Study of Peposertib in Combination With Capecitabine and RT in Rectal Cancer

Phase 1

Completed

Conditions: Locally Advanced Rectal Cancer

Interventions: Drug: Peposertib 100 mg
Drug: Peposertib 250 mg
Drug: Peposertib 150 mg
Drug: Peposertib 50 mg
Drug: Capecitabine
Radiation: Radiotherapy (RT)

Registration Number: NCT03770689

Lead Sponsor: 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).

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 19

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Peposertib 50 mg + RT + Capecitabine	Radiotherapy (RT)	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.
Peposertib 100 mg + RT + Capecitabine	Radiotherapy (RT)	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.
Peposertib 100 mg + RT + Capecitabine	Peposertib 100 mg	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.
Peposertib 250 mg + RT + Capecitabine	Peposertib 250 mg	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.
Peposertib 150 mg + RT + Capecitabine	Peposertib 150 mg	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.
Peposertib 250 mg + RT + Capecitabine	Radiotherapy (RT)	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.
Peposertib 50 mg + RT + Capecitabine	Peposertib 50 mg	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.
Peposertib 150 mg + RT + Capecitabine	Radiotherapy (RT)	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.
Peposertib 50 mg + RT + Capecitabine	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.
Peposertib 100 mg + RT + Capecitabine	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.
Peposertib 150 mg + RT + Capecitabine	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.
Peposertib 250 mg + RT + Capecitabine	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.

Primary Outcome Measures

Name	Time	Method
Number of Participants Who Experienced Dose Limiting Toxicity (DLT) Confirmed by Safety Monitoring Committee (SMC)	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

Name	Time	Method
Number of Participants With Markedly Abnormal Vital Sign Measurements	Time from first study intervention up to long term safety follow-up period (Up to Month 35)	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.
Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Findings	Time from first study intervention up to long term safety follow-up period (Up to Month 35)	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.
Disease-free Survival	Time from first study intervention up to approximately 35 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.
Percentage of Participants With Pathological Complete Response (pCR)	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.
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 from first study intervention up to long term safety follow-up period (Up to Month 35)	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.
Apparent Terminal Half-life (t1/2) of Peposertib	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).
Area Under the Plasma Concentration-time Curve From Time Zero to Last Sampling Time (Tlast) (AUC0-t) of Peposertib	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.
Time to Reach Maximum Plasma Concentration (Tmax) of Peposertib	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.
Number of Participants With Abnormalities [Grade Greater Than or Equals to (>=) 3] in Laboratory Test Values	Time from first study intervention up to long term safety follow-up period (Up to Month 35)	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.
Percentage of Participants With Composite Pathological Complete Response (pCR)/ Clinical Complete Response (cCR)	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.
Time From Surgery to Local Recurrence	Time from surgery up to 15 months	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.
Time From Surgery to Distant Metastasis	Time from surgery up to 15 months	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.
Maximum Observed Plasma Concentration (Cmax) of Peposertib	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).
Total Body Clearance Following Oral Administration (CL/f) of Peposertib	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.
Percentage of Participants With Clinical Complete Response (cCR)	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.
Neoadjuvant Rectal (NAR) Score	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.
Apparent Volume of Distribution (Vz/f) of Peposertib	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).

Trial Locations

Locations (14): Ohio State University Clinical Trials Management Office - Ohio State CTMO Parent
🇺🇸
Columbus, Ohio, United States
University of Colorado Cancer Center
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Aurora, Colorado, United States
Northwell Health, Inc
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Great Neck, New York, United States
Memorial Sloan-Kettering Cancer Center (MSKCC) - New York
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New York, New York, United States
University of Toledo Medical Center - Hematology/Oncology
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Toledo, Ohio, United States
Med. Univ. of South Carolina
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Charleston, South Carolina, United States
Greenville Hospital System University Medical Center (ITOR)
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Greenville, South Carolina, United States
The University of Texas MD Anderson Cancer Center
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Houston, Texas, United States
Hospital Universitario 12 de Octubre - Servicio de Oncologia
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Madrid, Spain
Hospital Universitari Vall d'Hebron - Dept of Oncology
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Barcelona, Spain
Hospital Regional Universitario de Malaga
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Málaga, Spain
Hospital Clinico Universitario de Valencia - Servicio de Hematologia y Oncologia Medica
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Valencia, Spain
Yale University - Pediatric Respiratory Medicine
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New Haven, Connecticut, United States
Montefiore Medical Center
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Bronx, New York, United States