| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic colorectal cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 27.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10052358 |
| E.1.2 | Term | Colorectal cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To demonstrate the superiority of S 95005 in combination with bevacizumab over capecitabine in combination with 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. |
|
| E.2.2 | Secondary objectives of the trial |
| To confirm clinical benefit for treatment through an evaluation of Overall survival (OS), Overall response rate (ORR), Disease control rate (DCR), Duration of response (DoR), Time to treatment failure (TTF) and to compare the safety and the impact on quality of life of S 95005 in combination with bevacizumab to capecitabine in combination with bevacizumab in first-line treatment of patients with unresectable metastatic colorectal cancer who are not candidate for intensive therapy. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- 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, including systemic use of chemotherapy agents as radiosensitizers. 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 partners 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.
- Written informed consent obtained.
|
|
| E.4 | Principal 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, prior 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 including those which were radically treated and for which the remission period at the time of the screening is less than five years. Exemptions for a minimally required duration of remission period may be applied for carcinoma in situ of the cervix and basal cell skin cancer that are deemed to be cured by adequate treatment.
- 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.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-free survival (PFS) based on investigator judgement |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Tumour assessments at baseline, every 8 weeks from C1D1 until radiological progression is documented and at the withdrawal visit if not done in the previous 8 weeks.
|
|
| E.5.2 | Secondary end point(s) |
- Overall survival (OS)
- Overall response rate (ORR)
- Disease control rate (DCR)
- Duration of response (DoR)
- Time to treatment failure (TTF)
- Safety and tolerability assessed by incidence of adverse events (AE), laboratory tests, physical examination and performance status (ECOG), vital signs, 12-leads ECG parameters
- Quality of life (QoL)
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- ORR, DCR, DoR, TTF: at baseline, every 8 weeks from C1D1 until radiological progression, and at withdrawal visit if not done in the previous 8 weeks.
- OS: survival status obtained at 8 week intervals until patient death or end of the study.
- AE: all over the study
- Laboratory tests, physical examination, ECOG, vital signs:
Within 4 days prior to randomisation,
At pre-dose of C1D1,
At C1D15 (not for coagulation, physical examination and ECOG),
Beginning with cycle 2, prior to start of study treatment in every cycle,
Only for haematology and vital signs: At CxD15 (experimental arm only) prior to bevacizumab injection,
Withdrawal visit.
- ECG: within 28 days prior to randomisation and at withdrawal visit.
- QoL: at baseline, every 6 weeks and at withdrawal visit. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 152 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Colombia |
| Ukraine |
| Australia |
| Brazil |
| Russian Federation |
| United Kingdom |
| Austria |
| Bulgaria |
| Czechia |
| Denmark |
| Estonia |
| France |
| Germany |
| Hungary |
| Ireland |
| Italy |
| Latvia |
| Lithuania |
| Netherlands |
| Poland |
| Portugal |
| Romania |
| Slovakia |
| Spain |
| Sweden |
| Türkiye |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| End of Trial is defined as the date of the last withdrawal visit of the last participant on treatment, or the date of the last contact attempt if the last patient is declared lost to follow-up. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
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