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NCT03770689

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

Completed Phase 1, PHASE2 Results posted Last updated 21 March 2023
What this trial tests

Phase 1, PHASE2 trial testing Peposertib 50 mg in Locally Advanced Rectal Cancer in 19 participants. Completed in 21 February 2022.

Timeline
20 March 2019
Primary endpoint
21 June 2021
21 February 2022

Quick facts

Lead sponsorEMD Serono Research & Development Institute, Inc.
PhasePhase 1, PHASE2
StatusCompleted
Study typeINTERVENTIONAL
Allocationnon randomized
Designsingle group
Maskingnone
Primary purposetreatment
Enrollment19
Start date20 March 2019
Primary completion21 June 2021
Estimated completion21 February 2022
Sites14 locations across United States, Spain

Drugs / interventions tested

Conditions studied

Sponsor

EMD Serono Research & Development Institute, Inc. — full company profile →

Who can join

18 and older, any sex, with Locally Advanced Rectal Cancer. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Number of Participants Who Experienced Dose Limiting Toxicity (DLT) Confirmed by Safety Monitoring Committee (SMC) Primary · 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 thrombocytopeni

GroupValue95% CI
Peposertib 50 mg + RT + Capecitabine:0
Peposertib 100 mg + RT + Capecitabine:1
Peposertib 150 mg + RT + Capecitabine:1
Peposertib 250 mg + RT + Capecitabine:3
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 Secondary · 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 anom

Participants with TEAEs
GroupValue95% CI
Peposertib 50 mg + RT + Capecitabine:1
Peposertib 100 mg + RT + Capecitabine:6
Peposertib 150 mg + RT + Capecitabine:6
Peposertib 250 mg + RT + Capecitabine:6
Participants with Treatment-Related TEAEs
GroupValue95% CI
Peposertib 50 mg + RT + Capecitabine:1
Peposertib 100 mg + RT + Capecitabine:6
Peposertib 150 mg + RT + Capecitabine:6
Peposertib 250 mg + RT + Capecitabine:6
Number of Participants With Abnormalities [Grade Greater Than or Equals to (>=) 3] in Laboratory Test Values Secondary · 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.

GroupValue95% CI
Peposertib 50 mg + RT + Capecitabine:1
Peposertib 100 mg + RT + Capecitabine:6
Peposertib 150 mg + RT + Capecitabine:6
Peposertib 250 mg + RT + Capecitabine:6
Number of Participants With Markedly Abnormal Vital Sign Measurements Secondary · 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.

GroupValue95% CI
Peposertib 50 mg + RT + Capecitabine:0
Peposertib 100 mg + RT + Capecitabine:0
Peposertib 150 mg + RT + Capecitabine:0
Peposertib 250 mg + RT + Capecitabine:0
Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Findings Secondary · 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.

GroupValue95% CI
Peposertib 50 mg + RT + Capecitabine:0
Peposertib 100 mg + RT + Capecitabine:0
Peposertib 150 mg + RT + Capecitabine:0
Peposertib 250 mg + RT + Capecitabine:0
Percentage of Participants With Composite Pathological Complete Response (pCR)/ Clinical Complete Response (cCR) Secondary · 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

GroupValue95% CI
Peposertib 50 mg + RT + Capecitabine:0.00.0 – 97.5
Peposertib 100 mg + RT + Capecitabine:16.70.4 – 64.1
Peposertib 150 mg + RT + Capecitabine:0.00.0 – 45.9
Peposertib 250 mg + RT + Capecitabine:0.00.0 – 45.9
Disease-free Survival Secondary · 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.

GroupValue95% CI
Overall Participants21.20.0 – 23.5
Percentage of Participants With Pathological Complete Response (pCR) Secondary · 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.

GroupValue95% CI
Peposertib 50 mg + RT + Capecitabine:0.00.0 – 97.5
Peposertib 100 mg + RT + Capecitabine:0.00.0 – 45.9
Peposertib 150 mg + RT + Capecitabine:0.00.0 – 45.9
Peposertib 250 mg + RT + Capecitabine:0.00.0 – 45.9
Percentage of Participants With Clinical Complete Response (cCR) Secondary · 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.

GroupValue95% CI
Peposertib 50 mg + RT + Capecitabine:0.00.0 – 97.5
Peposertib 100 mg + RT + Capecitabine:16.70.4 – 64.1
Peposertib 150 mg + RT + Capecitabine:16.70.4 – 64.1
Peposertib 250 mg + RT + Capecitabine:16.70.4 – 64.1
Time From Surgery to Local Recurrence Secondary · 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.

GroupValue95% CI
All ParticipantsNA2.8 – 15.0
Time From Surgery to Distant Metastasis Secondary · 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.

GroupValue95% CI
All ParticipantsNA2.8 – 15.0
Neoadjuvant Rectal (NAR) Score Secondary · 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.

GroupValue95% CI
Peposertib 100 mg + RT + Capecitabine:9.4± 7.95
Peposertib 150 mg + RT + Capecitabine:13.8± 1.69
Peposertib 250 mg + RT + Capecitabine:21.2± 12.11

Adverse events — posted to ClinicalTrials.gov

Time frame: Baseline up to long term follow-up period (approximately Month 35). Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Peposertib 50 mg + RT + Capecitabine:
Serious: 0/1 (0%)
Deaths: 0/1
Peposertib 100 mg + RT + Capecitabine:
Serious: 3/6 (50%)
Deaths: 1/6
Peposertib 150 mg + RT + Capecitabine:
Serious: 0/6 (0%)
Deaths: 1/6
Peposertib 250 mg + RT + Capecitabine:
Serious: 4/6 (67%)
Deaths: 1/6

Serious adverse events (11 terms)

ReactionSystemPeposertib 50 mg + RT + Ca…Peposertib 100 mg + RT + C…Peposertib 150 mg + RT + C…Peposertib 250 mg + RT + C…
EnterocolitisGastrointestinal disorders
DiarrhoeaGastrointestinal disorders
ProctitisGastrointestinal disorders
Small intestinal obstructionGastrointestinal disorders
PneumoniaInfections and infestations
SepsisInfections and infestations
Accidental overdoseInjury, poisoning and procedural complications
Alanine aminotransferase increasedInvestigations
Aspartate aminotransferase increasedInvestigations
Platelet count decreasedInvestigations
HypoalbuminaemiaMetabolism and nutrition disorders
Other adverse events (73 terms — click to expand)

ReactionSystemPeposertib 50 mg + RT + Ca…Peposertib 100 mg + RT + C…Peposertib 150 mg + RT + C…Peposertib 250 mg + RT + C…
DiarrhoeaGastrointestinal disorders
Rectal tenesmusGastrointestinal disorders
FatigueGeneral disorders
AnaemiaBlood and lymphatic system disorders
NauseaGastrointestinal disorders
ConstipationGastrointestinal disorders
ProctalgiaGastrointestinal disorders
ProctitisGastrointestinal disorders
Rectal haemorrhageGastrointestinal disorders
AstheniaGeneral disorders
Radiation skin injuryInjury, poisoning and procedural complications
Lymphocyte count decreasedInvestigations
Decreased appetiteMetabolism and nutrition disorders
DehydrationMetabolism and nutrition disorders
LeukopeniaBlood and lymphatic system disorders
LymphopeniaBlood and lymphatic system disorders
Anal incontinenceGastrointestinal disorders
Weight decreasedInvestigations
White blood cell count decreasedInvestigations
HypokalaemiaMetabolism and nutrition disorders
DermatitisSkin and subcutaneous tissue disorders
Palmar-plantar erythrodysaesthesia syndromeSkin and subcutaneous tissue disorders
NeutropeniaBlood and lymphatic system disorders
ThrombocytopeniaBlood and lymphatic system disorders
Vision blurredEye disorders
Abdominal distensionGastrointestinal disorders
Abdominal painGastrointestinal disorders
Abdominal pain lowerGastrointestinal disorders
Anal inflammationGastrointestinal disorders
ColitisGastrointestinal disorders
Dry mouthGastrointestinal disorders
DyscheziaGastrointestinal disorders
FlatulenceGastrointestinal disorders
HaematocheziaGastrointestinal disorders
Rectal ulcerGastrointestinal disorders
VomitingGastrointestinal disorders
Oedema peripheralGeneral disorders
Secretion dischargeGeneral disorders
BacteraemiaInfections and infestations
Candida infectionInfections and infestations

Most-reported serious reactions: Enterocolitis, Diarrhoea, Proctitis, Small intestinal obstruction, Pneumonia, Sepsis, Accidental overdose, Alanine aminotransferase increased.

Data from ClinicalTrials.gov NCT03770689 adverse events section.

Sponsor's own description

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).

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Tumor biomarkers for diagnosis, prognosis and targeted therapy.
    Zhou Y, Tao L, Qiu J, Xu J, et al · · 2024 · cited 379× · PMID 38763973 · DOI 10.1038/s41392-024-01823-2
  2. DNA Repair Pathways in Cancer Therapy and Resistance.
    Li LY, Guan YD, Chen XS, Yang JM, et al · · 2020 · cited 254× · PMID 33628188 · DOI 10.3389/fphar.2020.629266
  3. Biomarker-Guided Development of DNA Repair Inhibitors.
    Cleary JM, Aguirre AJ, Shapiro GI, D'Andrea AD. · · 2020 · cited 192× · PMID 32459988 · DOI 10.1016/j.molcel.2020.04.035
  4. Radiotherapy as a tool to elicit clinically actionable signalling pathways in cancer.
    Petroni G, Cantley LC, Santambrogio L, Formenti SC, et al · · 2022 · cited 154× · PMID 34819622 · DOI 10.1038/s41571-021-00579-w
  5. Leveraging the replication stress response to optimize cancer therapy.
    Cybulla E, Vindigni A. · · 2023 · cited 109× · PMID 36323800 · DOI 10.1038/s41568-022-00518-6
  6. Simultaneous precise editing of multiple genes in human cells.
    Riesenberg S, Chintalapati M, Macak D, Kanis P, et al · · 2019 · cited 101× · PMID 31392986 · DOI 10.1093/nar/gkz669
  7. A first-in-man phase 1 study of the DNA-dependent protein kinase inhibitor peposertib (formerly M3814) in patients with advanced solid tumours.
    van Bussel MTJ, Awada A, de Jonge MJA, Mau-Sørensen M, et al · · 2021 · cited 98× · PMID 33230210 · DOI 10.1038/s41416-020-01151-6
  8. Altering DNA Repair to Improve Radiation Therapy: Specific and Multiple Pathway Targeting.
    Biau J, Chautard E, Verrelle P, Dutreix M. · · 2019 · cited 91× · PMID 31649878 · DOI 10.3389/fonc.2019.01009

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Data sources for this page

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Primary sources · FDA · ClinicalTrials.gov · EMA · SEC EDGAR · ChEMBL · Wikidata · full sourcing