Few clinical studies have evaluated the role of anti-EGFR therapy rechallenge in metastatic
colorectal cancer patients and there is no prospective clinical trial assessing the activity
of treatment rechallenge with panitumumab-based therapy after initial progression. This study
aims at exploring the concept of evolution and expansion of RAS wild type clones in order to
restore sensitivity of the tumor to prior anti-EGFR therapy after a time interval in which a
different, non-anti-EGFR second-line therapy is administered. Based on aforementioned data,
it is hypothesized that rescue through rechallenge with panitumumab-based third-line therapy
combined with chemotherapy could be associated with further response and clinical benefit. A
significant component of the proposed prospective trial is exploratory translational: cell
free plasma and platelet-based genotyping for genetic mutations in different time points will
be undertaken in order to study the genetic composition of the metastatic tumour at
initiation of and at progression through, anti-EGFR rechallenge therapy.
Primary endpoint will be to evaluate the efficacy, in terms of overall response rate, of the
addition of panitumumab rechallenge to standard third-line irinotecan-based or
oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer initially
treated with, and benefiting from, first line irinotecan-based or oxaliplatin-based
chemotherapy combined with an anti-EGFR monoclonal antibody, followed by second line
chemotherapy not containing anti-EGFR agents.
Exploratory endpoints include to identify, in the context of translational research, tumour
tissue and blood-based biomarkers with prognostic/predictive significance in patients with
metastatic colorectal cancer treated with rechallenge panitumumab in combination with
standard third-line irinotecan-based or oxaliplatin-based chemotherapy, who were initially
treated with, and benefiting from, first line irinotecan-based or oxaliplatin-based
chemotherapy combined with an anti-EGFR monoclonal antibody, followed by second line
chemotherapy not containing anti-EGFR agent.
Inclusion Criteria:
- Signed and dated informed consent, and willing and able to comply with protocol
requirements,
- Histologically proven adenocarcinoma of the colon and/or rectum,
- Metastatic disease confirmed clinically/radiologically,
- Patients with Formalin-Fixed, Paraffin-Embedded tissue RAS wild type colorectal cancer
at diagnosis, who had initial clinical benefit [complete response, partial response or
stable disease] during first line irinotecan-based or oxaliplatin-based chemotherapy
in combination with cetuximab or panitumumab,
- First- line treatment duration (FOLFIRI, FOLFOX with anti-EGFR monoclonal antibody, of
whom at least 2/3 of cases will have involved panitumumab) of at least 3 months,
- Second line therapy consisting of any chemotherapy (with or without Bevacizumab)
definitely without anti-EGFR therapy of at least 2 months, followed by disease
progression,
- Eligible third line regimens include FOLFIRI or Irinotecan or FOLFOX, according to
standard practice and approved indications. It is required that the third line regimen
used will be different from the second line and similar to the first line regimen,
- At least one measurable or evaluable lesion as assessed by computed tomography scan or
Magnetic Resonance Imaging according to RECIST version 1.1,
- First course of treatment planned less than 1 week (7 days) after registration,
- Age ≥18 years,
- Eastern Cooperative Oncology Group (ECOG) Performance status 0-2,
- Adequate hematological status: neutrophils (ANC) ≥1.5x109/L; platelets ≥100x109/L;
haemoglobin ≥9g/dL,
- Adequate renal function: serum creatinine level <1.5 mg/dL or Glomelular Filtration
Rate (GFR) >50mL/min by Cockroft/Gault formula,
- Adequate liver function: serum bilirubin ≤1.5 x upper normal limit (ULN), alkaline
phosphatase, Aspartate aminotransferase (AST), Alanine aminotransferase (ALT) <5xULN,
- Regular follow up feasible.
- For female patients of childbearing potential, negative serum or urine pregnancy test
within 1 week (7 days) prior of starting study treatment
- Female patients must commit to using reliable and appropriate methods of contraception
until at least three months after the end of study treatment (when applicable). Male
patients with a partner of childbearing potential must agree to use contraception in
addition to having their partner use another contraceptive method during the trial,
- Archival tumor tissue is required for exploratory research at enrolment,
- Ability to undergo plasma sampling during the therapy course.
Exclusion Criteria:
- Presence of central nervous system metastasis unless adequately treated (e.g. non
irradiated central nervous system metastasis, seizures not controlled with standard
medical therapy constitute non-eligibility criteria),
- Active infection (ie, body temperature ≥38°C due to infection),
- Intestinal obstruction, pulmonary fibrosis or interstitial pneumonitis, renal failure,
liver failure, or cerebrovascular disorder,
- Uncontrolled diabetes,
- Myocardial infarction within the last 6 months, severe/unstable angina, symptomatic
congestive heart failure New York Heart Association class III or IV,
- Known human immunodeficiency virus or acquired immunodeficiency syndrome-related
illness, or hepatitis B or C,
- Autoimmune disorders or history of organ transplantation that require
immunosuppressive therapy,
- Other concomitant or previous malignancy, except: i/ adequately treated in-situ
carcinoma of the uterine cervix, ii/ basal or squamous cell carcinoma of the skin,
iii/ cancer in complete remission for >5 years,
- Major surgery or traumatic injury within the last 28 days,
- Pregnant or breastfeeding women,
- Patients with known allergy to any excipients to study drugs,
- Other serious and uncontrolled chronic non-malignant disease,
- Known dihydropyrimidine dehydrogenase deficiency,
- Palliative radiation therapy within 4 weeks prior to registration,
- Life expectancy less than 12 weeks in the opinion of the Investigator,
- Treatment with any other investigational medicinal product within 28 days prior to
study entry.
