Study of I Line FOLFOX + Panitumumab vs 5FU + Panitumumab in RAS and BRAF WT Metastatic Colorectal Cancer Elderly Patients

Randomized Phase II Study of First-Line FOLFOX Plus Panitumumab Versus 5FU Plus Panitumumab in RAS And BRAF Wild-Type Metastatic Colorectal Cancer Elderly Patients

• Few data are available about the treatment of metastatic colorectal cancer (mCRC) elderly patients with anti-EGFR agents in combination with chemotherapy. Up today, most of the available data are from retrospective/post-hoc analyses, making them difficult to translate to everyday clinical practice.
• FOLFOX plus panitumumab is a standard first-line therapy option for RAS wild-type untreated mCRC patients. Slight adjustments in chemo-dosage are commonly applied in routinary practice to elderly patients, but those modified schedules have never been prospectively tested.
• In elderly patients, a reasonable upfront treatment is a fluoropyrimidine-based monotherapy plus bevacizumab, irrespectively of the molecular status of RAS.
• BRAF mutation is a strong negative prognostic factor associated to advanced age, poor performance status (PS), extended and aggressive disease and is associated to a lack of benefit from anti-EGFR moAb.
• Clinical definition of elderly (over 70 years old) CRC patients that may deserve a more or less intensive combination therapy is still debated. The cut-off of 75 years old combined with ECOG PS assessment is a reasonable approach for clearly defining candidates to different approaches31.
• Several geriatric screening tools have been used to identify patients with a geriatric profile potentially predicting for overall survival and risk of toxicity. The G8 screening tool has been validated in cancer patients showing the strongest prognostic value for overall survival; the CRASH score is able to stratify patients according an estimated risk of treatment-related toxicities.

On the basis of these considerations, the investigators designed the present randomized phase II trial of first-line therapy panitumumab in combination with simplified FOLFOX or with 5-fluorouracil, in previously untreated elderly patients with RAS and BRAF wild-type unresectable mCRC.

Inclusion criteria

• Written informed consent to study procedures and to molecular analyses.
• Histologically proven diagnosis of colorectal cancer.
• Initially unresectable metastatic colorectal cancer not previously treated with chemotherapy for metastatic disease.
• At least one measurable lesion according to RECIST1.1 criteria.
• Availability of a tumoral sample (primary and/or metastatic sites).
• Age ≥ 70 years.
• ECOG PS 1 or 2 for patients aged 70 to 75 years; ECOG PS 0 or 1 for patients aged > 75 years.
• Life expectancy of at least 12 weeks.
• Previous adjuvant chemotherapy allowed only if with fluoropyrimidine monotherapy and more than 6 months elapsed between the end of adjuvant and first relapse.
• RAS and BRAF status wild-type of primary colorectal cancer or related metastasis, centrally assessed.
• Neutrophils ≥1.5 x 109/L, Platelets ≥100 x 109/L, Hgb ≥ 9 g/dl.
• Total bilirubin ≤ 1.5 time the upper-normal limits (UNL) of the normal values and ASAT (SGOT) and/or ALAT (SGPT) ≤ 2.5 x UNL (or <5 x UNL in case of liver metastases) alkaline phosphatase ≤ 2.5 x UNL (or <5 x UNL in case of liver metastases).
• Creatinine clearance ≥ 50 mL/min or serum creatinine ≤1.5 x UNL.
• Male subjects with female partners of childbearing potential must be willing to use adequate contraception as approved by the investigator (barrier contraceptive measure or oral contraception).
• Geriatric assessment by means of G8 screening tool and CRASH score.
• Will and ability to comply with the protocol.

Exclusion criteria

• Previous treatment for metastatic disease.
• Radiotherapy to any site within 4 weeks before the study.
• Previous adjuvant oxaliplatin-containing chemotherapy.
• Previous treatment with EGFR inhibitors.
• Untreated brain metastases or spinal cord compression or primary brain tumors.
• History or evidence upon physical examination of CNS disease unless adequately treated.
• Symptomatic peripheral neuropathy > 1 grade NCIC-CTG criteria.
• Creatinine clearance < 50 mL/min or serum creatinine >1.5 x UNL.
• Clinical signs of malnutrition.
• Neutrophils <1.5 x 109/L, Platelets <100 x 109/L, Hgb <9 g/dl.
• Diagnosis of interstitial pneumonitis or pulmonary fibrosis.
• Active uncontrolled infections or other clinically relevant concomitant illness contraindicating chemotherapy administration.
• 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 (CHF), serious cardiac arrhythmia requiring medication.
• Treatment with any investigational drug within 30 days prior to enrollment or 2 investigational agent half-lives (whichever is longer)
• 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.
• Definite contraindications for the use of corticosteroids and antihistamines as premedication.
• 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.
• Sexually active males unwilling to practice contraception (barrier contraceptive measure or oral contraception) during the study and until 6 months after the last trial treatment.