Evaluation of the personalised treatment of colorectal cancer by regorafenib based on therapeutic and pharmacological monitoring

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Hospitalier Universitaire De Rennes, Centre Hospitalier Universitaire De Rennes

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

Trial duration

22 Oct 2021 → 11 Apr 2025

Decision date (initial)

2024-09-26

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-517241-13-00

EudraCT number

2021-000252-18

ClinicalTrials.gov

NCT04874207

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Dose response

The primary objective of the trial is to determine whether "optimal exposure" to regorafenib based on plasma concentration of the drug and its metabolites can improve overall survival in mCRC patients.

Secondary objectives 10

1. To compare between patients with “optimal exposure” versus patients with “non optimal exposure” to regorafenib the overall survival at 10 months
2. To compare between patients with “optimal exposure” versus patients with “non optimal exposure” to regorafenib the objective response to treatment
3. To compare between patients with “optimal exposure” versus patients with “non optimal exposure” to regorafenib the disease control to treatment
4. To compare between patients with “optimal exposure” versus patients with “non optimal exposure” to regorafenib the time to progression
5. To compare between patients with “optimal exposure” versus patients with “non optimal exposure” to regorafenib the safety profile of regorafenib
6. To described the number of patients with “optimal exposure” at each cycle (C1 and C2)
7. To assess the prognostic value on overall survival of the accumulation ratio of plasma concentration of M-2 C2/C1
8. To assess the impact of genetic polymorphisms involved in drug metabolism on the pharmacokinetic of regorafenib and its metabolites
9. To assess study the relationships between body composition (sarcopenia and surface of visceral fat) and early toxicities and efficacy of regorafenib and trough blood concentrations of regorafenib
10. To assess the influence of plasma metabolomics biomarkers on regorafenib response

Conditions and MedDRA coding

metastatic colorectal cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. Male or female patients ≥ 18 years-old at time of Informed Consent Form (ICF) signature
2. Patients must have a histologically proven metastatic colorectal cancer
3. Patients who have previously been treated with standard therapy including a fluoropyrimidine, oxaliplatin, irinotecan, an anti-VEGF (bevacizumab or aflibercept) and an anti-EGFR (cetuximab or panitumumab) for patients who had a RAS wild-type tumor.
4. In mCRC with MSI-H, the patient must have received immunotherapy. For mCRC with BRAF mutation, the patient should have received a BRAF inhibitor if eligible.
5. ECOG PS = 0 or 1
6. Imaging target greater than one cm must be visible on CT
7. Patients must have adequate bone marrow, renal, and hepatic function, as evidenced by the pre-therapeutic check-up performed within 7 days before regorafenib initiation
8. INR/PTT ≤1.5 x ULN
9. Patients who are therapeutically treated with an agent such as warfarin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in coagulation parameters exists. For patient treated with VKA close monitoring of at least weekly evaluations will be performed until INR/PTT is stable based on a measurement that is pre-dose as defined by the local standard of care
10. Women of childbearing potential and male patients must agree to use adequate contraception for the duration of study participation and up to 3 months following completion of therapy
11. Women of childbearing potential must have a negative serum β-HCG pregnancy test within 7 days prior randomization
12. Patients must be willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures
13. Patients affiliated to the Social Security System
14. Signed and dated informed consent

Exclusion criteria 20

1. Prior treatment with regorafenib, and with any prior antiangiogenic inhibitor except bevacizumab
2. Hypersensitivity to the active substance or to any of the excipients
3. Systemic cancer therapy with unfinished washout (in general 3 weeks except for example for capecitabin which has a 1 week washout)
4. Concomitant treatment with a cytochrome P450 3A4 (CYP3A4) inducer or inhibitor or UGT1A9 inhibitor
5. Patients unable to swallow oral medication
6. Digestive obstruction, chronic inflammatory bowel disease or any malabsorption condition
7. Previous or concurrent cancer that is distinct in primary site or histology from colorectal cancer within 5 years prior to inclusion, except for curatively treated cervical cancer in situ, non-melanoma skin cancer and superficial bladder tumors (Ta [non-invasive tumor], Tis [carcinoma in situ] and T1 [tumor invades lamina propria])
8. Ongoing uncontrolled infection (viral, bacterial or fungal)
9. Known history of human immunodeficiency virus (HIV) infection, active hepatitis B or C or chronic hepatitis B or C requiring treatment with antiviral therapy
10. Breastfeeding
11. Uncontrolled hypertension (systolic blood pressure >140 mmHg or diastolic pressure >90 mmHg despite optimal medical management)
12. Arterial thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), within 6 months before the start of study medication
13. Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months)
14. Myocardial infarction less than 6 months before the start of study medication
15. Any hemorrhage or bleeding event ≥ Grade 3, NCI-CTCAE v 5.0 within 4 weeks prior to the start of study medication
16. Major surgical procedure, open biopsy or significant traumatic injury within 28 days before start of study medication
17. Non-healing wound, ulcer or bone fracture
18. Unresolved toxicity higher than Grade 1, NCI-CTCAE v 5.0, attributed to any prior therapy/procedure excluding alopecia, anemia, hypothyroidism and oxaliplatin induced neuropathy
19. Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
20. Adults legally protected (judicial protection, guardianship or supervision), person deprived of their liberty

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint is the overall survival defined as the time from inclusion to death from any cause. Two groups of patients will be defined a posteriori based on trough concentration of regorafenib and active metabolites: • Group with "optimal exposure": Csum on C1 and/or Csum on C2 within the range [2.5 – 5.5 mg/L]. • Group with "non optimal exposure": Csum on C1 and Csum on C2 outside the range [2.5 – 5.5 mg/L].

Secondary endpoints 10

1. 10-month survival rate (defined as the percentage of patients alive 10 months after inclusion)
2. Objective response Rate (ORR) according to RECIST 1.1 and assessed by the investigators. ORR is be defined as the rate of patients with complete or partial response
3. Disease Control Rate (DCR) according to RECIST 1.1 and assessed by the investigators. DCR is defined as the rate of patients with complete response, partial response or stable disease
4. Progression-free survival (PFS) according to RECIST 1.1, assessed by the investigators. PFS is defined as the time from inclusion to date of first observed disease progression (radiological or clinical) or death due to any cause, if death occurs before progression is documented. The actual date that the tumor scan was performed will be used for this calculation. PFS for patients without disease progression or death at the time of analysis will be censored at the last date of tumor evaluation
5. Percentage of patients with significant toxicities (≥ grade 3). AEs will be assessed from inclusion to 28 day after the discontinuation of the study drug and classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0
6. Percentage of patients with “optimal exposure” – i.e. with Csum at D15 within the range [2.5 – 5.5 mg/L]) – at cycle 1 and cycle 2
7. Overall survival for the half of patients with a low ratio of plasma concentration of M-2 C2/C1 compared to the overall survival for the half of patients with a high ratio of plasma concentration of M-2 C2/C1
8. Genetic polymorphisms in gene involved in regorafenib metabolism and plasma concentrations of regorafenib and its metabolites
9. Body composition will be determined on Computerized Tomography scan (CT-scan) imaging done at baseline and for tumor response evaluation during treatment.
10. Plasma metabolomics biomarkers (quantitative and qualitative composition) within 7 days before Day 1, at D15C1, D15C2 and end of treatment

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Hospitalier Universitaire De Rennes

Sponsor organisation

Centre Hospitalier Universitaire De Rennes

Address

2 Rue Henri Le Guilloux

City

Rennes

Postcode

35000

Country

France

Scientific contact point

Organisation

Centre Hospitalier Universitaire De Rennes

Contact name

Astrid LIEVRE

Public contact point

Organisation

Centre Hospitalier Universitaire De Rennes

Contact name

Astrid LIEVRE

Centre Hospitalier Universitaire De Rennes

Sponsor organisation

Centre Hospitalier Universitaire De Rennes

Address

2 Rue Henri Le Guilloux

City

Rennes Cedex 9

Postcode

35033

Country

France

Locations

1 EU/EEA country · 8 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 7 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications