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Clinical Trials

Date: 2016-09-09

Type of information: Presentation of results at a congress

phase: 3

Announcement: presentation of results at the 1st EBMT International Transplant Course

Company: MolMed (Italy)

Product: Zalmoxis® (investigational cell therapy product TK)

Action mechanism:

gene therapy/cell therapy. Zalmoxis® is atherapy based on genetically modified donor T lymphocytes to carry an inducible “suicide gene”. Administered to patients following HSCT from partially compatible donors (haploidentical HSCT), these cells foster an anti-leukaemia effect by eliminating post-transplant immunosuppression prophylaxis and inducing a rapid immune reconstitution. Furthermore, the suicide gene allows to readily control Graft versus Host Disease (GvHD), the most significant and serious adverse event in haploidentical transplantation, caused by the genetic disparity between patient and donor.

Disease: high-risk leukemia

Therapeutic area: Cancer - Oncology

Country: Italy, USA, France, Germany, Greece, Israel

Trial details:

TK008 is a pivotal randomised Phase III trial in adult patients affected by high-risk leukaemia undergoing transplant of haematopoietic stem cells collected from partially compatible (haplo-identical) family donors. The trial design has disease-free survival as the primary end-point - which includes both transplant-related mortality and disease relapse - evaluated on a patient population of 170 patients. The trial will compare the outcome of haplo-transplants with or without TK add-backs, with a 3:1 randomisation ratio in favour of the TK arm. Secondary end-points include overall survival, reduction of transplant-related mortality, safety and patients’ quality of life. With the aim to provide additional clinical benefit to patients and to significantly increase the potential participation of centres in the trial, the Company implemented in 2012 two important changes in the protocol design of Phase III trial TK008. The first consists in broadening the enrolment criteria to include patients in leukaemic relapse, in addition to those in disease remission; the second change provides for the introduction of a further treatment option in the control arm, based on the use of an unmanipulated transplant followed by cyclophosphamide administration during the post-transplantation period. (Trial identifier on ClinicalTrials.gov: NCT00914628).

Latest news:

 * On September 9, 2016, MolMed announced that detailed analysis of data provided to support
Conditional Marketing Authorisation (CMA) recently granted to Zalmoxis® have been presented at the 1st
EBMT International Transplant Course (Barcelona, Sept. 9 -11, 2016) during a symposium titled "A new era
of haplo-transplantation". On the 18th of August, the European Commission, following the CHMP recommendation issued on the 23rd of June, has granted a CMA for Zalmoxis® as adjunctive treatment in haploidentical haematopoietic stem-cell transplantation (HSCT) for adult patients with high-risk haematological malignancies.
The CMA decision is based on efficacy and safety data collected from patients enrolled in the Phase I/II trial
(TK007) and in the currently ongoing pivotal randomised Phase III trial (TK008). The Zalmoxis group comprised 30 patients from the TK007 trial and 15 patients from the experimental arm of the TK008 trial. The TK007 trial included patients with various types of high-risk haematologic malignancies, while the TK008 trial is enrolling patients with acute myeloid or lymphoblastic leukaemia in any complete remission or advanced-stage disease, or with secondary acute myeloid leukaemia. To support the European Authority assessment process, data of Zalmoxis-treated patients (n=37) have been compared with a 1-to-4 ratio to contemporaneous control patients (n=140) from the database of European Group for Blood and Marrow Transplantation (EBMT) Registry by a pair-matched analysis.
Outcomes of this pair-matched analysis, presented in Barcelona, showed a robust survival improvement
in Zalmoxis-treated patients, specifically driven by a reduction in mortality from both infection and GvHD (i.e.
in non-relapse mortality - NRM), which historically represent the main complications and causes of death after
haploidentical transplant. In fact, the 32% relative increase in overall survival in patients treated with Zalmoxis
compared with control patients (49% vs 37%) was mainly due to the halving in non-relapse mortality in
Zalmoxis-treated patients, as compared with controls (22% vs 43%). Among controls dying from non-relapse
causes, the majority (78%) indeed died for either infection (56%) or GvHD (22%), while the only adverse event
related to Zalmoxis treatment was GvHD, fully resolved by activating the suicide gene system with ganciclovir
treatment, without any GvHD-related death. In TK cells-treated patients, moreover, chronic GvHD was
extremely low in comparison with the control group (6% vs 25%). Therefore, the protective effects of TK cells
in controlling infection and GvHD mainly drove the decreased NRM in Zalmoxis group compared with control
patients.
This pair-matched analysis has clearly established the clinical benefit for Zalmoxis-treated patients compared
with contemporaneous EBMT controls, by means of clinically meaningful endpoints, such as overall survival,
non-relapse mortality and chronic GvHD. Furthermore, chronic GvHD reduction and acute and chronic GvHD
control by the suicide gene system has allowed Zalmoxis patients to benefit from long lasting and
immunosuppressive-free survival. So far, there were neither an approved therapy nor a widely accepted
standard of care able to overcome opportunistic infections and GvHD, the two problems that continue to
account for most of the non-relapse deaths, as well as to increase survival rates after haploidentical HSCT.
* On December 9, 2014, MolMed presented new data from three studies on the experimental TK cell therapy in patients with acute leukemia at high risk of relapse who underwent transplantation from a partially compatible donor (haploidentical) at the 56th annual meeting of the American Society of Hematology (ASH)). The results showed high survival rates, dose-related antileukemic activity and long-term efficiency in the control of GvHD (graft-versus-host disease). Results presented at the ASH meeting on a pooled analysis of the Phase II TK007 and Phase III TK008 trials confirmed the potent anti-leukemic effect of the TK cell therapy related to dose with strong statistical significance (p<0.001), as evidenced by the absence of leukemia relapse at 4 years after transplantation in those patients who received the highest dose of TK cells.
Claudio Bordignon, Chairman and CEO of MolMed, comments: "We are delighted by the new phase III data on the TK cell therapy confirming the high disease-free survival rates, the primary phase III trial endpoint and the scientific basis for the request of Conditional Marketing Authorization from the European regulatory authority. In addition, the long-term analyses have clearly demonstrated the ability of TK cells in inducing a dose-dependent anti-leukemic activity and in fully controlling a hard-to-treat complication such as GvHD." An application for conditional approval of the TK cell therapy has been filed in March 2014 in EU and the European Medicines Agency has validated the submission of the registration dossier. 
* On June 4, 2014, MolMed provided at the 50th ASCO annual meeting new data from the ongoing randomised pivotal Phase III study on its cell therapy product TK for high-risk acute leukaemia patients transplanted from partially matched (haplo-identical) donors. The intent-to-treat analysis of the first 24 patients treated with TK indicates a 74% 1-year disease free survival (DFS) as the primary study endpoint: this result largely exceeds the target of 52% DSF for the TK arm vs 30% for the control arm. Notably, 86% of patients treated with TK were alive at one year (the key secondary study endpoint) and the corresponding figures for patients who achieved immune reconstitution rose to 85% for disease free survival and 100% for overall survival.
The direct impact of TK cells on transplant outcome was confirmed by a very low incidence of relapse (16% - with no relapse in patients receiving higher TK cell doses) and non-relapse mortality (10% - with no deaths observed in patients achieving immune reconstitution).
* On December 9, 2013, MolMed has announced the presentation of the long term assessment of the immune-reconstitution and the related clinical benefit induced by its investigational cell therapy TK at the 55th Annual Meeting of the American Society of Hematology (ASH), taking place in New Orleans . Dr. Giacomo Oliveira from the San Raffaele Scientific Institute (Milan, Italy) gave an oral presentation entitled “Long-term immunological profile and T cell dynamics in patients treated with allogeneic transplantation and TK-cells for hematological malignancies”. Results show that in the majority of patients (90%) TK cells are still present, functional and susceptible to ganciclovir up to 14 years after the treatment, confirming the validity of the TK approach in inducing a long-term and complete immune reconstitution in patients suffering from high risk acute leukemia, without losing the ability to control GvHD. Moreover, immune-reconstitution observed in study subjects was characterized by full functionality of T cells and Natural Killer cells, key components of the anti-leukemic immune response. The overall analysis was performed on 14 patients who underwent the TK treatment between 1995 and 2010 (median follow-up 9 years, range 3-18), all currently in complete remission and disease-free. Notably, no adverse events correlated to the use of TK cells were ever reported during the follow-up period. Graft versus Host Disease (GvHD) was reported in 5 patients and was rapidly and completely controlled thanks to the TK technology without the need of post-transplant high-dose immunosuppression.
* On October 18, 2013, MolMed has announced the enrolment of the first patient in the United States, initiating the cross-Atlantic expansion of the pivotal Phase III trial (TK008) of its proprietary TK cell/gene therapy for high-risk leukaemia patients. The study, already ongoing in Europe, foresees patient enrolment in 16 clinical centres worldwide. Based on cumulative efficacy and safety data and on the Orphan Drug designation, MolMed expects to file a request for Conditional Marketing Approval of TK with the European Medicine Agency in 2013, and subsequent extension in the US.
* On June 4, 2013, MolMed  has provided at the 49th ASCO annual meeting an update with positive long-term safety and efficacy data with its cell therapy product TK for the treatment of hematologic malignancies with bone marrow transplantation from partially matched (haploidentical) donors. The analysis of a seven year follow-up of a large patient population indicates that overall and disease-free survivals from haploidentical family donors are fully comparable to those obtained from fully matched donors. These results are of particular relevance in light of the increased availability of this transplant, as the vast majority of the intent-to-treat population was actually transplanted. The contribution of TK to these patients will continue through a randomized multicentre Phase III trial currently on-going in Europe and the United States. The presentation reported the long-term safety and efficacy of TK assessed in 128 patients entering worldwide 10 phase 1-2 trials that used TK to improve Graft versus Leukemia (GvL), immune reconstitution (IR) and Graft-versus-Host Disease (GvHD) control. TK clinical benefit is indicated by tumour response and immune reconstitution. In addition, the presentation also showed the intent-to-treat analysis of 249 patients with high-risk hematologic malignancies treated with allogeneic transplant from matched related, unrelated and haploidentical donors. The aim of this study was to assess the long term safety and survival of transplants from haploidentical donors. In this patient population, which includes four parallel treatment protocols, the approach involving the use of TK cells translated into a survival comparable to standard matched transplants. TK cells, produced by MolMed, contributed to the study through a Phase II trial (TK007) in patients with hematologic malignancies and currently through a pivotal Phase III trial (TK008) reserved to patients with high-risk acute leukemia. Based on cumulative efficacy and safety data and on the Orphan Drug designation, the Company expects to file a request for Conditional Marketing Authorisation of TK with the European Medicine Authority in 2013.
* On February 16, 2013, MolMed has announced the results of the contribution given by its investigational cell-based therapy TK to the treatment of haematologic malignancies through bone marrow transplantation from partially matched donors, presented at the Blood & Marrow Transplantation (BMT) Tandem Meetings, the combined annual meeting of the Center for International Blood & Marrow Transplant Research (CIBMTR) and the American Society of Blood & Marrow Transplantation (ASBMT), taking place in Salt Lake City. The study concerns the overall intention to treat (ITT) analysis of 611 patients with high-risk haematologic malignancies (61% acute leukaemia) treated with bone marrow transplant from a healthy donor in a single centre, the San Raffaele Scientific Institute of Milan, in the past 8 years. The aim of the study was to assess the impact of transplants from partially compatible family donors (haplo-identical transplants), which were systematically offered to patients lacking a fully compatible donor, thus making the transplant option available to the largest number of patients within the time requested by disease progression.
In this patient population, which includes four treatment protocols conducted in parallel, the approach involving the use of TK cells produced by MolMed was previously tested in a Phase II trial (TK007) in patients with haematologic malignancies and currently in a pivotal Phase III trial (TK008) reserved for patients with high-risk acute leukaemia. As of today, bone marrow transplantation from a matched donor represents the standard treatment option for patients suffering from acute leukaemia, however only about 50% of patients have a fully matched donor available in the family or in the volunteer donor registry. The analysis presented at the BMT Tandem Meetings reveals that, in this large patient population, results of transplants from partially matched (haploidentical) family donors are fully comparable in terms of overall survival and disease-free survival to those obtained with transplants from fully matched donors. These results are of particular relevance in light of the fact that this type of transplant is available for almost all patients: over 80% of the intention to treat population actually received a transplant. The contribution of TK to this patient population will continue through the centre’s participation in the randomized multicentre Phase III trial.  Data available on the first 14 treated patients of this trial confirm the efficacy and safety profile of TK cells already observed in 123 patients treated in the Phase II and other previous studies.
MolMed is conducting an international pivotal randomised Phase III trial for high-risk leukaemia patients undergoing bone marrow transplants from haplo identical family donors, ongoing in Europe and the United States. Moreover, based on cumulative efficacy and safety data and on the Orphan Drug designation related to the incidence of leukaemia, the Company expects to file a request for Conditional Marketing Authorisation of TK to the European Authority in mid-2013.
* On January 6, 2011, MolMed announced that it received clearance from the FDA for an IND filed to conduct a Phase III clinical trial of TK, its investigational cell-based therapy for the treatment of high-risk leukaemia. The IND clearance allows MolMed to include in its ongoing Phase III trial (TK008) patients enrolled in clinical centres in the United States.  This is the second IND for a Phase III trial in the United States obtained by MolMed, following the one received from the FDA in May 2010 for its antitumour drug NGR-hTNF for the treatment of malignant pleural mesothelioma. Results of the completed, non-randomised multicentre Phase II trial of TK (TK007), published by The Lancet Oncology (Ciceri, Bonini et al, (2009)10:489-500), demonstrated that the introduction of TK in the context of haplo-transplant allowed a rapid and effective immune-reconstitution in adult patients affected by high-risk leukaemia, with remarkable reduction of transplant-related mortality and prolongation of long-term survival. Long-term follow up data of the trial presented in 2010 clarify how TK cells exert a direct role in restoring a fully functional immune system and in fighting disease relapse, i.e. by inducing the production of Interleukin-7, a protein that plays a key role in several steps of the immune response.

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