Results of the OPAL Study: A Phase II Study to Evaluate the Efficacy, Safety and Tolerability of Tosedostat (CHR-2797) in Elderly Subjects with Treatment Refractory or Relapsed Acute Myeloid Leukemia

Abstract Abstract 767 Background: Tosedostat is a novel oral inhibitor of the M1/17 family of aminopeptidases which induces an amino acid deprivation response that is selectively toxic for myeloid blasts (Leuk Res. 2011: 5:677-81) and has shown promising activity in elderly relapsed/refractory AML patients (J Clin Oncol 2010:28:4333-8). Aims: The OPAL study was undertaken to compare the activity of tosedostat at a once-daily dose of 120 mg for 24 weeks compared to 240 mg once daily for 8 weeks followed by 120 mg once daily for a further 16 weeks., as measured by bone marrow and hematology responses at 24 weeks. Methods: This was a phase II randomized (1:1) multi-center study. Patients were eligible if aged 60 years or older with previous CR lasting <12 months, or no CR after primary therapy, had a peripheral blast count <30,000/μl, PS<2 and adequate renal, hepatic and cardiac function. The primary analysis was performed at 24 weeks using IWG 2003 criteria. Results: Seventy-three patients were randomized and received tosedostat, 38 at 120 mg and 35 at 240 mg. Median age was 72 (range, 64 to 86), and 59% were male. Twenty-six patients (36%) had secondary or therapy-related AML, of which 19 (26%) had prior MDS. Median time since AML diagnosis was 211 days and 38% had received primary therapy with cytarabine/anthracyclines; 36% with a hypomethylating agent (HMA) and 23% with other cytarabine regimes. Fifty-two percent had been refractory to primary therapy, 19% had previously had a remission of up to 6 months and 29% a 6–12 month remission (mean 97 days including refractory). Twenty-three patients (32%) had no post-treatment bone marrow sample taken, predominantly due to early progression: 34% completed 12 weeks on study and 14% completed 24 weeks and were eligible to enter an extension study which is ongoing. The overall response rate was 22%; (CR/CRp/MLFS 12%; PR 10%) and an additional 29% had a best response of stable disease. The most common adverse events which occurred (total; grade 3 or worse) were diarrhea (58%; 4.1%), peripheral edema (55%; 0%), fatigue (49%; 21%), dyspnea (41%; 16%), nausea (38%; 0%), decreased appetite (37%; 3%), febrile neutropenia (36%; 29%) and hypotension (36%, 10%). Median overall survival (OS) (at 15 July 2011) was 126 days. Median OS in patients with CR/CRp/MLFS, PR and SD were 280, 195 and 162 days respectively, and 261.5 days for patients with a response of PR or better. Median OS for patients with progression of disease or who were unevaluable was 61 days. Similar responses were seen in the two dose groups. Additional non protocol-specified analyses showed that the following types of patient appeared to respond well: AML NOC vs other AML types 16% vs 29% response, median OS 75 vs 168 days; patients with poor risk cytogenetics compared to intermediate/better, median OS 159 vs 107 days; those who received prior HMA compared to others, 38% vs 13% response, median OS 171 vs 104 days; and absence of prior CR 29% vs 14% response and median OS 169 vs 103 days. Conclusions: These results provide further encouraging evidence of efficacy and a favorable toxicity profile in a difficult to treat patient population. A phase III program of pivotal studies with tosedostat in AML and MDS will start in the near future. Disclosures: Cortes: Chroma Therapeutics Ltd.: Consultancy, Research Funding. Feldman:Chroma Therapeutics Ltd.: Consultancy, Research Funding. Yee:Chroma Therapeutics Ltd.: Consultancy, Research Funding. Rizzieri:Chroma Therapeutics Ltd.: Consultancy, Research Funding. Advani:Chroma Therapeutics Ltd.: Consultancy, Research Funding. Charman:Chroma Therapeutics Ltd.: Employment, Equity Ownership. Toal:Chroma Therapeutics Ltd.: Employment, Equity Ownership. Kantarjian:Chroma Therapeutics Ltd.: Consultancy, Research Funding.

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A Multi-Lineage Oral Hemokine™ HQK-1002 Enhances Neutrophil Recovery in Sub-Lethally Irradiated Mice and in Baboons.

Blood ◽

10.1182/blood.v114.22.2509.2509 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2509-2509

Author(s):

Susan Perrine ◽

Michael Boosalis ◽

Stanley Kosanke ◽

Gary White ◽

Serguei A. Castaneda ◽

...

Keyword(s):

Bone Marrow ◽

Research Funding ◽

Acute Radiation ◽

Severe Neutropenia ◽

Employment Equity ◽

Once Daily ◽

Neutrophil Recovery ◽

Equity Ownership ◽

Orally Bioavailable

Abstract Abstract 2509 Poster Board II-486 Acute radiation syndrome and therapeutic radiation are associated with cytopenias, notably severe neutropenia, particularly when large regions of bone marrow are exposed. An orally-active neutrophil stimulant which reduces the duration or magnitude of neutropenia would offer therapeutic benefit in radiation therapy and would be useful for acute radiation exposure. Orally-bioavailable short-chain fatty acid derivatives (SCFAD, HemokinesTM HQK-1002 and its S-enantiomer HQK-1002S), which stimulate proliferation of growth factor-dependent hematopoietic cell lines and CFU-GM cultures, were evaluated for in vivo activity in irradiated and 5-FU-treated mice and in normal baboons. In sub-lethal irradiation studies, mice were irradiated (6 Gy single dose) and then treated with saline or HQK-1002 once daily, 5 days/week for 2 weeks, beginning on day 1 after irradiation, and absolute neutrophil counts (ANC) were determined. The mean nadir of absolute neutrophil counts (ANC) <500/mm3 was 6 days in sub-lethally-irradiated mice treated with HQK-1002, and 18 days in the saline treated controls. In HQK-1002 treated mice, ANC did not decline below 200/mm3, while saline-treated animals experienced 10 days of severe neutropenia with ANC <200/mm3. In lethally-irradiated (LD90) mice, either saline or the (S) enantiomer of HQK-1002 was administered daily. ANC and marrow pathology were compared between saline and HQK-1002S-treated animals. The duration of peripheral neutropenia was similar in controls and HQK-1002S-treated animals, but bone marrow pathology demonstrated profound ablation of all mature myeloid series (10-20% cellularity) in the saline controls, while HQK-1002S-treated animals had normal bone marrow cellularity (55–75%) with complete neutrophil maturation within 2 weeks following radiation. In 5FU-treated mice, neutrophil recovery was compared between HQK-1002, saline, or G-CSF treatment for 3 weeks. Recovery from profound neutropenia (nadir at Day 9) occurred by Day 13 in G-CSF- and HQK-1002 treated animals, 5 days before recovery was observed in saline controls. HQK-1002 and HQK-1002S were also administered to non-irradiated, normal juvenile baboons, once daily for 5 days, and CBCs and neutrophil counts were assayed. HQK-1002 or HQK-1002S treatment in 3 unchallenged baboons resulted in a two-fold to three-fold rises in ANC within 7 days. Collectively, these studies strongly suggest that HQK-1002 and HQK-1002S, orally-bioavailable SCFADs, stimulate myelopoiesis in vivo in normal animals and during sub-lethal radiation-induced bone marrow suppression, and merit further evaluation in neutropenia associated with marrow suppression. Disclosures: Perrine: HemaQuest Pharmaceuticals: Employment, Equity Ownership, Patents & Royalties, Research Funding. Boosalis:HemaQuest Pharmaceuticals: Equity Ownership. Thomson:HemaQuest Pharmaceuticals: Employment, Equity Ownership. Berenson:hemaQuest Pharmaceuticals: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Faller:HemaQuest Pharmaceuticals: Consultancy, Equity Ownership, Patents & Royalties, Research Funding.

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EZH2 Mutations and Impact on Clinical Outcome Analyzed in 1604 Patients with Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2018-99-114421 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1528-1528

Author(s):

Sebastian Stasik ◽

Jan Moritz Middeke ◽

Michael Kramer ◽

Christoph Rollig ◽

Alwin Krämer ◽

...

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Employment Equity ◽

Advisory Committees ◽

Mutational Status ◽

Equity Ownership ◽

Acute Myeloid

Abstract Purpose: The enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and key epigenetic regulator involved in transcriptional repression and embryonic development. Loss of EZH2 activity by inactivating mutations is associated with poor prognosis in myeloid malignancies such as MDS. More recently, EZH2 inactivation was shown to induce chemoresistance in acute myeloid leukemia (AML) (Göllner et al., 2017). Data on the frequency and prognostic role of EZH2-mutations in AML are rare and mostly confined to smaller cohorts. To investigate the prevalence and prognostic impact of this alteration in more detail, we analyzed a large cohort of AML patients (n = 1604) for EZH2 mutations. Patients and Methods: All patients analyzed had newly diagnosed AML, were registered in clinical protocols of the Study Alliance Leukemia (SAL) (AML96, AML2003 or AML60+, SORAML) and had available material at diagnosis. Screening for EZH2 mutations and associated alterations was done using Next-Generation Sequencing (NGS) (TruSight Myeloid Sequencing Panel, Illumina) on an Illumina MiSeq-system using bone marrow or peripheral blood. Detection was conducted with a defined cut-off of 5% variant allele frequency (VAF). All samples below the predefined threshold were classified as EZH2 wild type (wt). Patient clinical characteristics and co-mutations were analyzed according to the mutational status. Furthermore, multivariate analysis was used to identify the impact of EZH2 mutations on outcome. Results: EZH2-mutations were found in 63 of 1604 (4%) patients, with a median VAF of 44% (range 6-97%; median coverage 3077x). Mutations were detected within several exons (2-6; 8-12; 14-20) with highest frequencies in exons 17 and 18 (29%). The majority of detected mutations (71% missense and 29% nonsense/frameshift) were single nucleotide variants (SNVs) (87%), followed by small indel mutations. Descriptive statistics of clinical parameters and associated co-mutations revealed significant differences between EZH2-mut and -wt patients. At diagnosis, patients with EZH2 mutations were significantly older (median age 59 yrs) than EZH2-wt patients (median 56 yrs; p=0.044). In addition, significantly fewer EZH2-mut patients (71%) were diagnosed with de novo AML compared to EZH2-wt patients (84%; p=0.036). Accordingly, EZH2-mut patients had a higher rate of secondary acute myeloid leukemia (sAML) (21%), evolving from prior MDS or after prior chemotherapy (tAML) (8%; p=0.036). Also, bone marrow (and blood) blast counts differed between the two groups (EZH2-mut patients had significantly lower BM and PB blast counts; p=0.013). In contrast, no differences were observed for WBC counts, karyotype, ECOG performance status and ELN-2017 risk category compared to EZH2-wt patients. Based on cytogenetics according to the 2017 ELN criteria, 35% of EZH2-mut patients were categorized with favorable risk, 28% had intermediate and 37% adverse risk. No association was seen with -7/7q-. In the group of EZH2-mut AML patients, significantly higher rates of co-mutations were detected in RUNX1 (25%), ASXL1 (22%) and NRAS (25%) compared to EZH2-wt patients (with 10%; 8% and 15%, respectively). Vice versa, concomitant mutations in NPM1 were (non-significantly) more common in EZH2-wt patients (33%) vs EZH2-mut patients (21%). For other frequently mutated genes in AML there was no major difference between EZH2-mut and -wt patients, e.g. FLT3ITD (13%), FLT3TKD (10%) and CEBPA (24%), as well as genes encoding epigenetic modifiers, namely, DNMT3A (21%), IDH1/2 (11/14%), and TET2 (21%). The correlation of EZH2 mutational status with clinical outcomes showed no effect of EZH2 mutations on the rate of complete remission (CR), relapse free survival (RFS) and overall survival (OS) (with a median OS of 18.4 and 17.1 months for EZH2-mut and -wt patients, respectively) in the univariate analyses. Likewise, the multivariate analysis with clinical variable such as age, cytogenetics and WBC using Cox proportional hazard regression, revealed that EZH2 mutations were not an independent risk factor for OS or RFS. Conclusion EZH mutations are recurrent alterations in patients with AML. The association with certain clinical factors and typical mutations such as RUNX1 and ASXL1 points to the fact that these mutations are associated with secondary AML. Our data do not indicate that EZH2 mutations represent an independent prognostic factor. Disclosures Middeke: Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Rollig:Bayer: Research Funding; Janssen: Research Funding. Scholl:Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Abbivie: Other: Travel support; Alexion: Other: Travel support; MDS: Other: Travel support; Novartis: Other: Travel support; Deutsche Krebshilfe: Research Funding; Carreras Foundation: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Hochhaus:Pfizer: Research Funding; Incyte: Research Funding; Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Takeda: Research Funding. Brümmendorf:Janssen: Consultancy; Takeda: Consultancy; Novartis: Consultancy, Research Funding; Merck: Consultancy; Pfizer: Consultancy, Research Funding. Burchert:AOP Orphan: Honoraria, Research Funding; Bayer: Research Funding; Pfizer: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Research Funding. Krause:Novartis: Research Funding. Hänel:Amgen: Honoraria; Roche: Honoraria; Takeda: Honoraria; Novartis: Honoraria. Platzbecker:Celgene: Research Funding. Mayer:Eisai: Research Funding; Novartis: Research Funding; Roche: Research Funding; Johnson & Johnson: Research Funding; Affimed: Research Funding. Serve:Bayer: Research Funding. Ehninger:Cellex Gesellschaft fuer Zellgewinnung mbH: Employment, Equity Ownership; Bayer: Research Funding; GEMoaB Monoclonals GmbH: Employment, Equity Ownership. Thiede:AgenDix: Other: Ownership; Novartis: Honoraria, Research Funding.

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Randomized Phase II Study Evaluating the Efficacy and Safety of Romiplostim Treatment of Patients with Low or Intermediate Risk Myelodysplastic Syndrome (MDS) Receiving Lenalidomide.

Blood ◽

10.1182/blood.v114.22.1770.1770 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1770-1770 ◽

Cited By ~ 6

Author(s):

Roger M Lyons ◽

Richard A. Larson ◽

Michael A. Kosmo ◽

Sunil Gandhi ◽

Delong Liu ◽

...

Keyword(s):

Bone Marrow ◽

Research Funding ◽

Intermediate Risk ◽

Employment Equity ◽

Treatment Groups ◽

Platelet Counts ◽

Equity Ownership ◽

Clinically Significant ◽

Dose Reductions ◽

Platelet Transfusions

Abstract Abstract 1770 Poster Board I-796 Introduction Romiplostim is a peptibody protein designed to increase platelet production by binding to and activating the thrombopoietin receptor. Low platelet counts in patients with myelodysplastic syndromes (MDS) may be due to the underlying disease or to treatment with disease-modifying agents, and platelet transfusions are often the only treatment for clinically significant thrombocytopenia (CST) or bleeding. This was a phase 2 multi-center, randomized, double-blind, placebo-controlled, dose-finding study that evaluated the effect of romiplostim on the incidence of clinically significant thrombocytopenic events (grade 3 or 4 thrombocytopenia and/or receipt of platelet transfusions) and the safety of romiplostim in patients with low or intermediate risk MDS receiving lenalidomide. Patients and Methods Patients who were ≥18 years old, had MDS by bone marrow exam and WHO criteria, had low or Intermediate-1 risk category MDS using the IPSS, and were planning to receive lenalidomide were eligible. Patients were randomized 1:1:1 into treatment groups receiving placebo, 500 μg romiplostim, or 750 μg romiplostim by weekly subcutaneous injections in combination with lenalidomide (one 10 mg capsule by mouth daily for each 28-day cycle). Treatments continued for a total of four cycles. Results The median age of the 39 randomized patients was 74 years (range, 39 to 90); 15 (39%) had platelet counts <50 × 109/L, and 7 (18%) had del(5q). We report trends due to baseline imbalances between treatment groups, likely due to the limited sample size. The overall incidence rates of CST appeared to be greater in the placebo group than either romiplostim group (Table). In contrast to the placebo patients, median platelet counts remained above 50 × 109/L in both the 500 μg and 750 μg romiplostim groups for the treatment period. The incidence of platelet transfusions appeared to be lower in the 500 μg romiplostim group, and the incidence of adverse events was comparable between all of the groups. No deaths were reported during the treatment period. Twelve patients (31%) discontinued the study. Disease progression to AML was reported in 1 patient in the romiplostim 500 μg group. The patient withdrew consent and discontinued the study. No bone marrow was available to confirm AML by protocol-defined criteria. Fewer lenalidomide dose reductions and delays due to thrombocytopenia were seen in both of the romiplostim treated groups. The proportion of patients who achieved an MDS treatment response was 8%, 36% and 15% for the placebo, 500 μg romiplostim, and 750 μg romiplostim groups, respectively. MDS response rates appeared higher in the romiplostim group, regardless of baseline del(5q) status. Baseline imbalance between groups due to the small sample size limited our interpretation of the data. Conclusions Romiplostim appeared to be well-tolerated in low and intermediate risk MDS patients receiving lenalidomide. This preliminary information suggests that romiplostim may reduce the rate of clinically significant thrombocytopenic events in these patients while increasing platelet counts and decreasing the incidence of lenalidomide dose reductions and delays due to thrombocytopenia Disclosures Lyons: GlaxoSmithKline: Consultancy, Speakers Bureau; Johnson&Johnson: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy; Amgen Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau. Off Label Use: Use of romiplostim to treat Thrombocytopenia in MDS. Larson:Amgen Inc.: Equity Ownership, Research Funding. Liu:Amgen Inc.: Honoraria, Research Funding. Hu:Amgen Inc.: Employment, Equity Ownership. Franklin:Amgen Inc.: Employment, Equity Ownership. Berger:Amgen Inc.: Employment, Equity Ownership.

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Use of a New Rotary Powered Device for Bone Marrow Aspiration and Biopsy Yields Excellent Specimens Quickly and Efficiently.

Blood ◽

10.1182/blood.v114.22.4544.4544 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4544-4544

Author(s):

Ronan T. Swords ◽

Kevin R. Kelly ◽

Devalingam Mahalingam ◽

Stephen C. Cohen ◽

Larry J. Miller ◽

...

Keyword(s):

Bone Marrow ◽

Bone Marrow Biopsy ◽

Clinical Evaluation ◽

Research Funding ◽

Bone Marrow Aspiration ◽

Swine Model ◽

Employment Equity ◽

Equity Ownership ◽

Specimen Quality ◽

The Mean

Abstract Abstract 4544 Background The importance of bone marrow aspiration and biopsy in the evaluation of hematopoietic and non-hematopoietic disorders is well established. Recently, a new FDA-cleared battery powered bone marrow biopsy system was developed to allow operators access to the bone marrow space quickly and efficiently. Aims The first aim of this study was to evaluate the quality of core specimens using the new powered device compared to specimens obtained using the traditional manual technique in a swine model. The second aim was to evaluate the safety and efficacy of the device in patients presenting for outpatient hematology clinic visits. Materials and Methods For the pre-clinical evaluation of the device, three anesthetized pigs were used for the study. The powered device (OnControl, Vidacare Corporation, San Antonio, TX, USA) was comprised of a battery powered driver and needle set. The manual device used was a T-Handle Jamshidi bone marrow biopsy needle (Cardinal Health, Dublin, OH, USA). Core biopsy samples obtained were assessed for length and sample quality and then submitted for analysis to a pathologist blinded to the device used. The clinical evaluation of the device was conducted in accordance with practice guidelines and directions for use. Data collection included insertion success, time from insertion to removal, specimen quality, operator satisfaction with control/function of the device and overall operator satisfaction based on a scoring system (0-5; 0=totally unacceptable, 5=outstanding). Results Twenty six samples were collected from the swine model (19 samples using the powered device and 9 using the manual technique). No cellular artifact or thermal damage was reported in any of the samples obtained. The mean lengths for samples obtained using the powered and manual techniques were respectively 19.4mm±1.6mm and 18.6mm±5.3mm. For the clinical evaluation of the device, 16 patients were recruited from 2 centers. Mean insertion time was 11.25±3.39 seconds and mean time from needle contact with skin to needle removal was 38.5±13.94 seconds. No complications were reported. Five operators rated the overall use of the device as outstanding in 75% of cases. Conclusions In this study, the manual and powered samples were equivalent in specimen quality. The powered device however, captured longer biopsies when compared to the manual technique. In the patients evaluated, the device was easy to use as well as being safe and effective. The mean procedural time was significantly faster than previously reported with a manual technique. A randomized study of the powered device compared to the manual technique is underway. Disclosures: Swords: Vidacare Corporation: Research Funding. Kelly:Vidacare Corporation: Research Funding. Mahalingam:Vidacare Corporation: Research Funding. Cohen:Vidacare Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Miller:Vidacare Corporation: Employment, Equity Ownership. Philbeck:Vidacare Corporation: Employment, Equity Ownership. Brenner:Vidacare Corporation: Consultancy, Research Funding. Giles:Vidacare Corporation: Research Funding.

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Effect of the Cytochrome P450 3A4 Inducers, Rifampicin and Dexamethasone, on the Pharmacokinetic, Pharmacodynamic and Safety Profile of Bortezomib In Patients with Multiple Myeloma (MM) and Non-Hodgkin's Lymphoma (NHL)

Blood ◽

10.1182/blood.v116.21.3983.3983 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3983-3983

Author(s):

Andrzej Hellmann ◽

Simon A. Rule ◽

Jan Walewski ◽

Ofer Shpilberg ◽

Huaibao Feng ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Proteasome Inhibition ◽

Employment Equity ◽

Advisory Committees ◽

Time Curve ◽

Once Daily ◽

Cyp3a4 Inducer ◽

Equity Ownership ◽

The Mean

Abstract Abstract 3983 Background: Bortezomib is primarily metabolized by cytochrome P450 (CYP) 3A4 and 2C19 enzymes. Effects of co-administration of rifampicin (a potent CYP3A4 inducer) and dexamethasone (weak CYP3A4 inducer) on the pharmacokinetic (PK), pharmacodynamic (PD) and safety profiles of bortezomib were evaluated. Methods: Patients with relapsed or refractory multiple myeloma (MM) or non-Hodgkin's lymphoma (NHL) were enrolled in this open-label, 2-stage, parallel-group study. In stage 1, patients were randomized (1:1) to receive 3 cycles of bortezomib (1.3 mg/m2) on d 1, 4, 8, and 11 q3wk either alone or in combination with rifampicin 600 mg once-daily on d 4 to 10 of cycle 3 only. Stage 2 patients received bortezomib at same dose and schedule in combination with dexamethasone 40 mg once-daily on d 1 to 4 and d 9 to 12 of cycle 3 only. Patients could continue with bortezomib monotherapy for up to 10 cycles in case of clinical benefit. For PK/PD, blood samples were collected before and through 72 hours following bortezomib administration on d 11 of cycles 2 and 3. PK was the primary endpoint, secondary endpoints included PD (proteasome inhibition) and safety. Results: 61 patients were enrolled (39 MM, 22 NHL) in the study. 13 were treated with bortezomib + rifampicin, 18 with bortezomib + dexamethasone, and 30 with bortezomib only. Co-administration of rifampicin reduced the mean bortezomib maximum plasma concentration (Cmax) by approximately 23% (118 vs 93 ng/mL) and the mean area under plasma concentration-time curve from 0 to 72 hours (AUC72) by approximately 45% (223 vs 123 ng.h/mL). Co-administration of dexamethasone had no effect on mean AUC72 (179 vs 170 ng.h/mL). The mean bortezomib Cmax was 20% lower after co-administration of dexamethasone (140 vs 119 ng/mL); however this difference in Cmax was within the observed variability in Cmax during cycle 2 (CV=38%) and cycle 3 (CV=45%). Mean (SD) maximum percent proteasome inhibition (Emax) and area under percent proteasome inhibition-time curve from 0 to 72 hours (AUE72h) were comparable for bortezomib alone and in combination with rifampicin (Emax: 61.9 [4.56] vs. 62.3 [3.81] and AUE72h: 836 [323] vs. 777 [358]). Co-administration of dexamethasone did not affect the Emax (66.7 [4.27] vs. 61.8 [6.69]) or AUE72h (1329 [638] vs. 1157 [381]). Safety profiles were consistent with prior bortezomib experience in this population. Drug-related serious adverse events and treatment discontinuations were reported in 7/30 (23%) and 8/30 (27%) in bortezomib-only, in 3/13 (23%) and 3/13 (23%) in bortezomib + rifampicin, and 3/18 (17%) and 5/18 (28%) in bortezomib + dexamethasone subgroups. Investigator-assessed responses (CR+PR) were observed in 13/17 MM and 6/13 NHL patients in bortezomib-only, in 6/9 MM and 3/4 NHL patients in bortezomib + rifampicin, and in 10/13 MM and 2/5 NHL patients in bortezomib + dexamethasone subgroups. Conclusions: Co-administration of dexamethasone did not affect the PK or PD profiles of bortezomib. Co-administration of rifampicin reduced bortezomib exposure (AUC) by approximately 45%. Patients receiving bortezomib concomitantly with strong CYP3A4 inducers, such as rifampicin, should be monitored for reduction in clinical effect, while concomitant administration of weak CYP3A4 inducers, such as dexamethasone, is not expected to affect the bortezomib pharmacologic profile. Disclosures: Off Label Use: Discussion of Velcade in NHL subtypes other than mantle cell lymphoma is included. Rule:Johnson & Johson: Consultancy, Speakers Bureau; Roche: Consultancy. Walewski:Johnson & Johnson: Honoraria, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Investigators fee. Shpilberg:Johnson & Johnson: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Feng:Johnson & Johnson: Employment. van de Velde:Johnson & Johnson: Employment, Equity Ownership. Patel:Johnson & Johnson: Employment, Equity Ownership. Skee:Johnson & Johnson: Employment. Girgis:Johnson & Johnson: Employment. Louw:Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Key Oncologics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers-Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Final Results from an International, Multi-Center, Single-Arm Study Evaluating the Safety and Efficacy of Romiplostim in Adults with Primary Immune Thrombocytopenia (ITP),

Blood ◽

10.1182/blood.v118.21.3279.3279 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3279-3279 ◽

Cited By ~ 6

Author(s):

Ann Janssens ◽

Michael D. Tarantino ◽

Robert Bird ◽

Maria Gabriella Mazzucconi ◽

Ralph Vincent V. Boccia ◽

...

Keyword(s):

Bone Marrow ◽

Platelet Count ◽

Board Of Directors ◽

Research Funding ◽

Platelet Response ◽

Employment Equity ◽

Advisory Committees ◽

Platelet Production ◽

Platelet Counts ◽

Equity Ownership

Abstract Abstract 3279 Background: ITP is an autoimmune disorder characterized by increased platelet destruction and suboptimal platelet production. Romiplostim stimulates platelet production via the TPO-receptor, and is recommended for second- and third-line treatment of chronic ITP in adults. We report final data from a large prospective study of romiplostim in adults with ITP of varying duration and severity. Methods: Eligibility criteria were broad: patients ≥18 years of age, who had received prior ITP therapies (final protocol amendment: ≥1, previous amendments: ≥3), with low platelet counts (final amendment: ≤ 30 × 109/L, previous amendments: ≤ 10, ≤ 20 × 109/L) or experiencing uncontrolled bleeding. The only excluded comorbidities were: hematological malignancy, myeloproliferative neoplasms, MDS and bone marrow stem cell disorder. Romiplostim was initiated at 1 (final amendment) or 3 (previous amendments) μg/kg/week, with dose adjustments allowed to maintain platelet counts ≥50 × 109/L. Patients could continue on study until they had access to commercially available romiplostim. Rescue medications were allowed at any time; concurrent ITP therapies could be reduced when platelet counts were > 50 × 109/L. Primary endpoint was incidence of adverse events (AEs) and antibody formation. Secondary endpoint was platelet response, defined as either (1) doubling of baseline count and ≥ 50 × 109/L or (2) ≥20 × 109/L increase from baseline. Results: A total of 407 patients received romiplostim, 60% of whom were female. Median (Q1, Q3) time since ITP diagnosis was 4.25 (1.20, 11.40) years (maximum 57.1 years), with 51% of patients splenectomised and 39% receiving baseline concurrent ITP therapies. Seventy-one percent of patients completed the study, with requirement for alternative therapy and withdrawn consent the most common reasons for discontinuation (5% each). Median (Q1, Q3) on-study treatment duration was 44.29 (20.43, 65.86) weeks (maximum 201 weeks), with a total of 20,201 subject-weeks on study. Incidence and type of AEs were consistent with previous studies. The most common serious treatment-related AEs were cerebrovascular accident, headache, bone marrow reticulin fibrosis (with no evidence of positive trichrome staining for collagen and no evidence suggesting primary idiopathic myelofibrosis), nausea, deep vein thrombosis, hemorrhage and pulmonary embolism, with each reported in 2 of 407 (0.5%) patients. All other serious treatment-related AEs were each reported in one patient. Eighteen patients died; 3 deaths (hemolysis, intestinal ischaema, aplastic anemia) were considered treatment-related. No neutralizing antibodies to romiplostim or TPO were reported. Approximately 90% of patients achieved each of the platelet response definitions, regardless of splenectomy status. Overall, median (Q1, Q3) time to response was 2 (1, 4) weeks for response definition 1, and 1 (1, 3) week for response definition 2. Median (Q1, Q3) baseline platelet count was 14 (8, 21) × 109/L. After 1 week of treatment median (Q1, Q3) platelet count had increased to 42 (18, 101) × 109/L. From week 8 onwards, and excluding counts within 8 weeks of rescue medication use, median platelet counts were consistently above 100 × 109/L (range 101.0–269.5 × 109/L). Median (Q1, Q3) average weekly romiplostim dose was 3.62 (1.99, 6.08) μg/kg. Summary/conclusions: This is the largest prospective study in adult ITP reported to date. The data reported here are similar to those reported for previous romiplostim studies, with romiplostim able to safely induce a rapid platelet response in adult ITP patients with low platelet counts or bleeding symptoms. Romiplostim is an important, well-tolerated, treatment option for adult ITP patients, which significantly increases and maintains platelet counts. Adverse Event Subject Incidence Platelet Response Disclosures: Janssens: Amgen: Consultancy; Roche: Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees. Tarantino:Cangene corporation: Research Funding; Baxter: Research Funding; Talecris: Honoraria, Speakers Bureau; Up-to-date: Patents & Royalties; The Bleeding and Clotting Disorders Institute: Board Member. Bird:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees. Boccia:Amgen: Equity Ownership, Honoraria, Speakers Bureau. Lopez-Fernandez:Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kozak:Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Steurer:Amgen: Honoraria. Dillingham:Amgen Limited: Employment, Equity Ownership. Lizambri:Amgen: Employment, Equity Ownership.

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The Safety and Activity of BMS-906024, a Gamma Secretase Inhibitor (GSI) with Anti-Notch Activity, in Patients with Relapsed T-Cell Acute Lymphoblastic Leukemia (T-ALL): Initial Results of a Phase 1 Trial

Blood ◽

10.1182/blood.v124.21.968.968 ◽

2014 ◽

Vol 124 (21) ◽

pp. 968-968 ◽

Cited By ~ 22

Author(s):

Patrick A. Zweidler-McKay ◽

Daniel J. DeAngelo ◽

Dan Douer ◽

Hervé Dombret ◽

Oliver G. Ottmann ◽

...

Keyword(s):

Bone Marrow ◽

Research Funding ◽

Phase 1 ◽

Employment Equity ◽

Mutation Status ◽

Response Data ◽

Notch Receptors ◽

Equity Ownership ◽

Grade 3 ◽

Count Recovery

Abstract Background: Activating mutations in Notch receptors are found in multiple hematopoietic malignancies, including > 50% of patients with T-ALL, making it the most common genetic abnormality in this disease. GSIs block activation of Notch receptors and limit growth and survival in pre-clinical T-ALL models. However, various GSIs evaluated in clinical trials have had on target toxicities and have not been reported to show significant responses. CA216002 is a multicenter phase 1 trial designed to assess the safety of a novel intravenous GSI BMS-906024 in patients with relapsed or refractory T-ALL and T-cell lymphoblastic lymphoma (T-LL). We are presenting the initial toxicity profile and response data on this trial. Methods: Adults with relapsed/refractory T-ALL or T-LL were enrolled and received BMS-906024 intravenously weekly at doses of 0.6 mg, 4 mg, and 6 mg. Due to the rapid progression of T-ALL in many cases, administration of glucocorticoids or other agents was permitted and dosing guidelines for dexamethasone were provided in the protocol. Results: As of July 2, 2014, safety and response data are available on 25 patients (age 18-74 yrs) with relapsed/refractory T-ALL/T-LL that received at least one dose of BMS-906024, at doses of 0.6 mg (n=1), 4 mg (n=10), and 6 mg (n=14). Seven patients did not complete the first 4-week cycle due to rapid disease progression or disease-related death (n=5), infusion reaction (n=1), or an unrelated adverse event (n=1). Safety: The drug-related grade 3-5 adverse events included grade 4 events of anemia, hypophosphatemia, and thrombocytopenia, and grade 3 events of diarrhea, febrile bone marrow aplasia, hepatotoxicity, hypophosphatemia, pancytopenia, and tumor lysis syndrome (n=1 each). Drug-related diarrhea was common (n=11, 44%), consistent with expectations for Notch inhibition, but was generally grade 1-2 with only one grade 3 event. One dose-limiting toxicity involving grade 3 elevations of ALT and AST without bilirubin elevation (reported as grade 3 hepatotoxicity) occurred at the 4 mg dose level. One death not related to disease progression occurred, due to GI and post-surgical hemorrhage associated with pancytopenia; hemorrhage was considered not related, but pancytopenia was considered related to study drug. Responses: Eight patients (32%; 4 at 4 mg and 4 at 6 mg) had at least 50% reduction in bone marrow (BM) blasts, including one formal CR and one PR (both at 6 mg), and three of these eight had 98-100% clearance of BM blasts. (One patient, marked “*” below, began the study with 0.1% BM blasts and is not included in the eight.) The patient who achieved a CR began the study with 85% BM blasts and an absolute peripheral blood (PB) blast count of 38 k/mcL. By the end of the first cycle the BM and PB were cleared of blasts, and by the end of the second cycle there was count recovery. This patient received dexamethasone during the first cycle only, and left the study after 3 cycles in CR for an allogeneic transplant. The patient who achieved a PR began with 32% BM blasts, and by the end of the first cycle the BM blasts had decreased to 7% with improvement in ANC. The additional six patients with 50-100% decreases in BM blasts had residual lymphadenopathy, had incomplete count recovery or failed to meet other criteria which prevented them from being considered CR or PR based on the protocol definitions. One of these six patients also received hydroxyurea beginning on study day 16. Biomarkers: The figure shows change in BM blasts in 12 patients with paired BM assessments and Notch mutation status available. BM responses occurred in both Notch mutant and wildtype patients. Conclusions: Overall 8 of the 25 patients (32%) showed at least 50% reduction in BM blasts including one CR and one PR. Although the contribution of concurrent glucocorticoid therapy to the improvement in some patients is not clearly defined, the multiple responses on this trial suggest anti-leukemia activity of BMS-906024. This represents the first Notch targeting trial leading to multiple responses in relapsed/refractory T-ALL. BMS-906024 was relatively well tolerated, with minimal diarrhea in this population. The weekly dosing of this long-acting GSI shows promise for targeting Notch in T-ALL. Pharmacokinetic and additional biomarker data will be presented. Figure 1 Figure 1. Maximum Percent Reduction from Baseline of BM Blasts in Patients with Paired BM Assessments and Known Mutation Status Disclosures Zweidler-McKay: BMS: Research Funding. Off Label Use: BMS-906024 is in early Phase I clinical trials, and does not yet have an FDA-approved indication.. Douer:BMS: Research Funding. Ottmann:BMS: Consultancy, Honoraria, Research Funding. Vey:BMS: Honoraria. Thomas:BMS: Research Funding. Zhu:BMS: Employment. Huang:BMS: Employment, Equity Ownership. Bajaj:BMS: Employment. Fischer:BMS: Employment, Equity Ownership.

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Ublituximab, a Novel Glycoengineered Anti-CD20 Monoclonal Antibody (mAb), in Combination with TGR-1202, a Next Generation Once Daily PI3kδ Inhibitor, Demonstrates Activity in Heavily Pre-Treated and High-Risk Chronic Lymphocytic Leukemia (CLL) and B-Cell Lymphoma

Blood ◽

10.1182/blood.v124.21.801.801 ◽

2014 ◽

Vol 124 (21) ◽

pp. 801-801 ◽

Cited By ~ 1

Author(s):

Matthew A. Lunning ◽

Julie M. Vose ◽

Marshall T. Schreeder ◽

Nathan Fowler ◽

Loretta J. Nastoupil ◽

...

Keyword(s):

High Risk ◽

Research Funding ◽

Next Generation ◽

Employment Equity ◽

Once Daily ◽

Richter's Transformation ◽

Equity Ownership ◽

Anti Cd20 ◽

Ecog Ps ◽

11Q Deletion

Abstract Introduction: Ublituximab (UTX) is a novel chimeric mAb targeting a unique epitope on the CD20 antigen, glycoengineered to enhance affinity to FcγRIIIa receptors, thereby demonstrating significantly greater ADCC than rituximab. UTX monotherapy in patients (pts) with rituximab relapsed/refractory NHL and CLL has reported a 43% ORR (ASCO 2014). TGR-1202 is a next generation, once daily, oral PI3Kδ inhibitor which notably lacks the hepatotoxicity associated with other PI3Kδ inhibitors, and is active in pts with relapsed and refractory hematologic malignancies (EHA 2014). UTX and TGR-1202 have shown synergistic activity in-vitroin various lymphoid cell lines (Lugano 2013). This Phase 1 trial evaluates safety and efficacy of the combination of a glycoengineered anti-CD20 (UTX) and a PI3Kδ inhibitor (TGR-1202) in pts with heavily pre-treated relapsed or refractory CLL and NHL. Methods: Eligible pts have relapsed/refractory CLL or NHL with an ECOG PS ≤ 2. A 3+3 design evaluates cohorts of CLL and NHL pts independently with UTX dosed on Days 1, 8, 15 of Cycles 1 & 2 followed by maintenance therapy. UTX starts at 600 mg in Cohort 1 and increases to 900 mg for pts with CLL and is fixed at 900 mg for pts with NHL. TGR-1202 starts at 800 mg QD in Cohort 1 and is increased in subsequent cohorts. An amendment in July 2014 was introduced to include an improved micronized formulation of TGR-1202, starting at 400 mg once daily and increasing in subsequent cohorts. There are no limits on prior therapy, and patients with Richter’s Transformation or who are refractory to prior PI3Kδ inhibitors or BTK inhibitors are eligible. Primary endpoints: Safety and Dose Limiting Toxicities (DLT). Secondary endpoints: Efficacy (ORR, CR rate). Results: As of August 2014, 21 pts have been enrolled: 8 CLL/SLL, 7 DLBCL, 5 Follicular Lymphoma, and 1 patient with Richter’s Transformation. Median age is 64 years (range 35-82); 12 male/9 female. Median prior Tx = 3 (range 1-9); median ECOG PS = 1. All pts are evaluable for safety. Adverse events have been manageable with no safety concerns noted. Day 1 infusion related reactions (IRR) were the most common treatment related adverse event (48%), with all but one event Grade 1 or 2 in severity, followed by neutropenia (38%), diarrhea (29%), and nausea (29%). Notably, no events of TGR-1202 related hepatotoxicity have been reported to date. All IRR and neutropenia events have been manageable with dose delays. One neutropenia related dose delay in a CLL patient at UTX 600 mg + TGR 800 mg met the criteria for a DLT, necessitating enrollment of additional pts into this cohort. No other DLTs have been reported, including at higher dose levels. Fifteen pts were evaluable for efficacy with 6 pts too early for response assessment. Among evaluable pts, 80% displayed a reduction in tumor burden at first efficacy assessment, despite pts exhibiting a number of high-risk characteristics, including 3/5 CLL pts having 17p/11q deletion and a median of 6 prior lines of therapy amongst pts with FL. Objective responses are summarized below: Table TypePts (n)PRn (%)ORRn (%)PD(n)% pts ≥ SD for 12 wksMedian Prior Rx CLL/SLL54 (80%)4 (80%)-5 (100%)2 (1 – 3) Richter’s1---1 (100%)1 FL4---4 (100%)6 (3 – 8) DLBCL52 (40%)2 (40%)14 (80%)3 (1 – 6) Total156 (40%)6 (40%)114 (93%)3 (1 – 8) Amongst pts with CLL, 2/2 pts with normal cytogenetics achieved a PR including a patient with prior treatment with a BTK inhibitor, while 2/3 pts with presence of 17p/11q deletion achieved a PR, with the remaining patient having SD with a 44% nodal reduction at first assessment. Conclusions: Preliminary data suggests the combination of UTX + TGR-1202 is well tolerated with early signs of clinical activity in heavily pre-treated and high-risk patient subsets. Enrollment is ongoing with at least 30 patients anticipated. Disclosures Lunning: Onyx: Consultancy; Alexion: Consultancy; Gilead: Consultancy; Spectrum Pharmaceuticals: Consultancy. Schreeder:TG Therapeutics, Inc.: Research Funding. Pauli:TG Therapeutics, Inc.: Consultancy. Miskin:TG Therapeutics, Inc.: Employment, Equity Ownership. Sportelli:TG Therapeutics: Employment, Equity Ownership. Weiss:TG Therapeutics, Inc.: Employment, Equity Ownership. Vakkalanka:Rhizen: Employment, Equity Ownership. Viswanadha:Incozen: Employment. O'Brien:Amgen, Celgene, GSK: Consultancy; CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Emergent, Genentech, Gilead, Infinity, Pharmacyclics, Spectrum: Consultancy, Research Funding; MorphoSys, Acerta, TG Therapeutics: Research Funding.

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Ublituximab + TGR-1202 Demonstrates Activity and a Favorable Safety Profile in Relapsed/Refractory B-Cell NHL and High-Risk CLL: Phase I Results

Blood ◽

10.1182/blood.v126.23.1538.1538 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1538-1538 ◽

Cited By ~ 6

Author(s):

Matthew A. Lunning ◽

Julie Vose ◽

Nathan Fowler ◽

Loretta Nastoupil ◽

Jan A. Burger ◽

...

Keyword(s):

High Risk ◽

Phase I ◽

Research Funding ◽

Clinical Activity ◽

Employment Equity ◽

Once Daily ◽

Phase Ib ◽

Equity Ownership ◽

Favorable Safety ◽

Higher Doses

Abstract Introduction: Ublituximab (UTX) is a novel anti-CD20 mAb that has been glycoengineered for enhanced ADCC. TGR-1202 is a novel once daily oral PI3Kδ inhibitor with clinical activity in B-cell lymphoma and a notably differentiated tolerability profile compared to similar agents. The combination of UTX + TGR-1202 showed strong synergistic activity in-vitro (Lugano 2013). Herein we report the results from the Phase 1 (dose-escalation) and updated results from the Phase Ib (dose-expansion) evaluating the safety and efficacy of the combination of UTX + TGR-1202 in patients (pts) with heavily pre-treated rel/ref NHL and CLL. Methods: A 3+3 design was utilized with rel/ref NHL and CLL pts accruing independently and no limit on the number or type of prior therapies. Patients refractory to prior PI3K or BTK inhibitors were eligible. UTX was administered D1, 8, 15 of Cyc 1 & 2, followed by D1 of Cyc 4, 6, 9 & 12. TGR-1202 was administered orally once-daily starting on D1 of Cyc 1. Primary endpoints: Safety and dose limiting toxicities (DLT). Secondary endpoints: Efficacy (ORR, CR rate). Results: 56 patients have been enrolled to date and are evaluable for safety: 16 CLL/SLL, 16 FL, 16 DLBCL, 5 MZL, 2 MCL and 1 Richter's transformation. Med age 64 yo (range 29-86); 37 M/19 F; median # prior treatment regimens = 3 (range 1-9). Day 1 infusion reactions (2% G 3/4), neutropenia (23% G 3/4), diarrhea (2% G 3/4), and nausea (0% G 3/4) were the most commonly reported adverse events considered at least possibly related to either study drug. One patient (CLL cohort 1) with baseline Gr 3 neutropenia at study entry worsened to Gr 4 resulting in a dose delay which necessitated enrollment of an additional 3 pts at that dose level. Dose escalation continued into all planned subsequent NHL and CLL cohorts (up to 1200 mg). No MTD was observed in the Phase I portion and subtype specific expansion cohorts (Phase Ib) with 800 and 1200 mg dose of micronized TGR-1202 followed. Activity was observed at all dose levels; however a possible dose-response relationship was observed with TGR-1202 at higher doses compared to the lower doses. Of the 37 evaluable pts treated at the higher doses of TGR-1202 (1200 mg original formulation or > 600 mg micronized), overall response was as follows: CLL/SLL (5/7); FL/MZL (10/15); DLBCL (5/12); MCL (0/2) and Richter's (1/1). No CLL pts progressed at the first efficacy assessment, despite 4/5 having high-risk cytogenetics. Two CLL pts with SD include a 17p del, ibrutinib refractory patient who eventually progressed on treatment and the other remains on study awaiting future assessments. Of interest, 7 of the DLBCL pts were GCB subtype of which 71% were rituximab refractory, with 3/7 achieving an objective response, 2 remaining in stable disease (4+ and 5+ mos each), and 2 having progressed to date (avg time on study 7 mos, range 2 - 16+ mos). Conclusions: The combination of UTX + TGR-1202 is active and well tolerated in pts with both indolent and aggressive rel/ref NHL and CLL. The Phase I portion is complete and enrollment remains open in expansion cohorts for CLL, FL/MZL and DLBCL pts evaluating TGR-1202 micronized doses at 800 to 1200 mg in combination with UTX. Given the favorable safety profile and clinical activity observed, Phase 3 programs are planned with UTX + TGR-1202. Disclosures Lunning: BMS: Consultancy; Juno: Consultancy; Gilead: Consultancy; Genentech: Consultancy; Spectrum: Consultancy; TG Therapeutics: Consultancy. Vose:Seattle Genetics, Inc.: Honoraria, Research Funding. Nastoupil:Genentech: Honoraria; Celgene: Honoraria; TG Therapeutics: Research Funding; AbbVie: Research Funding; Janssen: Research Funding. Burger:Pharmacyclics LLC, an AbbVie Company: Research Funding. Schreeder:TG Therapeutics, Inc: Research Funding. Siddiqi:Seattle Genetics: Speakers Bureau; Pharmacyclics/Jannsen: Speakers Bureau; Kite pharma: Other: attended advisory board meeting. Flowers:Seattle Genetics: Consultancy; Millennium/Takeda: Research Funding; OptumRx: Consultancy; Millennium/Takeda: Research Funding; Infinity Pharmaceuticals: Research Funding; Onyx Pharmaceuticals: Research Funding; AbbVie: Research Funding; AbbVie: Research Funding; Acerta: Research Funding; Gilead Sciences: Research Funding; Celegene: Other: Unpaid consultant, Research Funding; Pharmacyclics: Research Funding; Spectrum: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; OptumRx: Consultancy; Spectrum: Research Funding; Onyx Pharmaceuticals: Research Funding; Gilead Sciences: Research Funding; Janssen: Research Funding; Genentech: Research Funding; Genentech: Research Funding; Seattle Genetics: Consultancy; Janssen: Research Funding; Infinity Pharmaceuticals: Research Funding; Celegene: Other: Unpaid consultant, Research Funding. Cutter:Clearview Cancer Center: Employment. Pauli:Clearview Cancer Institute: Employment; TG Therapeutics, Inc.: Consultancy, Research Funding. Sportelli:TG Therapeutics, Inc.: Employment, Equity Ownership. Miskin:TG Therapeutics, Inc.: Employment, Equity Ownership. Weiss:TG Therapeutics, Inc.: Employment, Equity Ownership.

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An All Antibody Approach for Conditioning Bone Marrow for Hematopoietic Stem Cell Transplantation with Anti-cKIT and Anti-CD47 in Non-Human Primates

Blood ◽

10.1182/blood-2019-131490 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4428-4428

Author(s):

Kristopher D Marjon ◽

James Y Chen ◽

Jiaqi Duan ◽

Timothy S Choi ◽

Kavitha Sompalli ◽

...

Keyword(s):

Bone Marrow ◽

Mast Cell ◽

Stem Cell ◽

Peripheral Blood ◽

Research Funding ◽

Mast Cell Degranulation ◽

Employment Equity ◽

Cell Counts ◽

Equity Ownership

Background Hematopoietic stem cell (HSC) transplantation (HSCT) is a well-established procedure that, with or without gene therapy, is curative for numerous severe life-threatening diseases including genetic blood disorders and blood cancers. While advances have been made, there are still substantial concerns since these chemo- and radiation therapy based procedures cause long-term toxicities such as infertility and secondary malignancies or even result in high mortality. We have previously established in a series of preclinical studies a novel chemo- and radiation-free non-toxic monoclonal antibody (Ab) -based conditioning regimen for autologous and allogeneic HSCT (Czechowicz et al., Akanksha et al. and George et al.). This cKIT-CD47 Ab-based regimen selectively depletes host HSCs for HSCT while sparing off-target toxicities caused by chemotherapy/radiation. By significantly decreasing morbidity/mortality associated with traditional conditioning regimens, antibody-mediated conditioning could expand the patient population eligible to receive HSCT for a variety of disorders. We developed a novel cKIT Ab (FSI-174), with an active Fc, and in combination with our CD47 magrolimab (previously 5F9, blocks the don't eat me pathway) could be utilized to translate the promising preclinical findings into clinical studies for safe and less toxic bone marrow conditioning for HSCT. Here we present the functional characterization of FSI-174 as single Ab and in combination with magrolimab in vitro and in non-human primate (NHP) studies. Methods We tested if FSI-174 could block stem cell factor signaling and we explored if FSI-174 alone or in combination with magrolimab could promote phagocytosis of cKIT positive cells (Kasumi-1). In addition, we determined if FSI-174 could cause mast cell degranulation. Subsequently, we explored the potential of FSI-174 alone (Phase A) or in combination with magrolimab (Phase B) to deplete HSCs in NHPs (rhesus macaques)in vivo. In Phase A, single doses of FSI-174 (0.3, 1, or 3 mg/kg) were administered alone. In Phase B, FSI-174 (0.3 or 3 mg/kg) was administered in combination with magrolimab (5mg/kg priming and 20 mg/kg maintenance dose). Bone marrow aspirates and core biopsies and peripheral blood were sampled before the study start and throughout the study. Frequency of bone marrow HSCs and cKIT receptor occupancy (RO) was determined by flow cytometry. In addition, the PK profile of FSI-174 was determined. Results In-vitro analysis demonstrated that FSI-174 decreases proliferation of HSPCs and enhances phagocytosis of cKIT positive cells, and the addition of magrolimab synergistically enhances the phagocytosis. Strikingly, FSI-174 did not cause mast cell degranulation in vitro. In the NHPs, complete (100%) cKIT receptor occupancy was achieved at all FSI-174 dose levels and was maintained for 1 to 9 days correlating with increasing doses and pharmacokinetics. The FSI-174 Cmax was found to be proportional to dose and mean Cmax increased from 6.25 ug/mL to 49.2 ug/mL. In Phase A, FSI-174 alone did not decrease the frequency of bone marrow HSCs compared to PBS control and had no effect on the peripheral blood cell counts. However, in Phase B, when FSI-174 was combined with magrolimab it significantly decreased the frequency of bone marrow HSCs with the nadir at day 9 and no recovery over 85 days compared to PBS control. Notably, there were no changes in peripheral blood cell counts over the course of the studies with no cytopenias in combination treatment. Conclusions We have developed a novel cKIT Ab (FSI-174) that meets the desired profile of stem cell factor block, promotion of phagocytosis, but without promoting mast cell degranulation. Furthermore, in the NHPs studies we have confirmed our chemo- and radiation-free cKIT-CD47 Ab -based conditioning approach with FSI-174 and magrolimab. As anticipated by our previous preclinical studies, monotherapy with FSI-174 does not deplete bone marrow HSCs in NHPs. Notably, no cytopenias are observed with either monotherapy or combination therapy. These data demonstrate the specificity, efficacy and safety of FSI-174/ magrolimab combination have great potential for conditioning regimen for HSCT in a chemotherapy and radiation free manner. Given the favorable safety profile of magrolimab across several clinical studies, these results are paving the way to the first-in-human trials for this novel conditioning for HSCT. Disclosures Marjon: Forty Seven Inc: Employment, Equity Ownership. Chen:Forty Seven Inc.: Consultancy, Equity Ownership. Duan:Forty Seven Inc.: Employment, Equity Ownership. Choi:Forty Seven inc: Employment, Equity Ownership. Sompalli:Forty Seven Inc: Employment, Equity Ownership. Feng:Forty Seven Inc: Employment, Equity Ownership. Mata:Forty Seven inc: Employment, Equity Ownership. Chen:Forty Seven Inc: Employment, Equity Ownership. Kean:HiFiBio: Consultancy; BlueBirdBio: Research Funding; Gilead: Research Funding; Regeneron: Research Funding; EMDSerono: Consultancy; FortySeven: Consultancy; Magenta: Research Funding; Bristol Meyers Squibb: Patents & Royalties, Research Funding; Kymab: Consultancy; Jazz: Research Funding. Chao:Forty Seven Inc: Employment, Equity Ownership. Chao:Forty Seven, Inc.: Employment, Equity Ownership, Patents & Royalties. Takimoto:Forty Seven, Inc.: Employment, Equity Ownership, Patents & Royalties. Agoram:Forty Seven Inc.: Employment, Equity Ownership. Majeti:FortySeven: Consultancy, Equity Ownership, Other: Board of Director; BioMarin: Consultancy. Weissman:Forty Seven Inc.: Consultancy, Equity Ownership, Patents & Royalties. Liu:Forty Seven Inc: Employment, Equity Ownership, Patents & Royalties. Volkmer:Forty Seven, Inc.: Employment, Equity Ownership, Patents & Royalties.

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