Safety and Preliminary Efficacy Results of a Phase I First-in-Human Study of the Novel Notch-1 Targeting Antibody Brontictuzumab (OMP-52M51) Administered Intravenously to Patients with Hematologic Malignancies

Abstract Background: The Notch pathway plays a key role in embryonic development and regulation of stem and progenitor cells, and is implicated in human cancer. Notch1 (N1) signaling is activated by various mechanisms including N1 activating mutations in certain hematologic tumors such as chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), diffuse large B cell lymphoma (DLBCL). Brontictuzumab (BRON) is a humanized IgG2 antibody that inhibits the signaling function of N1. As such, BRON is a novel anti-cancer agent that inhibits tumor growth through direct actions on tumor cells, including cancer stem cells, and tumor angiogenesis. Materials and methods: A phase I dose escalation and expansion study was initiated in patients (pts) with previously treated CLL, MCL, DLBCL, anaplastic large cell lymphoma (ALCL), transformed mycosis fungoides (TMF), Sezary Syndrome (SS), T-cell acute lymphoblastic leukemia (T-ALL), or other hematologic malignancies with known N1 activating mutation. BRON was administered intravenously to study safety, pharmacokinetics (PK), pharmacodynamics, preliminary efficacy, and to determine the maximum tolerated dose (MTD). Clinical trial information: NCT01778439. Results: Twenty-four pts were enrolled and 23 pts have been treated in 4 dose escalation cohorts at doses of 0.25 mg/kg every 4 weeks (Q4W), 0.5 mg/kg Q4W, 1 mg/kg Q4W, and 1 mg/kg every 2 weeks (Q2W). Tumor types included DLBCL (6 pts), CLL (5 pts), TMF (5 pts), MCL (4 pts), and one each with T-ALL, T-cell prolymphocytic leukemia (T-PLL), and follicular lymphoma (FL). Two pts experienced dose-limiting toxicity (DLTs) adverse events at the 1.0 mg/kg Q2W dose cohort: one pt had gr 5 acute renal failure in the setting of tumor lysis (1 mg/kg Q2W) and 1 pt had gr 3 diarrhea and gr3 acute on chronic renal failure (1 mg/kg Q2W). The most frequent treatment-related adverse events (AE) of any grade were: diarrhea (22%), fatigue (17%), anemia (13%), abdominal pain (9%), nausea (9%), vomiting (9%), peripheral edema (9%), increased bilirubin (9%), decreased appetite (9%), hypokalemia (9%), and acute renal failure (9%). One pt with TMF had partial response to treatment, after receiving 1 mg/kg Q2W. Two additional pts had stable disease as best overall response (1 with MCL, and 1 with TMF). Five of the 24 pts had N1 mutations that were predicted to be deleterious and 3 pts had unknown N1 mutation status. Of the 5 patients with N1 mutations, 3 had classical frame shift mutations in the N1 PEST domain and are validated to be activating mutations and 2 had mutations in EGF-like domain where the mutation significance is unknown. Of the three patients with known N1 activating mutations, 1 pt was treated at 0.25 mg/kg Q4W and had progressive disease at first assessment, 1 pt never received study drug, and 1 pt treated at 1 mg/kg Q2W had stable disease as best response and was on study 101 days. Conclusions: BRON is generally well tolerated and had moderate anti-tumor activity. Diarrhea is the primary toxicity of this antibody. The MTD has not been established. Updated efficacy, safety, N1 intracellular domain expression status, and PK results will be presented. Disclosures Casulo: Infinity: Consultancy, Honoraria; Celgene: Research Funding. Dang:Pharmacyclics LLC, an AbbVie Company: Research Funding; Seattle Genetics: Research Funding; Novartis: Honoraria; Eisai: Research Funding; Valor: Research Funding; Oncomed Pharmaceuticals Inc: Research Funding. Diefenbach:Gillead: Equity Ownership; BMS: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Research Funding. Porcu:miRagen: Other: Investigator in a clinical trial; celgene: Other: Investigator in a clinical trial; Innate Pharma: Other: Investigator in a clinical trial; Millenium: Other: investigator in a clinical trial. Faoro:OncoMed Pharmaceuticals: Employment, Equity Ownership. Dupont:OncoMed Pharmaceuticals: Employment, Equity Ownership. Kapoun:OncoMed Pharmaceuticals: Employment, Equity Ownership. Wang:OncoMed Pharmaceuticals: Employment, Equity Ownership. McGuire:OncoMed Pharmaceuticals: Employment, Equity Ownership. Flinn:Janssen: Research Funding; Gilead Sciences: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; ARIAD: Research Funding; RainTree Oncology Services: Equity Ownership.

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Blinatumomab Monotherapy Shows Efficacy in Patients with Relapsed Diffuse Large B Cell Lymphoma

Blood ◽

10.1182/blood.v118.21.1637.1637 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1637-1637 ◽

Cited By ~ 8

Author(s):

Andreas Viardot ◽

Mariele Goebeler ◽

Richard Noppeney ◽

Stefan W. Krause ◽

Stefan Kallert ◽

...

Keyword(s):

Adverse Events ◽

B Cell ◽

Phase Ii ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Employment Equity ◽

Large B Cell Lymphoma ◽

Equity Ownership ◽

Large B Cell

Abstract Abstract 1637 Blinatumomab (MT103) is a single-chain bispecific antibody construct with specificity for CD19 and CD3 belonging to the class of bispecific T cell engager (BiTE®). A phase I trial with indolent and mantle cell lymphoma patients established a maximal tolerable dose (MTD) at 60 μg/m2/d. The trial was subsequently amended to evaluate blinatumomab in patients with diffuse large B cell lymphoma (DLBCL). Patients were treated by 4–8-week continuous i.v. administration with the following dosing regimen: first week at 5 μg/m2/d, second week at 15 μg/m2/d and for the remaining treatment period at 60 μg/m2/d. Two cohorts each with 6 DLBCL patients were enrolled. The two cohorts solely differed by the dose and schedule of corticosteroid medication administered at the beginning of blinatumomab infusion for mitigation of adverse events. In the first cohort 100 mg prednisolone was applied 1 hour prior to start; and in the second cohort patients received dexamethasone on days 1, 2, and 3. Three sequential patients received dexamethasone also 6–12 hours prior to start of infusion. Out of the twelve patients, 5 were male and 7 female. The median age was 57 years (range from 26 to 78 years). Patients had received a median of 4 prior regimens (range from 2–6). All patients had been exposed to rituximab. Eight of the 12 patients had undergone autologous stem cell transplantation (ASCT). International prognostic index (IPI) at screening ranged from 1 to 3 with a median of 2. The most common clinical adverse events (AEs) regardless of causality (>30%) were pyrexia (81.8%), fatigue (54.5%), constipation (36.4%), headache (36.4%), tremor (36.4%) and weight increase (36.4%). The most frequent laboratory AEs regardless of causality (>30%) were hyperglycemia (63.6%), lymphopenia (54.5%), C-reactive protein increase (45.5%), gamma-glutamyltransferase increase (45.5%) and thrombocytopenia (36.4%). Most AEs occurred early and were reversible. Four of 12 patients discontinued infusion due to fully reversible CNS events, 2 of which qualified as dose limiting toxicities (DLTs). Although just one DLT (reversible CNS event grade 3) occurred in the prednisolone cohort, a further cohort applying prophylactic dexamethasone was opened to optimize management of CNS events. A further refinement of the dexamethasone schedule, starting longer time prior to start of blinatumomab, was introduced after one early patient in the cohort receiving dexamethasone had experienced a reversible CNS event leading to discontinuation. All three patients treated in this manner completed the first blinatumomab cycle without discontinuations. Only one showed a grade 1 tremor, and no other CNS AEs were reported in these three patients. Two of 12 patients were not exposed to 60 μg/m2/d due to early discontinuations and 1 patient is too early in treatment for response evaluation. Five out of the remaining 9 evaluable patients (56%) showed objective clinical responses (4 CR/CRu; 1 PR). Three out of the 5 patients with CR/CRu or PR had prior ASCT. Two patients achieved objective responses (1 CR, 1 PR) despite of discontinuation at 60 μg/m2/d. The median response duration is +182 days (longest current duration +428 days), with 4 out of 5 responses still ongoing. Further evaluation of the last cohort will refine the recommended phase II dose, and the intensity and timing of dexamethasone comedication. The observation of lasting CRs after blinatumomab monotherapy in DLBCL patients is promising and warrants further exploration in a phase II study. Disclosures: Krause: Micromet: Research Funding. Mackensen:Micromet Inc.: Research Funding. Topp:Micromet: Consultancy, Honoraria. Scheele:Micromet Inc.: Employment, Equity Ownership, Patents & Royalties. Nagorsen:Micromet Inc.: Employment, Equity Ownership, Patents & Royalties. Zugmaier:Micromet: Employment. Degenhard:Micromet Inc: Employment. Schmidt:Micromet AG: Employment. Kufer:Micromet Inc: Employment, Equity Ownership. Libicher:Micromet Inc.: Consultancy, Honoraria. Bargou:Micromet: Consultancy, Honoraria.

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Rapid and Robust Mobilization of CD34+ HSCs without G-CSF Following Administration of Mgta-145 Alone or in Combination with Plerixafor

Blood ◽

10.1182/blood-2019-127523 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1961-1961

Author(s):

John F. DiPersio ◽

Jonathan Hoggatt ◽

Steven Devine ◽

Lukasz Biernat ◽

Haley Howell ◽

...

Keyword(s):

Single Dose ◽

Adverse Events ◽

Board Of Directors ◽

Preliminary Data ◽

Research Funding ◽

Fold Change ◽

Employment Equity ◽

Advisory Committees ◽

Cd34 Cells ◽

Equity Ownership

Background Granulocyte colony-stimulating factor (G-CSF) is the standard of care for mobilization of hematopoietic stem cells (HSCs). G-CSF requires 4-7 days of injections and often multiple aphereses to acquire sufficient CD34+ cells for transplant. The number of CD34+ HSCs mobilized can be variable and patients who fail to mobilize enough CD34+ cells are treated with the combination of G-CSF plus plerixafor. G-CSF use is associated with bone pain, nausea, headaches, fatigue, rare episodes of splenic rupture, and is contraindicated for patients with autoimmune and sickle cell disease. MGTA-145 (GroβT) is a CXCR2 agonist. MGTA-145, in combination with plerixafor, a CXCR4 inhibitor, has the potential to rapidly and reliably mobilize robust numbers of HSCs with a single dose and same-day apheresis for transplant that is free from G-CSF. MGTA-145 plus plerixafor work synergistically to rapidly mobilize HSCs in both mice and non-human primates (Hoggatt, Cell 2018; Goncalves, Blood 2018). Based on these data, Magenta initiated a Phase 1 dose-escalating study to evaluate the safety, PK and PD of MGTA-145 as a single agent and in combination with plerixafor. Methods This study consists of four parts. In Part A, healthy volunteers were dosed with MGTA-145 (0.0075 - 0.3 mg/kg) or placebo. In Part B, MGTA-145 dose levels from Part A were selected for use in combination with a clinically approved dose of plerixafor. In Part C, a single dose MGTA-145 plus plerixafor will be administered on day 1 and day 2. In Part D, MGTA-145 plus plerixafor will be administered followed by apheresis. Results MGTA-145 monotherapy was well tolerated in all subjects dosed (Table 1) with no significant adverse events. Some subjects experienced mild (Grade 1) transient lower back pain that dissipated within minutes. In the ongoing study, the combination of MGTA-145 with plerixafor was well tolerated, with some donors experiencing Grade 1 and 2 gastrointestinal adverse events commonly observed with plerixafor alone. Pharmacokinetic (PK) exposure and maximum plasma concentrations increased dose proportionally and were not affected by plerixafor (Fig 1A). Monotherapy of MGTA-145 resulted in an immediate increase in neutrophils (Fig 1B) and release of plasma MMP-9 (Fig 1C). Neutrophil mobilization plateaued within 1-hour post MGTA-145 at doses greater than 0.03 mg/kg. This plateau was followed by a rebound of neutrophil mobilization which correlated with re-expression of CXCR2 and presence of MGTA-145 at pharmacologically active levels. Markers of neutrophil activation were relatively unchanged (<2-fold vs baseline). A rapid and statistically significant increase in CD34+ cells occurred @ 0.03 and 0.075 mg/kg of MGTA-145 (p < 0.01) relative to placebo with peak mobilization (Fig 1D) 30 minutes post MGTA-145 (7-fold above baseline @ 0.03 mg/kg). To date, the combination of MGTA-145 plus plerixafor mobilized >20/µl CD34s in 92% (11/12) subjects compared to 50% (2/4) subjects receiving plerixafor alone. Preliminary data show that there was a significant increase in fold change relative to baseline in CD34+ cells (27x vs 13x) and phenotypic CD34+CD90+CD45RA- HSCs (38x vs 22x) mobilized by MGTA-145 with plerixafor. Mobilized CD34+ cells were detectable at 15 minutes with peak mobilization shifted 2 - 4 hours earlier for the combination vs plerixafor alone (4 - 6h vs 8 - 12h). Detailed results of single dose administration of MGTA-145 and plerixafor given on one day as well as also on two sequential days will be presented along with fully characterized graft analysis post apheresis from subjects given MGTA-145 and plerixafor. Conclusions MGTA-145 is safe and well tolerated, as a monotherapy and in combination with plerixafor and induced rapid and robust mobilization of significant numbers of HSCs with a single dose in all subjects to date. Kinetics of CD34+ cell mobilization for the combination was immediate (4x increase vs no change for plerixafor alone @ 15 min) suggesting the mechanism of action of MGTA-145 plus plerixafor is different from plerixafor alone. Preliminary data demonstrate that MGTA-145 when combined with plerixafor results in a significant increase in CD34+ fold change relative to plerixafor alone. Magenta Therapeutics intends to develop MGTA-145 as a first line mobilization product for blood cancers, autoimmune and genetic diseases and plans a Phase 2 study in multiple myeloma and non-Hodgkin lymphoma in 2020. Disclosures DiPersio: Magenta Therapeutics: Equity Ownership; NeoImmune Tech: Research Funding; Cellworks Group, Inc.: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Consultancy; Incyte: Consultancy, Research Funding; RiverVest Venture Partners Arch Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; WUGEN: Equity Ownership, Patents & Royalties, Research Funding; Macrogenics: Research Funding, Speakers Bureau; Bioline Rx: Research Funding, Speakers Bureau; Celgene: Consultancy; Amphivena Therapeutics: Consultancy, Research Funding. Hoggatt:Magenta Therapeutics: Consultancy, Equity Ownership, Research Funding. Devine:Kiadis Pharma: Other: Protocol development (via institution); Bristol Myers: Other: Grant for monitoring support & travel support; Magenta Therapeutics: Other: Travel support for advisory board; My employer (National Marrow Donor Program) has equity interest in Magenta. Biernat:Medpace, Inc.: Employment. Howell:Magenta Therapeutics: Employment, Equity Ownership. Schmelmer:Magenta Therapeutics: Employment, Equity Ownership. Neale:Magenta Therapeutics: Employment, Equity Ownership. Boitano:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Cooke:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Goncalves:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Raffel:Magenta Therapeutics: Employment, Equity Ownership. Falahee:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Morrow:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Davis:Magenta Therapeutics: Employment, Equity Ownership.

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Safety and Tolerability of Conatumumab in Combination with Bortezomib or Vorinostat in Patients with Relapsed or Refractory Lymphoma.

Blood ◽

10.1182/blood.v114.22.1708.1708 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1708-1708 ◽

Cited By ~ 3

Author(s):

Anas Younes ◽

Mark Kirschbaum ◽

Lubomir Sokol ◽

Lorrin Yee ◽

Jorge Romaguera ◽

...

Keyword(s):

Research Funding ◽

Cell Lymphoma ◽

Death Receptor ◽

Large Cell ◽

Employment Equity ◽

Expansion Phase ◽

Mantle Cell ◽

Equity Ownership ◽

Refractory Lymphoma ◽

Grade 3

Abstract Abstract 1708 Poster Board I-734 Conatumumab is an investigational, fully human, monoclonal antibody agonist of human death receptor 5 (DR5 [TRAIL receptor 2]) that activates caspases and triggers apoptosis in sensitive tumor cells. DR5 is expressed by a variety of lymphoma cell lines, and TRAIL receptor agonists have been shown to induce apoptosis in lymphoma cells and lymphoma xenografts. Bortezomib and vorinostat are active and approved agents in certain lymphoma subtypes. In addition, they enhance death receptor-mediated apoptosis in multiple tumor models. In this 2-part study, we evaluated conatumumab in combination with bortezomib or vorinostat to treat patients (pts) with relapsed or refractory lymphoma. The dose-escalation phase evaluated the safety and tolerability of escalating doses of conatumumab in combination with bortezomib or vorinostat; the dose-expansion phase was designed to estimate the efficacy of conatumumab plus bortezomib in pts with mantle cell lymphoma (MCL). Here we present data from the dose-escalation phase. Eligibility criteria included: relapsed or refractory low-grade lymphoma, mantle cell lymphoma (MCL), diffuse large cell lymphoma, or Hodgkin lymphoma; age ≥ 18 years; informed consent; ECOG performance status of 0 or 1; life expectancy of > 3 months; adequate organ function; no prior treatment with bortezomib or vorinostat; no evidence of CNS involvement by lymphoma; and no primary CNS lymphoma. Three to 6 pts were enrolled into 1 of 3 sequential dose cohorts (1.5, 5, or 15 mg/kg) of conatumumab administered intravenously every 3 weeks (on day 1 of every 21-day cycle) in combination with either bortezomib (1.3 mg/m2 IV twice weekly for 2 weeks followed by a 10-day rest period) or vorinostat (400 mg orally daily). Endpoints included safety, maximum tolerated dose (MTD) of conatumumab, pharmacokinetics (PK) of conatumumab, incidence of anti-conatumumab antibodies, and best tumor response (complete response [CR] and partial response [PR]). CRs were confirmed by FDG-PET and bone marrow biopsy per Cheson criteria (2007). Monocyte DR5 occupancy by conatumumab was determined as an exploratory endpoint. As of July 9, 2009, 27 pts were enrolled and 23 received ≥1 dose of conatumumab: 3, 3, and 6 pts at 1.5, 5, and 15 mg/kg conatumumab + bortezomib; 7, 3, and 1 pt at 1.5, 5, and 15 mg/kg conatumumab + vorinostat. 15 pts were men; median (range) age was 53 (23 to 81) years; ECOG PS 0 = 65%, 1 = 26%, unknown = 9%; disease stage I = 4%, II = 4%, III = 39%, IV = 48%, unknown = 4%. Nine pts are still receiving treatment. The most common treatment-emergent adverse events (AE) were: fatigue (13 pts), diarrhea (9 pts), constipation (8 pts), nausea (8 pts), thrombocytopenia (8 pts), headache (7 pts), anemia (5 pts), dizziness (5 pts), and peripheral neuropathy (5 pts). A total of 6 and 3 pts reported worst grade 3 and 4 AEs, respectively, with no apparent differences between the 2 drug combinations. There were 2 DLTs: grade 3 prolonged Qt at 1.5 mg/kg conatumumab + vorinostat and grade 4 pulmonary embolism at 15 mg/kg conatumumab + bortezomib. An MTD has not been reached. Anti-conatumumb antibodies have not been detected in any pt. After one dose of conatumumab at 1.5, 5, or 15 mg/kg after bortezomib or vorinostat, conatumumab exposures were slightly higher (< 2-fold) than those in the first-in-human monotherapy study, indicating minimal effect of bortezomib or vorinostat on PK of conatumumab. Two pts had a confirmed CR: 1 pt with diffuse large cell lymphoma (1.5 mg/kg vorinostat cohort) at day 97 and 1 pt with nodular sclerosis Hodgkin lymphoma (5 mg/kg vorinostat cohort) at day 169. Thirteen pts had stable disease as their best objective response, 10 of whom had tumor shrinkage (range [based on sum of nodal and extra-nodal at each visit], -1.74% to -68.24%]). Receptor occupancy data will be presented. The combination of conatumumab with either bortezomib or vorinostat did not result in an unacceptable rate of dose-limiting toxicities and showed preliminary evidence of anti-tumor activity in pts with relapsed or refractory lymphoma. The expansion phase in pts with MCL treated with conatumumab plus bortezomib is currently enrolling. Disclosures Younes: Seattle Genetics: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Abbott Oncology: Consultancy; Genentech: Consultancy, Honoraria, Research Funding; Allos Therapeutics : Consultancy; Gloucester Pharm: Consultancy; Amgen: Consultancy, Honoraria, Research Funding; Tiba Oncology: Consultancy; Trubion Pharmaceuticals: Consultancy; Sanofi-Aventis: Honoraria, Research Funding; Methylgene: Honoraria, Research Funding; Pharmion: Honoraria, Research Funding; Xencor: Honoraria, Research Funding; Biogen Idec: Honoraria, Research Funding. Kirschbaum:Merck: Research Funding, Speakers Bureau. Romaguera:Wyeth: Research Funding; Millenium: Research Funding; Celgene: Research Funding. Goyal:Amgen Inc.: Employment, Equity Ownership. Hsu:Amgen Inc.: Employment, Equity Ownership. Hwang:Amgen Inc.: Employment, Equity Ownership. Gorski:Amgen Inc.: Employment, Equity Ownership. Wong:Amgen Inc.: Employment, Equity Ownership. Beaupre:Amgen Inc.: Employment, Equity Ownership.

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A Phase I/II Study of Lenalidomide in Combination with Rituximab in Relapsed/Refractory Mantle Cell Lymphoma.

Blood ◽

10.1182/blood.v114.22.2719.2719 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2719-2719 ◽

Cited By ~ 2

Author(s):

Luhua Wang ◽

Luis Fayad ◽

Fredrick B. Hagemeister ◽

Sattva Neelapu ◽

Felipe Samaniego ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Research Funding ◽

Cell Lymphoma ◽

Phase 1 ◽

Progression Free Survival ◽

Phase 2 ◽

Employment Equity ◽

Mantle Cell ◽

Equity Ownership ◽

Grade 3

Abstract Abstract 2719 Poster Board II-695 Background: Rituximab directly targets CD20 positive lymphoma cells while lenalidomide targets the microenvironment. This combination was proven effective in vitro and in vivo in mantle cell lymphoma (Wu et al, Clin Cancer Res 2008; Zhang et al, Am J Hematol 2009). Clinically, lenalidomide (Habermann et al, Br J Haematol 2009) and rituximab have single-agent activity in mantle cell lymphoma (MCL) and may be an effective combination. The goal of our study was to determine the maximum tolerated dose (MTD) in phase 1 and evaluate the efficacy and safety of lenalidomide plus rituximab in patients with relapsed/refractory MCL in phase 2. Methods: Patients with relapsed/refractory MCL received lenalidomide on days 1–21 of every 28-day cycle, and rituximab (375 mg/m2) weekly during cycle 1. Dose escalation was used to determine the MTD with lenalidomide (10 mg, 15 mg, 20 mg, and 25 mg). Dose-limiting toxicity (DLT) was defined as grade 3 or 4 non-hematologic, or grade 4 hematologic adverse events in cycle 1. Phase 2 has reached targeted enrolment with 45 patients treated at MTD. Kaplan-Meier method was used to estimate progression free survival rate and response duration. Median time to event in months with 95% confidence interval was calculated. Of 45 patients treated at the MTD, the median age was 66 (46–85), 91% were males. All patients had received prior rituximab and were enrolled regardless of prior rituximab sensitivity or resistance. Results: The median follow-up time for the censored observations was 11.4 months. Two DLTs occurred at 25 mg in phase 1 (hypercalcemia, non-neutropenic fever); therefore, the MTD was 20 mg. The grade 3–4 non-hematologic events included elevated AST, elevated ALT, fatigue, myalgia, tremors, ataxia, cough, deep vein thrombosis, dyspnea, edema (facial), infection, neuropathy sensory, rash, and respiratory failure. Grade 3–4 hematologic adverse events included neutropenia (37 events), neutropenic fever (4 events), and thrombocytopenia (16 events). There were no responses in patients treated at 10 mg or 15 mg. Thirty six patients (36) were evaluable for response. Nine (9) patients are too early in their treatment and are not yet eligible for response evaluation. Among the 36 evaluable patients, 11 (31%) patients achieved CR, 8 (22%) patients achieved PR, 3 (8%) patients had minor response, 6 (17%) patients had stable disease and 8 (22%) patients had progressive mantle cell lymphoma. The overall response rate (CR + PR) was 53%. Seventy eight (78%) patients achieved stable disease or better and benefited from oral Lenalidomide plus 4 doses of rituximab. The median time to response was 2 months (2–8), and the median duration of response for the 19 patients with CR or PR was 18 months (95% CI: 10.6, NA) (range1–30 months). The median progression free survival for all patients on phase 2 was 14 months (95% CI: 9.8, NA) (ranging from 1–32 months). Conclusion: Oral lenalidomide plus rituximab resulted in durable responses in relapsed/refractory MCL with a favourable toxicity profile. Disclosures: Wang: Celgene: Honoraria, Research Funding. Hagemeister:Celgene Corporation: Consultancy. Samaniego:Celgene Corporation: Research Funding. Yi:Celgene Corporation: Research Funding. Shah:Celgene Corporation: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Elan: Consultancy; Millennium: Research Funding, Speakers Bureau. Bell:Celgene Corporation: Employment, Equity Ownership. Knight:Celgene Corporation: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Zeldis:Celgene: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

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

Blood ◽

10.1182/blood.v118.21.602.602 ◽

2011 ◽

Vol 118 (21) ◽

pp. 602-602 ◽

Cited By ~ 3

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.

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Safety and Immunogenicity Of Inactivated Varicella-Zoster Virus Vaccine In Adults With Hematologic Malignancies Receiving Treatment With Anti-CD20 Monoclonal Antibodies

Blood ◽

10.1182/blood.v122.21.2290.2290 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2290-2290

Author(s):

Shelly McNeil ◽

Robert Betts ◽

Steven Lawrence ◽

Andrea Velardi ◽

Eva Kimby ◽

...

Keyword(s):

Immune Response ◽

Monoclonal Antibodies ◽

Research Funding ◽

Hematologic Malignancies ◽

Employment Equity ◽

Varicella Zoster ◽

Cell Responses ◽

Equity Ownership ◽

Ifn Γ ◽

Anti Cd20

Abstract Background Herpes zoster (HZ) incidence is higher in patients with hematologic malignancies (HM) (25-100 cases/1000 person-years) than in the general population (3-5 cases/1000 person-years). This immunocompromised population can experience significant morbidity and occasional mortality from complications associated with reactivation of the varicella-zoster virus (VZV). In general, there is limited data in the literature regarding the effect of anti-CD20 monoclonal antibodies, used in treatment of HM patients, on vaccine-related cell-mediated immune response. Due to the potential negative impact of anti-CD20 monoclonal antibodies on vaccine immunogenicity and efficacy, HM patients receiving anti-CD20 monoclonal antibodies have been excluded from prior inactivated VZV vaccine (inactivated-ZV) studies. This study evaluated the safety and immunogenicity of inactivated-ZV in HM patients receiving anti-CD20 monoclonal antibody therapy. Methods This was an open label, single arm, multicenter Phase I study of a 4-dose inactivated-ZV regimen (∼30 days between each dose) in patients ≥18 years old with HM receiving anti-CD20 monoclonal antibodies either as a single agent or in a combination chemotherapy regimen and not likely to undergo HCT (n=80). Blood samples were collected at baseline prior to dose 1 and 28 days postdose 4 to measure VZV-specific T-cell responses using interferon-gamma enzyme-linked immunospot (IFN-γ ELISPOT). The primary hypothesis was that inactivated-ZV would elicit significant VZV-specific immune responses at ∼28 days postdose 4, with the statistical criterion being that the lower bound of the two-sided 90% confidence interval (CI) on the geometric fold rise (GMFR) be >1.0. All vaccinated patients were evaluated for adverse events (AE), including VZV-like rashes, through 28 days postdose 4. Results The 4-dose inactivated-ZV regimen elicited a statistically significant VZV-specific immune response measured by IFN-γ ELISPOT at 28 days postdose 4 in the per-protocol population (GMFR = 4.34 [90% CI: 3.01, 6.24], p-value <0.001). As the lower bound of the 2-sided 90% CI for GMFR was >1.0, the pre-specified primary immunogenicity success criterion was met. Overall, 85% (68/80) of patients reported ≥1 AEs, 44% (35/80) reported ≥1 injection-site AEs, and 74% (59/80) reported ≥1 systemic AEs. The most common injection-site AEs were pain (32%), erythema (31%), and swelling (26%). The most common systemic AEs were pyrexia (25%) and diarrhea (14%). Twelve patients (15%) experienced serious AEs, including one event determined by the investigator to be vaccine-related (convulsion: day 8 postdose 1). One patient experienced a fatal serious AE (Richter’s transformation to Hodgkin’s disease; day 34 postdose 1) assessed as not vaccine-related by the investigator. In general, the frequencies of AEs did not increase with subsequent doses of vaccine. No inactivated-ZV recipient had a rash that was PCR positive for VZV vaccine strain. Conclusions In adults with HM receiving anti-CD20 monoclonal antibodies, inactivated-ZV was well tolerated and elicited statistically significant VZV-specific T-cell responses ∼28 days postdose 4. Disclosures: McNeil: Merck: investigator Other, Research Funding. Betts:Merck: investigator Other, Research Funding. Lawrence:Merck: investigator Other, Research Funding. Velardi:Merck: investigator Other, Research Funding. Kimby:Merck: investigator Other, Research Funding. Pagnoni:Merck: Employment, Equity Ownership. Stek:Merck: Employment, Equity Ownership. Zhao:Merck: Employment, Equity Ownership. Chan:Merck: Employment, Equity Ownership. Lee:Merck: Employment, Equity Ownership. Parrino:Merck: Employment, Equity Ownership.

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TGR-1202, a Novel Once Daily PI3Kδ Inhibitor, Demonstrates Clinical Activity with a Favorable Safety Profile, Lacking Hepatotoxicity, in Patients with Chronic Lymphocytic Leukemia and B-Cell Lymphoma

Blood ◽

10.1182/blood.v124.21.1984.1984 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1984-1984 ◽

Cited By ~ 14

Author(s):

Howard A. Burris ◽

Manish R. Patel ◽

Danielle M. Brander ◽

Owen A. O'Connor ◽

Changchun Deng ◽

...

Keyword(s):

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Hematologic Malignancies ◽

Tumor Burden ◽

Lymphocytic Leukemia ◽

Clinical Activity ◽

Employment Equity ◽

Previous Formulation ◽

Equity Ownership

Abstract Background: TGR-1202 is a novel oral, next generation PI3Kδ inhibitor which notably lacks the hepatotoxicity associated with other PI3Kδ inhibitors. Preliminary data from an ongoing Ph I study of TGR-1202 demonstrated clinical activity in patients with advanced hematologic malignancies (ASCO 2014). Herein we present updated results from this Phase I, first in human study of TGR-1202 in patients with relapsed and/or refractory CLL and B-cell lymphoma. Methods: TGR-1202 is administered orally once daily following a 3+3 dose escalation design. Previously treated patients with an ECOG PS ≤ 2 and confirmed diagnosis of B-cell non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), or other lymphoproliferative disorders are eligible. Endpoints include safety, PK/PD, and efficacy. Results: 49 patients have been enrolled to date of various lymphoma subtypes including CLL, follicular lymphoma (FL), Hodgkin’s lymphoma (HL), DLBCL, mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL). Demographics: 76% male, ECOG 0/1/2: 17/31/1, median age of 59 yrs (range: 22-85), median prior treatment regimens: 3 (range: 1-14), and 43% were refractory to prior treatment. 35 patients have been treated at doses ≥ 800 mg of a previous formulation where a threshold effect in activity was observed, and 6 have been treated with an improved micronized formulation (≥ 200 mg). TGR-1202 was well tolerated and no MTD has been reached to date. The only Gr≥3 AE occurring in >5% of patients was neutropenia (8%). AE’s of all grades occurring in >20% of patients were limited to diarrhea (24%), cough (22%), fatigue (20%), and nausea (20%). Notably, in comparison to other PI3Kδ inhibitors, no hepatotoxicity and no cases of colitis have been observed to date. Rates of infection and pneumonia have also been low (12% and 6%, respectively), and no cases of febrile neutropenia have been reported. Of the 41 patients treated at ≥ 800 mg of the previous formulation or with the micronized formulation, 32 are evaluable for efficacy (6 too early to evaluate, 2 non-compliant, 1 did not meet I/E criteria). Responses have been limited in patients with aggressive lymphoma and HL. Of the 9 evaluable CLL patients, 8 (89%) achieved a nodal PR (median nodal reduction of 71%), of which 5 achieved a PR per Hallek 2008 criteria with the remaining 4 having persistent lymphocytosis. The 1 CLL patient with SD had a >40% nodal reduction and remains on study. Of the 7 evaluable FL patients, all have shown clinical benefit with a reduction in tumor burden with 2 having achieved a PR, and the remaining 5 patients in SD. Additionally 2 MZL patients each achieved SD with >25% nodal reductions and remain on study. Notably, no patient with CLL or indolent lymphoma (FL & MZL) treated at ≥800 mg has progressed to date (median time on study of 20 weeks, range 6 – 73+), and no patient who achieved >50% reduction in tumor burden (including patients with CLL, FL, and HL) has progressed, with median time on study of 34 weeks (range 7 – 68+). Pharmacodynamic analysis in CLL patients indicates rapid suppression of pAKT at doses of 400 mg QD of the previous formulation. Conclusions: TGR-1202 is well tolerated in patients with relapsed and/or refractory hematologic malignancies with no reported hepatotoxicity or events of colitis and promising clinical activity. Enrollment continues in expansion cohorts and with the micronized formulation. Disclosures Brander: Celgene: Mentor received research funding Other. O'Connor:Celgene: Consultancy; Millennium Pharmaceuticals: Consultancy. Miskin:TG Therapeutics, Inc.: Employment, Equity Ownership. Sportelli:TG Therapeutics: Employment, Equity Ownership. Vakkalanka:Rhizen: Employment, Equity Ownership. Flinn:Infinity Pharmaceuticals: Consultancy.

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

Blood ◽

10.1182/blood.v126.23.3980.3980 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3980-3980 ◽

Cited By ~ 4

Author(s):

Kathryn Kolibaba ◽

John M. Burke ◽

Heather D. Brooks ◽

Daruka Mahadevan ◽

Jason Melear ◽

...

Keyword(s):

Atrial Fibrillation ◽

Monoclonal Antibody ◽

Mantle Cell Lymphoma ◽

Research Funding ◽

Cell Lymphoma ◽

Employment Equity ◽

Highly Active ◽

Mantle Cell ◽

Equity Ownership ◽

Anti Cd20

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 ADCC than rituximab and ofatumumab. In patients (pts) with rel/ref CLL, the combination of UTX with ibrutinib was well-tolerated and highly active demonstrating an 88% ORR (95% ORR in high-risk CLL) with responses attained rapidly (median time to iwCLL response of 8 weeks). Ibrutinib has demonstrated single agent activity in Mantle Cell Lymphoma (MCL), achieving a 68% ORR (21% CR) in a single arm trial in relapsed or refractory patients (Wang et al, NEJM 2013). Herein we report on the first combination of ibrutinib with a glycoengineered anti-CD20 mAb, UTX, in patients with Mantle Cell Lymphoma (MCL). Methods: Eligible patients had rel/ref MCL with an ECOG PS < 3. Prior ibrutinib treatment was permitted. UTX (900 mg) was administered on Days 1, 8, and 15 in Cycle 1 followed by Day 1 of Cycles 2 - 6. Ibrutinib was started on Day 1 and continued daily at 560 mg. Following Cycle 6, patients came off study but could remain on ibrutinib. Primary endpoints were safety and ORR with an emphasis on early activity with response assessments by CT scan scheduled prior to cycles 3 and 6 only (criteria per Cheson 2007). Results: 15 patients were enrolled: 13 M/2 F, median age 71 yr (range 55-80), ECOG 0/1: 9/6, median prior Tx = 3 (range 1-8), 53% with ≥ 2 prior anti-CD20 therapies, 40% prior bortezomib. Gr 3/4 AE's occurring in at least 5% of patients and at least possibly related to UTX and/or ibrutinib included: neutropenia (13%), fatigue (7%), rash (7%) and atrial fibrillation (7%). Ibrutinib was dose reduced due to an AE in 1 patient (rash) and discontinued in 1 patient due to atrial fibrillation. No UTX dose reductions occurred. All 15 pts are evaluable for response with best response to treatment as follows: 87% (13/15) ORR with 33% (5/15) Complete Response. Three of the CR's occurred at week 8. Of the two patients not achieving an objective response, one patient was stable at first scan and came off treatment prior to second efficacy assessment (ibrutinib related A-Fib) and one patient progressed at first assessment. Responses generally improved from first to second assessment with median tumor reduction of 64% by week 8 and 82% by week 20. Conclusions: Ublituximab, a glycoengineered anti-CD20 mAb, in combination with ibrutinib is both well-tolerated and highly active in pts with rel/ref MCL. Response rate, depth of response, and time to response compare favorably to historical data with ibrutinib alone. A randomized phase 3 trial with ibrutinib +/- ublituximab is currently ongoing in high-risk CLL pts and future studies using this combination in MCL are being evaluated. Disclosures Kolibaba: Janssen: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Gilead: Consultancy, Honoraria, Research Funding; TG Therapeutics: Research Funding; GSK: Research Funding; Genentech: Research Funding; Cell Therapeutics: Research Funding; Celgene: Research Funding; Amgen: Research Funding; Amgen: Research Funding; Acerta: Research Funding. Burke:Gilead: Consultancy; Millenium/Takeda: Consultancy; Seattle Genetics, Inc.: Research Funding; Incyte: Consultancy; Janssen: Consultancy; TG Therapeutics: Other: Travel expenses. Farber:TG Therapeutics, Inc.: Research Funding. Fanning:Celgene and Millennium/Takeda: Speakers Bureau. Schreeder:TG Therapeutics, Inc: Research Funding. Boccia:Incyte Corporation: Honoraria. Sportelli:TG Therapeutics, Inc.: Employment, Equity Ownership. Miskin:TG Therapeutics, Inc.: Employment, Equity Ownership. Weiss:TG Therapeutics, Inc.: Employment, Equity Ownership. Sharman:Roche: Research Funding; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Research Funding; Calistoga: Honoraria; Janssen: Research Funding; TG Therapeutics, Inc.: Research Funding; Celgene Corporation: Consultancy, Research Funding.

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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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Comparison of 2 Doses of Intravenous (IV) Temsirolimus (Temsr) in Patients with Relapsed/Refractory Mantle Cell Lymphoma (MCL)

Blood ◽

10.1182/blood.v128.22.1775.1775 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1775-1775

Author(s):

Wojciech Jurczak ◽

Sundra Ramanathan ◽

Pratyush Giri ◽

Francesco Di Raimondo ◽

Heidi Mocikova ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Disease Progression ◽

Safety Profile ◽

Dose Regimen ◽

Research Funding ◽

Cell Lymphoma ◽

Employment Equity ◽

Mantle Cell ◽

Equity Ownership ◽

Grade 3

Abstract Introduction: Temsr (Torisel®) administered at 175 mg IV once weekly for first 3 weeks, followed by 75mg IV once weekly (Temsr 175/75 mg) is approved in the European Union for the treatment of adult patients with relapsed and/or refractory MCL based on an overall positive benefit-risk relationship demonstrated for this treatment regimen in the pivotal phase III study (Hess et al. J Clin Oncol. 2009;27:3822-9). This ongoing phase 4, multicenter, randomized, open-label study was conducted to explore whether similar efficacy can be achieved for the treatment of patients with relapsed/refractory MCL with a Temsr regimen that is expected to yield fewer side effects than the Temsr 175/75 mg dose regimen, by skipping the first 3 doses of Temsr 175 (Clinicatrials.gov: NCT01180049). Methods: In this study, previously treated (2-7 lines of prior therapy) patients with relapsed/refractory mantle cell lymphoma were stratified by the histologic subtype (blastoid vs. non blastoid vs unknown histology) and randomized (1:1) to receive Temsr 175/75 mg, or 75mg IV once weekly (Temsr 75 mg). Treatment continued until disease progression, provided that patients were tolerating treatment and achieving clinical benefit. The primary endpoint was progression-free survival (PFS) based on independent assessment. Secondary endpoints included objective response rate (ORR), overall survival (OS) and safety with a particular focus on bleeding- and infection-related adverse events (AEs). Results: Of the 90 patients (77.8% males; 93.3% white, mean age 66.6 years) randomized, 47 were treated with Temsr 175/75 mg, 42 were treated with Temsr 75 mg, and 1 patient was randomized but not treated. At the cutoff date for analysis (November 12, 2015), 39 (83.0%) patients in Temsr 175/75 mg arm and 41 (95.3%) patients in Temsr 75 mg arm discontinued treatment with the primary reason being objective disease progression (53.8% in Temsr 175/75 mg and 56.1% in Temsr 75 mg). Median duration of treatment was comparable in the Temsr 175/75 mg arm and Temsr 75 mg arm (3.2 vs. 3.1 months). Median PFS (80% CI) was 4.3 (3.3-6.4) months in Temsr 175/75 mg arm versus 4.5 (2.7-4.9) months in Temsr 75 mg arm (hazard ratio [HR] 0.731; 80% CI 0.520-1.027). ORR (80% CI) was 27.7% (19.1%-37.7%) in Temsr 175/75 mg arm versus 20.9% (13.0%-31.0%) in Temsr 75 mg arm. Median OS (80% CI) was 18.7 (7.5-48.2) months in Temsr 175/75 mg arm versus 11.0 (6.3-16.2) months in Temsr 75 mg arm (HR 0.681, 80% CI 0.472-0.982). Median duration of response was comparable in both treatment arms (9.0 vs. 8.7 months in Temsr 175/75 mg and Temsr 75 mg arms, respectively). Overall, the safety profile was comparable in both treatment arms, although the number of patients with serious AEs, dose reduction and deaths was lower in the 175/75mg arm compared with 75 mg arm (57.4%, 48.9% and 48.9% vs. 73.8%, 64.3% and 65.1%, respectively), and the number of treatment discontinuations due to AEs was higher in the Temsr 175/75mg arm compared with 75mg arm (19.1% vs. 14.3%). Common (>10%) grade ≥3, all-causality, treatment-emergent AEs in the Temsr 175/75 mg arm and Temsr 75 mg arm, respectively, were thrombocytopenia (46.8% vs. 38.1%), neutropenia (25.5% vs. 21.4%), and pneumonia (10.6% vs. 19.0%). Treatment-emergent bleeding-related grade ≥2 AEs in the Temsr 175/75 mg arm and Temsr 75 mg arm, respectively, included epistaxis (10.6% vs. 2.4%) and ecchymosis (2.1% vs. 0). Only 1 grade 3 AE of epistaxis which was not related to Temsr was reported in the Temsr 175/75 arm, and no grade 3 events were reported in Temsr 75 arm. Pneumonia was the most commonly occurring treatment-emergent infection-related grade ≥2 AEs 12.8% in Temsr 175/75 mg arm and 19.0% in Temsr 75 mg arm. Of the 51 deaths reported during the study, none were treatment-related and most were due to disease progression. Conclusions: Overall, PFS, ORR and OS favored the Temsr 175/75 arm, although no formal statistical conclusions were made as the study was not powered for differences. The safety profile in both study arms was comparable, but there was a lower incidence of serious AEs, dose reductions and deaths in the 175/75 mg arm. Temsr 175/75 mg remains the preferred dose regimen for patients with relapsed/refractory MCL. Disclosures Jurczak: Sandoz - Novartis, Morphosys, Roche: Speakers Bureau; Acerta, Novartis, Pfizer, Celgene, Gillead, Janssen, Celtrion, Bayer, Morphosys, Takeda, Servier, Teva, and Roche: Research Funding; Morphosys: Consultancy. Clancy:Pfizer Inc: Consultancy. Lechuga:Pfizer Inc: Employment, Equity Ownership. Casey:Pfizer Inc: Employment, Equity Ownership. Boni:Pfizer Inc: Employment, Equity Ownership. Hess:Roche, CTI, Pfizer, Celgene: Research Funding; Janssen: Honoraria; Roche: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Pfizer: Honoraria.

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