Industry Update: Clinical trials

Latest developments compiled from 1—30 September 2016

Latest developments in the field of stem cell research and regenerative medicine compiled from publicly available information and press releases from nonacademic institutions, 1—30 September 2016, published in Volume 12 Issue 1 of Regenerative Medicine.

Asterias

Asterias Biotherapeutics (CA, USA; www.asteriasbiotherapeutics.com) presented positive interim efficacy data from the ten million cell cohort, in the ongoing AST-OPC1 SCiSTAR Phase I/IIa multicenter clinical study in complete cervical spinal cord injury (SCI) patients, at the 55th Annual Scientific Meeting of the International Spinal Cord Society in Vienna, Austria. AST-OPC1 is being administered 14—30 days postinjury at up to 20 million cells in 35 patients with subacute, C5—C7, motor complete cervical SCI. Patients are being followed by neurological exams and imaging procedures to assess the safety and activity of the product. Five out of five patients infused with 10 million cells exhibited improved upper extremity motor scores (UEMS) relative to baseline. At day 90 of follow-up, four of four patients dosed improved one motor level on at least one side, two of four patients improved two motor levels on at least one side and one patient improved two motor levels on both sides. The average UEMS improvement at day 90 for the four patients that have reached this follow up was 9.5 points. No serious adverse events related to AST-OPC1, the injection procedure, or immunosuppression with low-dose tacrolimus were found. In addition, data from the study indicate that AST-OPC1 can be safely administered to patients in the subacute period after severe cervical SCI. In the patient cohort treated with two million cells, three out of three patients exhibited improved UEMS relative to baseline, and the average UEMS improvement for the three patients was 5.0 points at day 90, and they continued to improve an average of 7.0 points at 1 year. The company expects to have data evaluating the efficacy results after implantation of 20 million AST-OPC1 cells in complete cervical SCI patients later in 2017. Additional information on the Phase I/IIa trial, including trial sites, can be found at: www.clinicaltrials.gov (ID: NCT02302157), and at the SCiStar Study website (www.scistar-study.com).

Bluebird

Bluebird Bio (MA, USA; www.bluebirdbio.com) has opened HGB-207, a Phase III, single-arm, global, multicenter study designed to evaluate the safety and efficacy of LentiGlobin BB305 drug product in 15 patients with transfusion-dependent β-thalassemia (TDT) and non-β0/β0 genotypes (www.clinicaltrials.gov, ID: NCT02906202). The study’s primary end point is transfusion independence, defined as a 12-month transfusion-free period after transplant. In this study, the process by which the patient’s cells are transduced with LentiGlobin will be modified by the addition of two transduction enhancers during the transduction step of the manufacturing process, intended to increase vector copy number and the percentage of cells successfully transduced. Bluebird also intends to incorporate these transduction enhancers into the manufacturing process for HGB-206, its ongoing study of LentiGlobin in patients with severe sickle cell disease.

Caladrius

Caladrius Biosciences (NJ, USA; www.caladrius.com) completed enrollment of the first patient cohort in the Phase II Sanford Project: T-Rex study occurred in August as planned. The T-Rex study is investigating Caladrius’ product candidate, CLBS03 (autologous expanded Tregs), for the treatment of recent onset Type 1 diabetes. The complete study targets inclusion of 111 patients, by design divided into an initial cohort of approximately 18 patients for an initial safety evaluation followed by a second cohort to meet patient enrollment goals. CLBS03 has received Fast Track and Orphan Drug designations from the US FDA as well as Advanced Therapeutic Medicinal Product classification from the EMA. Additional information on this prospective, randomized, placebo-controlled, double-blind Phase II clinical trial can be found at www.clinicaltrials.gov (ID: NCT02691247).

Gradalis

Gradalis (TX, USA; www.gradalisinc.com) announced that the first patient has been dosed in an open label, investigator-sponsored pilot study combining Vigil^® Engineered Autologous Tumor Cells (EATCs) with durvalumab — an investigational human monoclonal antibody directed against PD-L1 — in locally advanced or metastatic triple-negative breast cancer patients that have progressed following two prior lines of therapy. This is supported partly by a grant from Gradalis, to evaluate the safety, tolerability and efficacy of the combination of Vigil and durvalumab. Vigil is an investigational cellular immunotherapy technology that combines the concepts of genetic engineering with the science of immunooncology, to enable an immune response to cancer cells. A patient’s tumor cells are engineered with a plasmid carrying the gene vector for shRNA Furin and GMCSF to elicit a systemic T-cell directed immune response when administered to the patient through intradermal injections. By utilizing the patient’s own tumor as the antigen source, Vigil EATC is designed to elicit an immune response that is specifically targeted and broadly relevant to each patient’s unique tumor antigens. Vigil EATC is being studied in Ewing’s sarcoma and ovarian cancer as a single agent, and in breast cancer, non-small-cell lung cancer and melanoma in combination with PD-L1 inhibitors. More information about these studies can be found on www.vigilclinicaltrials.com. PD-L1 expression enables tumors to evade detection from the immune system through binding to PD-1 on cytotoxic T lymphocytes. Durvalumab blocks PD-L1 interaction with both PD-1 and CD80 on T cells, countering the tumor’s immune-evading tactics. Durvalumab is being investigated in an extensive clinical trial program, as monotherapy or in combination, in non-small-cell lung cancer, bladder, head and neck, gastric, pancreatic, hepatocellular carcinoma and blood cancers.

Juno

The Fred Hutchinson Cancer Research Center (WA, USA; www.fredhutch.org) published the data from an early-phase study of patients with advanced non-Hodgkin lymphoma receiving Juno Therapeutics’ (WA, USA; www.junotherapeutics.com) proprietary product, JCAR014, a chimeric antigen receptor (CAR) T-cell treatment, and chemotherapy [1]. JCAR014’s hallmark is its use of a one-to-one ratio of helper (CD4⁺) and killer (CD8⁺) CAR T cells, which are a patient’s own immune cells that are genetically engineered to identify and kill cancer cells. The paper reported the results of the first 32 patients in a dose-finding trial of JCAR014 following a round of lymphodepletion, designed to create a more favorable environment for the CAR T cells to grow in the patient’s body. Key findings of the study demonstrated the importance of the choice of lymphodepletion regimen and the effects of different doses of CAR T cells. Fifty percent of the 18 patients who were evaluable for efficacy after receiving CAR T cells and chemotherapy agents fludarabine and cyclophosphamide (Cy/Flu) had a complete response, which compares favorably to the 8% complete response rate in patients who received JCAR014 plus cyclophosphamide-based chemotherapy without fludarabine. Dose-limiting toxicities were observed in some patients in this dose-finding study who received the highest CAR T-cell dose. The study continues with the intermediate CAR T-cell dose. In patients that received Cy/Flu lymphodepletion and the intermediate dose of JCAR014, the data showed a promising early efficacy and side effect profile.

Kerastem

Kerastem (CA, USA: http://kerastem.com) has completed enrollment of STYLE, the company’s US Phase II clinical trial (www.clinicaltrials.gov, ID: NCT02503852). STYLE is a Phase II randomized, double-blind and controlled investigation of Kerastem therapy in early stage female and male pattern baldness. The Kerastem therapy is a combination of fat-based stem and regenerative cells and fat tissue purified with Puregraft (www.puregraft.com). The primary objective of this study is to evaluate the safety and feasibility of the Celution and Puregraft Systems in the processing and preparation of an autologous fat graft enriched with adipose-derived regenerative cells in the treatment of early alopecia androgenetica.

Kite

Kite Pharma (CA, USA; http://kitepharma.com) announced positive results from an interim analysis of ZUMA-1 for KTE-C19 in patients with chemorefractory diffuse large B-cell lymphoma. KTE-C19 is an investigational therapy in which a patient’s T cells are engineered to express a CAR to target the antigen CD19, a protein expressed on the cell surface of B-cell lymphomas and leukemias, and redirect the T cells to kill cancer cells. KTE-C19 met the primary end point of objective response rate (ORR), p < 0.0001 with an objective response rate of 76%, including 47% complete remissions. ZUMA-1 enrolled patients with chemorefractory aggressive non-Hodgkin lymphoma into two cohorts. Cohort 1 included patients with diffuse large B-cell lymphoma, and cohort 2 enrolled patients with transformed follicular lymphoma and primary mediastinal B-cell lymphoma. The interim analysis of ZUMA-1 evaluated the ORR in the first 51 patients in cohort 1 with at least 3 months of follow-up. This analysis also included an additional 11 patients in cohort 2. Across the combined 62 patients, the most common grade 3 or higher adverse events included neutropenia (66%), anemia (40%), febrile neutropenia (29%), thrombocytopenia (29%) and encephalopathy (26%). Grade 3 or higher cytokine release syndrome and neurological toxicity was observed in 18 and 34% of patients, respectively. Two patients died from KTE-C19 related adverse events (hemophagocytic lymphohistiocytosis and cardiac arrest in the setting of cytokine release syndrome). The Phase II interim outcomes in ZUMA-1 are largely consistent with results from the Phase I portion of the study and the National Cancer Institute study based on the same CAR construct a low-dose cyclophosphamide-fludarabine conditioning regimen.

SanBio

SanBio (CA, USA; http://sanbio.com) has begun a Phase II clinical trial of regenerative cell medicine SB623 for patients affected by traumatic brain injury in Japan. SanBio had previously announced the world’s first global Phase II clinical trial for chronic traumatic brain injury with allogeneic stem cells, with patient enrollments already begun in the USA. The STEMTRA trial is designed to study the safety and efficacy of SB623 cell therapy in treating patients with chronic motor impairments following traumatic brain injury. The trial will enroll 52 subjects, and Japanese patients will now be included in this trial (www.clinicaltrials.gov, ID: NCT02416492). SB623 cells are modified allogeneic MSCs, derived from bone marrow stromal cells isolated from healthy adult donors, which, administered into neural tissue, should promote recovery from injury by triggering the brain’s natural regenerative ability. SanBio recently completed a US-based Phase I/IIa clinical trial for SB623 in patients with chronic motor impairments of 6 months to 5 years following an ischemic stroke (www.clinicaltrials.gov, ID: NCT01287936). Based on these results, a Phase IIb randomized double blind clinical trial of 156 subjects began enrollment in December 2015 for the stroke indication (www.clinicaltrials.gov, ID: NCT02448641). The STEMTRA trial extends the evaluation of SB623 to patients afflicted by traumatic brain injury, which can result in lifelong motor deficits, and for which there are currently no approved medicine.