4SC Announces Positive Interim Results from Clinical Phase I/II SHORE Study

4SC AG has published positive interim results on safety, tolerability and pharmacokinetics from its clinical Phase I/II SHORE study with the anti-cancer compound resminostat in combination treatment with FOLFIRI chemotherapy in patients with advanced colorectal cancer (CRC).

The results successfully prove the safety and tolerability of the combined administration of resminostat and FOLFIRI.

This marks the achievement of the goal for the first part of the study (Phase I) and lays the foundations for commencing the study's Phase II part, which will assess the clinical efficacy of the resminostat-FOLFIRI-combination in advanced CRC patients.

Furthermore, the Phase I part of the study has already provided some initial encouraging data concerning the possible clinical benefit of this new therapeutic approach in this difficult-to-treat patient population.

These data showed that for some patients it was possible to administer the combination therapy over a comparatively long period of time - to a maximum of 33 weeks - while observing a stabilization of the tumour disease.

In the randomized, multi-centre, two-arm Phase II part of the SHORE study, planned to start soon in 2013, the combination therapy of resminostat with the FOLFIRI treatment regime will be assessed against sole treatment with FOLFIRI as a second-line treatment option for patients with advanced, KRAS-mutant colorectal cancer (CRC).

For this patient group, which constitutes around 40% of all patients with advanced CRC, there is a high medical need for new, additional therapy options.

In general, first-line therapy for advanced CRC patients consists of chemotherapy (FOLFOX or FOLFIRI) in combination with the drug Avastin®.

If, after a while, this therapy is no longer effective or tolerated - due to the development of resistance or the occurrence of side effects, for example - patients are switched over to second-line therapy.

In second-line, patients without a KRAS mutation have access to treatments aiming at the inhibition of epidermal growth factor receptor (EGFR) such as Erbitux® as a supplement to a further chemotherapy (FOLFIRI or FOLFOX).

However, CRC patients with a KRAS mutation in the EGFR pathway of their tumours, generally do not benefit from anti-EGFR therapy and, therefore, receive a chemotherapy such as FOLFIRI alone as second-line therapy.

Thus, for this KRAS-mutant CRC patient group there is a high medical need for new, supplementary therapy options which may be safely combined as second-line treatment with chemotherapy such as FOLFIRI to increase the latter's effectiveness - such as potentially resminostat.

Results from the Phase I part of the SHORE study
In the Phase I part of the SHORE study, a dose escalation for a total of 15 CRC patients to date was carried out to assess the safety and tolerability of a range of doses for resminostat up to 600 mg daily in combination with FOLFIRI, a multi-component chemotherapy regime that includes e.g. 5-fluorouracil (5-FU) and irinotecan, so as to determine the best possible dose for resminostat in combination with FOLFIRI. Pharmacokinetic parameters for resminostat and for the FOLFIRI components were also evaluated.

Resminostat proved to be generally safe and well-tolerated in all doses tested up to a daily single dosage of 600 mg in combination with the recommended standard dose from the FOLFIRI regime.

Accordingly, as regards combination therapy with FOLFIRI, the data confirmed the daily dosage of 600 mg already determined in earlier monotherapy and combination therapy studies with resminostat.

Observed side effects were generally mild to moderate and occurred, as expected, primarily as gastrointestinal and haematological effects.

FOLFIRI's known side-effect profile did not change as a result of the additional administration of resminostat. Furthermore, the study confirmed the compound's favourable pharmacokinetic profile which is, inter alia, reflected in the dose proportionality of resminostat blood levels - as already observed in other studies with resminostat.

No pharmacological interactions were observed between resminostat and the FOLFIRI components. The dosage of 600 mg for resminostat in combination with FOLFIRI is already being considered as a potential therapeutic dose for the Phase II part of the SHORE study.

In some patients in the Phase I part, it was possible to administer the combination therapy for several months (to a maximum of 33 weeks) while observing stabilization of the tumour disease. This substantiates the overall good tolerability and may also be considered as an initial indicator for the clinical benefit of this new therapeutic approach.

To allow for further expansion of the range of treatment options within this combination approach, a final, further dosage variant constituting the twice-daily administration of resminostat is currently under evaluation. This involves the clinical examination of a total daily dose of 800 mg of resminostat, taken as two doses of 400 mg in the morning and evening.

The medical-scientific rationale of the combination therapy of the epigenetically-active HDAC inhibitor resminostat - which can exert a substantial influence on key gene expressions - with traditional chemotherapy such as FOLFIRI, has been established on the basis of preclinical trials.

In these studies, resminostat combined with irinotecan, a component of the FOLFIRI regime, inhibited tumour growth more effectively than either substance when used as a monotherapy. It was also shown that resminostat - due to its gene regulatory properties - decreases the expression of the enzyme thymidylate synthase.

This enzyme triggers resistance mechanisms that target the compound 5-FU, which is an integral part of FOLFIRI. Accordingly, resminostat may work to sensitise tumour cells for treatment regimes containing 5-FU, such as FOLFIRI, as resminostat can be used to combat resistances that tumours have developed against 5-FU.

Dr Ulrich Dauer, Chief Executive Officer of 4SC, commented: 'We are pleased that the good safety and tolerability profile shown by resminostat in multiple Phase I and II studies has up to now also been confirmed in combination therapy with the FOLFIRI chemotherapy, and that we have already been able to treat some patients with advanced CRC over a period of several months with this new approach. We are particularly encouraged by the disease stabilization observed in individual patients. From our perspective, this constitutes a promising new therapeutic option for potential use in combination with FOLFIRI whose clinical efficacy we will now continue to evaluate next year in the randomized Phase II part of the SHORE study. K-RAS mutant patients, who account for 40% of all CRC patients, might particularly benefit from this additional therapeutic option since they have no access to EGFR-based therapies such as Erbitux® as a supplementary treatment to chemotherapeutics such as FOLFIRI in second-line CRC therapy.'