Ublituximab (TG-1101), a Novel Glycoengineered Anti-CD20 Monoclonal Antibody, in Combination with Ibrutinib Is Highly Active in Patients with Relapsed and/or Refractory CLL and MCL; Results of a Phase II Trial

Abstract Introduction: Ublituximab (UTX) is a novel, chimeric monoclonal antibody (mAb) which targets a unique epitope on the CD20 antigen and has been glycoengineered to enhance affinity for all variants of FcγRIIIa receptors, demonstrating greater antibody-dependent cellular cytotoxicity (ADCC) activity than rituximab and ofatumumab, particularly against cells that express low CD20 levels. Two Phase I trials of single agent UTX in relapsed/refractory CLL reported significant response rates with rapid and sustained lymphocyte depletion and a manageable safety profile. Ibrutinib, a novel oral BTK inhibitor approved for patients with previously treated CLL and MCL, displays high single agent activity and has reported increased activity in combination with non-glycoengineered anti-CD20 mAbs. Herein we report safety and efficacy data on the first combination of ibrutinib with a glycoengineered anti-CD20 mAb, UTX, from an ongoing Phase 2 trial. Methods: Eligible patients have relapsed or refractory CLL/SLL or MCL with an ECOG PS ≤ 2. The study was designed to assess safety, tolerability, and early overall response rate, with an initial safety run-in period consisting of 6 patients followed by open enrollment. UTX (Cohorts of 600 and 900 mg for CLL and at 900 mg for MCL patients) is administered on Days 1, 8, and 15 in Cycle 1 followed by Day 1 of Cycles 2 - 6. Ibrutinib is started on Day 1 and continues daily at 420 mg and 560 mg for CLL and MCL patients respectively. Following Cycle 6, patients come off study but remain on ibrutinib. Primary endpoint for safety: Adverse Events and Dose Limiting Toxicities (DLT) during safety run-in. Phase II primary efficacy endpoint: ORR with an emphasis on early activity with response assessments by CT scan scheduled prior to cycles 3 and 6 only. Results: 40 patients (33 CLL/ 7 MCL) have been enrolled to date with enrollment continuing. 23 M/17 F, median age 72 yr (range 52-86), ECOG 0/1/2: 20/19/1, median prior Tx = 2 (range 1-6), 38% with ≥ 2 prior anti-CD20 therapies; prior purine analog = 43%; prior alkylating agent = 68%; and prior purine and alkylating agent = 43%. No DLTs were observed during the safety run-in. Gr 3/4 AE’s occurring in at least 5% of patients and at least possibly related to UTX and/or ibrutinib included: neutropenia, thrombocytopenia, diarrhea, rash, leukocytosis, and infusion related reaction. There were no Grade 3/4 adverse events reported in ≥ 10% of patients. Ibrutinib was dose reduced due to an AE in 2 patients (1 diarrhea, 1 rash) and discontinued in 2 patients due to ibrutinib related AE’s (diarrhea and rash). IRR’s were managed with infusion interruptions with no patient requiring an ublituximab dose reduction. As of July 2014, 24/40 patients are evaluable for response. Best response to treatment is as follows: TableTypePts (n)CR (n)PR (n)SD (n)ORR (%)CLL non 17p/11q10-9190%17p/11q817-100%Total CLL18116194%MCL632183% The one CLL patient who achieved stable disease had a 46% nodal reduction. UTX appears to control ibrutinib related lymphocytosis with more than half of the patients within normal range for ALC by first efficacy assessment. Conclusions: Data suggests ublituximab, a glycoengineered anti-CD20 mAb, in combination with ibrutinib is both well-tolerated and highly active in patients with relapsed or refractory CLL and MCL. ORR was 94% in patients with CLL (100% in patients with high risk CLL: 17p, 11q del with 1 CR), with responses attained rapidly (median TTR: 8 weeks). In MCL, 83% of patients achieved a response at first efficacy assessment, with 50% of patients achieving a CR by week 20. For most patients, responses improved by the second efficacy assessment. The addition of ublituximab appears to mitigate ibrutinib related lymphocytosis producing earlier clinical responses than historically seen with ibrutinib monotherapy. Efficacy and safety will be updated on all enrolled patients. Disclosures Sharman: TG Therapeutics: Research Funding; Gilead: Consultancy, Research Funding; Roche: Research Funding; Pharmacyclics: Research Funding; Celgene: Consultancy, Research Funding. Farber:Leukemia Lymphoma Society NJ Chapter: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Alexion: Stock ownership Other. Schreeder:TG Therapeutics, Inc.: Research Funding. Kolibaba:TG Therapeutics: Research Funding; Gilead: Research Funding; Glaxo Smithkline: Research Funding. Sportelli:TG Therapeutics: Employment, Equity Ownership. Miskin:TG Therapeutics, Inc.: Employment, Equity Ownership. Weiss:TG Therapeutics, Inc.: Employment, Equity Ownership. Greenwald:TG Therapeutics: Research Funding.

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Rapid and Durable Responses with the SYK/JAK Inhibitor Cerdulatinib in a Phase 2 Study in Relapsed/Refractory Follicular Lymphoma-Alone or in Combination with Rituximab

Blood ◽

10.1182/blood-2019-124231 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3981-3981

Author(s):

Stephen D. Smith ◽

Javier Munoz ◽

Don Stevens ◽

Sonali M. Smith ◽

Tatyana A. Feldman ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Single Agent ◽

Employment Equity ◽

Advisory Committees ◽

Prior Therapy ◽

Equity Ownership ◽

Grade 3 ◽

Anti Cd20 ◽

Age Range

Background: Despite recent advances, follicular lymphoma (FL) remains incurable for most patients. Relapsed/refractory (r/r) FL is associated with decremental treatment responses, accumulating toxicity, and poor survival among early failures of 1st line chemoimmunotherapy. Underscored by the recent approvals of idelalisib, copanlisib, and duvelisib, targeting B-cell receptor (BCR) signaling produces ORR of ~50% in r/r patients; however, new agents with a better therapeutic index over long-term administration are needed. SYK is a key regulator of BCR signaling (upstream of BTK and PI3K), and its inhibition results in clinical activity in FL. Compared with unaffected nodes, lymph nodes from FL patients have greater numbers of follicular helper T cells that express high levels of IL-4, which may support the tumor via the JAK1/3 pathway. Cerdulatinib, an oral, reversible inhibitor of SYK and JAK kinases (JAK1, JAK3, TYK2), previously reported a ~45% overall response rate (ORR) in r/r FL as a single agent. Xenograft studies suggest cerdulatinib may combine with rituximab to enhance antitumor activity. We report updated results from a phase 2a study of single-agent cerdulatinib and initial results in combination with rituximab in r/r FL. Methods: This phase 2a study confirmed the safety and efficacy of cerdulatinib 30 mg BID in r/r B- and T-cell lymphoma patients. Dose reductions were permitted to 15 mg BID. Response was assessed by Lugano criteria. Results: A planned interim analysis was performed on July 18, 2019, in which enrollment was 40 patients in the single-agent cohort and 19 patients in the rituximab combination cohort. For the single-agent cohort, median age (range) was 64 (42-81) years and median prior therapies (range) was 3 (1-9). Ninety-five percent of patients had prior anti-CD20 therapy, and 25% had prior therapy with BCR pathway inhibitors. For the combination cohort, median age (range) was 67 (47-85) years and median prior therapies (range) was 3 (1-10). Eighty-eight percent of patients had prior anti-CD20 therapy, and 32% had prior therapy with BCR pathway inhibitors. The safety profile appeared similar in both cohorts. The most common treatment-emergent grade 3+ adverse events in ≥5% of patients for both cohorts were lipase increase (27%), neutropenia (18%), diarrhea (12%), amylase increase (10%), hypertension (8%), nausea (7%), and pneumonia (5%). Grade 3+ infections occurred in 17.5% of single-agent cohort patients and 15.8% of combination cohort patients. Amylase and lipase increases generally were not associated with abdominal pain or pancreatitis. In addition, to date there has been no evidence of cumulative toxicity. The ORR was 45% as a single agent (12.5% complete response [CR], 32.5% partial response [PR], with 25% stable disease [SD] and 5% progressive disease [PD] in 40 evaluable patients) and 59% in the combination cohort (11.7% CR, 47% PR, with 27.8% SD and no PD in 17 evaluable patients). Responses typically occurred after 2 cycles, generally improved over time, and were durable in the single-agent cohort, with 10 patients on drug for >1 year. Enrollment in the combination cohort is ongoing. Updated safety and efficacy will be presented. Conclusion: The recommended cerdulatinib phase 2 dose of 30 mg BID was tolerable and efficacious in heavily pretreated r/r FL. The cerdulatinib + rituximab combination appears to be well tolerated, with tumor reductions in all evaluable patients. The safety profile and unique mechanism of action of cerdulatinib support further combination studies in FL. Disclosures Smith: Pharmacyclics: Research Funding; Denovo Biopharma: Research Funding; Portola Pharmaceuticals: Research Funding; Seattle Genetics: Research Funding; Acerta Pharma BV: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte Corporation: Research Funding; Genentech: Research Funding; Bristol-Myers Squibb (spouse): Research Funding; Ignyta (spouse): Research Funding; Ayala (spouse): Research Funding; Merck Sharp & Dohme Corp: Consultancy, Research Funding. Munoz:AstraZeneca: Speakers Bureau; Pharmacyclics LLC an AbbVie Company: Consultancy, Research Funding, Speakers Bureau; Kite Pharma: Consultancy, Research Funding, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Fosunkite: Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Portola: Research Funding; Incyte: Research Funding. Stevens:Astellas: Consultancy. Smith:Portola Pharmaceuticals: Research Funding. Feldman:Kite Pharma: Honoraria, Other: Travel expenses, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau; Pharmacyclics: Honoraria, Other: Travel expenses, Speakers Bureau; AbbVie: Honoraria, Other: Travel expenses, Speakers Bureau; Viracta: Research Funding; Trillium: Research Funding; Roche: Research Funding; Amgen: Research Funding; Cell Medica: Research Funding; Roche: Research Funding; Corvus: Research Funding; Eisai: Research Funding; Kyowa Hakko Kirin: Research Funding; Pfizer: Research Funding; Portola Pharma: Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau. Ye:MingSight: Research Funding; Janssen: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Onyx: Research Funding; Celgene: Research Funding; Takeda: Research Funding; AbbVie: Research Funding; Portola Pharmaceuticals: Research Funding. de Vos:Verastem: Consultancy; Portola Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy. Miller:Verastem: Consultancy, Honoraria, Research Funding, Speakers Bureau; Incyte: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Takeda: Honoraria, Research Funding, Speakers Bureau. Birrell:Portola Pharmaceuticals: Employment, Equity Ownership. Leeds:Portola Pharmaceuticals: Employment, Equity Ownership. Coffey:Portola Pharmaceuticals: Employment, Equity Ownership, Research Funding. Conley:Portola Pharmaceuticals: Employment, Equity Ownership. Michelson:Portola Pharmaceuticals: Employment, Equity Ownership. Curnutte:Portola Pharmaceuticals: Employment, Equity Ownership.

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A Phase 1/2 Study of the Second Generation Selective Inhibitor of Nuclear Export (SINE) Compound, KPT-8602, in Patients with Relapsed Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v128.22.4509.4509 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4509-4509 ◽

Cited By ~ 4

Author(s):

R. Frank Cornell ◽

Adriana C Rossi ◽

Rachid Baz ◽

Craig C Hofmeister ◽

Chaim Shustik ◽

...

Keyword(s):

Clinical Trial ◽

Board Of Directors ◽

Nuclear Export ◽

Research Funding ◽

Low Dose ◽

Phase 1 ◽

Single Agent ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

Abstract Introduction - Inhibition of Exportin 1 (XPO1) is a novel treatment approach for multiple myeloma (MM). XPO1 mediates the nuclear export of cell-cycle regulators and tumor suppressor proteins leading to their functional inactivation. In addition, XPO1 promotes the export and translation of the mRNA of key oncoproteins (e.g. c-MYC, BCL-2, Cyclin D). XPO1 overexpression occurs in solid and hematological malignancies, including MM and is essential for MM cell survival. Selinexor, the first oral SINE compound, has shown promising anti-MM activity in phase 1 studies but has been associated with gastrointestinal and constitutional toxicities including nausea, anorexia and fatigue. KPT-8602 is a second generation oral SINE compound with similar in vitro potency to selinexor, however, has substantially reduced brain penetration compared with selinexor, and demonstrated markedly improved tolerability with minimal anorexia and weight loss in preclinical toxicology studies. In murine models of MM, KPT-8602 can be dosed daily (QDx5) with minimal anorexia and weight loss. We have therefore initiated a phase 1/2 first-in-human clinical trial. Methods - This phase 1/2 clinical trial was designed to evaluate KPT-8602 as a single agent and in combination with low dose dexamethasone (dex) in patients (pts) with relapsed / refractory MM (RRMM). KPT-8602 is dosed orally (QDx5) for a 28-day cycle with a starting dose of 5 mg. Low dose dex (20 mg, twice weekly) is allowed after cycle 1 if at least a minimal response (MR) is not observed. The primary objective is to evaluate the safety and tolerability including dose-limiting toxicity (DLT), determine the maximum tolerated dose (MTD), the recommended Phase 2 dose (RP2D), and evidence for anti-MM activity for KPT-8602 single agent and in combination with dex. The pharmacokinetic (PK) and pharmacodynamic (PDn; XPO1 mRNA) profile of KPT-8602 will also be determined. PDn predictive biomarker analysis and ex vivo drug response assays are underway using tumor cells from bone marrow aspirates before treatment, during and at relapse. These analyses include cell death pathway assays by flow and nuclear/cytoplasmic localization of XPO1, NF-ƙB, IƙBα, IKKα, NRIF and p53 by imaging flow and IHC. Results - As of 01-Aug-2016, 6 pts 2 M/4 F, (median of 6 prior treatment regimens, median age of 71) with RRMM have been enrolled. Common related grade 1/2 adverse events (AEs) include thrombocytopenia (3 pts), nausea (2 pts) and diarrhea (2 pts). Grade 3 AEs include neutropenia (1 pt) and dehydration (1 pt). No grade 4 or 5 AEs have been reported. No DLTs have been observed and the MTD has not been reached. 5 pts were evaluable for responses (1 pt pending evaluation): 1 partial response, 1 minimal response, and 3 stable disease; no pts have progressed on therapy with the longest on for >5 months. The PK properties following oral administration showed that 5 mg of KPT-8602 was rapidly absorbed (mean tmax= 1 hr, mean Cmax= 30.6 ng/mL). The mean AUCinf was calculated to be 141 ng•hr/mL. After tmax, KPT-8602 declined at an estimated mean t½ of 4 hr. At the same dose level, XPO1 mRNA expression was the highest (~2.5 fold) at 8 hr post dose. Conclusions - Oral KPT-8602 is well tolerated in heavily pretreated pts with RRMM. Gastrointestinal and constitutional toxicities observed with twice weekly selinexor have not been observed with 5x/week KPT-8602, including in pts on study for >4 months. PK was predictable and in line with selinexor. These early results show encouraging disease control with pts remaining on therapy. Enrollment is on-going. Disclosures Rossi: Takeda: Speakers Bureau; Janssen: Speakers Bureau; Onyx: Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Baz:Takeda/Millennium: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Signal Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Merck: Research Funding; Novartis: Research Funding. Hofmeister:Karyopharm Therapeutics: Research Funding; Arno Therapeutics, Inc.: Research Funding; Signal Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees; Janssen: Pharmaceutical Companies of Johnson & Johnson: Research Funding; Incyte, Corp: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Takeda Pharmaceutical Company: Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees. Shustik:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: 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. Richter:Amgen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Jannsen: Speakers Bureau. Chen:Janssen: Honoraria, Research Funding; Takeda: Research Funding; Celgene: Honoraria, Research Funding. Vogl:Takeda: Consultancy, Research Funding; Celgene: Consultancy; GSK: Research Funding; Calithera: Research Funding; Teva: Consultancy; Karyopharm: Consultancy; Acetylon: Research Funding; Constellation: Research Funding. Shacham:Karyopharm Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Baloglu:Karyopharm Therapeutics: Employment, Equity Ownership. Senapedis:Karyopharm Therapeutics: Employment, Equity Ownership. Ellis:Karyopharm Therapeutics: Employment, Equity Ownership. Friedlander:Karyopharm Therapeutics: Employment. Choe-Juliak:Karyopharm Therapeutics: Employment. Sullivan:Karyopharm Therapeutics: Research Funding. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

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Systemic Exposure of Rituximab Increased By Ibrutinib: Pharmacokinetic Results from the Helios Trial

Blood ◽

10.1182/blood.v128.22.4403.4403 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4403-4403

Author(s):

Paula Cramer ◽

Fatih Demirkan ◽

Graeme Fraser ◽

Alexander Pristupa ◽

Nancy L Bartlett ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Single Agent ◽

Systemic Exposure ◽

Tumor Burden ◽

Time Data ◽

Employment Equity ◽

Advisory Committees ◽

Concentration Time ◽

Equity Ownership

Abstract Background: Ibrutinib, an inhibitor of Bruton's tyrosine kinase, is indicated for the treatment of several B-cell malignancies. In the phase 3 HELIOS trial, the addition of ibrutinib to a bendamustine plus rituximab regimen significantly improved patient outcomes, including quality of life, overall response, and progression-free survival, in patients with relapsed/refractory chronic lymphocytic leukemia (CLL; Chanan-Khan, Lancet Oncol 2016; 17:200-211). Here we report the results from analyses exploring the pharmacokinetic (PK) interactions between ibrutinib, bendamustine, and rituximab from the HELIOS trial. Methods: In total, 578 patients were randomized to 420 mg ibrutinib (n = 289) or placebo (n = 289) in combination with 6 cycles of bendamustine and rituximab until disease progression or unacceptable toxicity. The bendamustine intravenous (IV) dose was 70 mg/m2 on days 2-3 of cycle 1 and days 1-2 of cycles 2-6; the rituximab IV dose was 375 mg/m2 on day 1 of cycle 1 and 500 mg/m2 in cycles 2-6. Infusion durations were typically 30 min for bendamustine and varied based on tolerability and infusion rates for rituximab. Ibrutinib PK samples were collected from all patients at predose, 1, 2, and 4 hr on day 1 of cycles 1 and 2. In a subset of patients, bendamustine PK samples were collected on day 2 of cycles 1 and 2 at predose, end of infusion, and at 1, 2, and 4 hr. Rituximab PK samples were collected on days 1 (predose) and 15 of cycle 1, day 1 (predose) of cycles 2-6, and on day 1 of cycles 7-9. Dose-normalized bendamustine and rituximab concentration-time data were stratified by treatment to evaluate the effect of ibrutinib on the PK of these drugs. Descriptive statistics were calculated using R (www.R-project.org). Results:PK samples from 178 patients were analyzed; 84 patients from the placebo arm and 94 patients from the ibrutinib arm. The mean dose ± standard deviation (SD) of bendamustine was 68.2 ± 6.3 mg/m2 and 68.9 ± 4.7 mg/m2 in patients receiving ibrutinib and placebo, respectively; the doses of rituximab were 468.1 ± 55.3 mg/m2 and 465.2 ± 65.0 mg/m2, respectively. The dose-normalized plasma concentration-time data of bendamustine (a cytochrome P450 1A2 substrate) from both arms were comparable, indicating that ibrutinib did not alter bendamustine PK. In contrast, systemic exposure of rituximab was higher in patients coadministered with ibrutinib than in patients who received placebo; mean predose serum concentrations were 2- to 3-fold higher in the first three cycles and 1.2- to 1.7-fold higher in subsequent cycles (Figure). The systemic exposure of ibrutinib (n = 280; mean area under the plasma drug concentration-time curve at steady state ± SD = 447.5 ± 298.2 ng•h/mL) in patients receiving the 420 mg dose was comparable to exposures observed in studies of single agent ibrutinib (Marostica, Cancer Chemother Pharmacol 2015; 75:111-121), indicating that bendamustine and rituximab did not impact the PK of ibrutinib. No relevant differences in safety profile were observed between the ibrutinib and placebo arm with the increase in systemic exposure of rituximab. All-grade infusion-related reactions were more frequent with placebo than with ibrutinib (22% vs. 16.7%, respectively), and the incidence of chills was comparable (~11%). Dose interruptions, dose reductions, and discontinuations due to infusion-related reaction were more frequent in the placebo arm (34.8% vs. 27.9%). Additional analyses to model the rituximab PK data using metrics of tumor burden as covariates (e.g., sum of the products of diameters) are currently ongoing and will be presented. Conclusions:Coadministration of ibrutinib with bendamustine and rituximab did not affect the PK of bendamustine or ibrutinib but led to greater dose-normalized systemic exposure of rituximab when compared to patients who received placebo. Rituximab has been reported to be characterized by target-mediated drug disposition (TMDD; Li, J Clin Pharmacol 2012; 52:1918-1926), which may describe many rituximab PK features, such as PK differences in CLL, non-Hodgkin's lymphoma, and rheumatoid arthritis and the dependency of PK behavior on baseline tumor burden. TMDD may account for the rituximab PK findings from this study, with the early decreased tumor burden following ibrutinib resulting in decreased rituximab clearance and hence higher systemic exposure. The clinical significance of this finding needs additional exploration. Disclosures Cramer: Mundipharma: Other: Travel, Accommodations, Expenses; Janssen-Cilag: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Astellas: Other: Travel, Accommodations, Expenses; Novartis: Consultancy, Research Funding; GlaxoSmithKline: Research Funding; Roche: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Other: Travel, Accommodations, Expenses, Research Funding. Demirkan:Amgen: Consultancy. Fraser:Celgene: Research Funding; Janssen: Honoraria, Research Funding, Speakers Bureau. Bartlett:Pharmacyclics: Research Funding; Janssen: Research Funding. Dilhuydy:Gilead: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria. Loscertales:Roche: Honoraria, Speakers Bureau; Gilead Sciences: 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, Speakers Bureau. Goy:Genentech: Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Writing support, Speakers Bureau; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Ganguly:Seattle Genetics: Speakers Bureau; Janssen: Research Funding; Onyx: Speakers Bureau. Poggesi:Janssen: Employment, Equity Ownership. de Jong:Janssen: Employment. Neyens:Janssen: Employment. Salman:Janssen Research & Development: Employment, Equity Ownership, Other: Travel, Accommodations, Expenses. Howes:Janssen Research & Development: Employment. Mahler:Janssen Research & Development: Employment.

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Results from Phase 1/2 Trial of Tagraxofusp in Combination with Pomalidomide and Dexamethasone in Relapsed or Refractory Multiple Myeloma

Blood ◽

10.1182/blood-2019-130410 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3145-3145 ◽

Cited By ~ 1

Author(s):

Paul G. Richardson ◽

Myo Htut ◽

Cristina Gasparetto ◽

Jeffrey A. Zonder ◽

Thomas G. Martin ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Peripheral Blood ◽

Research Funding ◽

Phase 1 ◽

Single Agent ◽

Advisory Board ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

Background: The bone marrow microenvironment of many multiple myeloma (MM) patients contains high levels of CD123-expressing plasmacytoid dendritic cells (pDCs). These pDCs have been shown to augment MM growth and contribute to drug resistance (Chauhan, et al., Cancer Cell, 2009). Tagraxofusp, a novel CD123 targeted therapy, has demonstrated high levels of anti-tumor activity in patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), an aggressive CD123+ malignancy of pDC origin. Tagraxofusp demonstrated potent in vitro and in vivo activity against MM cell lines and primary tumor samples via both a direct anti-MM effect and indirect pDC-targeting effect (Ray, et al., Leukemia, 2017), as well as demonstrating synergy in these systems when used in combination with traditional MM therapies including pomalidomide (POM). As such, targeting pDCs with tagraxofusp may offer a novel therapeutic approach in MM. Methods: This multicenter, single arm Phase 1/2 trial enrolled patients with relapsed or refractory (r/r) MM and tested two different doses of tagraxofusp (7 or 9 mcg/kg). Patients received tagraxofusp as a daily IV infusion for days 1-5 of a 28-day cycle as a single agent for the initial run-in cycle (cycle 0) and in combination with standard doses/administration of POM and dexamethasone (DEX) in cycles 1 and beyond. Objectives included evaluation of safety and tolerability, identification of the maximum tolerated or tested dose, and efficacy. Results: 9 patients with r/r MM received tagraxofusp (7 mcg/kg, n=7; 9 mcg/kg, n=2). 5 males, median age 65 years (range: 57-70), median 3 prior therapies (range 2-6). Median follow-up was 12 months (range: 7 - 19). The most common treatment-emergent AEs (TEAEs) were hypoalbuminemia 67% (6/9); chills, fatigue, insomnia, nausea and pyrexia each 56% (5/9); and dizziness, headache, hypophosphatemia, and thrombocytopenia each 44% (4/9). The most common grade 3 and 4 TEAEs were thrombocytopenia 44% (4/9) and neutropenia 33% (3/9). No grade 5 events reported. 5 patients treated with tagraxofusp and POM+DEX had a partial response (PR) after tumor evaluation. These patients demonstrated a rapid decrease in a set of myeloma-related laboratory values from pre-tagraxofusp treatment levels after the first combination cycle of tagraxofusp and POM+DEX. Additionally, these 5 patients demonstrated >50% decreases in peripheral blood pDC levels after both tagraxofusp monotherapy and combination therapy. Conclusions: Tagraxofusp was well-tolerated, with a predictable and manageable safety profile, when dosed in combination with POM+DEX in patients with r/r MM. Evidence of pDC suppression in peripheral blood and BM was observed in this patient population. 5 patients that received tagraxofusp and POM+DEX combination had PRs and decreases in pDC levels while on treatment with tagraxofusp. Given CD123 expression on pDCs in the tumor microenvironment and the potential synergy of tagraxofusp with certain MM agents including POM, tagraxofusp may offer a novel mechanism of action in MM. NCT02661022. Disclosures Richardson: Oncopeptides: 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; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding. Gasparetto:Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Zonder:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees. Martin:Roche and Juno: Consultancy; Amgen, Sanofi, Seattle Genetics: Research Funding. Chen:Stemline Therapeutics: Employment, Equity Ownership. Brooks:Stemline Therapeutics: Employment, Equity Ownership, Patents & Royalties. McDonald:Stemline Therapeutics: Employment, Equity Ownership. Rupprecht:Stemline Therapeutics: Employment, Equity Ownership. Wysowskyj:Stemline Therapeutics: Employment, Equity Ownership. Chauhan:C4 Therapeutics.: Equity Ownership; Stemline Therapeutics: Consultancy. Anderson:Gilead Sciences: Other: Advisory Board; Janssen: Other: Advisory Board; Sanofi-Aventis: Other: Advisory Board; OncoPep: Other: Scientific founder ; C4 Therapeutics: Other: Scientific founder .

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Efficacy and Safety of Single-Agent Ibrutinib in Patients with Mantle Cell Lymphoma Who Progressed after Bortezomib Therapy

Blood ◽

10.1182/blood.v124.21.4471.4471 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4471-4471 ◽

Cited By ~ 5

Author(s):

Michael Wang ◽

Andre Goy ◽

Peter Martin ◽

Rod Ramchandren ◽

Julia Alexeeva ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Response Rate ◽

Single Agent ◽

Complete Response ◽

Employment Equity ◽

Advisory Committees ◽

Bulky Disease ◽

Equity Ownership ◽

Grade 3

Abstract Introduction: Despite recent advances, mantle cell lymphoma (MCL) remains difficult to treat with frequent chemoresistance in the relapsed or refractory setting. Ibrutinib, a first-in-class, once-daily, oral covalent inhibitor of Bruton’s tyrosine kinase, demonstrated durable single-agent efficacy in a previous phase 2 study of patients with MCL who had received 1 to 5 prior therapies (Wang M, et al. N Engl J Med. 2013;369:507-516). In that study, the investigator-assessed overall response rate was 68% (complete response rate, 21%). The current study reports on the efficacy and safety of single-agent ibrutinib specifically in patients with MCL who had received a rituximab-containing regimen and had progressed after at least 2 cycles of bortezomib therapy. Methods: In this phase 2, multicenter, single-arm study, patients received 560 mg/day oral ibrutinib continuously until progressive disease or unacceptable toxicity. The primary end point was the overall response rate (ORR) in response evaluable patients, as assessed by an Independent Review Committee (IRC). Secondary end points, also assessed by IRC, included duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Results: 120 patients in this international multicenter study were enrolled. The median age was 67.5 years, ranging from 35 to 85 years with 62.5% ≥ 65 years. Most patients had stage IV disease at study entry (77.5%), and 9.2% were reported as blastoid variant (per investigator). 76.3% of patients had an intermediate or high risk simplified MIPI score, and 52.5% had bulky disease (longest diameter ≥ 5 cm). Forty two (35.0%), 67 (55.8%) and 11 patients (9.2%) had an ECOG score of 0, 1 and 2, respectively. The median number of prior lines of systemic therapy was 2 (range 1-8 lines) with almost half of the patients (47.5%) receiving 3 or more prior lines of therapy. Overall, 33% of patients had received prior stem cell transplantation. At the time of clinical cut-off for the primary analysis (29 April, 2014), median follow-up was 14.9 months with median treatment duration of 8 months (range: 0.5-20.9 months). The main reasons for treatment discontinuation were disease progression in 53 patients (44.2%) and an adverse event (AE) in 8 patients (6.7%). The ORR for response evaluable patients was 62.7% (95% confidence interval [CI]: 53.7%-71.8%) with a complete response rate of 20.9%. Subgroup analysis suggested that the ORR was independent of age, gender, geographic region, number of prior lines of therapies, baseline extranodal disease, simplified MIPI score, bulky disease, and stage of MCL. Median DoR by IRC was 14.9 months and the median time to first response was 2.1 months, ranging from 1.3 to 6.3 months. Median PFS was 10.5 months and 47% of the patients remained progression-free at 1 year. The OS rate at 18 months was 61%. The most common AEs were fatigue (any grade, 43.3%; grade 3 or 4, 3.3%) and diarrhea (any grade, 42.5%; grade 3 or 4, 2.5%). The most common grade 3 or higher AEs were neutropenia (20.8%), thrombocytopenia (13.3%), and pneumonia (12.5%). Any-grade hemorrhagic events were reported in 45 patients (37.5%), including 3 (2.5%) with major hemorrhagic events. The median time to initial hemorrhagic event was 84 days (range 1-515 days), with a median duration of 22 days (95% CI: 8-31 days). Atrial fibrillation was reported in 13 patients (10.8%), which was grade 3 or 4 in 6 patients (5%). AEs led to dose reductions in 8 patients (6.7%). Conclusion: Single agent ibrutinib is highly efficacious and well tolerated, with an acceptable toxicity profile in patients with MCL who progressed after rituximab-containing chemotherapy and bortezomib therapy. These results are consistent with previous ibrutinib studies, with no new safety signals. Disclosures Wang: Pharmacyclics, Janssen, Celgene, Onyx, OnyPep, : Research Funding; Onyx, Janssen: Honoraria. Goy:Janssen/Pharmacyclics: Honoraria, Speakers Bureau; Clinical Trials through Institution: Research Funding; Janssen/Pharmacyclics: Membership on an entity's Board of Directors or advisory committees. Martin:Janssen: Honoraria. Popat:Janssen: Honoraria. Advani:Seattle Genetics, Genetech, (Uncompensated): Membership on an entity's Board of Directors or advisory committees; Janssen, Pharmacyclics, Seattle Genetics: Research Funding. Le Gouill:Roche: Consultancy; Janssen: Consultancy. Yuan:Johnson & Johnson: Equity Ownership; Johnson & Johnson: Employment. Kranenburg:Johnson&Johnson: Equity Ownership; Janssen Biologics: Employment. Rizo:Janssen R&D: Employment, Equity Ownership. Zhuang:Johnson & Johnson: Employment, Equity Ownership. Deraedt:Johnson & Johnson: Employment, Equity Ownership. Rule:Pharmacyclics, J&J: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Four-Year Survival and Durability Results of Brentuximab Vedotin in Combination with CHP in the Frontline Treatment of Patients with CD30-Expressing Peripheral T-Cell Lymphomas

Blood ◽

10.1182/blood.v128.22.2993.2993 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2993-2993 ◽

Cited By ~ 4

Author(s):

Michelle A Fanale ◽

Steven M Horwitz ◽

Andres Forero-Torres ◽

Nancy L Bartlett ◽

Ranjana H Advani ◽

...

Keyword(s):

T Cell ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Single Agent ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

Alk Positive

Abstract Background Peripheral T-cell lymphomas (PTCLs) encompass ~10-15% of aggressive non-Hodgkin lymphomas. Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), or variations thereof, are the most commonly used treatment regimens with complete remission (CR) rates ranging from 39-55% (Reimer 2009, d'Amore 2012). With the exception of low international prognostic index (IPI)-anaplastic lymphoma kinase (ALK)-positive ALCL, with 4-year progression-free survival (PFS) and overall survival (OS) ranging from 25-35% and 30-40%, respectively (Ellin 2014). We previously reported the results of this phase 1 trial that evaluated brentuximab vedotin (BV) administered in sequence with CHOP, or in combination with CHP (CHOP without vincristine) in treatment-naive patients (pts) with CD30-expressing PTCL (NCT01309789). The combination therapy (BV+CHP) showed safety and activity at standard doses, with an objective response rate (ORR) of 100% and complete response (CR) rate of 88% (Fanale 2014). The most common adverse events (AEs) experienced by pts were nausea and peripheral sensory neuropathy (69% each). Four-year durability data and updated results on peripheral neuropathy (PN) resolution from the BV+CHP combination treatment arm are presented herein. Methods Adults with CD30-expressing PTCL, including systemic ALCL (anaplastic large cell lymphoma, ALK-negative, or ALK-positive with IPI score ≥2) were eligible for this study. CD30 expression for non-ALCL pts was defined as ≥1% CD30 expression in malignant cells. Pts on the combination treatment arm received 1.8 mg/kg BV and standard-dose CHP q3wk for up to 6 cycles. Pts who achieved at least a partial response (PR) following treatment could receive continued BV 1.8 mg/kg q3wk as single-agent for up to 10 additional cycles. Antitumor response was assessed by the investigator according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Results Twenty-six previously untreated pts received BV+CHP. Disease diagnoses included systemic ALCL (n=19; including ALK-negative, n=16 and ALK-positive, n=3), PTCL-NOS (n=2), angioimmunoblastic T-cell lymphoma (AITL, n=2), adult T-cell leukemia/lymphoma (ATLL, n=2), and enteropathy-associated T-cell lymphoma (EATL, n=1). Twenty-one of the 26 pts who achieved remission with combination treatment continued on to receive single-agent BV. Overall, the 26 pts received a median of 13 cycles (range, 3 to 16) of BV. After a median observation period of 52 months (range 4.6 to 58.3) from first dose, 18 pts remain on study. The estimated 4-year PFS and OS rates are 52% (95% CI: 31, 69) and 80% (95% CI: 59, 91), respectively. The median PFS has not been reached (95% CI: 12.3, -). To date, 15 of 19 ALCL (3/3 ALK-positive, 12/16 ALK-negative), and 6 of 7 non-ALCL pts were alive at last follow-up. Five pts (19%) received subsequent treatment with single-agent BV in long-term follow-up and 3 pts received stem cell transplants (1 autologous, 2 allogeneic) for relapsed disease. There were no pts who underwent a consolidative stem cell transplant. Of the 26 pts treated with combination therapy, 19 (73%) experienced PN. Of these pts, 95% (18 of 19) experienced complete resolution (8 pts), or some resolution or improvement (defined as a decrease by at least 1 grade from worst grade, 10 pts). Of the pts who experienced improvement, 1 pt each improved from Grade 3 to a lowest Grade 2 and from Grade 3 to a lowest Grade 1, and 5 pts improved from Grade 2 to a lowest Grade 1. The median time to resolution of PN symptoms was 5.7 months. Eleven pts had ongoing neuropathy at last follow-up, of which, 9 pts had Grade 1 severity and 2 pts had Grade 2. Conclusions These 4-year durability results demonstrate that among pts with PTCL, initial therapy with BV in combination with CHP can induce long-term remissions with a tolerable safety profile. A phase 3 randomized trial comparing BV+CHP with CHOP for the frontline treatment of CD30-expressing PTCL is ongoing (NCT01777152). Progression-free Survival Figure Figure. Disclosures Horwitz: Celgene: Consultancy, Research Funding; Takeda Pharmaceuticals International Co.: Consultancy, Research Funding; Infinity: Research Funding; Huya: Consultancy; FortySeven: Consultancy; Kyowa Hakka Kirin: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Spectrum: Consultancy, Research Funding. Forero-Torres:Seattle Genetics: Research Funding; Genentech/Roche: Research Funding; Juno: Research Funding; Incyte: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Pfizer: Research Funding. Bartlett:Gilead: Consultancy. Pro:Takeda: Honoraria; Seattle Genetics: Honoraria; Celegene: Honoraria. Chen:Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millenium: Consultancy, Research Funding, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Merck: Consultancy, Research Funding. Davies:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodation, expenses, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel to scientific conferences, Research Funding; GSK: Research Funding; Mundipharma: Honoraria; Janssen: Honoraria; Bayer: Research Funding; Karyopharma: Honoraria, Research Funding; Pfizer: Research Funding. Illidge:Seattle Genetics: Consultancy, Research Funding; Takeda Pharmaceuticals International Co.: Consultancy, Honoraria. Uttarwar:Seattle Genetics: Employment, Equity Ownership. Huebner:Takeda Pharmaceuticals International Co.: Employment, Equity Ownership. Ren:Seattle Genetics: Employment, Equity Ownership.

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Evaluation of Tagraxofusp (SL-401) Alone and in Combination with Ruxolitinib for the Treatment of Myeloproliferative Neoplasms

Blood ◽

10.1182/blood-2019-129397 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2967-2967 ◽

Cited By ~ 1

Author(s):

Aishwarya Krishnan ◽

Maria Pagane ◽

Mikhail Roshal ◽

Erin McGovern ◽

Zoe Stone-Molloy ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Myeloproliferative Neoplasms ◽

Single Agent ◽

Employment Equity ◽

Blast Phase ◽

Advisory Committees ◽

Provision Of Services ◽

Equity Ownership ◽

The Impact

Background: The introduction of the JAK1/2 inhibitor Ruxolitinib has resulted in significant benefits for patients with Myelofibrosis (MF) and Polycythemia Vera, including reduction of splenomegaly and improvement in symptom burden. However, Ruxolitinib has limited ability to alter the natural history and biology of disease in myeloproliferative neoplasms (MPNs). More importantly, patients often lose response to ruxolitinib or suffer disease progression despite therapy with ruxolitinib. These observations have prompted efforts to introduce novel therapeutic approaches and devise novel combinatorial treatment strategies to improve the outcomes of patients with MPNs. CD123 (interleukin-3 receptor-a; IL-3R-a) has been identified as a therapeutic target in several myeloid malignancies. CD123 is expressed in a variety of myeloid malignancies, including AML, myelodysplastic syndrome (MDS) and CMML. Further, Tagraxofusp (ELZONRIS®, SL-401), a targeted therapy directed to CD123 comprised of recombinant IL-3 fused to a truncated diphtheria toxin payload, was recently FDA approved for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN). In an ongoing Phase 1/2 trial, Tagraxofusp has demonstrated single agent clinical activity, with a predictable and manageable safety profile, in patients with relapsed/refractory MF. Thus, Tagraxofusp appears to have activity in MF. However, the utility of Tagraxofusp in more advanced forms of MPN (such as accelerated phase MPN), as well as the utility of combination Ruxolitinib and Tagraxofusp, have not been evaluated to date. To address these questions, we first evaluated CD123 expression using flow cytometry analysis of peripheral blood samples from patients with MF with progression to accelerated-phase (>10%) or blast-phase (>20%) disease. CD123 expression was generally noted to be higher than that observed in normal control samples, by mean florescence intensity (Figure 1A). We next sought to determine the effect of treatment with Tagraxofusp alone and in combination with Ruxolitinib in leukemia cell lines and primary patient samples. We performed cell viability assays using the JAK2V617F mutant cell line UKE1. We first determined the IC50 of Tagraxofusp in UKE1 cells (range 2.95-3.57nM). Using this data, we then tested the impact of the addition of Tagraxofusp to Ruxolitinib on UKE1 cell viability using a fixed concentration of Tagraxofusp (5nM). The IC50 of range of single agent Ruxolitinib was 44.42-70.93nM. However, the addition of Tagraxofusp to Ruxolitinib resulted in a decrease of the IC50 range to 11.72-21.6nM, indicating an effect of combination therapy (Figure 1B). We then determined the impact of Tagraxofusp both alone and in combination with Ruxolitinib using primary patient MPN peripheral blood mononuclear cells in methylcellulose. Patient characteristics are described in Table 1. In most samples, CD123 expression was confirmed. In all samples studied, Tagraxofusp was able to significantly reduce colony formation when compared to vehicle, at a dose range of 2.5nM to 20nM. Notably, this includes two samples (151, 455) from patients with accelerated-phase disease. As well, Tagraxofusp demonstrated activity across genotypes, including in cases with TP53 and ASXL1 mutations. A reduction in colony formation in samples treated with combination Ruxolitinib and Tagraxofusp beyond that observed with either agent alone was observed in several cases (Figure 1C). Conclusions: Current therapeutic options for patients with MF beyond Ruxolitinib are limited. This is particularly the case for patients with progression to accelerated and blast-phase MPN. Here, we demonstrate that CD123 expression is evident in many such cases. Further, therapeutic targeting of CD123 using Tagraxofusp either alone or in combination with Ruxolitinib has activity in primary patient samples, including those in accelerated-phase and with high molecular risk profiles. These data thus support further testing of Tagraxofusp in MPNs, and in advanced MPNs in particular. Disclosures Roshal: Auron Therapeutics: Equity Ownership, Other: Provision of services; Physicians' Education Resource: Other: Provision of services; Celgene: Other: Provision of Services. Chen:Stemline Therapeutics: Employment, Equity Ownership. Brooks:Stemline Therapeutics: Employment, Equity Ownership, Patents & Royalties. Levine:Imago Biosciences: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; C4 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Isoplexis: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy; Prelude Therapeutics: Research Funding; Celgene: Consultancy, Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees; Qiagen: Membership on an entity's Board of Directors or advisory committees; Lilly: Honoraria; Amgen: Honoraria; Roche: Consultancy, Research Funding. Rampal:Constellation, Incyte, and Stemline Therapeutics: Research Funding; Agios, Apexx, Blueprint Medicines, Celgene, Constellation, and Jazz: Consultancy.

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PD-L1 Blockade with Atezolizumab in Higher-Risk Myelodysplastic Syndrome: An Initial Safety and Efficacy Analysis

Blood ◽

10.1182/blood-2018-99-118577 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 466-466 ◽

Cited By ~ 7

Author(s):

Aaron T. Gerds ◽

Bart L Scott ◽

Peter L Greenberg ◽

Samer K. Khaled ◽

Tara L Lin ◽

...

Keyword(s):

Myelodysplastic Syndrome ◽

Board Of Directors ◽

Research Funding ◽

Causes Of Death ◽

Single Agent ◽

Early Termination ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

Grade 3

Abstract Introduction: Patients (pts) with higher-risk myelodysplastic syndrome (HR-MDS) and those who fail to respond to or relapse/progress after treatment with hypomethylating agents (HMA) have limited therapeutic options and poor prognosis. PD-L1 expression is upregulated in HR-MDS pts (compared with lower-risk MDS pts) and in those who fail HMA therapy. Combining inhibition of the PD-L1/PD-1 pathway with azacitidine may improve outcomes in MDS. Methods: We conducted a Phase Ib trial of the anti-PD-L1 monoclonal antibody atezolizumab, with or without azacitidine, in HMA-failure and HMA-naive MDS pts (NCT02508870). The primary objective was to determine the safety and tolerability of atezolizumab as a single agent or in combination with azacitidine. An initial safety evaluation was performed in three cohorts. Cohort A1 (10 pts) consisted of HMA-failure HR-MDS pts treated with atezolizumab alone (1200mg IV q3w). Cohort B1 (11 pts) consisted of HMA-failure HR-MDS pts treated with atezolizumab (840mg IV q2w) in combination with azacitidine (75mg/m2 qd for 7 days q4w) for 6 cycles, followed by atezolizumab maintenance alone (1200mg IV q3w). Cohort C1 (6 pts) consisted of HMA-naive HR-MDS pts treated with atezolizumab (840mg IV q2w) in combination with azacitidine (75mg/m2 qd for 7 days q4w). If atezolizumab alone or in combination with azacitidine was deemed safe and tolerable in Cohorts A1 and B1, an additional 1:1 randomization into two cohorts of 30 pts each (Cohorts A2 and B2) was planned. If the combination of atezolizumab and azacitidine was found to be safe and tolerable in Cohort C1, an additional expansion cohort (Cohort C2) of 14 pts with HMA-naive HR-MDS was planned. Primary endpoints included determining the safety and tolerability of atezolizumab-based regimens in HR-MDS and defining the recommended Phase II dose for the combination. Results: As of January 2018, 42 HR-MDS pts had been treated with atezolizumab-based regimens: Cohort A, 10 pts; Cohort B, 11 pts; Cohort C, 21 pts. Median age for the entire pt cohort was 76 years (range: 63−89). Median treatment duration for Cohorts A, B, and C was 4.2, 5.5, and 5.8 months, respectively. The overall response rate for Cohorts A, B, and C was 0%, 9% (hematologic improvement [HI]: 9%), and 62% (CR, 14%; mCR, 19%; mCR + HI, 10%; HI, 19%), respectively. All pts in Cohorts A and B have discontinued therapy, with a median overall survival (OS) of 5.9 months and 10.7 months, respectively. For pts in Cohort C, 8/21 pts remain on therapy, and median OS has not been reached. Grade 3−5 adverse events (AEs) in >10% of pts were primarily hematologic; grade 3−5 febrile neutropenia occurred in 29% of all pts and was particularly common in pts receiving the atezolizumab-azacitidine combination (Cohorts B [36%] and C [33%] compared with Cohort A [10%]; Table 1). In Cohort A, 70% (7/10) of pts died, as did 64% (7/11) of pts in Cohort B and 29% (6/21) of pts in Cohort C. Median time to death was 160 days (Cohort A), 299 days (Cohort B), and 53 days (Cohort C). Timing and causes of death were different in the three cohorts. Causes of death were more commonly from disease progression in Cohorts A and B, while serious AEs accounted for all deaths in Cohort C (Table 2). In addition, deaths within 3 months occurred in 10%, 18%, and 29% of pts in Cohorts A, B, and C, respectively. The high early death rate compared with historical controls observed in HMA-naive HR-MDS patients (Cohort C) led to early termination of the study prior to completing recruitment. Biomarker assessment demonstrated PD-L1 expression on variable proportions of AML blasts in samples from all pts analyzed. However, PD-L1 expression was not associated with clinical response (Figure). Conclusions: Combination of atezolizumab plus azacitidine in HMA-naive HR-MDS pts had an unfavorable safety profile, which led to early termination. Limited responses were observed with atezo-based regimens (with or without azacitidine) in HMA-failure HR-MDS pts, without excessive or unexpected toxicity. Better understanding of the reasons associated with the differential toxicity profile observed between HMA-naive versus HMA-failure HR-MDS pts will be crucial for potential future developments of this combination. Disclosures Gerds: Incyte: Consultancy; Celgene: Consultancy; CTI Biopharma: Consultancy; Apexx Oncology: Consultancy. Khaled:Daiichi: Consultancy; Alexion: Consultancy, Speakers Bureau; Juno: Other: Travel Funding. Lin:Jazz Pharmaceuticals: Honoraria. Pollyea:AbbVie: Consultancy, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Curis: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees. Dail:Genentech: Employment, Equity Ownership. Green:Genentech: Employment. Ma:Genentech: Employment. Medeiros:Genentech: Employment, Equity Ownership. Phuong:Genentech Inc: Employment, Equity Ownership, Other: Ownership interests PLC. Wenger:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership, Other: Ownership interests PLC. Yan:Roche: Employment.

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The Oral Selective Inhibitor of Nuclear Export (SINE) Selinexor (KPT-330) Demonstrates Broad and Durable Clinical Activity in Relapsed / Refractory Non Hodgkin’s Lymphoma (NHL)

Blood ◽

10.1182/blood.v124.21.396.396 ◽

2014 ◽

Vol 124 (21) ◽

pp. 396-396 ◽

Cited By ~ 17

Author(s):

John Kuruvilla ◽

John C. Byrd ◽

Joseph M Flynn ◽

Ramiro Garzon ◽

Pierluigi Porcu ◽

...

Keyword(s):

Board Of Directors ◽

Nuclear Export ◽

Research Funding ◽

Phase 1 ◽

Single Agent ◽

Objective Response ◽

Employment Equity ◽

Advisory Committees ◽

Heavily Pretreated ◽

Equity Ownership

Abstract Background: The nuclear export protein, XPO1 is overexpressed in all types of malignant lymphoma. The SINE selinexor (KPT-330) is a slowly reversible XPO1 antagonist that forces the nuclear retention and activation of over 10 tumor suppressor proteins (TSP) such as p53, IkB, FOXO and p21. In addition, selinexor inhibits the nuclear export and the translation of oncogenic mRNAs such as c-myc and Bcl-XL levels. Together these effects result in apoptosis of cancer cells in preclinical models of both T- and B- cell NHL. In DLBCL cell lines (n=10), selinexor induced potent cytotoxicity against both germinal center (GCB) and nonGCB including those with high MYC and/or BCL2/6 protein levels. Methods: Selinexor was administered orally for 4-10 doses in a 28-day cycle in this phase 1 study. Serial tumor biopsies were performed. Response evaluation was performed in cycle 1 and 2 and then every 2 cycles. All pts had heavily pretreated NHL with documented progressive disease (PD) on study entry. Results: 58 pts (34 males 24 females; median age 62 yrs; ECOG PS 0/1/2: 19/35/4; median prior regimens: 3) received selinexor across 13 dose levels (3 to 80 mg/m2). The recommended Phase 2 dose is 60 mg/m2 based on results across all Phase 1 studies. Grade 3/4 events (>5%) include thrombocytopenia (31%), neutropenia (22%), fatigue (10%), and anemia (7%). The most common Grade 1/2 AEs were: nausea (66%), anorexia (47%), fatigue (40%), and vomiting (40%) that were manageable with supportive care and were seen less frequently following cycle 1. Increases in XPO1 mRNA levels were observed at all doses and sustained for 4-48 hours, supporting twice weekly dosing. Tumor biopsies confirmed TSP nuclear localization, c-myc reductions, and apoptosis induction of cancer cells. Objective responses were observed in all classes of NHL studied (Table 1). An objective response rate (ORR) of 31% was observed across all NHL types. An ORR of 40% was observed in pts with rel/ref aggressive B-NHL (DLBCL, Follicular NHL grade 3b (FLgrd3b) and transformed NHL) at doses ³60 mg/m2 vs an ORR of 33% at 23-50 mg/m2 and 25% at ²20 mg/m2. Across all NHL types, time to best response was delayed, including 5 complete responses (CR) (4 in DLBCL and 1 T-NHL). Nine pts out of 34 have remained on therapy for >6-23 months without clinically significant cumulative toxicities or major organ dysfunction. Conclusions: Selinexor treatment is generally well tolerated with supportive care and can be given over a prolonged period. Durable single agent activity in pts with heavily pretreated NHL has been observed. Phase 2 studies in DLBCL, Richter's transformation and T-NHL of single agent selinexor as well as in combination with other agents including CD20 antibodies are expected to begin in the near future. Abstract 396. Table 1 Cancer Type Selinexor Dose (mg/m2) N* ORR (%) CR (%) PR (%) SD (%) PD (%) WC/NE (%) Aggressive B-NHL (DLBCL, FLgrd3b, Transformed) ≤20 4 1 (25%) -- 1 (25%) 1 (25%) 2 (50%) -- 20 – 50 21 7 (33%) 4 (19%) 3 (14%) 5 (24%) 6 (29%) 3 (14%) ≥60* 10 4 (40%) -- 4 (40%) 4 (40%) -- 2 (20%) Follicular & Other Indolent NHL ≤30 4 -- -- -- 4 (100%) -- -- ≥35 4 2 (50%) -- 2 (50%) 1 (25%) -- 1 (25%) Mantle Cell Lymphoma ≤30 2 1 (50%) -- 1 (50%) 1 (50%) -- -- ≥35 2 -- -- -- -- 1 (50%) 1 (50%) T-Cell Lymphoma ≤30 4 -- -- -- 2 (50%) -- 2 (50%) ≥35 1 1 (100%) 1 (100%) -- -- -- -- Richter's Transformation ≤30 3 1 (33%) -- 1 (33%) 2 (67%) -- -- ≥35 3 1 (33%) -- 1 (33%) -- -- 2 (67%) TOTAL 58 18 (31%) 5 (9%) 13 (22%) 20 (34%) 9 (16%) 11 (19%) * First pt in this population was dosed on 23-July-2012 ORR=Objective Response Rate; CR=Complete Response; PR=Partial Response; SD=Stable Disease; PD=Progressive Disease; WC=Withdrew Consent; NE=Non-Evaluable Disclosures Byrd: Pharmacyclics, Genentech: Research Funding. Porcu:Infinity: Research Funding; Seattle genetics: Research Funding; Actelion: Honoraria; Celgene: Honoraria; United States Cutaneous Lymphoma Consortium: Membership on an entity's Board of Directors or advisory committees; Cutaneous Lymphoma Foundation: Membership on an entity's Board of Directors or advisory committees. Stone:AbbVie, Inc: Consultancy; Agios: Consultancy; Amgen: Consultancy; Celator: Consultancy; Celgene: Consultancy; Roche: Consultancy. Baz:Celgene: Research Funding; Millennium: Research Funding; Bristol Myers Squibb: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding. Flinn:AstraZeneca: Research Funding. Kukreti:Celgene: Honoraria. Landesman:Karyopharm Therapeutics: Employment. Klebanov:Karyopharm Therpeutics: Employment. Shacham:Karyopharm Therapeutics: Employment. Saint-Martin:Karyopharm Therpeutics: Employment. Marshall:Karyopharm Therpeutics: Employment. McCartney:Karyopharm Therpeutics: Employment. McCauley:Karyopharm Therapeutics: Employment, Equity Ownership. Carlson:Karyopharm Therapeutics: Employment. Norori:Karyopharm Therpeutics: Consultancy. Savona:Karyopharm Therpeutics: Membership on an entity's Board of Directors or advisory committees. Rashal:Karyopharm Therapeutics: Employment. Mirza:Karyopharm Therpeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kauffman:Karyopharm Therapeutics: Employment, Equity Ownership. Shacham:Karyopharm Therpeutics: Employment, Equity Ownership.

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A Retrospective Analysis of Pneumocystis Jirovecii Pneumonia Infection in Patients Receiving Idelalisib in Clinical Trials

Blood ◽

10.1182/blood.v128.22.3705.3705 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3705-3705 ◽

Cited By ~ 17

Author(s):

Laurie H Sehn ◽

Michael Hallek ◽

Wojciech Jurczak ◽

Jennifer R. Brown ◽

Paul M. Barr ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Pneumocystis Jirovecii Pneumonia ◽

Employment Equity ◽

Advisory Committees ◽

Increased Risk ◽

Equity Ownership ◽

Cd20 Antibody ◽

Anti Cd20 ◽

Support Research

Abstract Introduction: Opportunistic infections such as Pneumocystis jirovecii pneumonia (PJP) occur commonly in immunocompromised hosts such as patients (pts) with cancer (especially hematological malignancies such as chronic lymphocytic leukemia [CLL] and indolent non-Hodgkin lymphoma [iNHL]) or those receiving immunosuppressive therapies (such as steroids, chemotherapy). Recently, an increased risk of PJP infection was identified in 3 ongoing phase 3 studies evaluating idelalisib, administered in combination with the standard regimens rituximab (R) or bendamustine and rituximab (BR), in front-line CLL and early-line iNHL. Subsequently, a comprehensive analysis evaluating PJP infection across the clinical development program was performed to identify possible risk factors for developing PJP infection, including age, concomitant therapy (co-therapy) administered, geographic distribution of PJP infection, and regional use of prophylaxis. Methods: A retrospective analysis of 2198 pts receiving study treatment with idelalisib alone or in combination with co-therapy (anti-CD20 antibody or BR) and pts receiving only co-therapy (anti-CD20 ± bendamustine) (n = 1391 and 807, respectively) across 8 studies (frontline/relapsed CLL and relapsed iNHL) between 2010 and 2016 was performed. PJP infection was defined based on MedDRA high-level term of pneumocystis infections. In this analysis, other parameters were included for evaluation of risk of developing PJP infection-prophylaxis for PJP, geographic region, age, and CD4 count. Results: The overall incidence of PJP infection was 2.5% in pts on idelalisib ± co-therapy vs 0.2% in pts receiving only anti-CD20 antibody alone or BR alone (relative risk = 12.5). The median time to PJP event was 141 days since initiation of IDELA or co-therapy. The incidence of PJP infection was similar, irrespective of pt age. In the pt population receiving IDELA ± co-therapy - prophylaxis for PJP reduced the incidence of infection to 1.3% (from 3.4% in pts not receiving prophylaxis). Additionally, analysis by type of co-therapy received - the incidence of PJP infection was 2.2% vs 3.1% with IDELA + BR and IDELA + anti-CD20 alone respectively. A correlation between CD4 count (<200 cells/mcL) and an increased risk of PJP infection was not observed. Additional data are provided in Table 1. Conclusion: There is a small but increased risk of PJP infection during treatment with idelalisib within the clinical trial program. These data suggest that prophylaxis for PJP may reduce the risk of infection by as much as 60%. Administration of PJP prophylaxis is now recommended in all pts receiving treatment with idelalisib. Disclosures Sehn: roche/genentech: Consultancy, Honoraria; amgen: Consultancy, Honoraria; seattle genetics: Consultancy, Honoraria; abbvie: Consultancy, Honoraria; TG therapeutics: Consultancy, Honoraria; celgene: Consultancy, Honoraria; lundbeck: Consultancy, Honoraria; janssen: Consultancy, Honoraria. Hallek:Mundipharma: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau. Jurczak:Gilead Sciences: Research Funding; Celltrion, Inc: Research Funding; Janssen: Research Funding; Bayer: Research Funding; Acerta: Research Funding. Brown:Infinity: Consultancy; Gilead Sciences: Consultancy; Janssen: Consultancy; Pfizer: Consultancy; Sun BioPharma: Consultancy; Celgene: Consultancy; Roche/Genentech: Consultancy; Abbvie: Consultancy. Barr:Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Consultancy. Catalano:Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees. Coutre:Gilead Sciences: Consultancy, Research Funding. Furman:Gilead Sciences: Consultancy; Pharmacyclics: Consultancy, Speakers Bureau; Janssen: Consultancy; Genentech: Consultancy; Abbvie: Consultancy, Honoraria. Lamanna:Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Research Funding. Zelenetz:Gilead Sciences: Research Funding. Sharman:Gilead Sciences, Inc.: Honoraria, Research Funding. Adewoye:Gilead Sciences: Employment, Equity Ownership. Kim:Gilead Sciences: Employment, Equity Ownership. Flinn:Janssen: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Gilead Sciences: Research Funding; ARIAD: Research Funding; RainTree Oncology Services: Equity Ownership. Salles:Gilead: Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria, Research Funding; Mundipharma: Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria.

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