Banerjee, Susana;
Michalarea, Vasiliki;
Ang, Joo Ern;
Ingles Garces, Alvaro;
Biondo, Andrea;
Funingana, Ionut-Gabriel;
Little, Martin;
... Banerji, Udai; + view all
(2022)
A phase I trial of CT900, a novel α-folate receptor-mediated thymidylate synthase inhibitor, with expansion cohorts in patients with high grade serous ovarian cancer.
Clinical Cancer Research
10.1158/1078-0432.CCR-22-1268.
(In press).
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Abstract
PURPOSE: CT900 is a novel small molecule thymidylate synthase inhibitor that binds to α-folate receptor (α-FR) and thus is selectively taken up by α-FR-overexpressing tumours. PATIENTS AND METHODS: A 3+3 dose escalation design was used. During dose escalation, CT900 doses of 1-6 mg/m2 weekly and 2-12 mg/m2 every 2 weeks (q2Wk) intravenously were evaluated. Patients with high-grade serous ovarian cancer (HGSOC) were enrolled in the expansion cohorts. RESULTS: 109 patients were enrolled, 42 patients in the dose escalation and 67 patients in the expansion cohorts. At the dose/schedule of 12 mg/m2/q2Wk (with and without dexamethasone, n=40), the most common treatment related adverse events were fatigue, nausea, diarrhoea, cough, anaemia and pneumonitis, which were predominantly grade 1 and grade 2. Levels of CT900 greater than 600 nM needed for growth inhibition in preclinical models were achieved for >65 hours at a dose of 12 mg/m2. In the expansion cohorts, the overall response rate (ORR), was 14/64 (21·9%). Thirty-eight response-evaluable patients in the expansion cohorts receiving 12 mg/m2/q2Wk had tumour evaluable for quantification of α-FR. Patients with high or medium expression had an objective response rate of 9/25 (36%) compared with 1/13 (7·7%) in patients with negative/very low or low expression of α‑FR. CONCLUSIONS: The dose of 12 mg/m2/q2Wk was declared the recommended phase II dose/schedule. At this dose/schedule, CT900 exhibited an acceptable side effect profile with clinical benefit in patients with high/medium α‑FR expression and warrants further investigation.
| Type: | Article |
|---|---|
| Title: | A phase I trial of CT900, a novel α-folate receptor-mediated thymidylate synthase inhibitor, with expansion cohorts in patients with high grade serous ovarian cancer |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1158/1078-0432.CCR-22-1268 |
| Publisher version: | https://doi.org/10.1158/1078-0432.CCR-22-1268 |
| Language: | English |
| Additional information: | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0). |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Respiratory Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10154165 |
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