A new targeted treatment for ovarian cancer has shown ‘very promising’ results in women in the advanced stages of the disease, shrinking tumours in around half of women who took part in a small UK trial.
Researchers had only been testing the drug to see if it was safe for humans to take, but found it had an almost instant clinical effect. But, the report says, it is hoped the drug could help women who have stopped responding to all other currently available treatments. So far, it has only been tested in 15 women, and the researchers say it may not be safe to take for more than a few months.
The researchers, from the Institute of Cancer Research and the Royal Marsden NHS Foundation Trust in London, wanted to establish whether the drug, known in the study as ONX-0801, was safe, so they tested it on a small number of patients.
But they found it significantly shrunk tumours in seven of the 15 patients who took the drug – all seven carrying a particular molecule that the drug was specifically designed to target.
ONX-0801 is the first in a new class of drugs which work by mimicking the ability of folic acid selectively to latch on to cancer cells, while leaving healthy tissue alone, thus reducing the side-effects often seen with traditional chemotherapy, such as infections, diarrhoea, nerve damage and hair loss.
Once locked on to a cancer cell, the drug disrupts its chemistry by blocking the action of a key molecule, causing widespread DNA damage and cell death.
The researchers, who hope to carry out bigger clinical trials as soon as possible, have also developed a test that can detect which women are most likely to benefit from the treatment.
Study leader Dr Udai Banerji said: “The results we have seen in this trial are very promising. It is rare to see such clear evidence of reproducible responses in these early stages of drug development.
“The beauty of this particular drug is that it is targeted to the cancer cell. This means there are fewer side-effects, making it a kinder treatment for ovarian cancer patients.
“It’s early days of course, but I’m keen to see this treatment assessed in later-stage clinical trials as soon as possible.”
Dr Catherine Pickworth, from Cancer Research UK, said: “It’s encouraging to see this new drug is showing promise as a potential new treatment for ovarian cancer.
“The next steps will be for researchers to test the drug in larger clinical trials to confirm it works and is safe, and to work out which women with ovarian cancer this drug could help.”
Professor Michel Coleman, of the London School of Hygiene & Tropical Medicine, urged caution. He said: “Shrinkage of tumours is important, but as the authors point out, that is not the same as producing the hoped-for extension of survival for women with ovarian cancer.
“The excitement of the investigators is completely understandable, but one should be cautious about interpreting this result as a breakthrough for ovarian cancer patients until data on longer-term outcomes are available.”
The report says the results of the trial were presented at the American Society of Clinical Oncology annual meeting in Chicago.
Background: ONX-0801 is a first-in-class alpha folate receptor (AFR) targeted thymidylate synthase inhibitor, engineered to differentially accumulate 6000-fold in AFR overexpressing cancer cells.
Methods: A 3+3 dose escalation design was used and two IV schedules were explored. Schedule A, weekly dosing (QW) and schedule B, once every 2 weeks dosing (Q2W). A cycle consisted of 4 weeks and treatment was stopped after 6 cycles in both schedules. An expansion cohort to evaluate clinical activity in patients with AFR overexpressing high grade serous ovarian cancer (HGSOC) was planned.
Results: 21 patients each were treated in schedule A and B exploring doses ranging from 1-6 mg/m2 and 2-12 mg/m2, respectively. The dose limiting toxicity on schedule A was G3 cellulitis; no dose limiting toxicity was seen on schedule B. The most common toxicities were fatigue 15/42 (36%), nausea 9/42 (21%) and dysgeusia 5/42 (12%). Within schedule A at 4 mg/m2, 2 patients developed suspected drug-related changes on pulmonary function tests (drop in Dlco > 15%) at cycles 5 and 6, respectively. No cases of suspected drug-related drop in Dlco were noted in patients treated in schedule B. No grade 3-4 diarrhea, mucositis or neutropenia were seen in either cohort. The Cmax, AUC and half-life at 12 mg/m2 were 4952 ng/mL, 85170 h*ng/mL and 26 h, respectively. Pre-clinical PK-PD modelling aimed to achieve concentrations between 0.05-1 µM and this was achieved for periods of 48 h at doses of 4 mg/m2and above. Based on safety and PK, the recommended phase II dose (RP2D) of ONX-0801 was 12 mg/m2 Q2W and an expansion in patients with HGSOC is ongoing. 5 patients with HGSOC had partial responses (PRs) in the dose escalation cohort. In the current expansion cohort in patients with HGSOC, 5/11 patients had PRs. Archival samples have been analyzed from 8/11 patients in the expansion cohort. 4/4 AFR+ve and 4/4 AFR-ve patients did and did not have a PR following treatment with ONX-0801, respectively.
Conclusions: The RP2D of ONX-0801 is 12 mg/m2 Q2W. At the RP2D, multiple patients with AFR overexpressing HGSOC have had PRs and further randomized biomarker prespecified phase II trials are warranted. Clinical trial information: NCT02360345
Udai Banerji, Alvaro Henrique Ingles Garces, Vasiliki Michalarea, Ruth Ruddle, Florence I Raynaud, Ruth Riisnaes, Daniel Nava Rodrigues, Nina Tunariu, Joanna C Porter, Sarah Emily Ward, Mona Parmar, Alison Joanne Turner, Satyanarayana Seeramreddi, Emma Hall, Emma Jane Dean, Bristi Basu, Angela George, Stan B Kaye, Susana N Banerjee, Johann S De Bono