Updated Results from a Phase II Study of the Fc Engineered CD19 Antibody MOR208 in Combination with Lenalidomide for Patients with Chronic Lymphocytic Leukemia (CLL) and Richter's Transformation or Ibrutinib for Patients with Ibrutinib-Resistant Clones

Abstract MOR208 is an Fc engineered CD19 monoclonal antibody with preliminary efficacy in CLL as a single agent (Woyach et al, Blood 2014). Compared to non-engineered antibodies, MOR208 has significantly enhanced antibody dependent cellular cytotoxicity (ADCC), which can be further augmented in vitro with the addition of lenalidomide. Given the potential synergy of these agents, acceptable individual safety profiles, and efficacy of each as a single agent, we chose to combine MOR208 and lenalidomide in patients (pts) with previously treated and previously untreated CLL and in pts who have undergone Richter's Transformation (RT). Because recent data show poor outcomes in pts who relapse after the Bruton's Tyrosine Kinase (BTK) inhibitor ibrutinib and the presence of mutations in BTK prior to relapse, we included a cohort of ibrutinib-treated pts with identified resistance mutations but no clinical relapse where MOR208 was added to ibrutinib. This study is a single institution phase II trial of MOR208 in combination with lenalidomide or MOR208 in combination with ibrutinib with an initial safety run-in as part of each cohort. In combination with lenalidomide, MOR208 was given at a dose of 1 mg/kg on cycle 1 day 1, 9 mg/kg on days 2, 8, 15, and 22 of cycle 1, and day 1 of cycles 2-12. Lenalidomide was started at a dose of 2.5 mg daily on cycle 1 day 8 and given continuously. The dose of lenalidomide could be escalated up to 10 mg daily in pts without toxicity. After 12 cycles, lenalidomide could be continued indefinitely in responding pts. In combination with ibrutinib, ibrutinib was continued at a dose of 420 mg daily, and MOR208 was given at a dose of 1 mg/kg on cycle 1 day 1, 12 mg/kg on days 2, 8, 15, and 22 of cycle 1, then weekly during cycles 2 and 3, and every other week through cycle 12. Toxicity was assessed using the National Cancer Institute's Common Criteria for Adverse Events (AE) v4.0 for non-hematologic toxicity, and IWCLL 2008 guidelines for hematologic toxicity. For pts on MOR208 plus ibrutinib, variant allele frequency of mutant BTK was measured every 3 cycles. In the previously untreated cohort, 11 pts have been enrolled, with a median age of 62 (range 44-75). 1 pt had both del(17p) and del(11q) on FISH. Grade 3/4 adverse events regardless of attribution have been uncommon and have included hypertension (3 pts), infusion reaction (2 pts), and fatigue, neutropenia, colitis, hyperglycemia, dyspnea, and sinusitis (1 pt each). After a protocol amendment augmenting steroid premedication, no further grade 3 infusion reactions were observed. In the previously treated cohort, 11 pts have been enrolled, with a median age of 70 (range 62-75). 2 pts each had del(17p) and del(11q) on FISH, and 8 have Zap-70 methylated disease. Grade 3/4 toxicities regardless of attribution have included neutropenia (6), hyperglycemia (2), hypertension (2), and thrombocytopenia, fatigue, anemia, upper respiratory infection, catheter related infection, hypercalcemia, hypophosphatemia, infection, respiratory failure, and sepsis in 1 pt each. In the RT cohort, 5 pts have been enrolled, with a median age of 60 (range 55-70). Four had previously treated CLL, and one was previously untreated. Three had del(17p) and 2 had del(11q) on FISH. Grade 3/4 toxicities included hyperglycemia (3) and hyponatremia, thrombocytopenia, and neutropenia in 1 pt each. In the cohort of pts with molecular progression on ibrutinib, 7 pts have been enrolled, with a median age of 62 (range 45-77). Five have del(17p), 1 of whom also has del(11q). Grade 3/4 toxicities have included hypertension (2) and hyperglycemia and hyperuricemia in 1 pt each. Four pts have been on study for at least 3 cycles. One pt had an increase in BTK C481S variant allele frequency (VAF) from 66.3% to 78.8% while the others all have decreased (15.1% to 3.7%, 46.4% to 34.9%, and 67.2% to 18.1%). No pt has developed progressive disease. In conclusion, this Phase II trial in progress demonstrates preliminary safety and activity of the combination of MOR208 and lenalidomide in pts with CLL. This combination also has the potential to positively modulate the immune system, and detailed correlative studies will evaluate T- and NK-cell function. MOR208 appears safe in combination with ibrutinib, and preliminary evidence of activity against CLL cells with BTK C481S has been observed. Trial accrual is ongoing and updated results will be presented at the meeting. Disclosures Woyach: Morphosys: Research Funding; Karyopharm: Research Funding; Acerta: Research Funding. Awan:Innate Pharma: Research Funding; Novartis Oncology: Consultancy; Pharmacyclics: Consultancy. 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. Andritsos:Hairy Cell Leukemia Foundation: Research Funding. Lozanski:Genentech: Research Funding; Stemline Therapeutics Inc.: Research Funding; Beckman Coulter: Research Funding; Boehringer Ingelheim: Research Funding.

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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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Safety and Efficacy of Combined Ruxolitinib and Thalidomide in Patients with Myelofibrosis: Initial Results of a Phase II Study

Blood ◽

10.1182/blood-2018-99-114125 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 354-354 ◽

Cited By ~ 7

Author(s):

Raajit K. Rampal ◽

Srdan Verstovsek ◽

Sean M Devlin ◽

Eytan M. Stein ◽

Tapan M. Kadia ◽

...

Keyword(s):

Platelet Count ◽

Combination Therapy ◽

Board Of Directors ◽

Phase Ii ◽

Research Funding ◽

Single Agent ◽

Response Assessment ◽

Platelet Response ◽

Advisory Committees ◽

Grade 3

Abstract Background: Among the most frequent and challenging hematologic manifestations of myelofibrosis (MF) are anemia and thrombocytopenia, the presence of which portends an adverse outcome. Few effective modalities to address these cytopenias exist, particularly thrombocytopenia. Further, although the FDA-approved JAK1/2 inhibitor Ruxolitinib (RUX) has demonstrated significant clinical efficacy in MF patients, RUX frequently results in anemia and thrombocytopenia. Thrombocytopenia in particular often results in dose attenuation of RUX. Thalidomide (THAL) is a first-in-class immunomodulatory agent. Studies of THAL in MF patients, alone and with prednisone, have demonstrated improvements in anemia and thrombocytopenia. We therefore sought to examine whether combination of RUX and THAL could result in improvement in both disease-related and therapy-related cytopenias, as well as improve overall disease response in patients with MF. Here we report initial analysis of this study (NCT03069326). Methods: We conducted a multicenter two stage phase II trial designed to assess the effect of RUX and THAL combination in subjects with primary, post-polycythemia vera, or post-essential thrombocythemia myelofibrosis. Patients taking RUX at the time of enrollment must have had less than PR per IWG-MRT/ELN 2013 criteria, or be refractory, to RUX single-agent therapy. Patients must have been taking RUX for a minimum of 3 months, and must have been on a stable dose of RUX for a minimum of 4 weeks immediately prior to enrollment. Treatment-naïve patients received single-agent RUX for 3 months (run-in phase) per label, and went on to combination therapy if they achieved less then a PR per IWG-MRT/ELN criteria. Each cycle of therapy was 28 days. Response assessment was evaluated according to the IWG-MRT/ELN 2013 criteria. Platelet response criteria in patients with baseline thrombocytopenia (less than lower limit of normal) included: Major response (≥75% increase in platelet count), Intermediate Response (≥50% increase) and Minor Response (≥25% increase). Adverse events were assessed using the NCI CTCAE v. 4.0. The primary endpoint was the proportion of treated subjects that achieved a response by IWG-MRT criteria and by platelet response criteria. Results: A total of 25 patients are planned to be accrued. At the time of this writing, a total of 18 patients have been accrued. The median age was 70.5 years (47-85). 8 patients had received prior therapies other than RUX, including imetelstat, momelotinib, danazol, pomalidomide, darbepoetin alpha and sotatercept. 7 patients enrolled to the run-in phase. 14 patients received red blood cell transfusions prior to study enrollment. Evaluation of platelet count in patients with baseline thrombocytopenia demonstrated a significant increase in platelet count at cycle 3 of therapy compared to baseline (Figure 1A and B; P<0.05). An increase in Hgb was observed over successive cycles of combination therapy (Figure 1C and D). 5 of 18 accrued patients completed ≥6 cycles of combined therapy at the time of abstract submission and were thus evaluable for response assessment. The overall response rate in these patients was 80% (4/5 patients). Clinical Improvement (Anemia response and Symptom response) occurred in 3 patients (both responses observed in all 3 patients). Major platelet response was observed in 4 of 5 patients with baseline thrombocytopenia. 1 patient met criteria for spleen response (Table 1). Grade 3/4 non-hematologic adverse events regardless of attribution included; limb edema, diverticulitis, hypertension, syncope. 1 patient experienced a thromboembolic event. 1 patient experienced a grade 3 hematologic AE (neutropenia). Conclusions: The combination of THAL and RUX has demonstrated a promising efficacy signal in this initial analysis of an ongoing phase II study, and appears to be well tolerated. Platelet count increases were observed in all patients who entered study with baseline thrombocytopenia, a response which appears to be maintained in the majority of patients observed 6 months after starting combination therapy. As well, anemia responses were observed in 3 of 5 evaluable patients. Collectively, these data indicate a potential role for this regimen in patients with anemia and/or thrombocytopenia, who otherwise have limited treatment options. Updated data on duration of response and overall response of all accrued patients will be presented. Disclosures Rampal: Constellation: Research Funding; Celgene: Honoraria; Incyte: Honoraria, Research Funding; Jazz: Consultancy, Honoraria; Stemline: Research Funding. Verstovsek:Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Stein:Celgene: Consultancy; Bayer: Consultancy; Agios: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Kadia:Pfizer: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Amgen: Consultancy, Research Funding; Takeda: Consultancy; Takeda: Consultancy; Celgene: Research Funding; BMS: Research Funding; Novartis: Consultancy; Abbvie: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Research Funding; BMS: Research Funding; Jazz: Consultancy, Research Funding; Abbvie: Consultancy; Jazz: Consultancy, Research Funding. Mauro:Bristol-Myers Squibb: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Takeda: Consultancy. Pemmaraju:SagerStrong Foundation: Research Funding; daiichi sankyo: Research Funding; novartis: Research Funding; abbvie: Research Funding; cellectis: Research Funding; samus: Research Funding; Affymetrix: Research Funding; stemline: Consultancy, Honoraria, Research Funding; celgene: Consultancy, Honoraria; plexxikon: Research Funding. Bose:Blueprint Medicines Corporation: Research Funding; Astellas Pharmaceuticals: Research Funding; Incyte Corporation: Honoraria, Research Funding; Constellation Pharmaceuticals: Research Funding; Celgene Corporation: Honoraria, Research Funding; Pfizer, Inc.: Research Funding; CTI BioPharma: Research Funding.

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Bendamustine Combined with Rituximab (BR) in First-Line Therapy of Advanced CLL: A Multicenter Phase II Trial of the German CLL Study Group (GCLLSG).

Blood ◽

10.1182/blood.v114.22.205.205 ◽

2009 ◽

Vol 114 (22) ◽

pp. 205-205 ◽

Cited By ~ 23

Author(s):

Kirsten Fischer ◽

Paula Cramer ◽

Stephan Stilgenbauer ◽

Raymonde Busch ◽

Leopold Balleisen ◽

...

Keyword(s):

Board Of Directors ◽

Phase Ii ◽

Research Funding ◽

Phase Ii Trial ◽

Study Group ◽

First Line ◽

Advisory Committees ◽

Multicenter Phase ◽

Grade 3 ◽

First Line Treatment

Abstract Abstract 205 Introduction: Bendamustine has shown considerable activity in monotherapy for lymphoid malignancies including chronic lymphocytic leukemia (CLL). In vitro studies have demonstrated synergistic pro-apoptotic effects of bendamustine and the CD20 antibody rituximab (BR) in primary CLL cells. Encouraging results have also been obtained using the BR combination treatment in previously treated CLL. This multicenter phase II trial (CLL2M) is the first study assessing the efficacy and toxicity of bendamustine in combination with rituximab in previously untreated CLL patients (pts). Patients and Methods: Between March 2007 and September 2008 117 pts with untreated CLL requiring therapy were enrolled into the protocol. Bendamustine was given at a dose of 90 mg/m2 on day 1 and 2, combined with 375 mg/m2 rituximab for the first cycle and 500 mg/m2 for subsequent cycles. BR treatment was administered every 28 days for up to 6 courses. Blood samples were taken for analysis by fluorescence in situ hybridization (FISH), the IgVH mutational status and expression of ZAP70/CD38. Minimal residual disease (MRD) was evaluated in peripheral blood and bone marrow by 4-color flow cytometry. Results: Data on the entire study population of 117 pts (median age 64 years) with a total of 583 treatment cycles are available. As of June 2009 the median observation time was 15.4 months (mo). 11.1% of the pts presented with stage Binet A, 41.0% with Binet B and 47.9% with Binet C disease. A mean number of 5.0 courses were delivered. 114 pts were evaluable for toxicity, 110 for response and 113 for progression free survival (PFS). The most frequent adverse events based on 583 treatment cycles were myelosuppression and infections: grade 3/4 anemia occurred in 4.9%, grade 3/4 leukopenia in 14.6%, grade 3/4 neutropenia and thrombocytopenia in 6.5% and 6.1% of all given courses, respectively. 29 episodes of CTC grade >3 infections were documented (5.1% of all courses). Treatment related mortality occurred in 2.6% of the pts: one liver failure after attempt of suicide with antihistamines, one fatal pneumonia and one sepsis in neutropenia. The overall response rate was 90.9% with 32.7% (36 pts) clinical complete remissions (CR). A nodular partial remission (nPR) was achieved in 2.7% (3 pts) and a partial response (PR) in 55.5% of the pts (61 pts), respectively. 9.1% of the pts (10 pts) had stable disease (SD) whereas none of the pts was progressive (PD). After 18 mo 75.8% of the pts were still in remission, median PFS has not been reached. An MRD level below 10E-4 was observed after completion of therapy in 29 of 50 evaluable pts in peripheral blood, while 7 of 25 pts achieved MRD negativity in bone marrow. Differences in response were observed among the genetic subgroups: 19 of 21 pts with 11q- achieved a remission with 10 PR and 9 CR (ORR: 90.5%). Accordingly, 17 of 19 patients with +12 responded (14 PR, 3 CR, ORR: 89.5%). In the high-risk group with 17p-, 3 of 7 pts showed a partial response (ORR: 42.9%). 56 of 63 pts (ORR: 88.9%) with unmutated IgVH status responded to BR. Conclusion: Bendamustine plus rituximab (BR) is effective and safe in the first-line treatment of CLL. Major side effects (myelosuppression and infections) were infrequent. Based on these encouraging phase II data the German CLL Study group is presently investigating the efficacy of BR in comparison to fludarabine-based immunochemotherapy (FCR) in the first-line treatment of CLL within a randomized phase III trial (CLL10 protocol). Disclosures: Fischer: Roche: travel expenses. Cramer:Roche: travel grants. Stilgenbauer:Bayer: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Fink:Roche: . Boettcher:Roche: Research Funding. Ritgen:Roche: Research Funding. Kneba:Roche: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Döhner:Roche: Research Funding. Eichhorst:Roche: Honoraria, Research Funding; Mundipharma: Research Funding; Hospira: Honoraria. Hallek:Roche: Consultancy, Honoraria, Research Funding. Wendtner:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer Schering: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Rituximab +/− Bevacizumab for Patients with Previously Treated Follicular Non-Hodgkins Lymphoma: A Randomized Phase II Trial of the Sarah Cannon Research Institute.

Blood ◽

10.1182/blood.v120.21.2749.2749 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2749-2749

Author(s):

John D. Hainsworth ◽

Dana S. Thompson ◽

F. Anthony Greco ◽

Eric Raefsky ◽

Scott Lunin ◽

...

Keyword(s):

Phase Ii ◽

Phase Ii Trial ◽

Single Agent ◽

Hematologic Toxicity ◽

Off Label ◽

Overall Response ◽

Randomized Phase Ii ◽

Previously Treated ◽

Grade 3 ◽

Tumor Types

Abstract Abstract 2749 Background: Single-agent rituximab produces an overall response rate of approximately 50% and a median PFS of 9 months in patients with previously treated follicular NHL. Since resistance to rituximab eventually develops in nearly all patients, a number of novel agents are currently being evaluated in combination with rituximab to improve treatment efficacy. Vascular endothelial growth factor (VEGF) promotes angiogenesis and is increased in many tumor types. In NHL, high levels of VEGF are correlated with disease progression. Bevacizumab, a monoclonal antibody inhibiting VEGF, has extended PFS in several solid tumor types when added to combination chemotherapy. In this randomized phase II trial, we compared the efficacy and toxicity of bevacizumab + rituximab versus single-agent rituximab, in patients with previously treated follicular NHL. Methods: Eligible patients had follicular NHL (grade 1 or 2); NHL progression after either 1 or 2 prior chemotherapy regimens; measurable or evaluable disease; and ECOG PS 0–2. Prior rituximab treatment was allowed as long as progression occurred > 6 months following completion of treatment. Patients were randomized to receive single-agent rituximab (Regimen A) or rituximab plus bevacizumab (Regimen B). All patients received 375 mg/m2IV of rituximab weekly for 4 weeks. Regimen B patients also received bevacizumab 10 mg/kg IV on days 3 and 15 during the 4-week course of rituximab. Response evaluations were performed at weeks 6 and 12 as well as 4 weeks after the completion of all therapy. Patients with objective response or stable disease at week 12 received 4 additional doses of rituximab administered at months 3 (week 12), 5, 7, and 9; in addition, regimen B patients received bevacizumab 10 mg/kg IV every 2 weeks for a total of 16 doses (also beginning week 12). Addition of bevacizumab was hypothesized to improve the median PFS from 15 months to 20 months. Accrual of 90 patients (45/arm) was initially planned; the study was stopped early due to slow accrual. Results: Between 8/2005 and 3/2012, 60 patients were enrolled (Regimen A, 30; Regimen B, 29). Key clinical characteristics including age, performance status, FLIPI score, and previous treatment were comparable in the 2 treatment groups. 95% of patients had received 2 previous regimens, and 78% had received previous rituximab. After a median followup of 36 months, 92% of patients have either completed (40%) or discontinued treatment (lymphoma progression 30%, toxicity 12%, patient/physician decision 8%). The overall response rates were 42% in Regimen A (CR rate 10%) and 45% in Regimen B (CR rate 17%). The median progression-free survivals for Regimens A and B were 10.4 and 18.4 months, respectively (HR 0.33, p=0.0090). Median OS has not been reached for either group; at 3 years, the estimated OS rates are 54% (Regimen A) and 81% (Regimen B) (p=0.12). Grade 3/4 hematologic toxicity was uncommon, with no grade 4 neutropenia or thrombycytopenia, and 1 episode of febrile neutropenia (Regimen B). No grade 4 non-hematologic toxicity occurred; grade 3 non-hematologic toxicity occurred in 3 patients (10%) on Regimen A (infusion reaction 1, hyperglycemia 1, pneumonia 1) and 7 patients (24%) on Regimen B (hypertension 3, epistaxis 1, abdominal wall hematoma 1, wound dehiscence 1, confusion 1). All 7 patients who discontinued treatment due to toxicity (3 during the first 12 weeks) were on regimen B; 5 had bevacizumab-related toxicity. There were no treatment-related deaths. Conclusion: The addition of bevacizumab to rituximab was feasible with a modest increase in toxicity in this group of patients with previously-treated follicular NHL. The toxicities observed were consistent with the known profiles of each agent. While response rates were similar between regimens, the addition of bevacizumab lengthened the progression-free survival when compared to rituximab alone (median 18.4 vs. 10.4 months). Although results of this study must be interpreted with caution due to its small size, further study of VEGF- targeted therapies in NHL may be warranted. Disclosures: Off Label Use: Off-label bevacizumab use for treatment of follicular non-Hodgkin's lymphoma. Reeves:Celgene: Equity Ownership.

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A Phase II Study of the Fc Engineered CD19 Antibody MOR208 in Combination with Lenalidomide for Patients with Chronic Lymphocytic Leukemia (CLL)

Blood ◽

10.1182/blood.v126.23.2953.2953 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2953-2953

Author(s):

Jennifer A. Woyach ◽

Amy S. Ruppert ◽

Farrukh Awan ◽

Jeffrey A. Jones ◽

Sharon Waymer ◽

...

Keyword(s):

Phase Ii ◽

Research Funding ◽

Phase Ii Trial ◽

Single Agent ◽

Hematologic Toxicity ◽

Treatment Naïve ◽

Infusion Reactions ◽

Grade 3 ◽

Relapsed Disease

Abstract MOR208 is an Fc engineered CD19 monoclonal antibody which has been shown in a Phase I trial in patients with relapsed and refractory CLL to be generally well tolerated and have preliminary efficacy, with an overall response rate (ORR) of 30% by IWCLL 2008 guidelines (Woyach et al, Blood 2014). Compared to non-engineered CD19 monoclonal antibodies, MOR208 has significantly enhanced antibody dependent cellular cytotoxicity (ADCC), which can be further augmented in vitro with the addition of lenalidomide. Given the in vitro synergy of these agents, acceptable individual safety profiles, and efficacy of each as a single agent, we chose to combine MOR208 and lenalidomide in patients with both previously treated and previously untreated CLL. This study is a single institution phase II trial of MOR208 in combination with lenalidomide with an initial safety run-in as part of each cohort. MOR208 was given at a dose of 1 mg/kg on cycle 1 day 1, then 9 mg/kg on days 2, 8, 15, and 22 of cycle 1, and then on day 1 of cycles 2-12. Lenalidomide was started at a dose of 2.5 mg daily on cycle 1 day 8 and given continuously. The dose of lenalidomide could be escalated up to 10 mg daily in patients without toxicity. After 12 cycles, lenalidomide could be continued indefinitely in responding patients. Toxicity was assessed using the National Cancer Institute's Common Criteria for Adverse Events v4.0 for non-hematologic toxicity, and IWCLL 2008 guidelines for hematologic toxicity. Disease response by IWCLL 2008 guidelines was assessed at cycle 7 day 1 and at the end of cycle 12. This study will enroll 20 patients with treatment-naïve CLL and 20 patients with relapsed/refractory CLL. At this time, 7 patients with relapsed/refractory disease and 5 patients with treatment-naïve disease have been enrolled and evaluated. The most common toxicities observed related to protocol therapy have been infusion related reactions, fatigue, thrombocytopenia, and neutropenia. In patients with relapsed disease, all toxicities except neutropenia have been grade 1 or 2, and 2 patients experienced grade 3 neutropenia. Of the 5 patients with treatment-naïve CLL, two experienced significant infusion reactions on cycle 1 day 1 that prevented further administration of MOR208. After a protocol amendment escalating steroid premedication, no further grade 3 infusion reactions have been observed. While the majority of patients were able to escalate lenalidomide to either 5 or 10 mg, all patients had lenalidomide eventually dose reduced to 2.5 mg daily due to cytopenias, rash, or fatigue. This combination has shown preliminary efficacy. In the cohort of patients with relapsed disease, two experienced progressive disease during cycle 2 and cycle 5 respectively. The remaining 5 patients achieved stable disease (SD, n=3) or a partial response (PR, n=2) at cycle 7 day 1, with one patient converting to PR by cycle 12. Three patients completed 12 cycles of therapy, and the remaining two completed 12 cycles and now remain on lenalidomide alone at cycle 18 and cycle 19 respectively. In the cohort of patients with treatment-naïve disease, three patients completed more than 1 day of therapy. All of these patients achieved a PR at cycle 7 day 1, and are now in cycle 10 (n=1) or cycle 11 (n=2). In conclusion, this Phase II trial in progress demonstrates preliminary safety and activity of the combination of MOR208 and lenalidomide in patients with CLL. This combination also has the potential to positively modulate the immune system, and detailed correlative studies are evaluating T cell and NK cell function in these patients. Trial accrual is ongoing and updated results will be presented at the meeting. Disclosures Jones: AbbVie: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding. Byrd:Acerta Pharma BV: Research Funding.

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Phase II Multicenter Study of the Safety and Efficacy of Single-Agent Lenalidomide in Subjects with Relapsed/Refractory Mantle Cell Lymphoma: Long-Term Follow-up Analysis of the NHL-003 Study.

Blood ◽

10.1182/blood.v120.21.2738.2738 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2738-2738

Author(s):

Pier Luigi Zinzani ◽

Julie M Vose ◽

Myron S. Czuczman ◽

Craig Reeder ◽

Corinne Haioun ◽

...

Keyword(s):

Board Of Directors ◽

Phase Ii ◽

Research Funding ◽

Cell Lymphoma ◽

Single Agent ◽

Advisory Committees ◽

Mantle Cell ◽

Grade 3

Abstract Abstract 2738 Background: Mantle cell lymphoma (MCL) is an uncommon type of non-Hodgkin's lymphoma (NHL) with poor prognosis that necessitates the development of new treatments. Lenalidomide is a unique immunomodulatory agent with antiproliferative and tumoricidal effects on MCL cells. NHL-003 was a phase II, open-label, multicenter trial for subjects with relapsed aggressive NHL that tested single-agent lenalidomide 25 mg PO days 1–21 every 28 days. The primary endpoint was overall response rate (ORR); secondary endpoints included complete response (CR) rate, duration of response (DOR), survival, and safety. At the time of the initial publication (Witzig et al. Ann Oncol.2011;22:1622–1627), MCL subgroup analysis showed an ORR of 42%; the median DOR had not been reached. The purpose of this report is to provide long-term efficacy and safety results for the MCL subgroup from NHL-003. Results: Subjects with MCL (N=57) had a median age of 68 y (range, 33–82), were predominantly male (77%) with good ECOG performance status (89% PS 0–1) and advanced-stage disease (88% stage III/IV). Subjects had received a median of 3 (range, 1–13) prior systemic therapies. According to the current central review at a median follow-up of 12.4 mo, subjects achieved an ORR of 35% (CR/CRu 12%) following lenalidomide, including a median DOR of 16.3 mo (Table 1). The ORR to single-agent lenalidomide was 44% (CR/CRu 21%) by independent assessment, with a median DOR not yet reached. Median PFS was 8.8 mo by central review and 5.7 mo according to investigators. Subjects responded quickly, with a median time to first response of 1.9 mo (central and investigator). Median DOR for subjects in CR and overall survival for all subjects have not yet been reached. The most common grade 3/4 adverse events (AEs) were neutropenia (46%), thrombocytopenia (30%), fatigue (9%), and diarrhea (5%). Other AEs included one subject with grade 1 to 2 tumor flare reaction, one subject with grade 3 deep vein thrombosis, and two subjects with second primary malignancies suspected of being related to treatment (one grade 3 squamous cell carcinoma of the skin that resolved and one grade 4 AML in a heavily pretreated individual with 5 prior cancer therapies). Conclusions: This subset analysis from a phase II study further confirms the efficacy of lenalidomide in subjects with relapsed MCL. Responders have a long DOR with manageable side effects. These results support continued investigation of lenalidomide alone or in combination for the treatment of MCL. Disclosures: Zinzani: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees. Off Label Use: This is a phase 2 clinical study of safety and efficacy for lenalidomide in patients with MCL. Czuczman:Celgene: Consultancy, Consultant Celgene Advisory Board Other. Reeder:Celgene: Mayo Clinic receives funding from Celgene to support clinical trials Other, Research Funding. Haioun:Celgene: Celgene Advisory Board Consultant Other, Consultancy. Tilly:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Pietronigro:Celgene: Employment. Ervin-Haynes:Celgene: Employment. Li:Celgene: Employment. Witzig:Celgene: Research Funding.

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Ixazomib, Thalidomide and Dexamethasone (IxaThalDex) in Relapsed/Refractory Multiple Myeloma (RRMM): An Interim Analysis of a Phase II Trial

Blood ◽

10.1182/blood.v128.22.3335.3335 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3335-3335 ◽

Cited By ~ 3

Author(s):

Heinz Ludwig ◽

Eberhard Gunsilius ◽

Michael Fridrik ◽

Richard Greil ◽

Andreas Petzer ◽

...

Keyword(s):

Board Of Directors ◽

Phase Ii ◽

Clinical Benefit ◽

Research Funding ◽

Phase Iii ◽

Hematologic Toxicity ◽

Advisory Committees ◽

Clinical Benefit Rate ◽

Grade 3

Abstract Introduction Ixazomib, a second generation proteasome inhibitor provides the advantage of combining oral administration with pronounced activity and a favorable toxicity profile. Phase II studies employing ixazomib-dexamethasone established a once weekly dosing regimen and showed substantial activity in RRMM yielding response rates of up to 58% when combined with lenalidomide-dexamethasone (Ld). A recent phase III trial proved the superiority of the triple combination ixazomib-Ld compared to Ld in patients with RRMM. Here, we evaluate the activity and tolerability of the all oral combination ixazomib-thalidomide-dexamethasone in patients with RRMM. Methods Patients with RRMM with at least 1 prior line of therapy were enrolled. Patients had to have measurable disease, ECOG performance status ≤2, ANC ≥1000/µL, platelet count ≥50000µL, GFR ≥15mL/min. The treatment regimen consisted of ixazomib (4mg, d 1, 8 and 15), thalidomide (100mg daily) and dexamethasone (40mg once weekly). Patients aged ≥75 years received a reduced dose of both thalidomide (50mg daily) and of dexamethasone (20mg, once weekly). A total of 8 cycles was planned, followed by ixazomib maintenance therapy (4mg, days 1, 8, 15 of a 28 cycle and 3mg in patients aged ≥75 years) for one year. Progression-free survival curves were estimated using the Kaplan-Meier method. The EORTC Q30 instrument was used for evaluation of changes in overall health and global QoL during therapy. Results Thirty-nine of 77 planned patients have been enrolled so far. Intent-to treat group (ITT), age, median: 67, range 42 to 85; ISS stage I: 13, II 14, III: 10, not known: 2, number of prior treatment lines, median: 2, (range: 1-5). Seven patients have discontinued treatment before completion of 2 cycles (early death: 3, progressive disease: 2, protocol violation: 1, patients request: 1). At present, 8 patients are too early (not yet completed 2 cycles) for evaluation per protocol (PP). Full documentation of at least 2 cycles of therapy is available for 24 patients. In this group, the median number of cycles administered is 4, and the median follow up is 4.5 months. Responses to IxaThalDex were seen in 14 patients (35.8% and 58.3% of ITT and PP group, respectively), 3 achieved ≥ VGPR (8%/ITT, 13%/PP), 10 PR (26%/ITT, 42%/PP) and 2 MR (5%/ITT, 8%/PP), yielding a clinical benefit rate of 38.5%/ITT, 62.5%/PP. FISH data are available in 17 of the 24 PP patients. Responses (≥PR) were seen in 5/6 patients with t (4;14) and/or t (14;16) and/or del17p and in 5/8 with standard risk cytogenetics. Median PFS at the time of reporting is 5.7 and 6.4 months in the ITT and PP group, respectively. An improvement in overall health and of general QoL was noted in 6 and 7 of the 14 responders, respectively. Toxicity data are presented for the PP group. Neutropenia was the most common hematologic toxicity noted in 20 (83.3%) patients; all of them had grade 1/2, and none higher grade neutropenia. Leukopenia was seen in 15 (62.5%) patients, (14 grade 1/2 and one grade 3). Sixteen (66.7%) had grade 1/2 anemia. Grade 1/2 thrombocytopenia was noted in 8 (33.3%) patients. The most frequent non hematological toxicity was infection seen in 7 (29%) patients. Six were grade 3; pneumonia was seen in 4, sepsis in 1 and other infections in 2 patients. Polyneuropathy at baseline was seen in 7 patients (grade 1 in 2, and grade 2 without pain in 6 patients). During the study the incidence of new PNP was relatively rare (3 new and one worsening PNP) with presently 9 (37.5%) patients with grade 1-2 and only 1 (4.2%) with grade 3. Other notable toxicities were acute renal failure (grade 3) in 2 (8.3%), fatigue in 8 (4 grade 1, 4 grade 2), constipation and diarrhea (all grade 1) each in 4, and edema and vision impairment (all grade 1), each in 3 patients. Conclusion The entirely oral IxaThalDex regimen resulted in an ORR of 58.3 in the PP and of 35.8% in the ITT population (with 8 patients being too early for PP evaluation and not having reached 2 cycles as yet). The clinical benefit rate was 62.5% and 38.5% for the PP and ITT group, respectively. Median PFS was 6.4 months in the PP group. General health and QoL improved in 42.8% and 50% of the responders. The ixazomib-thalidomide-dexamethasone regimen was well tolerated and with relatively few side effects being noted. As exposure to therapy is still short at this point of time it is anticipated that efficacy data will further improve with longer therapy and follow up. Updated results will be presented at the meeting. Disclosures Ludwig: Takeda: Research Funding, Speakers Bureau; Amgen: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Janssen: Speakers Bureau. Gunsilius:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Greil:Celgene: Research Funding; Takeda: Honoraria, Research Funding; Novartis: Research Funding; BMS: Honoraria; Celgene: Honoraria; Roche: Honoraria, Speakers Bureau. Petzer:Roche: Honoraria. Knop:Takeda: Consultancy. Poenisch:Mundipharma: Research Funding.

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Carfilzomib Thalidomide and Dexamethasone Is Safe and Effective in the Treatment of Relapsed/Refractory Multiple Myeloma: An Open Label Phase II Australasian Leukaemia and Lymphoma Group (ALLG) MM 018/ Asian Myeloma Network (AMN) 002 Study

Blood ◽

10.1182/blood-2020-139174 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 39-40

Author(s):

Hang Quach ◽

Simon J Harrison ◽

Je-Jung Lee ◽

Nichloas Murphy ◽

Jae Hoon Lee ◽

...

Keyword(s):

Multiple Myeloma ◽

Adverse Events ◽

Board Of Directors ◽

Phase Ii ◽

Primary Endpoint ◽

Research Funding ◽

Open Label ◽

Advisory Committees ◽

Open Label Phase ◽

Grade 3

Background: The combination of carfilzomib with immunomodulatory drugs (IMiDs) and dexamethasone is active in multiple myeloma (MM). Carfilzomib, thalidomide, and dexamethasone (KTd) has been studied in upfront MM treatment but has not been studied in the setting of relapsed/refractory myeloma (RRMM). The ALLG MM018/ AMN002 is an open-label phase II study of KTd in patients with RRMM. This study was conducted across 16 sites across Australia, New-Zealand, Singapore, South Korea and Taiwan. Method: Patients with RRMM with 1-3 prior lines of treatment were given carfilzomib [K: 20mg/m2 IV cycle 1 days 1 and 2, 56mg/m2 (36mg/m2 for patients age ≥75 years) from cycle 1 day 8 onwards], thalidomide (T: 100mg po nocte) and dexamethasone [dex: 40mg (20mg for patients age ≥75 years) po weekly], in a 28-day cycle. After 12 cycles, T was omitted, and K was given on days 1,2,15,16 and dex days 1,15 every 28-day cycles for a further six cycles. The primary endpoint was PFS. Secondary endpoints were ORR, overall survival, adverse events, and quality of life (QoL). The study had an 80% power to detect a ≥70% PFS at 6.5 months compared to historical ≤50% PFS at 6.5 months expected with Td (Kropff, M. et al. Haematologica 2012), at a significance level of 0.05. Results: This study has completed accrual. Eighty-three patients [median age of 66 years (42-85)] were enrolled with a median follow up of 15.9 (0.9-26) months. ORR rates were 86.4% (≥VGPR 70.2%). Median PFS was 20m (95% CI 15.9-26m). PFS at 6.5 months was 76.2% (95% CI 73.6-84.9%). Median OS has not been reached, and was 75% at 20 months. The most common grade ≥3/4 AEs were peripheral neuropathy (16%), upper respiratory tract infections (12%), dyspnoea (14%), and hypertension (10%). Grade ≥3/4 cardiac AEs occurred in 6%. The median carfilzomib dose that was delivered was 70.7% (32.8-92.6%) of the target dose. Thus far, 41% of patients have completed the intended 18 cycles of treatment. 21% of patients ceased therapy early. The most common reason for early treatment cessation was disease progression (30%) and adverse events (15%). Fifteen patients (18%) have died, 11 were due to MM, two from infection, one from an ischaemic cardiac event, and one from a traffic accident. QoL, as measured by the EQ-5D-5L instrument, remained stable throughout treatment. Conclusion: The ALLG MM018/AMN 002 study has met its primary endpoint. The KTd schedule as outlined in this study is efficacious in patients with RRMM, resulting in a prolonged PFS and a safety profile in line with previous reports for each of carfilzomib and thalidomide. KTd is an active option in jurisdictions where the cost of other IMiDs prohibits regulatory funding. Comparisons of efficacy and adverse events between the Caucasian and Asian populations will be presented at the meeting. Disclosures Quach: Celgene: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Glaxo Kline Smith: Consultancy, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Janssen Cilag: Consultancy, Honoraria; Sanofi: Consultancy, Research Funding. Harrison:Takeda: 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; F. Hoffmann-La Roche: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; CRISPR Therapeutics: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: wrt panobinostat; Haemalogix: Consultancy. Augustson:Roche: Other: Support of parent study and funding of editorial support. Campbell:Amgen, Novartis, Roche, Janssen, Celgene (BMS): Research Funding; AstraZeneca, Janssen, Roche, Amgen, CSL Behring, Novartis: Consultancy. Soo:Hanmi: Research Funding. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy.

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Primary Therapy of Waldenström's Macroglobulinemia (WM) with Weekly Bortezomib, Low-Dose Dexamethasone and Rituximab (BDR): A Phase II Study of the European Myeloma Network

Blood ◽

10.1182/blood.v116.21.1941.1941 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1941-1941 ◽

Cited By ~ 1

Author(s):

Meletios A. Dimopoulos ◽

Ramón García-Sanz ◽

Maria Gavriatopoulou ◽

Pierre Morel ◽

Marie-Christine Kyrtsonis ◽

...

Keyword(s):

Herpes Zoster ◽

High Risk ◽

Board Of Directors ◽

Phase Ii ◽

Standard Dose ◽

Single Agent ◽

Primary Therapy ◽

Advisory Committees ◽

Ortho Biotech ◽

Grade 3

Abstract Abstract 1941 Rituximab and bortezomib are active agents in the treatment of WM. Based on preclinical studies which indicated synergism between bortezomib and rituximab, in 2006 we designed a large phase II multicenter trial to evaluate the combination of these agents in previously untreated patients with WM requiring therapy based on consensus recommendations (Kyle et al, Sem Oncol 2003;30:116). This trial was conducted by the European Myeloma Network in 10 centers. In order to prevent the “IgM flare effect” seen with rituximab-based regimens, one course of single agent bortezomib was first administered at a standard dose of 1.3 mg/m2 IV on days 1, 4, 8 and 11. Ten days later, the patients received four courses of 35 days duration each. In courses 2 to 5, bortezomib was administered weekly at a dose of 1.6 mg/m2 on days 1, 8, 15 and 22. During courses 2 and 5, immediately after the administration of bortezomib, patients received dexamethasone 40 mg IV followed by rituximab 375 mg/m2 IV. Patients received a total of 8 infusions of rituximab. Bortezomib was administered weekly in order to reduce the incidence of neurotoxicity which can be significant in WM patients treated with standard schedule bortezomib (Treon et al, Clin Cancer Res 2007;13:3320). A single dose of dexamethasone was given before each dose or rituximab in order to take advantage of potential synergism with rituximab and to reduce allergic reactions but to avoid steroid-induced complications. During treatment, valacyclovir prophylaxis for herpes zoster was prescribed. After completion of treatment, patients with CR, PR, MR or SD according to consensus criteria (Kimby et al, CLM 2006;3:380) were followed without further therapy until there was evidence of progressive disease. Dose modifications for toxicity were allowed and bortezomib could be reduced from 1.6 mg/m2 to 1.3 mg/m2 to 1.0 mg/m2. The trial was initiated in March 2007, 61 patients were scheduled to be enrolled and the study completed accrual in June 2010. Patients characteristics included: age >65 years in 60% of patients, hemoglobin <11.5 g/dL in 82%, platelet count <100×109/L in 17%, β2-microglobulin >3 mg/dL in 63%, serum monoclonal protein >7 g/dL in 3.4%, lymphadenopathy in 42%, splenomegaly in 29%, and B-symptoms in 42% of patients. According to IPSS for WM, 18% of patients were rated as low risk, 23% as intermediate risk and 59% as high risk. The main reasons to start treatment included cytopenias in 43% of patients, hyperviscosity in 22%, presence of B-symptoms in 18% and lymphadenopathy in 8%. So far, 54 patients are evaluable for response. On an intent to treat, response rating include CR in 2 (4%), PR in 33 (61%), MR in 8 (15%), SD in 5 (9%) and PD in 6 (11%) patients. In responding patients, at least MR occurred within 2.3 months of treatment and the median time to best response is 4.8 months. Plasmapheresis was not required in any patient before or after treatment with BDR. An “IgM flare phenomenon” was not seen and this was attributed to the initial course of single agent bortezomib. Median follow up for all patients is 12 months, and so far 10 patients have progressed. Eight patients have died, 5 due to causes unrelated to WM or complications of treatment. Toxicities include: neutropenia (grade ≥3) in 13% of patients; thrombocytopenia (grade ≥3) in 5%; peripheral sensory neuropathy, grade 1,2 in 30%, but grade ≥3 in only 5%; neuropathic pain in 17%, but grade ≥3 in only 2%, gastrointestinal toxicity, grade 3 in 7%; and infections in 17% (grade ≥3 in 7%). One patient died of septic shock in absence of neutropenia. Three patients (5%) experienced pulmonary toxicity (grade 3/4) which was attributed to bortezomib and consisted of dyspnea, decrease of O2 saturation and diffuse pulmonary infiltrates on chest CT scan. This toxicity resolved completely after administration of steroids and 2 of 3 patients continued treatment as per protocol. Only one patient (who had discontinued valacylovir prophylaxis) developed herpes zoster. The dose of bortezomib was reduced in 30% of patients primarily because of peripheral neuropathy. This is the largest trial that has evaluated the role of a bortezomib-containing regimen in the frontline setting of symptomatic patients with WM, most of whom were rated as high risk according to IPSS. We conclude that the BDR regimen is active. An update on response, toxicity and time to progression will be performed in November 2010. Disclosures: Dimopoulos: Ortho-Biotech: Honoraria; Millennium: Honoraria. Off Label Use: Bortezomib for Waldenstrom's Macroglobulinemia. García-Sanz:Ortho-Biotech: Honoraria; Millennium: Honoraria; Celgene: Honoraria. Merlini:Millennium: Honoraria; Ortho-Biotech: Honoraria. Sonneveld:Ortho-Biotech: Membership on an entity's Board of Directors or advisory committees; Millennium: 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 1 Study of the Novel Kinesin Spindle Protein Inhibitor ARRY-520 + Carfilzomib in Patients with Relapsed and/or Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v120.21.4082.4082 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4082-4082 ◽

Cited By ~ 2

Author(s):

Jatin J. Shah ◽

Donna M. Weber ◽

Sheeba K. Thomas ◽

Raymond Alexanian ◽

Michael Wang ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Single Agent ◽

Autologous Stem Cell Transplant ◽

Hematologic Toxicity ◽

Cell Transplant ◽

Advisory Committees ◽

Kinesin Spindle Protein

Abstract Abstract 4082 Background: ARRY-520, a novel kinesin spindle protein (KSP) inhibitor, has been studied as a single agent and in combination with dexamethasone, and demonstrated promising clinical activity in patients with bortezomib- and lenalidomide-refractory multiple myeloma (MM). Carfilzomib, a novel irreversible proteasome inhibitor (PI), has also demonstrated single agent activity in relapsed and refractory MM, and recently received regulatory approval for this indication. Preclinical data support the presence of synergy with the combination of a PI and a KSP inhibitor via the latter's ability to down-regulate Mcl-1, supporting our hypothesis that the combination of carfilzomib and ARRY-520 (Car-ARRY) would be highly active in relapsed and/or refractory myeloma. We therefore aimed to combine these two agents for the first time, and here report the initial findings from the phase I dose-escalation in patients with relapsed and/or refractory MM. Methods: The primary objective was to determine the maximum tolerated dose (MTD) and the safety/tolerability of the Car-ARRY combination. Secondary objectives were to determine efficacy as measured by the overall response rate, time to progression, progression free survival and time to next therapy. Patients had to have myeloma that was relapsed and/or refractory, be ineligible for autologous stem cell transplant, bortezomib refractory/intolerant, and prior lenalidomide exposure. ARRY-520 was administered intravenously over 1 hour on days 1, 2, 15 and 16, while carfilzomib was administered intravenously over 30 minutes on days 1, 2, 8, 9, 15 and 16 on a 28 day cycle. All patients received growth factor support with filgrastim. Dose-escalation used a standard 3+3 schema proceeded based on dose-limiting toxicities (DLTs) during cycle 1, with planned escalation of the dose of ARRY-520. Dose level 1 was ARRY-520 0.75 mg/m2, and carfilzomib was dosed at 20 mg/m2 for cycle 1 on days 1 and 2 and all subsequent dose were at 27 mg/m2. Adverse events (AEs) were graded by NCI-CTCAE v4, while responses were assessed by the modified International Uniform Response Criteria. Results: To date, 8 patients have been enrolled in the ongoing dose escalation phase. The median age was 66 (range 47–80), 6/8 were males, and the median number of prior therapies was 4 (range 2–10). 7/8 patients had undergone prior autologous stem cell transplant, and all patients were bortezomib refractory or intolerant. In the first cohort, 3 patients were enrolled and no dole limiting toxicity (DLT) was observed. During the second cohort, ARRY-520 was escalated to 1 mg/m2 with carfilzomib at 20/27 mg/m2, and among the first 3 patients, one patient suffered a DLT in the form of an admission for influenza pneumonia with non-neutropenic fever. Expansion of cohort 2 is currently underway. Among the 6 patients who completed the first cycle of therapy, 5 remain on study. In the first cohort, one patient remains on study with 6 cycles and achieved a near complete remission, 1 patient achieved stable disease, and 1 patient suffered disease progression after first cycle. In the second cohort, all three patients who completed the first cycle have stable disease and remain on trial. In the first 6 toxicity-evaluable patients who have completed one cycle, grade (G) 3 events included one each of pneumonia, diarrhea, and hyperglycemia. There was limited hematologic toxicity with 4/6 patients with G1/2 thrombocytopenia, 3/6 patients with G1/2 anemia, and 1/6 patient with G1/2 neutropenia. Additional G1/2 non-hematologic toxicity included 3/6 patients with diarrhea, 3/6 patients with dyspnea, 3/6 patients with transient elevations in creatinine and 3/6 patients with aspartate aminotransferase elevations. An MTD has not been established and enrollment is ongoing in cohort 2 with carfilzomib at 20/27mg/m2 and ARRY-520 at 1.0 mg/m2. Conclusions: The combination of ARRY-520 and carfilzomib is well tolerated with limited hematologic toxicity and a manageable side effect profile. Notably, in this patient population, with patients who have bortezomib refractory/intolerant myeloma, the combination has demonstrated early signals of activity. Updated safety and efficacy data for all patients will be presented at the meeting. Disclosures: Shah: Onyx: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau. Off Label Use: This presentation will include information about Arry-520 which is not yet approved for use in patients with multiple myeloma. Wang:Pharmacyclic: Research Funding; onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hilder:Array BioPharma: Employment. Orlowski:onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; array biopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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