PAnitumumab REchallenge Followed by REgorafenib Versus the Reverse Sequence

NCT04787341 | Active Not Recruiting Phase 2

• 1 other identifier: EUDRACT 2019-002834-35
• Study Type: interventional
• Target: 214
• Locations: 1 country
• Sites: 1

Brief Summary

The association of doublet chemotherapy (FOLFOX and FOLFIRI) and anti-EGFR-moAbs (panitumumab or cetuximab) is a standard option for the first-line treatment of unresectable RAS and BRAF wt mCRC patients, especially with left-sided primary tumour. In RAS wt mCRC patients refractory to chemotherapy and anti-EGFR naive, the standard treatment sequence is an anti-EGFR-based therapy (panitumumab or cetuximab +/- irinotecan) followed by regorafenib. In a phase II randomized Japanese study named REVERCE, a higher OS was reported in favour of an experimental strategy of regorafenib followed at progression by cetuximab +/- irinotecan compared with the reverse standard sequence in chemorefractory and anti-EGFR-naïve, RAS wt mCRC patients. However, the limitations of the REVERCE study (phase II trial with a premature conclusion for poor accrual) do not allow us to draw definitive conclusions. In addition, nowadays, patients candidates to an anti-EGFR-based treatment, receive anti-EGFRMoAbs in earlier lines of therapy thus affecting the translation of these results in the current clinical practice. Retrospective analyses and a phase II single-arm trial showed promising activity of anti-EGFR rechallenge in patients who previously achieved benefit from a first-line anti- EGFR-based treatment and not bearing RAS mutation on ct-DNA at the rechallenge baseline. Based on these considerations, the Investigators designed the present phase II randomized study of panitumumab followed at progression by regorafenib versus the reverse sequence in RAS and BRAF wt mCRC patients with the following characteristics:

1. 1.previous treatment with, or not considered candidates for, fluoropyrimidine, oxaliplatin, irinotecan and an anti-angiogenic agent (bevacizumab or aflibercept);
2. 2.RECIST response or stable disease lasting at least 6 months to a previous first-line anti-EGFR-based treatment;
3. 3.RAS and BRAF wt ct-DNA at the time of screening. The aim of this study is to compare the two sequences in a Caucasian population of patients candidates to anti-EGFR rechallenge.

Conditions

Colorectal Cancer

Outcome Measures

Primary Outcomes (1)

• Overall survival

  time from randomization to the date of death due to any cause. For patients still alive at the time of analysis, the OS time will be censored on the last date the patients were known to be alive.

  30 months

Secondary Outcomes (6)

• Overall Toxicity Rate

  24 months

• G3/4 Toxicity Rate

  24 months

• 1st-Progression free survival

  21 months

• 2nd-Progression free survival

  24 months

• Time to Failure of strategy

  24 months

Study Arms (2)

Panitumumab followed by Regorafenib

ACTIVE COMPARATOR

Drug: Panitumumab

Regorafenib followed by Panitumumab

EXPERIMENTAL

Drug: Regorafenib

Interventions

Regorafenib DRUG

regorafenib administered until progression, unacceptable toxicity or patient's refusal followed after progression by panitumumab until further progression, unacceptable toxicity or patient's refusal in RAS and BRAF wt mCRC patients with the following characteristics: 1. previous treatment with, or not considered candidates for, fluoropyrimidine, oxaliplatin, irinotecan and anti-angiogenic agent (bevacizumab or aflibercept); 2. RECIST response or stable disease lasting at least 6 months to a previous first-line anti-EGFR-based treatment; 3. RAS and BRAF wt ct-DNA at the time of screening.

Also known as: panitumumab

Regorafenib followed by Panitumumab

Panitumumab DRUG

panitumumab administered until progression, unacceptable toxicity or patient's refusal followed after progression by regorafenib until further progression, unacceptable toxicity or patient's refusal in RAS and BRAF wt mCRC patients with the following characteristics: 1. previous treatment with, or not considered candidates for, fluoropyrimidine, oxaliplatin, irinotecan and anti-angiogenic agent (bevacizumab or aflibercept); 2. RECIST response or stable disease lasting at least 6 months to a previous first-line anti-EGFR-based treatment; 3. RAS and BRAF wt ct-DNA at the time of screening.

Also known as: regorafenib

Panitumumab followed by Regorafenib

Eligibility Criteria

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

You may qualify if:

• Age ≥ 18 years.
• Written informed consent to molecular analyses.
• Histologically proven diagnosis of CRC.
• At least one measurable lesion according to RECIST1.1
• ECOG PS ≤ 1.
• mCRC previously treated for metastatic disease with, or not considered candidates for, fluoropyrimidine, oxaliplatin, irinotecan and anti-angiogenic monoclonal antibody (bevacizumab or aflibercept).
• RAS (codons 12, 13, 59, 61, 117 and 146 of KRAS and NRAS genes) and BRAF (V600E mutation) wt status of primary CRC or related metastasis (local laboratory assessment).
• Previous first-line anti-EGFR-containing therapy producing at least a partial response or a stable disease ≥ 6 months.
• At least 4 months elapsed between the end of first-line anti-EGFR administration and screening.
• At least one line of therapy between the end of first-line anti-EGFR administration and screening.
• Availability of plasma sample for liquid biopsy within 28 days prior enrolment.
• RAS (codons 12, 13, 59, 61, 117 and 146 of KRAS and NRAS genes) and BRAF (V600E mutation) wt status of ct-DNA at screening (central laboratory assessment by means of IdyllaTM ctKRAS-NRAS-BRAF Mutation Test).
• Written informed consent to study treatment and procedures.
• Life expectancy of at least 12 weeks.
• Availability of archival tumour tissue (primary tumour and metastases or at least one of the two) for biomarker analysis.

You may not qualify if:

• Previous treatment with regorafenib.
• Radiotherapy to any site within 4 weeks before the study.
• Untreated brain metastases or spinal cord compression or primary brain tumours.
• Evidence of bleeding diathesis or coagulopathy.
• Uncontrolled hypertension and prior history of hypertensive crisis or hypertensive encephalopathy.
• Clinically significant (i.e. active) cardiovascular disease for example cerebrovascular accidents (≤6 months), myocardial infarction (≤6 months), unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication.
• Significant vascular disease (e.g. aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months of study enrolment.
• Any previous venous thromboembolism ≥ NCI CTCAE Grade 4.
• History of abdominal fistula, GI perforation, intra-abdominal abscess or active GI bleeding within 6 months prior to the first study treatment.
• Other co-existing malignancies or malignancies diagnosed within the last 5 years with the exception of localized basal and squamous cell carcinoma or cervical cancer in situ.
• Lack of physical integrity of the upper gastrointestinal tract, malabsorption syndrome, or inability to take oral medication.
• Known hypersensitivity to trial drugs or hypersensitivity to any other component of the trial drugs.
• Any concomitant drugs contraindicated for use with the trial drugs according to the product information of the pharmaceutical companies.
• Diagnosis of interstitial pneumonitis or pulmonary fibrosis.
• Active uncontrolled infections or other clinically relevant concomitant illness contraindicating administration of panitumumab and regorafenib.

Sponsors & Collaborators

• Gruppo Oncologico del Nord-Ovest: lead
• Bayer: collaborator
• Amgen: collaborator

Study Sites (1)

U.O. Oncologia 2 Universitaria

Pisa, PI, 56126, Italy

Location

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

regorafenib; 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 Design

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

Study Record Dates

• First Submitted: February 24, 2021
• First Posted: March 8, 2021
• Study Start: December 15, 2020
• Primary Completion: August 7, 2025
• Study Completion: March 31, 2026
• Last Updated: February 2, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)