Idetrexed plus olaparib for high-grade serous ovarian cancer

A Phase I/Ib Trial of Idetrexed (Alpha Folate Receptor Targeted Thymidylate Synthase Inhibitor) in Combination With Olaparib (a PARP Inhibitor) at Different Doses in Patients With Ovarian Cancer (IDOL)

This trial tests whether combining idetrexed and olaparib helps people with high-grade serous ovarian cancer that is resistant to standard treatments.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 33 (estimated)
• Ages: 18 Years and up
• Sex: Female
• Sponsor: Institute of Cancer Research, United Kingdom (Academic / other)
• Drugs / interventions: chemotherapy, immunotherapy, radiation
• Locations: 3 sites (Cambridge, Cambridgeshire and 2 other locations)
• Trial ID: NCT06976892 on ClinicalTrials.gov

What this trial studies

This Phase 1, multi-site dose-escalation and dose-expansion trial gives increasing doses of the folate-receptor-targeted thymidylate synthase inhibitor idetrexed together with the PARP inhibitor olaparib to determine safety, tolerability, and a recommended dose. Early cohorts follow a standard dose-escalation schema to define the maximum tolerated dose, followed by an expansion cohort enriched for tumors with medium-to-high alpha-folate receptor expression. The combination aims to increase DNA damage in cancer cells via thymidylate synthase inhibition while blocking DNA repair with a PARP inhibitor to enhance cancer cell death. Trial sites are established cancer centers in the United Kingdom and patients are followed for safety, pharmacokinetics, and preliminary anti-tumor activity.

Who should consider this trial

Good fit: Adults (≥18) with histologically confirmed high-grade serous ovarian cancer refractory to or without conventional treatment options, measurable or evaluable disease, WHO performance status 0–1, adequate organ function, and a life expectancy of at least 12 weeks are eligible, with dose-expansion patients needing medium-to-high alpha-folate receptor expression.

Not a fit: Patients whose tumors lack significant folate receptor expression, who have poor performance status or significant organ dysfunction, or who cannot meet safety lab and cardiac criteria are unlikely to benefit from this regimen.

Why it matters

Potential benefit: If successful, the combination could increase tumor responses or prolong disease control in folate-receptor–positive high-grade serous ovarian cancer.

How similar studies have performed: PARP inhibitors like olaparib have proven activity in ovarian cancer and combining DNA-damaging agents with PARP inhibition is a biologically supported strategy, but folate-receptor–targeted thymidylate synthase inhibitors such as idetrexed are relatively novel in the clinic.

Eligibility criteria

Inclusion Criteria:

* Histologically or cytologically proven high grade serous ovarian cancer refractory to conventional treatment, or for which no conventional therapy exists or is declined by the patient.
* Measurable (as defined by RECIST v1.1) or evaluable (based on tumour markers) disease.
* Life expectancy of at least 12 weeks.
* World Health Organisation (WHO) performance status of 0-1 (Appendix 1 of Protocol).
* Haematological and biochemical indices within the ranges shown in Protocol section 4.1.1). These measurements must be performed within one week (Day -7 to Day 1) prior to the patient's first dose of IMP.

Normal (no clinically significant abnormalities) 12-lead ECG, QTcF interval \<470 ms

* Pulmonary function test FVC of \>70%, DLCOc (DLCO corrected for Hb) of \>60%.
* 18 years or over.
* Written (signed and dated) informed consent and be capable of co-operating with treatment and follow-up.
* For dose expansion patients only, they must have medium to high α-folate receptor expression according to the Ventana FOLR1-2.1 IHC assay.

Exclusion Criteria:

* Radiotherapy (except for palliative reasons), endocrine therapy, immunotherapy or chemotherapy during the previous four weeks (six weeks for nitrosoureas, Mitomycin-C) and 4 weeks for investigational medicinal products) before treatment.
* Ongoing toxic manifestations of previous treatments. Exceptions to this are alopecia or certain Grade 1 toxicities, which in the opinion of the Investigator and the DDU should not exclude the patient.
* Patients with new brain metastases. Patients with treated (surgically excised or irradiated) and stable brain metastases are eligible as long as the treatment was at least 4 weeks prior to initiation of study drug and brain MRI within 2 weeks of initiation of study drug is negative for new metastases.
* Patients with pulmonary metastases.
* History of thoracic radiation or other history likely to create pre-existing lung disease
* Presence of significant clinical ascites and/or pleural effusions.
* Female patients of child-bearing potential (or are already pregnant or lactating). However, those patients who have a negative serum or urine pregnancy test before enrolment and agree to use two forms of contraception (one effective form plus a barrier method) \[oral, injected or implanted hormonal contraception and condom; intra-uterine device and condom; diaphragm with spermicidal gel and condom\] or agree to sexual abstinence (see Protocol Section 16.5 - Appendix 5), effective from signing the consent form, throughout the trial and for six months afterwards are considered eligible.
* Major thoracic or abdominal surgery from which the patient has not yet recovered.
* Patients with sub-acute bowel obstruction.
* Organ transplant patients.
* At high medical risk because of non-malignant systemic disease including active uncontrolled infection.
* Known to be serologically positive for hepatitis B, hepatitis C or human immunodeficiency virus (HIV).
* Patients with history of QT prolongation, clinically significant VT, VF, heart block, MI within 1 year, CHF NYHA Class III or IV, unstable angina, angina within 6 months, or other evidence of clinically significant coronary artery disease/
* Is a participant or plans to participate in another interventional clinical trial, whilst taking part in this Phase I/Ib study of Idetrexed and Olaparib. Participation in an observational trial would be acceptable.
* Inability to tolerate Olaparib.
* Any other condition which in the Investigator's opinion would not make the patient a good candidate for the clinical trial.
* Confirmed, current COVID-19 infection.

Where this trial is running

Cambridge, Cambridgeshire and 2 other locations

• Addenbrooke's Hospital — Cambridge, Cambridgeshire, United Kingdom (Not_yet_recruiting)
• Royal Marsden Hospital - Drug Development Unit — Sutton, London, United Kingdom (Recruiting)
• Velindre Cancer Centre — Cardiff, Wales, United Kingdom (Not_yet_recruiting)

Study contacts

• Principal investigator: Professor Udai Banerji — Institute of Cancer Research, United Kingdom
• Study coordinator: Alexander Cowley, Ph.D.

Conditions High Grade Serous Ovarian Cancer; Ovarian Cancer; idetrexed; olaparib