Efficacy Analyses from the Immune Thrombocytopenia (ITP) Clinical Development Program for Avatrombopag: Comparisons with Placebo and Eltrombopag

Background: Management of ITP following failure of 1st line therapy, such as corticosteroids or intravenous immunoglobulin, continues to evolve. The use of thrombopoietin receptor agonists (TPO-RAs) as a subsequent therapeutic approach has become more common, which is supported by the recent American Society of Hematology guidelines (Neunert 2019). The oral TPO-RA eltrombopag (ELT) has an established efficacy profile but also carries an FDA boxed safety warning for hepatotoxicity, necessitating hepatic function monitoring. Additionally, ELT acts as a chelating agent, thus requiring administration two hours prior to, or four hours after meals containing polyvalent cations such as calcium or magnesium, in order to mitigate clinically relevant effects on the pharmacokinetic profile. Avatrombopag (AVA) is an oral TPO-RA approved for patients (Pts) with ITP that has not been shown to induce hepatoxicity in clinical studies and carries no requirement for monitoring of liver function. AVA does not chelate polyvalent cations and therefore is administered with food and without restrictions regarding meal composition. Aims: To evaluate the efficacy profile of AVA across its clinical development program, comprised of four Phase 2 and 3 studies, and including previously unreported results of study 305, a head to head comparison trial of AVA and ELT that was discontinued early due to enrollment challenges. Methods: Two Phase 2 studies were conducted evaluating AVA in ITP. Study CL-003 was a 28-day fixed dose ranging evaluation with a placebo (PBO) control, and study CL-004 was a 6-month continuation of study CL-003 allowing for dose titration of AVA in all participants. Two Phase 3 trials evaluating AVA were also conducted in ITP Pts, including study 302 a 6-month placebo-controlled study, and study 305, a randomized 6-month,non-inferiority trial with ELT seeking to enroll 286 Pts, that was stopped early due to enrollment challenges (23 enrolled) based on required endoscopy and commercial availability of ELT. Various efficacy analyses from these studies were performed in order to understand the consistency of AVA response across different patient populations in reference to PBO and ELT. Results: 128 Pts treated with AVA, 22 with placebo, and 11 with ELT were evaluated in the different studies. 99.2% of Pts were treated with AVA for at least 7 days and 63.3% continued treatment for at least 180 days with an average duration of exposure of 206.4 days for AVA vs 73.5 for ELT and 54.9 with placebo. For study 305 specifically, 12 AVA and 11 ELT Pts were enrolled with mean duration of drug exposure in the core study of 15.6 (median 13.1) and 10.5 weeks (median 6.9) respectively, and the enrolled populations were similar in regard to baseline characteristics (age, sex, ethnicity, baseline PC, splenectomy status or use of concomitant ITP medications). The median cumulative number of weeks of platelet response (PC ≥ 50,000/µL) were 11.0 (AVA) and 0.0 (PBO) (p=0.0079) in the phase 2 studies (CL-003 and CL-004); 12.4 (AVA) and 0.0 (PBO) (p<0.0001) in study 302; and 5.1 (AVA) and 0.0 (ELT) (p=0.33) in study 305 (mean = 5.4 and 4.3 respectively). In study 305, 5 ELT Pts dropped out due to an inadequate therapeutic effect versus only 1 AVA patient. Achieving a PC ≥ 50,000/µL on Day 7 was noted in 55.2% of AVA and 0% of PBO Pts in study CL-003, though this number increased to 80% for AVA 20mg Pts, which was the top dose evaluated in this dose ranging study. Achieving a PC ≥ 50,000/µL on Day 8 was noted in 65.6% AVA and 0% PBO Pts in study 302 and in 45.5% AVA and 36.4% ELT Pts in study 305. Interestingly, as noted in Table 2, the mean and median PCs and PC change from baseline all begin to numerically separate at 2 weeks in favor of AVA in study 305. Data past week 6 are not shown due to the limited study population at week 8 and beyond (8 AVA and 4 ELT Pts at week 8). A higher number of ELT Pts exhibited bleeding symptoms during study 305 than AVA Pts (9 vs. 6), though there were no WHO grade 3 or higher bleeds noted in either group. Treatment-emergent, treatment-related and grade 3+ adverse events were similar between AVA and ELT in study 305. Conclusions: The accumulated efficacy data in the AVA development program demonstrates a consistent effect across different studies conducted in a variety of countries. Though difficult to draw clear conclusions due to the limited study population, head to head data comparing AVA and ELT provide an opportunity for individual interpretation. Disclosures Tarantino: Amgen: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Grifols: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octapharma: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; NovoNordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Biomarin: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees; Spark: Membership on an entity's Board of Directors or advisory committees; HRSA: Membership on an entity's Board of Directors or advisory committees; CDC: Membership on an entity's Board of Directors or advisory committees; Dova: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other. Vredenburg:Dova Pharmaceuticals: Current Employment. Tian:Dova Pharmaceuticals: Current Employment. Jamieson:Dova Pharmaceuticals: Current Employment. Patel:Dova Pharmaceuticals: Consultancy.

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Efficacy and Safety of Retreatment with Bortezomib in Patients with Multiple Myeloma: Interim Results From RETRIEVE, a Prospective International Phase 2 Study.

Blood ◽

10.1182/blood.v114.22.3866.3866 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3866-3866 ◽

Cited By ~ 2

Author(s):

Maria Teresa Petrucci ◽

Igor W. Blau ◽

Paolo Corradini ◽

Meletios A. Dimopoulos ◽

Johannes Drach ◽

...

Keyword(s):

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Phase 2 ◽

Efficacy And Safety ◽

Advisory Committees ◽

Bortezomib Treatment ◽

Best Response ◽

Phase 2 Study ◽

Grade 3

Abstract Abstract 3866 Poster Board III-802 Bortezomib (Velcade®) retreatment has been shown to be active and well tolerated in patients with relapsed multiple myeloma (MM) in a number of retrospective studies and a small prospective phase 4 study (EVEREST). This large, prospective, international, multi-center, open-label phase 2 study was conducted to confirm the efficacy and safety of retreatment with bortezomib in MM patients who had previously responded (at least partial response [PR]) to bortezomib-based therapy as their most recent prior treatment. Patients had to have previously tolerated bortezomib 1.0 or 1.3 mg/m2 alone or in combination and have had a treatment-free interval (TFI; time from last dose of initial bortezomib treatment to first dose of bortezomib retreatment) of ≥6 months. Additional eligibility criteria included progressive disease or relapse from complete response (CR) by EBMT criteria, no MM therapy (except maintenance with dexamethasone, thalidomide, or interferon) since the last dose of initial bortezomib treatment, KPS ≥60, and adequate renal, hepatic, and hematologic function; patients with grade ≥2 peripheral neuropathy or neuropathic pain (as defined by NCI CTCAE v3.0) were excluded. Patients received bortezomib at the last tolerated dose (1.0 or 1.3 mg/m2) during initial treatment on days 1, 4, 8, and 11 for up to eight 21-day cycles, either alone or in combination with dexamethasone at the investigator's discretion. Response was assessed by EBMT criteria every 6 weeks during treatment and then every 2 months until disease progression. Adverse events (AEs) were graded according to NCI CTCAE v3.0. A total of 130 patients received at least 1 dose of bortezomib retreatment and were included in the safety population. Patients had a median age of 67 years, 57% were male, and 16% had KPS '70%. Median time from diagnosis of MM was 4.5 years (range 0–14 years); median number of prior therapies was 2; 15, 80, 23, and 12 patients had received 1, 2, 3, and ≥4 prior lines of therapy (excluding initial bortezomib therapy). Best response by EBMT criteria to initial bortezomib treatment was CR in 26% and PR in 74% of patients; median time to progression and TFI after initial bortezomib treatment were 17.9 months and 14.3 months, respectively. Last tolerated dose of previous bortezomib therapy was 1.3 mg/m2 and 1.0 mg/m2 for 62% and 29% of patients, respectively; 9% received another dose. Patients received a median 7.0 (range 1–8) cycles of bortezomib retreatment (23% of patients completed all 8 cycles); 72% of patients received concomitant dexamethasone. A total of 126 patients were evaluable for response. In the 126 response-evaluable patients, the overall response rate (ORR; CR+PR) by best confirmed response (EBMT criteria) was 40%; in addition, 18% of patients achieved minimal response (MR), to give a CR+PR+MR rate of 58%. After a planned secondary efficacy analysis, the ORR (CR+PR) by single best response was 55% (75% ≥MR). Median time to best confirmed response (≥MR) was 2.9 months; time to first response was 1.5 months. Analysis of ORR by patient subgroups showed comparable results in patients who did versus did not receive concomitant dexamethasone (42% vs 32%), in those who received ≤1.0 mg/m2 vs 1.3 mg/m2 bortezomib (35% vs 41%), and in those aged ≤65 years vs >65 years (45% vs 36%). ORR was 67%, 39%, 33%, and 25% in patients who had received 1, 2, 3, and ≥4 prior lines of therapy (excluding initial bortezomib), respectively. Analysis of best confirmed responses according to response to initial bortezomib showed that 63% and 52% of patients who achieved a CR or PR, respectively, to initial bortezomib treatment responded to retreatment. Most (98%) patients experienced a treatment-emergent AE; 60% experienced a grade 3/4 AE, and 32% experienced a serious AE; there were 8 deaths, 2 of which (due to sepsis and stroke) were possibly treatment-related. The most common grade 3/4 AEs were thrombocytopenia (35%), neutropenia (7%), diarrhea (7%), and pneumonia (5%). AEs leading to dose reductions or discontinuations were reported for 22% and 12% of patients, respectively. The incidence of neuropathy was 39%, including 9% grade 3; 4% of patients discontinued treatment due to PN; 61% of neuropathy events resolved or improved within a median 1.3 months. These results confirm that bortezomib retreatment is a well-tolerated, feasible, and active therapeutic option for heavily pretreated MM patients without evidence of cumulative toxicity. Disclosures: Petrucci: Janssen-Cilag: Honoraria; Celgene: Honoraria. Dimopoulos:Ortho-Biotech: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Honoraria. Drach:Janssen-Cilag: Consultancy, Honoraria; Amgen: Honoraria; Celgene: Honoraria. Blade:Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria; Johnson and Johnson: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Alkaline Phosphatase (ALP) Variation During Carfilzomib Treatment Is Associated to Best Response in Multiple Myeloma.

Blood ◽

10.1182/blood.v114.22.2865.2865 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2865-2865 ◽

Cited By ~ 2

Author(s):

Maurizio Zangari ◽

Latha Polavaram ◽

Fenghuang Zhan ◽

Guido J. Tricot ◽

Ravi Vij ◽

...

Keyword(s):

Retrospective Analysis ◽

Board Of Directors ◽

Research Funding ◽

Single Agent ◽

Proteasome Inhibitors ◽

Phase 2 ◽

Two Phase ◽

Advisory Committees ◽

Best Response ◽

Ortho Biotech

Abstract Abstract 2865 Poster Board II-841 BACKGROUND: The ubiquitin-proteasome pathway, which has been shown to be an essential cellular degradative system in myeloma cells, can also regulate bone formation through its effects on osteoblast differentiation. Retrospective analysis of variation of ALP during treatment with bortezomib indicates a close correlation between myeloma response and serum ALP levels which multiple studies have shown to be of bone origin. To determine if this effect is a class effect of proteasome inhibitors (PIs), this retrospective study analyzed variation of ALP in relationship to myeloma response during treatment with carfilzomib, the first in a new class of selective epoxyketone PIs that has demonstrated encouraging safety and efficacy in two phase 2 studies of relapsed or refractory myeloma patients. METHODS: Retrospective analysis of serum ALP was performed on relapsed or refractory myeloma patients enrolled on two phase 2 studies (PX-171-003 and PX- 171-004) evaluating the safety and efficacy of single agent carfilzomib. We analyzed data from 38 patients in the first cohort of the PX-171-003 study, a relapsed and refractory myeloma trial for patients who have received ≥ 3 prior therapies including bortezomib and an IMiD and 29 patients in PX-171-004, a relapsed or refractory myeloma trial that included bortezomib naïve patients. All patients received 20 mg/m2 of carfilzomib on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. RESULTS: Seventy-seven patients were enrolled. The median age was 63 years with a median time since diagnosis of 4.6 years, 52% were male, 84.% had relapsed after autologous transplants, 82.% were previously exposed to bortezomib, and 92% were previously exposed to an IMiD. Sixty seven patients with ALP data were evaluable for response. In PX-171-003 the ORR (≥PR) was 18% and the clinical benefit response (CBR; ≥MR) was 26%, while in PX-171-004 the ORR was 35.5% overall and 57% in bortezomib naive patients. ALP increment from baseline, which was most evident during the second cycle of treatment, was statistically different in patients who achieved ≥VGPR compared to all others on Days 1 (P=0.0049) and 8 (P=0.006) of Cycle 2. In all patients achieving a VGPR or better, ALP increased more than 15 units per liter at Cycle 2 Day 1 over baseline An ALP increase over the same period of time was seen in 26 %, 13%, and 11% of patients achieving PR, MR, and SD, respectively. None of the patients with progressive disease exhibited a similar increase. Our study indicates that response first assessed on Day 15 of Cycle 1 parallels the ALP elevation which returned to baseline levels at the end of Cycle 3. CONCLUSIONS: This retrospective analysis on a subset of patients in these ongoing phase 2 studies of single agent carfilzomib in relapsed or refractory multiple myeloma suggests that elevation in ALP may be associated with best response. Taken with previous publications describing bortezomib treatment, these results suggest that this specific anabolic bone phenomenon could be a class effect of proteasome inhibitors. These phase 2 studies are ongoing with a higher dose of carfilzomib (27 mg/m2) being evaluated. The data from this small subset analysis suggests that further exploration of this relationship is warranted. Disclosures: Zangari: Milllennium: Honoraria, Research Funding; Novartis: Research Funding; Celgene: Honoraria; OrthoBiotech: Honoraria; Optum Health: Honoraria; Educational Concepts Group, LLC: Membership on an entity's Board of Directors or advisory committees. Vij:Proteolix: Consultancy, Research Funding. Jagannath:Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Merck: Honoraria. Siegel:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Stewart:Millennium: Consultancy, Research Funding; Proteolix: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Honoraria. Wang:Proteolix: Honoraria, Research Funding. Belch:Ortho Biotech: Honoraria, Research Funding. Jakubowiak:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Centocor Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers-Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Trudel:Celgene: Honoraria, Speakers Bureau; Ortho Biotech: Honoraria. Bahlis:Celgene: Honoraria, Speakers Bureau; Ortho Biotech: Honoraria, Speakers Bureau. Lonial:Celgene: Consultancy; Millennium: Consultancy, Research Funding; BMS: Consultancy; Novartis: Consultancy; Gloucester: Research Funding. Singhal:Celgene: Speakers Bureau; Millennium: Speakers Bureau.

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A Randomized Phase 2 Trial of Bortezomib–Dexamethasone Versus Bortezomib–Dexamethasone with Added Cyclophosphamide or Lenalidomide in Multiple Myeloma Patients Achieving Stable Disease After Four Cycles of Bortezomib–Dexamethasone Administered as Second-Line Treatment.

Blood ◽

10.1182/blood.v114.22.4937.4937 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4937-4937

Author(s):

Meletios A. Dimopoulos ◽

Huw Roddie ◽

Meral Beksac ◽

Lotfi Benboubker ◽

Romualdas Jurgutis ◽

...

Keyword(s):

Renal Function ◽

Board Of Directors ◽

Research Funding ◽

Safety Data ◽

Phase 2 ◽

Advisory Committees ◽

Ortho Biotech ◽

Function Group ◽

Grade 3 ◽

Renal Function Group

Abstract Abstract 4937 Bortezomib (Velcade®) plus dexamethasone (Vel/Dex) is known to be effective and well tolerated in patients with multiple myeloma (MM). As demonstrated in the frontline setting, the addition to Vel/Dex of cyclophosphamide (VCD) or lenalidomide (Revlimid®; VRD) may lead to improved efficacy, but may be associated with increased toxicities; however, few studies have prospectively assessed Vel/Dex as second-line therapy. This randomized, open-label, parallel-group, phase 2 study in patients who have relapsed after or are refractory to primary MM therapy is designed to evaluate the safety and efficacy of an additional 4 cycles of Vel/Dex, VCD, or VDR in patients achieving stable disease (SD) after 4 cycles of Vel/Dex. Bortezomib-naïve patients aged ≥18 years, with measurable MM, KPS ≥60, life expectancy ≥6 months, adequate hematologic and hepatic function, and without grade ≥2 peripheral neuropathy (PN) received 4 3-week cycles of Vel/Dex (Vel 1.3 mg/m2 IV on days 1, 4, 8, and 11, and Dex 20 mg PO on days 1, 2, 4, 5, 8, 9, 11, and 12). Patients then received a further 4 cycles of therapy as follows: patients achieving at least a partial response (PR) received Vel/Dex; patients with SD underwent central randomization to receive Vel/Dex, VCD, or VRD; patients with progressive disease (PD) discontinued treatment. Here we report efficacy and renal function improvement in patients who had the opportunity to complete the initial 4 cycles of Vel/Dex as of April 2009, and safety data for patients who received at least 1 dose of study drug. Response was assessed by IMWG uniform response criteria based on measurement of serum and urine M-protein prior to treatment on day 1 of each cycle, at end of treatment, and monthly thereafter. Renal function as defined by calculated glomerular filtration rate (GFR; Cockcroft–Gault formula) was assessed prior to treatment on day 1 of cycles 1–5. Adverse events (AEs) were graded using NCI CTCAE v3.0. A total of 122 patients have been enrolled; by data cut-off (July 21 2009), 24 (20%) had not completed a single treatment cycle and are excluded from the safety population (N=98). Eighteen had received <4 cycles at data cut-off. Of the remaining 80 who were eligible for response, 63 had completed 4 cycles, 6 discontinued prior to completing 4 cycles (due to PD in 3 patients, death in 1, drug-related AEs in 2), 9 were not under treatment at data cut-off, and 2 had died. Their median age was 62 years (range 34–86), 55% were male, 21.3% had KPS ≤70; median time from prior therapy was 18.6 months. Response rate in the efficacy population was 41/80 (51%) after 4 cycles, including 8% CR. Median times to first and best response were 37 and 57 days, respectively. Patient renal function (by GFR) at baseline, median improvement in GFR, and responses achieved by the 10 patients in whom GFR improved by at least one renal function group are shown in the Table. Among the 98 patients who received at least one treatment dose, mean cumulative doses of bortezomib and dexamethasone were 14.6 mg/m2 (4.9, 4.5, 4.4, and 4.3 mg/m2 in cycles 1–4) and 478 mg (151.8, 145.6, 145.4, and 144.0 mg for cycles 1–4), respectively. Most patients (90%) reported AEs, including 39% with grade 3/4 AEs and 23% with serious AEs, within the first 4 cycles. The most common grade 3/4 AEs included thrombocytopenia (13%), anemia (7%), and pneumonia (6%). AEs resulting in dose reductions/treatment stop were seen in 21%/10% of patients. Incidence of sensory PN and PN was 29% (3% grade 3/4); most PN events were reversible, with 68% resolving within a median 53 days. Updated efficacy and safety data for the first 4 cycles of Vel/Dex for all patients enrolled by July 31 will be presented. Table: Improvement in renal function (as measured by GFR)* Renal function group at baseline, n† <15 mL/min 3 15–<30 mL/min 6 30–<60 mL/min 33 ≥60 mL/min 36 Median GFR (median improvement from previous cycle), mL/min At baseline 58.3 After cycle 1 64.4 (4.8) After cycle 2 68.9 (2.9) After cycle 3 68.6 (9.9) After cycle 4 73.5 (9.4) Renal improvement by at least 1 grade, n (response achieved) 10 <15 to 15–<30 mL/min 1 (1 CR) 15–<30 to 30–<60 mL/min 1 (1 PR) 30–<60 to ≥60 mL/min 8 (2 CR, 1 VGPR, 3 PR, 2 SD) * 1 patient only had a baseline GFR measurement and was not included in the renal analysis † 1 patient had no baseline GFR measurement Disclosures Dimopoulos: Ortho Biotech: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Honoraria. Beksac:Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau. Langer:Celgene: Consultancy; Ortho Biotech: Consultancy. Facon:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees.

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An Open-Label Phase 2 Study Of Ofatumumab In Combination With a Novel AKT Inhibitor (Afuresertib) In Previously Treated Patients With Chronic Lymphocytic Leukemia (CLL)

Blood ◽

10.1182/blood.v122.21.4175.4175 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4175-4175

Author(s):

Christine I. Chen ◽

Susi Snitzler ◽

Trina Wang ◽

Harminder Paul ◽

Lisa W Le ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Single Agent ◽

Treatment Phase ◽

Phase 2 ◽

Akt Inhibitor ◽

Advisory Committees ◽

Phase 2 Study ◽

Previously Treated ◽

Grade 3

Abstract Introduction Ofatumumab is a novel anti-CD20 monoclonal antibody which led to impressive single-agent responses of 47-58% in a phase 2 study of CLL patients (pts) with refractory disease (Wierda et al 2010). Unfortunately, response durations were short (median 5.6-7.1 mos). In order to improve upon these results, we combined ofatumumab with a novel pan-AKT kinase inhibitor, afuresertib (GSK2110183). The AKT pathway plays a centralized role in tumor differentiation, migration, proliferation and survival and is frequently aberrantly activated in CLL (Longo et al 2007). Single agent afuresertib is very well-tolerated with minimal myelotoxicity in relapsed/refractory hematologic malignancies (Spencer et al ASH 2011). We present an interim analysis of the initial 19 of 31 planned pts in an ongoing trial of ofatumumab and afuresertib in relapsed/refractory CLL. Methods Previously treated CLL pts who have received at least one prior fludarabine-containing regimen with disease progression are eligible. During the initial 6 month Treatment Phase, ofatumumab 2000mg IV is administered weekly for 8 doses, then once every 4 week cycle for 4 doses (dose/schedule identical to the pivotal phase 2 trial) with afuresertib 125mg orally daily. An initial 10 day Lead-in Phase with afuresertib alone allows for evaluation of pharmacodynamic (PD) changes in phosphoproteins and pharmacokinetic (PK) studies. Pts are assessed for safety and response on day 1 of each cycle. Pts achieving SD, PR or CR by the end of the Treatment Phase proceed to the Maintenance Phase with single-agent afuresertib for a maximum of 12 mos (12 cycles). Results Demographics: To date, 19 pts have been enrolled. Median age is 65 yrs (range 43-76), baseline median Hb 108g/L (range 80-145), absolute lymphocytes 29.7 x109/L (range 1.0-464.9), β2M 4.42mg/L (range 1.42-3.21), bulky nodes ≥5cm in 5 pts (32%), organomegaly in 8 pts (42%), del17p/del11q on FISH in 9 pts (47%), and ZAP70+ in 13 pts (68%). Eight pts (42%) were fludarabine-refractory; only 2 pts had received prior alemtuzumab. The median number of prior therapies was 2 (range 1-6). Toxicity: Hematologic: 4 pts (21%) developed Gr 3-4 neutropenia during at least 1 cycle; 1 pt (5%) had a febrile neutropenia event. Only 2 pts (10.5%) have developed Gr 3-4 thrombocytopenia, without bleeding. Nonhematologic toxicity: Most common related grade 3-4 toxicities were GI: dyspepsia (53%), diarrhea (37%), nausea (21%), temporally related to oral afuresertib and easily managed symptomatically. Infusion reactions to ofatumumab were frequent (12 pts; 63%) with grade 3 reactions in 3 pts. Five pts (26%) developed non-infectious pneumonitis, with 3 pts requiring hospitalization. Two pts with preexisting atrial arrhythmias sustained exacerbation with weekly ofatumumab infusions. Most infections were mild, with only 1 grade 3 cellulitis. Efficacy: Of the 19 response-evaluable pts receiving a median of 6 cycles (range 1-9), 8 pts (42%) have achieved a PR, 11 SD (58%), and no CR. Response onset was rapid at a median 0.9 mos (range 0.8-2.8). At a median follow-up of 6.8 mos (range 0.3-12.9 mos), 5 pts (26%) have progressed and one patient has died after cycle 1 on therapy due to progressive CLL. PD Studies: CD19+ cells are assayed for phosphorylated AKT and its downstream targets RAS40 and GSK3 in addition to phospho-proteins of alternative pathways including ERK and pS6 by multiplexed phospho-flow cytometry. Peripheral blood samples are collected at screening and on cycle 1 day 10, after dosing with afuresertib. Of the 7 patients evaluated thus far, 5 demonstrated constitutive AKT phosphorylation at baseline. Partial inhibition of AKT signaling evidenced by increased phosphorylation of AKT and inhibition of GSK3 and/or RAS40 phosphorylation in response to BCR stimulation was observed post-treatment, indicating target engagement by afuresertib. PK Studies: Afuresertib exposure (Cmax and AUC) was similar when afuresertib was administered alone or in combination with ofatumumab. Conclusion Preliminary results from this phase 2 study suggests that a combination of ofatumumab plus a novel oral AKT inhibitor, afuresertib, has activity in previously treated CLL and is generally well-tolerated with minimal myelotoxicity. Response data are encouraging but whether durable responses can be achieved requires more mature follow-up. Disclosures: Chen: Johnson & Johnson: Consultancy, Research Funding; Lundbeck: Consultancy; Celgene: Consultancy, Research Funding; GlaxoSmithKline: Research Funding; Roche: Honoraria. Off Label Use: Off-label use of ofatumumab and afuresertib for the treatment of relapsed/refractory CLL. Smith:GSK: Employment, Equity Ownership. Johnston:Roche: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Lundbeck: Membership on an entity’s Board of Directors or advisory committees, Research Funding; GSK: Membership on an entity’s Board of Directors or advisory committees, Research Funding.

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Ibrutinib, Single Agent or in Combination with Dexamethasone, in Patients with Relapsed or Relapsed/Refractory Multiple Myeloma (MM): Preliminary Phase 2 Results

Blood ◽

10.1182/blood.v124.21.31.31 ◽

2014 ◽

Vol 124 (21) ◽

pp. 31-31 ◽

Cited By ~ 5

Author(s):

Ravi Vij ◽

Carol Ann Huff ◽

William I. Bensinger ◽

David S. Siegel ◽

Sundar Jagannath ◽

...

Keyword(s):

Multiple Myeloma ◽

Adverse Event ◽

Board Of Directors ◽

Plasma Cells ◽

Single Agent ◽

Phase 2 ◽

Efficacy And Safety ◽

Advisory Committees ◽

Grade 3 ◽

Anti Tumor Activity

Abstract Introduction: Multiple myeloma (MM) remains an incurable disease in need of new therapies with unique targets. Ibrutinib is a first-in-class, once-daily, oral, covalent inhibitor of Bruton’s tyrosine kinase (BTK), an essential enzyme in the B-cell receptor signaling pathway. While BTK is essential for the development and function of B cells and is down-regulated in plasma cells, the expression of BTK in malignant plasma cells is increased 4-fold and comparable to BTK expression levels in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). In addition, pre-clinical models show that BTK inhibition with ibrutinib led to direct inhibition of both osteoclast bone resorption and the release of osteoclast-derived tumor growth factors (Tai et al, Blood 2012). Taken together these data suggest that ibrutinib may have a role in the treatment of MM. Methods: This open label phase 2 dose escalation study was designed to enroll patients in 4 cohorts (Figure) to evaluate efficacy (≥MR) and secondary endpoints of safety, PK, ORR and DOR. Patients must have had documented non-responsive/progressive disease at the time of study entry following at least 2 prior lines of therapy including at least one immunomodulatory agent. Efficacy and safety were assessed at 4 weeks intervals using the IMWG response criteria for efficacy assessments (Rajkumar et al, Blood 2011), while safety was assessed according to CTCAE v4.0 criteria. Results: As of 15 May 2014 and a median follow up of 15.2 months, 69 patients with a median age of 64 years (range 43-81) were dosed, of which 20% had either a del 17p or p53 deletion. The number of median prior therapies was 4 (range, 2-14), 41% had ≥ 5 prior therapies and 80% had undergone autologous stem cell transplant. Sixty-two percent of patients were refractory to their last line of therapy and of the 65 patients that had received prior therapy with both an immunomodulatory agent and a proteasome inhibitor, 44% were refractory to both. Anti-tumor activity was noted across all cohorts. The highest activity with a clinical benefit rate (CBR) of 25% including 1 PR, 4 MR and 5 sustained (>4 cycles) SD was observed in Cohort 4. (Table) This led to expansion of Cohort 4 per protocol design. In Cohorts 1 and 3, 14 patients had dex added following PD, resulting in 1 PR and 9 SD. Overall, 57% experienced a Grade 3 or higher adverse event. The most commonly reported non-hematologic toxicities (any grade) were diarrhea (51%), fatigue (41%), nausea (35%), dizziness (25%), and muscle spasms (23%). The majority were Grade 1 and 2. Myelosuppression had a reported overall incidence of any grade anemia (29%), thrombocytopenia (23%), and neutropenia (7%) with 16%, 9% and 4% being Grade 3, respectively. There were no clinically meaningful differences among dose levels. Twenty-three patients experienced a SAE for a total of 47 reported events with 16 assessed as possibly/definitely related to ibrutinib per investigator. At least one dose modification occurred in 22% of patients, with 6 discontinuing due to an adverse event. At the time of the data cut-off 7 patients remain on study treatment. The most common reason for treatment discontinuation was PD in 47% of patients, with additional patients discontinuing due to investigator discretion (18%), patient decision (7%) and non-compliance (3%). Conclusions: In this heavily pre-treated patient population ibrutinib, as a single agent and in combination with dex, demonstrated evidence of anti-tumor activity. There was a trend toward improved efficacy (≥MR) in Cohort 4 and treatment was well tolerated with manageable toxicities. Ongoing correlative studies are being conducted to determine changes in cytokines, chemokines and indices of bone metabolism and to determine the effect of dex, a known CYP3A4/5 inducer, on the pharmacokinetic profile of ibrutinib. In addition, ibrutinib is currently being evaluated in combination with carfilzomib in an ongoing Phase1/2b study. (NCT01962792) Figure 1 Figure 1. Table Confirmed Response by Assigned Treatment Cohort Response, n (%) 1 (n=13) 2 (n=18) 3 (n=18) 4 (n=20) PR 1 1 - 1 MR 1 - - 4 SD ≥ 4 cycles 2 4 6 5 SD < 4 cycles 5 6 4 1 PD 4 5 7 5 Not evaluable - 2 1 4 Not evaluable – no post-baseline assessments Figure 2 Figure 2. Disclosures Off Label Use: Discussion of efficacy and safety data with ibrutinib as single-agent and in combination with dexamethasone in patients with relapsed and relapsed/refractory multiple myeloma treated in a phase 2 clinical trial. Huff:Celgene, Millenium: Consultancy. Bensinger:Pharmacyclics, Novartis, Celgene, Millenium, Sanofi, Acetylon: Consultancy, Research Funding. Siegel:Celgene, Millennium, Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jagannath:Celgene, BMS, Jansen, Sanofi-Aventis: Honoraria. Lebovic:Onyx, Celgene: Speakers Bureau. Anderson:Celgene, Millenium, Onyx, : Speakers Bureau. Elias:Pharmacyclics, Inc.: Employment. Clow:Pharmacyclics, Inc.: Employment. Fardis:Pharmacyclics: Employment. Graef:Pharmacyclics: Employment. Bilotti:Pharmacyclics: Employment. Richardson:Celgene, Millennium, Johnson&Johnson: Membership on an entity's Board of Directors or advisory committees.

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Safety and Efficacy of Abexinostat, a Pan-Histone Deacetylase (HDAC) Inhibitor, in Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia: Results of an Ongoing Phase 2 Study

Blood ◽

10.1182/blood.v126.23.256.256 ◽

2015 ◽

Vol 126 (23) ◽

pp. 256-256 ◽

Cited By ~ 2

Author(s):

Vincent Ribrag ◽

Won Seog Kim ◽

Reda Bouabdallah ◽

Soon Thye Lim ◽

Bertrand Coiffier ◽

...

Keyword(s):

Board Of Directors ◽

Progressive Disease ◽

Cell Lymphoma ◽

Hdac Inhibitors ◽

New Drugs ◽

Tumor Type ◽

Phase 2 ◽

Advisory Committees ◽

Free Survival ◽

Grade 3

Abstract Introduction: Histone deacetylase (HDAC) inhibitors, by blocking HDAC enzymes, can regulate acetylation states of histones and other non-histone proteins. Hyperacetylation of histones in cells can cause transcriptional activation of tumor suppressor genes, as well as genes involved in cell cycle control, cell division, and apoptosis, resulting in antitumor activity. Currently, 3 HDAC inhibitors (HDACi), vorinostat, romidepsin, and belinostat, are approved for the treatment of relapsed or refractory peripheral or cutaneous T-cell lymphoma (T-CL). HDACi in development also show promising results in B-cell malignancies and solid tumors. Abexinostat, an orally available hydroxamate-containing HDACi with good tolerability, differs from approved HDACi due to its unique pharmacokinetic profile and oral dosing schedule, twice daily 4 hours apart, which allows for continuous exposure at concentrations required for efficient tumor cell killing (Mitsiades, et al. Blood. 2003; unpublished data). Abexinostat may, therefore, offer an active and potentially less-toxic treatment option for cancer with a wider therapeutic index than other HDACi in development. Abexinostat showed manageable toxicity and durable responses, including some complete responses (CR), particularly in patients (pts) with relapsed/refractory follicular lymphoma (FL) (Evens ICML 2013; Morschhauser, Invest New Drugs, 2015). Methods: In this phase 2 trial, pts aged ≥18 years with relapsed/refractory NHL or CLL received oral abexinostat at 80 mg BID for 14 days of a 21-day cycle and continued until progressive disease or unacceptable toxicity. The 80 mg BID dose, which corresponds to the recommended phase 2 dose of 45 mg/m2 BID, was identified in phase 1 of the study (Morschhauser, Invest New Drugs, 2015). The primary endpoint was overall response rate (ORR); secondary endpoints included overall survival, progression-free survival, time to tumor progression, duration of response, disease-free survival, and time to treatment failure. Results: A total of 100 pts (median age, 66.5 years; 52% >65 years; 55% male) were enrolled between Oct 2011 and Jul 2014, including 16 with CLL, 17 with diffuse large B-cell lymphoma (DLBCL), 18 with FL, 16 with mantle cell lymphoma (MCL), 18 with T-CL, and 15 with marginal zone lymphoma (MZL) or other NHL subtypes. The median number of prior regimens across all lymphoma subtypes was 3 (range, 1-11) with a median of 4.5 prior regimens (range, 1-11) for FL pts. All pts received at least one dose of study drug; 55% discontinued due to progressive disease and 25% due to adverse events. Seven pts remain on treatment. Among the 87 pts evaluable for efficacy, ORR was 28% (CR, 5%). Responses by histology are shown in the table. Highest responses were observed in FL, T-CL, and DLBCL with ORRs of 56%, 40%, and 31% and median durations of response of 26.0 weeks (range, 0.1-90.4), 32.1 weeks (range, 6.3-51.3), and 8.1 weeks (range, 3.1-59.0), respectively. Grade ≥3 adverse events (AEs) and any serious AEs (SAEs) were reported in 86% and 46% of pts, respectively. The most frequently reported grade ≥3 treatment-emergent AEs were thrombocytopenia (80%), neutropenia (27%), and anemia (22%). The incidence of any-grade diarrhea was 47% (grade ≥3, 3%). The most commonly reported SAEs included thrombocytopenia (15%), anemia (7%), and pneumonia (6%). The most frequent toxicities that led to discontinuation included hematologic events, such as thrombocytopenia and neutropenia. Gastrointestinal toxicities leading to discontinuation were infrequent with 1 episode of vomiting being reported. Conclusions: Abexinostat has a manageable toxicity profile in pts with various NHL subtypes that is similar to other HDACi and comparable to other single-agent therapies currently in development. Promising efficacy was observed with abexinostat, especially in FL, T-CL, and DLBCL, with an ORR ≥30% in these subtypes, consistent with the results of an independent study of abexinostat in lymphomas that used a week-on-week-off schedule (Evens ICML 2013). Further investigation of the safety and efficacy of abexinostat in these indications implementing the less dose-intense interval on a week-on-week-off schedule is planned. Table. Response With Abexinostat by Tumor Type Tumor type ORR, % (CR, %) Overall (N=87) 28% (5%) FL (n=16) 56% (6%) T-CL (n=15) 40% (7%) DLBCL (n=16) 31% (6%) MCL (n=13) 15% (8%) MZL/other (n=13) 15% (0%) CLL (n=14) 0% (0%) Disclosures Ribrag: Pharmamar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: abexinostat in NHL and CLL. Coiffier:CELLTRION, Inc.: Consultancy, Honoraria. Luan:Pharmacyclics LLC, an AbbVie Company: Employment. Graef:AbbVie: Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Employment, Membership on an entity's Board of Directors or advisory committees. Morschhauser:Genentech Inc./Roche: Other: Advisory boards.

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Velcade, Vorinostat and Dexamethasone (V2 D) in Relapsed Myeloma: Results of the Phase 2 Muk Four Trial

Blood ◽

10.1182/blood.v126.23.1852.1852 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1852-1852

Author(s):

Matthew W Jenner ◽

Avie-Lee Tillotson ◽

Sarah R Brown ◽

Louise M Flanagan ◽

Debbie Sherratt ◽

...

Keyword(s):

Peripheral Neuropathy ◽

Disease Progression ◽

Board Of Directors ◽

Dose Reduction ◽

Response Rate ◽

Prior Treatment ◽

Phase 2 ◽

Advisory Committees ◽

Grade 3 ◽

Relapsed Myeloma

Abstract Introduction: Bortezomib (Velcade) and dexamethasone is a standard combination for relapsed myeloma. Both in vitro data and initial clinical trials signalled the efficacy of the combination of intravenous bortezomib and the oral histone deacetylase inhibitor vorinostat. Although the randomised phase 3 VANTAGE 088 trial identified an improvement in progression free survival with the combination of bortezomib and vorinostat compared to bortezomib monotherapy in relapsed myeloma, 50% of patients in the vorinostat group had at least one dose reduction compared with 25% in the placebo group, with potential impact on clinical outcomes. Subcutaneous bortezomib has now become the standard route of administration because of lower rates of peripheral neuropathy. MUK four is a single arm phase 2 multi-centre UK trial to evaluate the toxicity profile and efficacy of an alternative dosing schedule of vorinostat in combination with subcutaneous bortezomib and oral dexamethasone. We report the final analysis of toxicity and response data. Methods: Patients with relapsed myeloma treated with 1-3 prior lines of therapy received up to 8 cycles of V2 D (bortezomib 1.3 mg/m2 subcutaneously days 1, 4, 8 and 11, vorinostat 400 mg orally days 1-4, 8-11 and 15-18 and dexamethasone 20 mg orally days 1, 2, 4, 5, 8, 9, 11 and 12 of a 21 day cycle). Following completion of a minimum of 3 cycles of V2 D, participants received maintenance vorinostat (400 mg days 1-4 and 15-18 of a 28 day cycle) until disease progression, intolerance or participant withdrawal. Responses were assessed using the modified IMWG response criteria and toxicities graded using CTCAE v4.0. Results: Between August 2013 and November 2014, 16 participants were recruited to MUK four. Median age was 69.5 years (range 50.0-78.0) and median lines of prior treatment was 1 (1-3). Prior treatment included thalidomide-based combinations in 13/16 (81.3%), bortezomib-based in 7/16 (43.8%) and lenalidomide-based in 2/16 (12.5%). 9/16 (56.3%) participants had received prior high dose melphalan ASCT. Median time from diagnosis was 38.6 months (9.3-120.4). At analysis in June 2015 8/16 (50%) participants continued on maintenance vorinostat. All 16 patients were evaluable for response within the first 8 cycles of V2 D. Overall response rate was 81.3% (13/16, 95% CI [55.4-96.0]) consisting of CR in 4/16 (25.0%), VGPR 2/16 (12.5%) and PR in 7/16 (43.8%). The remaining 3/16 (18.8%) achieved MR giving a clinical benefit response rate of 16/16 (100%). Participants received a median of 6 cycles of initial treatment with 6/16 (37.5%) receiving all 8 cycles. Treatment was discontinued in 4/8 (50%) because of disease progression, in 2/8 (25%) because of toxicity and in 2/8 (25%) for clinician discretion. Overall 12/16 (75%) participants experienced a dose reduction of either vorinostat or bortezomib or terminated treatment early as a result of toxicity. 11/16 (68.8%) reduced vorinostat and 10/16 (62.5%) reduced bortezomib. The most frequent grade 2 toxicities during the first 8 cycles were fatigue in 8/16 (50%), anaemia in 7/16 (43.8%), diarrhoea in 5/16 (31.3%), nausea in 4/16 (25.0%) and peripheral neuropathy in 4/16 (25.0%). The most frequent grade 3-4 toxicities encountered during the first 8 cycles were thrombocytopenia in 8/16 (50%), anaemia in 1/16 (6.3%), diarrhoea in 1/16 (6.3%) and fatigue in 1/16 (6.3%). During maintenance vorinostat only 1 participant experienced an adverse reaction above grade 2 (grade 3 neutropenia). Conclusion: Bortezomib, vorinostat and dexamethasone is a highly effective combination in relapsed myeloma with good response rates. Maintenance vorinostat is well tolerated. Although toxicity and dose reductions are observed with combination therapy, this study demonstrates that the combination of proteasome inhibitor, HDAC inhibitor and dexamethasone offers promise. Further data on PFS will be presented. Disclosures Jenner: Amgen: Honoraria; Takeda: Honoraria. Off Label Use: Vorinostat for treatment of myeloma. Pawlyn:Celgene: Honoraria, Other: Travel support; The Institute of Cancer Research: Employment. Williams:Celgene: Consultancy, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau. Davies:Array-Biopharma: Membership on an entity's Board of Directors or advisory committees; Takeda-Millennium: Membership on an entity's Board of Directors or advisory committees; University of Arkansas for Medical Sciences: Employment; Onyx-Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

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Phase 2 Study of Nilotinib 400 Mg Twice Daily in Newly Diagnosed Patients with Accelerated Phase of Chronic Myeloid Leukemia, Results after 5.7 Years of Follow-up

Blood ◽

10.1182/blood-2018-99-120155 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3011-3011 ◽

Cited By ~ 1

Author(s):

Lucia Masarova ◽

Jorge E. Cortes ◽

Keyur P. Patel ◽

Susan M. O'Brien ◽

Graciela M. Nogueras González ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Phase 2 ◽

Advisory Committees ◽

Free Survival ◽

Genetics Research ◽

Phase 2 Study ◽

Grade 3

Abstract OBJECTIVES Nilotinib is a potent, second generation inhibitor of BCR-ABL tyrosine kinase (TKI) and represent a standard of care for patients with chronic myeloid leukemia (CML), including accelerated phase (AP-CML). In 2005, we initiated a phase 2 study of nilotinib 400 mg twice daily as a frontline therapy in patients with AP-CML, and herein present the efficacy and safety data after a median follow-up of 68.4 months (range, 0.3-124.8). METHODS This was a prospective, single institution, phase 2 study in patients of age ≥18 years with a newly diagnosed, untreated AP-CML (except for <1 month of previous imatinib) defined according to MD Anderson criteria (Kantarjian, 1988). Patients were treated with nilotinib 400 mg twice daily (BID). Data are presented on an intention to treat analysis with a cutoff date of June 30st, 2018. Response criteria are standard. Fisher exact test and χ2 were used for analysis of categorical variables; and survival probabilities were estimated using the Kaplan-Meier method. Time to events (e.g., overall survival, event free survival) was calculated from the date of treatment to the date of an event or to last follow-up as previously reported (Cortes et al, 2010). RESULTS Twenty two patients of a median age of 53.7 years (range, 26-79.7) were enrolled. Table 1 summarizes clinical characteristics of all patients. The median treatment duration was 47.3 months (range; 0.3-124.4), and the median follow-up 68.4 months (range, 0.3-124.8). All patients discontinued study as of January 2017 due to planned study closure; but 11 patients (50%) continued on nilotinib off protocol at data cut-off (400 mg BID [3]; 300 mg BID [2]; and 200 mg BID [6]). Median time to treatment discontinuation in the remaining 11 patients was 12.9 months (range, 0.3-112); reason for discontinuation was: inadequate response [3], toxicity [2], non-compliance/financial [4]; elective discontinuation after sustained MR4.5 >2 years [1]; and death due to stroke [1]. Sixteen patients (73%) achieved complete hematologic response (CHR). Overall rates of CCyR, MMR, MR4.5 and CMR (undetectable transcripts with at least 100,000 ABL copies) were 73%, 73%, 55%, and 41%, respectively. Median times to CCyR, MMR, and MR4.5 were 2.9 months (range, 2.7-6.4), 5.7 months (range, 2.7-99.2) and 6.0 months (range, 2.7-36), respectively. Seven patients (32%) achieved sustained MR4.5 >2 years. In total, 4 patients lost their best achieved response (CHR [1], CCyR [2] and MR4.5 [1]) while on study. All events were associated with acquired ABL domain mutation; Y253H [2], T315I [1], and F359I [1] with a median time to detection of 16.7 months (range, 7-40). During the study conduct, one patient progressed to blast phase after 2 months on nilotinib. Two patients died while on study, one due to stroke and one due to unrelated medical condition, after being on therapy for 3 and 0.4 months, respectively. One patient electively discontinued nilotinib after being in sustained MR4.5 for 107 months, and remains in MR4.5 after 6 months off therapy. Estimated overall survival and event free survival at 5 years were 84% and 70%, respectively (Figures 1a & 1b). On univariate analysis, age >55 years was associated with lower rate of MMR (p = 0.034; HR 0.34; 95% CI 0.12-0.92); MR4 (p = 0.013; HR 0.25; 95% CI 0.08-0.75); and MR4.5 (p = 0.01; HR 0.15; 95% CI 0.04-0.63). Overall survival was inferior in patients older than 55 years (p = 0.014; HR 2.4; 95% CI 2.36-not estimated); and in those with > 1 AP-CML defining abnormality (p = 0.018; HR 9.53; 95% CI 0.98-92). The most frequent non-hematologic adverse events (AEs) were hyperbilirubinemia (63% of patients), rash (63%), hypertension (59%), and transaminitis (50%). Grade ≥3 AEs observed in more than one patient were hyperbilirubinemia (n=2), and transaminitis (=2). Two patients developed arterio-thrombotic AEs: stroke and myocardial infarction (one each). Hematologic AEs included (all grades; grade ≥3): anemia (36%; 9%), thrombocytopenia (32%; 14%) and neutropenia (14%; 9%). Two patients (9%) discontinued therapy due to nilotinib related AE, one for G3 peripheral neuropathy and one for G3 hyperbilirubinemia with G2 thrombocytopenia. CONCLUSION Nilotinib is safe and highly effective in patients with AP-CML, and induces fast and durable responses. More than 50% of patients can achieve MR4.5. Clinical trial.gov: NCT00129740. Disclosures Cortes: novartis: Research Funding. O'Brien:Pfizer: Consultancy, Research Funding; Janssen: Consultancy; Aptose Biosciences Inc.: Consultancy; Kite Pharma: Research Funding; Regeneron: Research Funding; Vaniam Group LLC: Consultancy; Amgen: Consultancy; Pharmacyclics: Consultancy, Research Funding; Celgene: Consultancy; Alexion: Consultancy; Abbvie: Consultancy; GlaxoSmithKline: Consultancy; Acerta: Research Funding; Gilead: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Astellas: Consultancy; TG Therapeutics: Consultancy, Research Funding. Konopleva:Stemline Therapeutics: Research Funding; Immunogen: Research Funding; abbvie: Research Funding; cellectis: Research Funding. Verstovsek:Incyte: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Kadia:Celgene: Research Funding; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Abbvie: Consultancy; BMS: Research Funding; Novartis: Consultancy; Takeda: Consultancy; Celgene: Research Funding; BMS: Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Abbvie: Consultancy; Takeda: Consultancy; Amgen: Consultancy, Research Funding. Ravandi:Macrogenix: Honoraria, Research Funding; Orsenix: Honoraria; Orsenix: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Xencor: Research Funding; Sunesis: Honoraria; Bristol-Myers Squibb: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Jazz: Honoraria; Abbvie: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Macrogenix: Honoraria, Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding, Speakers Bureau; Jazz: Honoraria; Sunesis: Honoraria; Xencor: Research Funding; Seattle Genetics: Research Funding.

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The MP0250-CP201 Mirror Study: A Phase 2 Study Update of MP0250 Plus Bortezomib and Dexamethasone in Relapse/Refractory Multiple Myeloma (RRMM) Patients Previously Exposed to Proteasome Inhibitors and Immunomodulatory Drugs

Blood ◽

10.1182/blood-2019-129827 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1899-1899 ◽

Cited By ~ 2

Author(s):

Norbert Grząśko ◽

Stefan Knop ◽

Hartmut Goldschmidt ◽

Marc S Raab ◽

Jan Dürig ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Board Of Directors ◽

Research Funding ◽

Proteasome Inhibitors ◽

Immunomodulatory Drugs ◽

Phase 2 ◽

Advisory Committees ◽

Phase 2 Study ◽

Grade 3

Background Bone marrow neovascularization is a hallmark of multiple myeloma and progression is associated with a substantial increase in pro-angiogenic factors that promote bone marrow angiogenesis, including vascular endothelial growth factor (VEGF-A) and hepatocyte growth factor (HGF). At present, anti-angiogenic agents are not part of treatment strategies in multiple myeloma, neither alone nor in combination with approved agents. MP0250 is a first-in-class, tri-specific multi-DARPin® drug candidate neutralizing VEGF-A and HGF as well as binding to human serum albumin to increase plasma half-life. This is a report on early safety and efficacy of MP0250 in combination with bortezomib plus dexamethasone (Vd) in RRMM patients that have previously been exposed to proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs). Aims To assess the efficacy and safety of MP0250 in combination with bortezomib and dexamethasone in patients with RRMM (MiRRoR, NCT03136653). Trial Design This trial is recruiting adults ≥18 years of age with RRMM who have progressed after at least two prior treatment regimens including bortezomib and an IMiD. Patients were enrolled to receive iv MP0250 on day 1 + subcutaneous bortezomib 1.3 mg/m² on days 1, 4, 8, 11, oral dexamethasone 20 mg on days 1-2, 4-5, 8-9, 11-12 of each 21-day cycle. Patients will receive treatment until there is documented disease progression or unacceptable toxicity. Methods The primary endpoint is efficacy in terms of overall response rate (ORR) per International Myeloma Working Group criteria. Secondary endpoints include safety, immunogenicity, progression-free survival (PFS) and duration of response (DOR). Exploratory endpoints include overall survival, and pharmacokinetics. Exploratory biomarkers for HGF and cMET in bone marrow biopsies are detected by IHC; MM specific markers, circulating HGF and VEGF levels are measured using patient plasma samples. Results As of 01 July 2019, 20 patients (7 ongoing) received a total of 137 doses (1-33 cycles) of MP0250 at the maximum tolerated dose of 8 mg/kg on Day 1 of each 21-day cycle in combination with Vd. Median age was 61 years (46-76), median time since diagnosis was 6.7 years. Median number of prior therapies was 4 (range, 2-9). All 20 patients had prior exposure to IMiDs and PIs and 9 patients received PI-based regimens as their immediate prior line of therapy before start of MP0250 + Vd. Importantly, 6 out of these 9 patients achieved responses ≥ Partial Response (PR). Treatment had been discontinued in 40% of patients due to PD, 15% due to Adverse Event (AE), 5% due to physician's decision and in 1 case at patient's request. The most frequent drug-related grade 3/4 AEs were hypertension in 7/1 patients, thrombocytopenia in 4/1 patients, grade 3 proteinuria in 4 patients and grade 3 anemia in 4 patients. There were no infusion-related reactions. No treatment-related deaths were reported. 20 patients received ≥ 1 dose of MP0250 + Vd and had at least 1 assessment of response and were included in the efficacy analysis. 1 patient (5%) achieved Complete Response, 4 patients achieved Very Good Partial Response (20%) and 3 patients achieved PR (15%) for an ORR of 40%. DOR at cutoff date is 6 months (range, 2-21). Pharmacokinetic data show sustained exposure over multiple cycles with a mean half-life of 11 days (range, 6-17). No indication of ADA-mediated drug clearance was observed. Summary Combining MP250 at 8 mg/kg with standard doses of bortezomib and dexamethasone was generally well tolerated with discontinuation due to AE in only 15% of patients. No unexpected toxicity was observed and AEs consistent with the toxicity profile of the individual agents. Analysis of the preliminary efficacy results showed an encouraging ORR of 40%. Recruitment to this Phase 2 study is ongoing. Disclosures Knop: Janssen, AMGEN, Bristol-Myers Squibb, Celgene: Consultancy, Honoraria. Goldschmidt:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: 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; Amgen: Consultancy, Research Funding; John-Hopkins University: Research Funding; MSD: Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Research Funding; John-Hopkins University: Research Funding; Chugai: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Dietmar-Hopp-Stiftung: Research Funding; Molecular Partners: Research Funding; Mundipharma: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dürig:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Celgene: Consultancy, Other: Travel or accommodations, Speakers Bureau. Bringhen:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Bristol-Myers Squibb: Honoraria; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gamberi:Amgen: Honoraria; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees. Castellano Acosta:Molecular Partners AG: Employment. Lang:Molecular Partners AG: Employment. Lemaillet:Molecular Partners AG: Employment. Sudhir:Molecular Partners AG: Employment.

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Combination Treatment of the Bruton's Tyrosine Kinase Inhibitor Ibrutinib and Carfilzomib in Patients with Relapsed or Relapsed and Refractory Multiple Myeloma: Initial Results from a Multicenter Phase 1/2b Study

Blood ◽

10.1182/blood.v126.23.377.377 ◽

2015 ◽

Vol 126 (23) ◽

pp. 377-377 ◽

Cited By ~ 4

Author(s):

Ajai Chari ◽

Saurabh Chhabra ◽

Saad Usmani ◽

Sarah Larson ◽

Ruben Niesvizky ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Tyrosine Kinase ◽

Board Of Directors ◽

Research Funding ◽

Phase 1 ◽

Phase 2 ◽

Advisory Committees ◽

Bruton's Tyrosine Kinase ◽

Grade 3

Abstract Background: Recent advances have improved outcomes for patients (pts) with multiple myeloma (MM); however, novel agents targeting different pathways are still needed. Ibrutinib (ibr) is a first-in-class, once-daily, oral, covalent inhibitor of Bruton's tyrosine kinase (BTK), an enzyme overexpressed in malignant plasma cells, whose expression may positively regulate the myeloma stem cell-like population (Yang 2015). Clinical activity was observed at the 840-mg dose of ibr in heavily pretreated pts with relapsed or relapsed/refractory MM (RRMM), when combined with weekly dexamethasone (dex) (Vij 2014). Furthermore, BTK-mediated upregulation of NF-κB p65 contributes to proteasome inhibitor (PI) resistance in MM cell lines; thus, BTK inhibition with ibr may help overcome PI resistance (Murray 2015). In vitro, ibr has demonstrated synergy with PIs in MM (Rushworth 2013) and mantle cell lymphoma cells (Ou 2013). PCYC-1119 (NCT01962792) is an ongoing phase 1/2b study of ibr + carfilzomib (CFZ) ± dex in RRMM. Methods: Eligible pts received ≥2 prior therapies, including bortezomib (BTZ) and an immunomodulatory agent (IMiD) and had either no response or documented disease progression following the most recent treatment. Dose escalation followed a 3+3 design, followed by expansion of 2 cohorts (Table). Phase 1 primary objectives were maximum tolerated dose/recommended phase 2 dose (RP2D) determination and safety. Results: As of July 8, 2015, 40 pts were enrolled and received ibr combined with CFZ ± dex across multiple dose levels during the phase 1 portion. No dose-limiting toxicities (DLTs) were observed, and cohorts 2b and 3b were chosen for expansion to further evaluate safety and efficacy. Pts had a median age of 63 y (range, 44-83) and a median time from diagnosis of 4.3 y (range, 0.5-25.3). Cytogenetic assessment by FISH identified that 20% and 8% of pts had t4;14 and del17p, respectively. Overall, pts received a median of 3 prior lines of therapy (range, 2-11), including 10% prior CFZ, 25% pomalidomide, 25% thalidomide, 73% autologous stem cell transplant, and 100% BTZ and lenalidomide. Moreover, 88% of pts were refractory to their last therapy, with 73% refractory to BTZ, 73% refractory to lenalidomide, and 58% refractory both to IMiD and PI. No relevant differences were observed across cohorts. Thirty-six pts were evaluable for efficacy. With early follow-up, the initial objective response rate (ORR) was 58% and the clinical benefit rate (CBR) was 67%. In cohort 3b, the ORR and CBR were 65% and 77%, respectively, including 3 very good partial responses (VGPRs) and 1 stringent complete response (sCR). No clinically meaningful tolerability differences were seen between cohorts, and no new safety findings were observed. Across all cohorts, the most common all-grade nonhematologic adverse events (AEs) were diarrhea (43%), cough (35%), constipation and fatigue (30% each), and nausea (28%). Grade ≥3 hematologic AEs included thrombocytopenia (15%), anemia (13%), and neutropenia (5%). Grade ≥3 nonhematologic AEs occurring in ≥10% of pts were pneumonia and hypertension (15% each), diarrhea (13%), and fatigue (10%). Eleven pts reported treatment related SAEs. No clinically relevant differences in AEs were observed across cohorts. Ten pts discontinued study treatment due to progressive disease; an additional 6 pts discontinued due to an AE, and 6 pts discontinued due to investigator or pt decision. Duration of treatment ranged from 0.3 to 13.6 months, and 17 pts remain on treatment. Updated data will be presented. Conclusions: The initial phase 1 data indicated promising clinical potential for ibr + CFZ + dex, as it is well tolerated with no DLTs, no new toxicities, and no increase in the severity of known toxicities for the individual agents. The preliminary ORR of 58%, with 1 sCR and 3 VGPRs in cohort 3b, is encouraging in this mostly refractory patient population, especially with the high number refractory to BTZ. Cohort 3b was established as the RP2D and will be further evaluated in the phase 2 portion of the study. Table. Dosing Cohorts Cohort ibr* mg/qd CFZ† mg/m2 dex‡ mg 1(n=3) 560 20/27 - 2a(n=5) 560 20/36 - 2b(n=14) 560 20/36 20 3b(n=18) 840 20/36 20 *Starts on Day (D) 8 of Cycle (C) 1; continuous thereafter. †D1-2, 8-9, 15-16 through C12; thereafter D1-2, 15-16. ‡D1-2, 8-9, 15-16, 22-23; 10 mg for pts age ≥75 y; 4 mg prior to CFZ during C1 only (cohorts 1 and 2a) with re-initiation as needed. Disclosures Chari: Novartis: Consultancy, Research Funding; Millenium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Array: Consultancy, Research Funding. Off Label Use: ibrutinib in relapsed or relapsed/refractory MM. Usmani:Celgene: Consultancy, Research Funding, Speakers Bureau; Onyx: Consultancy, Research Funding, Speakers Bureau; Millenium: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Sanofi: Consultancy, Research Funding, Speakers Bureau; Array BioPharma: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Novartis: Speakers Bureau. Larson:BMS: Consultancy. Niesvizky:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millenium: Consultancy, Honoraria, Research Funding, Speakers Bureau. Matous:Celgene: Consultancy, Speakers Bureau; Millenium: Speakers Bureau; Onyx: Speakers Bureau. Gasparetto:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Honoraria; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Holkova:Seattle Genetics, Inc.: Research Funding. Lunning:TG Therapeutics: Consultancy; Gilead: Consultancy; Spectrum: Consultancy; Genentech: Consultancy; Celgene: Consultancy; BMS: Consultancy; Juno: Consultancy; Onyx: Consultancy. Valent:Celgene: Speakers Bureau; Takeda: Speakers Bureau. Anderson:Celgene: Speakers Bureau; Onyx: Speakers Bureau; Takeda: Speakers Bureau. Kwei:Pharmacyclics LLC, an AbbVie Company: Employment. Chang:Pharmacyclics LLC, an AbbVie Company: Employment. Graef:Pharmacyclics LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Bilotti:Pharmacyclics LLC, an AbbVie Company: Employment. McDonagh:Pharmacyclics LLC, an AbbVie Company: Research Funding; Sanofi: Research Funding; Onyx: Research Funding; Karyopharm: Research Funding.

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