To demonstrate the superiority of S 95005 + bevacizumab over capecitabine + bevacizumab in terms of Progression-free survival (PFS) based on Investigator assessment in first-line treatment of patients with unresectable metastatic colorectal cancer…
ID
Source
Brief title
Condition
- Gastrointestinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Progression-free survival (PFS) based on Investigator assessment .
Secondary outcome
Key secondary endpoint: Overall survival (OS)
Other secondary endpoints :
Overall response rate (ORR)
Disease control rate (DCR)
Duration of response (DoR)
Time to treatment failure (TTF)
Safety and tolerability
Quality of life (Qol) (EORTC QLQ-C30 and EQ-5D-5L)
Background summary
Very few clinical trials have been conducted in frail, elderly patients and/or
unfit patients to standard full dose irinotecan or oxaliplatin combination
chemotherapy. Therefore there is a high need to perform trials in this specific
population of patients to provide them with a new therapeutic option.
S 95005 is an oral administered combination of an antineoplastic
thymidine-based nucleoside analogue (trifluridine [FTD]) and a thymidine
phosphorylase inhibitor (tipiracil hydrochloride [TPI]).
Co-administration of TPI with FTD prevents the rapid degradation of FTD,
resulting in a significant increase in systemic exposure to FTD. Following
uptake into cancer cells, FTD is phosphorylated by thymidine kinase, further
metabolized in cells to a deoxyribonucleic acid (DNA) substrate, and
incorporated directly into DNA, thereby interfering with DNA function to
prevent cell proliferation.
FTD incorporation into DNA is markedly higher than that of other nucleoside
analogues.
FTD also exhibits thymidylate synthase inhibition (TSI). However, results of in
vivo studies show FTD incorporation into DNA to be the primary mechanism of
antitumour activity with oral administration.
This mechanism of action of S 95005 differentiates it from conventional
fluoropyrimidines, which are uracil-based, and for which the primary mode of
action is TSI.
In non clinical studies ,S 95005 demonstrated antitumor activity against both 5
FU sensitive and resistant colorectal cancer cell lines.
S95005 is approved as monotherapy for the treatment of adult patients with
advanced mCRC in different countries.
Non clinical research shows that combined S 95005 and bevacizumab treatment had
superior antitumor activity compared to either drug alone
The clinical rationale of the development in this indication is based on the
results of an Investigator Initiated phase I/II study of trifluridine/tipiracil
in combination with bevacizumab for mCRC refractory to standard therapies
(C-TASK FORCE) conducted in Japanese patients .
There is a similar ongoing phase 2 study (Cl2-95005-002). The analysis of the
primary endpoint (100 PFS) showed a median PFS of 9.23 months (95% CI
7.59-11.56) for trifluridine/tipiracil-bevacizumab and 7.82 months (95% CI
5.55-10.15) for capecitabine-bevacizumab. The Hazard Ratio adjusted on
stratification covariates was 0.71 (95% CI 0.48-1.06). The secondary endpoint
of OS was immature but followed a
positive trend with 18.00 months for trifluridine/tipiracil-bevacizumab and
16.16 months for capecitabine+bevacizumab.
Study objective
To demonstrate the superiority of S 95005 + bevacizumab over capecitabine +
bevacizumab in terms of Progression-free survival (PFS) based on Investigator
assessment in first-line treatment of patients with unresectable metastatic
colorectal cancer who are not candidate for intensive therapy.
Study design
International, open-label, controlled two-arm, randomised phase III study
comparing S 95005 in combination with bevacizumab versus capecitabine in
combination with bevacizumab in the first-line treatment of patients with
unresectable metastatic colorectal cancer (mCRC) who are not candidate for
intensive therapy.
854 patients will be randomised in a (1:1) ratio. The stratification factors
will be ECOG performance status (0 vs. 1 vs. 2), tumour localisation (right vs.
left) and reason why the patient is not candidate to intensive therapy
(clinical condition reason vs. non-clinical condition reason).
S 95005 + bevacizumab = 4 weeks cycle
or capecitabine + bevacizumab = 3 weeks cycle study scheme:
screening, inclusion, randomisation, visit on D1 + D15 each cycle in the
S95005+beva arm, and first cycle of cape+beva. In that arm afterwards only on
D1. Tumor measurements every 8 weeks. QoL questionnaires every 6 weeks.
Intervention
Blood and urine sampling, contrast enhanced CT, Qol questionnaires.
Study burden and risks
Cfr adverse events of medication and procedures described in patient
information.
Rue Carnot 50
Suresnes 92284
BE
Rue Carnot 50
Suresnes 92284
BE
Listed location countries
Age
Inclusion criteria
- Written informed consent obtained
- Male or female participant aged >=18 years old at the time of ICF signature
(or legal age depending on local country regulation).
- Has definitive histologically confirmed adenocarcinoma of the colon or rectum.
- Has at least one measurable metastatic lesion.
- RAS status based on local biological assessment of tumour biopsy must be
available.
- Patient is not a candidate for standard full dose combination chemotherapy
with irinotecan or oxaliplatin according to investigator*s judgment and
decision taken during a multidisciplinary meeting (if organised in the centre).
Reasons for non-eligibility to these standard treatments could be, but are not
limited to, age, performance status, low tumour burden, comorbidities or
non-clinical reasons.
- Patient is not a candidate for curative resection of metastatic lesions
according to investigator*s judgment and decision taken during a
multidisciplinary meeting (if organised in the centre).
- No previous systemic anticancer therapy for unresectable metastatic
colorectal cancer. Previous adjuvant or neoadjuvant chemotherapy is allowed
only if the patient has been disease free for at least 6 months after the
completion of the chemotherapy.
- Ability to swallow oral medication.
- Estimated life expectancy >=12 weeks.
- ECOG (Eastern Cooperative Oncology Group) performance status <=2.
- Adequate haematological, renal, hepatic and coagulation function.
- Women of childbearing potential must have been tested negative in a serum
pregnancy test. Within the frame of this study, female participants of
childbearing potential and male participants with partner of childbearing
potential must use an highly effective method of birth control as well as their
partners lasting at least 6 months after the last dose of IMP. Women using
hormonal contraceptive must also use a barrier method.
Exclusion criteria
- Unlikely to cooperate in the study.
- Pregnancy, breastfeeding or possibility of becoming pregnant during the study.
- Participation in another interventional study, major surgery, drainage for
ascites, pleural effusion or pericardial fluid, previous radiotherapy, within
the specified timeframes prior to the randomisation.
- Patients who have not recovered from clinically relevant non-hematologic
CTCAE grade >= 3 toxicity of previous anticancer therapy prior to the
randomisation.
- Symptomatic central nervous system metastases.
- Has certain serious illness or serious medical condition(s) described in the
protocol.
- Hereditary problems of galactose intolerance, the Lapp lactase deficiency or
glucose-galactose malabsorption.
- Other malignancies excluding malignancies that are in remission for more than
5 years, cervix carcinoma-in-situ deemed cured by adequate treatment or basal
cell carcinoma.
- Treatment with systemic immunosuppressive therapy (except steroids given in
prophylactic setting or at a chronic low dose (<=20mg/day prednisone
equivalent)).
- Criteria related to S 95005 administration:
Has previously received S 95005.
History of allergic reactions attributed to compounds of similar composition to
S 95005 or any of its excipients.
Any contraindication present in the SmPC of trifluridine/tipiracil.
- Criteria related to bevacizumab administration:
History of allergic reactions or hypersensitivity to bevacizumab or any of its
excipients.
History of hypersensitivity to Chinese Hamster Ovary (CHO) cell products or
other recombinant human or humanised antibodies.
Serious non-healing wound, non-healing ulcer or non-healing bone fracture.
Deep venous thromboembolic event within 4 weeks prior to randomisation.
Known coagulopathy that increases risk of bleeding, bleeding diatheses. Any
other haemorrhage/bleeding event CTCAE grade >= 3 within 4 weeks prior to
randomisation.
Any contraindication present in the SmPC of bevacizumab.
- Criteria related to capecitabine administration:
History of allergic reactions or hypersensitivity to capecitabine or any of its
excipients or fluorouracil.
History of severe and unexpected reaction to fluoropyrimidine therapy.
Known complete absence of dihydropyrimidine dehydrogenase (DPD) activity or
partial deficiency of DPD preventing the administration of the starting dose of
capecitabine as defined per study protocol.
Treatment with sorivudine or its chemical related analogues, such as brivudine,
within 4 weeks prior to the randomisation.
Any contraindication present in the SmPC of capecitabine.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2017-004059-22-NL |
| CCMO | NL68912.056.19 |