Preoperative Radiotherapy And ASTX660 in Rectum Cancer

NCT05912075 | Recruiting Phase 1

• 2 other identifiers: 2021-005363-432021/3339
• Study Type: interventional
• Target: 78
• Locations: 1 country
• Sites: 2

Brief Summary

Compare two arms:

• Chemotherapy followed by tolinapant (ASTX660) in combination with Long-Course Radio Chemotherapy (LCRT), and
• Tolinapant (ASTX660) in combination with Short-Course Radiotherapy (SCRT) followed by chemotherapy For each patient, the treatment arm will be allocated on the following basis: patients will be allocated to the chemotherapy followed by LCRT arm unless they present at least one of the following criteria: contraindication to receive mFOLFIRINOX (including intolerance to irinotecan and UGT1A1\*28 polymorphism), age \> 75, general condition incompatible with the radiotherapy schedule of LCRT. In such case, patients will be allocated to the SCRT arm. Tolinapant (ASTX660) will be administered orally once a day for 7 consecutive days every other week during 10 weeks (One week On / One week Off during 10 weeks). Both treatment arms will have a dose escalation part to determine the MTD and/or RP2D, followed by an expansion part where up to 21 subjects will be dosed at the RP2D. Both arms will enroll simultaneously.

Conditions

Locally-advanced Rectal Cancer

Outcome Measures

Primary Outcomes (1)

• Dose-limiting toxicities (DLTs)

  ASTX660-related toxicities graded using NCI CTCAE V5.0

  during the 10 weeks of tolinapant (ASTX660) treatment

Secondary Outcomes (4)

• Overall survival

  2 years after surgery

• Disease-free survival (DFS)

  2 years after surgery

• Local recurrence-free survival

  2 years after surgery

• Distant metastasis-free survival

  2 years after surgery

Study Arms (2)

LCRT

EXPERIMENTAL

LCRT: Long-course pelvic radiotherapy given concomitantly with capecitabine chemotherapy and TOLINAPANT (ASTX660): * mFOLFIRINOX will be given prior to tolinapant (ASTX660) for 6 cycles over 12 weeks; * Pelvic radiotherapy to a planned volume at a 50-Gy total dose in 25 daily fractions of 2 Gy (5 days per week from Monday to Friday) for 5 weeks; * Chemotherapy (capecitabine) at 800 mg/m2 bid for 5 days per week (From Monday to Friday) for 25 days will be given concomitantly during the 5 weeks of radiotherapy; * TOLINAPANT (ASTX660) starting from 14 days before the first dose of radiotherapy, for 10 weeks. Tolinapant (ASTX660) will be given concomitantly with RT and chemotherapy for 5 weeks.

Drug: mFOLFIRINOX; Radiation: Pelvic radiotherapy LCRT; Drug: Capecitabine; Drug: TOLINAPANT (ASTX660)

SCRT

EXPERIMENTAL

SCRT: Short course pelvic radiotherapy followed by chemotherapy in combination with TOLINAPANT (ASTX660): * Pelvic radiotherapy will be given to a planned volume at a total dose of 25 Gy, in 5 daily fractions of 5 Gy for 1 week (5 days from Monday-Friday) * Chemotherapy (FOLFOX4): given every 2 weeks for 9 cycles, starting 10 days after the last session of short course radiotherapy. Alternative: CAPOX given every 3 weeks for 6 cycles, starting 10 days after the last session of short course radiotherapy. * Tolinapant (ASTX660) starting from 14 days before the first dose of radiotherapy, for 10 weeks. Tolinapant (ASTX660) will be given concomitantly with RT for 5 days.

Drug: TOLINAPANT (ASTX660); Radiation: Pelvic radiotherapy SCRT; Drug: FOLFOX4; Drug: CAPOX

Interventions

mFOLFIRINOX DRUG

prior to tolinapant (ASTX660) for 6 cycles over 12 weeks

LCRT

Pelvic radiotherapy LCRT RADIATION

50-Gy total dose in 25 daily fractions of 2 Gy (5 days per week from Monday to Friday) for 5 weeks

LCRT

Capecitabine DRUG

800 mg/m2 bid for 5 days per week (From Monday to Friday) for 25 days will be given concomitantly during the 5 weeks of radiotherapy

LCRT

TOLINAPANT (ASTX660) DRUG

starting from 14 days before the first dose of radiotherapy, for 10 weeks.

LCRT; SCRT

Pelvic radiotherapy SCRT RADIATION

total dose of 25 Gy, in 5 daily fractions of 5 Gy for 1 week (5 days from Monday-Friday)

SCRT

FOLFOX4 DRUG

given every 2 weeks for 9 cycles, starting 10 days after the last session of short course radiotherapy

SCRT

CAPOX DRUG

every 3 weeks for 6 cycles, starting 10 days after the last session of short course radiotherapy.

Also known as: Capecitabine + Oxaliplatine

SCRT

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Locally advanced rectum cancer where primary resection without chemoradiotherapy is unlikely to achieve clear margins as defined by:
• a distance between the tumor or its lymph node and the mesorectal fascia ≤ 2 mm on the pelvic MRI at diagnosis.
• \*and/or N2
• No evidence of metastatic disease on CT-scan (chest and abdomen), including resectable metastases
• Age : ≥ 18 years old at the time of informed consent
• Successfully received at least 4 cycles and up to 6 cycles of mFOLFIRINOX (LCRT arm only)
• Eastern Cooperative Oncology Group (ECOG) performance status (PS): 0 or 1
• Acceptable organ functions, as evidenced by the following laboratory data:
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.0×upper limit of normal (ULN)
• Total serum bilirubin ≤1.5×ULN
• Absolute neutrophil count (ANC): ≥2,000 cells/mm\^3
• Platelet count: ≥100,000 cells/mm\^3
• Hemoglobin: ≥ 9.0 g/dL
• Serum creatinine levels ≤1.5×ULN, or calculated (by Cockcroft-Gault formula or other accepted formula) or measured creatinine clearance ≥50 mL/min
• Amylase and lipase ≤1.5xULN

You may not qualify if:

• Any contraindications to MRI (e.g. subjects with pacemakers, claustrophobia, excessive weight, etc).
• Participation in another clinical study with an investigational product during the last 3 months.
• No other anticancer therapy during study participation. (however, informed consent can be signed during mFOLFIRINOX for patients willing to enter the LCRT arm).
• Hypersensitivity to tolinapant (ASTX660) or excipients of the drug product, or to any other component of the study treatment regimen, including:
• FU, capecitabine and known dihydropyrimidine dehydrogenase (DPD) deficiency, or
• Oxaliplatin, or
• Irinotecan and known Gilbert disease or genotype UGT1A1 (LCRT arm only)
• Previous radiotherapy in the pelvic region
• Preexisting condition that would deter radiotherapy, e.g. fistulas, severe ulcerative colitis (including subjects currently taking sulphasalazine), active Crohn's disease, prior adhesions
• Preexisting condition that would deter chemotherapy, e.g. pneumonitis, pulmonary fibrosis, pernicious anemia or other anemias caused by vitamin B12 deficiency
• Prior rectal surgery
• Prior investigational treatment for rectal cancer
• Poor medical risk because of systemic diseases (e.g., uncontrolled infections, uncontrolled diabetes) in addition to the qualifying disease under study
• Life-threatening illness, significant organ system dysfunction, or other condition that, in the investigator's opinion, could compromise subject safety or the integrity of the study outcomes, or interfere with the absorption or metabolism of tolinapant (ASTX660)
• A history of, or at risk for, cardiac disease, as evidenced by 1 or more of the following conditions:

Sponsors & Collaborators

• Gustave Roussy, Cancer Campus, Grand Paris: lead

Study Sites (2)

Centre Léon Bérard

Lyon, Rhöne, 69373, France

NOT YET RECRUITING

Gustave Roussy

Villejuif, Val De Marne, 94805, France

RECRUITING

MeSH Terms

Interventions

Capecitabine; ASTX-660; Folfox protocol; Oxaliplatin

Intervention Hierarchy (Ancestors)

Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Fluorouracil; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Coordination Complexes; Organic Chemicals

Central Study Contacts

Eric DEUTSCH, MD, PhD

CONTACT

+33 (0)1 42 11 65 73; Eric.DEUTSCH@gustaveroussy.fr

Catherine RICHON

CONTACT

+33 (0)1 42 11 23 44; catherine.richon@gustaveroussy.fr

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Comparative phase 1b trial with randomization

Study Record Dates

• First Submitted: June 12, 2023
• First Posted: June 22, 2023
• Study Start: December 19, 2023
• Primary Completion (Estimated): January 1, 2028
• Study Completion (Estimated): January 1, 2029
• Last Updated: February 8, 2024

Record last verified: 2024-02

Locations

FR (2)