Date: 2014-05-28
Type of
information: Presentation of results at a congress
phase: 1
Announcement: presentation of results at the 50th annual meeting of the American Society of Clinical Oncology
Company: 4SC (Germany)
Product: 4SC-202
Action
mechanism: histone deacetylase inhibitor (HDAC inhibitor). ASC-202 is a benzamide type selective inhibitor of human class I HDAC isoenzymes 1, 2 and 3. HDAC inhibitors modify the DNA structure of tumour cells to cause their differentiation and programmed cell death (apoptosis) and are therefore considered to offer a mechanism of action that has the particular potential to halt tumour progression and induce tumour regression.
Disease: advanced hematological indications
Therapeutic
area: Cancer - Oncology
Country: Germany
Trial
details:
- • On April 13, 2011, 4SC has announced that the first patient has been treated in the Phase I TOPAS study with 4SC-202, a selective histone deacetylase (HDAC) inhibitor which is also characterized by an anti-mitotic mechanism of action. The study will evaluate the safety, pharmacokinetics and clinical efficacy of orally administered 4SC-202 in patients with advanced hematological indications, including acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myelodysplastic syndrome (MDS) and lymphomas. This mono-centric, single arm, open-label dose escalation Phase I study has been designed to evaluate daily doses between 25 and 400mg of 4SC-202 in six dose cohorts. Patients will be given 4SC-202 tablets once daily for 14 consecutive days (d1-14) in a 21-day treatment cycle (14+7 scheme). The main study phase will consist of two treatment cycles and patients benefiting from treatment at the end of the main study phase may remain on therapy in a subsequent follow-up phase. Stepwise escalation of the initial starting dose (25mg) will occur according to a standard 3+3 design. Each dose cohort will include up to 6 patients and the study is currently planned to enroll up to 36 patients in total. Depending on the observed pharmacokinetic profile and the tolerability of once daily doses of 4SC-202, alternative dosing schedules such as twice daily administration will also be evaluated.
The primary objective of the study is to investigate the safety, tolerability and pharmacokinetics of 4SC-202 and the associated determination of optimal doses and dosing regimens for patients with advanced hematological malignancies. Secondary objectives include the assessment of the clinical anti-tumour activity with respect to tumour response, duration of response (DOR) and progression-free survival (PFS) of the patients. Additional exploratory objectives include the evaluation of relevant biomarkers such as histone deacetylase (HDAC) enzymatic inhibition and induction of increased histone acetylation by 4SC-202 in peripheral mononuclear cells (PBMC) of patients as well as the analysis of altered gene expression profiles in patient blood. The study will be performed in one centre in Germany and is expected to report results in 2012. (NCT01344707)
Latest
news:
- • On May 28, 2014, 4SC, a discovery and development company of targeted small molecule drugs for cancer and autoimmune diseases, announced positive top line data from its clinical Phase I TOPAS study with the epigenetic cancer drug 4SC-202 in patients with advanced haematological tumours. 4SC-202, an oral small molecule inhibitor targeting WNT and Hedgehog (HH) signaling by specific inhibition of the epigenetic modifiers LSD1 and HDAC1, 2 and 3, was well tolerated, showed favorable pharmacokinetic properties and demonstrated promising signs of anti-tumour efficacy. The main study phase has been completed for all patients, with one complete responder patient still remaining on follow-up study treatment. In detail, 4SC will present initial data from the study in a poster presentation at the upcoming annual ASCO (American Society of Clinical Oncology) meeting in Chicago. The drug showed promising signs of efficacy, both in terms of long-term disease stabilisation of heavily pre-treated cancer patients and in terms of tumour shrinkage and objective radiological response. There was one complete remission (CR) and one partial remission (PR). 50% of patients (12 out of 24) had disease stabilisation and time on study medication for more than 100 days, 13% were stabilised for over a year, and one patient could be stabilised for more than 2 years. The patient with the CR has been on the trial now for over 16 months, with both study treatment and CR still ongoing to date.
- 4SC-202 was generally safe and well tolerated in the doses tested. Due to the clean safety profile, no formal DLT (dose limiting toxicity) or MTD (maximum tolerated dose) could be determined. A recommended dose of 200 mg 4SC-202 once daily or twice daily in a 14+7 dosing scheme (14 days treatment, 7 days rest) was established. The compound showed a favourable pharmacokinetic profile achieving potentially efficacious and well tolerated levels of 4SC-202 in patients. As for pharmacodynamics, the study showed promising biomarker responses including HDAC inhibition and a regulation of genes associated to the WNT signalling pathway in patient blood samples.
- 4SC will fully evaluate the data after final completion of the trial. In parallel, 4SC will investigate in particular WNT and HH related tumour indications for a possible Phase II development, and will also engage in talks with pharmaceutical partners interested in further development of the compound.
- Details of the Presentation at ACSO: Abstract No.: 8559 - Poster Title: First-in-human study of 4SC-202, a novel oral HDAC inhibitor in advanced hematologic malignancies (TOPAS study).
Is
general: Yes
