A Phase I Trial of TGR-1202, a Next Generation Once-Daily PI3Kδ Inhibitor, in Combination with Brentuximab Vedotin, in Patients with Relapsed/Refractory Hodgkins Lymphoma

Abstract Introduction: TGR-1202 is a once daily, oral PI3Kδ inhibitor that has demonstrated activity in patients (pts) with relapsed and refractory hematologic malignancies, with a favorable safety and tolerability profile compared to other PI3Kδ inhibitors (Burris, ASCO 2016). Brentuximab vedotin (BV) is a CD30 specific antibody-drug conjugate, which is FDA approved for the treatment of Hodgkin's Lymphoma (HL) and Systemic Anaplastic Large-cell Lymphoma (sALCL). BV has demonstrated impressive response rates in pts with rel/ref disease, however the duration of response is short in pts not achieving a complete response (median PFS of ~6 months for non-CR pts; Gopal et al, Blood 2015). Marked synergy has been demonstrated pre-clinically with TGR + BV, with the combination demonstrating a 3-fold increase in cell death in-vitro and a 55% increase in tumor growth inhibition over either TGR or BV alone in an in-vivo xenograft model of HL (Locatelli et al, ASH 2014). As the combination of TGR + BV displays strong synergy pre-clinically and incorporates non-overlapping mechanisms of activity, a Phase 1 trial evaluating the combination of TGR + BV in pts with rel/ref HL was undertaken. Methods: Eligible pts have relapsed or refractory HL, have received prior ASCT or at least 2 prior regimens, and have an ECOG PS < 3. Prior BV exposure is allowed. Two dose cohorts for TGR are evaluated (400 and 600 mg) dosed once daily with a fixed dose of BV 1.8 mg/kg on day 1 of each cycle (Cycle = 21 days) until off study. Safety is the primary endpoint evaluated by CTCAE v. 4.0. Efficacy (ORR and duration of response) is a secondary endpoint with responses determined according to response criteria of the International Working Group (Cheson, JCO 2007). Results: Fourteen pts have been enrolled. Median age is 34 (range 21 - 81); 9 Male/5 Female; Median ECOG PS = 1; with a median of 3 prior therapies (range 2 - 6). Seven pts had prior ASCT. Six pts had previously received BV, and all 6 were refractory to prior BV therapy. All pts are evaluable for safety. The most common AEs regardless of causality were nausea (71%; 0% Gr. 3/4), diarrhea (57%; 7% Gr. 3/4), neutropenia (50%; 43% Gr. 3/4), and rash (43%; 7% Gr. 3/4), followed by cough, dyspnea, and vomiting (36% each, all grades). Peripheral neuropathy was reported in 4 pts (29%), and were all Grade 1/2. Eleven pts were evaluable for efficacy, with 3 discontinuing prior to first efficacy assessment (1 withdrew consent, and 2 due to AEs). The ORR was 64% (7/11), with 45% (5/11) achieving a complete response with a median TTR of 8 weeks. Notably, 50% (3/6) of BV refractory patients responded to TGR-1202 + BV combination therapy (2 CRs, 1 PR). Three responding patients proceeded to stem cell transplant. Of the remaining 4 patients achieving a response, 2 patients remain in CR, and 2 have progressed (at 13 and 16.5 mos respectively). Conclusions: The combination of TGR-1202 + brentuximab vedotin exhibits an acceptable tolerability profile and is clinically active. Responses were observed in patients with advanced Hodgkin's Lymphoma, including responses in 50% of patients previously refractory to brentuximab vedotin. Further studies evaluating this combination are warranted. Disclosures Sportelli: TG Therapeutics, Inc.: Employment, Equity Ownership. Miskin:TG Therapeutics, Inc: Employment, Equity Ownership. Chen:Genentech: Consultancy, Speakers Bureau; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millenium: Consultancy, Research Funding, Speakers Bureau.

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Ublituximab, a Novel Glycoengineered Anti-CD20 Monoclonal Antibody (mAb), in Combination with TGR-1202, a Next Generation Once Daily PI3kδ Inhibitor, Demonstrates Activity in Heavily Pre-Treated and High-Risk Chronic Lymphocytic Leukemia (CLL) and B-Cell Lymphoma

Blood ◽

10.1182/blood.v124.21.801.801 ◽

2014 ◽

Vol 124 (21) ◽

pp. 801-801 ◽

Cited By ~ 1

Author(s):

Matthew A. Lunning ◽

Julie M. Vose ◽

Marshall T. Schreeder ◽

Nathan Fowler ◽

Loretta J. Nastoupil ◽

...

Keyword(s):

High Risk ◽

Research Funding ◽

Next Generation ◽

Employment Equity ◽

Once Daily ◽

Richter's Transformation ◽

Equity Ownership ◽

Anti Cd20 ◽

Ecog Ps ◽

11Q Deletion

Abstract Introduction: Ublituximab (UTX) is a novel chimeric mAb targeting a unique epitope on the CD20 antigen, glycoengineered to enhance affinity to FcγRIIIa receptors, thereby demonstrating significantly greater ADCC than rituximab. UTX monotherapy in patients (pts) with rituximab relapsed/refractory NHL and CLL has reported a 43% ORR (ASCO 2014). TGR-1202 is a next generation, once daily, oral PI3Kδ inhibitor which notably lacks the hepatotoxicity associated with other PI3Kδ inhibitors, and is active in pts with relapsed and refractory hematologic malignancies (EHA 2014). UTX and TGR-1202 have shown synergistic activity in-vitroin various lymphoid cell lines (Lugano 2013). This Phase 1 trial evaluates safety and efficacy of the combination of a glycoengineered anti-CD20 (UTX) and a PI3Kδ inhibitor (TGR-1202) in pts with heavily pre-treated relapsed or refractory CLL and NHL. Methods: Eligible pts have relapsed/refractory CLL or NHL with an ECOG PS ≤ 2. A 3+3 design evaluates cohorts of CLL and NHL pts independently with UTX dosed on Days 1, 8, 15 of Cycles 1 & 2 followed by maintenance therapy. UTX starts at 600 mg in Cohort 1 and increases to 900 mg for pts with CLL and is fixed at 900 mg for pts with NHL. TGR-1202 starts at 800 mg QD in Cohort 1 and is increased in subsequent cohorts. An amendment in July 2014 was introduced to include an improved micronized formulation of TGR-1202, starting at 400 mg once daily and increasing in subsequent cohorts. There are no limits on prior therapy, and patients with Richter’s Transformation or who are refractory to prior PI3Kδ inhibitors or BTK inhibitors are eligible. Primary endpoints: Safety and Dose Limiting Toxicities (DLT). Secondary endpoints: Efficacy (ORR, CR rate). Results: As of August 2014, 21 pts have been enrolled: 8 CLL/SLL, 7 DLBCL, 5 Follicular Lymphoma, and 1 patient with Richter’s Transformation. Median age is 64 years (range 35-82); 12 male/9 female. Median prior Tx = 3 (range 1-9); median ECOG PS = 1. All pts are evaluable for safety. Adverse events have been manageable with no safety concerns noted. Day 1 infusion related reactions (IRR) were the most common treatment related adverse event (48%), with all but one event Grade 1 or 2 in severity, followed by neutropenia (38%), diarrhea (29%), and nausea (29%). Notably, no events of TGR-1202 related hepatotoxicity have been reported to date. All IRR and neutropenia events have been manageable with dose delays. One neutropenia related dose delay in a CLL patient at UTX 600 mg + TGR 800 mg met the criteria for a DLT, necessitating enrollment of additional pts into this cohort. No other DLTs have been reported, including at higher dose levels. Fifteen pts were evaluable for efficacy with 6 pts too early for response assessment. Among evaluable pts, 80% displayed a reduction in tumor burden at first efficacy assessment, despite pts exhibiting a number of high-risk characteristics, including 3/5 CLL pts having 17p/11q deletion and a median of 6 prior lines of therapy amongst pts with FL. Objective responses are summarized below: Table TypePts (n)PRn (%)ORRn (%)PD(n)% pts ≥ SD for 12 wksMedian Prior Rx CLL/SLL54 (80%)4 (80%)-5 (100%)2 (1 – 3) Richter’s1---1 (100%)1 FL4---4 (100%)6 (3 – 8) DLBCL52 (40%)2 (40%)14 (80%)3 (1 – 6) Total156 (40%)6 (40%)114 (93%)3 (1 – 8) Amongst pts with CLL, 2/2 pts with normal cytogenetics achieved a PR including a patient with prior treatment with a BTK inhibitor, while 2/3 pts with presence of 17p/11q deletion achieved a PR, with the remaining patient having SD with a 44% nodal reduction at first assessment. Conclusions: Preliminary data suggests the combination of UTX + TGR-1202 is well tolerated with early signs of clinical activity in heavily pre-treated and high-risk patient subsets. Enrollment is ongoing with at least 30 patients anticipated. Disclosures Lunning: Onyx: Consultancy; Alexion: Consultancy; Gilead: Consultancy; Spectrum Pharmaceuticals: Consultancy. Schreeder:TG Therapeutics, Inc.: Research Funding. Pauli:TG Therapeutics, Inc.: Consultancy. Miskin:TG Therapeutics, Inc.: Employment, Equity Ownership. Sportelli:TG Therapeutics: Employment, Equity Ownership. Weiss:TG Therapeutics, Inc.: Employment, Equity Ownership. Vakkalanka:Rhizen: Employment, Equity Ownership. Viswanadha:Incozen: Employment. O'Brien:Amgen, Celgene, GSK: Consultancy; CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Emergent, Genentech, Gilead, Infinity, Pharmacyclics, Spectrum: Consultancy, Research Funding; MorphoSys, Acerta, TG Therapeutics: Research Funding.

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TGR-1202, a Novel Once Daily PI3K-Delta Inhibitor, Demonstrates Clinical Activity with a Favorable Safety Profile in Patients with CLL and B-Cell Lymphoma

Blood ◽

10.1182/blood.v126.23.4154.4154 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4154-4154 ◽

Cited By ~ 18

Author(s):

Owen A. O'Connor ◽

Ian W. Flinn ◽

Manish R. Patel ◽

Timothy S. Fenske ◽

Changchun Deng ◽

...

Keyword(s):

B Cell ◽

Safety Profile ◽

Research Funding ◽

Objective Response ◽

B Cell Lymphoma ◽

Tolerability Profile ◽

Employment Equity ◽

Once Daily ◽

Equity Ownership ◽

Pi3k Delta

Abstract Background: TGR-1202 is a novel, next generation PI3Kδ inhibitor which exhibits a differentiated safety profile from other PI3Kδ inhibitors, both approved and in development, and has demonstrated activity in patients (pts) with advanced heme malignancies (ASH 2014). Herein we present updated safety and efficacy results from a Ph I study of TGR-1202 in pts with rel/ref CLL and lymphoma. Methods: TGR-1202 is administered orally once-daily (QD) following a 3+3 dose escalation design. Eligible pts have rel/ref non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), or other B-cell malignancy and an ECOG PS ≤ 2. Endpoints include safety, PK/PD, and efficacy. Results: As of August 2015, 75 pts are evaluable for safety including pts with CLL, FL, Hodgkin's (HL), DLBCL, MCL, and MZL. Patients had a median age of 65 yo (range: 22-85), 67% male, ECOG 0/1/2: 26/47/2, median prior Tx: 3 (range: 1-14), and 49% refractory to prior Tx. No Gr≥3 AEs were observed in ≥10% of pts. AEs (all grades, all causality) in >20% of pts were limited to nausea (44%, Gr3/4 0%), diarrhea (36%, Gr3/4 1%), and fatigue (31%, Gr3/4 3%). Notably, general tolerability and the incidence of hepatotoxicity and colitis appear significantly less than that reported with other agents in this class. Expansion cohorts are open at 800 mg, 1000 mg, and 1200 mg QD. Of 16 evaluable CLL pts, 15 (94%) achieved a nodal PR (median nodal ↓ of 76%), of which 10 (63%) achieved a PR per Hallek 2008 criteria. Among the 32 evaluable NHL patients, 10 achieved an objective response, including 3/11 evaluable patients with DLBCL, while responses have been limited in pts with MCL (1/5) and HL (1/9). Of the 16 evaluable indolent NHL (FL & MZL) pts, 14 (88%) have achieved reductions in tumor burden with 6 pts on study for over 12 cycles (and durations upwards of 29+ cycles), with 5/12 FL and 1/4 MZL pts achieving an objective response to date. Notably, a strong exposure-response relationship has been observed. Of the 24 patients starting TGR-1202 at 800 mg or 1200 mg of the micronized formulation, 19 (79%) remain on therapy, with 9/18 (50%) evaluable pts (6 too early to evaluate) achieving an objective response to date (range on study 3 - 49+ weeks). Conclusions: TGR-1202 is well tolerated in pts with rel/ref heme malignancies with a distinct safety and tolerability profile from other PI3K-delta inhibitors (with 43% of pts on study 6+ Cyc) and promising activity in CLL and NHL. Enrollment continues in expansion cohorts and registration directed Phase 3 studies are planned. Disclosures Flinn: Celgene Corporation: Research Funding. Fenske:Millennium/Takeda: Research Funding; Celgene: Honoraria; Seattle Genetics: Honoraria; Pharmacyclics: Honoraria. Deng:TG Therapeutics, Inc.: Honoraria, Research Funding; Seattle Genetics: Research Funding. Kuhn:TG Therapeutics, Inc.: Consultancy; Otsuka American Pharmaceutical: Consultancy; Azaya Therapeutics: Consultancy. Miskin:TG Therapeutics, Inc.: Employment, Equity Ownership. Sportelli:TG Therapeutics, Inc.: Employment, Equity Ownership. Vakkalanka:Rhizen Pharmaceuticals SA: Employment, Equity Ownership.

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Effect of the Cytochrome P450 3A4 Inducers, Rifampicin and Dexamethasone, on the Pharmacokinetic, Pharmacodynamic and Safety Profile of Bortezomib In Patients with Multiple Myeloma (MM) and Non-Hodgkin's Lymphoma (NHL)

Blood ◽

10.1182/blood.v116.21.3983.3983 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3983-3983

Author(s):

Andrzej Hellmann ◽

Simon A. Rule ◽

Jan Walewski ◽

Ofer Shpilberg ◽

Huaibao Feng ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Proteasome Inhibition ◽

Employment Equity ◽

Advisory Committees ◽

Time Curve ◽

Once Daily ◽

Cyp3a4 Inducer ◽

Equity Ownership ◽

The Mean

Abstract Abstract 3983 Background: Bortezomib is primarily metabolized by cytochrome P450 (CYP) 3A4 and 2C19 enzymes. Effects of co-administration of rifampicin (a potent CYP3A4 inducer) and dexamethasone (weak CYP3A4 inducer) on the pharmacokinetic (PK), pharmacodynamic (PD) and safety profiles of bortezomib were evaluated. Methods: Patients with relapsed or refractory multiple myeloma (MM) or non-Hodgkin's lymphoma (NHL) were enrolled in this open-label, 2-stage, parallel-group study. In stage 1, patients were randomized (1:1) to receive 3 cycles of bortezomib (1.3 mg/m2) on d 1, 4, 8, and 11 q3wk either alone or in combination with rifampicin 600 mg once-daily on d 4 to 10 of cycle 3 only. Stage 2 patients received bortezomib at same dose and schedule in combination with dexamethasone 40 mg once-daily on d 1 to 4 and d 9 to 12 of cycle 3 only. Patients could continue with bortezomib monotherapy for up to 10 cycles in case of clinical benefit. For PK/PD, blood samples were collected before and through 72 hours following bortezomib administration on d 11 of cycles 2 and 3. PK was the primary endpoint, secondary endpoints included PD (proteasome inhibition) and safety. Results: 61 patients were enrolled (39 MM, 22 NHL) in the study. 13 were treated with bortezomib + rifampicin, 18 with bortezomib + dexamethasone, and 30 with bortezomib only. Co-administration of rifampicin reduced the mean bortezomib maximum plasma concentration (Cmax) by approximately 23% (118 vs 93 ng/mL) and the mean area under plasma concentration-time curve from 0 to 72 hours (AUC72) by approximately 45% (223 vs 123 ng.h/mL). Co-administration of dexamethasone had no effect on mean AUC72 (179 vs 170 ng.h/mL). The mean bortezomib Cmax was 20% lower after co-administration of dexamethasone (140 vs 119 ng/mL); however this difference in Cmax was within the observed variability in Cmax during cycle 2 (CV=38%) and cycle 3 (CV=45%). Mean (SD) maximum percent proteasome inhibition (Emax) and area under percent proteasome inhibition-time curve from 0 to 72 hours (AUE72h) were comparable for bortezomib alone and in combination with rifampicin (Emax: 61.9 [4.56] vs. 62.3 [3.81] and AUE72h: 836 [323] vs. 777 [358]). Co-administration of dexamethasone did not affect the Emax (66.7 [4.27] vs. 61.8 [6.69]) or AUE72h (1329 [638] vs. 1157 [381]). Safety profiles were consistent with prior bortezomib experience in this population. Drug-related serious adverse events and treatment discontinuations were reported in 7/30 (23%) and 8/30 (27%) in bortezomib-only, in 3/13 (23%) and 3/13 (23%) in bortezomib + rifampicin, and 3/18 (17%) and 5/18 (28%) in bortezomib + dexamethasone subgroups. Investigator-assessed responses (CR+PR) were observed in 13/17 MM and 6/13 NHL patients in bortezomib-only, in 6/9 MM and 3/4 NHL patients in bortezomib + rifampicin, and in 10/13 MM and 2/5 NHL patients in bortezomib + dexamethasone subgroups. Conclusions: Co-administration of dexamethasone did not affect the PK or PD profiles of bortezomib. Co-administration of rifampicin reduced bortezomib exposure (AUC) by approximately 45%. Patients receiving bortezomib concomitantly with strong CYP3A4 inducers, such as rifampicin, should be monitored for reduction in clinical effect, while concomitant administration of weak CYP3A4 inducers, such as dexamethasone, is not expected to affect the bortezomib pharmacologic profile. Disclosures: Off Label Use: Discussion of Velcade in NHL subtypes other than mantle cell lymphoma is included. Rule:Johnson & Johson: Consultancy, Speakers Bureau; Roche: Consultancy. Walewski:Johnson & Johnson: Honoraria, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Investigators fee. Shpilberg:Johnson & Johnson: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Feng:Johnson & Johnson: Employment. van de Velde:Johnson & Johnson: Employment, Equity Ownership. Patel:Johnson & Johnson: Employment, Equity Ownership. Skee:Johnson & Johnson: Employment. Girgis:Johnson & Johnson: Employment. Louw:Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: 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; Key Oncologics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers-Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Variation in Health-Related Quality of Life by ECOG Performance Status and Fatigue Among Patients with Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood.v118.21.4591.4591 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4591-4591 ◽

Cited By ~ 1

Author(s):

Chris L. Pashos ◽

Christopher R Flowers ◽

Mark Weiss ◽

Nicole Lamanna ◽

Charles M Farber ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Performance Status ◽

Clinical Practices ◽

Employment Equity ◽

Ecog Performance Status ◽

Advisory Committees ◽

Equity Ownership ◽

Ecog Ps ◽

The Impact

Abstract Abstract 4591 Introduction: Clinicians and investigators appreciate the value of measuring HRQOL for monitoring CLL and the impact of treatments, and commonly use ECOG performance status (PS) and clinician-reported patient fatigue as surrogates for HRQOL in clinical practice. However, limited data exist on the relationships between PS, fatigue, and HRQOL in CLL patients (pts) undergoing treatment in clinical practices. We examined the associations between these measures and 3 psychometrically validated, patient-reported, HRQOL instruments: the Brief Fatigue Inventory (BFI), EQ-5D, and Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu). Methods: Data were collected as part of Connect CLL®, a prospective observational registry initiated in March 2010 involving US practices. Data on pt demographics and clinical characteristics were provided by clinicians. HRQOL was self-reported by pts at enrollment using the BFI, EQ-5D, and FACT-Leu. Mean BFI, EQ-5D and FACT-Leu scores were analyzed by ECOG PS and clinician-reported fatigue. Differences in HRQOL scores between sub-cohorts were assessed by ANOVA. Results: HRQOL data were reported by 604 pts enrolled from 10 academic, 148 community, and 3 government centers. Pts were predominantly male (62%) and white (90%); mean age was 70 (standard deviation 11) years. BFI data (scale: 0 [no fatigue] - 10 [worst fatigue]) indicated that on average pts report that global fatigue, fatigue severity and fatigue-related interference worsen by ECOG severity (Table 1) and are statistically associated with clinician-reported fatigue (Table 2). Mean EQ-5D overall HRQOL as measured by a Visual Analogue Scale (VAS) from 0 (worst) to 100 (best) worsens by ECOG severity and is significantly worse in pts with fatigue. Mean EQ-5D domain scores (scale: 1 [no problem], 2 [some problems], 3 [incapacity]) indicated that pain/discomfort, mobility and usual activities increase in severity as ECOG worsens and in pts with fatigue. FACT-Leu domains except social/family were statistically worse with worse ECOG PS and in pts with fatigue. Conclusions: Initial results from Connect CLL® indicate that HRQOL worsens with worsening ECOG PS, especially in physical / functioning domains, pain/discomfort, and mobility, and worsens across multiple domains among pts whose physicians reported fatigue. Future analyses should be conducted on how HRQOL, PS and fatigue may change over time with changes in CLL, and how they are influenced by therapies. These results may serve as baseline reference. Disclosures: Pashos: Celgene: Membership on an entity's Board of Directors or advisory committees. Flowers:Genentech/Roche (unpaid): Consultancy; Celgene: Consultancy; Millennium/Takeda: Research Funding; Wyeth: Research Funding; Novartis: Research Funding. Weiss:Celgene: Membership on an entity's Board of Directors or advisory committees. Lamanna:Celgene: Membership on an entity's Board of Directors or advisory committees. Farber:Celgene: Membership on an entity's Board of Directors or advisory committees. Kipps:Igenica: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Abbot Industries: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; GSK: Research Funding; Gilead Sciences: Consultancy, Research Funding; Amgen: Research Funding. Lerner:Celgene: Membership on an entity's Board of Directors or advisory committees. Kay:Celgene: Membership on an entity's Board of Directors or advisory committees. Sharman:Celgene: Membership on an entity's Board of Directors or advisory committees. Grinblatt:Celgene: Membership on an entity's Board of Directors or advisory committees. Flinn:Celgene: Membership on an entity's Board of Directors or advisory committees. Kozloff:Celgene: Membership on an entity's Board of Directors or advisory committees. Swern:Celgene Corporation: Employment, Equity Ownership. Kahn:Celgene Corporation: Employment, Equity Ownership. Street:Celgene: Employment, Equity Ownership. Sullivan:Celgene: Employment, Equity Ownership. Keating:Celgene: Membership on an entity's Board of Directors or advisory committees.

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Results of the OPAL Study: A Phase II Study to Evaluate the Efficacy, Safety and Tolerability of Tosedostat (CHR-2797) in Elderly Subjects with Treatment Refractory or Relapsed Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v118.21.767.767 ◽

2011 ◽

Vol 118 (21) ◽

pp. 767-767

Author(s):

Jorge E. Cortes ◽

Eric J Feldman ◽

Karen Yee ◽

David A. Rizzieri ◽

Anjali S. Advani ◽

...

Keyword(s):

Bone Marrow ◽

Phase Ii ◽

Research Funding ◽

Phase Iii ◽

Elderly Subjects ◽

Primary Therapy ◽

Primary Analysis ◽

Employment Equity ◽

Once Daily ◽

Equity Ownership

Abstract Abstract 767 Background: Tosedostat is a novel oral inhibitor of the M1/17 family of aminopeptidases which induces an amino acid deprivation response that is selectively toxic for myeloid blasts (Leuk Res. 2011: 5:677-81) and has shown promising activity in elderly relapsed/refractory AML patients (J Clin Oncol 2010:28:4333-8). Aims: The OPAL study was undertaken to compare the activity of tosedostat at a once-daily dose of 120 mg for 24 weeks compared to 240 mg once daily for 8 weeks followed by 120 mg once daily for a further 16 weeks., as measured by bone marrow and hematology responses at 24 weeks. Methods: This was a phase II randomized (1:1) multi-center study. Patients were eligible if aged 60 years or older with previous CR lasting <12 months, or no CR after primary therapy, had a peripheral blast count <30,000/μl, PS<2 and adequate renal, hepatic and cardiac function. The primary analysis was performed at 24 weeks using IWG 2003 criteria. Results: Seventy-three patients were randomized and received tosedostat, 38 at 120 mg and 35 at 240 mg. Median age was 72 (range, 64 to 86), and 59% were male. Twenty-six patients (36%) had secondary or therapy-related AML, of which 19 (26%) had prior MDS. Median time since AML diagnosis was 211 days and 38% had received primary therapy with cytarabine/anthracyclines; 36% with a hypomethylating agent (HMA) and 23% with other cytarabine regimes. Fifty-two percent had been refractory to primary therapy, 19% had previously had a remission of up to 6 months and 29% a 6–12 month remission (mean 97 days including refractory). Twenty-three patients (32%) had no post-treatment bone marrow sample taken, predominantly due to early progression: 34% completed 12 weeks on study and 14% completed 24 weeks and were eligible to enter an extension study which is ongoing. The overall response rate was 22%; (CR/CRp/MLFS 12%; PR 10%) and an additional 29% had a best response of stable disease. The most common adverse events which occurred (total; grade 3 or worse) were diarrhea (58%; 4.1%), peripheral edema (55%; 0%), fatigue (49%; 21%), dyspnea (41%; 16%), nausea (38%; 0%), decreased appetite (37%; 3%), febrile neutropenia (36%; 29%) and hypotension (36%, 10%). Median overall survival (OS) (at 15 July 2011) was 126 days. Median OS in patients with CR/CRp/MLFS, PR and SD were 280, 195 and 162 days respectively, and 261.5 days for patients with a response of PR or better. Median OS for patients with progression of disease or who were unevaluable was 61 days. Similar responses were seen in the two dose groups. Additional non protocol-specified analyses showed that the following types of patient appeared to respond well: AML NOC vs other AML types 16% vs 29% response, median OS 75 vs 168 days; patients with poor risk cytogenetics compared to intermediate/better, median OS 159 vs 107 days; those who received prior HMA compared to others, 38% vs 13% response, median OS 171 vs 104 days; and absence of prior CR 29% vs 14% response and median OS 169 vs 103 days. Conclusions: These results provide further encouraging evidence of efficacy and a favorable toxicity profile in a difficult to treat patient population. A phase III program of pivotal studies with tosedostat in AML and MDS will start in the near future. Disclosures: Cortes: Chroma Therapeutics Ltd.: Consultancy, Research Funding. Feldman:Chroma Therapeutics Ltd.: Consultancy, Research Funding. Yee:Chroma Therapeutics Ltd.: Consultancy, Research Funding. Rizzieri:Chroma Therapeutics Ltd.: Consultancy, Research Funding. Advani:Chroma Therapeutics Ltd.: Consultancy, Research Funding. Charman:Chroma Therapeutics Ltd.: Employment, Equity Ownership. Toal:Chroma Therapeutics Ltd.: Employment, Equity Ownership. Kantarjian:Chroma Therapeutics Ltd.: Consultancy, Research Funding.

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Population Pharmacokinetic and Pharmacodynamic Modeling of an Anti–Interleukin-6 Chimeric Monoclonal Antibody, Siltuximab (CNTO 328), in Patients with B-Cell Non-Hodgkin's Lymphoma, Multiple Myeloma, or Castleman's Disease

Blood ◽

10.1182/blood.v120.21.1365.1365 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1365-1365 ◽

Cited By ~ 6

Author(s):

Lanyi Xie ◽

Lilian Y Li ◽

Razelle Kurzrock ◽

Frits van Rhee ◽

Xiang Qin ◽

...

Keyword(s):

Multiple Myeloma ◽

Monoclonal Antibody ◽

B Cell ◽

Treatment Period ◽

Research Funding ◽

Castleman’S Disease ◽

Hodgkin's Lymphoma ◽

Employment Equity ◽

Dosing Regimens ◽

Equity Ownership

Abstract Abstract 1365 Introduction Siltuximab (CNTO 328) is a chimeric, murine-human, monoclonal antibody that specifically binds human interleukin (IL)-6 with high affinity. C-reactive protein (CRP) can be a pharmacodynamic (PD) marker of IL-6 bioactivity, i.e., reductions in CRP suggest inhibition of systemic IL-6. A population mechanistic pharmacokinetic (PK)/PD model was developed to describe the relationship between siltuximab serum concentrations and CRP suppression in patients with B-cell non-Hodgkin's lymphoma (NHL), multiple myeloma (MM), or Castleman's disease (CD). Simulation was used to support the dose selection in the CD registration study and future clinical studies. Methods PK/PD data were obtained from a phase 1 clinical study examining multiple dosing regimens of siltuximab administered intravenously in patients with NHL, MM, or CD. Dosing regimens included siltuximab 2.8, 5.5, or 11 mg/kg every 2 weeks; 11 mg/kg every 3 weeks; or 5.5 mg/kg every week. Serial samples to determine serum concentration of siltuximab and serial CRP samples were collected following the first dose. NONMEM 7 was used to simultaneously fit a two-compartment PK model and an inhibitory indirect-response PD model to the observed data. Simulation of 1000 replications was then used to identify siltuximab dosage regimens that would maintain CRP suppression below the lower limit of quantification (LLOQ) of 1 mg/L. Results The mechanistic PK/PD model was able to describe the serum siltuximab and CRP concentration-time profiles. Volume of distribution and systemic clearance rate constant of siltuximab were estimated at 68.42 mL/kg and 0.0584/day, respectively. The PD parameter estimates (Kin and Kout of CRP) were 5.03 mg/L/day and 0.457/day, respectively, and were similar between the three disease types in this study. IC50was estimated at 9.73 μg/mL and was also similar between disease types. For all disease types, simulations showed that siltuximab 11 mg/kg every 3 weeks or 15 mg/kg every 4 weeks after the second dose would reduce serum CRP to below the LLOQ throughout the entire treatment period. However, lower dose intensive schedules, including a dose of 5.5 mg/kg every 2 weeks, would not reduce CRP to below the LLOQ at any time point during the treatment period. Conclusion The population PK/PD modeling and simulation support using a siltuximab dose of 11 mg/kg every 3 weeks or 15 mg/kg every 4 weeks in future clinical development studies. This dosing recommendation is supported by the observed efficacy dose-response relationship in patients with CD (J Clin Oncol 2010;28:3701–8). Disclosures: Xie: Johnson & Johnson: Employment, Equity Ownership. Li:Johnson & Johnson: Employment, Equity Ownership. Kurzrock:Johnson & Johnson: Honoraria, Research Funding. van Rhee:Johnson & Johnson: Research Funding. Qin:Johnson & Johnson: Employment, Equity Ownership. Reddy:Johnson & Johnson: Employment, Equity Ownership. Qi:Johnson & Johnson: Employment, Equity Ownership. Davis:Johnson & Johnson: Employment, Equity Ownership. Zhou:Johnson & Johnson: Employment, Equity Ownership. Puchalski:Johnson & Johnson: Employment, Equity Ownership.

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Pomalidomide (POM) with Low-Dose Dexamethasone (LoDEX) in Patients with Relapsed and Refractory Multiple Myeloma (RRMM): Outcomes Based on Prior Treatment Exposure

Blood ◽

10.1182/blood.v120.21.4070.4070 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4070-4070 ◽

Cited By ~ 1

Author(s):

Ravi Vij ◽

Craig C. Hofmeister ◽

Paul G. Richardson ◽

Sundar Jagannath ◽

David S. Siegel ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Low Dose ◽

Advisory Board ◽

Prior Exposure ◽

Employment Equity ◽

Advisory Committees ◽

Duration Of Response ◽

Equity Ownership ◽

Grade 3

Abstract Abstract 4070 Background: There are currently limited effective treatment options for patients (pts) with RRMM with prior exposure to lenalidomide (LEN), bortezomib (BORT) and chemotherapy. In a multicenter, randomized phase 2 study, POM with or without LoDEX (n=221) was active in RRMM pts who had received ≥2 prior therapies, including LEN and BORT (Richardson PG, et al. Blood 2011;118:abs 634); activity was also observed in those with disease refractory to LEN, BORT, or both (Vij R, et al. J Clin Oncol 2012;30:abs 8016). Here we characterize outcomes in the POM+LoDEX group (n=113) according to the prior treatment exposure. Methods: Pts with RRMM who had received ≥2 prior therapies, including LEN and BORT, and had progressive disease (PD) within 60 days of their last treatment were randomized (1:1 ratio) to POM+LoDEX (POM, 4 mg/day for days 1–21 of a 28-day cycle; LoDex, 40 mg/week) or POM alone. At randomization, pts were stratified by age, prior number of treatments, and prior thalidomide exposure. At progression, pts receiving POM alone could receive POM+LoDEX at investigator's discretion. All pts received thromboprophylaxis (daily low-dose aspirin). The endpoints in this study were progression-free survival (PFS), response rates (using European Bone Marrow Transplantation [EBMT] criteria), duration of response, time to response, overall survival (OS), and safety. Response data according to prior therapy were assessed by investigator assessment. Results: All 113 pts assigned to POM+LoDEX had prior exposure to LEN (100%), BORT (100%), and steroids (100%). Most pts had also received prior alkylator therapy (93%), stem cell transplant (SCT) (73%), and thalidomide (THAL) (68%); 49% had received prior anthracyclines. Regimens immediately prior to study entry included BORT (50%), LEN (39%), cyclophosphamide (13%), THAL (8%), vorinostat (8%), carfilzomib (5%), and melphalan (5%). The median number of exposures to LEN and BORT in prior lines was once (range 1–4) and twice (range 1–6), respectively. The majority of pts (80%) had received >3 prior therapies. The overall response rate (ORR) was 48% and 30% in pts who had received ≤3 and >3 prior therapies, respectively. Of the pts who had ≤3 vs > 3 prior therapies, 9% vs 1% pts achieved complete response (CR), 39% vs 29% pts achieved partial response (PR), 9% vs 12% pts achieved minimal response (MR) and 44% vs 36 % pts achieved stable disease (SD), respectively. ORR was 34% and appeared similar regardless of prior exposure to alkylators (33%), anthracyclines (35%), SCT (35%), or THAL (35%). Median duration of response was also similar in pts who had received prior alkylators (8.4 mos), anthracyclines (10.1 mos), SCT (7.7 mos), and THAL (7.7 mos). Of the 69 pts who had a best response of SD or PD to their last prior antimyeloma therapy, 21 pts (12 SD and 9 PD) achieved a PR and 3 pts (1 SD and 2 PD) achieved a CR with POM+LoDEX treatment. Responding pts had longer time to progression (TTP; 11.1 mos) with POM+LoDex compared with the TTP (4.4 mos) observed with their last antimyeloma regimen prior to study. The most common grade 3–4 adverse events in the POM+LoDEX group were neutropenia (41%), anemia (22%), pneumonia (22%), thrombocytopenia (19%), and fatigue (14%). The incidence of at least 1 grade 3–4 adverse event was 100% in pts with ≤ 3 prior therapies, and 88% in pts with >3 therapies. Conclusions: The combination of POM+LoDEX has demonstrated an ORR of 34% in heavily pretreated pts with RRMM who have been previously exposed to LEN, BORT, steroids, and other treatments. Early treatment of POM+LoDEX (≤3 prior therapies) achieved better ORR (48%) compared with pts who received POM+LoDex later (>3 prior therapies; ORR, 30%). Disclosures: Vij: Onyx: Consultancy, Research Funding; Millennium Pharma: Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau. Off Label Use: Pomalidomide is an investigational drug and is not approved for the treatment of patients with any condition. Hofmeister:Celgene: Advisory Board Other, Honoraria. Richardson:Celgene, Millennium, Johnson & Johnson: Advisory Board Other. Jagannath:Onyx Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck Sharp & Dohme: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Siegel:Onyx: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Millennium Pharma: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Celgene: Advisory Board Other, Honoraria, Speakers Bureau; Merck: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau. Baz:Celgene, Millennium, Bristol Myers Squibb, Novartis: Research Funding. Chen:Celgene: Employment, Equity Ownership. Zaki:Celgene: Employment, Equity Ownership. Larkins:Celgene: Employment, Equity Ownership. Anderson:Acetylon, Oncopep: Scientific Founder, Scientific Founder Other; Celgene, Millennium, BMS, Onyx: Membership on an entity's Board of Directors or advisory committees.

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Ublituximab + TGR-1202 Demonstrates Activity and a Favorable Safety Profile in Relapsed/Refractory B-Cell NHL and High-Risk CLL: Phase I Results

Blood ◽

10.1182/blood.v126.23.1538.1538 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1538-1538 ◽

Cited By ~ 6

Author(s):

Matthew A. Lunning ◽

Julie Vose ◽

Nathan Fowler ◽

Loretta Nastoupil ◽

Jan A. Burger ◽

...

Keyword(s):

High Risk ◽

Phase I ◽

Research Funding ◽

Clinical Activity ◽

Employment Equity ◽

Once Daily ◽

Phase Ib ◽

Equity Ownership ◽

Favorable Safety ◽

Higher Doses

Abstract Introduction: Ublituximab (UTX) is a novel anti-CD20 mAb that has been glycoengineered for enhanced ADCC. TGR-1202 is a novel once daily oral PI3Kδ inhibitor with clinical activity in B-cell lymphoma and a notably differentiated tolerability profile compared to similar agents. The combination of UTX + TGR-1202 showed strong synergistic activity in-vitro (Lugano 2013). Herein we report the results from the Phase 1 (dose-escalation) and updated results from the Phase Ib (dose-expansion) evaluating the safety and efficacy of the combination of UTX + TGR-1202 in patients (pts) with heavily pre-treated rel/ref NHL and CLL. Methods: A 3+3 design was utilized with rel/ref NHL and CLL pts accruing independently and no limit on the number or type of prior therapies. Patients refractory to prior PI3K or BTK inhibitors were eligible. UTX was administered D1, 8, 15 of Cyc 1 & 2, followed by D1 of Cyc 4, 6, 9 & 12. TGR-1202 was administered orally once-daily starting on D1 of Cyc 1. Primary endpoints: Safety and dose limiting toxicities (DLT). Secondary endpoints: Efficacy (ORR, CR rate). Results: 56 patients have been enrolled to date and are evaluable for safety: 16 CLL/SLL, 16 FL, 16 DLBCL, 5 MZL, 2 MCL and 1 Richter's transformation. Med age 64 yo (range 29-86); 37 M/19 F; median # prior treatment regimens = 3 (range 1-9). Day 1 infusion reactions (2% G 3/4), neutropenia (23% G 3/4), diarrhea (2% G 3/4), and nausea (0% G 3/4) were the most commonly reported adverse events considered at least possibly related to either study drug. One patient (CLL cohort 1) with baseline Gr 3 neutropenia at study entry worsened to Gr 4 resulting in a dose delay which necessitated enrollment of an additional 3 pts at that dose level. Dose escalation continued into all planned subsequent NHL and CLL cohorts (up to 1200 mg). No MTD was observed in the Phase I portion and subtype specific expansion cohorts (Phase Ib) with 800 and 1200 mg dose of micronized TGR-1202 followed. Activity was observed at all dose levels; however a possible dose-response relationship was observed with TGR-1202 at higher doses compared to the lower doses. Of the 37 evaluable pts treated at the higher doses of TGR-1202 (1200 mg original formulation or > 600 mg micronized), overall response was as follows: CLL/SLL (5/7); FL/MZL (10/15); DLBCL (5/12); MCL (0/2) and Richter's (1/1). No CLL pts progressed at the first efficacy assessment, despite 4/5 having high-risk cytogenetics. Two CLL pts with SD include a 17p del, ibrutinib refractory patient who eventually progressed on treatment and the other remains on study awaiting future assessments. Of interest, 7 of the DLBCL pts were GCB subtype of which 71% were rituximab refractory, with 3/7 achieving an objective response, 2 remaining in stable disease (4+ and 5+ mos each), and 2 having progressed to date (avg time on study 7 mos, range 2 - 16+ mos). Conclusions: The combination of UTX + TGR-1202 is active and well tolerated in pts with both indolent and aggressive rel/ref NHL and CLL. The Phase I portion is complete and enrollment remains open in expansion cohorts for CLL, FL/MZL and DLBCL pts evaluating TGR-1202 micronized doses at 800 to 1200 mg in combination with UTX. Given the favorable safety profile and clinical activity observed, Phase 3 programs are planned with UTX + TGR-1202. Disclosures Lunning: BMS: Consultancy; Juno: Consultancy; Gilead: Consultancy; Genentech: Consultancy; Spectrum: Consultancy; TG Therapeutics: Consultancy. Vose:Seattle Genetics, Inc.: Honoraria, Research Funding. Nastoupil:Genentech: Honoraria; Celgene: Honoraria; TG Therapeutics: Research Funding; AbbVie: Research Funding; Janssen: Research Funding. Burger:Pharmacyclics LLC, an AbbVie Company: Research Funding. Schreeder:TG Therapeutics, Inc: Research Funding. Siddiqi:Seattle Genetics: Speakers Bureau; Pharmacyclics/Jannsen: Speakers Bureau; Kite pharma: Other: attended advisory board meeting. Flowers:Seattle Genetics: Consultancy; Millennium/Takeda: Research Funding; OptumRx: Consultancy; Millennium/Takeda: Research Funding; Infinity Pharmaceuticals: Research Funding; Onyx Pharmaceuticals: Research Funding; AbbVie: Research Funding; AbbVie: Research Funding; Acerta: Research Funding; Gilead Sciences: Research Funding; Celegene: Other: Unpaid consultant, Research Funding; Pharmacyclics: Research Funding; Spectrum: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; OptumRx: Consultancy; Spectrum: Research Funding; Onyx Pharmaceuticals: Research Funding; Gilead Sciences: Research Funding; Janssen: Research Funding; Genentech: Research Funding; Genentech: Research Funding; Seattle Genetics: Consultancy; Janssen: Research Funding; Infinity Pharmaceuticals: Research Funding; Celegene: Other: Unpaid consultant, Research Funding. Cutter:Clearview Cancer Center: Employment. Pauli:Clearview Cancer Institute: Employment; TG Therapeutics, Inc.: Consultancy, Research Funding. Sportelli:TG Therapeutics, Inc.: Employment, Equity Ownership. Miskin:TG Therapeutics, Inc.: Employment, Equity Ownership. Weiss:TG Therapeutics, Inc.: Employment, Equity Ownership.

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Mature Follow up from a Phase 2 Study of PI3K-Delta Inhibitor Idelalisib in Patients with Double (Rituximab and Alkylating agent)-Refractory Indolent B-Cell Non-Hodgkin Lymphoma (iNHL)

Blood ◽

10.1182/blood.v124.21.1708.1708 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1708-1708 ◽

Cited By ~ 8

Author(s):

Ajay K. Gopal ◽

Brad S. Kahl ◽

Sven de Vos ◽

Nina D. Wagner-Johnston ◽

Stephen J. Schuster ◽

...

Keyword(s):

B Cell ◽

Research Funding ◽

Employment Equity ◽

Non Hodgkin Lymphoma ◽

Duration Of Response ◽

Equity Ownership ◽

Grade 3 ◽

Systemic Therapies

Abstract Introduction: Rituximab-alkylator combinations are the standard therapies for patients (pts) with iNHL, however, refractory disease nearly uniformly develops. Once iNHL becomes double-refractory to both rituximab + alkylating agents, there are limited options to induce durable remissions. PI3K-delta signaling is critical for activation, proliferation and survival of B cells, and is hyperactive in many B-cell malignancies. Idelalisib, a selective oral inhibitor of PI3Kd, demonstrated considerable clinical activity in double-refractory iNHL (Gopal NEJM 2014). FDA granted accelerated approval for Idelalisib (Zydelig®) in patients who have received at least two prior systemic therapies with relapsed FL or SLL. Based on these encouraging initial results, we now describe long-term follow up, safety, and remission durations of this double-refractory iNHL population treated with idelalisib. Methods: Eligible iNHL pts included those with measurable disease refractory to both rituximab and an alkylating agent. Refractory was defined as lack of response to, or progression of lymphoma within 6 months of completion of index therapy, confirmed by imaging. Idelalisib 150 mg PO BID was administered continuously until disease progression or intolerance. Responses were evaluated by an independent review committee, using standard criteria (Cheson, 2007, and Owen 2013). The new data cutoff date for this analysis was June 2014, 20 months after the last patient enrolled. Results: Enrolled pts (N = 125) had a median age of 64 years and included follicular lymphoma (FL) n=72 (58%), small lymphocytic lymphoma (SLL) n=28 (22%), marginal zone lymphoma (MZL) n=15 (12%) and lymphoplasmacytic lymphoma (LPL)/Waldenstrom's macroglobulinemia (WM) n=10 (8%). The median number of prior therapies was 4 [range 2-12], including bendamustine/rituximab (BR) (n=60) and rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) (n=56) and autologous transplant (n=14). 81 pts (65%) had prior bendamustine, of which 61/81 (75%) were refractory. 112 pts (90%) were refractory to their last regimen, and 99 pts (79%) were refractory to ≥2 regimens. 38 pts (30%) had elevated LDH, and 33 pts (26%) had bulky disease >7 cm. The median time to progression from last prior therapy was 3.9 months. With a median exposure of 11.1 months (range 0.7 to 35.4), the overall response rate (ORR) is 56% (95% CI = 46.8-64.9) with 70 responders, comprising 12 CRs (9.6%), 58 PRs (46.4%). The median time to response was 1.9 months (time of first evaluation) and time to CR was 4.5 months. There were 43 pts with stable disease (SD) (34.4%). 90% of pts experienced some decrease in tumor burden. ORR for iNHL subtypes is: FL (54%), SLL (61%), MZL (47%), and LPL/WM (70%). CR rate for iNHL subtypes is: FL (14%), SLL (4%), MZL (7%), and LPL/WM (0%). Among responders, median DOR is 13.9 (0.03-31.3) months. DOR for iNHL subtypes in months (Figure 1) is: FL 11.8, SLL 13.9, MZL 18.4, and LPL/WM (not yet reached). Median PFS for all pts is 11.0 months, in comparison to a median PFS of the last prior regimen of 3.9 months (p<.0001). The median PFS for individual subtypes in months was: FL 11.0, SLL11.1, MZL 6.6, and LPL/WM 22.2. The median overall survival of all patients was 30.8 months. The adverse events include (total%/≥ grade 3%) diarrhea/colitis (50/18), fatigue (30/2), nausea (31/2), cough (32/0), pyrexia (30/2), dyspnea (18/5), rash (14/2), pneumonia (14/11), and pneumonitis (4/3). Based on central laboratory measurements, Grade ≥3 ALT/AST elevations occurred in 18 pts (14%). Drug was temporarily held in these pts, and 11/15 pts (73%) were re-treated without recurrence of ALT/AST elevation. Overall, 30 pts (24%) have discontinued therapy due to adverse events. Conclusions: The prolonged administration of idelalisib was well tolerated, had an acceptable safety profile, and was highly effective in inducing and maintaining remissions in double-refractory iNHL population with an ORR of 56%, PFS of 11 months, and DOR of 13.9 months. The response rate and long term duration of responses in the small number of subjects with LPL/WM is very promising, and will be evaluated in larger trials of this disease. The observed disease control compared to prior regimens suggests the potential for prolonged clinical benefit in this challenging patient population with unmet medical need. Figure 1: Duration of Response by Disease Group. Figure 1:. Duration of Response by Disease Group. Disclosures Gopal: Gilead Sciences: Research Funding. Off Label Use: Zydelig is a kinase inhibitor indicated for the treatment of patients with: 1) Relapsed chronic lymphocytic leukemia (CLL), in combination with rituximab, in patients for whom rituximab alone would be considered appropriate therapy due to other co-morbidities; 2) Relapsed follicular B-cell non-Hodgkin lymphoma (FL) in patients who have received at least two prior systemic therapies; and 3) Relapsed small lymphocytic lymphoma (SLL) in patients who have received at least two prior systemic therapies.. Kahl:Gilead Sciences: Research Funding. de Vos:Gilead Sciences: Research Funding. Wagner-Johnston:Gilead Sciences: Research Funding. Schuster:Gilead Sciences: Research Funding. Jurczak:Gilead Sciences: Research Funding. Flinn:Gilead Sciences: Research Funding. Flowers:Gilead Sciences: Research Funding. Martin:Gilead Sciences: Research Funding. Viardot:Gilead Sciences: Research Funding. Blum:Gilead Sciences: Research Funding. Goy:Gilead Sciences: Research Funding. Davies:Gilead Sciences: Research Funding. Zinzani:Gilead Sciences: Research Funding. Dreyling:Gilead Sciences: Research Funding. Holes:Gilead Sciences: Employment, Equity Ownership. Sorensen:Gilead Sciences: Employment, Equity Ownership. Godfrey:Gilead Sciences: Employment, Equity Ownership. Salles:Gilead Sciences: Research Funding.

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Real-World Treatment Patterns and Overall Survival Among Medicare Fee-for-Service Beneficiaries Newly Diagnosed with Peripheral T-Cell Lymphoma

Blood ◽

10.1182/blood-2019-130973 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3492-3492

Author(s):

Anne Shah ◽

Allison Petrilla ◽

Mayvis Rebeira ◽

Joseph Feliciano ◽

Thomas W. LeBlanc ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Brentuximab Vedotin ◽

Treatment Patterns ◽

Fee For Service ◽

Newly Diagnosed ◽

Medicare Beneficiaries ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

Background: Peripheral T-cell lymphomas (PTCL) are a rare and heterogeneous group of lymphoid malignancies characterized by a clinically aggressive course with poor prognosis. A majority of PTCL patients are ≥60 years of age and typically present with advanced stage disease and multiple comorbidities. There remains no consensus standard of care for patients with most PTCL subtypes. Multi-agent chemotherapy, consisting of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or CHOP with etoposide (CHOEP), are guideline recommended options for nodal subtypes. Limited contemporary real-world data exist on the treatment patterns and overall survival (OS) of PTCL patients treated with CHOP or non-CHOP regimens in the United States before the FDA approval of brentuximab vedotin in combination with chemotherapy in November 2018 based on the ECHELON-2 trial. Objective: To evaluate treatment patterns and OS prior to the approval of brentuximab vedotin among Medicare Fee-for-Service (FFS) beneficiaries newly diagnosed with PTCL. Methods: The 100% sample of Medicare FFS claims (Parts A/B/D) was used to identify patients aged ≥65 years with ≥1 inpatient or ≥2 distinct outpatient diagnosis claims for PTCL (index event) from January 2011 to December 2017. Patients were required to have a least 6 months prior and 12 months post-index continuous Medicare enrollment, and were followed until disenrollment, death, or the end of the study period, whichever occurred first. OS, defined as the time from initial episode or treatment start date to the validated date of death, was measured using the Kaplan-Meier method; patients without a death date were assumed to be alive at the time of analysis and were censored. Results: A total of 2551 Medicare FFS beneficiaries with a PTCL diagnosis met study criteria and were included for analysis. The majority of patients were white (86.9%), over half were male (52.9%), and mean age was 75 years. Patients had multiple comorbidities at diagnosis (Charlson Comorbidity Index (CCI) score 4.47), including hypertension (77.3%), diabetes (32.9%), and chronic obstructive pulmonary disease (28.1%). Among the 2551 patients in the study cohort, 62.4% (n=1593 of 2551) received at least one identifiable drug regimen; 25.5% of treated patients received CHOP (n=407), 3.1% CHOEP (n=50) and 71.2% (n=1134) other regimens. Of patients treated with other regimens, 37.7% (n=427) received steroids only, 22.4% (n=254) steroids with unidentifiable chemotherapy, 6.9% (n=78) cyclophosphamide, 6.2% (n=70) methotrexate, 4.6% (n=52) brentuximab vedotin, 3.6% (n=41) bendamustine, 3.5% (n=40) romidepsin, and 15.2% (n=172) other therapy combinations. Among patients who were treated with CHOP, 16.6% (n=66) received an identifiable second line of therapy (LoT), 48.7% (n=194) an unidentifiable second LoT, and the remainder (34.7%, n=138) had no evidence of further anti-cancer treatment. The median time from CHOP initiation to a subsequent LoT was 5.6 months. The mean baseline CCI score for patients treated with CHOP was 4.33 (±2.93) compared with 4.76 (±2.97) for patients treated with other therapies (p=0.0118). In patients receiving an identifiable first LoT, median OS among CHOP and non-CHOP recipients was 4.8 years (95% CI 3.0-6.1) and 4.4 years (95% CI 3.0-4.9), respectively (Table). The 5-year OS estimate was 49% in patients receiving CHOP compared with 46% for non-CHOP recipients. Conclusions: Fewer than 30% of Medicare beneficiaries newly diagnosed with PTCL were treated with intensive chemotherapy as first LoT. Acknowledging a possible selection bias for more fit PTCL patients receiving CHOP, this group had increased OS compared with patients receiving non-CHOP therapy. However, the 5-year OS across all cohorts was less than 50%. New therapies such as brentuximab vedotin may fill the need for PTCL Medicare beneficiaries who may not be able to tolerate CHOP or CHOP-based regimens. Disclosures Shah: Avalere Health, An Inovalon Company: Employment. Petrilla:Avalere Health, An Inovalon Company: Employment. Rebeira:Seattle Genetics: Employment. Feliciano:Seattle Genetics: Employment, Equity Ownership. LeBlanc:Astra Zeneca: Consultancy, Research Funding; Duke University: Research Funding; Jazz Pharmaceuticals: Research Funding; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Helsinn: Consultancy; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; NINR/NIH: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Research Funding; CareVive: Consultancy; Celgene: Honoraria; Flatiron: Consultancy; American Cancer Society: Research Funding; Heron: Membership on an entity's Board of Directors or advisory committees; Medtronic: Membership on an entity's Board of Directors or advisory committees; Pfizer Inc: Consultancy. Lisano:Seattle Genetics, Inc.: Employment, Equity Ownership.

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