The following data were presented at the American Society of Hematology meeting in San Francisco.
Acetylon Pharmaceuticals Inc., of Boston, reported data from two ongoing phase Ib combination trials of ricolinostat, a selective HDAC6 inhibitor, for treatment of relapsed or refractory multiple myeloma. In combination with Revlimid (lenalidomide, Celgene Corp.) and dexamethasone, ricolinostat demonstrated an overall response rate of 64 percent, with 80 percent of patients achieving minimal response or better per modified International Myeloma Working Group (IMWG) criteria. The response rate in 21 relapsed, lenalidomide-refractory patients was 50 percent, whereas the response rate in 13 nonrefractory patients was 85 percent. In combination with Velcade (bortezomib, Takeda Oncology) and dexamethasone, ricolinostat demonstrated an overall response rate of 45 percent in disease evaluable patients and 30 percent in all patients, with 31 percent of all patients enrolled achieving minimal response or better per modified IMWG criteria.
Alexion Pharmaceuticals Inc., of Cheshire, Conn., said researchers presented data that continue to advance the understanding of atypical hemolytic uremic syndrome (aHUS) and paroxysmal nocturnal hemoglobinuria (PNH) and provide further insight into optimal care for patients. Results from two post-hoc subanalyses from two open-label single-arm trials of Soliris (eculizumab) in pediatric and adult patients with aHUS evaluated its safety and efficacy over 26 weeks in patients with or without identified genetic mutations at baseline. Platelet count normalization was achieved by 100 percent (11/11) of pediatric and 100 percent (21/21) of adult patients with an identified mutation and by 91 percent (10/11) of pediatric and 95 percent (19/20) of adult patients without an identified mutation. Mean change from baseline in platelet count was 172 x 109/L for pediatric and 101 x 109/L for adult patients with an identified mutation and 154 x 109/L for pediatric and 179 x 109/L for adult patients without an identified mutation. For patients on dialysis at baseline, 100 percent (5/5) of pediatric and 78.6 percent (11/14) of adult patients with an identified mutation discontinued dialysis by 26 weeks, as did 66.7 percent (4/6) of pediatric and 90 percent (9/10) of adult patients without an identified mutation. Researchers concluded that Soliris treatment resulted in clinically meaningful improvements in hematologic and renal parameters in adult and pediatric patients with aHUS regardless of the presence of an identified genetic mutation. Interim data from a multicenter observational study (OPTIMA) to determine the prevalence and clinical significance of PNH-type cells in patients with various bone marrow failure syndromes and those with suspected PNH were also presented. By implementing a uniform flow-cytometry protocol in six laboratories across the country, investigators enabled reliable detection of PNH-type cells through high-sensitivity flow cytometry.
Alnylam Pharmaceuticals Inc., of Cambridge, Mass., reported positive initial phase I data for ALN-AT3, an investigational RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders. Preliminary results from a single-dose cohort in healthy volunteers (n = 4) and from the initial multiple-dose cohorts of hemophilia subjects (n=4) in the ongoing phase I trial were presented. The effects of ALN-AT3 lasted for about 60 days after a single dose. ALN-AT3 was found to be well tolerated in both healthy volunteers and hemophilia subjects enrolled in the study. Those initial results show preliminary evidence for potency and durability of RNAi therapeutics at mcg/kg subcutaneous doses in human studies, and are the first clinical data to be reported for Alnylam's Enhanced Stabilization Chemistry (ESC)-GalNAc conjugate technology.
Amgen Inc., of Thousand Oaks, Calif., presented new data from a pivotal phase II study evaluating Blincyto (blinatumomab) for the treatment of adult patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (ALL). In one analysis from the '211 study, 40 percent of patients treated with Blincyto who achieved a complete remission (CR) or complete remission with partial hematologic recovery (CRh) were enabled to proceed to allogeneic hematopoietic stem cell transplant (HSCT). Additionally, a secondary analysis from the study found that 82 percent of patients who had a CR or CRh also had a minimal residual disease (MRD) response, a measure used to predict disease recurrence in patients with ALL. Median overall survival was longer among patients who had a CR or CRh and an MRD response compared to patients who didn't have an MRD response (11.5 months vs. 6.7 months, respectively).
Aptose Biosciences Inc., of Toronto, presented preclinical data from its lead investigational cancer therapeutic APTO-253. Company researchers reported the first set of in vivo murine xenograft study data for APTO-253 in hematologic malignancies, demonstrating antitumor activity as a single agent, and in combination with the hypomethylating agent, Vicaza (azacitadine, Celgene Corp.). Notably, combination therapy led to enhanced antitumor activity vs. either agent alone. Furthermore, single-agent and combination studies exhibited a favorable safety profile with no evidence of bone marrow suppression.
Celgene Corp., of Summit, N.J., presented results from a phase II/III study (DLC-001) of Revlimid (lenalidomide) compared with investigators' choice (IC) of therapy in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). The data suggest improved response rates, progression-free survival (PFS) and overall survival (OS) with lenalidomide compared with IC in the nongerminal B-cell (GCB) population as defined by immunohistochemistry (IHC). Those improved outcomes appeared more pronounced in the activated B-cell (ABC) subtype when assessed by gene expression profiling. Patients with GCB DLBCL treated with lenalidomide had an overall response rate of 26.1 percent (n = 23/102) compared to 28.6 percent in non-GCB DLBCL patients treated with lenalidomide (n = 28/102) per IHC. The data suggested greater improvements in PFS and OS with lenalidomide compared to IC in the non-GCB patients. Based on the results of that study, Celgene will open the ROBUST study evaluating lenalidomide plus Rituxan (rituximab, Biogen Idec Inc. and Roche AG), cyclophosphamide, doxorubicin, prednisone and vincristine (R2CHOP) compared with placebo plus R-CHOP in patients who have untreated ABC-type DLBCL.
CTI Biopharma Corp., of Seattle, announced data showing treatment with pacritinib, an investigational oral multikinase inhibitor in phase III development, preferentially killed acute myeloid leukemia (AML) cells with FLT3 mutations, overcame stromal protection and suppressed leukemic outgrowth from stroma adherent AML cells in both medium-term (seven to 14 days) and long-term (five to six weeks) assays. The authors concluded that pacritinib has the potential to overcome environmentally mediated drug resistance in FLT3-positive AML and demonstrated good synergy with cytarabine and an MEK inhibitor.
Glycomimetics Inc., of Gaithersburg, Md., presented data from research related to the company's E-Selectin antagonist (GMI-1271), focusing on its potential in treating blood cancers and coagulation disorders. GMI-1271 significantly enhanced the reconstitution potential of hematopoietic stem cells harvested when used in combination with granulocyte colony-stimulating factor (G-CSF), compared to G-CSF alone.
Idera Pharmaceuticals Inc., of Cambridge, Mass., presented data for its lead candidate, IMO-8400, that support continued development of the product as a therapy for genetically defined forms of B-cell lymphoma. Results from clinical trials in healthy volunteers and patients with psoriasis showed that IMO-8400 was well tolerated when administered weekly via subcutaneous injection at doses up to 0.6 mg/kg for up to 12 weeks. In those trials, there were no treatment-related serious adverse events, no drug-related discontinuations and no pattern of systemic adverse events or laboratory changes. In multiple in vivo studies in B-cell lymphoma models, combination therapy with IMO-8400 and Rituxan (rituximab, Biogen Idec Inc. and Roche AG) significantly improved measures of disease activity. In a preclinical DLBCL model, combination therapy with IMO-8400 and rituximab significantly reduced tumor volume and significantly decreased production of IL-10, a cytokine that enhances B-cell survival and proliferation, compared to monotherapy with either agent.
Infinity Pharmaceuticals Inc., of Cambridge, Mass., reported updated data from a phase I monotherapy study of duvelisib (IPI-145), a PI3K-delta and PI3K-gamma inhibitor, which showed activity among patients with relapsed/refractory indolent non-Hodgkin lymphoma (iNHL). Duvelisib demonstrated an overall response rate of 72 percent, including a 33 percent complete response rate, among 18 patients with iNHL who received the dose administered in ongoing registration-focused studies. In a separate presentation, the firm reported phase I data showing the activity of duvelisib in patients with relapsed/refractory T-cell lymphoma.
Janssen Research & Development, LLC, of Raritan, N.J., reported 111 patients in the phase II multicenter, open-label, PCYC-1104 study received 560 mg Imbruvica (ibrutinib) once daily until disease progression or unacceptable toxicity. Imbruvica was associated with a 67 percent investigator-assessed overall response rate (ORR) with median progression-free survival (PFS) of 13 months. Almost one-third of patients (31 percent) remain progression-free at two years and almost half (47 percent) of the 111 patients in the study remain alive. A separate analysis from the phase II SPARK study in patients with mantle cell lymphoma (MCL) identified a small subset of patients who had primary resistance to Imbruvica, which was from known and novel mutations. In contrast, almost 60 percent of patients had few or no mutations, which appeared to be associated with a prolonged PFS. Twenty-five of the 120 people enrolled in the study (22.7 percent) had IRC-confirmed disease progression. Those patients had already received a median of three prior lines of therapy (range one to five lines) prior to treatment with Imbruvica. After a median treatment duration of 1.54 months, data were collected from 23 of the 25 patients and analyzed for potential genetic mutations. The analysis identified 27 known and novel mutations which may have contributed to patients' primary resistance to Imbruvica, including genes involved in NF-kB signaling, as well as the PIM1 and ERBB4 kinases. Partner Pharmacyclics Inc., of Suunyvale, Calif., also presented Imbruvica phase II data demonstrating its potential utility as a combination therapy when used with Rituxan (rituximab, Biogen Idec Inc. and Roche AG). Data suggest that the overall efficacy and safety profile is well tolerated when combined with rituximab in patients with relapsed or refractory MCL. The combination therapy resulted in an 88 percent ORR in MCL patients with a complete response rate (CR) of 40 percent. Additionally, data from a phase Ib/II trial also suggest that when Imbruvica and rituximab are combined in patients with relapsed chronic lymphocytic leukemia, short-term lymphocytosis, which sometimes is associated with Imbruvica treatment, decreased and patients experienced faster clearing of leukemia cells from the bloodstream vs. patients who received Imbruvica alone.
Juno Therapeutics Inc., of Seattle, said clinical data from its most advanced chimeric antigen receptor (CAR) product candidates, JCAR017, JCAR015 and JCAR014, demonstrated encouraging evidence of clinical responses in acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL). Highlights from the research include high rates of tumor reduction in B-cell malignancies, including a complete remission rate of 89 percent in adult relapsed/refractory B-cell ALL with JCAR015; robust T-cell expansion and persistence and clinical remissions with JCAR017; and potential for prolonged T-cell persistence with WT-1, a high-affinity T-cell receptor (TCR) candidate, in acute myeloid leukemia.
Kadmon Corp. LLC, of New York, presented preclinical data showing that KD025, the company's phase II, orally bioavailable, highly selective inhibitor of ROCK2 (Rho-associated coiled-coiled kinase 2) effectively reverses chronic graft-vs.-host disease (GVHD) in murine models. Specifically, KD025 administration significantly improved pulmonary function in an aggressive multi-organ system rodent model of fibrotic disease driven by IL-21 responses, showing a dose-dependent decrease in the development of pathogenic pulmonary function to levels comparable to non-GVHD controls.
Kiadis Pharma BV, of Amsterdam, the Netherlands, reported positive interim data from the ongoing phase II study with its lead product, ATIR (Allo-depleted T-cells for Immune Reconstitution). In the multicenter study, including patients with acute myeloid leukemia, acute lymphoblastic leukemia and myelodysplastic syndrome, 23 patient were treated with ATIR as part of the transplant regimen. The primary endpoint of the study is the rate of transplant-related mortality (TRM) at six months after hematopoietic stem cell transplantation (HSCT). Data from the pre-specified interim analysis of the first 10 patients showed two cases of TRM at six months post-HSCT and both TRM cases resulted from a viral infection. Overall, six out of the 10 patients were completely free from severe infections after ATIR administration and up to six months after the transplant.
Promedior Inc., of Lexington, Mass, reported positive data from stage 1 of an adaptive two-stage phase II trial of PRM-151, an antifibrotic immunotherapy, in patients with myelofibrosis. The overall response rate (ORR), defined as IWG-MRT1 (International Working Group-Myeloproliferative Neoplasms Research and Treatment) responses or reduction in bone marrow fibrosis, was 43 percent at six months, surpassing the pre-specified efficacy criteria necessary to proceed to the next stage of Promedior's phase II trial. Data demonstrated reduction of bone marrow fibrosis by at least one grade observed in 42 percent of patients, which was associated in most patients with improvements in anemia and/or thrombocytopenia and, in some patients, by transfusion independence lasting at least 24 weeks.
Marina Biotech Inc., of Bothell, Wash., said its licensee, Pronai Therapeutics Inc., of Plymouth, Mich., reported that a number of patients with relapsed or refractory non-Hodgkin lymphoma treated with its first DNAi-based therapeutic, PNT2258, achieved meaningful therapeutic outcomes and continue to exhibit durable clinical responses. PNT2258 is one of two nucleic acid-based therapeutics in clinical development which are formulated with Marina's Smarticles delivery technology. Eleven of the 13 patients treated achieved clinical benefit, with ongoing progression-free survival extending to 18 months and beyond.
Omni Bio Pharmaceutical Inc., of Fort Collins, Colo., presented interim clinical data demonstrating the ability of plasma-derived alpha-1 antitrypsin (AAT) to reduce inflammation and promote healing of damaged tissues in patients with graft-vs.-host disease (GVHD). The positive interim results support continued clinical studies of that approach to treating GVHD and also highlight the potential value of Omni Bio's recombinant AAT candidate, AAT-Fc, currently in preclinical development. In the phase I/II study following allogeneic stem cell transplants to treat leukemic malignancies, the patients in the study all developed severe acute GVHD symptoms (severe diarrhea, loss of mucosal lining in the gut) but did not respond satisfactorily to standard treatment including high dose steroids. The first seven patients then received intravenous doses of plasma-derived AAT every other day for a total of eight doses in an attempt to alleviate their GVHD symptoms. Five of seven patients formed normal stools and were considered treatment successes; none required further treatment for GVHD.
Seattle Genetics Inc., of Bothell, Wash., announced four-year overall survival (OS) data from the Adcetris (brentuximab vedotin) pivotal phase II trial in relapsed or refractory systemic anaplastic large cell lymphoma (ALCL). Adcetris is an antibody-drug conjugate directed to CD30, which is expressed in classical Hodgkin lymphoma (HL) and systemic ALCL, a type of T-cell lymphoma. At a median follow-up of 46.3 months, the estimated four-year survival rate was 64 percent. The data estimate that more than 60 percent of the relapsed or refractory ALCL patients treated with Adcetris in that study are alive at four years, which may positively redefine outcome expectations in the difficult-to-treat cancer. Separately, the company reported data demonstrating that HL patients at risk of relapse following an autologous stem cell transplant (ASCT) who received Adcetris as consolidation therapy immediately after ASCT had significant improvement in progression-free survival compared to patients who received placebo (median of 43 months vs. 24 months, respectively; p = 0.001).
Sevion Therapeutics, of San Diego, presented results from the company's phase Ib/IIa trial of SNS01-T for the treatment of multiple myeloma and lymphoma. The open-label, multiple-dose, dose-escalation study evaluated the safety and tolerability of SNS01-T when administered by intravenous infusion to patients with relapsed or refractory multiple myeloma, mantle cell or diffuse large B-cell lymphoma. The primary objective of the study was to evaluate safety and tolerability. Of 22 patients treated, 14 patients were evaluable for dose-limiting toxicity. Of four dose cohorts tested, the maximum tolerated dose was determined to be the third dose group, at 0.2 mg/Kg. Two dose-limiting toxicities were observed, including grade 4 infusion reaction and grade 4 neutropenia.
TG Therapeutics Inc., of New York, reported results from a phase I/II study of TG-1101 (ublituximab), its glycoengineered anti-CD20 monoclonal antibody, in combination with TGR-1202, its once-per-day PI3K delta inhibitor, showing that all nine evaluable chronic lymphocytic leukemia and small lymphocytic leukemia patients exhibited nodal reductions, with six of those achieving partial responses. The remaining three patients achieved nodal reductions ranging from about 15 percent to 45 percent accompanied by either a normalization of ALC or a greater than 50 percent reduction of ALC. The combination was well tolerated in the 27 patients evaluable for safety.