Clinical Trials

Date: 2013-09-13

Type of information: Results

phase: 2

Announcement: results

Company: 4SC (Germany)

Product: resminostat (oral pan-histone deacetylase (HDAC) inhibitor)

Action mechanism: histone deacetylase inhibitor (HDAC inhibitor). Resminostat is an oral pan-histone-deacetylase (HDAC) inhibitor with an innovative, epigenetic mechanism of action that enables this compound to be deployed as a novel, targeted tumour therapy for a broad spectrum of oncological indications, particularly in combination with other anti-cancer drugs. Like other epigenetic therapies, resminostat has been shown to modify transcription of genes in cancer cells and, thereby, to reprogram the phenotypes of such cancer cells. Resminostat is therefore assumed to be able to halt tumour progression and induce tumour regression. Furthermore, due to its epigenetic mode of action resminostat is supposed to develop additional synergetic effects when combined with classical cancer therapies and thus also fight the development of tumour cell resistance.

Disease: advanced liver cancer - hepatocellular carcinoma

Therapeutic area: Cancer Oncology

Country:

Trial details: The two-arm, proof-of-concept, international Phase II SHELTER study evaluates resminostat as a second-line treatment alone or in combination with sorafenib (Nexavar^®), the current standard of care in advanced HCC, to see if it can prolong progression free survival (PFS) in patients who prior to study entry developed progressive disease under first-line treatment with sorafenib. In the first study arm, according to the study protocol, at least 12 evaluable patients are being treated with the recommended dose of the combination therapy (600 mg resminostat (OD) and 400 mg sorafenib (BID)) which was determined through an initial dose-escalation part of the study. In the second study arm, at least 12 evaluable patients discontinue sorafenib treatment prior to inclusion and then receive resminostat as monotherapy, administered orally, once daily, over five consecutive days, followed by a nine day treatment-free period (5+9 dosing schedule). In the combination arm, res minostat is administered in the same 5+9 dosing schedule, while sorafenib is administered daily throughout the cycle. In both study arms, this 14-day-cycle is repeated until there is evidence of progressive disease or until the patient leaves the study for other reasons. The first two radiological tumour stagings are performed after 6 and 12 weeks; after that, tumour stagings are performed every eight weeks. Patients who experience a clinical benefit, e.g. a stabilization of their progressive disease or tumour regression, may continue the study treatment. It is the study objective to halt the further progression of this particularly aggressive cancer disease in at least 20% of the patients treated and for at least 12 weeks in both therapy arms. The primary endpoint of the study is to determine the progression free survival rate (PFSR) after 12 weeks of treatment. Secondary endpoints include the analysis of time-to-progression (TTP), progression free survival time (PFS), over all survival (OS), drug safety and tolerability, pharmacokinetics and the investigation of biomarkers.

Latest news:

• • On September 13, 2013, 4SC has announced the presentation of results from an in depth analysis of biomarker data and patient characteristics and their respective relevance for survival outcomes in the Phase II clinical SHELTER trial in advanced liver cancer (HCC). The presentation is given at the upcoming 7th Annual Conference of the International Liver Cancer Association (ILCA) in Washington, D.C., USA (13-15 September 2013, by the coordinating investigator of the SHELTER trial, Prof. Michael Bitzer, University of Tübingen, Germany. As previously reported, in the study the resminostat/sorafenib combination therapy of 2nd line HCC patients who had shown prior progression on sorafenib monotherapy resulted in an overall survival (OS) of 8.1 months, while resminostat monotherapy of these difficult-to-treat patients resulted in an OS of 4.2 months. High expression of biomarker ZFP64 correlates with statistical significance (p=0.04) with doubling of overall survival in advanced HCC patients treated with resminostat.
• The key finding of the biomarker analysis in the SHELTER trial is the identification of the novel, potentially predictive biomarker ZFP64, which is strongly correlated with overall survival of advanced liver cancer (HCC) patients treated with resminostat. In this trial, patients with high expression of ZFP64 in blood samples at baseline (i.e. before treatment start) showed a doubling of the median overall survival (OS) compared to patients with low ZFP64 expression. The analysis has shown that roughly 2/3 of all HCC patients in the study were ZFP64 high-expressers, while 1/3 of patients showed low ZFP64 expression correlating with a markedly lower overall survival. This correlation between expression levels of ZFP64 in HCC patients at baseline and clinical outcome in the SHELTER trial was statistically significant (p=0.04). This observation was made in advanced HCC patients of the SHELTER study treated with either resminostat monotherapy or in combination of resminostat with sorafenib. Moreover, these findings have been similarly identified in a second Phase II clinical study (SAPHIRE trial) applying resminostat as single agent in patients with advanced Hodgkin lymphoma (HL), thus further confirming the correlation between ZPP64 expression and clinical outcome in a cancer indication different and unrelated to HCC. A patent application has been filed in order to provide adequate IP protection for these findings.
• As an epigenetic HDAC modifier of gene transcriptional activity, reminostat strongly suppresses ZFP64, a co-activator of the NOTCH pathway, which plays a key role in tumour growth and progression. ZFP64 (zinc finger protein 64) has been published to act as a transcriptional co-activator of NOTCH modulated gene regulations. It thus plays an important role in the NOTCH signalling cascade, which represents one of the key signalling pathways involved in the regulation of various cancers. Moreover, it was shown in 4SC's clinical trials that upon resminostat treatment gene expression levels of ZFP64 were strongly down-regulated in blood cells of both HCC and HL patients. Preclinically, a comparable down-regulation of ZFP64 expression levels has also been observed in a broad variety of tumour cell lines derived from different haematological and solid cancer indications, indicating that resminostat impacts negatively on ZFP64 gene expression levels not only in blood cells of patients but most likely also in their tumor tissues.
• According to the findings in the HCC and HL trials, the down-regulation of ZFP64 by resminostat treatment is assumed to result in an inhibition of the NOTCH pathway and therefore leads to a prolongation of patient survival. Therefore, the scientific rationale for the correlation between high ZFP64 expression and patient survival expectation is that the tumours with high ZFP64 levels are expectedly more dependent on ZFP64-controlled NOTCH pathways for their growth than tumours with low ZFP64 levels. Tumours with high ZFP64 levels are thus expected to respond particularly well to resminostat treatment resulting in improved clinical benefit for the patient.
• 4SC is currently designing a pivotal clinical development programme for resminostat applied in combination with sorafenib as new treatment option for advanced HCC patients. Notably, sorafenib on its own has no effect on ZFP64 expression levels according to 4SC's recent findings. 4SC plans to integrate the new findings about ZFP64 as a potentially predictive biomarker in the study design of a pivotal Phase II/III trial and to further discuss this with potential partners and regulatory authorities. It is 4SC's goal to develop resminostat, in conjunction with the use of biomarker ZFP64, as a personalized cancer medicine towards market approval.
• Other findings from 4SC reported at the ILCA conference will comprise data from the in depth analysis of further patient baseline characteristics and their influence on overall survival in the advanced HCC patient population of the SHELTER study, treated with either resminostat monotherapy or in combination with sorafenib. In the monotherapy arm, ECOG 0 status and pre-treatment with TACE (transcatheter arterial chemo-embolization) correlated with a longer survival outcome. In the combination therapy study population, in addition to ECOG 0, also a Child-Pugh A status and the absence of vascular invasion of the tumour were identified to correlate with a prolonged overall survival. However, in both treatment arms the time interval between the end of first-line sorafenib therapy and the start of treatment in the SHELTER study (so called 'drug holidays') had no influence on the median overall survival of SHELTER patients.
• 4SC plans to integrate these new findings about patients' baseline characteristics and their influence on patients' clinical outcome in the study design of the planned pivotal development programme of resminostat in advanced HCC.
• • On September 13, 2012, 4 SC  announced the publication of  overall survival data from a Phase II study with resminostat applied as a novel combination therapy approach with sorafenib in second-line advanced liver cancer at the 2012 annual meeting of the International Liver Cancer Association in Berlin, Germany, on 16 September 2012. The international, open-label, two-arm SHELTER study enrolled patients with advanced liver cancer (hepatocellular carcinoma, HCC) who had shown proven radiological tumor progression under first-line therapy with the cancer drug sorafenib (Nexavar®). The study investigated safety and efficacy of resminostat as a monotherapy and in combination with sorafenib in this patient group with currently no approved treatment option. Final median overall survival (OS) of 8.0 months was determined in the resminostat/sorafenib combination ‘intend-to-treat’ (ITT) population (n=26), i.e. all study patients who were treated with the combination of 600 mg resminostat total daily dose (TDD) and 400 mg sorafenib TDD. In the resminostat monotherapy group (ITT population, n=19), the final median OS value has been determined as 4.1 months. In both study arms, resminostat has proven to be safe and well tolerated. Notably, the overall health condition of the patients enrolled in the SHELTER study was particularly severe (measured by the clinical parameters ECOG status, BCLC stage and Child-Pugh class) compared to other clinical studies with alternative investigational drugs in second-line HCC patient populations. To the Company’s best knowledge, the 8.0 months median OS in the resminostat/sorafenib combination group is the highest median OS value achieved to date in clinical studies investigating the efficacy of new treatment options for second-line advanced HCC in comparable patient populations who have shown proven radiological tumour progression on first-line sorafenib therapy. Moreover based on survival data reported from the SHARP trial (which led to the approval of sorafenib), the survival expectation of advanced HCC patients after developing progressive tumour disease on this treatment is only 5.2 months. Resminostat progression-free survival (PFS) efficacy data of the SHELTER studyhave been presented earlier this year at the Annual Meeting of the American Society of Clinical Oncology (ASCO) on 4 June 2012 in Chicago (USA). The data for the resminostat/sorafenib combination therapy showed a progression-free survival rate (PFSR) after 12 weeks of treatment of 70.0% and a median PFS of 4.7 months – one of the highest PFS figures recorded to date by any second-line therapy in advanced clinical HCC studies. For the  resminostat monotherapy group, the final PFSR at 12 weeks is 35.3% and the median PFS is 2.2 months. 4SC is currently in discussions with regulatory agencies and potential partners in order to prepare a pivotal clinical study programme for resminostat in combination with sorafenib as a second-line treatment for patients with advanced HCC who show tumour progression on firstline treatment with sorafenib.
• • On May 31, 2012, 4SC has announced the presentation of results from its clinical Phase II SHELTER study with resminostat as a second-line therapy for patients with advanced liver cancer at  ASCO Conference in Chicago, USA, on 4 June 2012. (Abstract Title: Efficacy, safety, tolerability and PK of the HDAC inhibitor resminostat in sorafenib-refractory hepatocellular carcinoma (HCC): Phase II SHELTER study). The open-label, two-arm, international SHELTER study enrolled only patients who had exhibited radiologically proven tumour progression under first-line therapy with sorafenib. The study investigated the safety and efficacy of resminostat both as a monotherapy and in combination with sorafenib for this difficult to treat patient group, for which no approved treatment option is currently available.
• The determination of the primary trial endpoint of 'progression-free survival after 12 weeks' has been completed for the combination group. The study showed that resminostat in combination with sorafenib was able to prevent progression of the disease for at least 12 weeks in 14 of the 20 evaluable patients and even considerably longer - well over a year - in individual cases. After 12 weeks, the final progression-free survival rate (PFSR) was 70%, which is a further slight improvement on the preliminary trial data published at the ASCO Gastrointestinal Cancer Symposium in San Francisco on 19 January 2012 (See below). On that date, 4SC had announced that the primary trial endpoint had been achieved ahead of schedule with a PFSR of 66.7% based on 15 evaluable patients.
• Based on the final analysis of the data, median progression-free survival (PFS) is 4.7 months for the combination treatment group. Median PFS describes the (median) length of time for which the progression of the patient's disease can be halted. Thus resminostat as a combination therapy together with Sorafenib has achieved - to 4SC's best knowledge - the highest PFS figure recorded to date by any second-line therapy of advanced HCC in clinical Phase II/III studies. Four patients are currently continuing the combination therapy beyond the first 12 weeks of treatment. The patients are being monitored continuously for the purpose of determining the secondary trial endpoint of 'overall survival' (OS). The median OS figure has not yet been reached in both study arms.
• Based on the current analysis of the data, the progression-free survival rate (PFSR) for the monotherapy group is 35.7%. This means that in this group, five out of the 14 patients who were evaluable to date demonstrated disease stabilisation for at least 12 weeks. Progression-free survival (PFS) of this patient group is currently 2.2 months. Final results for the two endpoints, PFSR and PFS, could not yet be determined because in this patient group three patients are still undergoing treatment for whom no evaluation after 12 weeks is yet available and one patient is continuing treatment beyond the first 12 weeks of treatment.
• Resminostat has generally proven to be very safe and well tolerated during the study. The most frequent side-effects observed were of a gastrointestinal nature (diarrhoea, nausea). In the combination arm, in the majority of cases the side effects were attributed to the treatment with sorafenib. The majority of serious adverse events (SAEs) were attributed to the patient's underlying disease; a consistent profile of SAEs which were causally related to the study medication was not observed. The Phase II SHELTER trial is the first clinical study where this mechanism has been investigated for resminostat in combination with sorafenib, a tyrosine-kinase inhibitor (TKI), in the difficult to treat indication of advanced liver cancer (HCC). presentation of  Phase II at  ASCO Conference in Chicago, USA, on 4 June 2012 Abstract Title: Efficacy, safety, tolerability and PK of the HDAC inhibitor resminostat in sorafenib-refractory hepatocellular carcinoma (HCC): Phase II SHELTER study.
• • On January 19, 2012, 4SC AG has published encouraging efficacy data from the clinical Phase II SHELTER study with the cancer drug resminostat as a second-line therapy for patients with advanced liver cancer (hepatocellular carcinoma, HCC) who had exhibited radiologically proven tumour progression under first-line therapy with sorafenib (Nexavar®) prior to study entry.
• This open-label, two-arm, international study investigated the safety and efficacy of resminostat both as a monotherapy and in combination with sorafenib for this difficult to treat patient group, for which no approved treatment option is currently available. According to the data now presented, which is based on an advanced data set, the primary study endpoint of halting the further progression of this particularly agg ressive cancer in at least 20% of the patients treated and for at least 12 weeks has been achieved ahead of schedule in both therapy arms.
• Resminostat in combination with sorafenib was able to prevent further progression of the disease for at least 12 weeks in two-thirds of the currently 15 evaluable patients and considerably longer - well over a year - in individual cases. Accordingly, the progression-free survival rate (PFSR) after 12 weeks is currently 66.6% for the combination therapy group and 33.3% for the monotherapy group of currently 9 evaluable patients. Furthermore, median progression-free survival (PFS), which is defined as the period of time for which the progression of the disease can be halted, is presently 4.6 months (140 days) for the combination therapy group and 1.4 months (42 days) for the monotherapy group. In general, resminostat has proven to be safe and well-tolerated.
• The most frequent side-effects observed were of a gastrointestinal nature (diarrhoea, nausea). In the combination arm, in the majority of cases the side effects were attributed to the treatment with sorafenib. The majority of serious adverse events (SAEs) were attributed to the patient's underlying disease; a consistent profile of SAEs which were causally related to the study medication was not observed. The data presented now were analysed before database closure and are based on the analysis of the primary study endpoint 'progression-free survival at 12 weeks' conducted by the local trial centres. Currently, five patients who have not been evaluated after 12 weeks yet are undergoing study treatment, while another five patients continue treatment optionally after experiencing a clinical benefit through the halt of disease progression for at least 12 weeks of study participation. Patients withdrawing from the trial for other reasons than disease progression are qualified as 'drop outs' and therefore replaced. The final results of the SHELTER study, as determined following database closure and encompassing all patients enrolled as well as a final, centralised radiological report are expected to be presented at an international scientific conference in the course of 2012. Details of the efficacy data now presented based on the identification of the primary stud y endpoint 'progression-free survival at 12 weeks':

Treatment regime	Combination therapy Resminostat (600 mg) Sorafenib (400 mg)	Monotherapy Resminostat (600 mg)
Patients enrolled ('intention-to-treat', ITT)	26	12
of which drop-outs*	7	2
Currently evaluable patients after 12 weeks (EP)*	15	9
of which exhibiting stable disease (SD) i.e. showing 'progression-free survival' (PFS)	10	3
Of which exhibiting progressive disease (PD)	5	6
Progression-free survival rate after 12 weeks PFSR (=PFS/EP)	10/15 = 66.6%	3/9 = 33.3%

• *Patients who withdrew from the study before their tumour status was determined radiologically after 12 weeks - and for whom an evaluation of tumour progression or stabilisation was therefore not possible - have not been included in the evaluable patient population (EP). Of the nine patients listed as drop-outs most left the study for personal reasons (i.e. withdrawal of consent), all of them without an observed tumour progression. Early withdrawal because of side effects was a rare occurrence and only partly attributable to the study medication.

Is general: Yes