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ERASE CRC

Introduction

Stage III colorectal cancer (CRC) patients are currently treated with three- or six-months of adjuvant chemotherapy (ACT) using fluoropyrimidines and oxaliplatin depending on the risk subgroup (low vs high).
In stage II CRC patients ACT is still controversial: combination of fluoropyrimidines and oxaliplatin may be considered in the case of at least one major risk factor (i.e. pT4 stage, lymph nodes sampling less than 12 and clinical presentation with intestinal perforation) or in presence of multiple risk factors.
However, identifying CRC patients who will benefit from ACT remains an open question.
Post-surgery circulating tumor (ct-DNA) seems a promising marker of minimal residual disease (MRD) and a clinically relevant marker of poor prognosis.
Also the persistence of detectable ct-DNA at the end of the adjuvant treatment predicts high risk of recurrence.
In chemorefractory patients with HER2+ and RAS wild-type metastatic colorectal cancer, the combination of Trastuzumab and Tucatinib reported promising activity with an acceptable safety profile. The combination of Trastuzumab and Tucatinib with FOLFOX is currently under investigation in a phase 1b/2 study for patients with HER2+ gastrointestinal tumors and showed a manageable safety profile with antidiarrheal prophylaxis with loperamide.
Drawing from these considerations, we designed the present study, including three phase II trials:

  1. Part 1: resected stage III and high-risk stage II colon cancer patients with positive ct-DNA after surgery will be randomized to receive FOLFOX for 12 cycles or CAPOX for 8 cycles (at investigator choice) versus FOLFOXIRI for 12 cycles;
  2. Target-driven Part 1: resected stage III and high-risk stage II HER2+ and RAS wild-type colon cancer patients with positive ct-DNA after surgery will receive FOLFOX plus Trastuzumab and Tucatinib for 12 cycles;
  3. Part 2: resected stage III and high-risk stage II colon cancer patients with positive ct-DNA after the end of a fluoropyrimidine and oxaliplatin-based adjuvant therapy – either in the frame or outside of Part 1 – will be randomized to receive observation or trifluridine/tipiracil for 6 cycles.

Selection criteria

Part 1, target-driven Part 1, and Part 2:
– Histologically confirmed stage III or high-risk stage II adenocarcinoma of colon including intraperitoneal rectal cancer.
– adequate hematopoietic, liver and renal function.

Part 1 and target-driven Part 1
– no evidence of metastatic disease at post-operative CT scan.
– Positive ct-DNA after surgery (central assessment). The blood sample should be collected 2-6 weeks after the surgery.
Only for target-driven Part 1: HER2+ and RAS wild-type tumor as determined by central laboratory assessment and left ventricular ejection fraction ≥ 50%

Part 2
– Fluoropyrimidine and oxaliplatin-containing adjuvant treatment for at least 3 months.
– no evidence of metastatic disease at post-adjuvant CT scan.
– Positive ct-DNA after the end of adjuvant treatment (central assessment).

Objectives

The primary objectives of this study are to determine whether an intensified adjuvant regimen of FOLFOXIRI could increase the percentage of cases with undetectable ct-DNA following chemotherapy (Part 1), chemotherapy plus Trastuzumab and Tucatinib (target-driven Part 1) and whether an additional adjuvant regimen of FTD/TPI could do the same (Part 2) in a population at high risk of relapse.

Participating centers