Rechallenge With Panitumumab Driven by RAS Dynamic of Resistance

NCT03227926 | Completed Phase 2

• 2 other identifiers: 013-IRCC-10IIS-162016-002597-12
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 4

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.

Conditions

Colorectal Cancer

Keywords

RAS; Panitumumab; EGFR; Clonal evolution

Outcome Measures

Primary Outcomes (1)

• Overall response rate (ORR) to panitumumab according to RECIST v1.1.

  Main objective of the study is the evaluation of objective response rate according to RECIST 1.1 criteria

  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

Secondary Outcomes (3)

• 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

• 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

• 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

Study Arms (2)

Screening Phase

EXPERIMENTAL

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.

Diagnostic Test: Molecular Screening

Trial Phase

EXPERIMENTAL

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.

Drug: Panitumumab 20 MG/ML Intravenous Solution [VECTIBIX]

Interventions

Panitumumab 20 MG/ML Intravenous Solution [VECTIBIX] DRUG

Panitumumab 6 mg/kg in 100 cc 0.9% NaCl solution on Day 1 every two weeks by IV administration over 1 hour.

Also known as: VECTIBIX

Trial Phase

Molecular Screening DIAGNOSTIC_TEST

Patients without plasmatic evidence of potentially resistant clones harbouring RAS or EGFR-ectodomain mutations in the RML liquid biopsy, will be molecular eligible for the trial phase

Also known as: RML Liquid Biopsies analysis

Screening Phase

Eligibility Criteria

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

You may qualify if:

• Histologically confirmed diagnosis of metastatic colorectal cancer;
• Age ≥ 18 years;
• Written informed consent;
• Documented WT RAS exons 2, 3 and 4 (KRas and NRas) and WT BRAF V600E for anti-EGFR treatment.
• Complete or partial response to anti EGFR antibodies in any line either received as monotherapy or in combination with chemotherapy;
• Imaging documented progression while on therapy with a therapeutic regimen including anti-EGFR mAb;
• Imaging documented progression at the last treatment regimen that must be anti-EGFR free;
• Patient must be RAS and EGFR ectodomain wild type in a liquid biopsy performed no longer that 4 weeks after progression to the last anti-EGFR free treatment
• FFPE sample used for eligibility to anti-EGFR prescription (see criteria 4) must be available for custom gene panel profiling (as described in appendix B). Otherwise if sample is not available, center must have already perfomed a genotyping on this tissue sample according to appendix B.
• ECOG performance status ≤ 2;
• At least one measurable tumor lesion as per RECIST v1.1. Lesions in previously irradiated areas or those that have received other loco-regional therapies (i.e. percutaneous ablation) should not be considered measurable unless there is clear documented evidence of progression of the lesion since therapy. Imaging must be performed maximum within 28 days prior to registration;
• Normal organ functions;
• Negative serum pregnancy test within 1 week prior to the first study dose in all women of childbearing potential;
• Subjects and their partners must be willing to avoid pregnancy during the trial. Male subjects with female partners of childbearing potential and female subjects of childbearing potential must, therefore, be willing to use adequate contraception;
• Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.

You may not qualify if:

• History of severe infusion reactions to monoclonal antibodies cetuximab or panitumumab;
• Symptomatic or untreated leptomeningeal disease and symptomatic brain metastasis;
• Clinically significant cardiac disease including:
• congestive heart failure requiring treatment (NYHA grade ≥ 2), Left ventricular ejection fraction (LVEF) \< 45% as determined by Multigated acquisition (MUGA) scan or echocardiogram;
• history or presence of clinically significant ventricular arrhythmias or atrial fibrillation;
• clinically significant resting bradycardia;
• unstable angina pectoris ≤ 3 months prior to starting study drug;
• acute myocardial infarction ≤ 3 months prior to starting study drug;
• QTcF \> 480 msec;
• History of thromboembolic or cerebrovascular events within the last 6 months, including transient ischemic attack, cerebrovascular accident, deep vein thrombosis, or pulmonary embolism;
• Patients with interstitial pneumonitis or pulmonary fibrosis;
• Abnormal organ or bone marrow functions defined as:
• Absolute neutrophil count \< 1.5 x 10/L;
• hemoglobin \< 9 g/dL;
• alkaline phosphatase \> 2.5 x upper normal limit (ULN), if liver metastases \> 5 x ULN;

Sponsors & Collaborators

• Fondazione del Piemonte per l'Oncologia: lead

Study Sites (4)

Istituto Nazionale Tumori - IRCCS

Milan, Via Giacomo Venezian, 1, 20133, Italy

Location

Fondazione del Piemonte per l'Oncologia - IRCCS

Candiolo, 10060, Italy

Location

Grande Ospedale Metropolitano Niguarda

Milan, Italy

Location

Istituto Oncologico Veneto - IRCCS

Padua, 35128, Italy

Location

Related Publications (2)

• Ciardiello D, Martinelli E, Troiani T, Mauri G, Rossini D, Martini G, Napolitano S, Famiglietti V, Del Tufo S, Masi G, Santini D, Avallone A, Pietrantonio F, Lonardi S, Di Maio M, Zampino MG, Fazio N, Bardelli A, Siena S, Cremolini C, Sartore-Bianchi A, Ciardiello F. Anti-EGFR Rechallenge in Patients With Refractory ctDNA RAS/BRAF wt Metastatic Colorectal Cancer: A Nonrandomized Controlled Trial. JAMA Netw Open. 2024 Apr 1;7(4):e245635. doi: 10.1001/jamanetworkopen.2024.5635.

  PMID: 38592721 DERIVED

• Sartore-Bianchi A, Pietrantonio F, Lonardi S, Mussolin B, Rua F, Crisafulli G, Bartolini A, Fenocchio E, Amatu A, Manca P, Bergamo F, Tosi F, Mauri G, Ambrosini M, Daniel F, Torri V, Vanzulli A, Regge D, Cappello G, Marchio C, Berrino E, Sapino A, Marsoni S, Siena S, Bardelli A. Circulating tumor DNA to guide rechallenge with panitumumab in metastatic colorectal cancer: the phase 2 CHRONOS trial. Nat Med. 2022 Aug;28(8):1612-1618. doi: 10.1038/s41591-022-01886-0. Epub 2022 Aug 1.

  PMID: 35915157 DERIVED

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

Panitumumab

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

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Salvatore Siena, MD

  Grande Ospedale Metropolitano Niguarda - Milano

  STUDY CHAIR

• Alberto Bardelli, MD

  Fondazione del Piemonte per l'Oncologia

  STUDY CHAIR

• Silvia Marsoni, MD

  Fondazione del Piemonte per l'Oncologia

  STUDY CHAIR

Study Design

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

Model Details: 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. Patients resulting "molecularly eligible" at the RML checkpoint, upon Informed Consent signature and having satisfied all other eligibility criteria, will be treated in the Trial Phase with panitumumab monotherapy at standard dose until documented radiological progression or unacceptable toxicity or any other reason (See Section 9.2.3) whichever comes first.

Study Record Dates

• First Submitted: July 18, 2017
• First Posted: July 24, 2017
• Study Start: October 11, 2017
• Primary Completion: November 6, 2019
• Study Completion: December 31, 2021
• Last Updated: August 25, 2022

Record last verified: 2022-08

Locations

IT (4)