Date: 2016-12-06
Type of
information: Presentation of results at a congress
phase: 2
Announcement: presentation of results at the 58th Annual Meeting and Exposition of the American Society of Hematology (ASH)
Company: Kiadis Pharma (The Netherlands)
Product: ATIR101™
Action
mechanism:
- cell therapy/immunotherapy product. ATIR™ is a cell based medicinal product candidate enabling stem cell transplantations from mismatched (haploidentical) family donors to patients suffering from blood cancer. Stem cell transplantation is the only potentially curative option for many patients but a matching donor is available for only half of the patients in need. ATIR™ thus has the potential to address this unmet need and to make stem cell transplantations available for patients worldwide. Those T-cells in a haploidentical graft which would cause Graft-versus-Host-Disease (GvHD) are selectively eliminated using proprietary technology to produce ATIR™. ATIR™ is administered as an adjunctive treatment on top of a haploidentical stem cell transplantation enhancing early immune reconstitution without causing GvHD.
Disease: blood cancer patients for whom a matched donor is not available for a standard transplantation procedure
Therapeutic
area: Cancer - Oncology
Country: Belgium, Canada, Germany, UK
Trial
details:
- This CR-AIR-007 phase II international multi-center study with ATIR™ aims to corroborate and extend the safety and efficacy results of the previous successful Phase I/II study. A total of 23 leukemia patients, including patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) and myelodysplastic syndrome (MDS) will be enrolled and treated with the optimal dose identified in the Phase I/II study. The primary endpoint of the trial is the rate of transplant related mortality six months post a haploidentical stem cell transplant. Secondary endpoints include overall survival (OS) at one year after transplant as well as relapse rated mortality, non-relapse related mortality, incidence of acute and chronic Graft versus Host Disease (GvHD) and rate of severe infections. Enrollment of patients commenced in Canada and Belgium in April and August 2013, respectively, with the Maisonneuve-Rosemont Hospital in Montreal and Hamilton Health Sciences participating in Canada and the University Hospitals Leuven, the Institute Jules Bordet in Brussels and the Sint-Jan Academic Hospital in Bruges participating in Belgium. (NCT01794299)
Latest
news:
- • On December 6, 2016, Kiadis Pharma presented positive one-year data with ATIR101™ from the single dose Phase II trial at the 58th Annual Meeting and Exposition of the American Society of Hematology (ASH) in San Diego. The data presented at ASH in session 711 by Dr. Denis-Claude Roy, Professor of Medicine at the University of Montreal, one of the principal investigators for the trial and protocol chair, confirms that ATIR101™ can be safely infused and shows a significant reduction in Transplant Related Mortality (TRM) (primary endpoint) and a significant improvement in Overall Survival (OS) (secondary endpoint) in comparison to an observational control group of patients undergoing a T-cell depleted haploidentical donor transplantation only. Combined with the lack of severe Graft-versus-Host-Disease (GVHD) and limited relapse, this translates into favorable GVHD-free, relapse-free survival (GRFS) one-year post-transplantation.
- Kiadis Pharma will submit a Marketing Authorization Application to the European Medicines Agency (EMA) for its data in the first quarter of 2017 and the next immediate step is the initiation of atransatlantic randomized Phase III international controlled trial, comparing our ATIR101™ approach directly to the Baltimore approach.
Twenty-three leukemia patients with a median age of 41 years (range 21-64) were enrolled into and treated on this trial from sites in Canada, Belgium, Germany and the United Kingdom. Patients were eligible for an allogeneic hematopoietic stem cell transplantation (HSCT) but could not find a matching donor in time. Sixteen patients had acute myeloid leukemia and seven had acute lymphoblastic leukemia. Patients were either in first or second complete remission at the time of the HSCT. The majority of patients had a poor prognosis based on their Disease Risk Index (DRI) (57% high/very high risk), while the remaining 43% had an intermediate risk index. A myeloablative conditioning regimen was used and (haploidentical) donor grafts were depleted of T-cells (CD34+ selection) prior to transplantation. Patients engrafted rapidly (median twelve days) and ATIR101™ was subsequently infused at a fixed dose of 2x106 CD3+ cells/kg at a median of 28 days post-transplant without use of any post-transplant GVHD prophylaxis.
- The median follow-up, on November 28, 2016, was 485 days (range 110-742) post-HSCT, at which point all patients were beyond one year post-HSCT.
No patients (0/23) developed grade III-IV GVHD upon infusion of ATIR101™, confirming the efficacy of the elimination of allo-reactive T-cells from ATIR101™. Only three cases of grade II acute GVHD were reported after infusion of ATIR101™. In addition, one case of chronic GVHD was reported after infusion of ATIR101™.
Despite the fact that the majority of patients were at high risk for relapse (DRI-high) only two patients developed disease relapse within the first twelve months after HSCT (at day 61 and day 90 post-HSCT respectively). No mortality was observed within the first 100 days post-HSCT. Nine patients died within the first year after transplantation, seven due to TRM and two due to disease relapse, resulting in a one-year OS of 61%.
- When compared to control data from an observational cohort study (consisting of a group of 35 patients matching the inclusion and exclusion criteria of the company’s Phase II trial who underwent a similar HSCT procedure from haploidentical family members but without the addition of ATIR101™), OS was significantly higher (p=0.003) in patients who were given ATIR101™ after a T-cell depleted haploidentical transplantation. The one-year OS for HSCT + ATIR101™ is 61% versus 20% for HSCT only. TRM was significantly lower (p=0.007), the one-year TRM for HSCT + ATIR101™ being 32% versus 70% for HSCT only.
GRFS, defined as patients surviving without getting severe acute GVHD (grade III-IV) or chronic GVHD (requiring systemic treatment) and without relapsing, for patients treated with HSCT and an adjuvant infusion of ATIR101™ was 57% at one year. This compares favorably with patients in the contemporaneous observational control group undergoing an HSCT only (with GRFS at 20%) and also with patients in that same control group receiving a Matched Unrelated Donor transplantation (HLA 8/8 or 10/10 match), where the GRFS at one year is 41%. Compared to reported GRFS data for haploidentical transplants done using the post-transplant cyclophosphamide (PTCy) approach to control GVHD, the GRFS of 57% at one year for the HSCT + ATIR101™ group is favorable to the GRFS of 33% reported for the PTCy group (Solh et al, BBMT 2016).
- Patients will continue to be followed-up until two years post-HSCT in order to collect further long-term outcome data. Out of the 23 patients enrolled in the trial, five have already completed the full two year follow-up alive and four patients are still alive on study. The final data from this trial will be available in the second half of 2017.
- Based on the positive results from this Phase II trial, the Company is proceeding with the development of ATIR101™ by initiating a Phase III trial in which patients with acute leukemia will be randomized to receive a haploidentical HSCT according to either the PTCy approach or the Kiadis Pharma approach with a single dose of ATIR101™. This Phase III trial has been submitted to regulatory authorities and is currently under review for approval.
- • On April 4, 2016, Kiadis Pharma presented results on the primary endpoint of its single dose Phase II trial with ATIR101™ at the 42nd Annual Meeting of the European Society of Blood and Marrow Transplantation (EBMT) in Valencia, Spain. The data presented in session O042 by Dr. Denis-Claude Roy, Professor of Medicine at the University of Montreal and the principal investigator for the trial, confirms that ATIR101™ can be safely infused, does not cause grade III-IV Graft-versus-Host-Disease (GVHD) and shows a significant reduction in Transplant Related Mortality (TRM) and a significant improvement in Overall Survival (OS) in comparison to a historical control group of patients undergoing a T-cell depleted haploidentical donor transplantation only.
- Twenty-three leukaemia patients with a median age of 41 years (range 21-64) were enrolled into and treated on this trial from sites in Canada, Belgium, Germany and the United Kingdom. Patients were eligible for an allogeneic hematopoietic stem cell transplantation (HSCT) but could not find a matching donor in time. Sixteen patients had acute myeloid leukaemia (AML) and seven had acute lymphoblastic leukaemia (ALL). Patients were either in first or second complete remission at the time of the HSCT and the majority of patients (57%) had a poor prognosis based on their disease risk index and cytogenetic profile. A myeloablative conditioning regimen was used and (haploidentical) donor grafts were depleted of T-cells (CD34+ selection) prior to transplantation. Patients engrafted rapidly (median 12 days) and ATIR101™ was subsequently infused at a fixed dose of 2x106 CD3+ cells/kg at a median of 28 days post-transplant.
- The median follow-up, on March 24, 2016, was 414 days (range 110 – 742) post-HSCT, at which point all patients were beyond six months post-HSCT, allowing assessment of the primary endpoint of this trial, which is TRM at six months. Patients will be continued to be followed in order to collect further long-term outcome data.
- No patients (0/23) developed grade III-IV GVHD upon infusion of ATIR101™, confirming the efficacy of the elimination of allo-reactive T-cells from ATIR101™. Three cases of grade II acute GVHD were reported; one case developed before ATIR101™ infusion and the other two cases had a delayed onset, at day 173 and day 247 post-HSCT (145 and 219 days post ATIR101™ infusion) respectively. In the patient who developed GVHD before ATIR101™ infusion, GVHD resolved quickly and subsequently ATIR101™ was infused, not triggering any further GVHD.
- The primary endpoint of the trial is TRM within six months post-HSCT. Overall, three cases of TRM were reported within the first six months post-HSCT, giving a TRM rate of 13%. In all cases the cause of death was an infection. No mortality was observed within the first 100 days post-HSCT. In addition to the three TRM cases, only one patient died as a result of disease relapse within the first six months, resulting in an Overall Survival of 83%.
- When compared to a historic control group (N=35) consisting of patients matching the inclusion and exclusion criteria of the Company’s Phase II trial who underwent a similar HSCT procedure from haploidentical family members but without the addition of ATIR101™, TRM was significantly lower (p=0.005) in patients who were given ATIR101™ after a T-cell depleted haploidentical transplantation. The six month TRM for HSCT + ATIR101™ is 13% versus 37% for HSCT only.
- Disease relapse in the trial was limited, with only two patients developing disease relapse within the first 12 months after HSCT (at day 61 and 90 post HSCT respectively). Combined with the reduced rate of TRM, this translates into a significantly improved OS (p=0.0026) of patients undergoing HSCT + ATIR101™ compared to patients undergoing HSCT only. Based on the Kaplan-Meier estimates, the one-year survival in the HSCT + ATIR101™ group was 64% compared to only 20% in the historic control group.
- Based on the positive results from this Phase II trial, the Company will proceed with the development of ATIR101™ as an adjunctive immuno-therapeutic treatment to a haploidentical HSCT for patients with acute leukaemia, initiating a randomised Phase III trial in the second half of 2016. In addition, the Company will discuss the opportunity for potential conditional (accelerated) approval of ATIR101™ with the regulatory authorities.
- • On July 30, 2015, Kiadis Pharma announced full enrolment of patients into its ongoing Phase II clinical study with its lead product, ATIR101™. The primary endpoint of the study is the rate of Transplant Related Mortality (TRM) at six months after allogoneic hematopoietic stem cell transplantation (HSCT). To date, 21 out of the 23 enrolled patients have received their HSCT, 19 of which have also been dosed with ATIR101™. The remaining patients are at various stages of treatment, either being prepared for HSCT or being dosed with ATIR101™. The 23rd patient is expected to undergo treatment with ATIR101™ in Q3 2015 and the study will remain open for enrolment until this final patient has been treated. Read-out of the primary endpoint results is expected in Q1 2016. Interim data from a pre-specified interim analysis in this study were presented by Dr. Denis-Claude Roy, Professor of Medicine at the University of Montreal and Chair of the study, at the 2014 American Society of Hematology (ASH) Annual Meeting in San Francisco (see below).
- • On December 9, 2014, Kiadis Pharma announces positive interim data from the ongoing Phase II clinical study with its lead product ATIR™. The data were presented by Dr. Denis-Claude Roy, Professor of Medicine at the University of Montreal and Chair of the study, at the American Society of Hematology (ASH) Annual Meeting in San Francisco (Abstract 314). The primary endpoint of the study is the rate of Transplant Related Mortality (TRM) at 6 months after hematopoietic stem cell transplantation. Data from the pre-specified interim analysis of the first 10 patients showed only 2 cases of TRM at 6 months post-HSCT and both TRM cases resulted from a viral infection. Overall, 6 out of the 10 patients were completely free from severe infections (grade 3-5) after ATIR™ administration and up to 6 months after the transplant. These data are in line with the data previously reported from Kiadis Pharma’s Phase I/II study with 19 patients. The current study is progressing well with further enrollment of patients in Canada (Hôpital Maisonneuve-Rosemont (Montreal), Juravinski Hospital and Cancer Centre (Hamilton) and Princess Margaret Cancer Centre (Toronto)), Belgium (University Hospitals Leuven, AZ Sint Jan (Bruges) and Institut Jules Bordet (Brussels)) and Germany (University Hospital of Würzburg).
- • On November 18, 2013, Kiadis Pharma, a clinical stage biopharmaceutical company developing treatments for blood cancers, has announced the successful Phase II enrollment of approximately ten patients of whom the majority have already been transplanted and received ATIR™. Kiadis Pharma's lead program, ATIR™, is a cell-based product designed to enable stem cell transplantations from partially mismatched (haploidentical) family donors for blood cancer patients who do not have a standard of care stem cell donor available. Topline data from the trial (CR-AIR-007) is expected in the first half of 2014. Manfred Ruediger, PhD, Chief Executive Officer of Kiadis Pharma, commented: "We are delighted that the enrollment into CR-AIR-007 is progressing according to plan. This demonstrates the demand for ATIR™ and its significant potential as a lifesaving blood cancer treatment. All patients currently enrolled in the study are alive and doing well and none of them have yet to experience any acute GvHD or serious infections. The majority of patients have been on the study for between two to seven months. We look forward to reporting the topline Phase II data in the first half of 2014." He continues: "Having successfully transferred our manufacturing process for ATIR™ to our European CMO in Frankfurt am Main, Germany, we now have two manufacturing facilities using our robust process, one for our European sites and one in Montreal for our Canadian sites."Enrollment of patients commenced in Canada in April 2013 and in Europe in August 2013. Topline results are expected in H1 2014.
- • On February 26, 2013, Kiadis Pharma has received the No Objection Letter from Health Canada for its new clinical study with ATIR™. This study will be a Phase II international multi-center study with clinical sites in Canada and Belgium. Up to 23 patients will be treated in this study to corroborate and extend the safety and efficacy results from Kiadis Pharma‘s previous Phase I/II clinical study with ATIR™. The coordinating investigator for the study will be Denis-Claude Roy, MD, professor of medicine at the University of Montreal.
Is
general: Yes
