Date: 2015-12-07
Type of
information: discontinuation of development
phase: 2
Announcement: discontinuation of development
Company: Fate Therapeutics (USA - CA)
Product: Prohema® (16, 16-dimethyl prostaglandin E2, or dmPGE2, modulated cord blood)
Action
mechanism:
- stem cell therapy. Prohema® is a pharmacologically-modulated, cord blood-derived hematopoietic stem cell (HSC) therapeutic. Prohema® is produced through a proprietary, two-hour, ex vivo cell modulation process that results in rapid activation of key biological pathways involved in homing, proliferation and survival of HSCs. In preclinical testing, Prohema® has demonstrated the potential to accelerate engraftment and to drive durable hematopoietic reconstitution, without the need for multi-week expansion protocols. In an initial Phase 1b clinical trial in adult patients with hematologic malignancies undergoing double umbilical cord blood transplant (dUCBT), the median time to neutrophil recovery ( > 500 cells/µL) with Prohema® was 17.5 days, which compares favorably to historical norms for patients undergoing dUCBT. In that trial, 100-day survival with Prohema® was 100%, and Prohema® provided the dominant source of hematopoiesis in 10 of 12 evaluable subjects, suggesting that treatment with Prohema® may accelerate engraftment and drive durable and preferential hematologic reconstitution.
Disease: hematologic malignancies including acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML) and non-Hodgkin lymphoma (NHL)
Therapeutic
area: Cancer - Oncology
Country: USA
Trial
details:
- The PUMA (Prohema® in UMbilical cord blood transplant in Adults) study is a randomized, controlled, open-label Phase 2 clinical trial of Prohema® in adult subjects undergoing double umbilical cord blood transplantation for the treatment of hematologic malignancies including acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML) and non-Hodgkin lymphoma (NHL). Multiple clinical endpoints that contribute significantly to the overall morbidity and mortality of allogeneic HSCT are being investigated in the PUMA study to inform and support potential registrational strategies. These clinical endpoints include key measures of the hematopoietic reconstitution and immunotherapeutic potential of Prohema® including time to and incidence of neutrophil and platelet engraftment, engraftment failure, bacterial infections, viral reactivation, graft versus host disease, relapse of underlying disease and overall and disease-free survival. The Phase 2 PUMA study is designed to enroll 60 subjects. Eligible subjects are randomized, at a ratio of 2:1, with approximately 40 subjects intended to receive Prohema® plus an unmanipulated cord blood unit, and approximately 20 subjects intended to receive two unmanipulated cord blood units. Based upon physician choice, subjects are treated with one of two conditioning regimens, an intense myeloablative regimen or a reduced-intensity regimen, to destroy malignant cells and to prevent rejection of the donor hematopoietic cells. Randomization will be stratified by conditioning regimen. The primary endpoint of the 60-subject Phase 2 PUMA study is based on a categorical analysis of neutrophil engraftment, and the clinical trial is powered to show with statistical significance that 70% of subjects with neutrophil engraftment in the Prohema® treatment arm engraft prior to a pre-specified control day of neutrophil engraftment. The pre-specified control day of neutrophil engraftment, which is dependent on the conditioning regimen received by the subject, has been established as 26 days for subjects receiving myeloablative conditioning and 21 days for subjects receiving reduced-intensity conditioning. These pre-specified values are based on multi-center reports published in the literature of historical median times to neutrophil engraftment in adult patients undergoing double umbilical cord blood transplantation in the United States (Brunstein, Blood. 2010;116(22): 4693-4699; Cutler, Bone Marrow Transplantation. 2011;46(5): 659-67). The Phase 2 PUMA study utilizes the concurrent control arm to validate the pre-specified values of neutrophil engraftment and to provide context for interpretation of other clinical outcomes. Full data on the primary efficacy endpoint from the Phase 2 PUMA study are expected in mid-2015. (NCT01627314)
Latest
news:
- • On December 7, 2015, Fate Therapeutics announced data from its Phase 2 PUMA clinical trial of ProHema and provided an update on its therapeutic strategy for hematopoietic cell transplantation (HCT). The Company expects to initiate an open-label, randomized, controlled Phase 1/2 clinical trial of ProTmune in 2016 to investigate the potential of ProTmune to prevent acute graft-versus-host disease (GvHD) and severe viral infections in patients undergoing mobilized peripheral blood HCT. With the benefit of ProTmune advancing into the clinic, Fate Therapeutics will discontinue further development of ProHema in patients undergoing cord blood HCT. The open-label, randomized, controlled PUMA study was designed to assess ProHema in adult subjects undergoing cord blood HCT. Based on an October 15th data cut-off, an interim analysis of the PUMA study showed that subjects administered ProHema had an increase in the incidence of early neutrophil engraftment and a reduction in the incidence of severe viral infection-related adverse events (Grade 3-5) following HCT. 24 of 28 subjects administered ProHema achieved neutrophil engraftment. 16 of these 24 subjects (67%) achieved early neutrophil engraftment prior to a pre-specified historical control median time of engraftment (which has been established as Day 26 for subjects receiving myeloablative conditioning and Day 21 for subjects receiving reduced intensity conditioning). The overall reduction in the median time to neutrophil engraftment was 4.5 days, as compared to the applicable pre-specified historical control value.
- 14 of 15 concurrent control subjects achieved neutrophil engraftment. Eight of these 14 subjects (57%) achieved early neutrophil engraftment prior to the applicable pre-specified historical control median. The overall reduction in the median time to neutrophil engraftment was 2 days, as compared to the applicable pre-specified historical control value.
32% of subjects administered ProHema (9 of 28), as compared to 60% of concurrent control subjects (9 of 15), experienced one or more severe viral infection-related adverse events (Grade 3-5) following HCT; and, of the subjects who were cytomegalovirus (CMV)-seropositive at the time of HCT, 11% of subjects administered ProHema (2 of 18), as compared to 30% of concurrent control subjects (3 of 10), experienced one or more severe CMV-related adverse events (Grade 3-5) following HCT.
- Fate Therapeutics is also developing ProTmune, an adoptive immunotherapeutic programmed with two small molecules, to prevent acute GvHD while maintaining the cancer-fighting properties of donor mobilized peripheral blood (mPB) T cells. New preclinical data for ProTmune presented at the American Society of Hematology 2015 Annual Meeting show that a single administration of programmed mPB cells results in a statistically-significant reduction in GvHD score and improvement in survival as compared to vehicle-treated cells. Importantly, the Company has also shown that the cancer-fighting properties of adoptively transferred programmed T cells are preserved in preclinical models.
- • On December 18, 2014, Fate Therapeutics reported initial data from the first 12 subjects administered Prohema® in the Company's ongoing Phase 2 PUMA study and announced that the study's independent Data Monitoring Committee (iDMC) supported continuation of the clinical trial following a second planned interim safety review. These early data showed that subjects administered Prohema®, the Company's lead ex vivo programmed hematopoietic cellular therapeutic derived from umbilical cord blood, had an improved median time of neutrophil engraftment and an increased incidence of early neutrophil engraftment. Of the first 12 subjects administered Prohema® in the Phase 2 PUMA study, 10 subjects received myeloablative conditioning (MAC) and two subjects received reduced-intensity conditioning (RIC). Eight of 10 Prohema® subjects receiving MAC achieved neutrophil engraftment, with a median time of engraftment of 20 days. One of two Prohema® subjects receiving RIC achieved neutrophil engraftment, which was reached on Day 14. Historical median times of neutrophil engraftment are approximately 26 days for patients receiving MAC and 21 days for patients receiving RIC based on multi-center reports published in the literature of adult patients undergoing double umbilical cord blood transplantation in the United States. Six of the nine engrafting subjects administered Prohema® in the PUMA study achieved neutrophil engraftment prior to these historical median times.
- • On December 16, 2014, the PUMA study's iDMC conducted its second of two scheduled interim safety reviews of Prohema®. A total of 20 subjects, including 12 subjects that received Prohema® plus an unmanipulated cord blood unit and eight control subjects that received two unmanipulated cord blood units, were included in the interim review, which assessed safety, time to engraftment, rates of graft failure, early mortality, infection and graft versus host disease. Two early deaths prior to engraftment, which were both attributed to the toxicity of the conditioning regimen received by the subjects, were reported in the PROHEMA arm, and one subject administered Prohema® failed to achieve neutrophil engraftment. Based on its consideration of the data available on the first 20 subjects as well as historical outcomes reported from multi-center clinical experiences, the iDMC determined that Prohema® had met established safety criteria and supported continuation of the PUMA study. The Company believes that data from its Phase 2 control subjects are consistent with expected outcomes of patients undergoing double umbilical cord blood transplantation published in the literature, including historical median times of neutrophil engraftment. In addition to its conduct of the PUMA study, Fate Therapeutics is currently investigating the therapeutic potential of Prohema® in a Phase 1b clinical trial in pediatric patients with hematologic malignancies (PROMPT), and plans to initiate a Phase 1b.
- • On March 12, 2014, Fate Therapeutics announced the enrollment of the first patient in its "PUMA" (Prohema® in UMbilical cord blood transplant in Adults) study, a Phase 2 clinical trial of Prohema® (16, 16-dimethyl prostaglandin E2, or dmPGE2, modulated cord blood) using the Company's nutrient-rich media formulation. The PUMA study is designed to assess the efficacy and safety of Prohema® in a randomized, controlled setting in patients undergoing hematopoietic stem cell (HSC) transplantation for the treatment of hematologic malignancies. The trial has been approved for conduct at ten major HSC transplant centers in the United States. Safety reviews are planned after six and 12 subjects, respectively, have been treated with Prohema® in the PUMA study, and the Company intends to provide a clinical update following the completion of these reviews. Full data on the primary efficacy endpoint are expected in mid-2015.
- During 2013, scientists at Fate Therapeutics demonstrated that the therapeutic profile of Prohema® may be further enhanced, as compared to its previous clinical use, by incorporating the Company's nutrient-rich media (NRM) formulation into the manufacture of Prohema®. In in vivo preclinical studies, Prohema® manufactured using its NRM formulation exhibited improved HSC viability and a more than two-fold improvement in HSC engraftment as compared to a standard cell processing media used previously in the clinical development of Prohema®. The Company has worked closely with the FDA over the past nine months to enable the clinical manufacture of Prohema® using its NRM formulation for the PUMA study.
Is
general: Yes
