Clinical Trials

Date: 2018-03-19

Type of information: Presentation of results at a congress

phase: 1-2

Announcement: presentation of results at the 44th Annual Meeting of the European Society for Blood and Marrow Transplantation

Company: Fate Therapeutics (USA - CA)

Product: ProTmune™

Action mechanism:

cell therapy/cellular immunotherapy. ProTmune™ is an investigational programmed cellular immunotherapy undergoing clinical development for the prevention of acute GvHD and cytomegalovirus (CMV) infection in patients undergoing allogeneic HCT. The cell therapy is produced by modulating a donor-sourced, mobilized peripheral blood graft ex vivo with two small molecules (FT1050 and FT4145) to enhance the biological properties and therapeutic function of the graft's immune cells. The programmed mobilized peripheral blood graft is administered to a patient as a one-time intravenous infusion.
Fate Therapeutics is developing ProTmune as a preventative therapy to reduce the incidence and severity of acute graft-versus-host disease (GvHD) by Day 100 following HCT. Acute GvHD is the leading cause of early morbidity and mortality following allogeneic HCT. Extended use of immunosuppressive agents to treat acute GvHD compromises the anti-leukemia activity of the transplant procedure and significantly increases the risk of cancer relapse and mortality. Additionally, treatment of acute GvHD is ineffective in about half of patients, and these refractory patients have a dismal prognosis with mortality rates in excess of 70%. There are currently no therapies for the prevention of acute GvHD approved by the FDA.

Disease: prevention of acute graft-versus-host disease (GvHD)

Therapeutic area: Transplantation

Country:

Trial details:

The Phase 2 stage of PROTECT is a randomized, controlled and double-blinded clinical trial assessing the safety and efficacy of ProTmune in up to 60 adult subjects with hematologic malignancies undergoing matched unrelated donor HCT following myeloablative conditioning. Subjects are being randomized, in a 1:1 ratio, to receive either ProTmune or a conventional matched unrelated donor mobilized peripheral blood cell graft. The primary efficacy endpoint of PROTECT is cumulative incidence of Grades 2-4 acute GvHD by Day 100 following HCT, where prospective clinical studies have shown that 40% to 80% of patients undergoing matched unrelated donor transplant experience Grades 2-4 acute GvHD. Immunosuppressant treatments are effective in only about half of affected HCT patients and are associated with a marked increase in severe infections and cancer relapse. Additional endpoints, such as rates of cancer relapse, chronic GvHD, non-relapse mortality and overall survival, are also being assessed. Fourteen U.S. centers are currently open for enrollment in the Phase 2 stage of PROTECT. (NCT02743351)

Latest news:

PROTECT Day 100 Clinical Data
Subject	1	2	3	4	5	6	7
Hematologic Malignancy	MDS	AML	AML	ALL	ALL	ALL	AML
CD34+ cell dose (x10⁶/kg)	10.3	4.6	10.9	4.8	3.2	3.0	9.4
CD3+ cell dose (x10⁸/kg)	3.1	1.8	2.6	2.8	2.0	1.2	2.8
ProTmune-related SAEs	None	None	None	None	None	None	None
Day of Neutrophil Engraftment ¹	Day 14	Day 18	Day 22	Day 15	Day 16	Day 18	Day 19
Acute GvHD / Grade (CIBMTR)	None	None	Grade 2	None	Grade 2	Grade 3	None
Treatment Responsive	---	---	Yes	---	Yes	Yes	---
Time to Resolution of Maximum Grade	---	---	7 days	---	8 days	5 days	---
Cancer Relapse-free	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Survival	Yes	Yes	Yes	Yes	Yes	Yes	Yes
¹ As measured from the day following HCT

The randomized, controlled and double-blinded Phase 2 stage of PROTECT is enrolling subjects at 14 U.S. centers of excellence. All subjects receiving ProTmune™ in the PROTECT Phase 1 stage are being followed for a period of two years following HCT. As of a November 29, 2017 data cut-off, all subjects remained relapse-free, and there were no events of graft failure and no serious adverse events related to ProTmune reported by investigators. Non-relapse mortality was reported in two subjects (Subject 1 on Day 228; Subject 3 on Day 151). Five of seven subjects remained on study with median time on study of 154 days [Day 106 — 254]. • On January 5, 2017, Fate Therapeutics announced that the first patient has been treated in its PROTECT clinical trial of ProTmune™ for the prevention of acute graft-versus-host disease (GvHD). The PROTECT clinical trial is designed as a two-stage study intended to evaluate the safety and efficacy of ProTmune in adult subjects with hematologic malignancies. The Phase 1 stage is assessing the safety of ProTmune in up to 10 subjects. The randomized, controlled Phase 2 stage is intended to assess the efficacy of ProTmune in 60 subjects. In late 2016, the Company amended the PROTECT study's clinical protocol to blind both investigators and subjects, enhancing the potential of the PROTECT study to support accelerated registration. The primary endpoint of the PROTECT clinical trial is cumulative incidence of acute GvHD by Day 100 following HCT. Other key endpoints undergoing assessment include cumulative incidence of severe infections, cancer relapse, event-free survival and overall survival.

The primary objectives of the Phase 1/2 clinical trial are to evaluate safety and tolerability, and to assess the potential of ProTmune to prevent acute graft-versus-host disease (GvHD) and cytomegalovirus (CMV) infection, both of which are leading causes of morbidity and mortality in patients undergoing HCT. There are currently no approved therapies for the prevention of GvHD or CMV infection in patients undergoing allogeneic HCT, giving rise to a significant unmet medical need.

The clinical trial design consists of an initial 10-subject, Phase 1 stage, during which all subjects undergoing mPB HCT following myeloablative conditioning will receive ProTmune. Following an independent data monitoring committee safety review, a 60-subject, randomized, controlled Phase 2 stage is expected to enroll, during which subjects undergoing mPB HCT following myeloablative conditioning will be assigned in a 1:1 ratio to receive either ProTmune or unmanipulated mPB cells. Two Endpoint Adjudication Committees are expected to evaluate efficacy of ProTmune in the study, one through assessing acute GvHD and the other through assessing CMV tissue-invasive disease, viremia and additional clinical outcomes.

• On March 19, 2018, Fate Therapeutics announced additional clinical data from the Phase 1 stage of its PROTECT clinical trial of ProTmune™, its next-generation hematopoietic cell graft. The data is being featured in a poster presentation at the 44th Annual Meeting of the European Society for Blood and Marrow Transplantation. Seven adult subjects with hematologic malignancies undergoing matched unrelated donor hematopoietic cell transplantation (HCT) received ProTmune as the hematopoietic cell graft in the Phase 1 stage of PROTECT. As of a February 26, 2018 data cut-off, there have been no events of cancer relapse with a median time on study of 228 days. Additionally, no serious adverse events related to ProTmune have been reported by investigators. The randomized, controlled and double-blinded Phase 2 stage of PROTECT is currently enrolling up to 60 subjects at 14 U.S. centers.

Day 100 clinical data from the Phase 1 stage of PROTECT were previously presented at the 59^thAmerican Society of Hematology Annual Meeting and Exposition in December 2017. All seven subjects receiving ProTmune remained alive and relapse-free during the first 100 days following HCT. Three of the seven subjects experienced acute GvHD during the first 100 days following HCT, all of whom responded to standard-of-care steroid treatment. The median time to resolution of the maximum GvHD grade was seven days [range: 5-8 days].

Three subjects with acute lymphoblastic leukemia (ALL), three subjects with acute myeloid leukemia (AML) and one subject with myelodysplastic syndrome (MDS) received ProTmune as the hematopoietic cell graft in the Phase 1 stage. All subjects are being followed for a period of up to two years post-HCT. Non-relapse mortality deemed not attributable to ProTmune occurred in two subjects (Subject 1 on Day 228 from pulmonary edema; Subject 3 on Day 151 from atrial fibrillation). The remaining five of seven Phase 1 subjects are alive and relapse-free.

PROTECT Clinical Data – Time on Study ^*
Subject	1	2	3	4	5	6	7
Age / Gender	66 / F	56 / F	66 / F	34 / F	48 / M	56 / M	69 / F
Hematologic Malignancy	MDS	AML	AML	ALL	ALL	ALL	AML
CD34+ cell dose (x10⁶/kg)	10.3	4.6	10.9	4.8	3.2	3.0	9.4
CD3+ cell dose (x10⁸/kg)	3.1	1.8	2.6	2.8	2.0	1.2	2.8
Time on Study (Days)	228	343	151	251	243	208	195
ProTmune-related SAEs	None	None	None	None	None	None	None
Cancer Relapse-free	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Survival	No	Yes	No	Yes	Yes	Yes	Yes
* Data is based on a February 26, 2018 data cut-off. The database is not locked, and final data are subject to change.

• On December 11, 2017, Fate Therapeutics announced Day 100 clinical data from the Phase 1 stage of its PROTECT clinical trial of ProTmune™, the Company's next-generation hematopoietic cell graft for patients with hematologic malignancies. All seven subjects receiving ProTmune™ remained alive and relapse-free during the first 100 days following hematopoietic cell transplantation (HCT). Three of the seven subjects experienced acute graft-versus-host disease (GvHD) during the first 100 days following HCT. Each of these three subjects responded to standard-of-care steroid treatment with a median time to resolution of the maximum GvHD grade of 7 days [range: 5-8 days].

PROTECT Phase 1 Day 100 Clinical Results

Clinical data from the Phase 1 stage of PROTECT were presented by Dr. Maziarz during a poster session at the 59^th American Society of Hematology Annual Meeting and Exposition. The Phase 1 stage included seven adult subjects with hematologic malignancies undergoing matched unrelated donor HCT following myeloablative conditioning. During the first 100 days following HCT, all seven subjects receiving ProTmune remained alive and relapse-free. Three of the seven subjects experienced acute GvHD during the first 100 days following HCT, all of whom responded to standard-of-care steroid treatment. The median time to resolution of the maximum GvHD grade was 7 days [range: 5-8 days]. There were no events of graft failure, and there were no ProTmune™-related serious adverse events reported by investigators.• On January 26, 2016, Fate Therapeutics announced the FDA has cleared the Company's investigational new drug (IND) application for ProTmune™, a programmed cellular immunotherapy consisting of donor-sourced mobilized peripheral blood cells which have been functionally modulated using two small molecules. The IND is now active and Fate Therapeutics plans to initiate a multi-center, randomized, controlled Phase 1/2 clinical trial in adult patients with hematologic malignancies undergoing mobilized peripheral blood (mPB) hematopoietic cell transplantation (HCT) in mid-2016.

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