TGR-1202 in Combination with Ibrutinib in Patients with Relapsed or Refractory CLL or MCL: Preliminary Results of a Multicenter Phase I/Ib Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 641-641 ◽  
Author(s):  
Matthew S. Davids ◽  
Haesook T. Kim ◽  
Alyssa Nicotra ◽  
Alexandra Savell ◽  
Karen Francoeur ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Phase I ◽  
Dose Reduction ◽  
Median Time ◽  
Research Funding ◽  
Vitreous Hemorrhage ◽  
Employment Equity ◽  
Pi3k Inhibitors ◽  
Preliminary Results ◽  
Equity Ownership

Abstract Introduction The oral BTK inhibitor ibrutinib is highly effective at inducing partial responses (PR) in relapsed or refractory (R/R) CLL and MCL; however, complete responses (CR) are rare, and the durability of response for CLL patients (pts) with complex cytogenetics or del(17p) and for pts with MCL is limited. TGR-1202 is a novel oral PI3K-delta specific inhibitor designed to have less toxicity than other PI3K inhibitors, making it a logical drug to explore in combination regimens. We hypothesized that PI3K/BTK blockade would be tolerable and efficacious in R/R CLL and MCL. Methods This is a phase I/Ib investigator-initiated multicenter trial with primary objectives of determining the RP2D (recommended phase 2 dose) and the safety/tolerability of TGR-1202 plus ibrutinib in pts with R/R CLL or MCL. Secondary objectives are to assess overall response rates (ORR), CR rates, PFS, and OS. Pts receive continuous daily oral dosing of ibrutinib (420 mg CLL, 560 mg MCL) and TGR-1202. In phase I, TGR-1202 dose levels started at 400 mg daily and escalated in a standard 3 + 3 design to 600, then 800 mg daily. CLL and MCL pts were evaluated in separate arms, with a 28 day DLT observation period. Pts continue both drugs until progression or unacceptable toxicity. Eligibility criteria: ≥1 prior therapy, requiring treatment by IW-CLL criteria (CLL arm), ECOG PS ≤2, and adequate hematologic and organ function. Prior BTK or PI3K inhibitors were allowed. CTCAE v4 and IW-CLL or Cheson criteria (MCL) were used to evaluate toxicity and efficacy, with response evaluations after 2 mo., every 3 mo. up to 1 year, and every 6 mo. thereafter. Results As of July 26, 2016, 28 pts were evaluable, including 17 CLL and 11 MCL pts. The median age at enrollment was 67 yrs. (range 48-83). The median number of prior therapies was 2 for CLL (range 1-6, including 2 who started ibrutinib prior to enrollment and 3 with prior PI3Ki who came off prior PI3Ki for reasons other than progressive disease) and 3 for MCL (range 2-5, including 4 with prior autoSCT and 2 with prior ibrutinib). In CLL pts, del(17p) was present in 4/17 (24%), del (11q) in 7/17 (41%), unmutated IGHV in 11/17 (65%), and NOTCH1 or TP53 (without del(17p)) mutation in 2 pts each. In phase I, there were no DLTs in either arm, and the RP2D of TGR-1202 for both CLL and MCL was identified as 800 mg. Hematologic toxicities in CLL include: neutropenia (18%: 6% gr3, 12% gr4), thrombocytopenia (12%, all gr1), and anemia (12%, all gr1/2). All grade non-hematologic toxicities in >20% of CLL pts include: diarrhea (24%: 18% gr1, 6% gr2) and nausea (24%, all gr1). SAEs include gr 3 atrial fibrillation, lipase elevation, and adrenal insufficiency in 1 pt each, 1 pt with CNS aspergillus infection that likely preceded enrollment, and 1 case of sudden death of uncertain cause. Three CLL pts had dose-reduction of ibrutinib (atrial fibrillation, palpitations, vitreous hemorrhage). Hematologic toxicities in MCL include: neutropenia (18%, 6% gr4), thrombocytopenia (18%, 6% gr3), and anemia (18%, 6% gr3). All grade non-hematologic toxicities in >20% of MCL pts include: diarrhea (29%, all gr1), fatigue (29%, all gr1/2), and 24% each for nausea (all gr1/2) and dizziness (all gr1). SAEs included gr3 hypophosphatemia in 2 pts and gr4 lipase elevation in 1 pt. One MCL pt had dose reduction of TGR-1202 (dizziness). Study-wide, 5/28 (18%) pts had transaminitis, all gr1, and bleeding events included gr1 epistaxis, hematuria, and vitreous hemorrhage in 1 CLL pt each. For CLL, the ORR is 82% (14/17), with 35% PR-L (6/17), 41% PR (7/17), and 6% CR (1/17) with bone marrow MRD positivity. 6/8 CLL pts in PR on treatment for ≥6 mo. have residual LN's <2 cm in long axis. All 3 pts with prior PI3Ki exposure responded, and as did 1 of the 2 pts with prior ibrutinib exposure. The median time on study for CLL pts is 9.3 mo. (range 2.5-19.7 mo.). For MCL, the ORR is 67%, with 6/9 pts achieving PR including 1 of the 2 pts with prior ibrutinb. The median time on study for MCL pts is 10.9 mo. (range 1.1-19.8 mo.). Conclusions We report preliminary results of the first dedicated study to look at a PI3Ki plus BTKi doublet in B cell malignancies. TGR-1202 plus ibrutinib is well-tolerated in pts with R/R CLL and MCL, with no DLTs observed. The RP2D of TGR-1202 for both CLL and MCL is 800 mg daily. Preliminary efficacy data suggest a high response rate in both diseases, with several CLL pts close to radiographic CR. Phase Ib expansion cohorts at 800 mg continue to accrue in this ongoing study (NCT 02268851). Disclosures Davids: Infinity: Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Gilead: Honoraria; Abbvie: Consultancy, Honoraria; TG Therapeutics: Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding. Miskin:TG Therapeutics, Inc: Employment, Equity Ownership. Sportelli:TG Therapeutics, Inc.: Employment, Equity Ownership. Arnason:Gilead: Consultancy. Jacobson:Kite: Membership on an entity's Board of Directors or advisory committees. Fisher:Pharmacyclics: Consultancy. Brown:Janssen: Consultancy; Abbvie: Consultancy; Celgene: Consultancy; Infinity: Consultancy; Sun BioPharma: Consultancy; Roche/Genentech: Consultancy; Gilead Sciences: Consultancy; Pfizer: Consultancy.

Vorinostat in Combination with Decitabine for the Treatment of Relapsed or Newly Diagnosed Acute Myelogenous Leukemia (AML) or Myelodysplastic Syndrome (MDS): A Phase I, Dose-Escalation Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2089-2089 ◽  
Author(s):  
Mark Kirschbaum ◽  
Ivana Gojo ◽  
Stuart L. Goldberg ◽  
Lisa Kujawski ◽  
Ehab Atallah ◽  
...  
Keyword(s):  
Phase I ◽  
Board Of Directors ◽  
Research Funding ◽  
Sequential Therapy ◽  
Employment Equity ◽  
Advisory Committees ◽  
Concurrent Therapy ◽  
Equity Ownership ◽  
Experienced Treatment ◽  
Refractory Aml

Abstract Abstract 2089 Poster Board II-66 Introduction: Although the introduction of epigenetic therapies, such as the DNA methyltransferase inhibitor (DNMT) decitabine, has improved options for the treatment of myeloid malignancies, use is limited by sub-optimal response rates. Therefore, there remains a need for more effective treatment strategies to improve outcomes in AML/MDS. Preclinical and clinical data suggest that broadening epigenetic targeting by adding histone deacetylase (HDAC) inhibitors to DNMTs may improve responses. In addition, it has been reported that outcomes may differ according to the sequence in which HDAC and DNMT inhibitors are combined. Aim: Here we present preliminary data from a Phase I, open-label, multicenter, dose-escalating study, designed to determine the maximum-tolerated dose (MTD) and recommended Phase II dose of the HDAC inhibitor vorinostat combined either concurrently or sequentially with decitabine in patients (pts) with AML/MDS. Other endpoints include tolerability and exploratory assessments of activity. Methods: Pts (≥18 years) with intermediate-high risk MDS, relapsed/refractory AML, or untreated AML (≥60 years; unsuitable for standard chemotherapy), with an ECOG performance status of ≤2, were enrolled into one of six dosing levels (Table) and received treatment for up to 24 months or until disease progression (PD). Results: As of August 3, 2009, 72 pts have entered the study: median age was 68 years (range 18-85) and 58% were male. To date, 69 pts have discontinued due to PD/lack of efficacy (n=37), withdrawal of consent (n=12), adverse events (AEs) (n=16), physician decision (n=3), and protocol deviation (n=1). Of 70 pts evaluable for safety, 69 experienced AEs, the majority of which were Grade 1/2 in severity and included nausea (n=48), diarrhea (n=41), fatigue (n=36), constipation (n=32), and vomiting (n=28). 62 (89%) pts experienced treatment-related AEs and 17 (24%) pts experienced treatment-related serious AEs. 14 deaths occurred during the study, although none were related to study treatment. One dose-limiting toxicity, prolonged QT interval, was documented in dose level 3a. Combinations of vorinostat and decitabine in the schedules in this protocol did not reach MTD. As per protocol, dose levels 3 and 3a were the maximum administered doses and have been expanded. Of the 61 pts evaluable for response, 11 had MDS, 25 had relapsed/refractory AML, and 25 had untreated AML. In pts with MDS receiving concurrent therapy (n=5), complete remission (CR) was achieved in 2 pts, stable disease (SD) in 1 pt, partial remission (PR) in 1 pt, hematologic improvement (HI) in 1 pt; all 6 of the pts who received sequential treatment experienced SD. In pts with relapsed/refractory AML receiving concurrent therapy (n=12), CR was achieved in 1 pt, CR without recovery of counts (CRi) in 1 pt, HI in 1 pt, SD in 6 pts, while 3 pts had PD; in those receiving sequential therapy (n=13), SD was achieved in 9 pts while 4 had PD. In pts with untreated AML receiving concurrent therapy (n=12), CR was achieved in 4 pts, CRi in 1 pt, PR in 1 pt, and SD in 6 pts, and in those receiving sequential therapy (n=13), CR was achieved in 2 pts, CRi in 2 pts, PR in 1 pt, HI in 2 pts, and SD in 5 pts. Overall, CR or CRi was achieved by 18% pts with MDS, 8% with relapsed/refractory AML, and 36% with untreated AML; and HI was reported in 9% pts with MDS, 4% with relapsed/refractory AML, and 8% with untreated AML. Conclusion: These preliminary data indicate that the combination of vorinostat with decitabine, either concurrently or sequentially, is possible without significant toxicity. In addition, the combination shows promising activity in MDS and untreated AML. Disclosures: Kirschbaum: Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celegene: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Off Label Use: Vorinostat is a histone deacetylase (HDAC) inhibitor that was approved in the FDA in October 2006 for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma (CTCL) who have progressive, persistent, or recurrent disease on or following two systemic therapies. Goldberg:Merck: Research Funding. Marks:Merck: Research Funding. Di Gravio:Merck: Employment, Equity Ownership. Pyle:Merck: Employment, Equity Ownership. Rizvi:Merck: Employment, Equity Ownership. Issa:Eisai: Consultancy, Research Funding; Celegene: Research Funding; MGI Pharma: Research Funding.

A Phase I/II Study of BHQ880, a Novel Osteoblat Activating, Anti-DKK1 Human Monoclonal Antibody, in Relapsed and Refractory Multiple Myeloma (MM) Patients Treated with Zoledronic Acid (Zol) and Anti-Myeloma Therapy (MM Tx).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 750-750 ◽  
Author(s):  
Swaminathan Padmanabhan ◽  
Joseph Thaddeus Beck ◽  
Kevin R. Kelly ◽  
Nikhil C. Munshi ◽  
Andy Dzik-Jurasz ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Phase I ◽  
Bone Disease ◽  
Research Funding ◽  
Human Monoclonal Antibody ◽  
Wnt Signaling Pathway ◽  
Mineral Density ◽  
Employment Equity ◽  
Osteolytic Lesions ◽  
Equity Ownership

Abstract Abstract 750 Background: DKK1 is a negative regulator of the Wnt signaling pathway in bone that is overexpressed in a subset of newly-diagnosed MM patients with osteolytic lesions as well as in refractory and relapsed patients. Expression also correlates with the number of osteolytic lesions in untreated MM patients. BHQ880 is a novel anti-DKK1 human monoclonal antibody. Alleviation of DKK1 inhibition by BHQ880 results in activation of the Wnt signaling pathway, leading to increased bone mass mediated via upregulation of osteoblasts in mice and monkeys. In murine models of MM bone disease; this anabolic activity of BHQ880 increased trabecular and cortical bone density. Lytic bone disease in MM is caused by osteoclast activation and osteoblast inhibition. Current approved therapies for the treatment of MM bone disease are focused on osteoclast inhibition (e.g., bisphosphonates) and BHQ880 therapy may be able to reverse the effects of DKK1-induced osteoblast inhibition. Therefore, dual therapy with zoledronic acid to decrease bone resorption and BHQ880 to increase new bone formation may provide an effective treatment strategy for MM bone disease. Methods: In the phase I portion of this phase I/II study, patients with relapsed or refractory MM with prior skeletal-related event (SRE) were treated with BHQ880 as an IV infusion Q28 days. Patients also received Zol (4 mg) and approved MM Tx (bortezomib not allowed). Bone markers and total DKK1 levels along with bone mineral density are being measured. Full PK profiles were collected during the first and second cycle, after which predose (trough) samples were collected to assess accumulation. Results: Ten pts (6:M, 4:F), median age: 66.5 yrs (range 41- 70), performance status-0(5 pts), 1(4 pts), 2 (1 pts) have been enrolled in the following dose levels (mg/kg) 3 (2 pts), 10 (starting dose level -4 pts), 20 (4 pts) and have been on treatment for 1 day to 5 28-day cycles. No BHQ880-related AE's have been observed to date. Bone mineral density (BMD) data from the first two patients treated at 10 mg show the following: a.) Pt 1 (hip +5.8%, spine N/A due to surgery, wrist -1.8%); b.) Pt 2 (hip -0.2%, spine +6.1%, wrist not done). The biomarker data from these patients show: a.) Pt 1 shows a maximal +98% change over baseline in PINP at day 15 post-treatment, while osteocalcin (OC) changes +17% at day 15, reaching a +56% change over baseline at cycle 4 day 1; uNTx/Cr changes – 43 % at cycle 2 day 15. b) Partial data from Pt 2 suggests a -44 % change in PINP and –73 % change in OC and a +73% change in uNTx/Cr. Baseline total DKK1 levels on 3 patients ranged from 8.8 to 21.5 ng/mL. Preliminary PK analysis is available in 1 out of 3 patients treated at 10mg/kg. The Cmax achieved after the first infusion was 165 ug/mL and 201 ug/mL after the second infusion. Calculated t1/2 was 188 hours after the first infusion and 254 hours after the second infusion. Regarding overall exposure, AUC0-672 hours after first infusion was 36081 hr*ng/mL and 48533 hr*ng/mL after the second infusion. Conclusion: BHQ880 given IV Q28 days appears to be well tolerated in combination with Zol and chosen MM Tx. Once safety of 40 mg/kg BHQ880 or the MTD dose has been determined, pts will be enrolled in the phase II portion to assess activity on a SRE endpoint. Updated safety, efficacy, bone density and biomarker data will be presented on all patients at the upcoming ASH meeting. Disclosures: Padmanabhan: Genentech: Consultancy, Honoraria; GSK: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Off Label Use: BHQ880, a novel osteoblast activating, anti-DKK1 antibody. Dzik-Jurasz:Novartis: Employment, Equity Ownership. Gangolli:Novartis: Employment, Equity Ownership. Ettenberg:Novartis: Employment, Equity Ownership. Miner:Novartis: Employment, Equity Ownership. Bilic:Novartis: Employment, Equity Ownership. Whyte:Novartis: Employment, Equity Ownership. Mehdi:Novartis: Employment, Equity Ownership. Chiang:Novartis: Employment, Equity Ownership. Rae:Novartis: Employment, Equity Ownership. Shah:Novartis: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Millenium: Research Funding, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Elan: Consultancy. Giles:Novartis: Consultancy, Research Funding; BMS: Research Funding; Merck: Research Funding; Clavis: Research Funding. Stewart:Novartis: Consultancy; Amgen: Consultancy; Millenium: Consultancy, Research Funding; Proteolix: Consultancy; Celgene: Honoraria.

Evaluation of Oral Azacitidine Using Extended Treatment Schedules: A Phase I Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 603-603 ◽  
Author(s):  
Guillermo Garcia-Manero ◽  
Steven D. Gore ◽  
Christopher R. Cogle ◽  
Elias J. Jabbour ◽  
M. Renee Ward ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Phase I ◽  
Research Funding ◽  
Phase I Study ◽  
Treatment Schedule ◽  
Employment Equity ◽  
Transfusion Independence ◽  
Clinical Responses ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 603 Parenteral azacitidine (AZA) is approved for administration on days 1–7 of a 28-day treatment schedule. Based on the short plasma half-life of AZA, S-phase restricted incorporation into DNA, and rapid re-methylation of DNA, it is possible that chronic daily exposure could enhanced its clinical activity. An oral formulation would be convenient and allow evaluation of lower doses administered on extended schedules. The initial phase I study of oral AZA, administered daily on a 7-day schedule demonstrated that it was bioavailable, safe, and clinically active in patients with MDS and AML (Garcia-Manero G, et al. Blood 2009;114:A117). Here, we report the results of a multicenter phase I exploration of extended oral AZA schedules, including dose-limiting toxicities (DLTs), safety, pharmacokinetic (PK), pharmacodynamic (PD), and preliminary response data. Patients aged ≥ 18 years with MDS, CMML or AML (not candidates for other therapies) were enrolled in the study. Inclusion criteria were a hemoglobin level of ≤ 9.0 g/dL, and/or platelet count of ≤ 50 × 109/L, and/or be RBC transfusion-dependent; prior azanucleoside therapy was not permitted. Patients received oral AZA daily (QD) or twice daily (BID) on 14- or 21-days schedules, with starting at a dose of 300 mg for QD dosing and 200 mg for BID dosing. Patients were enrolled into cohorts of 6 and evaluated for DLTs at the end of Cycle 1. Patients were monitored continuously for adverse events (AEs) and assessed for disease response at the end of every second cycle. During Cycle 1, on the first and last day of treatment, PK parameters were derived from AZA concentrations in the plasma after the first dose of the day. PD samples were collected during the first 2 cycles and DNA methylation changes were evaluated using a LINE-1 assay. To date, 25 patients (median age 68 years [range 44–87]; 14 male and 11 female) with MDS (n = 13), AML (n = 7 de novo and n = 3 transformed), and CMML (n = 2) have received oral AZA on extended treatment schedules. Two DLTs, grade 3 nausea and grade 3 vomiting, occurred in 1 of 6 DLT-evaluable patients treated at 14-days QD (n = 7). No DLTs were observed on the 21-day QD (n = 6) or 14-day BID (n = 6) schedules; safety evaluation for the 21-day BID schedule is ongoing (n = 6). The maximum tolerated dose has not been reached on these schedules; no patient has received > 300 mg per dose. Overall rates of all grades nausea, vomiting, diarrhea, constipation, and abdominal pain with the extended schedules were similar to those observed with the oral 7-day schedule. The rate of febrile neutropenia (all grades) was higher in the 21-day QD cohort. This was observed in 4 patients with baseline ANC < 500 and/or AML diagnosis. Most common grade 3/4 AEs in the QD schedules were febrile neutropenia (14-day, 1/7; 21-day, 4/6), anemia (14-day, 1/7; 21-day, 0/6), thrombocytopenia (14-day, 1/7; 21-day, 1/6), diarrhea (14-day, 0/7; 21-day, 1/6), nausea (14-day, 1/7; 21-day, 0/6), and vomiting (14-day, 1/7; 21-day, 0/6). Extended BID schedules are under evaluation. PK data have been generated for 19 of 25 patients. For the 300 mg 14-day QD, 300 mg 21-day QD, and 200 mg 14-day BID schedules, using mean AUC (first and last day) results, extrapolated cumulative exposures per cycle were ~28%, 42% and 26%, respectively, compared with historical exposure observed following subcutaneous administration. AZA exposure increased with increasing dose, but was not dose-proportional. Clinical responses were observed for MDS/CMML patients on both extended QD schedules, with assessment ongoing for BID schedules (Table). In summary, extended (14- and 21-day) dosing of oral AZA is generally well tolerated, with no AZA accumulation, and promising clinical responses were observed, including complete remission (CR), marrow CR (mCR), and hematologic improvement (HI). Table. Parameter, n (%) Oral AZA Treatment Schedule MDS/CMML Responders/Evaluable patients, (%) 14-day QD 21-day QD Overall response* (CR, mCR, any HI) 5/6 (83) 3/3 (100) CR 0/6 2/3 (67) mCR 0/6 3/3 (100) HI 5/6 (83) 3/3 (100) HI-erythroid 3/5 (60) 1/1 (100) HI-platelet† 2/5 (40) 3/3 (100) HI-neutrophil 0/1 0/1 Transfusion independence 3/4 (75) 1/2 (50) RBC 1/2 (50) 1/1 (100) Platelet 2/2 (100) 0/1 * International Working Group 2006 criteria, patients only counted once for overall response, but may be counted more than once in individual response categories. † Includes patients achieving partial (≥ 50%) or complete platelet transfusion independence. Disclosures: Gore: Celgene: Consultancy, Equity Ownership, Research Funding. Cogle:Celgene: Research Funding, Speakers Bureau. Ward:Celgene: Equity Ownership. MacBeth:Celgene: Employment, Equity Ownership. Laille:Celgene: Employment. Giordano:Celgene: Employment, Equity Ownership. Kantarjian:Celgene: Research Funding. Skikne:Celgene: Employment.

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

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

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

The Bruton's Tyrosine Kinase Inhibitor Ibrutinib (PCI-32765) Is Active and Tolerated in Relapsed Follicular Lymphoma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 156-156 ◽  
Author(s):  
Nathan H Fowler ◽  
Ranjana H Advani ◽  
Jeff Sharman ◽  
Sonali M. Smith ◽  
Jesse McGreivy ◽  
...  
Keyword(s):  
Phase I ◽  
Follicular Lymphoma ◽  
B Cell ◽  
Median Time ◽  
Phase I Study ◽  
Study Drug ◽  
Employment Equity ◽  
Phase Ii Studies ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 156 Background Bruton's tyrosine kinase (BTK) is a central mediator of B-cell receptor (BCR) signaling and is essential for normal B-cell development. Subtypes of non-Hodgkins lymphoma (NHL) may be dependent on chronic activation of the BCR pathway and primary follicular lymphoma (FL) cells have been found to maintain enhanced signaling when compared to normal B-cells (Irish JM, et al. Blood 2006; 108: 3135). Ibrutinib is an orally administered, covalently-bound inhibitor of BTK which induces apoptosis and inhibits cellular migration and adhesion in malignant B-cells. Based on promising preclinical data in B-cell malignancies, a phase I study was conducted to test the safety, tolerability, pharmacokinetics, and pharmacodynamics of ibrutinib in relapsed NHL. We report the long-term tolerability and sustained activity of ibrutinib in FL patients in this study with extended follow-up. Methods Adult patients with relapsed or refractory B-cell lymphoma were eligible for trial entry and 16 patients with FL were enrolled in this Phase I study. Ibrutinib was administered orally with dose escalation according to protocol-defined dose-limiting toxicities (DLT) to define a maximum tolerated dose (MTD) or until 3 dose levels above attainment of full BTK occupancy. A 28-day on/7-day off (intermittent) schedule was evaluated in 5 cohorts (1.25–12.5 mg/kg PO qd) and a once daily oral dose (without a drug holiday) in 2 cohorts (8.3 mg/kg and 560-mg fixed dose). Patients were evaluable for safety if they received study drug. Efficacy was evaluated in all patients who received 2.5 mg/kg or higher (which achieves full BTK occupancy) and had one on-study imaging assessment. Efficacy was also analyzed at higher doses to determine if there was improved efficacy. Responses were assessed every 2 months using the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Results Median age 60 (41–71), equal numbers of males and females, median time from diagnosis 54 months (19–186), median number of prior therapies 3 (1–5) including: stem cell transplantation (6%), alkylators (88%), anthracyclines (56%), nucleoside analogs (19%), and rituximab (100%). FLIPI scores at baseline: low risk = 19%, intermediate risk = 37%, high risk = 44%. Treatment-emergent AEs occurring in ≥ 25% included: diarrhea (50%), fatigue (44%), nausea (38%), cough (31%) and myalgia (25%). Observed grade 3 AEs included: anemia, anxiety, hypersensitivity, hypokalemia, hypophosphatemia, decreased neutrophil count, non-cardiac chest pain, pancytopenia, pneumonia and vomiting (one event each). A Grade 4 hypokalemia occurred and was considered to be related to study drug by the investigator. One case of myelodysplastic syndrome occurred 29 days after the last dose of ibrutinib in a patient with pre-existing anemia and multiple lines of prior treatment and was considered to be unrelated by the investigator. One patient in the 2.5 mg/kg/day intermittent cohort experienced DLTs of grade 2 neutropenia resulting in the ibrutinib dose being held > 7 days and a grade 4 hypokalemia. One patient in the 8.3 mg/kg/day intermittent cohort experienced a Grade 3 hypersensitivity reaction. No DLTs were observed in the 12.5 mg/kg/day cohort and the MTD was not reached. In the 16 patients with FL, 11 patients received ibrutinib at 2.5 mg/kg or higher and were evaluable for efficacy (2 patients at 2.5 mg/kg, 1 at 5 mg/kg, 3 at 8.3 mg/kg intermittent, 3 at 12.5 mg/kg, 2 at 8.3 mg/kg continuous dosing). Median time on ibrutinib was 7 months (0–29). Overall response rate (ORR) 54.5% (3 CRs, 3 PRs), duration of response (DOR) 12.3 months, median PFS 13.4 months. In the 9 patients who received ibrutinib at 5 mg/kg or higher, the median time on ibrutinib, ORR and DOR were similar to the efficacy in the 11 patients. However, there was a slight trend toward improved PFS of 19.6 months; 2 patients are still responding to ibrutinib at 25 and 29 months. Conclusions The BTK inhibitor ibrutinib (PCI-32765) is well tolerated and active in patients with relapsed FL. Based upon drug occupancy and clinical responses, a dose of 5 mg/kg/day or above is recommended for phase II studies. Extended dosing did not appear to increase toxicity and response rates improved with continued treatment in some patients. Phase II studies with ibrutinib in FL are planned. Disclosures: Advani: Pharmacyclics, Inc: Research Funding. Sharman:Celgene: Consultancy; Pharmacyclics: Honoraria; Calistoga: Honoraria; Portola pharmaceuticals: Consultancy. McGreivy:pharmacyclics: Employment. Kunkel:Pharmacyclics: Employment, Equity Ownership. Troung:Pharmacyclics, Inc: Employment, Equity Ownership. Zhou:Pharmacyclics, Inc.: Employment, Equity Ownership.

Interim Results of an International, Multicenter, Phase 2 Study of Bruton's Tyrosine Kinase (BTK) Inhibitor, Ibrutinib (PCI-32765), in Relapsed or Refractory Mantle Cell Lymphoma (MCL): Durable Efficacy and Tolerability with Longer Follow-up

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 904-904 ◽  
Author(s):  
Michael Wang ◽  
Simon A. Rule ◽  
Peter Martin ◽  
Andre Goy ◽  
Rebecca Auer ◽  
...  
Keyword(s):  
B Cell ◽  
Median Time ◽  
Research Funding ◽  
Tumor Response ◽  
Single Agent ◽  
Safety Data ◽  
Phase 2 ◽  
Employment Equity ◽  
Equity Ownership

Abstract Abstract 904 Background Bruton's tyrosine kinase (BTK) is a central mediator of B-cell receptor (BCR) signaling which is essential for normal B-cell development. Ibrutinib is an orally administered inhibitor of BTK that induces apoptosis and inhibits cellular migration and adhesion in malignant B-cells. MCL is an aggressive subtype of NHL, and despite high response rates to initial therapy, patients often relapse with acquired chemotherapy resistance and short response durations to conventional therapy. Preliminary results in 51 evaluable patients from the Phase 2 PCYC-1104 study demonstrated ibrutinib could achieve rapid nodal responses (including complete responses) in relapsed and refractory MCL patients (Wang et al, ASH 2011). Treatment with ibrutinib was associated with a transient increase in peripheral lymphocyte count representing a compartmental shift of cells with the CD19+/CD5+ phenotype from nodal tissues to peripheral blood (Chang et al, ASH 2011). Reported here are interim results of an international study of single-agent ibrutinib in previously treated MCL. Methods Subjects with relapsed or refractory MCL who were either bortezomib-naïve or bortezomib-exposed (prior treatment with at least 2 cycles of bortezomib) were enrolled. Ibrutinib was administered orally at 560mg daily (in continuous 28-day cycles) until disease progression. Bortezomib-naive and bortezomib-exposed cohorts were evaluated separately. Tumor response was assessed every 2 cycles according to the revised International Working Group for NHL criteria. The primary endpoint of the study is overall response rate (ORR). Secondary endpoints include: duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Subjects A total of 115 subjects (65 bortezomib-naïve and 50 bortezomib-exposed) were enrolled between February 15, 2011 and July 3, 2012. Of the 111 subjects treated, 109 subjects were evaluable for efficacy (received at least one dose of ibrutinib and underwent ≥ 1 tumor response assessment). Baseline characteristics include median age 68 years (40–84), median time since diagnosis 42 months, median number of prior treatments 3 (1–6), bulky disease (≥ 10 cm) 13%, Ann Arbor stage IV at screening 77.4%, prior stem cell transplant 9.6%, high risk by MIPI score at baseline assessment 48.7%, and refractory disease 44.3%. Results Safety data are available for 111 subjects. Treatment-emergent AEs occurring in ≥ 15% of subjects: diarrhea (35%), fatigue (32%), upper respiratory tract infections (23%), nausea (21%), rash (21%), dyspnea (20%), and oedema peripheral (15%). Grade 3 or higher AEs occurring in ≥ 5% of subjects were neutropenia (11%), anemia (5%), diarrhea (5%), dyspnea (5%), pneumonia (5%), and thrombocytopenia (5%). Grade 4 treatment-related AEs were neutropenia (5%), hyperuricaemia (2%), and pancytopenia (1%). One grade 5 AE, pneumonia, was thought to be treatment-related. In the efficacy evaluable subjects, the ORR (complete + partial responses) is reported in Table 1. The median time on treatment was 6.0 months (0.7-16.6 months); 53% of subjects remain on treatment. Median DOR, PFS and OS have not been reached: 9 month DOR 65%, 12 month estimation of PFS 53% and OS 67%. Responses to ibrutinib increase with longer time on study treatment. Time to PR ranged from 1.4 – 8.3 months (median 1.9) and CR ranged from 1.7 – 11.2 months (median 3.9). This is seen with longer follow-up on the initial 51 subjects reported at ASH 2011: median time on study treatment was 3.8 months and is now 11.3 months; ORR was 69% and is now 74.5%; CR rate was 16% and is now 35.3%. Conclusions Longer follow up demonstrates the durability of responses and confirms the unprecedented single agent activity of ibrutinib in relapsed or refractory MCL in terms of ORR. The treatment- emergent AEs were consistent with safety data previously reported. A pivotal study in relapsed and refractory MCL patients following bortezomib treatment has been initiated. Disclosures: Wang: Pharmacyclic: Research Funding. Off Label Use: Ibrutinib is a novel agent being studied in a clinical trial. Rule:Pharmacyclics: Research Funding. Martin:Pharmacyclics: Research Funding. Goy:Pharmacyclics: Research Funding. Auer:Pharmacyclics: Research Funding. Kahl:Pharmacyclics: Research Funding. Jurczak:Pharmacyclics: Research Funding. Advani:Pharmacyclics: Research Funding. McGreivy:pharmacyclics: Employment, Equity Ownership. Clow:Pharmacyclics: Employment, Equity Ownership. Stevens-Brogan:Pharmacyclics: Employment, Equity Ownership. Kunkel:Pharmacyclics: Employment, Equity Ownership. Blum:Pharmacyclics: Research Funding.

Relationship Between Lenalidomide Dose Modification and Duration Of Treatment In Newly Diagnosed Multiple Myeloma Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2944-2944
Author(s):  
Kathy Lang ◽  
Gary Binder ◽  
Iris Lin ◽  
Dejan Milentijevic ◽  
Huan Huang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Dose Reduction ◽  
Research Funding ◽  
Duration Of Treatment ◽  
Employment Equity ◽  
Medical Claims ◽  
Dose Modification ◽  
Equity Ownership ◽  
Dose Change ◽  
Dose Reductions

Abstract Introduction A number of studies have shown clinical benefits for multiple myeloma (MM) patients who continue to stay on therapy with lenalidomide (LEN), including progression-free survival (PFS) and overall survival (OS) (Palumbo A, et al. NEJM. 2013, McCarthy P, et al. NEJM. 2013, Boccadoro. JCO. 2013). Dose modification is one factor used by physicians to achieve sustained duration of treatment (DOT), particularly to manage toxicities and/or pursue a continuous therapy regimen; in a clinical trial of LEN in newly diagnosed MM (NDMM) patients (pts) followed-up for a median of 30 mos, 42% of pts experienced a dose reduction (Palumbo A, et al. NEJM. 2012). This analysis evaluated whether there is supporting evidence, in a real-world setting, for physicians using LEN dose modification to achieve a longer time on therapy. Objective Medical claims analysis was performed to evaluate the relationship between lenalidomide (LEN), dose modification and DOT among patients with NDMM. Methods A retrospective cohort analysis was conducted using a claims database from a large US payer, covering approximately 14 million commercially insured and Medicare advantage members. Patients with at least two outpatient or one inpatient medical claims associated with a diagnosis of MM (ICD-9-CM code: 203.0x) between Jan 1, 2008 and Oct 31, 2012 were extracted from the database. Index date was defined as the date of the first diagnosis of MM. A minimum of 12 months pre-index and 6 months post-index enrollment with no MM treatment was required to define the NDMM patient population. To avoid DOT limitations imposed by fixed-length induction therapy, only pts without claims for stem cell transplant (SCT) were evaluated. DOT was compared among the group treated with LEN who had dose modification (increase or decrease in number of mg per day) relative to the group with no dose modification. Results Among the 236 pts meeting the inclusion criteria, 69 (29%) pts had LEN dose reductions, 15 (6%) had dose increases, and 152 (64%) had no dose change. DOT in pts without a dose change was 7.33 months ± 7.62 (mean ± SD), while pts who had a dose reduction had significantly longer DOT of 14.63 months ± 10.47 (p<0.01). Of the 69 pts with dose reductions, DOT before dose reduction was 5.18 months ± 4.82 compared with 9.46 months ± 10.26 after dose reduction (p<0.01, paired). The subset of pts who were still on LEN therapy at the end of the data window (N=27) showed a similar association between dose reduction and DOT, with DOT of 20.29 months ± 11.62 and 11.99 months ± 9.29 in dose reduction and non-dose reduction subgroups (p<0.01), respectively. Conclusion NDMM pts who had dose reductions of LEN had twice the duration of therapy compared with pts without dose reductions. This analysis suggests that dose modification of MM treatment may be an effective tool to help pts achieve the benefits associated with longer time on therapy. Future clinical studies are needed to determine the best approaches to dose adjustment to improve disease control. Disclosures: Lang: Celgene: Research Funding. Off Label Use: Lenalidomide is a thalidomide analog indicated for the treatment of multiple myeloma, in combination with dexamethasone, in patients who have received at least one prior therapy. Binder:Celgene: Employment, Equity Ownership. Lin:Celgene: Research Funding. Milentijevic:Celgene: Consultancy. Huang:Celgene: Research Funding. Nagarwala:Celgene: Employment, Equity Ownership. Harwin:Celgene: Honoraria.

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

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1538-1538 ◽  
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.

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 ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3980-3980 ◽  
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.

scholarly journals Phase I Trial of Targeted Alpha-Particle Therapy Using Actinium-225 (225Ac)-Lintuzumab (Anti-CD33) in Combination with Low-Dose Cytarabine (LDAC) for Older Patients with Untreated Acute Myeloid Leukemia (AML)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5293-5293 ◽  
Author(s):  
Joseph G Jurcic ◽  
Farhad Ravandi ◽  
John M. Pagel ◽  
Jae H Park ◽  
B. Douglas Smith ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase I ◽  
Dose Escalation ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Phase I Trial ◽  
Particle Therapy ◽  
Employment Equity ◽  
Molecular Abnormalities ◽  
Equity Ownership

Abstract Background: Lintuzumab, a humanized anti-CD33 monoclonal antibody, targets myeloid leukemia cells but has only modest activity in AML. To increase the antibody’s potency yet avoid nonspecific cytotoxicity of β-emitting isotopes, 225Ac (t½=10 d), a radiometal that yields 4 α-particles, was conjugated to lintuzumab. A phase I trial showed that 225Ac-lintuzumab is safe at doses ≤ 3 µCi/kg and has anti-leukemic activity across all dose levels studied (Jurcic et al. ASH, 2011). We are conducting a multicenter, phase I dose-escalation trial to determine the maximum tolerated dose (MTD), toxicity, and biological activity of fractionated-dose 225Ac-lintuzumab in combination with LDAC. Patients and Methods: Patients ≥ 60 yrs who had untreated AML with poor prognostic factors, e.g., an antecedent hematologic disorder, unfavorable cytogenetic or molecular abnormalities, and significant comorbidities, were eligible. Patients received LDAC 20 mg twice daily for 10 d every 4-6 wks for up to 12 cycles. During Cycle 1, beginning 4-7 days after completion of LDAC, two doses of 225Ac-lintuzumab were given approximately one week apart. To prevent radiation-induced nephrotoxicity, patients were given furosemide while receiving 225Ac-lintuzumab and spironolactone for one year afterward. Results: Nine patients (median age, 76 yrs; range, 73-81 yrs) were treated. Seven patients (78%) had a history of myelodysplastic syndromes (MDS), for which five (56%) received prior therapy with hypomethylating agents (n=4) or allogeneic hematopoietic cell transplantation (n=1). One patient (11%) had chronic myeloid leukemia in a molecularly undetectable state at the time of AML diagnosis. Six patients (67%) had intermediate-risk cytogenetics, and three (33%) had unfavorable cytogenetics. The median CD33 expression was 76% (range, 45-100%). Patients received 225Ac-lintuzumab at doses of 0.5 (n=3) or 1 (n=6) μCi/kg/fraction. Total administered activity ranged from 68-199 μCi. The median number of cycles administered was 2 (range, 1-4). Dose-limiting toxicity was seen in one patient receiving 1 µCi/kg/fraction who had grade 4 thrombocytopenia with bone marrow aplasia persisting > 6 wks after receiving 225Ac-lintuzumab. Hematologic toxicities included grade 4 neutropenia (n=1) and thrombocytopenia (n=3). Grade 3/4 non-hematologic toxicities included febrile neutropenia (n=6), pneumonia (n=2), bacteremia (n=1), cellulitis (n=1), transient increase in creatinine (n=1), hypokalemia (n=1), and generalized weakness (n=1). Bone marrow blast reductions were seen in 5 of 7 patients (71%) evaluated after Cycle 1. Mean blast reduction was 61% (range, 34-100%). Three of the 7 patients (43%) had marrow blast reductions of ≥ 50%; however, no remissions were observed. Median progression-free survival (PFS) was 2.5 mos (range, 1.7-15.7+ mos). Median overall survival (OS) from study entry was 5.4 mos (range, 2.2-24 mos). For the 7 patients with prior MDS, median OS was 9.1 mos (range 2.3-24 mos). Conclusions: Fractionated-dose 225Ac-linutuzmab in combination with LDAC is feasible, safe, and has anti-leukemic activity. Dose escalation continues to define the MTD, with planned doses up to 2 µCi/kg/fraction. Additional patients will be treated at the MTD in the phase II portion of this trial to determine response rate, PFS, and OS. Disclosures Ravandi: Actinium Pharmaceuticals, Inc.: Research Funding. Pagel:Actinium Pharmaceuticals, Inc.: Equity Ownership, Research Funding. Park:Actinium Pharmaceuticals, Inc.: Research Funding. Wahl:Actinium Pharmaceuticals, Inc.: Research Funding. Earle:Actinium Pharmaceuticals, Inc.: Employment, Equity Ownership. Cicic:Actinium Pharmaceuticals, Inc.: Employment, Equity Ownership. Scheinberg:Actinium Pharmaceuticals, Inc.: Equity Ownership, Research Funding.

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