A Phase II Pilot Study of Kinase Inhibition in Relapsed/Refractory Acute Leukemias: Using an in Vitro Kinase Inhibitor Panel to Select Individualized, Targeted Therapies

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4051-4051
Author(s):  
Stephen E Spurgeon ◽  
Rachel Cook ◽  
Elie Traer ◽  
Uma Borate ◽  
Richard T. Maziarz ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Board Of Directors ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Clinical Activity ◽  
Advisory Committees ◽  
In Vitro Sensitivity ◽  
Equity Ownership ◽  
Correlative Studies

Abstract Despite improved understanding of molecular lesions in relapsed/refractory acute leukemia, outcomes remain dismal. Aberrantly activated tyrosine kinase signaling pathways play a critical role in the pathogenesis of acute leukemia. Identification of drugs that target the drivers of disease has the potential to improve treatment. We have developed an FDA regulated (IDE# G110198) in vitro kinase inhibitor assay that can identify potential therapeutic targets in primary acute leukemia samples and provide individualized treatment options in a clinically relevant time frame. We designed a Phase 2 clinical trial (NCT01620216) to validate the role of this pre-clinical kinase inhibitor screen for selecting effective individualized therapies. After obtaining informed consent, peripheral blood or bone marrow is isolated using a ficoll-density gradient and plated with dose-escalating concentration gradients of five kinase inhibitors (nilotinib, dasatinib, sorafenib, sunitinib, and ponatinib). Cell line controls are used for each drug. Samples are deemed sensitive based on IC50 and comparison to the median of all samples tested in our laboratory (over 1000 primary samples to date). Patients who satisfy eligibility are treated with FDA approved dosing using the selected inhibitor. Inclusion is limited to patients age ≥ 21 with relapsed/refractory acute leukemia (AML and ALL) and patients age ≥ 65 with a history of myelodysplasia who have developed AML, have failed hypomethylating agents, and are not candidates for standard induction. Only patients with samples that demonstrate in vitro sensitivity to 1 of the trial drugs are eligible. Additional eligibility includes: ECOG ≤ 2, adequate organ function, and no active GVHD. Cycles are 28-days. Marrow biopsy for response assessment and correlative studies is obtained on days 15, 28, and day 1 of subsequent cycles. The primary objective is to determine the clinical activity, defined as > 25% decrease in bone marrow blast counts. Secondary objectives include overall response (defined by the International Working Group), overall survival, and progression free survival. Correlative studies include high-throughput sequencing, expression profiling, correlation of target inhibition with clinical response, and PK analysis. The treatment approach is deemed worthy of ongoing study if clinical activity is observed in at least 4 of 24 patients. 43 patients have been screened with 12 demonstrating in vitro sensitivity. Nine have been enrolled on treatment. Median age is 64 (31-71) years with 5 males and 4 females. Two patients had ALL. The remainder had AML. Drugs utilized to date include dasatinib (n=3) and sorafenib (n=6). Of the three patients who exhibited in vitro sensitivity but were not enrolled, sensitivity to sorafenib, sunitinib, and dasatinib was seen. Clinical activity was seen in 4 subjects with AML -all treated with sorafenib- with median change in marrow blast in this group of 69% (44-95%). Median time on treatment for responding patients was 39 days (18-110 days). One subject with refractory AML who had failed allogeneic transplant had a 95% decrease in marrow blasts with prolonged disease control (Figure 1). Two patients were taken off study due to drug-related AEs (pancreatitis and diarrhea). No unanticipated AEs were seen. Our in vitro kinase inhibitor assay identified potential therapies for the treatment of ALL and AML. Although the numbers are too small to draw any specific conclusions regarding response, the 4 responders were FLT3-ITD+ AML, a known target of sorafenib, and appear to have proliferative disease with higher baseline blast counts. The relatively small panel of available treatment drugs with overlapping target profiles may have contributed to the preferential treatment of patients with FLT3-ITD+ AML and to the significant screen fail rate. Our results using a larger panel of targeted agents have shown a high level of sensitivity to at least one drug. Accordingly, we are expanding the platform of clinically available targeted agents. The study continues to enroll patients with the goals of defining additional molecular abnormalities and optimizing assay characteristics, while prospectively testing the therapeutic potential of additional drugs. Correlative studies are ongoing. We have initiated another study using this assay to help select targeted therapies to be added to AML induction (NCT02779283). Figure Figure. Table Table. Disclosures Spurgeon: Gilead Sciences: Research Funding; Bristol Myers Squibb: Research Funding; Acerta Pharma: Research Funding; Genentech: Research Funding; Janssen: Research Funding. Maziarz:Incyte: Membership on an entity's Board of Directors or advisory committees; Athersys: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Tyner:Janssen Research & Development: Research Funding; Inctye: Research Funding; Genentech: Research Funding; Constellation Pharmaceuticals: Research Funding; AstraZeneca: Research Funding; Leap Oncology: Consultancy; Agios Pharmaceuticals: Research Funding; Array Biopharma: Research Funding; Aptose Biosciences: Research Funding; Seattle Genetics: Research Funding; Takeda Pharmaceuticals: Research Funding. Druker:Agios: Honoraria; Ambit BioSciences: Consultancy; ARIAD: Patents & Royalties, Research Funding; Array: Patents & Royalties; AstraZeneca: Consultancy; Blueprint Medicines: Consultancy, Equity Ownership, Other: travel, accommodations, expenses ; BMS: Research Funding; CTI: Equity Ownership; Curis: Patents & Royalties; Cylene: Consultancy, Equity Ownership; D3 Oncology Solutions: Consultancy; Gilead Sciences: Consultancy, Other: travel, accommodations, expenses ; Lorus: Consultancy, Equity Ownership; MolecularMD: Consultancy, Equity Ownership, Patents & Royalties; Novartis: Research Funding; Oncotide Pharmaceuticals: Research Funding; Pfizer: Patents & Royalties; Roche: Consultancy.

scholarly journals The 3-Drug Combination Treatment ART838, ABT199 Plus Sorafenib Is Effective Against AML Xenografts, Possibly Via Cooperative Targeting of MCL1

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4044-4044
Author(s):  
Blake S Moses ◽  
Jennifer Fox ◽  
Xiaochun Chen ◽  
Samantha McCullough ◽  
Sang Ngoc Tran ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Board Of Directors ◽  
Cell Lines ◽  
Drug Combination ◽  
Research Funding ◽  
Leukemia Cell ◽  
Advisory Committees ◽  
Leukemia Cell Lines ◽  
Equity Ownership

Abstract Antimalarial artemisinins have broad antineoplastic activity in vitro, are well tolerated and inexpensive, and can be parenterally or orally administered in humans. Artemisinin-derived trioxane diphenylphosphate dimer 838 (ART838; a potent artemisinin-derivative) inhibited acute leukemia growth in vivo and in vitro, at doses where normal human CD34+ hematopoietic stem-progenitor cell clonogenicity was essentially unaffected (Fox et al, Oncotarget 2016, PMID: 26771236). In our focused drug combination screen for drugs that synergize with ART838, the only BCL2 inhibitors in the screen library of 111 emerging antineoplastic compounds, navitoclax (ABT737) and venetoclax (ABT199; FDA-approved), were identified as 2 of the top 3 candidates. Synergies between ART838 and BCL2 inhibitors were validated in multiple acute leukemia cell lines and primary cases. This ART838-BCL2 inhibitor synergy may be due to reduced levels of MCL1 protein that we and others have observed in multiple acute leukemia cell lines and primary cases treated with artemisinins (Budhraja et al, Clin Cancer Res 2017, PMID: 28974549). Treatment of acute leukemia xenografts with the ART838 plus ABT199 combination reduced leukemia growth rates and prolonged survivals, compared to vehicle or either ART838 or ABT199 alone. To add to the efficacy of this ART838 plus ABT199 treatment regimen, we sought to rationally add a third low-toxicity active antileukemic agent. Sorafenib (SOR; FDA-approved) inhibits multiple kinases which may mediate its antileukemic activity, with the importance of the targets varying from case to case; e.g. FLT3 is an important target in many AMLs. In addition, several reports have found that SOR reduces MCL1 protein stability and translation through inhibition of the ERK and PI3K pathways (Wang et al, Clin Cancer Res 2016, PMID: 26459180; Huber et al, Leukemia 2011, PMID: 21293487). In all acute leukemia cell lines tested, we observed large reductions in MCL1 protein levels with SOR treatment, which may further rationalize the addition of SOR to our ART838 plus ABT199 antileukemic regimen. We had previously observed strong in vitro synergy between ART838 and SOR (PMID: 26771236). Treatment of acute leukemia xenografts with the ART838 plus SOR combination reduced leukemia xenograft growth rates and prolonged survivals, compared to single drugs. Mice bearing luciferase-labelled acute leukemia xenografts were treated (PO daily x5) with single drug or 2-drug or 3-drug combinations of ART838, ABT199, and SOR, each at their individual maximally tolerated doses. Treatment with this 3-drug combination caused rapid regression of luciferase-labelled MV4;11 AML xenografts (Fig 1A). The 5-day treatment cycles were repeated every other week, and mice receiving this 3-drug combination survived >4 times longer than vehicle-treated mice (Fig 1B). Mouse body weights were stable during treatment. Although myelosuppression is the human clinical dose-limiting toxicity of each of these 3 drugs, mouse blood cell counts during 3-drug combination treatment were in the normal range. Treatment of a luciferase-labelled primary AML leukemia xenograft with this 3-drug combination reduced leukemia growth more than the single drugs or 2-drug combinations (Fig 1C). Assessment of efficacy and pharmacokinetics-pharmacodynamics against diverse acute leukemia xenografts will test this combination of ART838, ABT199 plus SOR as a rational low-toxicity drug triad for treatment of acute leukemias and potentially other cancers. Disclosures Fox: Intrexon Corporation: Employment. Tyner:Genentech: Research Funding; Janssen: Research Funding; AstraZeneca: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Constellation: Research Funding; Array: Research Funding; Takeda: Research Funding; Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees; Aptose: Research Funding. Civin:ConverGene LLC: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; GPB Scientific LLC: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; 3DBioWorks Inc: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; BD (Becton Dickinson): Honoraria.

scholarly journals Concomitant Targeting of FLT3 and BTK with CG'806 Overcomes FLT3-Inhibitor Resistance through Inhibition of Autophagy

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2635-2635
Author(s):  
Weiguo Zhang ◽  
Guopan Yu ◽  
Hongying Zhang ◽  
Charlie Ly ◽  
Bin Yuan ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Board Of Directors ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Leukemia Cell ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Induced Apoptosis ◽  
Inhibitor Resistance

Abstract Fms-like tyrosine kinase 3 (FLT3)-targeted therapy represents an important paradigm in the management of patients with highly aggressive FLT3 mutated acute myeloid leukemia (AML). However, clinical efficacy is usually transient and followed by emergence of resistance to FLT3-inhibitors (Borthakur et al., 2011; Cortes et al., 2013; Zhang et al., 2008). Such resistance often results from acquired mutations of TKD, which are frequently identified in D835, Y842 and F691 residues (Smith et al., 2015; Smith et al., 2012; Zhang et al., 2014). It was reported that the FLT3-ITD-targeting drug sorafenib can induce autophagy in human myeloid dendritic cells (Lin et al., 2013). Induction of autophagy has also been reported to play a crucial role in resistance to BCR-ABL targeted imatinib therapy in CML (Hekmatshoar et al., 2018). Additionally, inhibition of autophagy can re-sensitize cancer cells to apoptosis induction (Fitzwalter et al., 2018; Piya et al., 2017), suggesting that inhibition of autophagy may represent a novel therapeutic strategy for overcoming resistance to FLT3-targeted therapy. In the present study, we assessed autophagy levels in leukemia cell lines bearing different FLT3 mutations and in AML patient samples obtained from sorafenib-resistant patients. All tested resistant cell lines bearing TKD or ITD+TKD mutations showed increased basal autophagy levels. Resistant AML patient samples also demonstrated greater autophagy compared to matched pre-treatment samples in FLT3-mutated, but not in FLT3-wild type samples. Upregulation of autophagy was also observed in the bone marrow (BM)-mimetic microenvironment (i.e., hypoxia and the presence of mesenchymal stem cells (MSCs) in vitro. Inhibition of autophagy with chloroquine (CQ) potentiated quizartinib-induced apoptosis and partially abrogated MSC-mediated protection in FLT3-ITD- and/or D835-mutated AML cells by suppressing c-Myc, mTOR/S6K signaling and activating transcription factor 4 (ATF4). We also observed upregulation of BTK activation accompanied by increased autophagy levels in hypoxic/MSC co-culture with leukemic cells and in resistant primary patient samples. Co-targeting BTK and FLT3 with ibrutinib (or BTK siRNA) and quizartinib enhanced leukemic cell killing and abrogates MSC-mediated protection of FLT3 mutated leukemia cells. We further investigated a novel, highly potent small molecule pan-FLT3/pan-BTK kinase inhibitor CG-806 (IC50s 0.8 and 5.0 nM against FLT3-ITD and BTK, respectively) (Aptose, San Diego, CA). CG'806 abolished MSC/hypoxia-mediated protection of AML cells and induced apoptosis in FLT3-mutated cells in vitro. Of note, CG'806, but not quizartinib, exerted profound pro-apoptotic effects in primary AML patient cells harboring ITD+D835 mutations ex vivo. Further evaluation in a PDX leukemia model inoculated with the ITD+D835 mutated primary AML cells showed that CG'806 significantly reduced leukemia cell burden and benefited for mouse survival. Taken together, autophagy is associated with AML resistance to FLT3-targeted therapy, which can be overcome by the pan-FLT3/pan-BTK kinase inhibitor CG-806 through concomitant blockade of FLT3 and BTK. Co-targeting FLT3 and BTK might provide a strategy for preventing/overcoming FLT3 inhibitor resistance in AML patients with FLT3 mutations. Phase I trials of CG'806 are in preparation. Disclosures Zhang: Aptose Biosciences, Inc: Employment. Battula:United Therapeutics Inc.: Patents & Royalties, Research Funding. Konopleva:Stemline Therapeutics: Research Funding. Rice:Aptose Biosciences, Inc: Equity Ownership. Andreeff:Eutropics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Reata: Equity Ownership; SentiBio: Equity Ownership; Oncolyze: Equity Ownership; Astra Zeneca: Research Funding; Jazz Pharma: Consultancy; Oncoceutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; United Therapeutics: Patents & Royalties: GD2 inhibition in breast cancer ; Aptose: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Patents & Royalties: MDM2 inhibitor activity patent, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy.

A Phase I Study of Bendamustine Combined with Lenalidomide and Dexamethasone in Patients with Refractory or Relapsed Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1856-1856 ◽  
Author(s):  
Suzanne Lentzsch ◽  
Amy O’Sullivan ◽  
Silvana Lalo ◽  
Carrie Kruppa ◽  
Diane Gardner ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Board Of Directors ◽  
Dose Level ◽  
Research Funding ◽  
Advisory Board ◽  
Clinical Activity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 1856 Poster Board I-882 Background: Lenalidomide is an analog of thalidomide that has shown significant clinical activity in patients with relapsed or refractory multiple myeloma (MM), both as a single agent and in combination with dexamethasone. Bendamustine is a bifunctional alkylating agent that is approved for the treatment of chronic lymphocytic leukemia and indolent non-Hodgkin's lymphoma that has progressed during or relapsed within 6 months following a rituximab-containing regimen. Bendamustine combined with lenalidomide may be an effective treatment option for MM patients, particularly those with preexisting or bortezomib-induced neuropathy. Our primary objective was to determine the maximum tolerated dose (MTD) and safety profile of bendamustine and lenalidomide when administered with dexamethasone for patients with relapsed or refractory MM. Methods: Patients aged ≥18 years with confirmed, measurable stage 2 or 3 MM that was refractory to or progressed after 1 or more prior therapies, including lenalidomide, received bendamustine by intravenous infusion on days 1 and 2, oral lenalidomide on days 1–21, and oral dexamethasone on days 1, 8, 15, and 22 of each 28-day cycle. Treatment was continued until a plateau of best response, as determined by the IBMTR/ABMTR, was reached. Study drug doses were escalated through 4 levels (Table), with 3–6 patients enrolled at each level depending on the rate of dose-limiting toxicity (DLT). After determining the MTD, up to an additional 12 patients will be enrolled in an MTD expansion arm to better evaluate toxicity and clinical activity. Secondary endpoints included preliminary efficacy, as evidenced by objective response, time to disease progression, and overall survival. Results: To date, 11 patients have been enrolled, with a median age of 63 years (range, 38–75 years). The MTD of bendamustine and lenalidomide has not been identified at this point; currently, patients are enrolling on dose level 3 with 100 mg/m2 bendamustine and 10 mg lenalidomide. Thus far, DLT included 1 grade 4 neutropenia at dose level 2. Nine of 11 patients are currently eligible for response assessment. A partial response was observed in 67% of patients, including 1 very good partial response and 5 partial responses (PR). Two patients experienced stable disease and 1 exhibited progressive disease. Grade 3/4 adverse events included grade 3 neutropenia, thrombocytopenia, anemia, hyperglycemia, and prolonged QTC, and 1 grade 4 neutropenia. Conclusions: Bendamustine, lenalidomide, and dexamethasone form a well-tolerated and highly active regimen even in heavily pretreated MM patients, with a PR rate of 67%. Additional updates on response and MTD will be available at the time of presentation. Disclosures: Lentzsch: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cephalon: Consultancy, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Bendamustine is not FDA approved for the treatment of multiple myeloma in the USA. Burt:Millennium: Honoraria; Celgene: Honoraria. Mapara:Resolvyx: Consultancy, Research Funding; Genzyme: Membership on an entity's Board of Directors or advisory committees; Gentium: Equity Ownership; Celgene: Spouse is consultant , has received research funding, and participates on advisory board; Cephalon: Spouse has received funding for clinical trial and participates on advisory board. Redner:Biogen: Equity Ownership; Wyeth: Equity Ownership; Glaxo-Smith-Kline: Equity Ownership; Pfizer: Equity Ownership; Genzyme: Membership on an entity's Board of Directors or advisory committees. Roodman:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy; Acceleron: Consultancy. Zonder:Amgen: Consultancy; Pfizer: Consultancy; Cephalon: Consultancy; Millennium: Consultancy, Speaking (CME only); no promotional talks.

Identification of Alpha 1-Acid Glycoprotein (AAG) As a Potential Patient Selection Biomarker for Improved Clinical Activity of the Novel KSP Inhibitor ARRY-520 in Relapsed and Refractory Multiple Myeloma (MM)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1868-1868 ◽  
Author(s):  
Brian Tunquist ◽  
Karin Brown ◽  
Gary Hingorani ◽  
Sagar Lonial ◽  
Jonathan L. Kaufman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Response Rate ◽  
Phase 1 ◽  
Clinical Activity ◽  
Advisory Committees ◽  
Blood Samples ◽  
Refractory Multiple Myeloma

Abstract Abstract 1868 Background ARRY-520 is a kinesin spindle protein (KSP) inhibitor that has demonstrated clinical activity in patients with relapsed and refractory multiple myeloma (MM). Although ARRY-520 is administered IV, it displays variable pharmacokinetics (PK) among patients. The degree of binding of certain drugs to serum proteins can alter their free fraction (fu) and PK, with a possible impact on clinical activity. Alpha 1-acid glycoprotein (AAG) is an acute-phase reactant protein that is often elevated in the blood of patients with cancer, including multiple myeloma. We investigated the significance of the interaction of ARRY-520 with AAG, and other relevant blood proteins, using both in vitro models and clinical data. Methods Compound-protein binding was assessed using several in vitro assays. In addition, the effect of increasing concentrations of AAG on MM cell line viability was measured. Patient data were obtained from 3 clinical studies of ARRY-520: a Phase 1 solid tumor study, a Phase 1/2 AML study, and a Phase 1/2 study in MM. The MM Phase 2 portion consists of 2 separate, 2-stage cohorts. Cohort 1 evaluated ARRY-520 administered as a single agent, and cohort 2 investigated ARRY-520 in combination with low-dose dexamethasone (LoDex). The concentrations of multiple proteins, including AAG, and the degree of ARRY-520 total protein binding, were measured in pre- and post-dose blood samples for patients in the analysis. AAG levels in MM patients were further correlated with time-on-study and clinical response rate. Results ARRY-520 exhibits low micromolar affinity for AAG in in vitro assays, but not for other common serum proteins, such as albumin. To investigate whether AAG binding impacts biological activity, we found that increasing AAG concentrations within a clinically relevant range resulted in increasing IC50 values for ARRY-520 on MM cell line viability. Of other MM agents tested, none exhibited high affinity binding to AAG in vitro, and a range of AAG concentrations did not alter the cellular activity of these compounds. Pre-dose concentrations of AAG were measured using blood samples collected from patients on all 3 ARRY-520 studies (0.4 – 4.1 g/L AAG in solid tumor study; 0.5 – 2.4 g/L in AML study; 0.2 – 2.8 g/L in MM study). Post-dose blood samples from the MM study also indicated that AAG levels do not significantly change with time. The fu of ARRY-520 in blood was meaningfully reduced among patients with the highest AAG concentrations. Furthermore, AAG and fu were correlated with changes in clinical PK: CL and Vd decreased with increasing AAG, trends consistent with a lower fu. Among the MM patients, 72 patients were evaluable for AAG determination (27 from the dose-escalation portion, 27 from Cohort 1, and 18 from Stage 1 of Cohort 2). Across all of these cohorts, the group of patients with AAG above an empirically-determined cutoff of 1.1 g/L showed a decreased median time on study (1.5 months vs 4.7 months) and no clinical responses (0/19 vs 12/53) as compared to patients below this cutoff. For example, as reported separately, ARRY-520 in combination with LoDex showed a promising 22% overall response rate (≥PR) in the 1st-stage of Cohort 2. In this cohort, 6 patients were determined to have AAG concentrations above the empirical cutoff. None of these patients had clinical benefit. Excluding these 6 patients would significantly improve the overall response rate (≥PR) from 22% (4/18) to 33% (4/12). Summary AAG has been proposed as a prognostic marker for MM disease severitya. Our preliminary data suggest that AAG levels can affect the free fraction of ARRY-520 in blood over a clinically relevant range both preclinically and in clinical studies. In retrospective analysis, patients with higher AAG levels show a lower fu and therefore may not achieve sufficient exposure to gain therapeutic benefit from ARRY-520. In preclinical analyses, this effect is specific to ARRY-520, suggesting that AAG levels may be predictive for ARRY-520 activity relative to other MM drugs. We hypothesize that prospective screening for AAG may enable exclusion of patients who may not achieve therapeutic exposure to ARRY-520, increasing the overall activity of ARRY-520 and preventing exposure of non-responders to an ineffective therapeutic dose. Further, experiments are currently underway to investigate the relevance of other acute-phase proteins in blood. Disclosures: Tunquist: Array BioPharma: Employment. Off Label Use: ARRY-520 alone and with dexamethasone for the treatment of relapsed/refractory multiple myeloma. ARRY-520 is not currently approved for any indication. Brown:Array BioPharma: Employment. Hingorani:Array BioPharma: Employment. Lonial:Millennium Pharmaceuticals, Inc.: 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; Bristol-Meyers Squibb: 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; Onyx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kaufman:Millenium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Onyx: Consultancy. Zonder:Celgene: Honoraria, Research Funding; Millenium: Honoraria, Research Funding. Orlowski:Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Shah:Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Hilder:Array BioPharma: Employment. Ptaszynski:Array BioPharma: Consultancy. Koch:Array BioPharma: Employment. Litwiler:Array BioPharma: Employment. Walker:Array BioPharma: Employment.

Selinexor Demonstrates Marked Synergy with Dexamethasone (Sel-Dex) in Preclinical Models and in Patients with Heavily Pretreated Refractory Multiple Myeloma (MM)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4773-4773 ◽  
Author(s):  
Christine I. Chen ◽  
Martin Gutierrez ◽  
David S. Siegel ◽  
Joshua R. Richter ◽  
Nina Wagner-Johnston ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Transcriptional Activation ◽  
Nuclear Export ◽  
Research Funding ◽  
Phase 1 ◽  
Advisory Committees ◽  
Nuclear Retention ◽  
Heavily Pretreated ◽  
Equity Ownership

Abstract Introduction: The nuclear export protein exportin 1, (XPO1) is overexpressed in a wide variety of cancers including MM and often correlate with poor prognosis. Selinexor (KPT-330) is an oral Selective Inhibitor of Nuclear Export (SINE) XPO1 antagonist in Phase 1 and 2 clinical studies. Selinexor forces nuclear retention and reactivation of tumor suppressor proteins (TSPs) and reduction of many proto-oncogenes, including MDM2, MYC and Cyclin D. In addition, selinexor potently deactivates NF-κB, through forced nuclear retention of IκBα. Together these effects induce selective apoptosis in MM cells and inhibition of NF-κB dependent osteoclast activation. XPO1 is also responsible for nuclear export of the glucocorticoid receptor (GR). We hypothesized that selinexor will enhance the activity of dexamethasone (DEX)-bound GR, resulting in synergistic tumor cell killing. Methods: In vitro tumor cell viability measurements were based on MTT (CellTiter 96¨/Promega) and combination indices were calculated using CalcuSyn software. For xenograft studies, utilized NOD-SCID mice with subcutaneous inoculation of MM.1s cells. GR nuclear localization was measured with immunofluorescent anti-GR (phosphor-S211) antibody and quantitative imaging. To assess GR transcriptional activation, GR binding to a GCR consensus sequence was measured in nuclear extracts using an ELISA method (GR ELISA kit/Affymetrix). Patients (pts) with heavily pretreated refractory MM were dosed with oral selinexor at doses of up to 60 mg/m2 (8-10 doses/4 wk cycle) as part of a Phase 1 program in advanced hematological malignancies. Response we defined based on the IMWG criteria. The effect of combining DEX with selinexor was analyzed in all pts who received selinexor at moderate to high doses (30-60 mg/m2). Safety and efficacy were analyzed separately in three groups: no DEX, <20 mg DEX and 20 mgs DEX. Results: In MM.1s cells Sel-Dex showed synergy for nuclear retention of the DEX activated GR (Ser211-phosphorylated) and concomitant GR transcriptional activation. Sel-Dex showed highly synergistic cytotoxicity in MM.1s cells in vitro and in vivo, with a corresponding increase in apoptosis. Selinexor alone was potently cytotoxic in the DEX resistant MM cell lines MM.1R and ANBL6, but addition of DEX provided no additional effect. Twenty-eight pts with heavily pretreated refractory MM (16 M, 12 F; median age 62; ECOG PS 0/1: 7/21; median prior regimens: 6) received selinexor at 30 – 60 mg/m2 with either 0, <20, or 20 mgs DEX. All pts have received a proteasome inhibitor and an Imid and the majority of the pts have received pomalidomide (68%) and/or carfilzomib (36%). The most common Grade 1/2 AEs for these three groups were: nausea (82%/86%/70%), fatigue (55%/86%/40%), anorexia (36%/71%/60%), and vomiting (36%/57%/10%). Of the 28 pts treated; 10 heavily pretreated refractory MM pts treated with a combination of selinexor (45 mg/m2 twice weekly) and DEX (20 mg with each selinexor dose) were found to have dramatically improved disease response (n=10, ORR 60%), with one stringent complete response (sCR, 10%), 5 partial responses (PR, 50%) and clinical benefit rate (CBR) rate of 80% (Figure 1). Treatment with ³30mg/m2 selinexor and <20 mg DEX (n=7), resulted in ORR of 14% and CBR of 86%, while treatment with selinexor (30-60 mg/m2) without DEX (n=12) showed best response of stable disease (50%). Sel-Dex was also associated with an increase in time on study relative to selinexor alone, with 7 of out 10 pts in the 20 mg DEX combo group still on study (11-25 weeks). Five additional pts were treated with selinexor at a dose of 60 mg/m2 in combination with 20 mg DEX. Response evaluation is pending. Conclusions: Sel-Dex combination is markedly synergistic in preclinical models, which is supported by the preliminary clinical data presented. One potential mechanism underlying this synergy is the amplification of GR activity due the combined effects of selinexor-induced nuclear retention of activated GR coupled with DEX-mediated GR agonism. These results provide a promising basis for the continuing study of Sel-Dex for treatment of pts with refractory MM. Phase 2 studies of Sel-Dex in pts with MM refractory to both pomalidomide and carfilzomib are planned for early 2015. Disclosures Chen: Celgene: Honoraria; Janssen: Honoraria. Off Label Use: Lenalidomide maintenance therapy after ASCT. Gutierrez:Senesco: PI Other. Siegel:Celgene, Millennium, Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Baz:Celgene: Research Funding; Millennium: Research Funding; Bristol Myers Squibb: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding. Kukreti:Celgene: Honoraria. Azmi:Karyopharm Therpeutics: Research Funding. Kashyap:Karyopharm Therapeutics: Employment. Landesman:Karyopharm Therapeutics: Employment. Marshall:Karyopharm Therpeutics: Employment. McCartney:Karyopharm Therpeutics: Employment. Saint-Martin:Karyopharm Therpeutics: Employment. Norori:Karyopharm Therpeutics: Consultancy. Savona:Karyopharm Therpeutics: Membership on an entity's Board of Directors or advisory committees. Rashal:Karyopharm Therapeutics: Employment. Carlson:Karyopharm Therapeutics: Employment. Mirza:Karyopharm Therpeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Shacham:Karyopharm Therapeutics Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Kauffman:Karyopharm Therapeutics: Employment, Equity Ownership. Reece:Millennium: Honoraria, Research Funding; Millennium: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Merck: Research Funding; Merck: Research Funding; BMS: Research Funding; BMS: Research Funding; Novartis: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen : Honoraria; Amgen : Honoraria.

Inhibition of USP10 Induces Degradation of Oncogenic FLT3: A Novel Approach to Therapy of Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 524-524
Author(s):  
Sara Buhrlage ◽  
Ellen Weisberg ◽  
Nathan Schauer ◽  
Jing Yang ◽  
Ilaria Lamberto ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Leukemia Cell ◽  
Initial Assessment ◽  
Large Trial ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. Overall, the survival with current chemotherapy is only 20-40%, declining steadily with advancing age. Approximately 30% of AML patients have mutations that constitutively activate the FLT3 gene. The most common FLT3 mutation results in tandem duplications within the juxtamembrane domain, observed in 20-25% of AML patients (internal tandem duplication, ITD), associated with markedly decreased survival. FLT3 kinase domain inhibitors, including SU11248, SU5416, CEP-701 and PKC412 (midostaurin), have been shown to induce partial, and usually brief, remissions in clinical trials of relapsed AML patients when administered as single agents. In a large trial in newly diagnosed patients, however, midostaurin was shown to increase survival when combined with standard chemotherapy.[1] This study supports the notion that inhibition of FLT3 may be important, at least in patients with mutations in the FLT3 gene. Since drug resistance develops in some patients with newly diagnosed AML and virtually all patients with advanced disease, additional strategies to target FLT3 would be of value. We discovered that the deubiquitinating enzyme (DUB) ubiquitin specific protease 10 (USP10) removes a degradative ubiquitin tag from mutant FLT3 thereby contributing to high levels of the oncogenic protein in AML (Fig 1a). Screening of our preclinical DUB inhibitor library for ability to selectively kill growth factor-independent FLT3-ITD-positive Ba/F3 cells over IL-3-dependent parental Ba/F3 cells identified HBX19818, a reported USP7 inhibitor, as the top hit. The effects are not unique to the Ba/F3 system: when profiled against a panel of 7 leukemia cell lines, HBX19818 conferred a substantial growth suppressive effect only to those expressing the FLT3-ITD oncoprotein (Fig 1b). As an initial assessment of the mechanism of HBX19818 we confirmed that it does promote ubiquitin-mediated degradation of FLT3-ITD (Fig 1c) and that the effect is selective as HBX19818 does not impact protein levels of wt FLT3. HBX19818 is published as an irreversible USP7 inhibitor,[2] however DUBome selectivity profiling data we generated identifies USP10 as the most potently inhibited DUB of the compound (USP10 IC50 = 14 µM). We went on to validate USP10 as the DUB that stabilizes FLT3-ITD using a combination of small molecule and genetic experiments. Notably, HBX19818 binds and inhibits USP10 in cells (data not shown), small hairpin knockdown of USP10 phenocopies the antiproliferative and FLT3 degradation effects of HBX19818 (Figure 1d and data not shown), and a direct interaction between USP10 and FLT3-ITD is observed in co-immunoprecipitation experiments (Fig 1e). Additionally, SAR studies reveal correlation among USP10 IC50, FLT3-ITD degradation and anti-proliferative effects for the HBX19818 chemical series, and we identified a second chemotype that phenocopies its effects. In support of the translational potential of USP10 inhibition for FLT3 mutant AML, we observed that both USP10 inhibitor series synergize with FLT3 kinase inhibitors, suppress growth of mutant FLT3-expressing primary AML cells and primagraft AML cells and, importantly, display the ability to overcome the FLT3 inhibitor-resistant mutant FLT3-ITD-F691L among other FLT3 kinase inhibitor-resistant mutants (Fig. 1f and data not shown). Overall, our data strongly support degradation of mutant FLT3 as an alternative approach to therapeutically target FLT3. This approach, which focuses on targeting USP10, could prove more efficacious than kinase inhibitors by simultaneously blocking both enzymatic and scaffolding functions of FLT3, and blocking compensatory increases in FLT3 protein or resistant point mutations associated with some kinase inhibitors. Importantly, this is the first demonstration of stabilization of an AML mutant driver protein by a DUB enzyme and introduces a novel therapy for FLT3 mutant-positive AML. References: 1. Stone, R.M., ASH, 2015. 2. Reverdy, C., et al., Chem Biol, 2012. 19, 467-77. Figure 1. Figure 1. Disclosures Weisberg: novartis: Research Funding. Weinstock:Novartis: Consultancy, Research Funding. Stone:Celator: Consultancy; Pfizer: Consultancy; Xenetic Biosciences: Consultancy; Novartis: Consultancy; Seattle Genetics: Consultancy; Roche: Consultancy; Amgen: Consultancy; ONO: Consultancy; Xenetic Biosciences: Consultancy; Sunesis Pharmaceuticals: Consultancy; Juno Therapeutics: Consultancy; Sunesis Pharmaceuticals: Consultancy; Karyopharm: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy; Agios: Consultancy; Jansen: Consultancy. Gray:Gatekeeper: Equity Ownership; Petra: Consultancy, Equity Ownership; C4: Consultancy, Equity Ownership; Syros: Consultancy, Equity Ownership. Griffin:Janssen: Research Funding; Novartis: Consultancy, Research Funding.

scholarly journals Targeting Wnt/β-Catenin and BCL-2, Two Critical Survival Factors, Synergistically Induces Apoptosis in AML Via Rac1-Mediated MCL-1 Inhibition

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1442-1442
Author(s):  
Xiangmeng Wang ◽  
Po Yee Mak ◽  
Wencai Ma ◽  
Xiaoping Su ◽  
Hong Mu ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Board Of Directors ◽  
Cell Lines ◽  
Research Funding ◽  
Single Agent ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Critical Survival

Abstract Wnt/β-catenin signaling regulates self-renewal and proliferation of AML cells and is critical in AML initiation and progression. Overexpression of β-catenin is associated with poor prognosis. We previously reported that inhibition of Wnt/β-catenin signaling by C-82, a selective inhibitor of β-catenin/CBP, exerts anti-leukemia activity and synergistically potentiates FLT3 inhibitors in FLT3-mutated AML cells and stem/progenitor cells in vitro and in vivo (Jiang X et al., Clin Cancer Res, 2018, 24:2417). BCL-2 is a critical survival factor for AML cells and stem/progenitor cells and ABT-199 (Venetoclax), a selective BCL-2 inhibitor, has shown clinical activity in various hematological malignancies. However, when used alone, its efficacy in AML is limited. We and others have reported that ABT-199 can induce drug resistance by upregulating MCL-1, another key survival protein for AML stem/progenitor cells (Pan R et al., Cancer Cell 2017, 32:748; Lin KH et al, Sci Rep. 2016, 6:27696). We performed RNA Microarrays in OCI-AML3 cells treated with C-82, ABT-199, or the combination and found that both C-82 and the combination downregulated multiple genes, including Rac1. It was recently reported that inhibition of Rac1 by the pharmacological Rac1 inhibitor ZINC69391 decreased MCL-1 expression in AML cell line HL-60 cells (Cabrera M et al, Oncotarget. 2017, 8:98509). We therefore hypothesized that inhibiting β-catenin by C-82 may potentiate BCL-2 inhibitor ABT-199 via downregulating Rac1/MCL-1. To investigate the effects of simultaneously targeting β-catenin and BCL-2, we treated AML cell lines and primary patient samples with C-82 and ABT-199 and found that inhibition of Wnt/β-catenin signaling significantly enhanced the potency of ABT-199 in AML cell lines, even when AML cells were co-cultured with mesenchymal stromal cells (MSCs). The combination of C-82 and ABT-199 also synergistically killed primary AML cells (P<0.001 vs control, C-82, and ABT-199) in 10 out of 11 samples (CI=0.394±0.063, n=10). This synergy was also shown when AML cells were co-cultured with MSCs (P<0.001 vs control, C-82, and ABT-199) in all 11 samples (CI=0.390±0.065, n=11). Importantly, the combination also synergistically killed CD34+ AML stem/progenitor cells cultured alone or co-cultured with MSCs. To examine the effect of C-82 and ABT-199 combination in vivo, we generated a patient-derived xenograft (PDX) model from an AML patient who had mutations in NPM1, FLT3 (FLT3-ITD), TET2, DNMT3A, and WT1 genes and a complex karyotype. The combination synergistically killed the PDX cells in vitro even under MSC co-culture conditions. After PDX cells had engrafted in NSG (NOD-SCID IL2Rgnull) mice, the mice were randomized into 4 groups (n=10/group) and treated with vehicle, C-82 (80 mg/kg, daily i.p injection), ABT-199 (100 mg/kg, daily oral gavage), or the combination for 30 days. Results showed that all treatments decreased circulating blasts (P=0.009 for C-82, P<0.0001 for ABT-199 and the combination) and that the combination was more effective than each single agent (P<0.001 vs C-82 or ABT-199) at 2 weeks of therapy. The combination also significantly decreased the leukemia burden in mouse spleens compared with controls (P=0.0046) and single agent treated groups (P=0.032 or P=0.020 vs C-82 or ABT-199, respectively) at the end of the treatment. However, the combination did not prolong survival time, likely in part due to toxicity. Dose modifications are ongoing. These results suggest that targeting Wnt/β-catenin and BCL-2, both essential for AML cell and stem cell survival, has synergistic activity via Rac1-mediated MCL-1 inhibition and could be developed into a novel combinatorial therapy for AML. Disclosures Andreeff: SentiBio: Equity Ownership; Oncolyze: Equity Ownership; Oncoceutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Consultancy; Amgen: Consultancy, Research Funding; Eutropics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Patents & Royalties: MDM2 inhibitor activity patent, Research Funding; Aptose: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Reata: Equity Ownership; Astra Zeneca: Research Funding; Celgene: Consultancy; United Therapeutics: Patents & Royalties: GD2 inhibition in breast cancer . Carter:novartis: Research Funding; AstraZeneca: Research Funding.

scholarly journals First-in-Human, Phase 1/2 Trial to Assess the Safety and Clinical Activity of Subcutaneous GEN3013 (DuoBody®-CD3×CD20) in B-Cell Non-Hodgkin Lymphomas

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 758-758 ◽  
Author(s):  
Pieternella Lugtenburg ◽  
Rogier Mous ◽  
Michael Roost Clausen ◽  
Martine E.D. Chamuleau ◽  
Peter Johnson ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Clinical Activity ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Introduction: CD20-specific monoclonal antibodies (mAbs) have demonstrated efficacy in the treatment of B-cell non-Hodgkin lymphomas (B-NHL); however, a significant proportion of patients (pts) present with refractory disease or will experience relapse. GEN3013 (DuoBody®-CD3×CD20) is the first subcutaneously administered IgG1 bispecific antibody (bsAb) that targets the T-cell surface antigen CD3 and the B-cell surface antigen CD20, triggering T-cell-mediated killing of B cells. In vitro, GEN3013 efficiently activates and induces cytotoxic activity of CD4+ and CD8+ T cells in the presence of B cells (Hiemstra et al. Blood 2018), and results in long-lasting depletion of B cells in cynomolgus monkeys. Subcutaneous (SC) GEN3013 in cynomolgus monkeys resulted in lower plasma cytokine levels, and similar bioavailability and B-cell depletion, compared with intravenous administration. GEN3013 has higher potency in vitro than most other CD3×CD20 bsAbs in clinical development (Hiemstra et al. HemaSphere 2019). SC GEN3013 in pts with B-NHL is being evaluated in a first-in-human, Phase 1/2 trial (NCT03625037), which comprises a dose-escalation part and a dose-expansion part. Here we report preliminary dose-escalation data. Methods: Pts with CD20+ B-NHL with relapsed, progressive, or refractory disease following anti-CD20 mAb treatment, and ECOG PS 0-2 were included. During dose escalation, pts received SC GEN3013 flat dose in 28-day cycles (q1w: cycle 1-2; q2w: cycle 3-6; q4w thereafter) until disease progression or unacceptable toxicity. Risk of cytokine release syndrome (CRS) was mitigated with the use of a priming dose and premedication with corticosteroids, antihistamines, and antipyretics. Primary endpoints were adverse events (AEs) and dose-limiting toxicities (DLTs). Secondary endpoints included pharmacokinetics (PK), immunogenicity (anti-drug antibodies [ADA]), pharmacodynamics (PD) (cytokine measures; laboratory parameters), and anti-tumor activity (tumor size reduction; objective and best response). Results: At data cut-off (June 28, 2019), 18 pts were enrolled into the dose-escalation part of the trial, with safety data available for pts receiving doses starting at 4 µg. Most pts had diffuse large B-cell lymphoma (DLBCL; n=14) and were heavily pre-treated; 10 pts had received ≥3 prior lines of therapy (overall median [range]: 3 [1-11]). The median age was 58.5 years (range: 21-80), and 13 pts were male. At a median follow-up of 1.9 months, pts received a median of 5 doses (range: 1-14); treatment is ongoing in 6 pts. Twelve pts discontinued treatment due to progressive disease. Six pts died (2 during treatment, 4 during survival follow-up), all due to disease progression and unrelated to treatment. The most common (n≥5) treatment-emergent AEs were pyrexia (n=8), local injection-site reactions (n=7), diarrhea (n=5), fatigue (n=5), and increased aspartate aminotransferase (n=5). The most common Grade (G) 3/4 AEs were anemia (n=3) and neutropenia (n=3). Despite increasing GEN3013 doses, all CRS events were non-severe (initial observation: 3/8 pts, G1: n=1, G2: n=2; following modification of premedication plan [corticosteroids for 3 days]: 6/10 pts, G1: n=4, G2: n=2). Increases in peripheral cytokine (IL6, IL8, IL10, IFNγ, TNFα) concentrations after GEN3013 dosing correlated with clinical symptoms of CRS in most pts. No pts had tumor lysis syndrome or neurological symptoms. No DLTs were observed. GEN3013 PK profiles reflect SC dosing; Cmax occurred 2-4 days after dosing. No ADAs were detected. PD effects following GEN3013 dosing were observed at dose levels as low as 40 µg and included rapid, complete depletion of circulating B cells (if present after prior anti-CD20 therapy) and peripheral T-cell activation and expansion. The first evidence of clinical activity was observed at a dose level of 120 µg, with complete metabolic response observed in a pt with DLBCL. Conclusions: Subcutaneously administered GEN3013, a potent CD3×CD20 bsAb, shows good tolerability and early evidence of clinical activity at low dose levels in heavily pretreated pts with relapsed or refractory B-NHL. All CRS events were non-severe and did not lead to discontinuation. No DLTs were observed. Dose escalation is ongoing; updated data will be presented. Dose expansion will begin upon determining the recommended Phase 2 dose (RP2D) (NCT03625037). Disclosures Lugtenburg: Janssen Cilag: Honoraria; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria; Servier: Consultancy, Honoraria, Research Funding; Genmab: Consultancy, Honoraria; BMS: Consultancy; Takeda: Consultancy, Honoraria, Research Funding. Mous:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Sandoz: Honoraria; Roche: Honoraria; Abbvie: Honoraria; Takeda: Honoraria, Research Funding; Janssen Cilag: Consultancy, Honoraria; MSD: Honoraria; Gilead: Consultancy, Honoraria, Research Funding. Clausen:Abbvie: Other: Travel grant to attend ASH 2019. Johnson:Boehringer Ingelheim: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria; Epizyme: Honoraria, Research Funding; Incyte: Honoraria; Takeda: Honoraria; Genmab: Honoraria; Bristol-Myers Squibb: Honoraria; Kite: Honoraria; Novartis: Honoraria. Rule:Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Napp: Consultancy; Kite: Consultancy. Oliveri:Genmab: Employment, Equity Ownership. DeMarco:Genmab: Employment, Equity Ownership. Hiemstra:Genmab: Employment, Equity Ownership, Other: Warrants. Chen:Genmab: Employment. Azaryan:Genmab: Employment. Gupta:Genmab: Employment, Equity Ownership. Ahmadi:Genmab Inc: Employment, Other: stock and/or warrants. Hutchings:Incyte: Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Genmab: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Janssen: Research Funding; Pfizer: Research Funding.

Biomarkers and In Vivo Responses to the BH3 Mimetic, ABT-263, in Patients (pts) with Chronic Lymphocytic Leukemia (CLL).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2374-2374
Author(s):  
Seong Lin Khaw ◽  
David C. Huang ◽  
Simon He ◽  
John F Seymour ◽  
Dennis Carney ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase 1 ◽  
Advisory Committees ◽  
Bulky Disease ◽  
In Vitro Sensitivity ◽  
Bh3 Mimetic

Abstract Abstract 2374 Poster Board II-351 ABT-263 is a first-in-class BH3 mimetic inhibitor of 3 pro-survival members of the BCL2 protein family (BCL2, BCLXL, BCLW). Consistent with potent activity against BCL2-overexpressing cell lines and primary CLL cells in vitro, and BCL2-overexpressing lymphoid murine tumors in vivo, ABT-263 demonstrated significant antitumor activity in pts with relapsed, refractory CLL and small lymphocytic lymphoma (SLL) in 2 phase 1/2a studies. To date, 42 pts (35 evaluable) with CLL/SLL have been treated with ABT-263 (40-440 mg/d). 51% (18/35) with a baseline lymphocytosis >5,000 have achieved '50% reduction in lymphocytosis, while 34% (12/35; 5 bulky disease) with measurable nodal disease at initiation have achieved a partial response. Overall, some manifestation of antitumor activity was observed in 60% (21/35). Responses tend to be durable, with the median PFS not reached as yet while the median time on study for M06-873 pts is 9 mos for pts on the M06-873 study. Responses were observed in pts who received >4 lines of prior therapy and in those who were fludarabine refractory and/or had bulky disease. BCL2 is highly expressed in all CLL/SLL, yet only a subset of pts responded. We tested whether additional intrinsic biological characteristics of CLL were associated with response to ABT-263 in vivo. Potential biomarkers, both standard (FISH for 17p13, 11q22.3) and investigational (in vitro sensitivity; quantitative expression of BCL2, MCL1, BIM, BAX) were measured at study entry, during therapy and where possible at progression in a subset of pts treated in the phase 1 study in CLL (M06-873). Of 21 pts receiving >40mg/d ABT-263 for >7d, FISH data for 17p13 and 11q22.3 were available for 16, of which only 5 were normal; 4 and 6 had deleted 17p13 or 11q22.3 respectively, and 2 had deletions for both in >5% of cells examined. Similar majorities of pts with del17p13 (4/6) or del11q22.3 (5/8), or with neither abnormality (4/5), achieved either a >50% fall in peripheral blood lymphocytes, reduction in nodal size, or both. None of the pts without del17p13 or del11q22.3 have progressed after median 285 d (range 167-484 d) on drug, while only 1/6 with del17p13 and 2/8 with del11q22.3 have progressed (all 3 within 3 mos). CLL cells from 12 pts were tested for in vitro sensitivity to ABT-737, a BH3 mimetic with the same specificity and activity in vitro as ABT-263. LC50 were all <50 nM at baseline (mean 5.5±5.1 nM). LC50 at baseline correlated inversely with % reduction of lymphocytosis at both Cycle1/Day 14 (C1D14) and C3D1 (r2=-0.51 & 0.44, p=0.01 & 0.03, respectively), although in vitro LC50 was not predictive of whether a partial response was ultimately achieved. Reassessment of in vitro LC50 after 14 days on ABT-263 and at C3D1 revealed a modest reduction in sensitivity of residual CLL cells: C1D14 12±9.4 nM, C3D1 11±9.6 nM (p<0.05 for difference between baseline and later timepoints; repeated measures ANOVA). Expression levels of BCL2, BIM and BAX did not correlate with % reduction in lymphocytosis at either C1D14 or C3D1 in vivo responses. Higher basal expression of MCL1 was negatively correlated with % reduction in lymphocytes after 2 cycles (n=8; r2 = -0.55, p=0.03). When MCL1 expression was measured in residual CLL cells collected at C1D14 or C3D1, no change from baseline was observed. These preliminary data indicate that ABT-263 is active in pts with relapsed refractory CLL carrying adverse genetic markers, and that expression patterns of BCL2 family member proteins do not strongly predict response to this drug. While in vitro LC50 did correlate with the degree of initial fall in lymphocytosis, residual cells after 2 treatment cycles were only modestly less intrinsically sensitive in vitro, expressing higher levels of MCL1. Additional factors, presumably extrinsic to the CLL cells appear to significantly influence in vivo responses to ABT-263. Disclosures: Off Label Use: ABT-263 is an experimental drug that is not yet registered. It is designed to induce apoptosis in tumor cells.. Seymour:Bayer Schering: Consultancy, Membership on an entity's Board of Directors or advisory committees, Travel grants; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel Grants. Chyla:Abbott: Employment. Litvinovich:Abbott: Employment. McKeegan:Abbott: Employment. Krivoshik:Abbott: Employment. Enschede:Abbott: Employment. Humerickhouse:Abbott: Employment. Roberts:Abbott : Research Funding; Genentech: Research Funding.

Final Phase I Results of Perifosine In Combination with Lenalidomide and Dexamethasone In Patients with Relapsed or Refractory Multiple Myeloma (MM)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3064-3064
Author(s):  
Andrzej J Jakubowiak ◽  
Paul G Richardson ◽  
Todd M Zimmerman ◽  
Melissa Alsina ◽  
Jonathan L. Kaufman ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Clinical Activity ◽  
Final Phase ◽  
Employment Equity ◽  
Advisory Committees ◽  
Prior Therapy ◽  
Ortho Biotech ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 3064 Introduction: Perifosine (Peri) a novel, oral signal transduction modulator with multiple effects including inhibition of Akt and activation of JNK, has demonstrated clinical activity when combined with dexamethasone (Dex) in patients (pts) with relapsed/refractory MM (ASH 2007 #1164). Lenalidomide (Revlimid , Rev) a novel, oral immunomodulatory drug has activity against MM when combined with Dex. We previously reported encouraging safety data and observed clinical activity of the oral triplet combination (ASH 2008 # 3691). We now report the final phase I results of this study which aimed to determine the MTD and to evaluate activity of Peri + Rev + Dex, as an oral combination in pts with relapsed or refractory MM. Methods: Four cohorts ( 6 pts each) were planned, dosing Peri at 50 or 100mg (daily), Rev 15 or 25mg (d 1–21) and Dex 20mg (d 1–4, 9–12 and 17–20 for 4 cycles, then 20 mg d 1–4) in 28-d cycles. To limit dex-related toxicities, the protocol was amended to use weekly dex (40 mg), applying to cohorts 3, 4, and the MTD cohort. Toxicity was assessed using NCI CTCAE v3.0; DLT was defined as grade (G) 3 non-hematologic toxicity, G4 neutropenia for 5 d and/or neutropenic fever, or platelets <25,000/mm3 on >1 occasion despite transfusion. Response was assessed by modified EBMT criteria. Pts had to have received at least 1 prior therapy and no more than 4. Pts refractory to Rev/Dex were excluded. Results: 32 pts (17M/15F, median age 64 y, range 37 – 79) were enrolled; 6 pts in cohort 1 (Peri 50mg, Rev 15mg, Dex 20mg); 6 pts in cohort 2 (Peri 50mg, Rev 25mg, Dex 20mg); 8 pts in cohort 3 (Peri 100mg, Rev 15mg, Dex 40mg/wk); 6 pts in cohort 4 (Peri 100mg, Rev 25mg, Dex 40mg/wk) and 6 pts at MTD (Cohort 4). Median prior lines of treatment was 2 (range 1–4) with a median PS of 1. Relapsed (53%), Refractory to last therapy prior to study entry (47%). Prior therapy included dex (94%), thalidomide (75%), bortezomib (44%), and stem cell transplant (72%). Two pts (6%) were previously treated with Rev. 63% (15/24) of the prior thalidomide + dex (Thal/Dex) treated pts had progressed on a Thal/Dex regimen while 43% (6/14) of the prior bortezomib (Vel) treated pts had progressed on a prior Vel based regimen. Two pts did not complete one full cycle (non-compliance and adverse event not related to study drugs – both in cohort 3) and were not included in the efficacy analysis. 31/32 pts were evaluable for safety (non-compliant patient never took study drug and was excluded). The most common grade 1/2 events (any causality) included fatigue (48%), diarrhea (45%), upper respiratory infection (35%), nausea (32%) and hyperglycemia (32%). Grade 3/4 events > 10% included neutropenia (26%); hypophosphatemia (23%); thrombocytopenia (16%) and leucopenia (13%). There was one reported DLT in cohort 3 (Nausea). No grade 3/4 events of peripheral neuropathy or DVT were reported. Rev dose was reduced in 11 pts, Peri reduced in 9 pts and Dex reduced in 7 pts: 30 pts are evaluable for response, with best response as follows: Median progression-free survival (PFS) for all pts was 10.8 mos (CI: 4.6, 27.7) and 7 pts have not progressed. The median overall survival (OS) was 30.6 mos (CI: 16.7, NR) with 15/30 pts still alive. Of the 8 thalidomide naïve pts, 4 have progressed with a median projected PFS of 30 mos and all 8 pts remain alive (range 28 – 43 mos). Conclusions: Pts have tolerated Peri + Rev + Dex well with manageable toxicity, and with promising clinical activity demonstrated by an ORR (≥ PR) of 50%, an extended PFS and OS. Given that most pts were exposed to Thal/Dex with more than half refractory to a prior Thal/Dex regimen, the encouraging response rates and survival appear to suggest benefit with the addition of perifosine to Rev/Dex. This data thus warrants further study, including a potential randomized trial to confirm the activity of perifosine added to Rev/Dex. A randomized phase III trial of Peri/Vel/Dex vs. Vel/Dex is underway for previously Vel exposed MM patients. Disclosures: Jakubowiak: Millennium, Celgene, Bristol-Myers Squibb, Johnson & Johnson Ortho-Centocor: Honoraria; Millennium, Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Millennium, Celgene, Centocor-Ortho Biotech: Speakers Bureau. Off Label Use: Perifosine in combination with Lenalidomide and Dexamethasone. Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees. Zimmerman:Millennium, Celgene: Speakers Bureau. Alsina:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Ortho Biotech: Research Funding. Kaufman:Celgene, Millenium: Consultancy; Celgene, Merck: Research Funding. Sportelli:Keryx Biopharmaceuticals: Employment, Equity Ownership. Gardner:Keryx Biopharmaceuticals: Employment, Equity Ownership. Anderson:Celgene: Consultancy, Honoraria, Speakers Bureau; Millennium: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau.

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