scholarly journals Next-Generation Functional Drug Screening for Patients with Aggressive Hematologic Malignancies

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 855-855
Author(s):  
Philipp Bernhard Staber ◽  
Berend Snijder ◽  
Gregory Ian Vladimer ◽  
Nikolaus Krall ◽  
Katsuhiro Miura ◽  
...  
Keyword(s):  
Clinical Response ◽  
Board Of Directors ◽  
Drug Screening ◽  
Research Funding ◽  
Hematologic Malignancies ◽  
Aggressive Lymphoma ◽  
Intratumor Heterogeneity ◽  
Next Generation ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Background. Patients with aggressive hematologic malignancies failing at least two lines of therapy are without further standard treatment options and have a poor prognosis. Identifying effective therapies with genomic-based precision medicine is hampered by intratumor heterogeneity and incomplete understanding of the contribution of various mutations within specific cancer phenotypes. Next-generation functional drug screening (ngFDS) in patient samples promises to overcome these challenges, however, proof of its clinical utility is limited. Methods. We investigated the feasibility and clinical impact of ngFDS measured at single-cell resolution using high-throughput automated microscopy in blood, bone marrow, pleural effusions, or excised lymph node biopsies (Figure 1A and Valdimer G et al. Nat Chem Biol. 2017). First, the accuracy of ngFDS to predict clinical outcome was evaluated in a retrospective cohort of 20 previously untreated patients with acute myeloid leukemia (AML). Then, 48 patients with aggressive hematologic malignancies failing at least two lines of treatment were prospectively evaluated for ngFDS guided therapy, of which 17 could receive ngFDS-guided treatment. Individual ngFDS-guided treatment regimens were selected by a committee (EXALT-board) of hemato-oncologists, pathologist, and pharmacists based on top-candidate treatments identified by ngFDS, considering drug availability as well as safety profiles of single agents and previously reported combinations (Figure 1B). The majority of these patients (12/17) presented with aggressive lymphoma and had seen in median three (2-7) prior treatment lines (Figure 2A). Overall response rate (ORR) and progression-free survival (PFS) of ngFDS-guided treatment were compared with ORR and PFS for the most recent regimen (MRR) on which patients had previously progressed. Results. ngFDS accurately predicted individual clinical response of AML patients to initial therapy. From prospectively analyzed patients receiving ngFDS guided treatment the ORR-ngFDS was 88% (15/17) compared to ORR-MRR of 24% (4/17; P<0.0004). Twelve (70%) of 17 patients had a PFS ratio of ≥1.3 and the mean PFS increased 3.9-fold, from 5.7 weeks to 22.6 weeks (P<0.007) (Figure 2B). Furthermore, analysis of an independent cohort revealed that ngFDS could positively and negatively predict patients' outcome to drug treatment. Conclusions. Automatedmicroscopy-based ngFDS is feasible and accurately predicts clinical response. It can successfully guide personalized treatment of aggressive refractory hematological malignancies. Figure 1 Figure 1. Disclosures Staber: Takeda: Honoraria; Abbie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria; Amgen: Honoraria; Gilad: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees. Snijder: Allcyte: Equity Ownership, Other: founder and shareholder of Allcyte GmbH that holds a worldwide exclusive license for and commercializes the Pharmacoscopy high content imaging technology.. Vladimer: Allcyte Gmbh: Equity Ownership. Krall: Allcyte Gmbh: Equity Ownership. Hoermann: Ariad: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Gilead: Honoraria, Research Funding. Sperr: Teva: Honoraria; Meda: Research Funding; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Phadia: Research Funding; Novartis: Other: Register. Gisslinger: Janssen Cilag: Honoraria; Takeda: Honoraria; Shire: Honoraria; PharmaEssentia: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; AOP Orphan Pharmaceuticals AG: Consultancy, Honoraria. Valent: Incyte: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Deciphera: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Ariad: Honoraria, Research Funding; Teva: Honoraria; Celgene: Honoraria, Research Funding; Blueprint: Research Funding. Jaeger: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses. Superti-Furga: Allcyte GmbH: Equity Ownership.

Comparison of Steady-State Imatinib (IM) Trough Levels, Clinical Response, and Safety Between Caucasian and Asian Patients with Chronic Lyeloid Leukemia in Chronic Phase (CML-CP) Treated with 400mg and 800mg Daily Doses of IM in the Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1127-1127
Author(s):  
Dong-Wook Kim ◽  
Camille Granvil ◽  
Eren Demirhan ◽  
John Reynolds ◽  
Yu Jin ◽  
...  
Keyword(s):  
Adverse Event ◽  
Steady State ◽  
Clinical Response ◽  
Board Of Directors ◽  
Research Funding ◽  
Average Dose ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3 ◽  
Trough Levels

Abstract Abstract 1127 Poster Board I-149 Background In the TOPS study, IM trough levels (Cmin) were collected from different race groups, mainly Caucasian and Asian, but also Black and others. Inter-ethnic differences in the PK of a drug are known to be important factors accounting for inter-individual variation in drug responsiveness. This analysis reports the comparison between Caucasian and Asian CML patients (pts) treated at doses of 400 mg QD and 400 mg bid (800 mg daily) of IM Cmin on Day 29 of initial treatment, clinical response, safety and tolerability. Methods Steady state IM Cmin on Day 29 and clinical response and safety data obtained during the first 12 months (mos) of treatment were obtained from pts randomized 2:1 to 800 mg or 400 mg daily IM. The steady-state Cmin was defined as predose concentration collected approximately within ±3 hours of the scheduled dosing time on Day 29. The associations of race with the rates of major molecular response (MMR) and complete cytogenetic response (CCyR) were evaluated. Correlation of IM exposure with clinical response (MMR and CCyR) was assessed by grouping pts into quartiles based on their measured IM Cmin levels at Day 29. The safety endpoint for each pt was the presence or absence of an adverse event (AE) of grade 3 or higher in the first 12 mos from the first dose. Results IM Cmin levels were available from 229 pts in TOPS including 54 Caucasians, 18 Asians, and 14 Black and others at 400 mg (total 86) and 103 Caucasians, 29 Asians, and 11 Black and others at 800 mg (total 143). For the first 12 mos, the means of the average dose intensities for Asian (mean [range], 362 [267-400] in 400 mg and 666 [226-800] in 800 mg) were not significantly different from Caucasian (386 [204-597] in 400 mg and 666 [289-800] in 800 mg) (P=0.070 and P=0.995 for the 400 mg and 800 mg arms, respectively). Mean (± SD) of IM Cmin levels (ng/mL) with respect to race are shown in Table 1. IM Cmin was slightly over-proportional to dose and showed large interpatient variability (CV=42-60%) for both dose groups regardless of the race group. In the lower quartile Cmin group (Cmin<1290 ng/mL), the differences in CCyR and MMR rates between Asian and Caucasian pts were significant (P=0.031 and P=0.022 respectively), which was probably due to a higher rate of dose interruptions in the 1st 12 mos in Asian pts. A definitive conclusion cannot be drawn due to the small number of Asian pts. Occurrences of at least one grade 3 or 4 adverse event were found to be significantly higher in Asian pts (69% and 75% in the 1st 6 and 12 mos respectively) compared to Caucasian pts (53% and 57% in the 1st 6 and 12 mos respectively) (P=0.028 and P=0.008 respectively). Conclusion The results of this analysis from TOPS show that IM Cmin levels were similar between Caucasian and Asian CML pts in each treatment arm. There were no major differences in efficacy, as measured by MMR and CCyR rates by 12 mos, between Asian and Caucasian pts. There were no unexpected differences in patterns of AEs between Caucasian and Asian pts; however, occurrences of one or more grade 3 AEs were higher in Asian. Further analysis on a larger group of CML pts will be needed to evaluate the impact of AE rate differences between Caucasian and Asian pts. Disclosures Kim: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Wyeth: Research Funding. Granvil:Novartis: Employment. Demirhan:Novartis: Employment. Reynolds:Novartis: Employment. Jin:Novartis: Employment. Wang:Novartis: Employment, Equity Ownership. Baccarani:Novartis Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Mayer Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau. Cortes-Franco:Novartis: Honoraria, Research Funding, Speakers Bureau; Wyeth: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau. Druker:OHSU patent #843 - Mutate ABL Kinase Domains: Patents & Royalties; MolecularMD: Equity Ownership; Roche: Consultancy; Cylene Pharmaceuticals: Consultancy; Calistoga Pharmaceuticals: Consultancy; Avalon Pharmaceuticals: Consultancy; Ambit Biosciences: Consultancy; Millipore via Dana-Farber Cancer Institute: Patents & Royalties; Novartis, ARIAD, Bristol-Myers Squibb: Research Funding. Hughes:Bristol-Myers Squibb: Advisor, Honoraria, Research Funding; Novartis: Advisor, Honoraria, Research Funding. Guilhot:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria.

Subset Analysis of Response to Treatment of Chronic Phase CML in a Phase 1 Study of Ponatinib in Refractory Hematologic Malignancies

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 602-602 ◽  
Author(s):  
Jorge E. Cortes ◽  
Hagop M. Kantarjian ◽  
Neil Shah ◽  
Dale Bixby ◽  
Michael J. Mauro ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Phase 1 ◽  
Chronic Phase ◽  
Hematologic Malignancies ◽  
Employment Equity ◽  
Advisory Committees ◽  
Mutation Status ◽  
Equity Ownership

Abstract Abstract 602 Background: Ponatinib is a potent, oral, pan-BCR-ABL inhibitor active against the native enzyme and all tested resistant mutants, including the uniformly resistant T315I mutation. Initial findings of a phase 1 trial in patients (pts) with refractory hematologic malignancies have been reported. The effect of duration of treatment, prior treatment, and mutation status on response to treatment was examined in CML chronic phase (CP) pts who responded to ponatinib. Methods: An open-label, dose escalation, phase 1 trial of ponatinib in pts with hematologic malignancies is ongoing. The primary aim is to assess the safety; anti-leukemic activity is also being investigated. Pts resistant to prior treatments or who had no standard treatment available were enrolled to receive a single daily oral dose of ponatinib (2 mg to 60 mg). Subset analyses of factors impacting cytogenetic and molecular response endpoints (MCyR and MMR) were performed for pts with CP-CML. Data are presented through April 15, 2011. Results: In total, 81 pts (54% male) received ponatinib. Overall, 43 pts had CP with 34 ongoing at analysis. MCyR was observed as best response in 31/43 (72%), 27 (63%) CCyR. The median time to MCyR was 12 (3 to 104) wks. Response rates were assessed by duration of treatment (1 pt in CCyR at entry was excluded; 6 pts in PCyR had to achieve CCyR). At the 3 month assessment, 22/42 (52%) CP pts achieved MCyR; at 6 months, 24/42 (57%); at 12 months, 29/42 (69%) had MCyR. The impact of prior treatment on response and time to response was assessed. 42 pts (98%) had >2 prior TKIs and 28 (65%) ≥3 prior TKIs, including investigational agents. Of approved TKIs, all pts were previously treated with imatinib, 19 dasatinib or nilotinib after imatinib, and 21 both dasatinib and nilotinib after imatinib. MCyR rate decreased with number of prior TKIs (2 prior TKIs 13/14 [93%], ≥3 prior TKIs 17/28 [61%]) and number of approved TKIs (imatinib followed by dasatinib or nilotinib 17/19 [90%], or by both dasatinib and nilotinib 12/21 [57%]). Time to response was prolonged in pts more heavily treated with prior TKIs. Median time to MCyR increased with the number of prior TKIs and approved TKIs (2 TKIs 12 wks, ≥3 TKIs 32 wks). The effect of mutation status on response and time to response was also evaluated. At entry, 12 pts had the T315I mutation, 15 had other BCR-ABL kinase domain mutations, 12 had no mutations detected, 4 did not allow sequencing. MCyR response rate for CP pts with T315I was 11/12 (92%); for other mutations, 10/15 (67%); and no mutation, 7/12 (58%). Similarly, mutation status had an impact on time to response: median time to MCyR was 12 wks for those with T315I or other mutations and 32 wks in resistant pts with no mutation. All CP patients were evaluable for MMR. At analysis, MMR was 17/43 (40%). MMR rate was inversely related to number of prior TKIs (2 TKIs 10/14 [71%], ≥3 TKIs 6/28 [21%]), approved TKIs (imatinib followed by dasatinib or nilotinib 12/19 [63%], or by both dasatinib and nilotinib 4/21 [19%]), and was higher for T315I pts (7/12, 58%) and those with other mutations (7/15, 47%) compared with no mutation (2/12, 17%). Median time to MMR for CP pts was 97 wks; median time to MMR was shorter for pts who were less heavily treated (2 prior TKIs 24 wks) and those with T315I or other mutations (63 wks). Conclusion: In this subset analysis of the phase 1 data, ponatinib had substantial activity in all subgroups analyzed. Time on treatment, less prior therapy and kinase domain mutations were associated with higher response rates and early responses in CP pts. Cytogenetic responses improved over the first 12 months of treatment and were higher in less heavily treated pts. Disclosures: Cortes: Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding. Kantarjian:Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; ARIAD: Research Funding. Shah:Ariad: Consultancy, Research Funding. Bixby:Novartis: Speakers Bureau; BMS: Speakers Bureau; GSK: Speakers Bureau. Mauro:ARIAD: Research Funding. Flinn:ARIAD: Research Funding. Hu:ARIAD: Employment. Clackson:ARIAD: Employment, Equity Ownership. Rivera:ARIAD: Employment, Equity Ownership. Turner:ARIAD: Employment, Equity Ownership. Haluska:ARIAD: Employment, Equity Ownership. Druker:MolecularMD: OHSU and Dr. Druker have a financial interest in MolecularMD. Technology used in this research has been licensed to MolecularMD. This potential conflict of interest has been reviewed and managed by the OHSU Conflict of Interest in Research Committee and t. Deininger:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: 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; Celgene: Research Funding; Genzyme: Research Funding. Talpaz:ARIAD: Research Funding.

Indatuximab Ravtansine (BT062) in Combination with Low-Dose Dexamethasone and Lenalidomide or Pomalidomide: Clinical Activity in Patients with Relapsed / Refractory Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4486-4486 ◽  
Author(s):  
Kevin R. Kelly ◽  
David S. Siegel ◽  
Asher A. Chanan-Khan ◽  
George Somlo ◽  
Leonard T. Heffner ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Clinical Response ◽  
Board Of Directors ◽  
Research Funding ◽  
Low Dose ◽  
Prior Exposure ◽  
Tolerability Profile ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Background: BT062 (Biotest AG, Dreieich, Germany) is an antibody-drug conjugate (ADC) comprising a CD138-binding chimerized antibody and the cytotoxic maytansinoid, DM4. It is designed to target and kill CD138-positive cancer cells. CD138 (Syndecan-1) is highly expressed on a number of solid tumors and hematological malignancies and is one of the most reliable markers for multiple myeloma (MM) cells. BT062 was previously evaluated as a monotherapy in patients with heavily pretreated relapsed/refractory MM and found to have an acceptable tolerability profile with preliminary evidence of activity (Heffner et al, Blood. 2012; 120: Abstract 4042). Phase I/IIa testing was initiated with BT062 in combination with lenalidomide (Len) and low-dose dexamethasone (dex). The combination was well tolerated at BT062 doses up to 100 mg/m², defined to be the recommended Phase 2 dose (RPTD), and induced meaningful responses, including in patients previously treated with both Len and bortezomib (Bort) (Kelly et al, Blood. 2014; 124: Abstract 4736). Based on these promising results, further investigation of BT062 in combination with pomalidomide (Pom) and dex was initiated in patients with prior Len and Bort exposure, a patient population known to have a poor outcome. Objectives: To evaluate the safety and activity of BT062 (on days 1, 8, and 15 in a 4-week cycle) used in combination with dex (20-40 mg on days 1, 8, 15, and 22) and Len (25 mg, daily on days 1-21) or Pom (4 mg, daily on days 1-21) in patients with relapsed/refractory MM. Methods: This is a prospective, open label, multicenter Phase I/IIa study. The RPTD of BT062 in combination with Len/dex was defined to be 100 mg/m², and 38 patients were treated with BT062/Len/dex at the BT062 RPTD. An additional 17 patients were treated with BT062/Pom/dex at the BT062 RPTD. Patients aged ≥18 years with relapsed/refractory MM were eligible to participate. Prior treatment with Len, Pom, and/or dexamethasone (any dose) was allowed. To qualify for treatment with BT062/Len/dex at the BT062 RPTD, patients must have received at least one but no more than six prior therapies.To qualify for treatment with BT062/Pom/dex, patients must have received at least two prior therapies, including both Len and Bort, and progressed on or within 60 days of completion of their last therapy, with no limit on number of prior therapies. Patients with clinical response (or no evidence of disease progression) without unacceptable toxicities were eligible to receive additional treatment cycles. Toxicities were assessed by CTCAE v4. Clinical response was assessed by the investigator according to International Myeloma Working Group criteria. Results: Sixty-four patients have received BT062 in combination with dex and Len or Pom in this ongoing study. The combinations have been generally well tolerated, with approximately 90% of adverse events (AEs) reported CTC grade 1 or 2. The most common AEs reported are diarrhea, fatigue, and nausea. Forty-seven patients have received BT062 with Len/Dex (3 at 80 mg/m², 38 at 100 mg/m², 6 at 120 mg/m²), with 8 patients still on treatment. Among these 47 patients, median progression-free survival (PFS) was 16.4 months. Forty-three patients completed at least two treatment cycles and were evaluable for response. Of these patients 33 achieved a partial response (PR) or better, with an overall response rate (ORR) of 77% and a median duration of response (DOR) of 21.0 months. Thirteen of the evaluable BT062/Len/dex-treated patients had prior exposure to both Len and Bort and progressed on or within 60 days of their last therapy. ORR was 54% among these patients, including 1 complete response (CR), 4 very good partial responses (VGPR) and 2 PRs. Seventeen patients were treated with BT062/Pom/dex, all had prior exposure to both Len and Bort and progressed on or within 60 days of their last therapy. ORR was 79%, with 4 VGPR and 7 PR among the 14 patients evaluable for efficacy. Median PFS has not been reached after 7.5 months median follow up, with 7 patients still on treatment. Updated safety and activity data will be presented. Conclusion: BT062 has been found to be well tolerated when used in combination with Len/dex or Pom/dex, with encouraging activity even in patients with Len- and Bort-pretreated disease progressing on or within 60 days of completion of their last therapy. Disclosures Kelly: Novartis: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Siegel:Novartis: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Merck: Honoraria. Somlo:Millennium: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Heffner:Millennium: Research Funding; AbbVie: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding. Madan:Onyx: Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Celgene: Speakers Bureau. Lonial:Celgene: Consultancy; Celgene: Consultancy; BMS: Consultancy; Onyx: Consultancy; Millenium: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Onyx: Consultancy; Janssen: Consultancy; Merck: Consultancy; BMS: Consultancy. Barmaki-Rad:Biotest AG: Employment. Rühle:Biotest AG: Employment. Herrmann:Biotest AG: Employment. Wartenberg-Demand:Biotest AG: Employment. Haeder:Biotest AG: Employment. Anderson:Celgene: Membership on an entity's Board of Directors or advisory committees; Oncoprep: Equity Ownership; Acetylon: Equity Ownership; Acetylon: Equity Ownership; Gilead: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Oncoprep: Equity Ownership; Millennuim: Membership on an entity's Board of Directors or advisory committees; Millennuim: Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Equity Ownership; C4 Therapeutics: Equity Ownership; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Combination of Umbralisib, Ublituximab, and Bendamustine Is Safe and Highly Active in Patients with Advanced Diffuse Large B-Cell Lymphoma and Follicular Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4197-4197 ◽  
Author(s):  
Matthew A. Lunning ◽  
Philip Bierman ◽  
R. Gregory Bociek ◽  
Marshall T. Schreeder ◽  
Tanya Siddiqi ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
B Cell Lymphoma ◽  
Hematologic Malignancies ◽  
Employment Equity ◽  
Advisory Committees ◽  
Large B Cell Lymphoma ◽  
Equity Ownership ◽  
Ecog Ps

Abstract Introduction: Umbralisib (UMB) is a next generation, once daily, PI3Kδ/CK1ε inhibitor, active in patients with relapsed or refractory (rel/ref) hematologic malignancies that, in long-term follow-up, has demonstrated a uniquely differentiated safety profile from prior PI3Kδ inhibitors (Davids, 2018). Ublituximab (UTX) is a novel glycoengineered mAb targeting a unique epitope on the CD20 antigen. Bendamustine (Benda) is an active chemotherapy agent in pts with lymphoma. The combination of UMB + UTX (U2) is tolerable and active in patients with rel/ref hematologic malignancies and registration directed trials for patients with CLL & NHL are ongoing. This Phase 1 trial evaluates the safety and efficacy of U2 + Benda in patients with advanced diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). Methods: Eligible patients had rel/ref DLBCL or FL with an ECOG PS ≤ 2 w/o limit to number of prior therapies. ANC of ≥ 750 and Platelets ≥ 50,000 were required; no growth factor support was permitted in Cycle 1 (cohort escalation group only). Patients refractory to prior PI3Kδ, Benda, or anti-CD20's were eligible. UTX was dosed on Days 1, 8, 15 of Cycle 1, Day 1 of Cycle 2-6, followed by Cycle 9 & 12. UMB was started at 800 mg QD with a -1 dose reduction cohort at 600 mg if not tolerated in ≥ 2/6 patients. Benda was dosed at 90 mg/m2 on Days 1 & 2 of Cycles 1-6 only. Primary endpoints included safety and efficacy (Cheson 2007). Results: Thirty-nine patients were evaluable for safety: 26 DLBCL and 13 FL. Med age 67 yo (range 31-81); 23 M/16 F; median prior treatment regimens = 2 (range 1-6); 22 pts (56%) were refractory to prior treatment and 6 patients had progressed post-transplant; ECOG PS 0/1/2 (12/25/2). Initially 2/4 patients at 800 mg UMB experienced AE's in Cycle 1 that led to treatment interruption (rash, neutropenia) thus the 600 mg dose of TGR-1202 was explored. No additional Cycle 1 treatment delays were reported at the 600 mg dose level, which was later expanded and the 800 mg UMB dose was evaluated with the use of growth factor support in cycle 1 permitted. The most common AE's regardless of causality included diarrhea (54%; G3/4 15%), nausea (49%; G3/4 5%), vomiting (38%; G3/4 0%), neutropenia (33%; G3/4 33%) and pyrexia (31%; G3/4 0%). Thirty-eight patients (25 DLBCL/13 FL) were evaluable for efficacy (1 DLBCL patient came off study for G4 neutropenia prior to first assessment). ORR in the respective groups is shown in Table 1. The median time to response was 8 weeks. The median DOR was 9.6 months (95% CI: 2.5-NR) for patients with DLBCL, and was not reached (95% CI: 8.0-NR) for patients with FL, at a median duration of follow-up for responders of 11.5 months (range 2.9 - 30+ mos). Conclusions: The combination of U2 + bendamustine has exhibited manageable toxicity with significant activity in advanced DLBCL and FL patients, including an encouraging CR rate in advanced patients. Based upon the early activity of the triplet, a registration directed study is underway for patients with rel/ref DLBCL (UNITY-NHL). Disclosures Lunning: Gilead: Consultancy; Astra-Zeneca: Consultancy; Genentech: Consultancy; Spectrum: Consultancy; TG Therapeutics: Consultancy; Bayer: Consultancy; Celgene: Consultancy; AbbVie: Consultancy; Genzyme: Consultancy; Kite: Consultancy; Juno: Consultancy; Genentech: Consultancy; Portola: Consultancy; Janssen: Consultancy; Seattle Genetics: Consultancy; Verastem: Consultancy. Siddiqi:Juno Therapeutics: Other: Steering committee. Flowers:Abbvie: Research Funding; TG Therapeutics: Research Funding; Gilead: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; Genentech/Roche: Research Funding; Genentech/Roche: Consultancy; Pharmacyclics: Research Funding; V Foundation: Research Funding; Abbvie: Consultancy, Research Funding; Bayer: Consultancy; Karyopharm: Consultancy; Burroughs Wellcome Fund: Research Funding; Celgene: Research Funding; BeiGene: Research Funding; Gilead: Consultancy; Millennium/Takeda: Research Funding; OptumRx: Consultancy; Pharmacyclics/ Janssen: Consultancy; Spectrum: Consultancy; Janssen Pharmaceutical: Research Funding; Denovo Biopharma: Consultancy; Acerta: Research Funding. Cohen:Millennium: 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; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Infinity Pharmaceuticals: 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; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Janssen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: 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; Takeda: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioInvent: Consultancy; Takeda: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioInvent: Consultancy. Blumel:TG Therapeutics, Inc.: Consultancy. Cutter:TG Therapeutics, Inc.: Consultancy. Pauli:TG Therapeutics, Inc.: Consultancy. Sportelli:TG Therapeutics: Employment, Equity Ownership. Miskin:TG Therapeutics: Employment, Equity Ownership. Weiss:TG Therapeutics: Employment, Equity Ownership. Vose:Kite Pharma: Research Funding; Legend Pharmaceuticals: Honoraria; Roche: Honoraria; Incyte Corp.: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Honoraria, Research Funding; Abbvie: Honoraria; Seattle Genetics, Inc.: Research Funding; Merck Sharp & Dohme Corp.: Research Funding; Acerta Pharma: Research Funding; Epizyme: Honoraria; Celgene: Research Funding.

Dynamics of Improvement in Health-Related Quality of Life (HRQoL) with Long-Term Eltrombopag Treatment in Adults with Chronic Immune Thrombocytopenia (ITP) in EXTEND.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2199-2199
Author(s):  
Kelly M Grotzinger ◽  
James B Bussel ◽  
Mansoor N Saleh ◽  
Christine Bieri ◽  
Yuliya Orlova ◽  
...  
Keyword(s):  
Clinical Response ◽  
Board Of Directors ◽  
Research Funding ◽  
Immune Thrombocytopenia ◽  
Positive Association ◽  
Advisory Committees ◽  
Sf 36 ◽  
Equity Ownership ◽  
Hrqol Assessment

Abstract Abstract 2199 Background: Eltrombopag is an oral thrombopoietin receptor agonist approved for treatment of chronic immune thrombocytopenia (cITP). EXTEND is an ongoing, open-label extension study of long-term cITP treatment with eltrombopag in patients completing a prior eltrombopag study. EXTEND consists of 4 stages (stg): 1, initial treatment with eltrombopag to increase the platelet count (PC) ≥50,000/μL; 2, reduction/elimination of concomitant ITP medication; 3, re-establishing the minimum dose maintaining PC with minimum use of concomitant ITP medication; and 4, long-term treatment. Interim EXTEND data describing efficacy, safety, and HRQoL have been reported (Bussel 2008, 2009, 2012; Grotzinger 2012), but the dynamics of HRQoL effects have not. Previous results reported statistically significant (P<0.05) yet modest clinically meaningful mean improvement from baseline (BL) at every stg of EXTEND for FACIT-Fatigue (FACIT-F) and 6 items from FACT-Thrombocytopenia (FACT-Th6), during Stg 2–4 for the MEI-SF, and Stg 1, 3, and 4 for the physical component summary (PCS) of the SF-36. However, these reports did not address when improvements in fatigue and functioning might occur, nor how HRQoL improvements might be associated with multiple definitions of clinical response. Aim: To assess timing and significance of patients' personal Best Response HRQoL (BRqol) effects of eltrombopag and the association of HRQoL improvements with multiple clinical measures of response for cITP patients in EXTEND. Methods: EXTEND data through Feb 2011 was included; median treatment duration was 2.3 years. Self-reported HRQoL (7-day recall) was obtained at BL and serially afterwards, using the SF-36 mental component summary (MCS) and PCS, FACIT-F, MEI-SF, and FACT-Th6. Proportions of patients reaching BRqol at each stg of EXTEND were assessed for all patients. HRQoL association with clinical response was assessed for all patients with a BL and ≥1 post-BL HRQoL assessment, using 3 definitions of clinical response: • Achieving a doubling of BL PC (Ra) • PC >50,000/μL (Rb) • Achieving guideline-defined (Neunert 2011) responses (Rc), defined as PC ≥100,000/μL (or ≥30,000/μL and >2x BL) on 2 occasions >7 days apart in the absence of bleeding. A similar analysis was completed for a subset of patients with PC <30,000/μL at BL. Results: With minor variation among HRQoL tools, 25–33% of patients reached their BRqol within 90 days and 57–67% within 1 year (Fig 1) of initiating EXTEND. Of those patients who went through each respective stage of EXTEND, 38–43% achieved a BRqol for at least one HRQoL tool during Stg 1 (n=174), 26–35% during Stg 2 (n=54), 33–38% during Stg 3 (n=178), and 44–59% during Stg 4 (n=135). There is little variation in time to BRqol by HRQoL tool among those achieving BRqol in Stg 1, 3, and 4. For the patients who went through Stg 2 and achieved BRqol during Stg 2, median days to BRqol varied by HRQoL tool (eg, 229 for the SF-36 MCS, 84 for the FACT-Th6, and 125 for the SF-36 PCS). All patients completing or continuing in EXTEND reported PC > BL and HRQoL assessment > BL at least once while on therapy. Improvements in MEI-SF, FACIT-F, FACT-Th6, and SF-36 MCS were positively associated (P≤0.05) with each definition of clinical response, except a non-significant association of the MEI-SF with guideline-defined responses (Rc); in addition, there was a positive association (P≤0.05) with SF-36 PCS and PC >50,000/μL (Rb). A similar pattern is evident among the subset of patients with BL PC <30,000/μL. Summary/conclusions: These results suggest BRqol may be achieved by up to 1/3 of patients within 3 months and 2/3 of patients within 12 months of initiating eltrombopag treatment. These data further demonstrate the variability of time to BRqol, and how improvements in HRQoL reflect achievement of multiple clinical goals such as those analyzed in EXTEND. HRQoL improvement may be associated with both simple increases in PC as well as broader definitions of clinical response. Neither guideline-defined responses nor elevating PC to “normal” range are usually the primary goals of treatment of cITP. Critical to note, therefore, is the positive association observed between HRQoL improvements and the straightforward, achievable clinical goals of doubling of PC or achieving PCs >50,000/μL and the time to achieve them. Disclosures: Grotzinger: GlaxoSmithKline: Employment. Bussel:Symphogen: Membership on an entity's Board of Directors or advisory committees; Sysmex: Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai, Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Immunomedics: Research Funding; IgG of America: Research Funding; Genzyme: Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Consultancy. Bieri:GlaxoSmithKline: Research Funding. Orlova:GlaxoSmithKline: Research Funding. Brainsky:GlaxoSmithKline: Employment, Equity Ownership, Patents & Royalties.

Identification of Effective Targeted Drug Combinations Using Functional Ex Vivo Screening of Primary Patient Specimens

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 865-865 ◽  
Author(s):  
Stephen E Kurtz ◽  
Elie Traer ◽  
Jakki Martinez ◽  
Andrew Park ◽  
Jake Wagner ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Kinase Inhibitors ◽  
Ex Vivo ◽  
Single Agent ◽  
Hematologic Malignancies ◽  
Drug Combinations ◽  
Advisory Committees ◽  
Heat Map ◽  
Equity Ownership

Abstract Introduction: The intratumoral heterogeneity of Acute Myeloid Leukemia (AML) and other hematologic malignancies presents a challenge in developing effective single-agent targeted treatments. Furthermore, the emergence of genetically heterogeneous subclones leading to relapse suggests that effective therapies associated with discrete genotypes may require drug combinations, each of which modulates distinct pathways. In addition, microenvironmental rescue signals as well as tumor-intrinsic feedback pathways in AML and other hematologic malignancy subsets will necessitate combinatorial therapy approaches. Towards the goal of identifying new therapeutic combinations for AML and other hematologic malignancies, we assessed the sensitivity of primary patient samples to various drug combinations using an ex vivo functional platform. Methods: We have previously screened over 1000 primary patient specimens against a panel of single-agent small-molecule inhibitors. Using these historical drug sensitivity data, we ranked drugs by their IC50, and used these rankings to assemble an initial panel (1) of 44 drug combinations consisting primarily of kinase inhibitors with non-overlapping pathways. Primary patient samples (n = 74) with various hematologic malignancies were assessed for sensitivities to these combinations by culturing cells in the presence of fixed molar concentrations of the drugs over a dose series. Sensitivity was assessed by a viability assay on day 3 using a tetrazolium reagent. IC50 values for samples sensitive to a combination were sorted according to disease type and compared to those for each single agent to derive an index of effectiveness. Based on data from panel 1, we generated a second panel (2) consisting of 44 drug combinations, including new combinations of kinase inhibitors as well as combinations of drugs from different classes, such as bromodomain inhibitors, BH3 mimetics, proteasome inhibitors, IDH1/2 inhibitors coupled with kinase inhibitors. Primary patient samples (n = 78) were assessed for sensitivities to these combinations. Results: The performance of drug combinations across AML, ALL, CLL, CML or other MDS/MPN specimens are displayed in a heat map (Figure 1) representing the sensitivities of each drug combination relative to either of the single agents comprising that combination (the combination IC50 divided by the lowest single agent IC50 is our combination ratio). For each combination, we then compared the combination ratio of each individual specimen to the median combination ratio across all specimens tested, and cases with a combination ratio value less than 20% of the median were considered hypersensitive to that combination. We calculated the percentage of cases that were sensitive to each combination within the diagnostic subsets of AML, ALL, CLL, CML, and MDS/MPN and subsets with the most frequent sensitivity to a drug combination are indicated on the heat map (<20%, dark red; 20-50%, dark pink; 50-80%, light pink; and >80%, white). Combinations of two kinase inhibitors that included the p38MAPK inhibitor, doramapimod, were generally more effective on AML and CLL samples than other diagnostic subsets (panel 1). For CLL sample, combinations including midostaurin and either alisertib, ruxolitinib or sorafenib were particularly effective. Among combinations on panel 2, doramapimod coupled with an apoptosis inducer (ABT-199) exhibited broad efficacy on AML samples. In addition, combinations with the bromodomain inhibitor, JQ1, or the BH3 mimetic, ABT-199, were more broadly effective across diagnostic subsets than many of the kinase-kinase pairs tested. To validate the apparent synergies observed with patient samples, we tested selected combinations on AML-derived cell lines and observed synergies, which were supported with combination indices derived by the Chou-Talalay method. Conclusions: These data suggest that specific drug combinations formed either with two kinase inhibitors or with two compounds from different drug classes are effective in a patient-specific manner with enrichment for certain drug pairs within specific diagnostic subsets. While a secondary evaluation is necessary to validate the initial observation of sensitivity, linking this methodology with genetic attributes for patient samples will identify effective combinations of targeted agents and add therapeutic options for AML treatment. Figure 1. Figure 1. Disclosures Pandya: Microsoft: Employment, Equity Ownership. Bolosky:Microsoft: Employment, Equity Ownership. Druker:Oregon Health & Science University: Patents & Royalties; Henry Stewart Talks: Patents & Royalties; CTI Biosciences: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Research Funding; Aptose Therapeutics, Inc (formerly Lorus): Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; McGraw Hill: Patents & Royalties; Leukemia & Lymphoma Society: Membership on an entity's Board of Directors or advisory committees, Research Funding; MolecularMD: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Roche TCRC, Inc.: Consultancy, 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; Bristol-Myers Squibb: Research Funding; Millipore: Patents & Royalties; AstraZeneca: Consultancy; Oncotide Pharmaceuticals: Research Funding; Cylene Pharmaceuticals: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Fred Hutchinson Cancer Research Center: Research Funding; ARIAD: Research Funding; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sage Bionetworks: Research Funding. Tyner:Incyte: Research Funding; Janssen Pharmaceuticals: Research Funding; Constellation Pharmaceuticals: Research Funding; Array Biopharma: Research Funding; Aptose Biosciences: Research Funding.

scholarly journals Results from REACH1, a Single-Arm Phase 2 Study of Ruxolitinib in Combination with Corticosteroids for the Treatment of Steroid-Refractory Acute Graft-Vs-Host Disease

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 601-601 ◽  
Author(s):  
Madan Jagasia ◽  
Miguel-Angel Perales ◽  
Mark A Schroeder ◽  
Haris Ali ◽  
Nirav N Shah ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Hematologic Malignancies ◽  
Phase 2 ◽  
Advisory Committees ◽  
Graft Vs Host Disease ◽  
Phase 2 Study ◽  
Grade Ii ◽  
Equity Ownership ◽  
Grade Iii

Abstract Introduction: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment option for patients with high-risk or relapsed hematologic malignancies. Development of acute graft-vs-host disease (aGVHD) is a risk factor for nonrelapse mortality after allo-HSCT. Systemic corticosteroids (CS) are recommended first-line treatment for aGVHD, but <50% of patients (pts) achieve sustained responses, and there are no approved therapies for steroid-refractory (SR) aGVHD. Ruxolitinib (RUX) is an oral, selective inhibitor of Janus kinase (JAK)1/JAK2 signaling, implicated in GVHD pathogenesis. Retrospective studies showed clinical benefit from RUX in pts with SR aGVHD. Here, we report results from the REACH1 trial (NCT02953678) evaluating RUX plus CS in SR aGVHD. Methods: REACH1 was an open-label, single-cohort, multicenter, phase 2 study. Eligible pts were ≥12 years old, had an allo-HSCT from any donor source for hematologic malignancies, developed grade II-IV SR aGVHD per Mount Sinai Acute GVHD International Consortium criteria, and had ≤1 systemic treatment in addition to CS for aGVHD. SR aGVHD was defined as GVHD that progressed after 3 days or had not improved after 7 days of primary treatment with methylprednisone ≥2 mg/kg/d (or equivalent), development of GVHD in another organ after receiving CS (≥1 mg/kg/d methylprednisone) for skin or skin plus upper gastrointestinal GVHD, or inability to tolerate CS taper. Pts received RUX 5 mg twice daily (BID), with optional increase to 10 mg BID in the absence of cytopenias. The primary endpoint was overall response rate (ORR) at Day 28, defined as the proportion of pts having complete response (CR), very good partial response, or partial response (PR). The key secondary endpoint was 6-month duration of response (DOR; time from first response to GVHD progression or death). Results: At the primary analysis of ORR (02 Apr 2018), 71 pts received ≥1 dose of RUX. Mean (range) age was 52.9 (18-73) years; 49.3% of pts were men. Acute myeloid leukemia (AML) and myelodysplastic syndrome were the most common primary malignancies (28.2% each). Most pts (80.3%) received peripheral blood stem cells; 18.3% received bone marrow, and 1.4% received cord blood as the stem cell source. Treatment was ongoing in 17 pts (23.9%) at data cutoff. At baseline, 23 pts (32.4%) had grade II aGVHD, 34 (47.9%) had grade III, and 14 (19.7%) had grade IV; 36 pts (50.7%) had ≥2 organs involved. Before starting RUX, 19 pts (26.8%) had progressive aGVHD after 3 days of CS treatment, 30 (42.3%) had no response after 7 days of CS, 8 (11.3%) developed new organ involvement on CS <2 mg/kg, and 14 (19.7%) were taper intolerant. At Day 28, ORR (95% CI) was 54.9% (42.7%-66.8%) with responses observed irrespective of grade or SR criteria (Table 1). Median DOR among Day 28 responders has not been reached (lower limit, 159 days; Figure 1). Event-free probability estimates (95% CI) for Day 28 responders at 3 and 6 months were 79.0% (62.3%-88.9%) and 67.0% (47.3%-80.7%), respectively. Best ORR at any time was 73.2% (CR, 56.3%). Median (range) time to response was 7.0 (6-49) days. Two pts had malignancy relapse (AML in both). At Day 28, 43 pts were on RUX and CS treatment; 55.8% (24/43) of these pts had a 50% reduction from baseline in CS dose (Figure 2). Most pts (69/71) initiated RUX at 5 mg BID. At Day 28, 46.5% of pts (20/43) received RUX 10 mg BID. The most common treatment-emergent adverse events (TEAEs; any grade, grade 3/4) were anemia (60.6%, 46.5%), hypokalemia (47.9%, 18.3%), decreased platelet count (43.7%, 38.1%), peripheral edema (43.7%, 11.3%), and decreased neutrophil count (36.6%, 31.0%). Cytomegalovirus (CMV) infection, viremia, and chorioretinitis occurred in 9 (12.7%), 4 (5.6%), and 1 (1.4%) pts, respectively (43.7% of pts were CMV+ at baseline). Fatal treatment-related TEAEs were sepsis and pulmonary hemorrhage (1 pt each) and were attributed to both RUX and CS. Conclusion: In this first prospective trial of RUX in pts with SR aGVHD, RUX treatment resulted in overall responses in 54.9% of pts with SR aGVHD by Day 28, many of whom (68%) had grade III/IV disease at baseline. Best ORR at any time was 73.2% (CR, 56.3%). Responses were rapid and durable. Most pts achieved sustained reductions in CS dose. The AE profile was consistent with expectations for RUX and pts with SR aGVHD. RUX represents a promising therapeutic strategy; a phase 3 trial of RUX vs best available therapy in SR aGVHD is underway. Disclosures Jagasia: Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Perales:Merck: Other: Personal fees; Abbvie: Other: Personal fees; Takeda: Other: Personal fees; Novartis: Other: Personal fees; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees and Clinical trial support. Schroeder:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Ali:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Shah:Lentigen Technology: Research Funding; Miltenyi: Other: Travel funding, Research Funding; Juno Pharmaceuticals: Honoraria; Geron: Equity Ownership; Exelexis: Equity Ownership; Oncosec: Equity Ownership. Chen:Magenta Therapeutics: Consultancy; Takeda Pharmaceuticals: Consultancy; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; REGiMMUNE: Consultancy. Arbushites:Incyte Corporation: Employment, Equity Ownership. Dawkins:Incyte Corporation: Employment. Tian:Incyte Corporation: Employment. Khoury:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Molecular Profiling and Relationship with Clinical Response in Patients with IDH1 Mutation-Positive Hematologic Malignancies Receiving AG-120, a First-in-Class Potent Inhibitor of Mutant IDH1, in Addition to Data from the Completed Dose Escalation Portion of the Phase 1 Study

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1306-1306 ◽  
Author(s):  
Courtney DiNardo ◽  
Stéphane de Botton ◽  
Daniel A Pollyea ◽  
Eytan M Stein ◽  
Amir T. Fathi ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Hematologic Malignancies ◽  
Molecular Profiling ◽  
Idh1 Mutation ◽  
Clinical Activity ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Abstract INTRODUCTION: Somatic mutations in the metabolic enzymes isocitrate dehydrogenase 1 and 2 (IDH1/2) confer gain-of-function activity in cancer cells, resulting in accumulation of the oncometabolite D-2-hydroxyglutarate (2-HG). High levels of 2-HG result in epigenetic changes and impaired cellular differentiation. IDH mutations have been identified in a spectrum of solid tumors and hematologic malignancies, with mutations in DNMT3A and NPM1 co-occurring with IDH1 most frequently (Molenaar et al. Leukemia 2015). AG-120 is a first-in-class, oral, potent, reversible, selective inhibitor of the IDH1 mutant enzyme being evaluated in an ongoing, first-in-human, phase 1, open-label study (NCT02074839). We report data, including clinical activity and safety, based on patients from the completed dose escalation phase. Molecular profiling, including observations of co-occurring genomic alterations at baseline, and relationship with clinical activity is also presented. METHODS: Patients with advanced IDH1 mutation-positive hematologic malignancies, diagnosed by local evaluation, receive AG-120 as a single agent orally once daily (QD) or twice daily (BID) continuously, in 28-day cycles. Bone marrow is examined on Days 15, 29, 57, and every 56 days thereafter. Primary objectives are safety, determination of maximum tolerated dose (MTD) and selection of a dose schedule for expansion cohorts and future phase 2 studies. Secondary objectives include clinical activity assessed by investigators using modified 2003 International Working Group Criteria in AML (Cheson et al). Molecular profiling was performed with the FoundationOne Heme next-generation sequencing (NGS) test on bone marrow and/or peripheral blood from all patients at pre-defined time points throughout the study. RESULTS: As of July 1, 2015, 66 patients were treated in the dose escalation phase, of whom 25 remain on treatment. Therapy has been well tolerated and the MTD was not reached. Dosing in the first cohort was 100 mg BID. The long half-life of AG-120 supported QD dosing subsequently, and 1200 mg QD was the highest dose evaluated. Dose escalation is now closed. The majority of adverse events (AEs) were grade 1 and 2, the most common being diarrhea (23%), fatigue (22%), and pyrexia (22%); the most common Grade ≥3 AE was febrile neutropenia (11%). The majority of serious AEs were disease-related. Of the 66 patients, 61 are response evaluable (patients with a Day 28 or later response assessment or who discontinued earlier than Day 28 for any reason). In all response evaluable patients, an estimated 55% had treatment durations of at least 3 months. Objective responses have been observed in 22 subjects (11 complete remissions [CR], 1 CR with incomplete platelet recovery, 4 partial responses and 6 marrow CRs), with a CR rate of 18% and an overall response rate (ORR) of 36% (22/61). Responses are durable, with a median duration of response among responders of 5.6 months [1.9, NE], including responses ≥11 months. Molecular profiling data from screening bone marrow was available in 38 patients. Among these 38, the most common co-mutations associated with IDH1 mutation were DNMT3A (67%) and NPM1 (24%). Incidence of additional co-mutations was <22%, with FLT3 in 7 patients (21%). Additional samples for longitudinal NGS sequencing were further analyzed at specified time points throughout the study. Updates from the completed dose escalation phase and further molecular profiling analysis will be presented. Three dose expansion arms are currently enrolling at 500 mg QD in relapsed/refractory AML, untreated AML, or other IDH1 mutation-positive advanced hematologic malignancies (n=125, n=25, and n=25, respectively, as of July 1, 2015). In addition, safety and efficacy data from the ongoing study will be included as of an October 2015 data cut-off date. CONCLUSION: AG-120, a potent, selective, oral inhibitor of mutant IDH1, is well tolerated in patients with advanced hematologic malignancies, and induces objective durable responses, with an ORR of 36%, including complete remissions. Molecular profiling may provide insights into the mechanisms of response and resistance. The data support the efficacy of AG-120 and provide continued validation of mutant IDH1 as a therapeutic cancer target. Disclosures DiNardo: Novartis: Research Funding. de Botton:Agios pharmaceuticals: Research Funding. Pollyea:Glycomimetics: Other: Member of data safety monitoring board; Pfizer: Consultancy; Karyopharm: Consultancy; Agios Pharmaceuticals: Consultancy; Celgene: Consultancy, Research Funding; Ariad: Consultancy. Stein:Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees. Fathi:Agios Pharmaceuticals: Other: Advisory Board participation; Seattle Genetics: Other: Advisory Board participation, Research Funding; Merck: Other: Advisory Board participation. Flinn:Cephalon, Inc; Teva Pharmaceutical Industries Ltd; Genentech, inc; Gilead: Research Funding. Altman:Astellas: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Ariad: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Derti:Agios Pharmaceuticals: Employment, Equity Ownership. Goldwasser:Agios Pharmaceuticals: Employment, Equity Ownership. Prahl:Agios Pharmaceuticals: Employment, Equity Ownership. Wu:Agios: Employment, Equity Ownership. Yen:Agios: Employment, Equity Ownership. Agresta:Agios Pharmaceuticals: Employment, Equity Ownership. Stone:Agios: Consultancy; Novartis: Research Funding; AROG: Consultancy; Merck: Consultancy; Celator: Consultancy; Roche/Genetech: Consultancy; Karyopharm: Consultancy; Sunesis: Consultancy, Other: DSMB for clinical trial; Abbvie: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Juno: Consultancy.

A Phase 1 Study of TTI-621, a Novel Immune Checkpoint Inhibitor Targeting CD47, in Patients with Relapsed or Refractory Hematologic Malignancies

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1812-1812 ◽  
Author(s):  
Stephen Ansell ◽  
Robert W Chen ◽  
Ian W. Flinn ◽  
Michael B. Maris ◽  
Owen A. O'Connor ◽  
...  
Keyword(s):  
Platelet Count ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase 1 ◽  
Receptor Occupancy ◽  
Hematologic Malignancies ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Dose Dependent

Abstract Introduction The phagocytic activity of macrophages is regulated by activating ("eat") and inhibitory ("do not eat") signals. Under normal physiologic conditions, the ubiquitously expressed cell surface antigen CD47 suppresses phagocytosis by binding to signal regulatory protein alpha (SIRPα) on macrophages. It is hypothesized that overexpression of CD47 by cancer cells enables immune evasion. Blockade of CD47 results in phagocytosis of cells bearing "eat" signals and primes effective anti-tumor T cell responses. TTI-621(SIRPαFc)is a soluble recombinant fusion proteinconsisting of the CD47 binding domain of human SIRPα linked to the Fc region of human IgG1designed to both: 1) block the CD47 "do not eat" signal, and 2) engagemacrophage Fcγ receptors with IgG1 Fc to enhance phagocytosis and antitumor activity.In vitro, TTI-621 binds to normal human cells, platelets, a wide range of human primary tumor cells and cell lines, but only minimally to human erythrocytes. TTI-621 selectively promotes macrophage-mediated phagocytosis of hematologic and solid tumors over that observed with normal monocytes, and exhibits antitumor activity in xenograft mouse models. Methods A first-in-human, phase 1, open label, multicenter study (NCT02663518) is ongoing to evaluate the safety and tolerability, and to identify the maximum tolerated dose of TTI-621 in patients (pts) with relapsed/refractory lymphomas using a 3+3 dose-escalation design. Once the optimal dose has been determined in the dose-escalation phase, multiple expansion cohorts will be enrolled comprising pts with various relapsed/refractory hematologic malignancies. Assessments include peripheral receptor occupancy, serum cytokine levels, pharmacokinetics, and immunogenicity. Eligible pts are adults with advanced, measurable, hematologic malignancies, who have progressed on standard anticancer therapy or for whom no other approved therapy exists. Pts are required to have baseline hemoglobin ≥10 g/dL, platelets ≥75 x 109/L, and be transfusion- and growth factor-independent. Pts with cutaneous T-cell lymphoma, high-grade lymphoma, and acute promyelocytic leukemia are excluded. TTI-621 is administered IV once weekly at protocol-defined doses. Treatment may continue until disease progression or unacceptable toxicity. Results Eleven pts (6M/5F, age 21-72 years) have been enrolled as of the data cut-off date of 28 July 2016. Lymphoma diagnoses included Hodgkin (N=4), diffuse large B cell (DLBCL) (N=4), follicular (N=2), and mantle cell (N=1). Treatment has been reasonably well tolerated by pts in the 0.05 mg/kg (N=3), 0.1 mg/kg (N=3), and 0.3 mg/kg (N=5) dose cohorts. The majority of pts experienced mild to moderate infusion-related events. Hemoglobin levels have remained stable or improved with treatment. Transient, dose-dependent decreases in platelets and leukocytes occurred in the hours following infusion in all pts without clinical sequelae. The 0.3 mg/kg dose was associated with reversible, dose-limiting toxicity (DLT) in 2 of 5 pts: one pt with G3 elevated ALT/AST and G4 platelet count, and a second pt with G4 platelet count who was transfused. Dosing at 0.2 mg/kg is now being explored. Aside from the DLTs and 2 non-DLT G3 platelet count (all in 0.3 mg/kg cohort), treatment-related adverse events have been ≤G2. CD47 receptor occupancy increased with each cohort, peaking at the end of infusion and remaining detectable 24 hrs after the 1st infusion in Cohort 3. Macrophage-associated cytokines, including MIP-1α and MIP-1β, increased during the 4 hrs after infusion. Six pts continue to receive weekly infusions of TTI-621; one pt with DLBCL and another with FL have experienced progression-free intervals of 161 and 70 days, respectively. Conclusions TTI-621 has been reasonably well tolerated. Pts retained stable hemoglobin levels consistent with minimal drug binding to erythrocytes. Manageable, dose-dependent thrombocytopenia was likely due to increased phagocytic clearance of platelets. TTI-621 binds to CD47+ cells in a dose-dependent manner, potently yielding increases in cytokines associated with augmented phagocytic activity. Enrollment continues at the 0.2 mg/kg dose level; updated data will be provided at the meeting. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Ansell: BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Chen:Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millenium: Consultancy, Research Funding, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Merck: Consultancy, Research Funding. Flinn:Janssen: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Gilead Sciences: Research Funding; ARIAD: Research Funding; RainTree Oncology Services: Equity Ownership. O'Connor:Bristol Myers Squibb: Research Funding; Spectrum: Research Funding; TG Therapeutics: Research Funding; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; TG Therapeutics: Research Funding. Johnson:Trillium Therapeutics: Employment. Irwin:Hoffmann La Roche: Employment, Equity Ownership; Trillium Therapeutics: Employment, Equity Ownership. Petrova:Trillium Therapeutics Inc: Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Uger:Trillium Therapeutics: Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Sievers:Seattle Genetics: Employment, Equity Ownership; Trillium Therapeutics: Employment, Equity Ownership; MEI Pharma: Consultancy.

scholarly journals A Phase 1/2 Study of the Oral Novel JAK1 Inhibitor INCB052793 As Monotherapy and in Combination with Standard Therapies in Patients with Advanced Hematologic Malignancies

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 640-640
Author(s):  
Amer M. Zeidan ◽  
Rachel J. Cook ◽  
Rodolfo Bordoni ◽  
Ekaterine Asatiani ◽  
Gongfu Zhou ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase 1 ◽  
Hematologic Malignancies ◽  
Phase 2 ◽  
Employment Equity ◽  
Advisory Committees ◽  
Safety And Efficacy ◽  
Equity Ownership

Abstract Background: The JAK/STAT pathway plays an important role in cytokine and growth factor signal transduction. Dysregulation of the JAK/STAT pathway is associated with the pathogenesis of various hematologic malignancies. INCB052793, a small molecule JAK1 inhibitor, is being evaluated in an ongoing phase 1/2 study of INCB052793 as monotherapy or in combination with standard therapies in patients with advanced hematologic malignancies. Preliminary safety and efficacy data are reported. Methods: Phase 1 consisted of a monotherapy dose escalation (phase 1a) and combination therapy dose expansion (phase 1b). In phase 1a, patients with advanced hematologic malignancies received INCB052793 monotherapy (25, 35, and 50 mg QD). Phase 1b evaluated INCB052793 (25 and 35 mg QD) in patients with advanced multiple myeloma (MM) in combination with dexamethasone (DEX); or in patients with advanced acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or MDS/myeloproliferative neoplasm (MPN) overlap syndromes in combination with azacitidine (AZA). The study employed a 3+3 dose-escalation design until dose-limiting toxicities occurred. Patients were treated in continuous 21-day (monotherapy) or 28-day (combination therapy) cycles until study termination, consent withdrawal, disease progression, or unacceptable toxicity. Phase 2 is evaluating INCB052793 combination therapy in patients with AML and high-risk MDS who failed prior therapy with hypomethylating agents (HMAs). Primary study objectives included safety, tolerability, and dose selection for expansion of INCB052793 monotherapy and combination therapy (phase 1) and safety and efficacy of INCB052793 combination therapy in patients with AML and higher-risk MDS (phase 2). Responses were recorded according to malignancy-specific criteria. Results: We report data on the first 39 patients with hematological malignancies enrolled in the study.At data cutoff (June 19, 2017),11 patients (MDS/MPN, n=4; MM, n=3; diffuse large B-cell lymphoma, n=2; chronic lymphocytic leukemia, n=1; Hodgkin's lymphoma, n=1) received INCB052793 monotherapy. INCB052793+DEX combination therapy was received by 7 patients with MM; 21 patients received INCB052793+AZA combination therapy (AML, n=12; MDS, n=7; MDS/MPN, n=2). Prior HMA treatment was received by 0 patients in the INCB052793+DEX group and 71.4% (15/21) of patients in the INCB052793+AZA group. The median (range) duration of treatment was as follows: INCB052793 monotherapy, 104 (14‒528) days; INCB052793+DEX, 51 (15‒96) days; INCB052793+AZA, 125 (15‒456) days. Grade ≥3 adverse events (Table 1) were observed in 45% of patients receiving INCB052793 monotherapy, 86% of patients receiving INCB052793+DEX (most common: anemia, hypercalcemia, hypophosphatemia, pneumonia, sepsis, and thrombocytopenia), and 95% of patients receiving INCB052793+AZA (most common: febrile neutropenia, anemia, neutropenia, and thrombocytopenia). Most patients discontinued treatment (INCB052793 monotherapy, 91%; INCB052793+DEX, 100%; INCB052793+AZA, 90%), with the primary reasons being disease progression (INCB052793 monotherapy, 55%; INCB052793+DEX, 57%) or adverse event (INCB052793+AZA, 24%). Of 11 patients who received INCB052793 monotherapy, 1 with MDS/MPN had complete response (CR) and remains on study at data cutoff; 2 with MDS/MPN had partial remission (PR; Table 2). Of 7 patients with MM in the INCB052793+DEX group, 2 had a minimal response with a reduction in M protein. The overall response rate (ORR) was 67% (8/12) for patients with AML treated with INCB052793+AZA, with 1 CR, 1 morphologic leukemia-free state, and 6 PRs. The ORR was 56% (5/9) for patients with MDS or MDS/MPN who received INCB052793+AZA. Of 7 patients with MDS in the INCB052793+AZA group, 3 had CR. Of 2 patients with MDS/MPN in the INCB052793+AZA group, 1 had CR and 1 had PR. Conclusion: Preliminary findings from this phase 1/2 trial indicate that INCB052793 has encouraging clinical activity, especially in combination with AZA, in patients with advanced myeloid malignancies, including those who previously failed HMAs. These data indicate that INCB052793 might (re)-sensitize HMA-refractory or relapsed patients to the effects of HMAs. Preliminary safety and efficacy data support further evaluation of INCB052793 in this setting. Enrolment is ongoing in phase 2 and expanded data, including PK/PD, will be presented. Disclosures Zeidan: Otsuka: Consultancy; Takeda: Speakers Bureau; AbbVie, Otsuka, Pfizer, Gilead, Celgene, Ariad, Incyte: Consultancy, Honoraria. Cook: Syros Corporation: Membership on an entity's Board of Directors or advisory committees. Bordoni: Merck: Honoraria, Speakers Bureau; Genentech: Honoraria, Speakers Bureau; Abbvie: Honoraria, Speakers Bureau. Asatiani: Incyte Corporation: Employment, Equity Ownership. Zhou: Incyte Corporation: Employment, Equity Ownership. Faivre: Incyte Corporation: Employment, Equity Ownership. Byrne: Karyopharm: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Concert Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Savona: Sunesis: Research Funding; Incyte Corporation: Consultancy, Research Funding; Takeda: Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Equity Ownership; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees.

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