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

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.

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)

Population: Dose escalation (DE) analysis set included all participants treated in dose escalation cohorts, who received at least 80% of peposertib, 50% of capecitabine, and 80% of RT planned dose and complete DLT period (5 or 5.5 weeks after start of treatment or for the entire duration of treatment). DE set also included participants treated in dose escalation cohorts who experience a DLT during DLT period regardless of the amount of each study intervention received/completion of the DLT period.

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).

Time frame: Pre-dose, 1, 2, 3, 4 and 6 hour post-dose on Fraction Day 1 and Fraction Day 9

Population: PK analysis set was used. Here, Number of participants analyzed signifies those participants who were evaluable for this outcome measure. Here, Number Analyzed signified those participants who were evaluable at specified timepoint.

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).

Time frame: Pre-dose, 1, 2, 3, 4 and 6 hour post-dose on Fraction Day 1 and Fraction Day 9

Population: PK analysis set was used. Here, Number of participants analyzed signifies those participants who were evaluable for this outcome measure. Here, Number Analyzed signified those participants who were evaluable at specified timepoint.

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 frame: Pre-dose, 1, 2, 3, 4 and 6 hour post-dose on Fraction Day 1 and Fraction Day 9

Population: PK analysis set was used. 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).

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.

Time frame: Time from first study intervention up to approximately 35 months

Population: FAS include all participants who are enrolled in the study and received at least 1 dose of study intervention. As per the planned analysis, Kaplan-Meier estimates were planned to be presented as overall, together with a summary of associated statistics for this outcome measure.

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).

Time frame: Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Fraction Day 1 and Fraction Day 9

Population: Pharmacokinetic (PK) analysis set included participants who received at least 1 dose of peposertib and have sufficient peposertib plasma concentration data to enable the calculation of at least 1 PK parameter. Sufficient concentration data is defined as at least 3 valid, post dose, concentration points in the PK profile to obtain any PK parameter.

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.

Time frame: At Week 15

Population: FAS include all participants who are enrolled in the study and received at least 1 dose of study intervention. Here, Number of participants analyzed signifies those participants who were evaluable for this outcome measure.

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.

Time frame: Time from first study intervention up to long term safety follow-up period (Up to Month 35)

Population: SAF analysis set included all participants who received at least 1 dose of study intervention.

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.

Time frame: Time from first study intervention up to long term safety follow-up period (Up to Month 35)

Population: SAF analysis set included all participants who received at least 1 dose of study intervention.

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.

Time frame: Time from first study intervention up to long term safety follow-up period (Up to Month 35)

Population: SAF analysis set included all participants who received at least 1 dose of study intervention.

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.

Time frame: Time from first study intervention up to long term safety follow-up period (Up to Month 35)

Population: SAF analysis set included all participants who received at least 1 dose of study intervention.

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.

Time frame: At Week 15

Population: FAS include all participants who are enrolled in the study and received at least 1 dose of study intervention.

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 frame: At Week 15

Population: Full analysis set (FAS) include all participants who are enrolled in the study and received at least 1 dose of study intervention.

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.

Time frame: At Week 15

Population: FAS include all participants who are enrolled in the study and received at least 1 dose of study intervention.

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.

Time frame: Time from surgery up to 15 months

Population: FAS include all participants who are enrolled in the study and received at least 1 dose of study intervention. Here, number of participants analyzed signifies those participants who underwent rectal surgery. As per the planned analysis, Kaplan-Meier estimates were planned to be presented overall, together with a summary of associated statistics for this outcome measure.

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 frame: Time from surgery up to 15 months

Population: FAS include all participants who are enrolled in the study and received at least 1 dose of study intervention. Here, number of participants analyzed signifies those participants who underwent rectal surgery. As per the planned analysis, Kaplan-Meier estimates were planned to be presented overall, together with a summary of associated statistics (median survival time and survival rate estimates) including the corresponding 2-sided 95% Confidence Intervals (CIs) for this outcome measure.

Time to reach the maximum plasma concentration (Tmax) was obtained directly from the concentration versus time curve.

Time frame: Pre-dose, 1, 2, 3, 4 and 6 hour post-dose on Fraction Day 1 and Fraction Day 9

Population: PK analysis set was used. 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).

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.

Time frame: Pre-dose, 1, 2, 3, 4 and 6 hour post-dose on Fraction Day 1

Population: PK analysis set was used. 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). Here, Number of participants analyzed signifies those participants who were evaluable for this outcome measure.