Clinical trial NCT03635021: Study to Evaluate the Efficacy of FOLFOX + Panitumumab Followed by FOLFIRI + Bevacizumab (Sequence 1) Versus FOLFOX + Bevacizumab Followed by FOLFIRI + Panitumumab (Sequence 2) in Untreated Patients With Wild-type RAS Metastatic, Primary Left-sided, Unresectable Colorectal Cancer
Official title: Phase III Randomized Sequential Open-label Study to Evaluate the Efficacy of FOLFOX + Panitumumab Followed by FOLFIRI + Bevacizumab (Sequence 1) Versus FOLFOX + Bevacizumab Followed by FOLFIRI + Panitumumab (Sequence 2) in Untreated Patients With Wild-type RAS Metastatic, Primary Left-sided, Unresectable Colorectal Cancer: The CR-SEQUENCE
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Colorectal Cancer
Keywords: colorectal cancer
FOLFOX
FOLFIRI
panitumumab
bevacizumab
wild-type RAS
primary left-sided
Lead sponsor: Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD)
Sponsor class: OTHER
Collaborators: name: Amgen
First posted: 2018-08-17
Enrollment: 419
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to assess the efficacy of FOLFOX + panitumumab followed by FOLFIRI + bevacizumab (Sequence 1) versus FOLFOX + bevacizumab followed by FOLFIRI + panitumumab (Sequence 2) in untreated patients with wild-type RAS metastatic, primary left-sided, unresectable colorectal cancer


Eligibility criteria: Inclusion Criteria:

1. Man or woman at least 18 years old.
2. Capable of understand, sign and date an informed consent approved by an IEC.
3. Histologically confirmed adenocarcinoma of the left colon or rectum (originate in the splenic flexure, descending colon, sigmoid colon, or rectum) in patients with unresectable (not amenable to radical surgery of metastases at the study inclusion) metastatic (M1) disease.
4. Patients who had wild-type RAS status confirmed as per standard of care according to international guidelines prior to first-line initiation.

   \*RAS analysis should include at least KRAS exons 2, 3 and 4 (codons 12, 13, 59, 61, 117 and 146) and NRAS exons 2, 3 and 4 (codons 12, 13, 59, 61 and 117)
5. At least one unidimensionally measurable lesion per RECIST criteria (version 1.1).
6. ECOG performance status \< 2.
7. Adequate bone marrow function: neutrophils ≥1.5 x109 / L; platelets ≥100 x109 /L; haemoglobin ≥ 9 g/dL.
8. Hepatic, renal and metabolic function as follows:

   * Total bilirubin count ≤1.5 x upper limit of normal (ULN), serum glutamic pyruvic transaminase/alanine aminotransferase (SGPT/ALT) and serum glutamic oxaloacetic transaminase/aspartate aminotransferase (SGOT/AST) ≤ 2.5 x ULN (5 x ULN for subjects with liver involvement of their cancer or 10 x ULN for subjects with bone involvement).
   * Renal function, calculated as creatinine clearance or 24-hour creatinine clearance ≥ 50 mL/min.

Exclusion Criteria:

1. History of prior or concurrent central nervous system metastases.
2. History of another primary cancer, except: curatively treated in situ cervical cancer, or curatively resected non-melanoma skin cancer, or other primary solid tumour curatively treated with no known active disease present and no treatment administered for ≥ 5 years before randomization.
3. Prior chemotherapy or other systemic anticancer therapy for treatment of metastatic colorectal carcinoma.
4. Prior adjuvant chemotherapy for colorectal cancer (stage I, II or III) terminated less than 6 month before metastatic disease was diagnosed.
5. Unresolved toxicities of a previous systemic treatment that, in the opinion of the Investigator, cause the patient unfit for inclusion.
6. Prior use (as monotherapy or adjuvant treatment) of anti-EGFR antibody therapy (e.g. cetuximab), anti-VEGF or small molecule EGFR inhibitors (e.g. erlotinib).
7. Prior hormonal therapy, immunotherapy or approved or experimental antibody/proteins ≤ 30 days before inclusion.
8. Significant cardiovascular disease including unstable angina or myocardial infarction within 12 months before initiating study treatment or a history of ventricular arrhythmia.
9. Uncontrolled hypertension.
10. History of interstitial pneumonitis or pulmonary fibrosis or evidence of interstitial pneumonitis or pulmonary fibrosis on baseline chest computerised tomography (CT).
11. Treatment for systemic infection within 14 days before the start of study treatment.
12. Acute or subacute intestinal occlusion and/or active inflammatory bowel disease or other bowel disease that causes chronic diarrhoea (defined as grade ≥ 2 diarrhoea according to NCI-CTCAE version 4.03).
13. Clinically significant peripheral sensory neuropathy.
14. Evidence of previous acute hypersensitivity reaction, of any grade, to any component of the treatment.
15. History of Gilbert disease or known dihydropyrimidine deficiency syndrome.
16. Recent (within 6 months before the start of study treatment) gastroduodenal ulcer to be active or uncontrolled.
17. Recent (within 6 months before the start of study treatment) pulmonary embolism, deep vein thrombosis, or other significant venous event.
18. Pre-existing bleeding diathesis and/or coagulopathy with exception of well-controlled anticoagulation therapy (within 6 months before the start of study treatment)
19. Recent (within 4 weeks prior to inclusion in the study) major surgical procedure, open biopsy, or significant traumatic injury not yet recovered from prior major surgery
20. History of any disease that may increase the risks associated with study participation or may interfere with the interpretation of study results.
21. Known positive test for human immunodeficiency virus infection, hepatitis C virus, and chronic active hepatitis B infection.
22. Any disorder that compromises the patient's ability to provide written informed consent and/or comply with study procedures.
23. Any investigational agent within 30 days prior to inclusion.
24. Pregnant or breastfeeding woman.
25. Surgery (excluding diagnostic biopsy or placement of a central venous catheter) and/or radiotherapy within 28 days prior to inclusion in the study.
26. Male or female of childbearing age who do not agree with taking adequate contraceptive precautions, i.e. use contraception double barrier (e.g. diaphragm plus condoms) or abstinence during the course of the study and for 6 months after the last administration of study drug for women and 1 month for men.
27. The patient is unwilling or unable to meet the requirements of the study.
28. Psychological, geographical, familial or sociological conditions that potentially prevent compliance with the study protocol and follow-up schedule.

Primary outcomes:
measure: Progression-free survival rate at 35 months
timeFrame: 35 months after date of randomization
Secondary outcomes:
measure: overall survival rate at 35 months
timeFrame: 35 months after date of randomization
measure: overall survival
timeFrame: Baseline through the end of the study (up 72 months)
measure: progression-free from randomization to second progression or death
timeFrame: Baseline through the end of the study (up 72 months)
measure: progression-free survival in first-line treatment and in second-line treatment
timeFrame: Baseline through the end of the study (up 72 months)
measure: time to first-line treatment failure and to second-line treatment failure
timeFrame: 72 months
measure: objective response rate
timeFrame: Baseline through the end of the study (up 72 months)
measure: proportion of patients with Early Tumour Shrinkage
timeFrame: Baseline through the end of the study (up 72 months)
measure: Depth of Response
timeFrame: Baseline through the end of the study (up 72 months)
measure: disease control rate
timeFrame: Baseline through the end of the study (up 72 months)
measure: duration of disease control
timeFrame: Baseline through the end of the study (up 72 months)
measure: duration of response
timeFrame: Baseline through the end of the study (up 72 months)
measure: time to response
timeFrame: Baseline through the end of the study (up 72 months)
measure: Incidence and severity of AEs CTCAE v4.03 criteria
timeFrame: Baseline through the end of the study (up 72 months)
Other outcomes:
measure: Impact of baseline biomarkers predictive of the efficacy
timeFrame: Baseline through the end of the study (up 72 months)
measure: clinical impact of clonal dynamics by longitudinal analysis of circulating tumour deoxyribonucleic acid (ctDNA) in plasma
timeFrame: Baseline through the end of the study (up 72 months)
Locations:
city: Madrid
country: Spain
facility: Spanish Cooperative Group for the Treatment of Digestive Tumors
Study officials:
affiliation: Instituto Catalán de Oncología. Hospital Duran i Reynals
name: Ramón Salazar, MD, PhD
role: STUDY_CHAIR
affiliation: Hospital Universitario Ramon y Cajal
name: Alfredo Carrato, MD, PhD
role: STUDY_CHAIR
References: