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

Study Overview
=================
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).

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

Conditions
-----------------
Locally Advanced Rectal Cancer

Intervention / Treatment
-----------------
* Drug: Peposertib 50 mg
* Drug: Peposertib 100 mg
* Drug: Peposertib 150 mg
* Drug: Peposertib 250 mg
* Drug: Capecitabine
* Radiation: Radiotherapy (RT)


Participation Criteria
=================
Eligibility 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Peposertib 50 mg + RT + Capecitabine<br>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<br>* Participants received peposertib 50 milligram (mg) once daily 5 days per week up to 5.5 weeks.<br>* Other names: MSC2490484A;Drug: Capecitabine<br>* 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.<br>Radiation: Radiotherapy (RT)<br>* 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.<br>|
| Experimental: Peposertib 100 mg + RT + Capecitabine<br>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<br>* Participants received peposertib 100 mg once daily 5 days per week up to 5.5 weeks.<br>Drug: Capecitabine<br>* 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.<br>Radiation: Radiotherapy (RT)<br>* 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.<br>|
| Experimental: Peposertib 150 mg + RT + Capecitabine<br>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<br>* Participants received peposertib 150 mg once daily 5 days per week up to 5.5 weeks.<br>Drug: Capecitabine<br>* 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.<br>Radiation: Radiotherapy (RT)<br>* 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.<br>|
| Experimental: Peposertib 250 mg + RT + Capecitabine<br>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<br>* Participants received peposertib 250 mg once daily 5 days per week up to 5.5 weeks.<br>Drug: Capecitabine<br>* 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.<br>Radiation: Radiotherapy (RT)<br>* 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.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experienced Dose Limiting Toxicity (DLT) Confirmed by Safety Monitoring Committee (SMC) | 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 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) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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 from first study intervention up to long term safety follow-up period (Up to Month 35) | 
| Number of Participants With Abnormalities [Grade Greater Than or Equals to (>=) 3] in Laboratory Test Values | 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 from first study intervention up to long term safety follow-up period (Up to Month 35) | 
| Number of Participants With Markedly Abnormal Vital Sign Measurements | 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 from first study intervention up to long term safety follow-up period (Up to Month 35) | 
| Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Findings | 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 from first study intervention up to long term safety follow-up period (Up to Month 35) | 
| Percentage of Participants With Composite Pathological Complete Response (pCR)/ Clinical Complete Response (cCR) | 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. | At Week 15 | 
| Disease-free Survival | 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 from first study intervention up to approximately 35 months | 
| Percentage of Participants With Pathological Complete Response (pCR) | 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. | At Week 15 | 
| Percentage of Participants With Clinical Complete Response (cCR) | 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. | At Week 15 | 
| Time From Surgery to Local Recurrence | 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 up to 15 months | 
| Time From Surgery to Distant Metastasis | 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 from surgery up to 15 months | 
| Neoadjuvant Rectal (NAR) Score | 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. | At Week 15 | 
| Maximum Observed Plasma Concentration (Cmax) of Peposertib | 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). | Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Fraction Day 1 and Fraction Day 9 | 
| Area Under the Plasma Concentration-time Curve From Time Zero to Last Sampling Time (Tlast) (AUC0-t) of Peposertib | 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. | Pre-dose, 1, 2, 3, 4 and 6 hour post-dose on Fraction Day 1 and Fraction Day 9 | 
| Time to Reach Maximum Plasma Concentration (Tmax) of Peposertib | Time to reach the maximum plasma concentration (Tmax) was obtained directly from the concentration versus time curve. | Pre-dose, 1, 2, 3, 4 and 6 hour post-dose on Fraction Day 1 and Fraction Day 9 | 
| Total Body Clearance Following Oral Administration (CL/f) of Peposertib | 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. | Pre-dose, 1, 2, 3, 4 and 6 hour post-dose on Fraction Day 1 | 
| Apparent Volume of Distribution (Vz/f) of Peposertib | 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). | Pre-dose, 1, 2, 3, 4 and 6 hour post-dose on Fraction Day 1 and Fraction Day 9 | 
| Apparent Terminal Half-life (t1/2) of Peposertib | 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). | Pre-dose, 1, 2, 3, 4 and 6 hour post-dose on Fraction Day 1 and Fraction Day 9 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
DNA-PK inhibitor, Peposertib, capecitabine