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
Overview
- Phase
- Phase 1
- Intervention
- Peposertib 100 mg
- Conditions
- Locally Advanced Rectal Cancer
- Sponsor
- EMD Serono Research & Development Institute, Inc.
- Enrollment
- 19
- Locations
- 14
- Primary Endpoint
- Number of Participants Who Experienced Dose Limiting Toxicity (DLT) Confirmed by Safety Monitoring Committee (SMC)
- Status
- Completed
- Last Updated
- 3 years ago
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).
Investigators
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.
Arms & Interventions
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.
Intervention: Peposertib 100 mg
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.
Intervention: Peposertib 50 mg
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.
Intervention: Capecitabine
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.
Intervention: Radiotherapy (RT)
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.
Intervention: Capecitabine
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.
Intervention: Radiotherapy (RT)
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.
Intervention: Peposertib 150 mg
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.
Intervention: Capecitabine
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.
Intervention: Radiotherapy (RT)
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.
Intervention: Peposertib 250 mg
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.
Intervention: Capecitabine
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.
Intervention: Radiotherapy (RT)
Outcomes
Primary Outcomes
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 Outcomes
- 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))
- 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))
- Disease-free Survival(Time from first study intervention up to approximately 35 months)
- Percentage of Participants With Pathological Complete Response (pCR)(At Week 15)
- 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))
- 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)
- 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)
- 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)
- 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))
- Percentage of Participants With Composite Pathological Complete Response (pCR)/ Clinical Complete Response (cCR)(At Week 15)
- Time From Surgery to Local Recurrence(Time from surgery up to 15 months)
- Time From Surgery to Distant Metastasis(Time from surgery up to 15 months)
- 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)
- 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)
- Percentage of Participants With Clinical Complete Response (cCR)(At Week 15)
- Neoadjuvant Rectal (NAR) Score(At Week 15)
- 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)