scholarly journals Long-Term Follow-up of Ibrutinib Treatment for Rituximab-Refractory Waldenström's Macroglobulinemia: Final Analysis of the Open-Label Substudy of the Phase 3 iNNOVATETM Trial

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 38-39
Author(s):  
Judith Trotman ◽  
Christian Buske ◽  
Alessandra Tedeschi ◽  
Jeffrey V. Matous ◽  
David MacDonald ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Single Agent ◽  
Final Analysis ◽  
Publicly Traded ◽  
Open Label ◽  
Advisory Committees ◽  
Heavily Pretreated ◽  
Travel Grant

Background : Ibrutinib is the only once-daily Bruton's tyrosine kinase inhibitor approved in the US and EU either as single-agent therapy or in combination with rituximab for treatment of patients with Waldenström's macroglobulinemia (WM) across all lines of therapy. The open-label substudy of the phase 3 iNNOVATE trial (PCYC-1127; NCT02165397) demonstrated that single-agent ibrutinib was highly efficacious (90% overall response rate [ORR] per investigator) with improved responses over time in heavily pretreated, rituximab-refractory patients with WM (Buske Blood 2018). Here, we present results from the final analysis of the iNNOVATE open-label substudy. Methods : Patients with WM who failed to achieve at least a minor response (MR) or who relapsed <12 months after their last rituximab-containing therapy received once-daily ibrutinib 420 mg. Endpoints included progression-free survival (PFS) and ORR (≥MR) per Independent Review Committee (IRC), overall survival (OS), hemoglobin (Hgb) improvement, and safety; serum immunoglobulin M (IgM) reduction was also assessed. Results : Thirty-one patients with rituximab-refractory disease were enrolled; median age was 67 years (range 47-90), and median number of prior therapies was 4 (range 1-7). Median baseline Hgb was 103 g/L (range 64-146). Median baseline IgM was 39 g/L (range 9-107). Median follow-up was 58 months (range 9-61). Median PFS was 39 months (95% CI 25-NE); the PFS rate at 60 months was 40%. Median PFS was not reached (95% CI 27-NE) in patients with the MYD88L265P/CXCR4WT genotype and was 18 months (95% CI 3-28) in patients with the MYD88L265P/CXCR4WHIM genotype. ORR was 87%, with similar ORR observed across genetic subtypes (MYD88L265P/CXCR4WT, 88% [15/17]; MYD88L265P/CXCR4WHIM, 86% [6/7]); major response rates (≥PR) among these genotypes were 88% (15/17) and 71% (5/7), respectively (Figure 1A). Median OS was not reached in the full cohort of patients, regardless of number of prior therapies (1-2 vs ≥3). Improvements in IgM and Hgb were generally rapid and sustained (Figure 1B). Twenty-two patients (71%) had sustained improvement in Hgb, including 17/21 (81%) with baseline Hgb ≤110 g/L. Median change in IgM from baseline to nadir (month 54) was -37 g/L (range -75 to -5). Median duration of ibrutinib treatment was 41 months. The most common reason for discontinuing ibrutinib while on study was progressive disease (42%). At time of study closure, 14 patients (45%) remained on treatment; of these, 6 went on to receive ibrutinib in the commercial setting and 8 enrolled in a treatment extension study. Overall, 97% of patients experienced a treatment-emergent adverse event (TEAE), most commonly diarrhea (48%; grade ≥2, 13%) and pyrexia (35%; grade ≥2, 6%). Grade 3/4 TEAEs occurred in 81% of patients; the most common were neutropenia (16%), hypertension (10%), and anemia (10%). No deaths occurred due to AEs, and no patients died while on treatment. Ibrutinib dose was reduced in 5 patients (16%) due to an AE, and 2 patients (6%) discontinued treatment because of an AE. No patients experienced major hemorrhage or atrial fibrillation. Conclusions : In this final analysis of the open-label substudy of the iNNOVATE trial, single-agent ibrutinib continued to show sustained efficacy in patients who had heavily pretreated, rituximab-refractory WM. Responses to ibrutinib were consistent across genotypes, although subgroup numbers were small. Ibrutinib maintained a manageable safety profile, and no new safety signals were identified with over 5 years of overall follow-up. Disclosures Trotman: Celgene: Research Funding; PCYC: Research Funding; Takeda: Research Funding; BeiGene: Research Funding; F. Hoffmann-La Roche: Research Funding. Buske:Roche, Janssen, Bayer, MSD: Research Funding; Roche, Janssen, AbbVie, Pfizer, Celltrion: Honoraria, Speakers Bureau; Morphosys: Membership on an entity's Board of Directors or advisory committees. Tedeschi:BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Department of Hematology Niguarda Hospital Milano: Current Employment; Sunesis: Consultancy; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen spa: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Matous:Celgene: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy. MacDonald:Roche Canada: Consultancy, Honoraria; AstraZeneca: Honoraria; Janssen: Honoraria. Tam:BeiGene: Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria; AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Tournilhac:INNATE Pharma: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other: Travel grant; Janssen: Consultancy, Honoraria, Other: Travel grant; GILEAD: Consultancy, Honoraria, Other: Travel Grant; ABBVIE: Consultancy, Honoraria, Other: Travle grant. Ma:Genentech: Consultancy, Honoraria; Novartis: Research Funding; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; BeiGene: Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding; TG Therapeutics: Research Funding; Bioverativ: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Juno: Research Funding. Treon:Janssen: Consultancy, Other: Travel/accommodations/expenses; BeiGene: Consultancy; Bristol-Myers Squibb: Research Funding; BioGene: Other: Travel/accommodations/expenses; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: Travel/accommodations/expenses, Research Funding. Oriol:Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy; Sanofi: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Ping:Pharmacyclics LLC, an AbbVie Company: Current Employment; AbbVie: Current equity holder in publicly-traded company. Briso:Pharmacyclics GmbH, an AbbVie Company: Current Employment; AbbVie: Current equity holder in publicly-traded company. Arango-Hisijara:Pharmacyclics LLC, an AbbVie Company: Current Employment; Bristol-Myers Squibb: Current equity holder in publicly-traded company; AbbVie: Current equity holder in publicly-traded company. Dimopoulos:Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy.

Blinatumomab in Children with Relapsed or Refractory B-Precursor Acute Lymphoblastic Leukemia (R/R-ALL): Final Results of 110 Patients Treated in an Expanded Access Study (RIALTO)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 24-25
Author(s):  
Franco Locatelli ◽  
Gerhard Zugmaier ◽  
Noemi Mergen ◽  
Peter Bader ◽  
Sima Jeha ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Board Of Directors ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Final Analysis ◽  
Publicly Traded ◽  
Primary Analysis ◽  
Advisory Committees ◽  
Grade 3

Introduction: The open-label, expanded access study (RIALTO) demonstrated that blinatumomab is efficacious with a manageable safety profile in children with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (R/R BCP-ALL). Blinatumomab is a BiTE® (bispecific T-cell engager) immuno-oncology therapy that activates cytotoxic T cells to kill target B cells. Here, findings from the final analysis of RIALTO are presented (NCT02187354). Methods: Enrolled in the study were children >28 days and <18 years of age with R/R CD19+ BCP-ALL (defined as ≥2 relapses, relapse after allogeneic hematopoietic stem cell transplant [alloHSCT], or refractory to prior treatments) and ≥5% blasts or <5% blasts but with minimal residual disease (MRD) level ≥10−3. Blinatumomab was given as continuous infusion in a 6-week cycle (4 weeks on and 2 weeks off) for up to 5 cycles and safety follow-up visit 30 days post-treatment. Patients with <25% blasts were dosed at 15 µg/m2/day, whereas those with ≥25% blasts were dosed at 5 µg/m2/day (days 1-7 of cycle 1) followed by dose increase to 15 µg/m2/day. Primary endpoint was incidence of treatment-emergent (TE) and treatment-related (TR) adverse events (AEs). Secondary endpoints included complete response (CR; <5% blasts) and MRD response (<10−4 blasts by PCR or flow-cytometry) in the first 2 cycles, relapse-free survival (RFS), overall survival (OS), and alloHSCT rate after blinatumomab treatment. Results: As of the data cutoff date (January 10, 2020) for the final analysis, demographics and baseline characteristics of 110 patients enrolled (median age, 8.5 years [95% CI 0.4-17.0]), 61% had <50% blasts at baseline, and 11% had <5% blasts (n=12; with MRD ≥10−3) remain unchanged compared with the primary analysis (Table 1). For best treatment response within the first 2 cycles, results are comparable to that of the primary analysis. Among 110 patients, overall CR rate was 62.7% (n= 69). Of 98 patients with ≥5% blasts at baseline, 59% (n=58) achieved CR; of them, 79% (n=46) achieved an MRD response and 62% (n=39) proceeded to HSCT. The 2 patients with t(17;19) achieved CR with an MRD response. Of the 4 patients with germline trisomy 21 (Down syndrome), 3 achieved CR with an MRD response Among the 12 patients with <5% blasts but with MRD ≥10−3 at baseline, 92% (n=11) achieved CR and MRD response; 75% (n=9) proceeded to HSCT (Table 2). Of the 5 patients who had received prior blinatumomab , 4 achieved CR. Of 110 patients treated with blinatumomab, median OS (95% CI) was 14.6 (11-24.5) months with median follow-up time of 18.2 months, which increased by 1.5 months compared with that reported in the primary analysis, with 29.9% of patients still surviving at month 24. Median RFS (95% CI) remains unchanged at 8.5 months (4.7-14.0), with a median follow-up time of 11.5 months in patients who achieved CR; 38% of patients relapsed and 9% died. RFS was more favorable for patients who received HSCT post blinatumomab (70%) than for those who did not (30%) at month 12, respectively, which is consistent with the results from primary analysis. Among patients who had HSCT prior to blinatumomab (n= 45), median OS (95%) was 16.6 (7.1-NE) months vs 14.6 (10.9-24.5) months in patients without HSCT prior to blinatumomab (n= 65). Compared with the primary analysis, 5 additional patients received HSCT after achieving CR in the final analysis. Median OS among patients in CR after HSCT by MRD responders vs MRD non-responders was NE at 15-month analysis (Figure). Safety results in the final analysis were consistent with those reported in the primary analysis. Of 110 patients, 99% experienced TEAEs, with 65% being grade ≥3 (see Table 3 for details). TRAEs were reported in 74% of patients; 26% were grade ≥3 and 19% were deemed serious. Details on grade ≥3 TRAEs are shown in Table 3. The 9 fatal AEs, unrelated to blinatumomab, occurred due to relapse and progressive nature of the disease (Table 3). Conclusions: Overall, the safety and efficacy results from the final analysis are consistent with those reported in the primary analysis as no new safety signals were observed. These findings strengthen the observation that blinatumomab demonstrates durable efficacy and is a suitable treatment option in children with R/R BCP-ALL. Table 1. Disclosures Locatelli: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Medac: Speakers Bureau; Miltenyi: Speakers Bureau; Bellicum Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceeutical: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Zugmaier:Amgen: Current Employment, Other: Personal Fees ; 20190300609: Patents & Royalties: Licensed patient . Mergen:Amgen: Current Employment, Current equity holder in publicly-traded company. Bader:Medac: Patents & Royalties, Research Funding; Amgen: Consultancy, Speakers Bureau; Neovii: Research Funding; Celgene: Consultancy; Novartis: Consultancy, Speakers Bureau; Riemser: Research Funding. Schlegel:bluebird bio: Honoraria. Bourquin:Servier: Other: Travel Support. Handgretinger:Amgen: Honoraria. Brethon:Amgen: Other: invitation to meetings, remunerations for oral presentations, advices for the record of Blinatumomab in pediatrics in France. Rössig:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Pfizer: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; EUSA Pharma: Membership on an entity's Board of Directors or advisory committees; Genetech: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Kormany:Amgen: Current Employment, Current equity holder in publicly-traded company. Viswagnachar:IQVIA: Current Employment.

A Phase 1/2 Multi-Center, Randomized, Open Label Dose Escalation Study to Determine the Maximum Tolerated Dose, Safety, and Efficacy of Pomalidomide Alone or in Combination with Low-Dose Dexamethasone in Patients with Relapsed and Refractory Multiple Myeloma Who Have Received Prior Treatment That Includes Lenalidomide and Bortezomib.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 301-301 ◽  
Author(s):  
Paul Richardson ◽  
David Siegel ◽  
Rachid Baz ◽  
Susan L. Kelley ◽  
Nikhil C. Munshi ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Maximum Tolerated Dose ◽  
Open Label ◽  
Advisory Committees ◽  
Dose Escalation Study ◽  
Safety And Efficacy ◽  
Heavily Pretreated ◽  
Grade 3 ◽  
Dose Dependent Increase

Abstract Abstract 301 Background: Pomalidomide (POM) is an IMiD® derived from thalidomide with a modified chemical structure with improved potency in vitro and potential efficacy and safety benefits in vivo. Two phase (Ph) 1b, single-center, ascending dose, open-label studies in pts with relapsed/refractory multiple myeloma (MM; Schey et al, 2004, Streetly et al, 2008) identified maximum tolerated dose (MTD) as 2mg QD or 5mg on alternate days (28 of each 28-day cycle). High response rates of POM alone in heavily pretreated pts were encouraging. To evaluate the MTD, safety and efficacy of POM alone or with Dexamathasone (dex) on a 21/28 day schedule, a Ph 1/2, multicenter, randomized, open-label, 3×3 dose-escalation study was initiated in pts with relapsed/refractory MM after at least 2 prior regimens, including bortezomib and lenalidomide. Methods: The study has a Ph 1 POM MTD (n=32) portion, followed by Ph 2 open-label randomized POM+ dex vs POM alone (192 pts planned). Eligible pts had documented relapsed/refractory MM. All pts received low-dose prophylactic aspirin QD and monitored for venous thromboembolic events (VTE). In Ph 1, POM was given QD on Days 1–21 of 28-day cycle: 4 dose levels of POM (2, 3, 4, 5mg) were studied with option to add dex at 40 mg/wk after 4 cycles for lack of response or progressive disease (PD). Pts enrolled in Ph 1 and discontinued either for intolerance or PD could not be enrolled in Ph 2. Toxicities and responses were assessed using CTCAE v3 and modified European Group for Blood and Marrow Transplantation (EBMT) criteria. Results: Results from Ph 1 of the study are reported with 32 pts enrolled to date. Fifteen pts discontinued therapy and 17 pts are ongoing for both safety and efficacy analyses. Mean age is 66.6 yrs (range 38–84), with median number of prior regimens 7 (range 2–18). MTD has not yet been reached. There were 4 dose reductions due to POM (5mg [2-neutropenia, 1-rash]; 3mg [1-neutropenia]) after 108 completed cycles. Neutropenia and thrombocytopenia were the most common grade 3/4 toxicities, with no dose-dependent increase apparent so far: 12 serious adverse events (SAEs) occurred in 10 pts; drug related events included POM (VTE, syncope, 3rd degree AV block, asthenia, diarrhea, neutropenia, anemia, rash); dex (lung infection with neutropenia); POM + dex (sepsis with pharyngeal abscess). AEs such as somnolence (1) VTE (1) neuropathy (2), and constipation (4) were uncommon. There were 3 deaths on study not attributed to POM; 2 pts died of rapid PD, 1 pt died of gastrointestinal perforation due to amyloidosis. Responses were seen at each dose level (Table 1). In 20/21 (95%) evaluable pts, clinical activity (SD or better) was reported. During treatment with POM alone, overall response rate (ORR; 1 CR, 2 PR, 5 MR) was 38% (8/21), mean duration of response (DOR) was 11.1 (range 4–32) wks, mean time to progression (TTP) was 8.3 (range 2–36) wks. Median completed cycles of POM +/− dex overall was 4 (range 1–12), with 13/21 evaluable pts (62%) having dex added to their regimens at various different cycles (median cycle 3, range 2–9) for PD or lack of response. During treatment with POM+dex, ORR (2 PR, 3 MR) was 38%, mean DOR of 14.2 (range 4–32) wks, and mean TTP of 20 (range 4–52) wks. In addition, there were 9 stable diseases (SD) on POM alone with mean DOR of 7.1 (range 4–16) wks, and 6 SD on POM + dex with mean DOR of 10.7 (range 8–16) wks. In 5/13 pts (38%), responses improved after dex was added (2 PR, 2 MR, 1 SD). Conclusions: These preliminary results indicate that POM alone or in combination with dex is associated with 38% MR or better, while SD was achieved in 43% (POM alone) and 46% (POM + dex), amongst heavily pretreated pts with relapsed/refractory MM. The incidence of SAEs and discontinuations decreased with increased dose of POM with no dose-dependent increase in grade 3/4 hematological toxicities. The MTD has not been reached to date. Overall, these data indicate that POM has an acceptable safety profile and is a clinically active therapeutic option for advanced refractory MM, warranting further investigation in this patient population. Disclosures: Richardson: Gentium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Keryx Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Millenium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Pomalidomide is an anti-proliferative and immunomodulatory agent that is in clinical development for relapsed/refractory MM. Siegel:Celgene: Speakers Bureau; Millenium Pharmaceuticals: Speakers Bureau. Baz:Celgene: Research Funding. Munshi:Novartis Pharmaceuticals: Consultancy, Speakers Bureau; Millenium Pharmaceuticals: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Sullivan:Merck: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Merrion: Membership on an entity's Board of Directors or advisory committees. Doss:Celgene: Speakers Bureau. Larkins:Celgene: Employment, Equity Ownership. Jacques:Celgene: Employment. Donaldson:Celgene: Employment. Anderson:Celgene: Consultancy, Honoraria, Speakers Bureau; Millenium Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau.

An Open-Label, Dose Escalation, Multi-Center Phase 1 Study of PRLX 93936, an Agent Synthetically Active Against the Activated Ras Pathway, in the Treatment of Relapsed or Relapsed and Refractory Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2140-2140 ◽  
Author(s):  
Peter M Voorhees ◽  
Robert L. Schlossman ◽  
Cristina J Gasparetto ◽  
Jesus G. Berdeja ◽  
John Morris ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Progressive Disease ◽  
Phase 1 ◽  
Single Agent ◽  
Open Label ◽  
Advisory Committees ◽  
Ras Pathway ◽  
Label Dose

Abstract Introduction: Overall survival for patients with multiple myeloma (MM) has improved, but most patients relapse and eventually succumb to complications of the disease. The development of new therapeutic agents to treat relapsed and relapsed/refractory MM is therefore vital. Proteins of the Ras family are frequently mutated in human cancers, including MM. However, direct, selective, potent inhibitors of mutant Ras proteins are not clinically available. Extensive efforts have been made to identify agents which are "synthetically active" against the activated Ras pathway which may not inhibit the Ras protein itself, but target other molecules selectively important for cells with, but not those without, Ras mutation. PRLX 93936, 3-(2-ethoxyphenyl)-2-[(1-piperazinyl)methyl]-4(3H)-quinazolinone, is an analog of such a "synthetically active" compound against the activated Ras pathway. The compound has demonstrated promising efficacy in preclinical laboratory studies and mouse models of MM with an improvement in survival and 30% suppression in tumor growth at the lowest tested dose. A phase 1, multi-center, open-label, dose escalation trial was conducted to determine the maximum tolerated dose (MTD), assess toxicities, and evaluate response to treatment with monotherapy of PRLX 93936 in patients with relapsed or relapsed/refractory MM. Methods: Patients (Pts) with relapsed or relapsed/refractory MM in whom at least two prior anti-myeloma regimens had failed (including a proteasome inhibitor and/or immunomodulatory drug) were considered. PRLX 93936 as a single agent was given intravenously 3 days/week for 3 weeks followed by a 9 day rest period constituting a 28-day treatment cycle. Sequential cohorts of at least three pts were treated with escalating doses of PRLX 93936 beginning at 10 mg/m2 and increasing the dose in increments of 5mg/m2 until the MTD was established. Pts received a minimum of 2 cycles of treatment at their assigned dose level for evaluation of anti-myeloma activity of PRLX 93936 and could receive up to 8 cycles followed by an option of maintenance therapy. Dexamethasone at a dose of 20 mg provided on each day of PRLX 93936 infusion could be added at the investigator’s discretion after a minimum of 2 cycles or after cycle 1 for patients with progressive disease. Adverse events were assessed according to version 4.0 of the CTC, and response per the International Myeloma Working Group uniform response criteria, incorporating the modified EBMT response criteria, were assessed with each cycle. Correlative studies from peripheral blood and bone marrow were collected. Results: To date, 14 pts (4 women, 10 men) enrolled in the trial and 13 have completed therapy. Mean age was 61 years (range, 48-81). Prior to enrollment, pts had received an average of 5 lines of therapy (median 4, range 2-9) including 6 who received stem cell transplantation (4 autologous, 2 allogeneic). The median time since diagnosis was 5 years (range 2-11.5). Of the 13 pts whom completed treatment, 11 completed at least one full 28 day cycle (range 1-15). This includes 3 pts at the 10mg/m2 dose, 3 pts at the 15mg/m2 dose, 5 pts at the 20 mg/m2 dose, and 2 pts at the 25mg/m2 dose. Of the 13 pts who completed study therapy, 7 experienced at least one serious adverse event (SAE). The most frequently reported SAEs (2 each) included sepsis and cellulitis. Four SAEs were considered related to PRLX 93936 by the investigator (thrombocytopenia, neutropenia, nausea, and vomiting). The MTD was determined to be 20 mg/m2. Dose limiting toxicities that occurred at the next higher level of 25mg/m2 included nausea, vomiting, and neutropenia (both pts) and thrombocytopenia, weakness, elevated AST, and elevated creatinine (1 pt). The best response among 11 evaluable pts was minimal response (MR) in 2 pts (18%). Stable disease (n=4) and progressive disease (n=5) was observed in the remaining pts. Analysis of the impact of dexamethasone is on-going, but no significant additive toxicity has been seen. Conclusions: PRLX 93936, a “synthetically active” compound against the activated Ras pathway, has demonstrated activity as a single agent in relapsed and refractory MM patients with MR in 18% of patients to date. Toxicity has proven manageable and the MTD has been defined at 20 mg/m2. Additional studies, including those involving PRLX 93936 as part of combination therapy and correlative studies to determine those pts most likely to benefit, are warranted. Disclosures Voorhees: Millennium: The Takeda Oncology Company : Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees. Off Label Use: PRLX 93936 is a non-FDA approved drug currently in phase 1 development in multiple myeloma. Gasparetto:Millenium: Honoraria; Celgene: Consultancy, Honoraria. Jacobstein:Prolexys Pharmaceuticals, Inc: Employment. Anderson:BMS: Consultancy; Sanofi Aventis: Consultancy; Gilead: Consultancy; Onyx: Consultancy; Millenium: Consultancy; Celgene: Consultancy; Oncopep/Acetylon: Equity Ownership. Mitsiades:Millennium: A Takeda Oncology Company: Consultancy; Celgene: Consultancy; Johnson & Johnson: Research Funding; Amgen: Research Funding. Laubach:Celgene: Research Funding; Novartis: Research Funding; Millennium: A Takeda Oncology Company: Research Funding; Onyx: Research Funding. Richardson:Janssen: Membership on an entity's Board of Directors or advisory committees; Millennium: The Takeda Oncology Co.: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

Five-Year Experience with Single-Agent Ibrutinib in Patients with Previously Untreated and Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 233-233 ◽  
Author(s):  
Susan M. O'Brien ◽  
Richard R. Furman ◽  
Steven E. Coutre ◽  
Ian W. Flinn ◽  
Jan Burger ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Board Of Directors ◽  
Research Funding ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3 ◽  
Over Time

Abstract Background: Ibrutinib (ibr), a first-in-class, once-daily Bruton's tyrosine kinase inhibitor, is approved by the US FDA for treatment of patients (pts) with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) including pts with del17p. The phase 1b/2 PCYC-1102 trial showed single-agent efficacy and tolerability in treatment-naïve (TN; O'Brien, Lancet Oncol 2014) and relapsed/refractory (R/R) CLL/SLL (Byrd, N Engl J Med 2013). We report efficacy and safety results of the longest follow-up to date for ibr-treated pts. Methods: Pts received 420 or 840 mg ibr QD until disease progression (PD) or unacceptable toxicity. Overall response rate (ORR) including partial response (PR) with lymphocytosis (PR-L) was assessed using updated iwCLL criteria. Responses were assessed by risk groups: unmutated IGVH, complex karyotype (CK; ≥3 unrelated chromosomal abnormalities by stimulated cytogenetics assessed by a reference lab), and in hierarchical order for del17p, then del11q. In the long-term extension study PCYC-1103, grade ≥3 adverse events (AEs), serious AEs, and AEs requiring dose reduction or discontinuation were collected. Results: Median age of the 132 pts with CLL/SLL (31 TN, 101 R/R) was 68 y (range, 37-84) with 43% ≥70 y. Baseline CK was observed in 41/112 (37%) of pts. Among R/R pts, 34 (34%) had del17p, 35 (35%) del11q, and 79 (78%) unmutated IGVH. R/R pts had a median of 4 prior therapies (range, 1-12). Median time on study was 46 m (range, 0-67) for all-treated pts, 60 m (range, 0-67.4) for TN pts, and 39 m (range, 0-67) for R/R pts. The ORR (per investigator) was 86% (complete response [CR], 14%) for all-treated pts (TN: 84% [CR, 29%], R/R: 86% [CR, 10%]). Median progression-free survival (PFS) was not reached (NR) for TN and 52 m for R/R pts with 60 m estimated PFS rates of 92% and 43%, respectively (Figure 1). In R/R pts, median PFS was 55 m (95% confidence intervals [CI], 31-not estimable [NE]) for pts with del11q, 26 m (95% CI,18-37) for pts with del17p, and NR (95% CI, 40-NE) for pts without del17p, del11q, trisomy 12, or del13q. Median PFS was 33 m (95% CI, 22-NE) and NR for pts with and without CK, and 43 m (95% CI, 32-NE) and 63 m (95% CI, 7-NE) for pts with unmutated and mutated IGVH, respectively(Figure 2). Among R/R pts, median PFS was 63 m (95% CI, 37-NE) for pts with 1-2 prior regimens (n=27, 3 pts with 1 prior therapy) and 59 m (95% CI, 22-NE) and 39 m (95% CI, 26-NE) for pts with 3 and ≥4 prior regimens, respectively. Median duration of response was NR for TN pts and 45 m for R/R pts. Pts estimated to be alive at 60 m were: TN, 92%; all R/R, 57%; R/R del17p, 32%; R/R del 11q, 61%; R/R unmutated IGVH, 55%. Among all treated pts, onset of grade ≥3 treatment-emergent AEs was highest in the first year and decreased during subsequent years. With about 5 years of follow-up, the most frequent grade ≥3 AEs were hypertension (26%), pneumonia (22%), neutropenia (17%), and atrial fibrillation (9%). Study treatment was discontinued due to AEs in 27 pts (20%) and disease progression in 34 pts (26%). Of all treated pts, 38% remain on ibr treatment on study including 65% of TN pts and 30% of R/R pts. Conclusions: Single-agent ibrutinib continues to show durable responses in pts with TN or R/R CLL/SLL including those with del17p, del11q, or unmutated IGVH. With extended treatment, CRs were observed in 29% of TN and 10% of R/R pts, having evolved over time. Ibrutinib provided better PFS outcomes if administered earlier in therapy than in the third-line or beyond. Those without CK experienced more favorable PFS and OS than those with CK. Ibrutinib was well tolerated with the onset of AEs decreasing over time, allowing for extended dosing for 65% of TN and 30% of R/R pts who continue treatment. Disclosures O'Brien: Janssen: Consultancy, Honoraria; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding. Furman:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Speakers Bureau. Coutre:Janssen: Consultancy, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding. Flinn:Janssen: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Gilead Sciences: Research Funding; ARIAD: Research Funding; RainTree Oncology Services: Equity Ownership. Burger:Pharmacyclics, LLC, an AbbVie Company: Research Funding; Gilead: Research Funding; Portola: Consultancy; Janssen: Consultancy, Other: Travel, Accommodations, Expenses; Roche: Other: Travel, Accommodations, Expenses. Sharman:Gilead: Research Funding; TG Therapeutics: Research Funding; Acerta: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding. Wierda:Abbvie: Research Funding; Genentech: Research Funding; Novartis: Research Funding; Acerta: Research Funding; Gilead: Research Funding. Jones:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding. Luan:AbbVie: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment, Other: Travel, Accommodations, Expenses. James:AbbVie: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment. Chu:Pharmacyclics, LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership.

scholarly journals Safety and Efficacy of Romiplostim in over 200 Children with Immune Thrombocytopenia (ITP): Results of an Integrated Database of 5 Clinical Trials

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2428-2428 ◽  
Author(s):  
Michael D. Tarantino ◽  
Jenny M. Despotovic ◽  
John Roy ◽  
John Grainger ◽  
Nichola Cooper ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Board Of Directors ◽  
Research Funding ◽  
Platelet Response ◽  
Open Label ◽  
Advisory Committees ◽  
Baseline Platelet Count ◽  
Platelet Counts

Abstract Background: Romiplostim is approved globally for use in adults with ITP and in the EU for children with ITP. More comprehensive data are needed on the use of romiplostim in children with ITP. Objective: To examine the safety and efficacy of romiplostim in trials in children with ITP. Methods: Data were combined from 5 romiplostim trials in children with ITP, both placebo-controlled (a phase 1/2 and a phase 3 trial) and open-label (a 3-year trial and 2 extension trials); trial data have been reported previously (Bussel Blood 2011, Bussel PBC 2014, Tarantino Lancet 2016, Tarantino ASH 2017, Grainger ASH 2017). Platelet counts in the 4 weeks after use of rescue medication were excluded from analyses. Descriptive statistics were used. Number (n), mean, standard deviation (SD), median, quartile range (Q1, Q3), minimum (min), and maximum (max) for continuous variables, and number and percentage for categorical variables were provided. Results: Patients (N=286, 24 initially placebo and 262 initially romiplostim) had median (Q1, Q3) age of 10 (6, 13) years, ITP duration of 1.9 (1, 4) years, and baseline platelet count of 14 (8, 23)×109/L. Previously, 88% had received corticosteroids, 87% IVIg, and 21% rituximab; 23% had received >3 prior treatments and 7% had prior splenectomy. Of the 282 patients exposed to romiplostim (20 initially received placebo), the median (min, max) duration of treatment was 65 (8, 471) weeks, with a median (min, max) average weekly dose of 6.6 (0.1, 9.7) μg/kg; total exposure was 468 patient-years. The most common reasons for discontinuing the parent study for romiplostim-treated patients were per protocol (19%; eg, sponsor decision, death, lost to follow-up), consent withdrawn (3%), noncompliance (1%), and administrative decision (1%). Of romiplostim-treated patients, 24% had serious adverse events (SAEs), most commonly epistaxis, low platelet counts, and headache (Table). There were 7 cases of postbaseline neutralizing antibody against romiplostim: 2 transient and 5 persistent. There were no neutralizing antibodies against endogenous TPO. For patients undergoing bone marrow biopsies in the 3-year open-label trial, there were no findings of collagen or bone marrow abnormalities (Year 1 n=27, Year 2 n=5, vs. baseline) (Grainger et al, ASH 2017). One patient had an increase in modified Bauermeister bone marrow grade from 0 to 2 (fine reticulin fiber network) with no associated AEs (the only AEs were a cold and injection site pain); per protocol, there was no follow-up biopsy. Once at a steady dose of 10 μg/kg, most (11/16) of this patient's platelet counts were ≥30×109/L. Investigators reported thrombocytosis AEs; 1 patient had a platelet count of 1462×109/L at Week 14 for 1 week and another had elevated platelet counts 10 times between Weeks 20-172 (max of 872×109/L); there were no associated thrombotic events. Median platelet counts rose quickly and were over 50×109/L from Week 12 on (Figure). Platelet response rates also rose quickly. Overall, 89% of romiplostim-treated patients (vs 8% of placebo) had a platelet response (platelet counts ≥50×109/L; Figure). For romiplostim-treated patients, the first platelet responses occurred after a median of 6 weeks. The median % (Q1, Q3) of months responding was 76% (25%, 93%) and # of months responding was 11 (3, 20); from time of first monthly response, the median (Q1, Q3) % of months responding was 92% (75%, 100%) and # of months responding was 14 (7, 23). Nineteen romiplostim-treated patients discontinued all ITP therapies including romiplostim for ≥6 months while maintaining platelet counts ≥50×109/L (here defined as remission). These treatment-free periods lasted a median (Q1, Q3) of 12 (8, 14) months; no placebo patients remained free of treatment. There were no clear differences between those who did and did not enter remission (ie, age, sex, race, past treatment, ITP duration, baseline platelet count). Bleeding was reported for most (68%) patients: mostly grade 1/2, with 10% having grade 3 bleeding (most commonly epistaxis in 13 patients) and 2 patients having grade 4 bleeding (both reported as "ITP"). Conclusions: In this comprehensive database of romiplostim ITP trials in 286 children with 468 patient-years of romiplostim exposure, romiplostim was well tolerated. With romiplostim, the vast majority (89%) of patients had a platelet response, with some children able to discontinue all ITP treatments for ≥6 months. Disclosures Tarantino: Health Resources and Services Administration: Research Funding; Centers for Disease Control and Prevention: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Other: Reviews grants; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Grifols: Research Funding, Speakers Bureau. Despotovic:AmGen: Research Funding; Sanofi: Consultancy; Novartis: Research Funding. Grainger:Biotest: Consultancy; Ono Pharmaceuticals: Consultancy; Amgen: Consultancy, Honoraria, Other: Educational grant; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cooper:Amgen, Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Kim:Amgen Inc.: Employment, Equity Ownership. Eisen:Amgen Inc.: Employment, Equity Ownership.

scholarly journals Safety and Antitumor Activity Study Evaluating Loncastuximab Tesirine and Rituximab Versus Immunochemotherapy in Diffuse Large B-Cell Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 9-10
Author(s):  
Yuliya Linhares ◽  
Mitul D Gandhi ◽  
Michael Chung ◽  
Jennifer Adeleye ◽  
David Ungar ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Advisory Board ◽  
Publicly Traded ◽  
Advisory Committees ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Introduction: Patients with diffuse large B-cell lymphoma (DLBCL) who fail immunochemotherapy (IC) and are unsuitable for autologous stem cell transplantation (ASCT) and those who relapse shortly after ASCT have extremely poor prognosis and need additional treatment options. Loncastuximab tesirine (Lonca) is an antibody-drug conjugate (ADC) composed of a humanized anti-CD19 antibody conjugated to a pyrrolobenzodiazepine dimer toxin. In a Phase 2 study (NCT03589469), Lonca demonstrated single-agent antitumor activity with manageable toxicity in patients with relapsed/refractory (R/R) DLBCL. Rituximab is a CD20-targeting monoclonal antibody used in front-line IC for DLBCL and in salvage regimens, such as rituximab/gemcitabine/oxaliplatin (R-GemOx). The addition of rituximab to a CD19-targeting pyrrolobenzodiazepine ADC appears to prolong tumor control in preclinical studies, providing the rationale for evaluating Lonca combined with rituximab (Lonca-R) as a treatment for R/R DLBCL. Study Design and Methods: This is a Phase 3, randomized, open-label, 2-part, 2-arm, multicenter study of Lonca-R versus standard IC in patients with R/R DLBCL (NCT04384484). Part 1 is a nonrandomized safety run-in with Lonca-R. The toxicity of Lonca-R will be compared with previous single-agent Lonca safety data after 20 patients have completed Cycle 1 in Part 1. Provided no significant increase in toxicity is observed, Part 2 will be initiated. Part 2 is a randomized study of Lonca-R versus R-GemOx (Figure 1). Key inclusion and exclusion criteria are reported in Table 1. The primary objective of Part 2 is to evaluate the efficacy of Lonca-R versus R-GemOx, using progression-free survival (PFS) as the primary endpoint. PFS will be defined as the time between randomization and first documentation of recurrence, disease progression or death (central review) and the primary analysis will compare PFS between treatment arms using stratified log-rank testing. Secondary objectives include evaluation of safety, pharmacokinetics, and immunogenicity of the combination, in addition to the impact of treatment on symptoms, patient-reported outcomes and patients' overall health. In Part 1 and in the Lonca-R arm of Part 2, patients will receive intravenous (iv) Lonca at 150 µg/kg on day 1 of each 21-day cycle for 2 cycles, then at 75 µg/kg on day 1 for up to 6 additional cycles. Rituximab 375 mg/m2 iv will be administered subsequent to Lonca infusion on day 1 of each cycle. Patients treated with Lonca-R will also be given dexamethasone 4 mg (oral, twice a day), where not contraindicated, on the day before, the day of, and the day after Lonca-R infusion. In the R-GemOx arm, patients will receive rituximab 375 mg/m2, gemcitabine 1000 mg/m2, and oxaliplatin 100 mg/m2 iv on day 1 of each 14-day cycle up to a total of 8 cycles. Patients will receive premedication and supportive care according to the respective prescribing information for rituximab, gemcitabine, and oxaliplatin. The trial is planned to open in Q3/Q4 2020, and target enrollment is 350 patients. Funding: This study is sponsored by ADC Therapeutics SA; https://clinicaltrials.gov/ct2/show/NCT04384484. Disclosures Linhares: Jazz Pharmaceuticals: Consultancy; ADC Therapeutics, Verastem Oncology, Bristol Myers-Squibb (Juno), AstraZeneca: Research Funding; Miami Cancer Institute, Baptist Health South Florida: Current Employment. Gandhi:TG Therapeutics (Advisory board), GlaxoSmithKline (Advisory board): Membership on an entity's Board of Directors or advisory committees. Adeleye:ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. Ungar:ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. Hamadani:ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme, AstraZeneca: Speakers Bureau; Janssen R&D; Incyte Corporation; ADC Therapeutics; Celgene Corporation; Pharmacyclics, Omeros, AbGenomics, Verastem, TeneoBio: Consultancy; Takeda Pharmaceutical Company; Spectrum Pharmaceuticals; Astellas Pharma: Research Funding. OffLabel Disclosure: Rituximab is licensed for treatment of NHL but is being used in combination with an unlicensed drug (loncastuximab tesirine) in this study

scholarly journals Dreamm-5 Platform Trial: Belantamab Mafodotin (Belamaf) in Combination with Four Different Novel Agents in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 1-2
Author(s):  
Paul G. Richardson ◽  
Ajay Nooka ◽  
Hang Quach ◽  
Suzanne Trudel ◽  
David Routledge ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Combination Treatment ◽  
Research Funding ◽  
Single Agent ◽  
Gamma Secretase ◽  
Publicly Traded ◽  
Advisory Committees ◽  
For Profit ◽  
Secretase Inhibitor ◽  
Gamma Secretase Inhibitor

Introduction: Single-agent belamaf (GSK2857916), a B-cell maturation antigen-targeting antibody-drug conjugate, induced deep and durable responses in patients with RRMM, with a manageable safety profile with 13 months of follow-up (DREAMM-2; NCT03525678; Lonial et al, ASCO 2020, Poster 436). A platform trial design allows efficient evaluation of belamaf in combination with other anti-myeloma agents, such as a humanized wild-type IgG1 anti-OX40 agonist, an IgG4-inducible T-cell co-stimulator (ICOS) agonist, a gamma-secretase inhibitor, and a humanized programmed cell death (PD)-1 antagonist. The unique, multimodal mechanisms of action (MoAs) of belamaf, in combination with MoAs of these agents, has the potential to achieve synergistic effects in RRMM to further enhance anti-myeloma activity without compromising safety. Methods: DREAMM-5 (NCT04126200) is a Phase I/II study that utilizes a master protocol with separate substudies comprised of sequential dose-exploration (DE) and cohort-expansion (CE) phases, to identify promising, effective belamaf combinations when compared with a shared single-agent belamaf control arm (CE phase only). The DE phase consists of multiple dosing cohorts with belamaf combinations in which patients are assigned to treatment slots by a predetermined algorithmic approach (N≤10 per cohort). A recommended Phase II dose (RP2D) for each combination treatment will be identified based on the safety and preliminary efficacy in the DE phase. At the end of the DE phase, an interim analysis of safety, pharmacokinetic, and efficacy data will also be performed for each substudy treatment combination to determine whether the combination should move forward at the RP2D to the CE phase. Patients in the CE phase (N≥35 per cohort) will be randomized to a substudy and within a substudy to either combination treatment or the belamaf monotherapy control arm; patients will also be stratified by number of prior therapies). Eligible patients will have RRMM and will have received ≥3 prior therapy lines, which includes a prior immunomodulatory agent, proteasome inhibitor, and anti-CD38 antibody; all patients will provide informed consent for participation. The primary objectives of the study are to identify the RP2D (DE phase) and the overall response rate (≥partial response, CE phase), along with safety and tolerability, for each combination treatment. Substudies 1 (combination with GSK3174998, OX40 agonist antibody), 2 (combination with GSK3359609, ICOS agonist antibody), and 3 (combination with nirogacestat [PF-03084014; SpringWorks Therapeutics], gamma-secretase inhibitor) are currently open to enrollment. Substudy 4 (combination with dostarlimab; PD-1 antagonist antibody) is under review. Additional substudies will be explored based on scientific rationale and/or preclinical combination study results. Funding: GSK (Study 208887); belamaf drug linker technology licensed from Seattle Genetics; belamaf monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa; nirogacestat gamma-secretase inhibitor produced by and used in collaboration with SpringWorks Therapeutics. Figure: DREAMM-5 study design Figure 1 Disclosures Richardson: Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. Nooka:GlaxoSmithKline: Consultancy, Honoraria, Other: Personal Fees: Travel/accomodations/expenses, Research Funding; Karyopharm Therapeutics, Adaptive technologies: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Spectrum Pharmaceuticals: Consultancy; Adaptive Technologies: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding. Quach:Amgen, sanofi, celgene, Karyopharm, GSK: Research Funding; Amgen, Celgene, karyopharm, GSK, Janssen Cilag, Sanofi.: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline, Karyopharm, Amgen, Celgene, Janssen Cilag: Consultancy; GlaxoSmithKline, Karyopharm, Amgen, Celgene, Janssen Cilag: Honoraria. Trudel:Celgene, Janssen, Takeda, Sanofi, Karyopharm, Amgen Canada: Honoraria; Celgene, Amgen, GSK: Consultancy, Research Funding; GSK, Celgene, Janssen, Amgen, Genentech: Research Funding. Routledge:Celgene, Sandoz: Consultancy; Amgen, BMS, Celgene, Sandoz: Honoraria. Song:Otsuka: Honoraria; Janssen: Honoraria, Research Funding; Amgen, Celgene,Takeda: Consultancy, Honoraria; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Paul:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Khan:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Brouch:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Ferron-Brady:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Yeakey:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Shelton:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Montes de Oca:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Smith:SpringWorks: Current Employment, Current equity holder in publicly-traded company. Im:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Ahlers:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Paul:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Holkova:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Gupta:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company; Novartis: Current equity holder in publicly-traded company. Kremer:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Rodriguez-Otero:GlaxoSmithKline: Consultancy, Current Employment, Current equity holder in publicly-traded company, Honoraria; Kite: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Medscape: Membership on an entity's Board of Directors or advisory committees; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Sanofi: Consultancy, Honoraria.

The Use of Chemoimmunotherapy Improves the Outcome of Patients with Chronic Lymphocytic Leukaemia (CLL) – a Metaanalysis of Five Trials of the German CLL Study Group (GCLLSG)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3936-3936
Author(s):  
Paula Cramer ◽  
Susanne Isfort ◽  
Jasmin Bahlo ◽  
Raymonde Busch ◽  
Petra Langerbeins ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Initial Treatment ◽  
Research Funding ◽  
Single Agent ◽  
Cytotoxic Agents ◽  
Phase Iii ◽  
Line Treatment ◽  
Advisory Committees ◽  
Line Therapy ◽  
Travel Grant

Abstract Abstract 3936 Introduction: A substantial improvement of treatment outcomes in patients with CLL was achieved during the last decades, but almost all patients (pts) eventually relapse. According to ESMO-guidelines, a repetition of 1st-line therapy is a reasonable approach in case of a relapse >24 months after initial treatment [Eichhorst et al., Ann Oncol., 2011]. This recommendation has not yet been confirmed by clinical trials and little is known which therapy should be chosen in case of an earlier relapse. Methods: 1558 pts treated in five prospective trials of the GCLLSG were included in the analysis. Three randomised phase-III-trials for 1st-line treatment evaluated fludarabine (F) vs. F + cyclophosphamide (FC) [CLL4], chlorambucile (Clb) vs. F [CLL5] and FC without or with rituximab (FCR) [CLL8]. Two trials were designed for both 1st-line and relapse treatment and tested FC + alemtuzumab (FCC) [CLL2L] as well as bendamustine + rituximab (BR) [CLL2M]. For statistical analyses Kaplan-Meier estimators and curves, as well as log-rank tests were used. Results: Most common 1st-line therapies were those tested in the above mentioned five GCLLSG-trials: 588 pts received FC (38%), 402 pts FCR (26%), 299 pts F (19%), 134 pts Clb with/without steroids (9%) and 116 pts BR (7%). Treatment-free (TFS) and overall survival (OS) were shorter in pts treated with Clb, F or FC in comparison to patients treated with FCR or BR chemoimmunotherapy (see figure 1). So far, 704 of 1558 pts received 2nd-line treatment for progressive CLL. These 2nd-line therapies were quite heterogeneous, most common regimen were: FC (79 pts, 11%), BR (75 pts, 11%), F (65 pts, 9%), B with/without steroids (63 pts, 9%), CHOP-R (56 pts, 8%), Clb with/without steroids (55pts, 8%), FCR (54 pts, 8%), as well as alemtuzumab with/without steroids (43 pts, 6%) and FCC (32 pts, 5%). Patients treated with antibody-based regimen had a significantly longer OS than patients never treated with antibodies (OS after 60 months: 76% vs 64%, p<0,001). However, the timepoint of administration of the antibody (1st-line vs. ≥2nd-line treatment) appeared to be less important. 315 pts requiring a 2nd-line therapy within 24 months after initial treatment were identified. Treatment regimen were heterogeneous, most common therapies were the combination of cyclophosphamide, doxorubicine, vincristine, and prednisolone either with rituximab (R-CHOP, n=32) or without (CHOP, n=24) and alemtuzumab (n=27). Treatment regimens were summarized to 3 different groups: therapies containing an antibody with/without <3 cytotoxic agents, single-agent chemotherapies, and therapies containing anthracyclines and/or ≥3 cytotoxic agents. TFS for all three groups was 24.5, 18.7 and 16.4 months (p=0.009) and OS was 78.3, 58.2, and 42.0 months (p=0.012). Aside from a higher median age in the single-agent chemotherapy group no differences in other baseline-characteristics were found. Conclusion: This metaanalysis confirms that the use of monoclonal antibodies in 1st-line and relapse therapy leads to a prolongation of TFS and OS. In patients with a relapse ≤24 months, the use of standard-chemoimmunotherapies or single-agent alemtuzumab seems to be more efficient compared to therapies that contain ≥3 cytotoxic agents and/or anthracyclines (e.g. R-CHOP, CHOP or FCM). In addition, the poor outcome of early relapsing patients underscores the need for alternative treatment approaches with either allogeneic stem cell transplantation or use of novel drugs in order to further improve the survival of these pts. Disclosures: Cramer: Roche: Travel grant Other; Mundipharma: Travel grant, Travel grant Other. Bahlo:Roche: Honoraria. Fink:Roche: Travel grant Other. Goede:Roche: Honoraria, Travel grant Other. Elter:Roche: Honoraria, Travel grant Other. Stilgenbauer:Roche: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau. Wendtner:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Fischer:Roche: Honoraria, travel grants Other; Mundipharma: Honoraria. Hallek:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Eichhorst:Roche: Honoraria, Research Funding; Mundipharma: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees.

The Novel KSP Inhibitor ARRY-520 Is Active Both with and without Low-Dose Dexamethasone in Patients with Multiple Myeloma Refractory to Bortezomib and Lenalidomide: Results From a Phase 2 Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 449-449 ◽  
Author(s):  
Jatin J. Shah ◽  
Jeffrey A. Zonder ◽  
Adam Cohen ◽  
William Bensinger ◽  
Jonathan L. Kaufman ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Low Dose ◽  
Treatment Time ◽  
Single Agent ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Heavily Pretreated ◽  
Ksp Inhibitor

Abstract Abstract 449 Background ARRY-520 is a kinesin spindle protein (KSP) inhibitor that arrests cells in mitosis and induces apoptosis due to degradation of the BCL2 family survival protein MCL-1. As previously reported, ARRY-520 has demonstrated single-agent activity in relapsed and refractory multiple myeloma (RRMM). In preclinical myeloma models, the addition of dexamethasone (Dex) increases the activity of ARRY-520, supporting clinical investigation of ARRY-520 combined with low-dose Dex (LoDex). Here, the efficacy and safety of ARRY-520 is compared in 2 Phase 2 cohorts in RRMM: as a single agent (Cohort 1) and in combination with LoDex (Cohort 2). Methods Both cohorts were designed as 2-stage single-arm Phase 2 studies. Cohort 1 evaluated the efficacy and safety of 1.5 mg/m2/d ARRY-520 administered intravenously on Days 1 and 2 every 2 weeks with prophylactic granulocyte colony-stimulating factor (G-CSF) support. Eligible patients had RRMM with 2 prior lines of therapy that included both bortezomib (BTZ) and an immunomodulatory agent (IMiD), unless refusing or ineligible for this therapy. Cohort 2 is evaluating the efficacy and safety of the same dose and schedule of ARRY-520 and G-CSF with LoDex (40 mg PO weekly). Eligible patients had RRMM with 2 prior lines of therapy, and had disease refractory to (progressed on or ≤ 60 days of treatment) their last line of therapy and that was refractory to BTZ, lenalidomide (Len) and dexamethasone. Data from Cohort 1 and the first stage of Cohort 2 are reported. Results At the time of data cutoff, a total of 32 patients were enrolled into Cohort 1 with a median age of 65 years (range 51–82) and a median of 6 prior regimens (range 2–19). All patients received prior IMiD, 90% received prior BTZ and 78% had prior autologous stem cell transplant (ASCT). The defined first stage of Cohort 2 has been enrolled with 18 evaluable patients. These patients had a median age of 67 years (range 53–78) and were more heavily pretreated, with a median of 10 prior therapies (range 5–13). Safety was similar for both cohorts. A possible trend for more infections in Cohort 2 was noted. The most commonly reported (20% of patients) treatment-related adverse events (AEs) in both cohorts included thrombocytopenia, anemia, neutropenia and fatigue. No treatment-related events of neuropathy were observed in either cohort. The most common Gr 3/4 AEs (in Cohort 1, Cohort 2) included neutropenia (38%, 33%), thrombocytopenia (44%, 44%) anemia (28%, 50%), pneumonia (3%, 17%) and fatigue (16%, 11%). Treatment discontinuations due to AEs were infrequent (9%, 11%). Of 32 patients in Cohort 1, confirmed responses (≥ Minor Response (MR)) were observed in 6 patients (19%) with 5 Partial responses (PR) (16%) per International Melanoma Working Group (IMWG) and European Group for Blood and Marrow Transplantation (EBMT) criteria. The median treatment time was 2.1 months. In the subset of patients with disease refractory to both BTZ and Len, a 15% overall response rate (ORR ≥ MR) was observed. Among the 18 evaluable patients in Cohort 2, the ORR (≥ MR) was 28% (5/18), with 4 patients ≥ PR (22%). At the time of data cutoff, the median treatment time was 3.9 months. Summary Patients with RRMM refractory to both IMiD and proteasome inhibitor therapy have a poor prognosis with median survival of as little as 6 months1. New drugs with clinically meaningful activity in this population are needed. ARRY-520 is a novel agent with a distinct mechanism of action relative to other myeloma drugs and shows promising clinical activity both alone and combined with Dex in RRMM. Notably, in patients with triple-refractory MM, ARRY-520 + LoDex has shown a preliminary 28% ORR (≥ MR), with a manageable safety profile. These data are comparable to those reported for pomalidomide or carfilzomib in less heavily pretreated patients. Both the median time on study and ORR in Cohort 2 were greater than the activity seen for Cohort 1, despite the more advanced stage of these patients and the fact that they were heavily pretreated with Dex, suggesting that LoDex may enhance ARRY-520 activity. Based on this evidence of activity, further development of ARRY-520 + LoDex is warranted in patients who have exhausted other therapeutic options. Disclosures: Shah: Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Off Label Use: ARRY-520. Zonder:Millenium: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Kaufman:Onyx: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Millenium: Consultancy. Orlowski:Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Walker:Array BioPharma: Employment. Hilder:Array BioPharma: Employment. Ptaszynski:Array BioPharma: Consultancy. Lonial:Onyx: 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; Bristol-Meyers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Ponatinib In Patients (pts) With Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL) Resistant Or Intolerant To Dasatinib Or Nilotinib, Or With The T315I BCR-ABL Mutation: 2-Year Follow-Up Of The PACE Trial

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 650-650 ◽  
Author(s):  
Jorge E. Cortes ◽  
Dong-Wook Kim ◽  
Javier Pinilla-Ibarz ◽  
Philipp D le Coutre ◽  
Ronald Paquette ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Stock Options ◽  
Research Funding ◽  
Response Rates ◽  
Advisory Committees ◽  
Advisory Boards ◽  
Common Drug ◽  
Heavily Pretreated ◽  
History Of

Abstract Background Ponatinib is a potent, oral, pan-BCR-ABL inhibitor with activity against native and mutant forms of BCR-ABL, including the tyrosine kinase inhibitor (TKI)-resistant T315I mutant. The efficacy and safety of ponatinib (45 mg orally QD) were evaluated in the phase 2, international, open-label clinical trial (PACE) in pts with CML or Ph+ ALL. Methods 449 pts resistant or intolerant (R/I) to dasatinib or nilotinib or with the T315I mutation confirmed at entry were enrolled. Five pts (3 CP-CML, 2 AP-CML) without confirmed T315I and not R/I to dasatinib or nilotinib were treated, but not assigned to a cohort; they were included in safety analyses only. The primary endpoint was major cytogenetic response (MCyR) at any time within 12 mos for CP-CML, major hematologic response (MaHR) at any time within 6 mos for advanced Ph+ leukemia. Data are as of 1 April 2013, with a median follow-up of 19 (0.1-30) mos, and 18 mos minimum follow-up for pts remaining on study. Results Median age was 59 (18-94) yrs; 53% were male. Median time from diagnosis to ponatinib was 6 (0.3-28) yrs. Pts were heavily pretreated: 96% received prior imatinib, 84% dasatinib, 65% nilotinib, 7% bosutinib; 58% received ≥3 TKIs. In pts previously treated with dasatinib or nilotinib (N=427), 88% had a history of resistance, 12% were purely intolerant to dasatinib or nilotinib. Best prior response to most recent dasatinib or nilotinib was 26% MCyR or better in CP-CML, 23% MaHR or better in advanced Ph+ leukemia. The most common BCR-ABL mutations at baseline were 29% T315I, 8% F317L, 4% E255K, 4% F359V, 3% G250E. No mutations were detected in 44% of pts (Sanger sequencing). At the time of analysis, 46% of pts remained on study (60% CP-CML). The most common reasons for discontinuation: progressive disease (20%), adverse events (AEs; 13%; most common was thrombocytopenia, 4%). Response rates are shown in the table. Response rates were higher in CP-CML T315I vs R/I cohorts, however, a post-hoc multivariate analysis previously showed that T315I was not an independent predictor of MCyR. Other features, especially higher dose intensity and younger age in T315I pts, may explain the higher response rates. In CP-CML, responses were deep and durable; 91%, 91%, and 75% of pts with MCyR, CCyR, or MMR, respectively, were estimated to remain in response at 12 mos; progression-free survival (PFS) and overall survival (OS) were estimated to be 80% (median 27 mos) and 94% at 12 mos, respectively; progression to AP/BP occurred in 3 CP-CML pts , 2 other pts with a history of AP re-entered AP. 49% of AP-CML pts with MaHR were estimated to remain in response at 12 mos (median 12 mos); PFS and OS were estimated to be 56% (median 14 mos) and 84% at 12 mos. 36% of BP-CML pts with MaHR were estimated to remain in response at 12 mos (median 5 mos); PFS and OS were estimated to be 18% (median 4 mos) and 30% (median 7 mos) at 12 mos. 8% of Ph+ ALL pts with MaHR were estimated to remain in MaHR at 12 mos (median 3 mos); PFS and OS were estimated to be 7% (median 3 mos) and 39% (median 8 mos) at 12 mos. The most common drug-related AEs (>30%) were thrombocytopenia (37%), rash (34%), and dry skin (32%). Pancreatitis was the most common drug-related serious AE (5%); it occurred early and was primarily managed with dose modification, 1 pt discontinued. Serious cardiovascular, cerebrovascular, and peripheral vascular AEs occurred in 6%, 3%, and 2% of pts (drug-related: 2%, 1%, 1%). Conclusions Ponatinib has substantial activity in these heavily pretreated Ph+ leukemia pts who have limited available treatment options, with a safety profile reflective of the population. Updated data with a minimum follow-up of 2 yrs will be presented. Disclosures: Cortes: Ariad, Pfizer, Teva: Consultancy; Ariad, BMS, Novartis, Pfizer, Teva: Research Funding. Kim:BMS, Novartis, IL-Yang: Consultancy; BMS, Novartis, Pfizer, ARIAD, IL-Yang: Research Funding; BMS, Novartis, Pfizer, IL-Yang: Honoraria; BMS, Novartis, Pfizer: Speakers Bureau; BMS, Pfizer: Membership on an entity’s Board of Directors or advisory committees. Pinilla-Ibarz:Novartis, Ariad: Research Funding; Novartis, Ariad, BMS and Pfizer: Speakers Bureau. le Coutre:Novartis: Research Funding; Novatis, BMS, Pfizer: Honoraria. Paquette:ARIAD, BMS, Novartis: Consultancy, Honoraria, Speakers Bureau. Chuah:Novartis, Bristol-Myers Squibb: Honoraria. Nicolini:Novartis, Ariad, Teva, Pfizer: Membership on an entity’s Board of Directors or advisory committees; Novartis, BMS, Teva: Speakers Bureau; Novartis, BMS, Teva, Pfizer, Ariad: Honoraria; Novartis & Bristol Myers Squibb: Research Funding; Novartis, Ariad and Teva: Consultancy. Apperley:Novartis: Research Funding; Ariad, Bristol Myers Squibb, Novartis, Pfizer, Teva: Honoraria. Talpaz:Ariad, BMS, Sanofi, INCYTE: Research Funding; Ariad, Novartis: Speakers Bureau; Ariad, Sanofi, Novartis: Membership on an entity’s Board of Directors or advisory committees. DeAngelo:Araid, Novartis, BMS: Consultancy. Abruzzese:BMS, Novartis: Consultancy. Rea:BMS, Novartis, Pfizer, Ariad, Teva: Honoraria. Baccarani:Ariad, Novartis, BMS: Consultancy; Ariad, Novartis, BMS, Pfizer, Teva: Honoraria, Speakers Bureau. Müller:Novartis, BMS, Ariad: Consultancy, Honoraria; Novartis, BMS: Research Funding. Gambacorti-Passerini:Pfizer: Research Funding; Pfizer, BMS: Honoraria. Lustgarten:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Rivera:ARIAD: Employment. Clackson:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Turner:ARIAD: Employment. Haluska:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Deininger:BMS, ARIAD, NOVARTIS: Consultancy; BMS, NOVARTIS, CELGENE, GILEAD: Research Funding; ARIAD, NOVARTIS: Advisory Boards, Advisory Boards Other. Hochhaus:Ariad, Novartis, BMS, MSD, Pfizer: Research Funding; Novartis, BMS, Pfizer: Honoraria. Hughes:Novartis, BMS, ARIAD: Honoraria, Research Funding. Goldman:Ariad: Honoraria. Shah:Ariad, Bristol-Myers Squibb: Consultancy, Research Funding. Kantarjian:ARIAD, Novartis, BMS, Phizer: Research Funding.

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