A Phase 1b/2 study of arfolitixorin as part of 5-fluorouracil-based treatment regimens in the first-line treatment of metastatic colorectal cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Isofol Medical AB (publ)

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

9 Apr 2025 → ongoing

Decision date (initial)

2024-12-23

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Isofol Medical AB (publ), Sweden

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Pharmacokinetic, Dose response

Phase 1b:
- To evaluate the safety and tolerability of arfolitixorin, 5-FU, and oxaliplatin (ARFOX) + bevacizumab in patients with metastatic colorectal cancer (mCRC).

Phase 2:
- To evaluate the safety and tolerability of 2 pre-defined dose levels of arfolitixorin (MTD and a dose level below MTD; arfolitixorin in eligible 5-FU based backbones) with SoC used as an internal control, in patients with mCRC.
- To assess early signals of the anti-tumor activity of 2 pre-defined dose levels of arfolitixorin (MTD and a dose level below MTD; arfolitixorin in eligible 5-FU based backbones) with SoC used as an internal control, in patients with mCRC, in terms of ORR and DOR.

Secondary objectives 5

1. Phase 1b: To assess the anti-tumor activity of ARFOX + bevacizumab in patients with mCRC in terms of objective response rate (ORR), progression free survival (PFS) and overall survival (OS).
2. Phase 1b: To determine the PK profile of arfolitixorin, administered in combination with bevacizumab, oxaliplatin and 5-FU.
3. Phase 2: To assess the anti-tumor activity of 2 pre-defined dose levels of arfolitixorin (MTD and a dose level below MTD; arfolitixorin in eligible 5-FU based backbones) with SoC used as an internal control, in patients with mCRC, in terms of OS, PFS, TTR, DCR, and DpR.
4. Phase 2: To assess OS as a safety outcome for 2 pre-defined dose levels of arfolitixorin (MTD and a dose level below MTD; arfolitixorin in eligible 5-FU based backbones) with SoC used as an internal control, in patients with mCRC.
5. Phase 2: To assess the effect of 2 pre-defined dose levels of arfolitixorin (MTD and a dose level below MTD; arfolitixorin in eligible 5-FU based backbones) with SoC used as an internal control, in patients with mCRC, in terms of qualification for curative metastasis resection.

Conditions and MedDRA coding

metastatic colorectal cancer

Study design 2 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. 1. Signed Informed Consent Form (ICF) and ability to comply with protocol requirements.
2. 6. Age ≥18 years at the time of signing the ICF.
3. 7. Radiographically measurable disease per RECIST (version 1.1) within 28 days of treatment allocation.
4. 8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
5. 9. Life expectancy of >12 weeks.
6. 10. Female patients must be surgically sterile, postmenopausal (for at least 1 year), or have negative results for a pregnancy test at screening, on a serum or urine sample obtained within 72 hours prior to initiation of study treatment.
7. 11. Female patients of childbearing potential must agree to use highly effective contraceptive measures while on study treatment and for at least 15 months (or longer if according to local labels) after study treatment discontinuation. Highly effective methods are those that achieve a failure rate of less than 1% per year when used consistently and correctly (as per the Clinical Trial Coordination Group [CTCG] Recommendations related to contraception and pregnancy testing in clinical trials, Version 1.2, 07 Mar 2024)
8. 13. Male patients with female partners of childbearing potential must agree to use adequate contraceptive measures while on study treatment and for at least 12 months (or longer if according to local labels) after study treatment discontinuation.
9. 2. Phase 1b: Histologically confirmed RAS mutant, microsatellite stable (MSS)/proficient mismatch repair (pMMR), colorectal adenocarcinoma with metastatic disease, eligible for first-line therapy with 5-FU, oxaliplatin, and bevacizumab regimen. Phase 2: Histologically confirmed, colorectal adenocarcinoma with metastatic disease, eligible for first-line therapy with 5-FU based backbones, i.e.: - Patients with mutated RAS who are candidates for therapy with FOLFOX or FOLFIRI plus bevacizumab. - Patients with WT RAS or WT BRAF and left-sided tumors who are candidates for therapy with FOLFOX or FOLFIRI plus cetuximab or panitumumab.
10. 3. Tumor specimen (formalin-fixed, paraffin-embedded [FFPE]) available.
11. 4. Acceptable hematologic laboratory values defined as: a) Hemoglobin ≥90 g/L. b) Absolute neutrophil count (ANC) ≥1.5 × 109/L. c) Platelets ≥100 × 109/L.
12. 5. Adequate organ function as defined by the following laboratory values: a) Total serum bilirubin ≤1.5 × upper limit of normal (ULN). b) Alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤3 × ULN (≤5 × ULN in case of hepatic metastases). c) Creatinine ≤1.5 × ULN, or creatinine clearance ≥50 mL/min (as measured according to Cockcroft-Gault equation).
13. 12. Female patients should agree to refrain from egg cell donation while on study treatment and for at least 15 months after the last dose of study treatment.
14. 14. Male patients should agree to refrain from sperm donation while on study treatment and for at least 12 months after the last dose of study treatment.

Exclusion criteria 16

1. 1. Indication for any mCRC surgery or anti-cancer treatment other than study treatment, including but not limited to resection as confirmed by a MTB.
2. 11. Current evidence of any condition that could lead to higher risk or otherwise make participating in this study not in the best interest of the patient, including, but not limited to: a) Myocardial infarction or unstable angina within the past 6 months. b) Other structural heart disease (e.g., myocarditis, ventricular hypertrophy). c) New York Heart Association (NYHA) functional classification Class II or greater. d) QT prolongation syndrome >450 ms. e) Slow or irregular ventricular rates; other serious arrhythmias requiring medication for treatment. f) Left ventricular ejection fraction (LVEF) <55%. g) Active infection requiring i.v. antibiotics. h) Ongoing drug or alcohol abuse. i) Inadequately controlled hypertension (defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure >100 mmHg). Initiation of antihypertensives is permitted provided adequate control is documented over at least 1 week before starting treatment.
3. 12. Sensory peripheral neuropathy Grade ≥2.
4. 13. Pregnancy or lactation.
5. 14. Any medical condition, or going treatmetn with contraindicated drugs, which in the opinion of the Investigator, places the patient at an unacceptably high risk for toxicities, or any psychological, familial, sociological or geographical condition that potentially hampers compliance with the study protocol and follow-up schedule.
6. 2. Concomitant malignancies or previous malignancies with less than a 2-year disease-free interval at the time of signing consent. Patients with adequately treated basal or squamous cell carcinoma of the skin, or adequately treated carcinoma in situ (e.g., cervix) may enroll irrespective of the time of diagnosis. Patients with controlled, advanced prostate cancer are permitted. Ongoing adjuvant antihormonal therapy after breast or prostate cancer is permitted.
7. 3. Prior 5-FU, oxaliplatin, irinotecan, bevacizumab, cetuximab or panitumumab administration for mCRC.
8. 5. Known history of central nervous system (CNS) metastases or carcinomatous meningitis.
9. 6. Receipt of any investigational product within 14 days or 5 half-lives prior to study treatment initiation, whichever is shortest. Note that participation in any other clinical study is not allowed as long as the patient is on study treatment.
10. 7. Prior exposure to arfolitixorin.
11. 8. Major surgery, or significant traumatic injury within 8 weeks of study treatment initiation.
12. 9. Hypersensitivity to arfolitixorin, 5-FU, oxaliplatin or other platinum agent, irinotecan, bevacizumab, cetuximab or panitumumab, or to their excipients.
13. 10. Dihydropyrimidine dehydrogenase (DPD) enzyme deficiency test with a Clinical Pharmacogenetics Implementation Consortium (CPIC) activity score <1.
14. 4. More than 6 cycles (3 months) of oxaliplatin exposure during adjuvant treatment.
15. 15. BRAF-mutant or dMMR/MSI-H mCRC.
16. 16. Eligibility for treatment with FOLFIRINOX regimens.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 4

1. Phase 1b: Number and severity of AEs, including clinically significant abnormal laboratory findings, regardless of causal relationship to ARFOX + bevacizumab. The outcome of Phase 1b is to determine the MTD of arfolitixorin (ARFOX + bevacizumab) in patients with mCRC.
2. Phase 2: ORR, defined as the proportion of patients who have BOR of CR, or PR, measured from the start of the study treatment until the EOT by RECIST (version 1.1).
3. Phase 2: Number and severity of AEs, including clinically significant abnormal laboratory findings, regardless of causal relationship to given treatment.
4. Phase 2: DOR, defined as the duration of CR or PR.

Secondary endpoints 9

1. Phase 1b: ORR, defined as the proportion of patients who have BOR of CR, or PR, measured from the start of the study treatment until the EOT by RECIST (version 1.1).
2. Phase 1b and Phase 2: PFS, defined as the time from date of the first study dose to the date of first documentation of confirmed disease progression or death (whichever occurs first).
3. Phase 1b and Phase 2: OS, measured from the date of study treatment initiation to the date of death.
4. Phase 1b: Plasma concentration of arfolitixorin.
5. Phase 2: TTR, defined as the time from the first study dose date to the date of first documentation of CR or PR measured by RECIST (version 1.1).
6. Phase 2: DCR, defined as the proportion of patients who have BOR of CR, PR, or SD ≥8 weeks.
7. Phase 2: DpR, defined as the maximum percentage change in tumor size compared with baseline.
8. Phase 2: OS, measured from the date of study treatment initiation to the date of death.
9. Phase 2: Proportion of patients qualifying for curative metastasis resection after treatment with study drug.

Investigational products

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

Test 1

Comparator 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Isofol Medical AB (publ)

Sponsor organisation

Isofol Medical AB (publ)

Address

Biotech Center, Arvid Wallgrens Backe 20 5 Tr, Goteborgs Annedal Arvid Wallgrens Backe 20 5 Tr Goteborgs Annedal

City

Goteborg

Postcode

413 46

Country

Sweden

Scientific contact point

Organisation

Isofol Medical AB (publ)

Contact name

Sponsor Information Desk

Public contact point

Organisation

Isofol Medical AB (publ)

Contact name

Sponsor Information Desk

Third parties 6

Locations

1 EU/EEA country · 3 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 8 files

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

Application history

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