FOLFIRI + Panitumumab First-line Treatment in Elderly Patients With Unresectable Metastatic Colorectal Cancer, RAS/BRAF Wild-type and Good Performance Status (OPALO)

A Phase II Trial to Evaluate the Efficacy and Safety of FOLFIRI + Panitumumab as First-line Treatment in Elderly Patients With RAS/BRAF Wild-type Unresectable Metastatic Colorectal Cancer and Good Performance Status

To estimate progression-free survival at one year in elderly patients with RAS/BRAF wild-type unresectable mCRC and good performance status treated with FOLFIRI + panitumumab as first-line therapy.

The clinical hypothesis of this study is that the combination of panitumumab and FOLFIRI is a good treatment option in elderly patients with good performance status and RAS/BRAF wild-type unresectable mCRC. Another purpose of this clinical trial is to determine the RAS/BRAF mutation status in liquid biopsies at baseline and at the time of disease progression.

Study Overview

• Status: Completed
• Conditions: Neoplasm Metastasis; Colorectal Neoplasms; Colorectal Cancer Metastatic; Colorectal Carcinoma
• Intervention / Treatment: Drug: Panitumumab; Drug: Folinic acid; Drug: 5-FU; Drug: Irinotecan

Detailed Description

Phase II, multicentre, single-arm trial. Elderly patients with good performance status and RAS/BRAF wild-type unresectable mCRC will be evaluated before being included in this trial. Eligible patients will receive panitumumab plus FOLFIRI for disease control until disease progression, unacceptable toxicity, investigator decision or the patient's withdrawal of consent.

Tumour response will be evaluated by investigators using RECIST criteria (Response Evaluation Criteria in Solid Tumours) version 1.1. Tumour response will be evaluated every 8 weeks until disease progression is documented. Disease response will be confirmed no less than 28 days after the criteria for response are first met. Radiographic progression of subjects with symptoms indicating disease progression will be evaluated at the time of symptom onset.

Following disease progression, information will be collected on the subsequent lines of treatment chosen by the investigator and survival at follow-up visits held every 12 weeks (± 4 weeks) until completion of the trial (approximately 24 months after inclusion of the last patient in the trial).

A blood sample will be taken at baseline and at the time of disease progression in order to determine the RAS/BRAF mutation status.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2

Contacts and Locations

Study Locations

• Spain
  • Barcelona, Spain, 08036
    • Hospital Clínic
  • Elda, Spain, 03600
    • Hospital General Universitario de Elda
  • Lleida, Spain, 25198
    • Hospital Universitario Arnau de Vilanova
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz
  • Murcia, Spain, 30008
    • Hospital General Universitario Morales Meseguer
  • Palma, Spain, 07020
    • Hospital Universitario Son Espases
  • Sabadell, Spain, 08208
    • Hospital Parc Tauli
  • Zaragoza, Spain, 50009
    • Hospital Clinico Universitario Lozano Blesa
  • Barcelona
    • L'Hospitalet de Llobregat, Barcelona, Spain, 08908
      • ICO L´Hospitalet de Llobregat - Hospital Durán i Reynals
    • Sant Joan Despí, Barcelona, Spain, 08970
      • Hospital Sant Joan Despí-Moisés Broggi
  • Madrid
    • Majadahonda, Madrid, Spain, 28222
      • Hospital Universitario Puerta de Hierro-Majadahonda
    • Móstoles, Madrid, Spain, 28933
      • Hospital Universitario Rey Juan Carlos

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 70 years and older (OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Males or females ≥ 70 years,
2. Able to understand, sign and date an informed consent form approved by the IEC,
3. Histologically confirmed colorectal carcinoma with metastatic disease,
4. RAS/BRAF wild-type status in solid biopsy confirmed prior to inclusion of the study,
5. No previous treatment for metastatic disease,
6. Patients starting therapy with FOLFIRI + panitumumab with a treatment aim other than achieving potential resectability of the disease,
7. Independence in activities of daily living (ADL) based on the Katz Index and in instrumental activities of daily living (IAL) based on the Lawton Index,
8. Having no or only one comorbidity according to the Charlson Comorbidity Index. The following ones are not considered comorbidities as long as it is provided they are adequately controlled with medication: gastroduodenal ulcer, diabetes without target organs' damage, chronic respiratory disease and connective tissue disease.
9. Presence of at least one unidimensional measurable lesion ≥ 10 mm according to RECIST criteria (version 1.1),
10. ECOG (Eastern Cooperative Oncology Group) performance status of 0-1,
11. Adequate bone marrow function: neutrophils ≥ 1.5 x 10^9/l; platelets ≥ 100 x 10^9/l; haemoglobin ≥ 9 g/dl,

12. Hepatic, renal and metabolic function as follows:

    1. Total bilirubin count ≤ 1.5 x ULN; ALT and AST < 5 x ULN;
    2. Renal function, calculated creatinine clearance or 24-hour creatinine clearance ≥ 50 ml/min;
    3. Magnesium > LLN

Exclusion Criteria:

1. Diagnosed or suspected central nervous system (CNS) metastasis,
2. Patients with initially resectable metastases at the time of diagnosis of metastatic disease.
3. History or presence of another malignancy, with the exception of curatively treated in situ carcinoma of the cervix or non-melanoma skin cancer or any curatively treated solid tumour, with no active disease or administration of treatment within 5 years prior to inclusion in the study,
4. Prior treatment with irinotecan,
5. Prior adjuvant chemotherapy for colorectal cancer terminated less than 6 months before metastatic disease was diagnosed,
6. Prior anti-epidermal growth factor receptor (EGFR) antibody therapy (eg, cetuximab), anti- vascular endothelial growth factor (VEGF) or treatment with small molecule EGFR inhibitors (eg, erlotinib),
7. Unresolved toxicities from prior systemic treatment that, in the investigator's opinion, make the patient unsuitable for inclusion,
8. Hormone therapy, immunotherapy with experimental or approved antibodies/proteins (e.g. bevacizumab) ≤ 30 days prior to inclusion,
9. Evidence of previous acute hypersensitivity reaction of any grade to any of the components of the treatment,
10. History of interstitial lung disease or pulmonary fibrosis or signs of interstitial lung disease or pulmonary fibrosis on baseline CT,
11. Presence of geriatric syndromes, defined as dementia, repeated falls, fecal incontinence or urinary incontinence,
12. Acute or subacute bowel obstruction and/or active bowel disease or another bowel disease causing chronic diarrhoea (defined as diarrhoea of grade ≥ 2 according to the NCI (National Cancer Institute) Common Terminology Criteria for Adverse Events (CTCAE version 4.03),
13. Significant cardiovascular disease, including unstable angina pectoris or myocardial infarction within 12 months prior to inclusion in the study,
14. History of Gilbert's syndrome or dihydropyrimidine dehydrogenase deficiency,
15. Positive test result for human immunodeficiency virus, hepatitis C virus, chronic active hepatitis B infection,
16. Treatment for systemic infection within 14 days prior to the start of the study treatment,
17. Clinically significant sensory peripheral neuropathy,
18. Any concurrent disease that may increase the risk associated with study participation or may interfere with the interpretation of study results,
19. Any investigational product within 30 days prior to inclusion,
20. Surgery (not including diagnostic biopsy or the placement of a central line) and/or radiotherapy within 28 days prior to inclusion in the study,
21. Males whose partner is of child-bearing age and who does not agree to use adequate contraceptive precautions, i.e. double-barrier methods (e.g. diaphragm plus condom) or abstinence for the duration of the study and for 1 month after the last administration of the study drug,
22. Subjects who do not agree or are unable to meet the study requirements,
23. Psychological, familial, sociological or geographical conditions potentially hampering compliance with the study protocol and the follow-up schedule. Such conditions should be discussed with the patient before enrolment in the clinical trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: FOLFIRI + panitumumab; All patients will receive panitumumab plus FOLFIRI for disease control in 14-day cycles until disease progression, unacceptable toxicity, investigator's decision or patient withdrawal of consent, at the following doses: Panitumumab: 6 mg/kg administered by intravenous (IV) infusion over 60 min on days 1 and 14 of every cycle just before administration of chemotherapy; FOLFIRI; Irinotecan: 150 mg/m2 as IV infusion over 90 min on day 1of first treatment cycle. If tolerance of this first dose is good, it will be scaled to a full dose of 180 mg/m2 starting from the second treatment cycle.; Folinic acid: (leucovorin) 200-400 mg/m2 IV over 2 hours on day 1; 5-FU: 400 mg/m2 bolus followed by 2400 mg/m2 IV continuous infusion over 46-48 hours on days 1 and 2

Drug: Panitumumab; Panitumumab 6 mg/kg will be administered by intravenous (IV) infusion over 60 min on days 1 and 14 of every cycle just before administration of chemotherapy; Other Names: Vectibix; Drug: Folinic acid; Folinic acid 200-400 mg/m2 will be administered as IV infusion over 2 hours on day 1; Other Names: Leucovorin; Any marketed; Drug: 5-FU; 5-FU will be administered IV 400 mg/m2 bolus followed by 2400 mg/m2 IV continuous infusion over 46-48 hours on days 1 and 2; Other Names: 5-fluorouracil; Any marketed; Drug: Irinotecan; Irinotecan 150 mg/m2 will be administered as IV infusion over 90 min on day 1of first treatment cycle. If tolerance of this first dose is good, it will be scaled to a full dose of 180 mg/m2 starting from the second treatment cycle; Other Names: Any marketed

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival at one year	Percentage of subjects still alive and progression free 12 months after inclusion in the study	12 months after inclusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival (PFS)	Time (months) from inclusion in the trial until disease progression or death	42 months
Objective response rate	Proportion of patients with an objective response (complete or partial response) according to RECIST 1.1 criteria	42 months
Disease control rate	Proportion of patients with disease control (complete response, partial response or stable disease)	42 months
Duration of response	Time (months) from the first confirmation of objective response according to RECIST 1.1 criteria until disease progression or death	42 months
Time to response	Time (months) from inclusion in the trial until the date of the first confirmation of objective response according to RECIST 1.1 criteria	18 months
Overall survival (OS)	Time (months) from inclusion in the trial until death of the patient	42 months
Time to treatment failure	Time (months) from inclusion in the trial until progression, death or discontinuation due to toxicity	18 months
Proportion of patients with early tumour shrinkage (ETS)	Defined as tumour shrinkage ≥ 30% at the first tumour assessment based on RECIST 1.1 criteria	2 months
Depth of response (DpR)	Measured as the maximum reduction ratio (percentage) of the tumour compared with baseline measurement (sum of diameters of the lesions) at the different assessments based on RECIST 1.1 criteria	18 months
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]	Incidence and severity of adverse events. AEs description according to the NCI (National Cancer Institute) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03	42 months
Combined analysis of prognostic factors in metastatic disease	To analyse the number of lesions in liver and lung disease (1-3 vs 4-9 or ≥10), and the size of the largest lesion (<5 cm or ≥ 5 cm), in correlation with the analytical values, mainly LDH and AP values.	42 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
RAS/BRAF conversion proportion	Conversion rate of RAS/BRAF status at first-line treatment initiation and at the time of disease progression	At treatment initiation and at the time of PD (42 months)
RAS/BRAF mutations' detection proportion	Detection rate of RAS/BRAF mutations in liquid biopsies at baseline in subjects with RAS/BRAF wild-type mCRC according to the solid biopsy analysis	At baseline

Collaborators and Investigators

• Sponsor: Grupo Espanol Multidisciplinario del Cancer Digestivo
• Collaborators: Amgen; Pivotal S.L.
• Investigators: Study Director: Jaime Feliu, MD, Hospital Universitario La Paz

Publications and helpful links

Helpful Links

• GEMCAD web page

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 31, 2017
• Primary Completion (ACTUAL): January 21, 2021
• Study Completion (ACTUAL): January 21, 2021

Study Registration Dates

• First Submitted: May 2, 2017
• First Submitted That Met QC Criteria: May 3, 2017
• First Posted (ACTUAL): May 5, 2017

Study Record Updates

• Last Update Posted (ACTUAL): June 21, 2021
• Last Update Submitted That Met QC Criteria: June 18, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Keywords: Elderly; Safety; Monoclonal antibody; Tolerability; Panitumumab; Aged; Clinical Trial, Phase II; FOLFIRI; Disease-Free Survival; Chemotherapy regimen; RAS/BRAF Wild-type
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Neoplastic Processes; Neoplasms; Colorectal Neoplasms; Neoplasm Metastasis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Micronutrients; Vitamins; Topoisomerase I Inhibitors; Antidotes; Vitamin B Complex; Hematinics; Fluorouracil; Leucovorin; Irinotecan; Levoleucovorin; Folic Acid; Panitumumab
• Other Study ID Numbers: GEMCAD-16-03; 2017-001639-38 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No