Hypofractionated Radiotherapy Combined With NALIRIF, PD-1 Antibody in Locally Recurrent Rectal Cancer(NOVELTY-R)

Official title

Hypofractionated Radiotherapy Combined With Irinotecan Hydrochloride Liposome, 5-FU, Leucovorin, PD-1 Antibody and Target Therapy in Locally Recurrent Rectal Cancer(NOVELTY-R)

Overview

This is an open-label, single arm, phase 2 study. The study is to evaluate the activity of combination therapy of hypofractionated radiotherapy, Irinotecan Hydrochloride Liposome plus 5-FU and leucovorin (NALIRIF), Anti-PD1 and target therapy in patients with locally recurrent rectal cancer (LRRC). The inclusion LRRC patients were failed to oxaliplatin treatment in prior chemotherapy or chemoradiotherapy due to toxicity or progression. Patients will receive 25-40Gy/5Fx irradiation or 15-30Gy/5Fx reirradiation for pelvic recurrence, 25-50Gy/5Fx irradiation for all metastasis sites, and 8 cycles of NALIRIF + anti-PD1 + target therapy, followed by multidisciplinary team (MDT) for decision: radical surgery, sustained system +/- local treatment of non resection. The primary endpoint was local objective response rate. Secondary endpoints were extrapelvic objective response rate, complete response rate, R0 resection rate, duration of response, progression-free survival, overall survival, and safety and tolerability of the treatment.

Interventions

• Radiation radiotherapy
  25-40Gy/5Fx or 15-30Gy/5Fx (previous pelvic radiation) for pelvic recurrence. 25-50GY/5Fx for all metastasis tumors. Dose Constraints are based on SABR-COMET 10 trial.
• Drug Irinotecan Hydrochloride Liposome
  70mg/m2 (UGT1A1\*28 6/6) or 55mg/m2 (UGT1A1\*28 6/7), IV, q2w
• Drug 5-FU
  400 mg/m\^2 bolus over 2 hours followed by 2400 mg/m\^2 continuous infusion over 48 hours d1, q2w
• Drug Leucovorin
  400mg/m2, IV, q2w
• Drug SG001
  240mg, IV, q2w
• Drug C225
  500 mg/m2, IV, q2w
• Drug Bevacizumab
  5mg/kg, IV, q2w

Primary outcome measures

• Local objective response rate [Time frame: up to 1 year]

Secondary outcome measures (7)

• Extrapelvic objective response rate [Time frame: up to 1 year]
• Complete response rate [Time frame: up to 1 year]
• R0 resection rate [Time frame: up to 1 year]
• Duration of response (DOR) [Time frame: up to 3 year]
• Progression-Free Survival(PFS) [Time frame: up to 3 year]
• Overall Survival [Time frame: up to 3 year]
• Safety and tolerability of the treatment [Time frame: up to 1 year]

Eligibility criteria

Inclusion criteria

Patient is 18-75 years old at the time of signing the informed consent form. ECOG performance status 0-1. MRI/enhanced CT confirmed pelvic recurrence. According to RECIST 1.1, there is at least one measurable pelvic lesion.

Distant metastasis lesions are no more than 5 and metastatic organ are no more than 3.

No prior radiotherapy within 6 month. Failed to oxaliplatin treatment in prior chemotherapy or chemoradiotherapy due to toxicity or progression.

Has an investigator determined life expectancy of at least 24 weeks. Demonstrate adequate organ function (bone marrow, liver, kidney and clotting function) within 7 days before the first administration without using blood products or hematopoietic stimulating factors.

Non pregnant or lactating patients. Effective contraceptive methods should be used during the study and within 6 months of the last administration.

Fully informed and willing to provide written informed consent for the trial.

Exclusion criteria

Previous immunotherapy or Irinotecan Hydrochloride Liposome treatment. Neutrophil < 1.5×10\^9/L, PLT < 100×10\^9/L (PLT < 80×10\^9/L in patients with liver metastasis), or Hb < 90g/L; blood transfusion within 2 weeks before enrollment is not allowed to meet the enrollment criteria.

TBIL > 1.5 ULN, or TBIL > 2.5 ULN in patients with liver metastasis. AST or ALT > 2.5 ULN, or ALT and / or AST > 5 ULN in patients with liver metastasis.

Cr > 1.5 ULN, or creatinine clearance < 50ml / min (calculated according to Cockcroft Gault formula).

APTT > 1.5 ULN, PT > 1.5 ULN (subject to the normal value of the clinical trial research center).

Serious electrolyte abnormalities. Urinary protein ≥ 2+, or 24-hour urine protein ≥1.0g/24h. Uncontrolled hypertension: SBP >140mmHg or DBP > 90mmHg. The presence of gastrointestinal diseases such as gastric or duodenal active ulcers, ulcerative colitis or unresected tumours with active bleeding; or other conditions likely to cause gastrointestinal bleeding or perforation; or unhealed gastrointestinal perforation or gastrointestinal fistula after surgical treatment.

A history of arterial thrombosis or deep vein thrombosis within 6 months; a history of bleeding or evidence of bleeding tendency within 2 months.

A history of heart disease within 6 months (including congestive heart failure, acute myocardial infarction, severe/unstable angina, coronary artery bypass grafting, cardiac insufficiency ≥ NYHA grade 2 and LVEF<50%).

Uncontrolled malignant pleural effusion, ascites, or pericardial effusion. The presence of a clinically detectable second primary malignancy, or history of other malignancies within 5 years excluding adequately treated non-melanoma skin cancer, carcinoma in situ of cervix and superficial bladder tumour (non-invasive tumour, or carcinoma in situ, or T1).

A history of liver disease including, but not limited to HBV infection or HBV DNA positive(≥1×10\^4/ml), HCV infection or HCV DNA positive(≥1×10\^3/ml) and liver cirrhosis.

Pregnant or lactating women or women who may be pregnant have a positive pregnancy test before the first medication; Or the female participants themselves and their partners who were unwilling to implement strict contraception during the study period.

The investigator considers that the subject is not suitable to participate in this clinical study due to any clinical or laboratory abnormalities or compliance problems.

Serious mental abnormalities. The diameter of brain metastasis is greater than 3cm or the total volume is greater than 30cc.

Clinical or radiological evidence of spinal cord compression, or tumours within 3 mm of the spinal cord on MRI.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Fudan University Shanghai Cancer Center — Shanghai

Identifiers

NCT: NCT07183865 · FDRT-2024-383-3937

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗