Date: 2015-01-19
Type of information: Initiation of the trial
phase: 2
Announcement: initiation of the trial
Company: Hybrigenics (France)
Product: inecalcitol
Action
mechanism: vitamin D analog. Inecalcitol has already been granted Orphan Drug status for acute myeloid leukemia both in Europe and the Unites States on the basis of encouraging in vitro and in vivo preclinical results. The molecular basis of the synergy between decitabine, a hypomethylating agent, and inecalcitol has been established: decitabine “unmasks” the gene coding for vitamin D receptors (by reducing the methylation of its promoter region). As a consequence, more vitamin D receptors are expressed and available to be activated by inecalcitol.
Disease: chronic myeloid leukemia (CML)
Therapeutic area: Cancer - Oncology
Country: France
Trial details:
Latest
news: * On February 9, 2017, Hybrigenics has given an update on the Phase II clinical study of inecalcitol in chronic myeloid leukemia administered in addition to imatinib, the reference inhibitor of BCR-ABL kinase used as standard of care for CML. In CML, the quantitative parameter predicting efficacy of BCR-ABL kinase inhibitors is the reduction in expression of the BCR-ABL fusion gene causative in CML cases: a 3 log decrease (1,000-fold) in BCR-ABL is called a major molecular response (MMR) and a 4.5 log decrease (31,623-fold) a deep molecular response (DMR). Between the MMR and DMR levels, the disease is considered to be under control with continuous daily administration. With levels sustained in DMR, the minimal residual CML disease is sufficiently low that treatment cessation can be considered and functional cure achieved in some patients. * On January 19, 2015, Hybrigenics, a bio-pharmaceutical company with a focus on research and development of new treatments against proliferative diseases, announced the launch of clinical Phase II study of inecalcitol in chronic myeloid leukemia (CML). The rationale for this clinical Phase II study in CML results from the antiproliferative effects of inecalcitol and its synergy with imatinib demonstrated by Prof. A. Thuran’s INSERM U935 research group on in vitro cultures of CML stem cells directly taken from CML patients. The results recently obtained in the clinical Phase II study of inecalcitol in chronic lymphocytic leukemia (CLL) at the dose of 2 milligram per day, i.e. 52% of patients experiencing stabilization or decrease of blood leukemic lymphocytes counts, have also supported the idea to test inecalcitol in CML.
The ongoing, open-label Phase II study evaluates the efficacy of oral inecalcitol added to oral imatinib in CML patients who, after at least two years of treatment with imatinib alone, have achieved MMR but not DMR, with the objective to reach DMR within one year of treatment. Twenty-one patients have been enrolled to date: twelve remain under treatment and nine have completed one year of treatment. At this intermediate stage of study, 43% of the patients (6 out of 14) have shown further decrease in BCR-ABL from MMR at three months, and after one
year of treatment, 33% (3 out of 9) have demonstrated reduction in BCR-ABL beyond DMR, i.e. undetectable biomarker traces. These results can be compared with two recently published independent reports which
demonstrate a simple 7.5% yearly increase in the percentage of patients reaching DMR under imatinib alone (Hochhaus et al., Leukemia, March 2016; Cortes et al., Journal of Clinical Oncology, July 2016).
Based on these intermediate results and a very low study drop-out rate, the sample size of this pilot study has been reduced to 42 patients, with a target completion in H2 2018. Hybrigenics’ Clinical Advisory Board has reviewed these preliminary observations and made suggestions to widen the scope of the potential clinical use of inecalcitol in CML.
In the clinical Phase II study in CML, oral inecalcitol will be given at the dose of 4 milligram per day to patients already under treatment by oral imatinib (Gleevec®) for more than two years, but who still present a residual disease as measured in the blood by the specific CML biomarker called BCR-ABL. The objective of the treatment with inecalcitol is to improve the patients’ condition by further reducing the BCR-ABL biomarker to 10 times lower or even undetectable levels, which could be the sign of a possible cure. The CML patients will be treated for one year.
The clinical Phase II study in CML will be implemented in at least 5 centres in France, including Paris-Sud 11 Kremlin-Bicetre University Hospital (Division of Hematology, Prof. A. Thuran), and coordinated by Prof. H.-A. Johnson-Ansah from Caen University Hospital. The goal of the study is to enrol 54 patients within one year.
* On July 16, 2014, Hybrigenics, a bio-pharmaceutical company listed on the Alternext market of Euronext in Paris, with a focus on research and development of new treatments against proliferative diseases, announced the authorization by the French drug agency to start a clinical Phase II study in chronic myeloid leukemia (CML). The French drug agency has granted authorization to a Clinical Trial Application submitted by Hybrigenics to study oral inecalcitol in CML patients treated by oral imatinib (Gleevec®) with a stable but sub-maximal level of efficacy, as measured in blood by the Bcr-Abl biomarker. The objective is to add inecalcitol to imatinib to investigate if the Bcr-Abl biomarker can be furthered reduced down to levels where cure of the disease could be achieved. Inecalcitol and imatinib have already demonstrated a synergistic inhibitory effect on CML stem cells isolated from patient blood and grown in vitro. The aim of the study is to translate this initial laboratory finding into clinical research in CML patients. Hybrigenics’ objective is to enrol and treat the first CML patient before the end of 2014.
