A Prospective Study Utilizing Circulating Cell Free DNA (cfDNA) Use in the Detection of RAS Mutations in Patients With Advanced Colorectal Cancer.

NCT04775862 | Unknown Phase 2

• 1 other identifier: RC20/170/R
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

Brief Summary

Colorectal cancer remains the commonest cancer among men, and third commonest among women in Saudi Arabia . Presentation with metastatic disease occurs in almost one third of patients , with 5-year survival decreasing significantly from 90% in stage 1 to 14% once the disease is metastatic . There is enthusiasm in the potential for liquid biopsies to provide easily accessible genetic biomarkers for mutational cancer characterization . Epidermal growth factor receptor (EGFR) monoclonal antibodies are widely used in the treatment of advanced colorectal cancer that do not harbor RAS mutations (RAS wild type). Hence genotyping of oncogenic RAS mutations is essential prior to the initiation of systemic therapy for such patients as the presence of these mutations predict resistance to EGFR targeted antibodies such as Cetuximab and Panitumumab . Detection of such mutations has been done on tissue biopsies with the disadvantage of this being an invasive procedure, and data suggesting that such testing may not be reflective of the true mutational burden of the disease since a single fragment of tissue may be inadequate to reflect the intratumoral heterogeneity. There is increasing evidence suggesting that liquid biopsies or blood based mutational profiling can provide a more comprehensive molecular profile of the disease, and carries the advantage of being minimally invasive. Serial liquid biopsies can act as a tool to identify spatial and temporal heterogeneity predicting response or resistance to targeted agents, and can shed light into the emergence (or disappearance) of specific mutations that may potentially be targeted with newer anti cancer agents . Circulating cell free DNA (cfDNA) consists of small nucleic acid fragments liberated from cells by rupture, necrosis or apoptosis, and is now increasingly being used to detect RAS (and other) mutations in patients with advanced colorectal cancers. KRAS has remained an "undruggable" target for decades until the most recent evidence that showed a new anticancer drug that targets KRAS G12C mutation. The investigators aim to perform cfDNA testing on patients with advanced colorectal cancers who have no RAS mutations (and hence start on EGFR inhibitors) as baseline, compare the results with mutational analysis on fresh tumor tissue, and perform cfDNA at first progression to determine what mutations have emerged, and specifically look for KRAS G12C mutation, which can be targeted with a new novel anti cancer drug . These patients will be collected over a 12 month period (with the aim of performing this on at least 100 patients), and followed from diagnosis (with baseline cfDNA) and until progression on EGFR inhibitors (where another cfDNA sample will be taken). A detailed proposal delineating this process will follow once accepted. This project is unique as it examines mechanisms of resistance to anti-EGFR inhibitors in our patients with advanced colorectal cancers, determines the prevalence of a specific mutation using liquid biopsies and examining cfDNA use, and may have therapeutic implications in facilitating obtaining KRAS G12C inhibitors for such patients.

Conditions

Colon Cancer

Keywords

colon cancer; Circulating cell free DNA; Colorectal cancer; NGS

Outcome Measures

Primary Outcomes (2)

• Objective response rates (ORR)

  ORR is defined as the percentage of patients, relative to the total of enrolled subjects, achieving a complete response (CR) or partial response (PR) according to RECIST v1.1 criteria.

  3.5 years

• Progression-free survival (PFS)

  PFS is defined as the time from the start of therapy until the first documentation of objective disease progression or death due to any cause, whichever comes first.

  3.5 years

Secondary Outcomes (2)

• Determine proportion of patients with mCRC who are RAS wt after 2nd progression using cfDNA

  3.5 years

• Determine the prevalence of RAS G12C mutation via using cfDNA

  3.5 years

Study Arms (2)

RAS wild type; investigator choice re-challenge with anti EGFR Rx

EXPERIMENTAL

Drug: investigator choice re-challenge with anti EGFR Rx

RAS mutant; investigator choice of SOC third line Rx

ACTIVE COMPARATOR

Drug: investigator choice re-challenge with anti EGFR Rx

Interventions

investigator choice re-challenge with anti EGFR Rx DRUG

Upon second progression, patients will be enrolled into the study as per inclusion criteria and consent, and a cfDNA blood test will be drawn, and RAS status will be examined. If RAS is wildtype, then the investigator will decide whether to re-challenge with an anti EGFR antibody , or give SOC third line chemotherapy (Regorafenib or TAS-102).

RAS mutant; investigator choice of SOC third line Rx; RAS wild type; investigator choice re-challenge with anti EGFR Rx

Eligibility Criteria

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

You may qualify if:

• Adult patients aged \>18 years who are diagnosed histologically with advanced/ metastatic colorectal adenocarcinoma.
• Primary disease must be in left side of colon.
• ECOG performance status of \</= 2.
• The primary treating physician believes that the patient has a life expectancy of more than 3 months at enrollment.
• Tumor characteristics at baseline must be RAS/ BRAF wildtype.
• Must have RECIST measurable disease.
• Metastatic burden \</= 3 organ involvement.
• Adequate bone marrow, liver and renal function assessed within 14 days before starting systemic treatment.
• Signed informed consent before any study specific procedures.

You may not qualify if:

• Patients with peritoneal metastases.
• Life expectancy of less than 3 months in the opinion of the investigator.
• Refusal to consent.
• Past or current history of malignancy other than colorectal carcinoma, except for curatively treated basal or squamous cell carcinoma of the skin or in situ carcinoma of the cervix.
• Pregnant women.

Sponsors & Collaborators

• National Guard Health Affairs: lead

Study Sites (1)

Ministry of National Guard - Health Affairs

Riyadh, Saudi Arabia

RECRUITING

MeSH Terms

Conditions

Colonic Neoplasms; Colorectal Neoplasms

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 21, 2021
• First Posted: March 1, 2021
• Study Start: February 21, 2021
• Primary Completion: February 1, 2024
• Study Completion: February 1, 2024
• Last Updated: March 1, 2021

Record last verified: 2021-02

Locations

SA (1)