Rechallenge With Panitumumab Driven by RAS Dynamic of Resistance
- Conditions
- Colorectal Cancer
- Interventions
- Diagnostic Test: Molecular Screening
- Registration Number
- NCT03227926
- Lead Sponsor
- Fondazione del Piemonte per l'Oncologia
- Brief Summary
This is a hypothesis driven, open label, single-arm, multiple centers, Phase II trial. The trial has been designed to prove or disprove whether a rechallenge with panitumumab can achieve an objective response rate (ORR= CR+PR) of 30% or more in a population of RAS wild type mCRC patients selected on the basis of RAS extended clonal evolution in their plasma.
- Detailed Description
Colorectal cancer (CRC) is the third most common cancer in the world and the second leading cause of cancer death in the United States and the European Union. In the last decade, substantial advances in the treatment of the metastatic disease (mCRC) have more than doubled overall survival (OS) from 12 months to 30 months due to the refinement of fluoropirimidine-based chemotherapy and the introduction of antiangiogenics and targeted therapies.
Pharmacologic blockade of the epithelial growth factor receptor (EGFR) with specific monoclonal antibodies, namely, cetuximab and panitumumab, represents the mainstay of tumour targeted therapy for mCRC in patients with tumors not harboring extended RAS pathway mutations (KRAS, NRAS, or BRAF). Such alterations, which constitutively activate typical EGFR downstream transducers, have been shown to trigger substitute survival pathways that bypass therapeutic blockade of EGFR signalling, thus abating the efficacy of anti-EGFR antibodies ("primary resistance"). Even when response to anti-EGFR therapy occurs in the context of appropriate molecular selection, acquired ("secondary") resistance inevitably arises in all cases. Our group has extensively studied this phenomenon and has shown that extended-RAS alterations are the principal culprit of anti EGFR acquired resistance, and that altered RAS clones decay upon anti-EGFR treatment withdrawal, while tumor cells regain sensitivity to anti EGFR treatment. We have also documented that ctDNA profiles of individuals who benefit from multiple challenges with anti-EGFR antibodies, exhibit pulsatile levels of mutant KRAS. Collectively, these results indicate that the CRC genome adapts dynamically to intermittent anti-EGFR drug schedules, and provide a molecular explanation for the efficacy of re-challenge therapies based on EGFR blockade. Our results also give experimental support to the empirical-based clinical benefit observed, following cetuximab or panitumumab rechallenge in two small series of originally KRAS exon 2 wild type mCRC patients.
We propose to assess the efficacy and safety of re-challenging with panitumumab RAS-extend wild type mCRC patients with ctDNA-confirmed secondary resistance to anti EGFR treatment, after progression on second or further lines chemotherapy. As proof-of-concept, patients will be blood monitored throughout their therapeutic itinerary for the presence of extended-RAS alterations and EGFR-ectodomain mutations by ctDNA determination (liquid biopsy). We also include in our ddPCR panel 7 different EGFR extracellular domain (ECD) mutations as they occur in 15-20% of patients who acquired resistance to anti-EGFR drugs.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 32
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Trial Phase Panitumumab 20 MG/ML Intravenous Solution [VECTIBIX] Patients resulting "molecularly eligible" at the RML (Rechallenge Mutational Load) checkpoint, upon Informed Consent signature and having satisfied all other eligibility criteria, will be treated with panitumumab monotherapy at standard dose until documented radiological progression or unacceptable toxicity or any other reason whichever comes first. Screening Phase Molecular Screening Patiens will be first enrolled in a Molecular Screening (MS) Phase to determine the "molecular eligibility" of the patients for third line panitumumab re-challenge. During MS phase, patients will be liquid biopsied (LB) at different check-points (BML which is optional, Basal Mutational Load and RML which is mandatory, Rechallenge Mutational Load) and their ctDNA tested by ddPCR to monitor the presence of RAS and EGFR ECD altered clones. Patients with no RAS and EGFR ECD mutations in the RML will be declared "molecularly eligible" for the Trial Phase.
- Primary Outcome Measures
Name Time Method Overall response rate (ORR) to panitumumab according to RECIST v1.1. Tumor assessments every 8 weeks from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 48 months Main objective of the study is the evaluation of objective response rate according to RECIST 1.1 criteria
- Secondary Outcome Measures
Name Time Method Toxicity according to CTCAE version 4.03. every 2 weeks from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 48 months Toxicity will be assessed using the Common Toxicity Criteria for Adverse Events version 4.03 (CTCAE).
Progression Free Survival every 2 weeks from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 48 months PFS is defined as the time from first treatment to the time of disease progression
Overall Survival every 2 weeks from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 48 months OS is defined as the length of time from the start of treatment to death from any cause
Trial Locations
- Locations (4)
Istituto Nazionale Tumori - IRCCS
🇮🇹Milano, Via Giacomo Venezian, 1, Italy
Grande Ospedale Metropolitano Niguarda
🇮🇹Milano, Italy
Fondazione del Piemonte per l'Oncologia - IRCCS
🇮🇹Candiolo, Italy
Istituto Oncologico Veneto - IRCCS
🇮🇹Padova, Italy