Zhiguo Li

Despite the exciting advancement of novel therapies, chronic graft-versus-host disease (cGVHD) remains the most common cause of non-relapse mortality after allogeneic hematopoietic stem cell transplantation (HCT). Frontline treatment of cGVHD involves systemic steroids, which are associated with significant morbidities. We previously found that inhibition of spleen tyrosine kinase (SYK) with fostamatinib preferentially eradicated aberrantly activated B cells in both ex vivo studies of cGVHD patient B cells, as well as in vivo mouse studies. These and other preclinical studies implicated hyper-reactive B-cell receptor signaling and increased SYK expression in the pathogenesis of cGVHD and compelled this first in-human allogeneic HCT clinical trial. We investigated the safety and efficacy of the oral SYK inhibitor, fostamatinib, for both the prevention and treatment of cGVHD. The primary objective was to evaluate the safety of fostamatinib and determine its maximum tolerated dose in the post-HCT setting. Secondary objectives included assessing the efficacy of fostamatinib in preventing and treating cGVHD, as well as examining alterations in B-cell compartments with treatment. This was a single-institution phase I clinical trial that evaluated the use of fostamatinib in allogeneic HCT patients before the development of cGVHD or at the time of steroid-refractory cGVHD (SR-cGVHD). Patients received fostamatinib at one of three dose levels using a continual reassessment algorithm to determine the maximum tolerated dose. Multiparameter flow cytometry was used to evaluate changes in B cell subpopulations over the first year of treatment with fostamatinib. Nineteen patients were enrolled in this phase I trial, with 5 in the prophylaxis arm and 14 in the therapeutic arm. One patient (5%) required discontinuation of therapy for a dose-limiting toxicity. At a median follow-up of over 3 years, no patients had cancer relapse while on fostamatinib treatment, and recurrent malignancy was observed in 1 patient 2 years after the end of therapy. In the prophylaxis arm, 1 of 5 patients (20%) developed cGVHD while on fostamatinib. In the therapeutic arm, the overall response rate was 77%, with a complete response rate of 31%. The median duration of response was 19.3 months and the 12-month failure-free survival was 69% (95% confidence interval, 48-100). Patients were able to reduce their steroid dose by a median of 80%, with 73% remaining on a lower dose at 1 year compared to baseline. There was an early reduction in the proportion of IgD-CD38hi plasmablast-like cells with fostamatinib treatment, particularly in those SR-cGVHD patients who had an eventual response. B-cell reconstitution was not significantly impacted by fostamatinib therapy after allogeneic HCT. Fostamatinib featured a favorable safety profile in the post-HCT setting. Our data suggests an early efficacy signal that was associated with effects on expected cell targets in both the prophylaxis and treatment of cGVHD, providing rationale for a phase II investigation.

Multiple myeloma (MM) remains an incurable disease and there is an unmet medical need for novel therapeutic drugs that do not share similar mechanisms of action with currently available agents. Sphingosine kinase 2 (SK2) is an innovative molecular target for anticancer therapy. We previously reported that treatment with SK2 inhibitor opaganib inhibited myeloma tumor growth in vitro and in vivo in a mouse xenograft model. In the current study, we performed a phase I study of opaganib in patients with relapsed/refractory multiple myeloma (RRMM). Thirteen patients with RRMM previously treated with immunomodulatory agents and proteasome inhibitors were enrolled and treated with single-agent opaganib at three oral dosing regimens (250 mg BID, 500 mg BID, or 750 mg BID, 28 days as a cycle). Safety and maximal tolerated dose (MTD) were determined. Pharmacokinetics, pharmacodynamics, and correlative studies were also performed. Opaganib was well tolerated up to a dose of 750 mg BID. The most common possibly related adverse event (AE) was decreased neutrophil counts. There were no serious AEs considered to be related to opaganib. MTD was determined as at least 750 mg BID. On an intent-to-treat basis, one patient (7.7%) in the 500 mg BID dose cohort showed a very good partial response, and one other patient (7.7%) achieved stable disease for 3 months. SK2 is an innovative molecular target for antimyeloma therapy. The first-in-class SK2 inhibitor opaganib is generally safe for administration to RRMM patients, and has potential therapeutic activity in these patients. Clinicaltrials.gov: NCT02757326.

<jats:title>Abstract</jats:title> <jats:p>Background: Relapsed Acute Lymphoblastic Leukemia (ALL) is not curable with standard therapies. Effective outpatient treatment, allowing patients to maintain a good quality of life, while offering a meaningful chance of remission, is an appealing alternative to prolonged admission required for currently available multi-agent regimens.</jats:p> <jats:p>Vincristine sulfate liposomal injection (Marqibo) was approved in 2012 for treatment Ph-ALL in second or greater relapse, originally developed to overcome pharmacokinetic and pharmacodynamic limitations of vincristine. Approved dosing is 2.25 mg/m 2 without a dose cap. Pre-clinical studies showed it increases plasma circulation time, increases tumor tissue delivery, accumulates in tumor tissue, and slowly releases vincristine in tumor tissues rather than into systemic circulation. In a phase 2 trial, as a weekly administered single agent, CR/CRi rate was 20%, with median duration of 23 weeks and overall response rate of 35%.</jats:p> <jats:p>Blinatumomab is a murine recombinant single-chain antibody construct belonging to a class of bispecific T-cell engager (BITE) immuno-oncology. BITE molecules are designed to direct T-effector memory cells towards target cells, triggering cell-specific cytotoxicity. Blinatumomab specifically targets cells that express CD19 and the presence of both, CD19+ target cells and T cells are required for its cytotoxic activity. In previous phase 2 trials, responses to single agent blinatumomab in the relapsed setting were near 60%, although only 34% (44%, including partial and incomplete hematologic recovery) in the pivotal phase 3. Median duration of remission was only 7.3 months and half were very heavily pretreated.</jats:p> <jats:p>Here, we describe a trial designed to target ALL cells with Marquibo as a microtubule inhibitor and blinatumomab as a BiTE immuno-oncology therapy and evaluate whether this combination results in an effective and safe therapeutic option for relapsed/refractory ALL patients.</jats:p> <jats:p>We anticipate additive benefits of the regimen and define a clinically meaningful outcome as &amp;gt;75% (CR/CRi) rate and median progression-free survival (PFS) of ≥1 year. This higher rate of response is expected as many patients are using blinatumomab at first relapse, and therefore we anticipate less prior therapy than overall in the pivotal phase 3 study. Further, we hypothesize that the combination will result in a high rate of response, allowing enhanced immunologic recovery.</jats:p> <jats:p>Study Design/Methods: This is a phase 2, single arm, trial to evaluate the efficacy of blinatumomab and vincristine sulfate liposomal injection. The study will include up to 35 participants who are ≥18years of age, with Ph-, CD19+ ALL, and are either relapse or refractory to ≥2 prior regimens, have ≥5% blasts in the bone marrow or peripheral blood or persistent extranodal/marrow site or have an Eastern Cooperative Oncology Group (ECOG) performance status ≤2.</jats:p> <jats:p>The active study period includes a 3-week screening phase, followed by a treatment period (induction phase and consolidation phase) of up to 58 weeks (6 cycles), a safety follow-up 30 days later and a long-term follow-up period of up to 18 months.</jats:p> <jats:p>The induction phase includes two cycles of blinatumomab and liposomal vincristine. A single cycle is defined as 6 weeks in duration, which includes 4 weeks of continuous intravenous infusion (CIVI) of blinatumomab (initial dose 9 μg/day for first 7 days, then escalated to 28 μg/day starting on day 8 (week 2) through day 29 (week 4), followed by a 2-week treatment-free interval and 3 weekly doses of liposomal vincristine, administered intravenously at 2.25 mg/m 2, with no dose cap (per label),in the outpatient setting over 1 hour. Subjects who achieve at least stable disease within 2 induction cycles may continue to the consolidation phase to receive up to a maximum of 6 cycles under the same treatment schedule.</jats:p> <jats:p>The primary objectives are to evaluate whether the combination will result in a median PFS of ≥1 year, and if the CR/CRi rate is ≥75% following 2 cycles and duration of remission. Secondary outcomes will include evaluation of the rate of Minimal Residual Disease (MRD) and duration, the proportion of patients who are able to progress to allogeneic transplantation, the safety of blinatumomab and liposomal vincristine sulfate in combination and the effect of the combination and response on measures of immune reconstitution.</jats:p> <jats:p>Figure 1 Figure 1.</jats:p> <jats:p /> <jats:sec> <jats:title>Disclosures</jats:title> <jats:p>Rizzieri: Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Honoraria, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Acrotech: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Celltrion: Membership on an entity's Board of Directors or advisory committees; Mustang: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria; Pharmacyclics: Honoraria. Leonard: Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. Badar: Pfizer Hematology-Oncology: Membership on an entity's Board of Directors or advisory committees. Shah: Bristol-Myers Squibb/Celgene: Consultancy, Other: Expenses; Adaptive Biotechnologies: Consultancy; Novartis: Consultancy, Other: Expenses; Incyte: Research Funding; Jazz Pharmaceuticals: Research Funding; Servier Genetics: Other; Kite, a Gilead Company: Consultancy, Honoraria, Other: Expenses, Research Funding; Precision Biosciences: Consultancy; Pharmacyclics/Janssen: Honoraria, Other: Expenses; Acrotech/Spectrum: Honoraria; BeiGene: Consultancy, Honoraria; Pfizer: Consultancy, Other: Expenses; Amgen: Consultancy.</jats:p> </jats:sec>

Many patients with multiple myeloma (MM) have comorbidities and are treated with PPAR agonists. Immunomodulatory agents (IMiDs) are the cornerstones for MM therapy. Currently, little is known about how co-administration of PPAR agonists impacts lenalidomide treatment in patients with MM. Here, we determined the effects of PPAR agonists on anti-myeloma activities of lenalidomide in vitro and in a myeloma xenograft mouse model. Genetic overexpression and CRISPR/cas9 knockout experiments were performed to determine the role of CRBN in the PPAR-mediated pathway. A retrospective cohort study was performed to determine the correlation of PPAR expression with the outcomes of patients with MM. PPAR agonists down-regulated CRBN expression and reduced the anti-myeloma efficacy of lenalidomide in vitro and in vivo. Co-treatment with PPAR antagonists increased CRBN expression and improved sensitivity to lenalidomide. PPAR expression was higher in bone marrow cells of patients with newly diagnosed MM than in normal control bone marrow samples. High PPAR expression was correlated with poor clinical outcomes. Our study provides the first evidence that PPARs transcriptionally regulate CRBN and that drug-drug interactions between PPAR agonists and IMiDs may impact myeloma treatment outcomes.