastasis [ Time Frame: Time from surgery up to approximately 1 year ]
    Time from surgery to distant metastasis defined as time from day of surgery to the date of the first documentation of progression of disease, flagged as distant metastasis. Median time from surgery to distant metastasis was estimated according to Kaplan-Meier method.

  11. Neoadjuvant Rectal (NAR) Score [ Time Frame: At Week 15 ]

    The NAR formula includes the clinical tumor (cT) stage, pathologic tumor (pT), and node (pN) stage according to the tumor, node, metastasis classification system for colorectal cancers. The NAR formula is as follows:

    [5pN- 3 (cT- pT) + 12]2 / 9.61

    NAR score ranges from 0 to 100, whereas a score close to 100 is indicative of a poorer prognosis.


  12. Maximum Observed Plasma Concentration (Cmax) of Peposertib [ Time Frame: Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Fraction Day 1 and Fraction Day 9 ]
    Cmax was obtained directly from the concentration versus time curve. One participant was assigned to receive peposertib 100 mg; however, this participant took peposertib 50 mg for FD 1 through FD 10 and then took peposertib 100 mg for remainder of study participation. PK results for this participant was summarized by actual dose received (50 mg) whereas non-PK results are summarized by planned dose (100 mg).

  13. Area Under the Plasma Concentration-time Curve From Time Zero to Last Sampling Time (Tlast) (AUC0-t) of Peposertib [ Time Frame: Pre-dose, 1, 2, 3, 4 and 6 hour post-dose on Fraction Day 1 and Fraction Day 9 ]
    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 (LLQ). AUC0-t was to be calculated according to the mixed log-linear trapezoidal rule.

  14. Time to Reach Maximum Plasma Concentration (Tmax) of Peposertib [ Time Frame: Pre-dose, 1, 2, 3, 4 and 6 hour post-dose on Fraction Day 1 and Fraction Day 9 ]
    Time to reach the maximum plasma concentration (Tmax) was obtained directly from the concentration versus time curve.

  15. Total Body Clearance Following Oral Administration (CL/f) of Peposertib [ Time Frame: Pre-dose, 1, 2, 3, 4 and 6 hour post-dose on Fraction Day 1 ]
    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.

  16. Apparent Volume of Distribution (Vz/f) of Peposertib [ Time Frame: Pre-dose, 1, 2, 3, 4 and 6 hour post-dose on Fraction Day 1 and Fraction Day 9 ]
    The apparent volume of distribution during the terminal phase following extravascular administration, based on the fraction of dose absorbed. Vz/f = Dose/(AUC0-inf multiplied by Lambda z) following single dose. Vz/f= Dose/(AUCtau*Lambda z) following multiple dose. One participant was assigned to receive peposertib 100 mg; however, this participant took peposertib 50 mg for FD 1 through FD 10 and then took peposertib 100 mg for remainder of study participation. PK results for this participant was summarized by actual dose received (50 mg) whereas non-PK results are summarized by planned dose (100 mg).

  17. Apparent Terminal Half-life (t1/2) of Peposertib [ Time Frame: Pre-dose, 1, 2, 3, 4 and 6 hour post-dose on Fraction Day 1 and Fraction Day 9 ]
    Terminal half-life is the time measured for the concentration to decrease by one half. Terminal half-life calculated by natural log 2 divided by lambda z. One participant was assigned to receive peposertib 100 mg; however, this participant took peposertib 50 mg for FD 1 through FD 10 and then took peposertib 100 mg for remainder of study participation. PK results for this participant was summarized by actual dose received (50 mg) whereas non-PK results are summarized by planned dose (100 mg).



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 3)
  • Participants who received induction chemotherapy are allowed to be enrolled to this study except this induction is resulting in clinical complete response (cCR) or tumor progression
  • 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 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


Locations
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United States, Colorado
University of Colorado Cancer Center
Aurora, Colorado, United States, 80045
United States, Connecticut
Yale University - Pediatric Respiratory Medicine
New Haven, Connecticut, United States, 06520
United States, New York
Montefiore Medical Center
Bronx, New York, United States, 10461
Northwell Health, Inc
Great Neck, New York, United States, 10042
Memorial Sloan-Kettering Cancer Center (MSKCC) - New York
New York, New York, United States, 10065
United States, Ohio
Ohio State University Clinical Trials Management Office - Ohio State CTMO Parent
Columbus, Ohio, United States, 43210
University of Toledo Medical Center - Hematology/Oncology
Toledo, Ohio, United States, 43614
United States, South Carolina
Med. Univ. of South Carolina
Charleston, South Carolina, United States, 29425
Greenville Hospital System University Medical Center (ITOR)
Greenville, South Carolina, United States, 29605
United States, Texas
The University of Texas MD Anderson Cancer Center
Houston, Texas, United States, 77030
Spain
Hospital Universitari Vall d'Hebron - Dept of Oncology
Barcelona, Spain
Hospital Universitario 12 de Octubre - Servicio de Oncologia
Madrid, Spain
Hospital Regional Universitario de Malaga
Málaga, Spain
Hospital Clinico Universitario de Valencia - Servicio de Hematologia y Oncologia Medica
Valencia, Spain
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
  Study Documents (Full-Text)

Documents provided by EMD Serono ( EMD Serono Research & Development Institute, Inc. ):
Study Protocol  [PDF] May 6, 2021
Statistical Analysis Plan  [PDF] July 7, 2021

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
Results First Posted: July 7, 2022
Last Update Posted: July 7, 2022
Last Verified: June 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: We are committed to enhancing public health through responsible sharing of clinical trial data. Following approval of a new product or a new indication for an approved product in both the US and the European Union, the study sponsor and/or its affiliated companies will share study protocols, anonymized patient data and study level data, and redacted clinical study reports with qualified scientific and medical researchers, upon request, as necessary for conducting legitimate research. Further information on how to request data can be found on our website bit.ly/IPD21

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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
Peposertib
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
Peposertib
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors