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Rechallenge With Panitumumab Driven by RAS Dynamic of Resistance (CHRONOS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03227926
Recruitment Status : Unknown
Verified November 2017 by Fondazione del Piemonte per l'Oncologia.
Recruitment status was:  Recruiting
First Posted : July 24, 2017
Last Update Posted : November 17, 2017
Sponsor:
Information provided by (Responsible Party):
Fondazione del Piemonte per l'Oncologia

Brief Summary:
Open label, single-arm, multiple centers, Phase II trial. The trial has been designed to prove or disprove whether a third line 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.

Condition or disease Intervention/treatment Phase
Colorectal Cancer Drug: Panitumumab 20 MG/ML Intravenous Solution [VECTIBIX] Phase 2

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 fluoropyrimidine-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"). Unfortunately even when response to anti-EGFR therapy occurs in the context of appropriate molecular selection, acquired ("secondary") resistance inevitably arises in all cases. Investigators 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. Investigators 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. These 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.

Study purpose is 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 line chemotherapy. As proof-of-concept, patients will be blood monitored throughout their therapeutic itinerary for the presence of extended-RAS alterations by ctDNA determination (liquid biopsy).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 129 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:

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, Basal Mutational Load and RML, Rechallenge Mutational Load) and their ctDNA tested by ddPCR to monitor the emergency, and subsequent decay, of RAS altered clones. Patients showing a >50% drop in RAS mutational load at RML compared to BML 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.

Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Trial of Rechallenge With Panitumumab Driven by RAS Clonal-mediated Dynamic of Resistance
Actual Study Start Date : October 11, 2017
Estimated Primary Completion Date : July 2019
Estimated Study Completion Date : January 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Panitumumab

Arm Intervention/treatment
No Intervention: Molecular Screening
Molecular Screening Phase will determine the "molecular eligibility" of the patients for 3rd line panitumumab re-challenge. Patients will be liquid biopsied (LB) at different check-points and their ctDNA tested by ddPCR to monitor the emergency, and subsequent decay, of RAS altered clones. The RAS Baseline Mutational Load (BML) will be defined within 15 days from last anti-EGFR dose prior documented 1st line PD. Only patients with a > 3% RAS fractional mutational abundance (RAS+) will move to the next step of the screening. RAS+ patients will receive a 2nd line anti-EGFR-free chemotherapy according to physician choice. RAS+ patients progressing during or after 2nd line therapy will be retested at the Rechallenge Mutational Load (RML) checkpoint. Patients showing a >50% drop in RAS mutational load at RML compared to BML will be declared "molecularly eligible" for the Trial Phase.
Experimental: Trial Phase
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]
Panitumumab 6 mg/kg in 100 cc 0.9% NaCl solution on Day 1 every two weeks by IV administration over 1 hour.




Primary Outcome Measures :
  1. Overall response rate (ORR) to panitumumab according to RECIST v1.1. [ Time Frame: 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 Outcome Measures :
  1. Progression Free Survival [ Time Frame: 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 ]
  2. Overall Survival [ Time Frame: 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 ]
  3. Toxicity according to CTCAE version 4.03. [ Time Frame: 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 ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

INCLUSION CRITERIA

Molecular Screening

  • Histologically confirmed diagnosis of metastatic colorectal cancer;
  • Age ≥ 18 years;
  • Documented WT RAS exons 2, 3 and 4 (KRas and NRas) and WT BRAF V600E;
  • Complete or partial response to frontline chemotherapy including anti-EGFR mAb.
  • Written informed consent;
  • Availability of the diagnostic FFPE or slides
  • Imaging documented progression while on therapy or maintenance regimen including anti-EGFR mAb;
  • RAS-extended mutational load with > 3% fractional abundance, measured on plasma ctDNA at BML (maximum within 2 weeks of last anti EGFR administration);
  • Planned 2nd line chemotherapy of any type with the exclusion of further anti EGFRs (regorafenib is allowed).

Trial phase

  • Written informed consent;
  • ECOG performance status ≤ 2;
  • Imaging documented progression at a 2nd line chemotherapy;
  • RAS-extended mutational load measured on plasma ctDNA at RML (as soon as possible, since the turned around time for the test is 2-3 weeks);
  • A > 50% drop in RAS-extended mutational load between BML and RML;
  • 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.

EXCLUSION CRITERIA

Molecular Screening

  • History of severe infusion reactions to monoclonal antibodies cetuximab or panitumumab;
  • Symptomatic or untreated leptomeningeal disease and symptomatic brain metastasis;
  • Clinically significant cardiac disease;
  • History of thromboembolic or cerebrovascular events within the last 6 months;
  • Previous or concurrent second malignancy. Exceptions: basal cell or squamous cell skin cancer, in situ carcinoma of the cervix, or other solid tumor without evidence of recurrence for at least 3 years prior to study entry.
  • History of severe infusion reactions to monoclonal antibodies cetuximab or panitumumab;
  • Symptomatic or untreated leptomeningeal disease and symptomatic brain metastasis;
  • Second line regimen including an anti EGFR antibody.

Trial phase

  • 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; aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) > 2.5 x ULN, if liver metastases > 5 x ULN; bilirubin > 1.5 x ULN, if liver metastases > 2 x ULN; serum creatinine > 1.5 x ULN and/or creatinine clearance ≤ 50 mL/min calculated according to Cockroft-Gault; Patients with platelet count <100 x 10^9/L
  • Previous or concurrent second malignancy. Exceptions: adequately treated basal cell or squamous cell skin cancer; in situ carcinoma of the cervix, treated curatively and without evidence of recurrence for at least 3 years prior to study entry; or other solid tumor treated curatively and without evidence of recurrence for at least 3 years prior to study entry.
  • Patients with positive serology for HIV, HBV, HCV.
  • Patients with a history of severe or life threatening hypersensitivity to the active substance or to any of the excipients.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03227926


Contacts
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Contact: Filippo Montemurro, MD +390119933111 filippo.montemurro@ircc.it

Locations
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Italy
AOU Policlinico S. Orsola Malpighi Not yet recruiting
Bologna, Italy
Contact: Francesca Di Fabio, MD         
Fondazione del Piemonte per l'Oncologia - IRCCS Recruiting
Candiolo, Italy, 10060
Contact: Francesco Leone, MD         
Grande Ospedale Metropolitano Niguarda Recruiting
Milano, Italy
Contact: Andrea Sartore-Bianchi, MD         
Istituto Oncologico Veneto - IRCCS Recruiting
Padova, Italy, 35128
Contact: Sara Lonardi, MD         
Policlinico Universitario Campus Biomedico Not yet recruiting
Roma, Italy
Contact: Giuseppe Tonini, MD         
Sponsors and Collaborators
Fondazione del Piemonte per l'Oncologia
Investigators
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Study Chair: 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
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Responsible Party: Fondazione del Piemonte per l'Oncologia
ClinicalTrials.gov Identifier: NCT03227926    
Other Study ID Numbers: 013-IRCC-10IIS-16
2016-002597-12 ( EudraCT Number )
First Posted: July 24, 2017    Key Record Dates
Last Update Posted: November 17, 2017
Last Verified: November 2017

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Fondazione del Piemonte per l'Oncologia:
RAS
Panitumumab
EGFR
Clonal evolution
Additional relevant MeSH terms:
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Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Panitumumab
Antineoplastic Agents, Immunological
Antineoplastic Agents