Safety of Trifluridine/tipiracil in patients with dihydropyrimidine dehydrogenase deficiency diagnosed with metastatic colorectal or gastroesophageal cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Unicancer

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

10 Dec 2024 → ongoing

Decision date (initial)

2024-07-26

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Servier

External identifiers

EU CT number

2023-508724-35-00

ClinicalTrials.gov

NCT06245356

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To evaluate the specific safety and preliminary efficacy of an alternative chemotherapy option, namely Trifluridine/tipiracil, as replacement of 5FU- or capecitabine-based chemotherapy in pMMR/MSS metastatic colorectal or metastatic gastroesophageal adenocarcinomas first line regimens for patients with partial or complete DPD deficiency.

Secondary objectives 4

1. Overall safety of combination treatment
2. Compliance with treatment, in particular during the first 2 cycles (before Cycle 3)
3. Efficacy of the combination treatment in terms of: - Progression Free Survival (PFS) - Overall Survival (OS) - Objective Response Rate (ORR) - Disease Control Rate (DCR)
4. The effect of treatment on quality of life.

Conditions and MedDRA coding

Patients with pMMR/MSS metastatic adenocarcinoma of the colon or rectum or gastroesophageal cancer (lower esophagus, gastroesophageal junction and gastric) and with known dihydropyrimidine dehydrogenase (DPD) deficiency defined as plasma uracil concentration ≥16 ng/ml, who undergo first-line treatment

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Patient must have signed and dated a written informed consent form prior to any trial specific procedures. When the patient is physically unable to give their written consent, a trusted person of their choice, independent from the investigator or the sponsor, can confirm in writing the patient’s consent.
2. Histological or cytological documentation of proficient mismatch repair or microsatellite stable (pMMR/MSS) adenocarcinoma of the colon or rectum OR gastroesophageal cancer (lower oesophagus, gastroesophageal junction and gastric)
3. Unresectable synchronous or metachronous metastatic colorectal or gastroesophageal cancer
4. Presence of at least one measurable lesion according to RECIST v1.1
5. No prior therapy for metastatic disease
6. Known DPD deficiency defined as plasma uracil concentration≥16 ng/ml
7. Age ≥18 years
8. Eastern Cooperative Oncology Group (ECOG) performance status ≤1
9. Adequate bone marrow, renal, and liver functions as evidenced by the laboratory requirements within 7 days prior to study treatment initiation
10. For women of reproductive potential, negative serum beta human chorionic gonadotropin (β- HCG) pregnancy test obtained within 7 days before the start of study treatment. Women not of reproductive potential are female patients who are postmenopausal or permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy)
11. For women of childbearing potential and men, agreement to use an adequate contraception for the duration of study participation and up to 7 months following completion of therapy
12. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and other study procedures
13. Affiliation to the Social Security System (or equivalent).

Exclusion criteria 27

1. Previous or concurrent cancer that is distinct in primary site or histology from colorectal or gastroesophageal cancer within 5 years prior to study inclusion, except for curatively treated cervical cancer in situ, non-melanoma skin cancer and superficial bladder tumours [Ta (non invasive tumour), Tis (carcinoma in situ) and T1 (lamina propria invasion)]
2. Patients with colorectal cancer with high microsatellite instability (MSI-H) or mismatched repair disease (dMMR) tumor
3. Patients with CPS≥1 HER2-positive gastroesophageal adenocarcinomas with planned treatment of pembrolizumab if access to pembrolizumab is available.
4. Patients with resectable metastases of colorectal cancer.
5. Radiotherapy within 28 days prior to first dose of treatment
6. Active cardiac disease or abnormal cardiac function including any of the following: a. QT/QTc interval longer than 450 msec for men and longer than 470 msec for women monitored by an ECG at inclusion b. Symptomatic Congestive heart failure ≥New York Heart Association (NYHA) class 3 or 4 c. Severe Unstable angina (angina symptoms at rest) d. Myocardial infarction less than 12 months before first dose of treatment
7. Uncontrolled hypertension (Systolic blood pressure ≥140 mmHg or diastolic pressure ≥ 90 mmHg) despite optimal medical management for treatement by bevacizumab
8. Ongoing infection ≥Grade 2 (NCI CTCAE v.5.0)
9. Known history of human immunodeficiency virus (HIV) infection
10. Chronic hepatitis B or C infection (if hepatitis status cannot be obtained from medical records, re-testing is required)
11. Seizure disorder requiring medication
12. Symptomatic metastatic brain or meningeal tumours
13. History of organ allograft
14. Known hypersensitivity to any of the study drugs, study drug classes, or any constituent of the products
15. Use of live or live attenuated vaccines
16. Ongoing toxicities: a. Peripheral neuropathy >Grade 1 (NCI CTCAE v.5.0) b. Unresolved Grade 3 or 4 non-haematological clinically relevant toxicity from prior therapies
17. Hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption or any uncontrolled malabsorption condition
18. Inability to swallow oral medication
19. In case of planned treatment with nivolumab: a. Participant has received systemic steroid therapy (>10 mg daily prednisone or equivalent) or is receiving any other form of immunosuppressive medication. b. Active autoimmune disease or medical conditions requiring systemic immunosuppression that has required systemic treatment
20. In case of planned treatment with trastuzumab: a. a threshold value for the left ventricular ejection fraction (LVEF) measured at inclusion that does not allow treatment with trastuzumab (<55%), b. severe dyspnoea at rest due to complications of advanced malignancy or requiring supplementary oxygen therapy c. Known hypersensitivty to murine proteins
21. In case of planned treatment with bevacizumab: a. Proteinuria that does not allow treatment with bevacizumab, b. Pre-existing gastrointestinal or non-gastrointestinal fistula, c. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to first dose of treatment d. Evidence or history of any bleeding diathesis, irrespective of severity. Any hemorrhage or bleeding event ≥CTCAE v 5.0 Grade 3 within 4 weeks prior to the start of study medication e. Prior arterial thromboembolic reactions, including cerebrovascular accidents, transient ischaemic attacks less than 12 months before first dose of bevacizumab f. Known hypersensitivity to Chinese Hamster Ovary (CHO) cell products or other recombinant human or humanized antibodies
22. In case of planned treatment with trastuzumab or panitumumab or bevacizumab: Interstitial lung disease with ongoing signs and symptoms
23. Pregnant or breast-feeding subjects. Women of childbearing potential must have a serum pregnancy test performed a maximum of 7 days before start of treatment, and a negative result must be documented before start of study drug
24. Patients unwilling or unable to comply with the medical follow-up required by the trial because of geographic, familial, social, substance abuse, medical or psychological reasons, or any condition that, in the opinion of the investigator, would interfere with the patient’s participation in the study or evaluation of study treatment or interpretation of patient safety or study results
25. Participation in another clinical study with an investigational product during the last 30 days before inclusion
26. Patients who might be interconnected with or dependent on the sponsor site or the investigator
27. Persons deprived of their liberty or under protective custody or guardianship, or legal incapacity or limited legal capacity

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The co-primary endpoint including: the rate of patients without specific toxicities defined as grade 3-4-5 digestive toxicities (diarrhoea and/or stomatitis) and grade 4-5 neutropenia or febrile neutropenia over the first 2 cycles (1 month of treatment) of first-line metastatic treatment (NCI CTCAE v5.0) AND the disease control rate after the 1st evaluation at 2 months of treatment.

Secondary endpoints 4

1. Safety of combination treatment (NCI CTCAE v5.0) determined through the incidence of adverse events, treatment-related adverse events, serious adverse events (SAE), and death; for the whole population and depending on glomerular filtration rate ([50-60[ vs [60- 90[ vs ≥90 mL/min per 1.73 m2)
2. Dose intensity of combination treatment per patient and per cycle for cycle 1 and cycle 2 before third cycle
3. Treatment efficacy : PFS, Overall survival, Objective response rate, Disease control rate
4. Health-related quality of life will be assessed using the EORTC QLQ-C30 and EORTC QLQ-OG25 questionnaires for patients with gastroesophageal adenocarcinomas or EORTC QLQ-CR29 for patients with colorectal adenocarcinomas at baseline and every 2 months until disease progression and/or at least 3 months after study treatment stop

Investigational products

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

Test 7

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Unicancer

Sponsor organisation

Unicancer

Address

101 Rue De Tolbiac

City

Paris

Postcode

75013

Country

France

Scientific contact point

Organisation

Unicancer

Contact name

Nourredine AIT RAHMOUNE

Public contact point

Organisation

Unicancer

Contact name

Nourredine AIT RAHMOUNE

Locations

1 EU/EEA country · 20 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 22 files

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

Application history

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