Study of FOLFIRI + Panitumumab Using Ultra-selection Technology of Patients With Stage IV Colorectal Cancer Refractory to Irinotecan Without Any Mutation on KRAS, PIK3Ca, BRAF and NRAS Genes Detected With Highly Sensitive Techniques (ULTRA)

Open Label Phase II Study of FOLFIRI + Panitumumab Using Ultra-selection Technology With Next Generation High Sensitivity Genotyping of Patients With Stage IV Colorectal Cancer Refractory to Irinotecan Without Any Mutation on KRAS, PIK3Ca, BRAF and NRAS Genes Detected With Highly Sensitive Techniques.

Open label Phase II study of FOLFIRI + Panitumumab using ultra-selection technology with next generation high sensitivity genotyping of patients with stage IV colorectal cancer refractory to irinotecan without any mutation on KRAS, PIK3Ca, BRAF and NRAS genes detected with highly sensitive techniques.

Study Overview

• Status: Completed
• Conditions: Stage IV Colorectal Cancer
• Intervention / Treatment: Drug: panitumumab; Drug: FOLFIRI

• Study Type: Interventional
• Enrollment (Actual): 72
• Phase: Phase 2

Contacts and Locations

Study Locations

• Spain
  • Madrid, Spain, 28046
    • Spanish Cooperative Group for Digestive Tumour Therapy

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Competent to understand, sign and date an IEC-approved informed consent form.
2. Men or women 18 years of age or older at the time the written informed consent is obtained.
3. Histologically confirmed metastatic adenocarcinoma of the colon or rectum Wild-Type RAS (No mutation) with at least 1 measurable metastatic lesion following RECIST criteria v 1.1 and initially irresectable (non suitable for radical surgery at the inclusion time).
4. Obtention of DNA from tumor tissue blocks sent to central lab (ICO) that is amenable for highly sensitive techniques
5. Previous irinotecan based chemotherapy +/- bevacizumab for metastatic CCR during at least 6 weeks.
6. Irinotecan based chemotherapy does not need to be the most recent chemotherapy administrated. There are no restrictions on numbers of treatments lines before study inclusion.
7. Disease progression during irinotecan treatment or within 6 months after irinotecan treatment.
8. Karnofsky status ≥ 70% .

9. Adequate bone marrow, hepatic, renal and metabolic functions,

   1. Adequate bone marrow function: neutrophils ≥ 1.5x109/ L; platelets ≥ 100x109/L; hemoglobin ≥ 9g/dL.
   2. Hepatic functions as follows: total bilirubin count ≤ 1.5 x ULN; ALAT and ASAT ≤ 2.5 x ULN (≤ 5 x ULN in case of liver metastasis).
   3. Renal function: creatinine clearance > 50 ml/min (according Cockcroft y Gault formulae)
   4. Metabolic functions: magnesium ≥ lower limit of normal (LIN)
10. Life expectancy ≥ 3 months.

Exclusion Criteria:

1. Prior malignant tumor in the last 5 years, except a history of basal cell carcinoma of the skin or pre-invasive cervical cancer.
2. Unresolved toxicities from prior systemic therapy and/or radiotherapy that, in the opinion of the investigator, does not qualify the patient for inclusion.
3. Documented or suspected central nervous system metastases.
4. Any previous antitumoral treatment (chemotherapy, hormonal therapy, radiation treatment, surgery, immunotherapy, biologic therapy) ≤ 28 days before study inclusion.
5. Significant cardiovascular disease including unstable angina or myocardial infarction within 12 months before initiating study treatment or a history of ventricular arrhythmia.
6. Prior anti-EGFr antibody therapy (eg, Cetuximab) or treatment small molecule EGFr tyrosine kinase inhibitors (eg, Erlotinib). Subjects who discontinue their first dose of anti-EGFR therapy (Cetuximab) because of an infusion reaction may participate in this clinical trial.
7. Paraffin-embedded tissue or unstained tumor slides from primary or metastatic tumor not available or quality ADN not available for biomarker determination by highly sensitive techniques.
8. History of interstitial pneumonitis or pulmonary fibrosis or evidence of interstitial pneumonitis or pulmonary fibrosis.
9. Treatment for systemic infection within 14 days before study inclusion.
10. Acute or sub-acute intestinal occlusion and /or active inflammatory bowel disease or other bowel disease causing chronic diarrhoea (defined as > 4 loose stools per day).
11. History of Gilbert's syndrome or dihydropyrimidine deficiency.
12. History of any medical condition that may increase the risks associated with study participation or may interfere with the interpretation of the study results.
13. Known positive test for human immunodeficiency virus infection, hepatitis C virus, and chronic active hepatitis B infection.
14. Subject allergic to the ingredients of the study medication or to Staphylococcus protein A.
15. Any co-morbid disease that would increase risk of toxicity.
16. Any kind of disorder that compromises the ability of the subject to give written informed consent and/or comply with the study procedures.
17. Subject who is pregnant or breast feeding.
18. Surgery (excluding diagnostic biopsy or central venous catheter placement) ≤ 28 days prior study inclusion.
19. Woman or man of childbearing potential not consenting to use adequate contraceptive precautions.
20. Subject unwilling or unable to comply with study requirements.
21. Psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental; FOLFIRI + panitumumab	Drug: panitumumab; Panitumumab 6,0 mg/kg day 1 i.v. 60 min; Drug: FOLFIRI; Irinotecan 180 mg/m2 day 1 i.v. 30-90 min Folinic acid 400 mg/ m2 day 1 i.v. 120 min 5-FU 400 mg/ m2 day 1 Bolus 5-FU 2.400 mg/ m2 day 1 i.v. 46 hours

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Objective response rate (TRO)	4 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Adverse events	4 years
disease control rate (TCE)	4 years
duration of response (DR)	4 years
time to response(THR)	4 years
time to progression (THP)	4 years
time to treatment failure (THF)	4 years
duration of stable disease (DEE)	4 years
Progression free survival (SLP)	4 years
Overall survival (SG)	4 years

Collaborators and Investigators

• Sponsor: Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD)
• Investigators: Study Chair: Ramón Salazar, MD, PhD, Institut Català d´Oncologia (ICO) L'Hospitalet; Study Chair: Gabriel Capella, Institut Català d´Oncologia (ICO) L'Hospitalet

Publications and helpful links

General Publications

• Santos C, Azuara D, Vieitez JM, Paez D, Falco E, Elez E, Lopez-Lopez C, Valladares M, Robles-Diaz L, Garcia-Alfonso P, Buges C, Duran G, Salud A, Navarro V, Capella G, Aranda E, Salazar R. Phase II study of high-sensitivity genotyping of KRAS, NRAS, BRAF and PIK3CA to ultra-select metastatic colorectal cancer patients for panitumumab plus FOLFIRI: the ULTRA trial. Ann Oncol. 2019 May 1;30(5):796-803. doi: 10.1093/annonc/mdz082.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: October 1, 2012
• Primary Completion (Actual): July 1, 2016
• Study Completion (Actual): July 1, 2016

Study Registration Dates

• First Submitted: September 27, 2012
• First Submitted That Met QC Criteria: October 10, 2012
• First Posted (Estimate): October 11, 2012

Study Record Updates

• Last Update Posted (Actual): August 1, 2017
• Last Update Submitted That Met QC Criteria: July 31, 2017
• Last Verified: July 1, 2017

More Information

Terms related to this study

• Keywords: colorectal cancer; Panitumumab; FOLFIRI; KRAS, PIK3Ca,BRAF and NRAS genes; highly sensitive techniques
• Additional Relevant MeSH Terms: Digestive System Diseases; Immune System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Hypersensitivity; Colorectal Neoplasms; Antineoplastic Agents; Antineoplastic Agents, Immunological; Panitumumab
• Other Study ID Numbers: TTD-12-03; 2012-001955-38 (EudraCT Number)