Biomarker-Driven Phase Ib Clinical Trial of OPB-111077 in Acute Myeloid Leukemia Increases Overall Response Rates

Background: Phase I clinical trial for oncology drugs have the highest clinical failure rate. Drug candidates may be discarded if they don´t show activity. Yet these drugs may have valuable activity in patient subgroups. Biomarkers attempt to identify these sensitive subpopulations, but are normally evaluated and validated in Phase II when good drugs may have been discarded. OPB-111077 is a novel, oral, low-molecular-weight compound that inhibits STAT3 and mitochondrial electron transport. A prior Phase I trial on 145 patients from all tumor types gave only 1 partial response (PR). A strong anti-proliferative activity was identified in Acute Myeloid Leukemia (AML) samples ex vivo. This new biomarker was used for patient selection in this trial. We present a novel design of a Phase Ib trial directly selecting patients with a potential biomarker, that can benefit the patient without increasing toxicity risks, in Relapsed/Refractory (RR) AML patients. Method: This is an open-label, phase Ib dose-escalation clinical trial to evaluate the safety profile, maximum tolerated dose (MTD) and preliminary efficacy of oral OPB-111077 in AML relapsed or refractory to chemotherapy patients. Patients > 18 years old with high risk AML, ECOG ≤2 and adequate organ functions were selected for biomarker screening. Biomarker consisted on a dose response curve for antiproliferative activity of agent in a bone marrow sample of patients incubated 72-96-120h (Figure), quantified as the Area Under the Curve (AUC). Patient samples whose ex vivo biomarker showed low sensitivity (70% worst) we excluded, since they were potentially predicted as resistant to the agent. The remaining 30% with higher sensitivity were included. OPB-111077 was administered orally on a once daily dose schedule in 28-day cycles until intolerable toxicity or disease progression. Two dose schemas were evaluated: 200 (DL1) and 250 mg/day (DL2). Dose limiting toxicities were any Grade ≥ 3 non-hematologic toxicity and any unexpected non-tolerable grade II that requires delay beyond 1 week until recovery and evaluated during the first 28 days of treatment. Adverse events were graded according to NCI-CTCAE vs 4.03 and response criteria was based on those given by Cheson et al. IC50 and area under the curve (AUC) determined by the Vivia ex vivo biomarker were correlated with clinical response. Results: We screened 47 RR AML patients, twelve patients were included and selected by personalized medicine test (5 in DL1 and 7 in DL2), median age 76 years, 92% men, 42% ECOG 0 were included in the study. AML patients were refractory in 41.7% and patients were in median of relapses 2 (range 1-6). No DLT was reported. Adverse events related to study treatment were reported in three patients, all G 1-2: in DL1 one patient had vomiting; in DL2 one patient had extrasystoles and other had anorexia, diarrhoea, epigastric discomfort, nausea and vomiting. Two patients died during study treatment due to disease progression and respiratory infection. Half of the patients discontinued study treatment due to disease progression and 25% due to adverse events (respiratory failure G5, respiratory infection G5 and extrasystoles G2). Over the 6 patients evaluable for efficacy, 3 of them achieved PR and 3 treatment failure as best response. Progression free survival and overall survival were 57 days (95% CI: 37 - 77) and 95 days (95% CI: 27 - 163) respectively. The biomarker AUC and IC50 values stratified patients consistent with their clinical response, although without enough sampling potency for statistical significance. Figure shows the relative position of patients included in the study in the context of the overall population of samples considered to build up the mixed effect population pharmacodynamic model used to analyze samples results and define inclusion criteria. In green those that correspond to patients who showed a positive response; in orange those who failed. Conclusions: OPB-111077 is generally well tolerated and has a manageable toxicity profile. The MTD was not reached. The 50% PR rate achieved by OPB-111077, albeit in a few patients, is substantially higher that the 0.7% (1/145) PR rate achieved in a prior phase I trial on all tumor types1. This innovative Phase Ib design selecting patients using a biomarker may enable to rescue drug failures in the future. References: 1. Tolcher A, Flaherty K, Shapiro GI et al. Oncologist. 2018, 23(6):658-e72 Figure Disclosures Martinez-Lopez: Hosea: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; BMS: Research Funding, Speakers Bureau; Amgen: Speakers Bureau; Roche: Speakers Bureau; Janssen: Speakers Bureau; Vivia Biotech: Honoraria; Altum: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Novartis: Research Funding; Takeda: Speakers Bureau; Incyte: Research Funding, Speakers Bureau. Gorrochategui:VIVIA BIOTECH: Current Employment. Rojas:VIVIA BIOTECH, S.L.: Current Employment. Primo:Vivia Biotech: Current Employment. Perez De Oteyza:MACROGENICS: Research Funding. Ballesteros:Vivia Biotech: Current Employment.

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Phase Ib Study of Oral Panobinostat In Combination with 5-Azacitidine (5-aza) In Patients with Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukemia (CMML), or Acute Myeloid Leukemia (AML)

Blood ◽

10.1182/blood.v116.21.4957.4957 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4957-4957 ◽

Cited By ~ 1

Author(s):

Pierre Fenaux ◽

Daniel J DeAngelo ◽

Guillermo Garcia-Manero ◽

Michael Lübbert ◽

Anand P. Jillella ◽

...

Keyword(s):

Febrile Neutropenia ◽

Adverse Events ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Chronic Myelomonocytic Leukemia ◽

Advisory Committees ◽

Dose Cohort ◽

Phase Ib ◽

Myelomonocytic Leukemia

Abstract Abstract 4957 Background: Panobinostat is a potent pan-deacetylase inhibitor (pan-DACi) that causes increased acetylation of target proteins such as HSP90, p53, α-tubulin and HIF-1α which are involved in cell cycle regulation, gene transcription, angiogenesis, and tumor cell survival. Preliminary evidence from phase I trials has demonstrated anti-tumor activity in patients with hematologic malignancies including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). The advent of hypomethylating agents, such as 5-aza, represent a significant advancement in the treatment of MDS, chronic myelomonocytic leukemia (CMML), and AML. Although an improvement in clinical outcomes has been observed, including increased overall survival in patients with MDS, a substantial number of patients do not benefit from the therapies currently available. Preclinical studies suggest that the combination of a demethylating agent and a pan-DACi represents a rational strategy to reverse silencing of tumor suppressor genes, which contributes to the malignant phenotype, and improve outcomes in patients with MDS and AML. In this study, the combination of the pan-DACi, panobinostat, and the hypomethylating agent, 5-aza, was evaluated in patients with MDS, CMML and AML. Methods: This phase Ib, open-label, multicenter, dose-finding study is comprised of 2 stages: a dose-escalation stage to determine the maximum tolerated dose (MTD) of panobinostat in combination with standard dose 5-aza, and a subsequent expansion stage to evaluate safety, tolerability, and preliminary activity at the MTD dose level. The primary endpoint is incidence of dose-limiting toxicity (DLT) and secondary endpoints include type, duration, frequency, and relationship of adverse events (AEs) to the combination. Exploratory endpoints include clinical response and hematologic improvement according to IWG response criteria, and biomarker analysis of methylation status and expression of disease-associated genes in peripheral blood cells prior to and during therapy. Adult patients with IPSS INT-2 or high-risk MDS, CMML, or AML with multi-lineage dysplasia and ≤ 30% marrow blasts who are candidates for therapy with 5-aza and have not received a prior hypomethylating agent or pan-DACi are eligible for enrollment on the trial. Oral panobinostat was administered on Days (D) 3, 5, 8, 10, 12, and 15, starting at 20 mg, in combination with 5-aza (75 mg/m2 sc D 1–7) during a 28-D cycle. Patients received treatment for ≤ 6 cycles or until progression of disease, incidence of unacceptable toxicity, or withdrawal of consent. Results: To date, 11 patients have been enrolled including 9 patients with MDS, 1 patient with AML and 1 patient with CMML. The median age of patients enrolled on the trial was 69.0 (60-80). Patients have been evaluated at 2 panobinostat dose cohorts; 6 (20 mg) and 5 (30 mg). The AE analysis is based on 9 patients (6 from 20 mg cohort and 3 from 30 mg cohort) and the nature and incidence of AEs observed in the two cohorts were similar. Adverse events regardless of study drug relationship included nausea (4 [44%]), vomiting, fatigue (5 [55%] each) and asthenia (3 [33%]). Grade 3/4 AEs suspected to be treatment related included thrombocytopenia (2 [22%], febrile neutropenia and arthritis (1 [11%] each). Serious adverse events observed included febrile neutropenia, asthenia (2 [22%] each), atrial fibrillation and septic shock (1 [11%] each). One DLT has been observed (grade 4 febrile neutropenia) in the 20 mg panobinostat dose cohort. Conclusions: Panobinostat has been well tolerated up to a dose of 30 mg in combination with 5-aza (75 mg/m2) with dose escalation ongoing. Patients are currently being enrolled at the 40mg dose cohort. The most common AEs observed included febrile neutropenia, thrombocytopenia with one DLT observed (grade 4 febrile neutropenia) in the 20mg panobinostat dose cohort. The current data show that the addition of panobinostat to 5-aza is safe with no unexpected toxicities. Updated data, including safety and preliminary efficacy data will be presented at the meeting. Disclosures: Fenaux: Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding; ROCHE: Honoraria, Research Funding; AMGEN: Honoraria, Research Funding; GSK: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Cephalon: Honoraria, Research Funding. Off Label Use: Panobinostat is an investigational agent currently being evaluated for the treatment of hematologic and solid malignancies. DeAngelo: Novartis: Membership on an entity's Board of Directors or advisory committees. Sekeres: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Winiger: Novartis Pharma AG: Employment. Squier: Novartis: Employment. Li: Novartis: Employment. Ottmann: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Low-Dose Azacitidine, Pioglitazone and All-Trans Retinoic Acid Versus Standard-Dose Azacitidine in Patients ≥ 60 Years with Acute Myeloid Leukemia Refractory to Standard Induction Chemotherapy (AMLSG 26-16/AML-ViVA): Results of the Safety Run-in Phase I

Blood ◽

10.1182/blood-2019-129977 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1382-1382 ◽

Cited By ~ 4

Author(s):

Daniel Heudobler ◽

Sebastian Klobuch ◽

Florian Lüke ◽

Joachim Hahn ◽

Matthias Grube ◽

...

Keyword(s):

Adverse Events ◽

Phase I ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Low Dose ◽

Advisory Committees ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Refractory Aml

Introduction: Patients (pts) with acute myeloid leukemia (AML) who are refractory to intensive frontline treatment have a dismal outcome. In case of ineligibility for allogeneic stem cell transplantation (HSCT), the median survival of chemo-refractory AML is about 2 months and less than 5% of these pts are alive after 1-year (retrospective analysis from the AMLSG database). To date, there is no universally accepted standard approach for the treatment of chemo-refractory AML in older pts. Several retrospective studies have assessed the role of hypomethylating agents in this patient group, but complete remission (CR) rates were disappointingly low (≤10%) when compared to first line treatment. The presented study represents a novel approach focusing on hematopoietic tissue reprogramming (i.e. anakoinosis) (ClinicalTrials.gov Identifier: NCT02942758). Methods: The initial dose-finding phase I of the study evaluated the combination of azacitidine (AZA) 75 mg/d s.c. for 7 days, repeated every 28-days, pioglitazone 45 mg/d p.o. continuously from day 1 and all-trans retinoic acid (ATRA). A modified 3+3 design has been used to establish the maximum-tolerated dose of ATRA. Patients have been enrolled at an ATRA dose of 45 mg/m²/d from day 1 to day 28 and 15 mg/m²/d continuously thereafter if no dose limiting toxicity (DLT) occurred until start of next cycle on day 29. The safety DLTs were defined as toxicities attributable to ATRA, expected or unexpected, except if these are likely associated with another cause. Eligible patients had confirmed diagnosis of AML refractory to induction therapy and were not eligible for further intensive induction therapy or were not immediate candidates for allogeneic HSCT. The severity of adverse events was graded using the Common Terminology Criteria for Adverse Events (CTCAE) V. 4.03. The response to treatment was evaluated using standard criteria defined by the expert panel on behalf of the European LeukemiaNet and international working group (IWG) response. Results: Ten pts were enrolled in the safety-run-in phase I (one pt withdrew informed consent on day 9 of cycle 1). Among all treated pts, the median age was 67 years (range, 62-76 years), and the majority of pts (70%) had an ECOG PS of 1 (see table 1). Two pts had secondary AML; another two pts had therapy-related AML (t-AML). Eight pts had a complex karyotype. Concerning safety, hematological adverse events (AEs) were the most common toxicities observed. Because pts with baseline cytopenia were included (leukopenia n=8; 80%; thrombocytopenia n=9; 90%), occurrences of many hematological AEs began before study drug initiation and were attributed to underlying hematologic disease. Common 3°/4° AEs included neutropenia (50%), anemia (50%), thrombocytopenia (30%), and infections (40%). 50% of pts experienced a serious AE; one 5° AE (gastric hemorrhage) occurred. No DLTs were observed. Five pts discontinued the study, with progressive disease (PD) or relapse being the most common reason for discontinuation. Concerning efficacy, 3 pts (30%) achieved a CR and one pt a long-lasting stable disease (14 months). Morphologic review showed signs of differentiation of blasts in responding pts, which has already been shown in in-vitro analysis. In line with this observation, one pt demonstrated resolution of fungal pneumonia during the study. Conclusions: In summary, the low-intensity, biomodulatory regimen of low-dose AZA, pioglitazone, and ATRA demonstrated a tolerable safety profile and encouraging signals for efficacy in pts with AML refractory to standard induction chemotherapy warranting further investigation. S.T. and A.R. contributed equally to this abstract as senior co-authors. Disclosures Paschka: Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Speakers Bureau; Abbvie: Other: Travel expenses; Amgen: Other: Travel expenses; Otsuka: Membership on an entity's Board of Directors or advisory committees; BMS: Other: Travel expenses, Speakers Bureau; Astex: Membership on an entity's Board of Directors or advisory committees, Travel expenses; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Other: Travel expenses; Takeda: Other: Travel expenses; Sunesis: Membership on an entity's Board of Directors or advisory committees. Döhner:Celgene, Novartis, Sunesis: Honoraria, Research Funding; AROG, Bristol Myers Squibb, Pfizer: Research Funding; AbbVie, Agios, Amgen, Astellas, Astex, Celator, Janssen, Jazz, Seattle Genetics: Consultancy, Honoraria. Thomas:Celgene: Consultancy, Other: Travel support, Research Funding, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Medigene AG: Consultancy, Other: Travel support; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Medac: Other: Travel support; Janssen: Other: Travel support.

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The Pro-Inflammatory Cytokine Interleukin-1 Is Essential for Clonal Expansion and Disease Progression in Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v126.23.866.866 ◽

2015 ◽

Vol 126 (23) ◽

pp. 866-866

Author(s):

Alyssa Carey ◽

Megan M Cleary ◽

David K Edwards ◽

Christopher A. Eide ◽

Elie Traer ◽

...

Keyword(s):

Bone Marrow ◽

Disease Progression ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Ex Vivo ◽

Clonal Expansion ◽

Advisory Committees ◽

Clonogenic Potential ◽

Equity Ownership

Abstract Background: Recent 'omics'-based approaches have revealed that acute myeloid leukemia (AML) has significant genetic heterogeneity, and that clonal evolution in AML occurs through stepwise acquisition of somatic mutations. However, extrinsic factors may also influence this process. Here we provide strong evidence that inflammatory cytokines secreted in the AML microenvironment play a critical role in clonal expansion and disease progression. Specifically, we show that the proinflammatory cytokine IL-1 promotes in vitro clonal expansion in a large subset of primary AML samples and in vivo disease progression in a murine AML model. Methods: We used several functional assays to determine which extrinsic cytokine-activated pathways are essential for AML cell survival. We analyzed 90 primary AML samples ex vivo in the absence and presence of dose gradients of 98 distinct cytokines. We used stromal cells conditioned media and a recombinant cytokine cocktail (IL-3, IL-6, SCF, GCSF, FLT3L) for positive controls. The distributions for the positive and negative control allowed us to derive rigorous empirical thresholds to define cytokine dependence for individual samples. We also performed siRNA screens targeting 188 cytokine and growth factor receptors, and measured 30 different cytokines secreted in the plasma of peripheral blood and bone marrow samples using a multiplex Luminex assay. Functionally relevant pathways were validated using shRNA and genetic mouse models. Results: Several of the 98 cytokines promoted the growth of primary AML cells, including IL-1, GM-CSF, G-CSF, TPO, CXCL-1, IL-3, M-CSF, MCPs, TNF-α, and BMP-4. Many of these are known to induce an inflammatory response and cluster with the growth response to IL-1, a master mediator of innate immunity and inflammation. IL-1α and IL-1β had the most profound effect on the clonal expansion of myeloid progenitors, leading to 3- to 20-fold growth increase in 70% (63/90) of primary AML samples. Consistent with our findings from the cytokine screen, treatment of CD34+ AML cells with IL-1 led to increases in cell growth, survival, and clonogenic potential. Paradoxically, IL-1 suppressed both growth and colony formation in normal CD34+ cells. In support of these ex vivo findings, IL-1β was overexpressed in IL-1-sensitive AML bone marrow and peripheral blood samples compared to non-sensitive AML samples and normal samples. Intracellular FACS showed that 80% of the total IL-1β is secreted by monocytes, and to some extent by myeloid progenitors and stromal cells, but not by B or T cells in the AML bone marrow microenvironment. Consistent with this, most of the IL-1-sensitive AML samples exhibited monocytic and myelomonocytic features. These results suggest that IL-1 secreted in the bone marrow microenvironment regulates AML cell growth in a paracrine manner. Silencing of the IL-1 receptor, IL1R1, reduced the viability of AML primary samples by 60-80% and led to a significant ablation of clonogenic potential (80% reduction) of oncogene-induced leukemic cells (AML1-ETO9a, NRASG12D and MLL-ENL) in mouse bone marrow. In a murine bone marrow transplantation model, recipients of IL1R1-/- marrow transduced with AML1-ETO9a/NRASG12D survived significantly longer (39 days; range: 28-118) than did recipients of wild-type marrow (30 days; range: 27-61; p=0.012). Mechanistically, IL-1β regulates phosphorylation of p38MAPK, a downstream component of the IL-1 pathway, in AML progenitors and IL-1-sensitive AML samples exhibit more p38 phosphorylation as compared to normal cells. Conversely, knocking down IL1R1 or treating AML cells with p38MAPK inhibitors such as doramapimod reduced the growth of AML cells by decreasing p38MAPK phosphorylation. Conclusion: These results demonstrate a novel role for IL-1 and its receptor in promoting clonal growth and disease progression in a large subset of AML patients. Our findings suggest that AML patients may benefit from drugs targeting IL-1/IL1R1/p38MAPK signaling because of their potential to enhance normal hematopoiesis while inhibiting AML -- a significant clinical advantage over traditional chemotherapy, which kills both normal and leukemic cells.Since IL-1 and its receptors are not mutated in these patients, our data also highlight the importance of ex vivo functional screening for microenvironmental stimuli for the identification of novel therapeutic targets. Disclosures Tyner: Constellation Pharmaceuticals: Research Funding; Array Biopharma: Research Funding; Aptose Biosciences: Research Funding; Incyte: Research Funding; Janssen Pharmaceuticals: Research Funding. Druker:Cylene Pharmaceuticals: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; CTI Biosciences: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Research Funding; Roche TCRC, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aptose Therapeutics, Inc (formerly Lorus): Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Millipore: Patents & Royalties; McGraw Hill: Patents & Royalties; Henry Stewart Talks: Patents & Royalties; Fred Hutchinson Cancer Research Center: Research Funding; MolecularMD: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Leukemia & Lymphoma Society: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sage Bionetworks: Research Funding; ARIAD: Research Funding; AstraZeneca: Consultancy; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oregon Health & Science University: Patents & Royalties; Oncotide Pharmaceuticals: Research Funding. Agarwal:CTI BioPharma: Research Funding.

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Unexpected Toxicities When Nivolumab Was Given after Allogeneic Stem Cell Transplantation

Blood ◽

10.1182/blood-2019-123887 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1956-1956

Author(s):

Amy Wang ◽

Justin Kline ◽

Wendy Stock ◽

Satyajit Kosuri ◽

Andrew S. Artz ◽

...

Keyword(s):

Clinical Trial ◽

Overall Survival ◽

Stem Cell ◽

Adverse Events ◽

Maintenance Therapy ◽

Board Of Directors ◽

Research Funding ◽

Checkpoint Inhibitors ◽

Advisory Committees ◽

Relapsed Disease

Background:Treatment options are limited for patients (pts) with hematologic malignancies who relapse after allogeneic stem cell transplantation (allo-SCT). We hypothesized that checkpoint inhibitors may offer a novel approach for maintaining remission after allo-SCT. Data from pre-clinical studies have suggested a potential role for PD-1/PD-L1 inhibitors in acute myeloid leukemia (AML) (Zhang et al., Blood 2009), so it is possible that immunomodulation with checkpoint inhibitors could stimulate the donor anti-leukemia immune response and prevent disease relapse. However, the safety of checkpoint blockade early after allografting remains to be established. Methods:We conducted a pilot study to assess the tolerability and efficacy of Nivolumab, a PD-1 inhibitor, as maintenance therapy after allo-SCT (NCT02985554). Pts were eligible if they were post allo-SCT without evidence of relapse or active graft-vs-host disease (GVHD) or history of prior greater than stage I skin acute GVHD. Nivolumab was to be administered intravenously at 1mg/kg every 2 weeks for 4 doses followed by dosing every 12 weeks. Treatment started 4 weeks after routine immunosuppression was discontinued until 2 years after the transplant. The primary objective was to determine the tolerability of Nivolumab on this schedule. Secondary objectives were evaluation of adverse events, relapse, and overall survival. Results:Four pts were enrolled from December 2017 through November 2018. (Table 1)All pts experienced immune-related adverse events (irAE) from Nivolumab, and 2 (50%) pts experienced serious adverse events. (Table 2)One pt developed grade (G) 4 neutropenia soon after the first dose. (Figure 1)The absolute neutrophil count nadired at 20 cells/µL, at which point pegfilgrastim was administered. An interim bone marrow biopsy (BMBx) confirmed no evidence of relapsed disease. Full neutrophil recovery occurred approximately 3 months after the initial dose, and no subsequent toxicities occurred. Another pt developed G3 autoimmune encephalopathy concurrently with G2 transaminitis and G2 thrombocytopenia after one dose of Nivolumab. (Figure 2)Intravenous methylprednisolone (1mg/kg daily for 3 days) and immunoglobulin (2g/kg in 4 divided doses) were administered, followed by a 7-week steroid taper with full resolution of symptoms. Relapsed disease was ruled out by a BMBx. A third pt developed G2 skin rash approximately 10 days after the first dose of Nivolumab. Skin biopsy demonstrated drug hypersensitivity reaction vs GVHD, and the pt was treated with a 3-week prednisone course (starting at 1mg/kg followed by a taper). A mild flare recurred 2 weeks later, which was treated with topical steroids only. However, Nivolumab was not resumed. The fourth pt developed G2 elevated TSH approximately 2 months into therapy and after 4 doses of Nivolumab. Thyroid hormone replacement was initiated with subsequent symptom improvement and normalization of TSH over a 4-month period. As a result of these unexpected severe toxicities, the study was closed to further enrollment, and further Nivolumab administration ceased. Thus far, one pt (#1) relapsed after a total remission duration of 530 days; the remission duration after starting Nivolumab was 318 days. One pt has mild chronic skin GVHD. All 4 patients remain alive with a median overall survival of 2.3 years (range, 1.9-4.7). Conclusions:Even at low doses, the use of Nivolumab as maintenance therapy in the post allo-SCT setting was not tolerable at the current dosing and schedule due to an unexpected number of high grade irAEs. Additional studies of dose and timing after allo-SCT are needed to improve safety and tolerability, in conjunction with correlative studies to better understand the immunomodulatory processes in the post-transplant setting. Disclosures Kline: Merck: Honoraria; Merck: Research Funding. Stock:Kite, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; UpToDate: Honoraria; Research to Practice: Honoraria. Artz:Miltenyi: Research Funding. Larson:Agios: Consultancy; Novartis: Honoraria, Other: Contracts for clinical trials; Celgene: Consultancy. Riedell:Novartis: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Speakers Bureau; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau. Bishop:CRISPR Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Juno: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Liu:Arog: Other: PI of clinical trial; BMS: Research Funding; Agios: Honoraria; Novartis: Other: PI of clinical trial; Karyopharm: Research Funding. OffLabel Disclosure: Nivolumab used as maintenance therapy in the post-transplant setting

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A Phase I Study of Selinexor in Combination with Daunorubicin and Cytarabine in Patients with Newly Diagnosed Poor-Risk Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v128.22.4040.4040 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4040-4040 ◽

Cited By ~ 3

Author(s):

Kendra L. Sweet ◽

Rami S. Komrokji ◽

Eric Padron ◽

Christopher L Cubitt ◽

Leyla Khavarian ◽

...

Keyword(s):

Clinical Trial ◽

Overall Survival ◽

Febrile Neutropenia ◽

Phase I ◽

Board Of Directors ◽

Induction Chemotherapy ◽

Research Funding ◽

Newly Diagnosed ◽

Advisory Committees ◽

Poor Risk

Abstract Background: Induction chemotherapy for older adults with poor-risk AML has remained largely unchanged over the past 40 years, with complete remission (CR) rates ranging from 20-50%. Five-year overall survival (OS) ranges from 2-15%, illustrating the need for novel treatment strategies. Selinexor is an oral selective inhibitor of nuclear export (SINE) that has shown promising single agent activity in AML (NCT01607892). By inhibiting the primary export protein, XPO1, selinexor localizes tumor suppressor proteins to the nucleus leading to their activation. Furthermore, selinexor inhibits DNA damage repair, rationalizing its use in combination with DNA damaging agents. Preclinical data from our institution suggest Selinexor synergizes with daunorubicin when used in CD34+ AML cells. Here we report early results from a phase I clinical trial with selinexor plus cytarabine and daunorubicin in patients (pts) with newly diagnosed, poor-risk AML. Methods: This is a single institution phase I clinical trial with a 3+3 design and an expansion phase at the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D). The primary endpoint was to determine the MTD/RP2D of selinexor. Secondary endpoints included rate of CR/CRi, overall survival (OS), relapse free survival (RFS) and toxicity assessment. Eligible pts had a diagnosis of previously untreated AML (non-M3), with poor-risk features based on karyotype, mutational profile, secondary AML (sAML) arising from an antecedent hematologic disorder (AHD) or prior chemotherapy, or age ≥60 years. Prior treatment for an AHD was allowed. Induction included daunorubicin 60 mg/m2/day on days 1-3 and cytarabine 100 mg/m2/day CIVI days 1-7 (7+3) with two dose cohorts of selinexor: 60 mg and 80 mg PO. Selinexor was given on days 1, 3, 8, 10, 15 and 17. Re-induction with 5+2 plus selinexor was allowed if indicated. Once in CR, pts received 1-2 cycles of consolidation with 5+2 plus selinexor followed by maintenance selinexor on days 1 and 8 of a 21 day cycle for up 12 months. Selinexor was given at the same dose for all phases of the study. Pts could proceed to hematopoietic stem cell transplant (HCT) at any time after achieving CR. Results: 21 pts (14 (67%) M / 7 (33%) F) were enrolled from June 2015 to June 2016. Median age was 68 years (range 37-77); 18 (86%) were age ≥60 and 9 (43%) were age ≥70. Nineteen (90%) pts were considered poor-risk (unrelated to age), and two (10%) were eligible due to age ≥60 only. Each cohort enrolled 4 pts, and 13 pts were enrolled in the expansion. One pt in each cohort was replaced before completing the 28-day DLT period; one withdrew consent and the second died on day 23 from acute renal failure related to antibiotics. At data cutoff, 18 pts were included in the safety and efficacy assessment. Three additional patients have not completed induction. The early death rate (≤60 days) was 4.8%. No DLTs occurred in the dose-escalation cohorts. The MTD of selinexor was not reached and the RP2D was 80 mg twice weekly. The most common grade 3/4 non-hematologic, treatment emergent AEs in all pts were febrile neutropenia (56%), diarrhea (22%), hyponatremia (22%) and sepsis (17%). Nine patients (50%) achieved CR/CRi. Of the 14 pts treated at the RP2D (selinexor 80 mg), 6 (43%) achieved CR/CRi. In the entire cohort, the median age of the responders was 69 (61-77) and 4 (44%) were age ≥70. Seven (78%) were considered high-risk. Four (44%) had sAML. Two (22%) required a second induction. The median time to response was 47 days (range 28-77) At a median follow up of 8.7 months in the 9 responding pts, 7 (78%) remain in remission. Overall, 4 pts (44%) underwent HCT, and 1 (11%) relapsed just prior to HCT. Conclusion: Results from this phase I trial suggest that selinexor 80mg PO twice weekly can be safely administered in combination with induction chemotherapy using cytarabine and daunorubicin to pts with poor-risk AML, including older pts. The most prominent AEs were febrile neutropenia, diarrhea and hyponatremia. Response rates are encouraging and many elderly pts proceeded to transplant, suggesting this regimen warrants further investigation in this challenging population. Disclosures Sweet: Karyopharm: Honoraria, Research Funding; Incyte Corporation: Research Funding; Novartis: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau; Pfizer: Speakers Bureau. Komrokji:Novartis: Consultancy, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Sullivan:Karyopharm: Research Funding. Shah:Incyte: Research Funding; Rosetta Genomics: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Baxalta: Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria; Pfizer: Honoraria.

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A Phase I/II Study of Lenalidomide Plus Obinutuzumab in Relapsed Indolent Lymphoma

Blood ◽

10.1182/blood-2019-131045 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 348-348 ◽

Cited By ~ 6

Author(s):

Nathan H Fowler ◽

Loretta J. Nastoupil ◽

Collin Chin ◽

Paolo Strati ◽

Fredrick B. Hagemeister ◽

...

Keyword(s):

Adverse Events ◽

Phase I ◽

Board Of Directors ◽

Research Funding ◽

Marginal Zone ◽

Advisory Board ◽

Indolent Lymphoma ◽

Advisory Committees ◽

Grade 3

Background: Patients with advanced indolent non-Hodgkin lymphoma (iNHL) can develop chemoresistance and most relapse following standard therapy. Although multiple treatment options exist, most are associated with short remission or intolerable side effects. Lenalidomide activates NK cells ± T cells and leads to in vivo expansion of immune effector cells in NHL models. The combination of rituximab and lenalidomide (R2) in relapsed iNHL is highly active and was recently approved. Obinutuzumab is a glycosylated type II anti-CD20 molecule with enhanced affinity for the FcγRIIIa receptors leading to improved ADCC. The primary objective of this phase I/II study was to determine the maximum tolerated dose (MTD), safety, and efficacy of lenalidomide and obinutuzumab in relapsed indolent lymphoma. Methods: Patients with relapsed small lymphocytic lymphoma (SLL), marginal zone, and follicular lymphoma (gr 1-3a) were eligible. Patients enrolled in three predefined dose cohorts of lenalidomide (10mg,15mg, 20mg) given on days 2-22 of a 28 day cycle. Obinutuzumab was given at a fixed dose (1000mg) IV on days 1,8,15 and 22 of cycle 1 and day 1 of subsequent cycles for 6 cycles. The combination was given for up to 12 cycles in responding pts. Antihistamines were given in pts who developed rash. Prophylactic growth factor was not allowed. In the absence of progression or toxicity, single agent obinutuzumab was continued every 2 months for maximum of 30 months on study. Traditional 3+3 dose escalation was used with dose limiting toxicities (DLT) assessed during cycle 1. Once the MTD was established, 60 additional patients were enrolled in the phase II portion of the study. Adverse events were graded using CTCAE version 4.03. Results: 66 pts were enrolled between May 2014 until March 2019, and all are eligible for safety and response assessment. No DLTs were observed in dose escalation, and 60 pts were enrolled in the phase II portion of the study at 20mg of lenalidomide daily. Histologies included follicular lymphoma (FL) n=57, marginal zone n=4, SLL n=5. The median age was 64 (36-81), with 2 (1-5) median prior lines of treatment. For 53% of pts, the combination represented the third or greater line of treatment. The overall response (OR) rate for all pts was 98% with 72% attaining a complete response (CR). Eighteen pts (27%) had a partial response, and stable disease was noted in 1 (2%). At a median follow up of 17 months, 14 pts have progressed, with an estimated 24mo progression-free survival (PFS) of 73% (57-83% 95% CI). The estimated 24 mo PFS for ≥ third line pts was 63%. Twenty five pts (38%) remain on treatment and 95% remain alive at last follow up. The most common grade ≥ 3 non-hematologic toxicities included fatigue (5 pts), rash (4 pts), and cough (3 pts). Grade ≥3 neutropenia and thrombocytopenia occurred in 11 (17%) and 7 (11%) pts respectively. Two pts stopped treatment due to adverse events, including 1 transient bradycardia and 1 grade 3 fatigue. Conclusion: The combination of 20 mg of lenalidomide and 1000mg obinutuzumab is safe and effective in patients with relapsed indolent lymphoma. Adverse events appeared similar to our prior experience with lenalidomide and rituximab and were generally well tolerated. Overall response rates were high, with many pts achieving prolonged remission, including pts who had relapsed after 2 or more lines of prior therapy. Validation studies in the frontline and salvage setting are ongoing. Disclosures Fowler: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; TG Therapeutics: 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, Research Funding. Nastoupil:TG Therapeutics: Honoraria, Research Funding; Novartis: Honoraria; Janssen: Honoraria, Research Funding; Spectrum: Honoraria; Gilead: Honoraria; Genentech, Inc.: Honoraria, Research Funding; Bayer: Honoraria; Celgene: Honoraria, Research Funding. Westin:Novartis: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; Janssen: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding; Unum: Research Funding; MorphoSys: Other: Advisory Board; Genentech: Other: Advisory Board, Research Funding; Curis: Other: Advisory Board, Research Funding; 47 Inc: Research Funding. Neelapu:Precision Biosciences: Consultancy; Merck: Consultancy, Research Funding; Cellectis: Research Funding; Novartis: Consultancy; BMS: Research Funding; Karus: Research Funding; Acerta: Research Funding; Poseida: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Incyte: Consultancy; Celgene: Consultancy, Research Funding; Unum Therapeutics: Consultancy, Research Funding; Allogene: Consultancy; Pfizer: Consultancy; Cell Medica: Consultancy.

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Development and Testing of a Lymphoma Clinical Trials Specific Frailty Index: A Secondary Analysis of the LY.12 Clinical Trial

Blood ◽

10.1182/blood-2021-153037 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4076-4076

Author(s):

Abi Vijenthira ◽

Xinzhi Li ◽

Michael Crump ◽

Annette E. Hay ◽

Lois E. Shepherd ◽

...

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Adverse Events ◽

Board Of Directors ◽

Research Funding ◽

Frailty Index ◽

Secondary Analysis ◽

Advisory Committees ◽

Frail Patients ◽

The Impact

Abstract Background: Frailty is common in older patients with lymphoma. However, it remains unknown whether frailty is prevalent in patients included in clinical trials of lymphoma, as those with frailty may meet inclusion criteria of a trial which do not include functional information beyond performance status (PS). Understanding the prevalence and impact of frailty in clinical trials is important to direct future stratification criteria, as well as to have robust data to counsel frail patients on their potential outcomes. Methods: We conducted a secondary analysis using data from the phase III LY.12 clinical trial in which patients with relapsed aggressive non-Hodgkin lymphoma were randomized to gemcitabine-dexamethasone-cisplatin or dexamethasone-high dose cytarabine-cisplatin chemotherapy prior to autologous stem cell transplant. The primary objective of our study was to construct a lymphoma clinical trials specific frailty index (FI) using previously described methods (Searle. BMC Geriatr. 2008;8:24). Secondary objectives were to describe the association of frailty (binary variable) with overall survival (OS), event-free survival (EFS), hospitalization, adverse events (AE), serious adverse events (SAE), and proceeding to transplant, and to describe the association of frailty with these outcomes, controlling for important covariates (age, sex, immunophenotype, revised international prognostic index score (rIPI), Eastern Cooperative Oncology Group (ECOG) PS, stage, and response to previous chemotherapy). Results: 619 patients in the LY12 trial were used to construct the frailty index (Table 1). Using a binary cut-off for frailty (<0.2), 15% (N=93) of patients were classified as frail. There were no differences in age or sex between frail and non-frail patients; however they differed in terms of other lymphoma-related characteristics (Table 2). Frailty was strongly associated with OS (HR 2.012, 95% CI 1.57-2.58), EFS (HR 1.94, 95% CI 1.53-2.46), frequency of the worst overall Grade >3 AE (OR 2.65 (15% vs. 6%), p=0.003), and likelihood of proceeding to ASCT (OR 0.26, 95% CI 0.15-0.43), but not hospitalization (OR 1.52, 95% CI 0.97-2.40) or SAE (6% vs. 4%, p=0.3). In multivariable analysis, frailty was not significantly associated with OS, EFS, likelihood of proceeding to ASCT, nor hospitalization (Table 3), though there was a trend to significance for ASCT. However, rIPI remained significantly associated with OS and EFS, ECOG remained significantly associated with OS (Table 3) Conclusion: A potentially broadly applicable lymphoma clinical trials specific FI was constructed through secondary analysis of LY12 data. 15% of patients were classified as frail. Frailty was significantly associated with OS, EFS, frequency of grade >3 AE and likelihood of proceeding to transplant. However, this relationship no longer was significant when controlling for lymphoma-related prognostic variables, suggesting that the impact of poor prognostic features of lymphoma supersede the impact of frailty alone in this younger clinical trial population. Interestingly, rIPI and ECOG demonstrated their value as simple predictors that are highly associated with OS and/or EFS even when controlling for other important covariates including frailty. These findings require further testing in an external data set, and would be particularly valuable to test in an older population. Calibration of the FI against clinical frailty assessment (e.g. Clinical Frailty Scale, Comprehensive Geriatric Assessment) would also be meaningful to confirm its ability to classify frail versus non-frail patients. Figure 1 Figure 1. Disclosures Crump: Epizyme: Research Funding; Roche: Research Funding; Kyte/Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Hay: Merck: Research Funding; Roche: Research Funding; Abbvie: Research Funding; Amgen: Research Funding; Karyopharm: Research Funding; Seattle Genetics: Research Funding. Prica: Astra-Zeneca: Honoraria; Kite Gilead: Honoraria.

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A Phase 1a/b Dose Escalation Study of the MYC Repressor Apto-253 in Patients with Relapsed or Refractory AML or High-Risk MDS

Blood ◽

10.1182/blood-2021-150049 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3411-3411

Author(s):

Maro Ohanian ◽

Martha L. Arellano ◽

Moshe Y. Levy ◽

Kristen O'Dwyer ◽

Hani Babiker ◽

...

Keyword(s):

Clinical Trial ◽

High Risk ◽

Adverse Events ◽

Board Of Directors ◽

Research Funding ◽

Publicly Traded ◽

Advisory Committees ◽

Grade 3 ◽

Refractory Aml

Abstract INTRODUCTION: APTO-253 represses expression of the MYC oncogene by targeting a conserved G-quadruplex structure in its promoter, down-regulates MYC mRNA and protein levels and induces apoptosis in AML cell lines and marrow samples from patients with AML, MDS, and MPN in vitro. After injection, a large fraction of APTO-253 binds iron and transforms to the Fe(253) 3 complex which retains full activity. APTO-253 has been granted orphan drug designation for AML by the US FDA and is being studied in a Phase 1a/b clinical trial in patients with relapsed or refractory AML (R/R AML) or high-risk myelodysplasias (high-risk MDS) (NCT02267863). AIMS: Primary objectives are to determine the safety and tolerability of APTO-253, MTD, dose limiting toxicities (DLT), and the RP2D. Key secondary objectives are to assess the pharmacokinetic (PK) profile, pharmacodynamic (PD) activity, and preliminary evidence of antitumor activity. METHODS: Eligible patients have R/R AML or high-risk MDS for which either standard treatment has failed, is no longer effective, or can no longer be administered safely. Treatment- emergent adverse events (TEAEs) and tumor responses are evaluated using International Working Group criteria. APTO-253 is administered by IV infusion once weekly on days 1, 8, 15, and 22 of each 28-day cycle; ascending dose cohorts were enrolled at a starting dose of 20 mg/m 2 with planned escalation to 403 mg/m 2. RESULTS: As of June 7, 2021, a total of 18 patients (median age 64.0 years, 16 AML and 2 high-risk MDS) with a median of 2.5 prior treatments (range of 1 - 9) have been treated with APTO-253 at doses of 20 (n=1), 40 (n=1), 66 (n=4), 100 (n=4) and 150 mg/m 2 (n=8). Most patients were RBC (87.5% of AML and 100% of MDS) and/or platelet (75% of AML and 50% MDS) transfusion-dependent. No DLTs or drug-related serious adverse events have been reported. Only 1 patient had a drug-related TEAE of grade 3 or greater (fatigue, Grade 3, probably related). Preliminary PK analysis (Figure 1) showed that serum levels of APTO-253 were dose proportional. C max and AUC 0-72h for C1D1 dosing were 0.06, 0.02, 0.36 ± 0.37, 0.44 ± 0.41 and 0.72 ± 0.70 µM and 0.11, 0.15, 3.98 ± 1.77, 4.79 ± 0.87 and 2.51 ± 1.73 µM*h for dose levels of 20, 40, 66, 100 and 150 mg/m 2, respectively. Plasma levels for Fe(253) 3 were significantly higher than those for the APTO-253 monomer. For example, C max and AUC 0-72h of Fe(253) 3 for C1D1 dosing of patients in Cohort 150 mg/m 2 were 2- and 20- fold higher than the ATPO-253 monomer at 15.09 ± 0.42 µM and 51.52 ± 28.26 µM*h, respectively. Following dosing at 150 mg/m 2, serum concentrations of Fe(253) 3 were above 0.5 µM for > 48 h, which approaches the therapeutic range based on in vitro studies. CONCLUSIONS: APTO-253 has been well-tolerated at doses of 20, 40, 66, 100 and 150 mg/m 2 over multiple cycles and escalated to 210 mg/m 2 (Cohort 6). PK analysis revealed that APTO-253 is rapidly transformed to and co-exists with the Fe(253) 3 in serum from R/R AML and high-risk MDS patients. Enrollment of patients at the 210 mg/m 2 dose level is ongoing and updated clinical data will be presented at the meeting. Figure 1 Figure 1. Disclosures Arellano: KITE Pharma, Inc: Consultancy; Syndax Pharmaceuticals, Inc: Consultancy. Levy: AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Other: Promotional speaker; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Morphosys: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Epizyme: Consultancy, Other: Promotional speaker; Takeda: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Dova: Consultancy, Other: Promotional speaker; Novartis: Consultancy, Other: Promotional speaker; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Speakers Bureau; Beigene: Consultancy, Honoraria, Speakers Bureau; Amgen Inc.: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau. Mahadevan: caris: Speakers Bureau; Guardanthealt: Speakers Bureau; PFIZER: Other: Clinical trial Adverse events committee; TG Therapeuticals: Other: Clinical trial Adverse events committee. Zhang: Aptose Biosciences, Inc.: Current Employment. Rastgoo: Aptose Biosciences, Inc.: Current Employment. Jin: Aptose Biosciences, Inc.: Current Employment. Marango: Aptose Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Howell: Aptose Biosciences, Inc.: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Research Funding. Rice: Aptose Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties; Oncolytics Biotech Inc.: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Bejar: Aptose Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company; Takeda: Research Funding; BMS: Consultancy, Research Funding; Gilead: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Astex: Consultancy; Silence Therapeutics: Consultancy.

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Blockade of IL-15 Utilizing Bnz-1, a Selective γ-Chain Inhibiting Peptide, Is Safe and Has Clinical Activity in Patients with T-Cell Large Granular Lymphocytic Leukemia (T-LGLL): Results of a Phase I/II Multi-Center Clinical Trial

Blood ◽

10.1182/blood-2019-129291 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2835-2835 ◽

Cited By ~ 1

Author(s):

Jonathan E. Brammer ◽

Lubomir Sokol ◽

Yutaka Tagaya ◽

Kerry Rogers ◽

Anjali Mishra ◽

...

Keyword(s):

Clinical Trial ◽

T Cell ◽

Phase I ◽

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Weekly Dose ◽

Advisory Committees ◽

Large Granular Lymphocytic Leukemia

T-cell large granular lymphocytic leukemia (T-LGLL) is an incurable, and likely under-diagnosed leukemia characterized by abnormal clonal proliferation of CD8+ memory T-cells. The clonal outgrowth of T-LGLL cells can lead to the development of profound neutropenia and anemia which results in frequent infections, transfusion dependence, and impairment in quality of life and lifespan. There have been few prospective clinical trials in this disease, and no drugs have been FDA approved for its treatment. The primary driver of leukemogenesis in T-LGLL is known to be interleukin-15 (IL-15), a gamma-chain cytokine that induces proliferation of T-LGLL cells. BNZ-1 is a novel pegylated peptide antagonist that inhibits IL-15 by binding to the common γ-chain receptor for cytokines IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Studies utilizing BNZ-1 in vitro on T-LGLL cell lines, and ex vivo on clinical patient samples demonstrated significant inhibition of downstream signaling and increased LGLL cell apoptosis (Wang et al., Leukemia 2018). Given these results, we conducted a phase I/II dose escalation study to evaluate the safety, maximum tolerated dose (MTD), and preliminary efficacy of BNZ-1 in T-LGLL (NCT03239393). Patients with T-LGLL were eligible if they had one or more of the following: absolute neutrophil count (ANC) <500 cells/m3, neutropenia with recurrent infections, or symptomatic or transfusion-dependent anemia. Diagnosis of T-LGLL required: >400/mm3 CD3+CD57+ cells or >650 mm3 CD8+ cells, with a clonal T-cell receptor rearrangement. No prior therapy within 30 days or 5 half-lives was permitted. MTD was evaluated using a standard 3+3 design; with a dose escalation strategy using four doses of BNZ-1: 0.5 mg/kg, 1 mg/kg, 2 mg/kg, and 4 mg/kg. BNZ-1 was administered by infusion on Days 1, 8, 15, and 22 of a 4-week cycle. Patients then had the option to enter the 3-month extension period, at the same weekly dose. Efficacy was determined utilizing criteria from the ECOG5998 study in T-LGLL. CR was defined as complete normalization of blood counts. Partial response (PR) in neutropenic patients was determined by 4 weeks or greater response with ANC >500 cells/mm3 if >/=50% improvement from baseline. For transfusion-dependent anemia patients, a >/=50% decrease in monthly transfusions for at least 2 months was required for a PR. For patients with symptomatic anemia, improvement in hemoglobin >/=1 g/dL with improvement in symptoms constituted a PR. Patients with a response were permitted to remain on a long-term extension (LTE). Eighteen patients, at 3 US centers were enrolled on study including: 3 patients at 0.5 mg/kg, 4 at 1 mg/kg, 5 at 2 mg/kg, and 6 at 4 mg/kg. 10 patients were enrolled for neutropenia, 4 for transfusion dependent anemia, 2 for symptomatic anemia, and 2 with anemia and neutropenia. 15 patients (83%) completed all 16 weeks of treatment, 2 patients declined to enter the extension phase, and one patient on the 2 mg/kg dosage was taken off study at 4 weeks due to neutropenia <100 thought secondary to T-LGLL. One patient developed grade 2 hyperbilirubinemia, which was thought possibly due to study drug though was grade 1 at baseline.The MTD was not reached. Four patients attained a PR: 3 patients with transfusion-dependent anemia became transfusion independent, while one patient with neutropenia had significant resolution of her neutropenia (Table). These three patients remain on the LTE, though one patient is under observation. Correlative studies demonstrated apoptosis of T-LGLL cells on flow cytometry utilizing CD3 T-cell gating within 24 hours of the first dosage of BNZ-1 (a representative example is shown in the Figure), confirming in patients that inhibition of IL-15 induces apoptosis of T-LGLL cells. In this Phase I/II clinical trial, IL-15 blockade utilizing BNZ-1 demonstrated increased apoptosis in patients with T-LGLL, with early evidence of clinical response, particularly amongst patients with transfusion-dependent anemia. Remarkably, these patients remained transfusion-independent while on BNZ-1. The MTD was not reached in this cohort of patients, and there were minimal AEs associated with BNZ-1. Further analysis of responding patients is underway to determine the most effective approach utilizing BNZ-1 in this rare disease. Table Disclosures Brammer: Celgene: Research Funding; Seatlle Genetics: Honoraria, Speakers Bureau. Sokol:EUSA: Consultancy. Tagaya:Bioniz: Membership on an entity's Board of Directors or advisory committees; Bioniz: Research Funding. Rogers:AbbVie: Research Funding; Acerta Pharma: Consultancy; Genentech: Research Funding; Janssen: Research Funding. Waldmann:Bioniz: Membership on an entity's Board of Directors or advisory committees. Azimi:Bioniz: Employment. Frohna:Bioniz: Employment. Ratnayake:Bioniz: Employment. Loughran:Bioniz: Membership on an entity's Board of Directors or advisory committees; Keystone Nano: Membership on an entity's Board of Directors or advisory committees.

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An Ongoing Phase 3 Study of Bosutinib (SKI-606) Versus Imatinib In Patients with Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia

Blood ◽

10.1182/blood.v116.21.208.208 ◽

2010 ◽

Vol 116 (21) ◽

pp. 208-208 ◽

Cited By ~ 16

Author(s):

Carlo Gambacorti-Passerini ◽

Dong-Wook Kim ◽

Hagop M. Kantarjian ◽

Tim H. Brummendorf ◽

Irina Dyagil ◽

...

Keyword(s):

Adverse Events ◽

Median Time ◽

Myeloid Leukemia ◽

Research Funding ◽

Chronic Phase ◽

Molecular Response ◽

Employment Equity ◽

Phase 3 ◽

Advisory Committees ◽

Equity Ownership

Abstract Abstract 208 Bosutinib is an orally bioavailable dual Src/Abl tyrosine kinase inhibitor (TKI), with minimal inhibitory activity against PDGFR or c-kit. In a phase 2 study, bosutinib demonstrated activity in patients with Philadelphia chromosome–positive (Ph+) chronic phase (CP) chronic myeloid leukemia (CML) in the second- and third-line treatment settings (Cortes JE, et al. ASCO 2010, Abstract #6502; Khoury JH, et al. ASCO 2010, Abstract #6514), as well as in patients with advanced Ph+ leukemias (Gambacorti-Passerini C, et al. ASCO 2010, Abstract #6509) following resistance or intolerance to imatinib and other TKIs. The current randomized, open-label, phase 3 study compared the activity and safety of bosutinib with that of imatinib in newly diagnosed patients with CP CML. The study enrolled adults aged 318 years with cytogenetic diagnosis of Ph+ CP CML within 6 months, adequate hepatic and renal function, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients were randomized to daily oral treatment with 500 mg bosutinib or 400 mg imatinib. Adverse events were graded using the National Cancer Institute Common Terminology Criteria, version 3.0. The primary efficacy endpoint was the rate of complete cytogenetic response (CCyR) at 1 year; the rates of hematologic response, molecular response, and progression and transformation to accelerated or blast phase were also evaluated. The study randomized 502 patients: 56.6% male, median age of 48 years (range, 18–91 years), and median time since diagnosis of 0.7 months (range, -0.3-7.9 months; the range minimum is negative due to CML diagnosis during the study screening period, and the range maximum is >6 months because of 1 patient considered a major protocol violator). The median duration of treatment was 11.1 months (range, 0.03–24.8 months). At Week 48 (approximately 11 months), 71.5% and 74.8% of patients (both treatment arms combined) were in CCyR and complete hematologic response (CHR), respectively. During the study, 81.4% of patients achieved a CCyR at or before Week 48, with a median time to CCyR of 24 weeks; 82.6% of patients achieved a CHR, with a median time to CHR of 8 weeks; and 40.6% of patients achieved a major molecular response (MMR), with a median time to MMR of 49 to 61 weeks for the 2 treatment arms. For the combined treatment arms, common treatment-emergent adverse events included diarrhea (43.7%), nausea (32.3%), vomiting (22.0%), rash (16.8%), pyrexia (11.6%), and fatigue (11.0%). The only grade 33 treatment-emergent adverse event observed in 32% of patients was diarrhea (5.2%), which was usually limited to the first weeks of treatment. Grade 33 hematologic laboratory abnormalities included neutropenia (14.2%), thrombocytopenia (12.4%), and anemia (5.8%). Other grade 33 laboratory abnormalities (35% of patients) included alanine aminotransferase elevation (11.6%), phosphatemia (7.6%), and aspartate aminotransferase elevation (6.4%). Overall, 22.2% patients discontinued therapy; adverse events led to discontinuation or death in 12.8% of patients, and 4.2% of patients discontinued due to disease progression. The high combined percentage of patients achieving MMR, CCyR, and CHR and the relatively low incidence of generally manageable grade 33 events observed suggest good efficacy and an overall favorable safety profile. Data for individual treatment arms will be unblinded by the end of August 2010, and will be presented at the meeting. Disclosures: Gambacorti-Passerini: Pfizer Inc: Research Funding. Kim:BMS, Novartis, Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kantarjian:Novartis: Consultancy, Research Funding; BMS, Pfizer: Research Funding. Brummendorf:Pfizer Inc: Membership on an entity's Board of Directors or advisory committees. Griskevicius:Pfizer Inc: Research Funding. Goh:Novartis and Janssen Ciliag: Research Funding. Wang:Pfizer Inc: Employment, Equity Ownership. Gogat:Pfizer Inc: Employment, Equity Ownership. Cortes:Pfizer Inc: Consultancy, Research Funding.

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