Professor
Per Pfeiffer
Deparment of Oncology, Odense University Hospital
| Projekt styring | ||
| Projekt status | Planning | |
| Data indsamlingsdatoer | ||
| Start | 01.07.2017 | |
| Slut | 30.06.2019 | |
Lonsurf (TAS-102) with or without bevacizumab in patients with chemo-refractory metastatic colorectal cancer. A randomized phase II study
Short summary
The purpose of this study is to evaluate the efficacy and tolerability of Lonsurf with or without bevacizumab in Caucasian patients with chemo-refractory metastatic colorectal adenocarcinoma.
Primary objective:
- Progression-free survival (PFS)
Secondary objectives:
- Overall survival (OS)
- Response rate (RR) according to RECIST criteria version 1.1
- Toxicity
- Correlation between tumour markers and outcome
Rationale
Colorectal cancer (CRC) is among the most prevalent cancer diseases worldwide accounting annually for more than 1.200.000 new cases (Meyerhardt et al, 2005). Despite optimized surgical procedures and adjuvant combination chemotherapy, still many of these patients experience disease recurrence, most often with a fatal course. When relapsed, only few systemic medical treatment options are available, and moreover, a large percentage of the patients will not benefit from the treatment while they may experience substantial side effects.
The routine clinical management (Van Cutsem et al, Ann Oncol. 2012) of patients with metastatic colorectal cancer (mCRC) include oxaliplatin-containing therapy followed by irinotecan-containing therapy at progression (or the opposite sequence). Chemotherapy may be combined with the EGF-receptor targeted antibodies cetuximab or panitumumab in patients with RAS wild type tumours, and patients with RAS mutated tumours will often receive the VEGF targeted antibody bevacizumab with first and/or second line therapy. The objective response rates to first line systemic treatment of mCRC are approximately 50%, but only 10% of mCRC patients will obtain tumour shrinkage during second-line treatment, and in the third line situation tumour regression is rarely observed (Nielsen et al, 2014).
Despite progressive disease to 5FU, irinotecan and oxaliplatin many patients with mCRC maintain an excellent performance status, and further effective therapy is definitely indicated as PFS and OS is short without further therapy.
In patients pre-treated with 5FU, irinotecan, oxaliplatin and EGFR inhibitor (only RASwt) the median PFS and median OS is short, no effective treatment is presently available in Denmark (Regorafenib has not been approved for routine use in Denmark) and no chemotherapeutics have shown efficacy in Western studies (Nielsen et al, CTRev 2014).
Lonsurf (TAS-102) is a new well tolerated oral drug (Mayer et al, NEJM 2015). The anti-tumour agent in Lonsurf is trifluridine (TFD), a nucleoside that is incorporated into the DNA of actively dividing cells including tumour cells and inhibits cell division (Figure 1). TFD is broken down to an inactive form when taken orally but the second agent in Lonsurf, tipiracil hydrochloride (TPI), inhibits the enzyme that catalyses this breakdown and maintains plasma levels of the active cytotoxic drug. Lonsurf significantly prolongs survival in patients with metastatic colorectal cancer that is refractory to standard therapies (Yoshino et al, Lancet Oncol 2012; Mayer et al, NEJM 2015).
At ESMO 2015, a Japanese group presented a phase I/II study showing promising activity of Lonsurf in combination with bevacizumab in 25 mCRC patients with refractory disease (Yamazaki et al, ESMO 2015: abs 2116). Median PFS was 5.6 months and median OS was 11.4 months and thus promising compared to recent phase III studies evaluating regorafenib or Lonsurf in mCRC patients with refractory disease (Table 2).
However, prospective Western studies are needed to confirm these promising results, and therefore activity and toxicity of Lonsurf with or without bevacizumab will be evaluated in patients with mCRC where no standard therapy is available.
Description of the cohort
Inclusion criteria:
Eligible patients are patients with non-resectable metastatic colorectal cancer, age 18 or older, with histologically verified colorectal adenocarcinoma, measurable or non-measurable disease, performance status (WHO) of 0-1 and a life expectancy of at least 3 months, with adequate haematological and organ function, and failure of previous (or intolerance to) fluoropyrimidines, irinotecan, oxaliplatin, cetuximab or panitumumab (only for RAS wild type); prior bevacizumab, aflibercept or regorafenib allowed but not mandatory.
Data and biological material
Clinical data is obtained based on history and clinical evaluation at the Department of Oncology, Odense University Hospital.
Patients will have blood samples collected and stored at baseline, at treatment cycle 3 and at end of treatment or at progression.
Collaborating researchers and departments
Department of Oncology. Odense University Hospital
- Professor Per Pfeiffer, PhD
Department of Oncology, Herlev Hospital
- Physician Benny Vittrup Jensen
Department of Oncology, Aalborg University Hospital, Denmark
- Physician Mette Yilmaz