Decision-making of ctDNA in Patients With mCRC After Failure of First-line Treatment Containing Cetuximab - a Single-center, Phase II Clinical Study

• ClinicalTrials.gov Identifier: NCT04831528
• Recruitment Status: Not yet recruiting
• First Posted: April 5, 2021
• Last Update Posted: April 5, 2021
• Sponsor: Fudan University
• Information provided by (Responsible Party): Fudan University

Study Description

Brief Summary:

This study aimis at detecting the genomic changes of ctDNA in patients of RAS and BRAF wild-type mCRC, who failed after first line treatment containing cetuximab. According to the results of ctDNA detection, individualized second-line targeted therapy strategies were developed to explore the disease control rate and prognostic significance of ctDNA-guided treatment for metastatic colorectal cancer.

Condition or disease	Intervention/treatment
Metastatic Colorectal Cancer	Drug: Cetuximab Ab; Bevacizumab; Vermofenib + cetuximab;Trastuzumab+lapatinib or trastuzumab+pertuzumab; others

Study Design

• Study Type: Observational
• Estimated Enrollment: 100 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: The Role of Circulating Tumor DNA in Decision-making of Patients With Metastatic Colorectal Cancer After Failure of First-line Treatment Containing Cetuximab - a Single-center, Phase II Clinical Study
• Estimated Study Start Date: April 10, 2021
• Estimated Primary Completion Date: June 30, 2025
• Estimated Study Completion Date: June 30, 2026

Groups and Cohorts

Group/Cohort	Intervention/treatment
No secondary changes of drug resistance	Drug: Cetuximab Ab; Bevacizumab; Vermofenib + cetuximab;Trastuzumab+lapatinib or trastuzumab+pertuzumab; others; After PD, patients received ctDNA testing, and different research protocols were selected according to different gene states of ctDNA, as follows: 1.No secondary changes related to drug resistance were found. Cetuximab cross-line + second-line chemotherapy (FOLFOX/FOLFIRI/ Irinotecan monotherapy, etc.) was used.2. If there is a RAS secondary mutation, change of beacizumab bead sheet resistance + second-line chemotherapy (FOLFOX/XELOX/stand for kang single-agent FOLFIRI mXEIRI/Iraq, etc.);3. If BRAF secondary mutation occurs, replace it with vimofenib + cetuximab + irinotecan;4. If HER2 amplification occurs, replace it with trastuzumab + lapatinib or trastuzumab + pertuzumab;5. In case of other secondary mutations, bevacizumab plus second-line chemotherapy should be replaced.
Secondary mutations of RAS	Drug: Cetuximab Ab; Bevacizumab; Vermofenib + cetuximab;Trastuzumab+lapatinib or trastuzumab+pertuzumab; others; After PD, patients received ctDNA testing, and different research protocols were selected according to different gene states of ctDNA, as follows: 1.No secondary changes related to drug resistance were found. Cetuximab cross-line + second-line chemotherapy (FOLFOX/FOLFIRI/ Irinotecan monotherapy, etc.) was used.2. If there is a RAS secondary mutation, change of beacizumab bead sheet resistance + second-line chemotherapy (FOLFOX/XELOX/stand for kang single-agent FOLFIRI mXEIRI/Iraq, etc.);3. If BRAF secondary mutation occurs, replace it with vimofenib + cetuximab + irinotecan;4. If HER2 amplification occurs, replace it with trastuzumab + lapatinib or trastuzumab + pertuzumab;5. In case of other secondary mutations, bevacizumab plus second-line chemotherapy should be replaced.
Secondary mutation of BRAF	Drug: Cetuximab Ab; Bevacizumab; Vermofenib + cetuximab;Trastuzumab+lapatinib or trastuzumab+pertuzumab; others; After PD, patients received ctDNA testing, and different research protocols were selected according to different gene states of ctDNA, as follows: 1.No secondary changes related to drug resistance were found. Cetuximab cross-line + second-line chemotherapy (FOLFOX/FOLFIRI/ Irinotecan monotherapy, etc.) was used.2. If there is a RAS secondary mutation, change of beacizumab bead sheet resistance + second-line chemotherapy (FOLFOX/XELOX/stand for kang single-agent FOLFIRI mXEIRI/Iraq, etc.);3. If BRAF secondary mutation occurs, replace it with vimofenib + cetuximab + irinotecan;4. If HER2 amplification occurs, replace it with trastuzumab + lapatinib or trastuzumab + pertuzumab;5. In case of other secondary mutations, bevacizumab plus second-line chemotherapy should be replaced.
HER2 amplification	Drug: Cetuximab Ab; Bevacizumab; Vermofenib + cetuximab;Trastuzumab+lapatinib or trastuzumab+pertuzumab; others; After PD, patients received ctDNA testing, and different research protocols were selected according to different gene states of ctDNA, as follows: 1.No secondary changes related to drug resistance were found. Cetuximab cross-line + second-line chemotherapy (FOLFOX/FOLFIRI/ Irinotecan monotherapy, etc.) was used.2. If there is a RAS secondary mutation, change of beacizumab bead sheet resistance + second-line chemotherapy (FOLFOX/XELOX/stand for kang single-agent FOLFIRI mXEIRI/Iraq, etc.);3. If BRAF secondary mutation occurs, replace it with vimofenib + cetuximab + irinotecan;4. If HER2 amplification occurs, replace it with trastuzumab + lapatinib or trastuzumab + pertuzumab;5. In case of other secondary mutations, bevacizumab plus second-line chemotherapy should be replaced.
Other secondary mutations	Drug: Cetuximab Ab; Bevacizumab; Vermofenib + cetuximab;Trastuzumab+lapatinib or trastuzumab+pertuzumab; others; After PD, patients received ctDNA testing, and different research protocols were selected according to different gene states of ctDNA, as follows: 1.No secondary changes related to drug resistance were found. Cetuximab cross-line + second-line chemotherapy (FOLFOX/FOLFIRI/ Irinotecan monotherapy, etc.) was used.2. If there is a RAS secondary mutation, change of beacizumab bead sheet resistance + second-line chemotherapy (FOLFOX/XELOX/stand for kang single-agent FOLFIRI mXEIRI/Iraq, etc.);3. If BRAF secondary mutation occurs, replace it with vimofenib + cetuximab + irinotecan;4. If HER2 amplification occurs, replace it with trastuzumab + lapatinib or trastuzumab + pertuzumab;5. In case of other secondary mutations, bevacizumab plus second-line chemotherapy should be replaced.

Outcome Measures

Primary Outcome Measures :

1. Objective response rate [ Time Frame: April 10,2021-June 30,2021 ]
   The percentage of patients whose tumors shrink by a certain amount and remain so for a certain amount of time, including patients with CR and PR.Objective tumor response was assessed using the Response Assessment Criterion for Solid Tumors (RECIST 1.1).

Secondary Outcome Measures :

1. overall survival [ Time Frame: April 10,2021-June 30,2021 ]
   Time from enrollment to death from any cause.Lost visitors to the last follow-up time.
2. progress free survival [ Time Frame: April 10,2021-June 30,2021 ]
   Patients were randomized to solstice for any recorded time of tumor progression or death from any cause.
3. Safety and tolerability [ Time Frame: April 10,2021-June 30,2021 ]
   NCI -- CTC AE 4.0 will be used to evaluate the clinical safety of the treatment in the study.The incidence of adverse events in the subjects should be assessed at each clinical visit.
4. duration of response [ Time Frame: April 10,2021-June 30,2021 ]
   This is the time between the first assessment of a tumor as CR or PR and the first assessment as PD or death from any cause.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Gender Based Eligibility: Yes
• Gender Eligibility Description: ≥18y
• Accepts Healthy Volunteers: No
• Sampling Method: Probability Sample

Study Population

Patients who met the entry criteria, failed after receiving first-line treatment containing cetuximab, and were judged to have progressive disease (PD) by imaging evaluation were eligible for inclusion.

Criteria

Inclusion Criteria:

1. Age ≥18, gender unlimited;
2. Proven histologically by colorectal adenocarcinoma, local lesions can not be radical resection or metastatic colorectal cancer;
3. Patients with RAS and BRAF wild-type tissue genetic testing, receiving first-line treatment containing cetuximab, and radiographic evaluation of disease progression;
4. Eastern Cooperative Oncology Group (ECOG) physical condition score (PS) 0 ~ 2;
5. Expected survival of more than 3 months;
6. Within 7 days before screening (including 7 days), laboratory test data requirements were as follows: neutrophil count ≥1.5×109/L, platelet count ≥100×109/L, hemoglobin ≥90g/L (no blood transfusion within 14 days), serum total bilirubin ≤1.25 times the upper normal limit (ULN);ALT and AST≤ 2.5 x ULN (≤5x ULN in patients with liver metastasis);Serum creatinine ≤1.0 x ULN and creatinine clearance rate ≥60 mL /min;Left ventricular ejection fraction in ultrasound examination >55%;
7. At least one measurable lesion (RECIST 1.1 criteria);
8. Subjects (or their legal representative/guardian) must sign the informed consent indicating that they understand the purpose of the study, understand the necessary procedures of the study, and are willing to participate in the study.

Exclusion Criteria:

Those who have one or more of the following will not be included in the study:

1. Have received any experimental drugs or anti-tumor drugs within 4 weeks before enrollment;
2. A history of other tumors in the past five years, except for cervix cancer or basal cell carcinoma of the skin that has been cured;
3. Patients with obvious intracranial hypertension or neuropsychiatric symptoms due to uncontrolled primary brain tumor or central nerve metastatic tumor
4. Pregnant or lactating women;Those who are fertile but do not take adequate contraceptive measures;
5. Alcoholism or drug addiction;
6. with pleural effusion or ascites, causing respiratory syndrome (≥CTCAE2 grade dyspnea), requiring local treatment;
7. Patients with the following serious or uncontrolled diseases: severe heart disease, unstable condition after treatment, myocardial infarction, congestive heart failure, unstable angina pectoris, pericardial effusion with obvious symptoms or unstable arrhythmia within 6 months before enrollment;Definite neuropathy or psychosis, including dementia or seizures;Severe or uncontrolled infections;Patients with active and disseminated intravascular coagulation and significant bleeding tendency
8. known hypersensitivity or anaphylaxis to any component of the study drug to be applied.
9. The function of important organs is obviously impaired
10. Other circumstances under which the investigator considers that the patient should not participate in the study

Contacts and Locations

Contacts

Contact: Zhiyu Chen, Professor; 021-64175590; chanhj75@aliyun.com

Sponsors and Collaborators

Fudan University

More Information

• Responsible Party: Fudan University
• ClinicalTrials.gov Identifier: NCT04831528
• Other Study ID Numbers: FDZL-ctDNA
• First Posted: April 5, 2021
• Last Update Posted: April 5, 2021
• Last Verified: April 2021

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Bevacizumab; Trastuzumab; Cetuximab; Pertuzumab; Lapatinib; Antineoplastic Agents, Immunological; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Physiological Effects of Drugs; Growth Inhibitors; Tyrosine Kinase Inhibitors; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action