A Phase I Study of Escalated Dose Subcutaneous Alemtuzumab Given Weekly with Rituximab In Relapsed CLL/SLL.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1381-1381
Author(s):  
Jennifer R Brown ◽  
Bradley Messmer ◽  
Lillian Werner ◽  
Evgeny Mikler ◽  
David C. Fisher ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Injection Site ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Study Entry ◽  
Ct Scans ◽  
Advisory Committees ◽  
Grade 3 ◽  
Study Therapy

Abstract Abstract 1381 Alemtuzumab is an anti-CD52 antibody originally approved for intravenous administration three times per week to CLL patients refractory to fludarabine and previously exposed to alkylators. Since that time subcutaneous administration three times per week has become widespread because of its reduced infusional toxicity and recently demonstrated equivalent efficacy. In this study we assessed the tolerability, efficacy and pharmacokinetics of administering alemtuzumab subcutaneously weekly at up to 90 mg per dose following an initial 3+3 dose escalation (see table); we further added weekly rituximab in hopes of enhancing activity in lymph nodes. Treatment was administered in up to two eight week blocks with response evaluation between; the second 8 week block continued the dose and schedule used in weeks 5–8. No more than 45 mg was given per subcutaneous injection site. 28 patients were enrolled on this study between 7/2006 and 1/2010. The median age was 62 (range 47–76), and 75% were male. The median time from diagnosis to starting study therapy was 94 mos (14-236 mos). A majority of patients (82%) had Rai stage 3–4 disease and the median number of prior therapies was 4 (1-11). 20/28 patients (71%) had high risk deletions of 17p or 11q. 13/16 (81%) had unmutated IGVH, and 14/19 (74%) were positive for ZAP70. Early study withdrawals occurred due to pre-existing and persistent thrombocytopenia requiring study therapy to be held (n=2), persistent fever attributed to alemtuzumab (n=1), PML in retrospect present prior to study entry (n=1), and a DLT (grade 3 rituximab reaction) which was observed on dose level 2 prior to dose escalation of alemtuzumab. Overall, therapy was well tolerated; injection site reactions were minimal, primarily grade 1 (n=11) with only two grade 2 events. Other toxicities were as expected with alemtuzumab in this patient population, including grade 3–4 neutropenia (54%), grade 3–4 thrombocytopenia (57%), and single cases each of grade 3 rash, AIHA, pulmonary embolism, MRSA bacteremia, diverticular abscess, pulmonary Cryptococcus, EBV lymphoma and metastatic colon cancer. The ORR by NCI-WG criteria at wk 8 was 61% (95% CI 42–76%), with CR rate 11% (95% CI 4–27%). Two of 14 patients who completed a second eight week cycle improved their response (one PR from SD, and one CR from PR). A planned endpoint of this study was to compare lymph node staging by CT to PE, and we found that using CT scans to evaluate nodal response at 8 weeks decreased the ORR rate to 14% (95% CI 6–31%), with no CRs. Bone marrow was completely cleared of disease by 8 weeks in 8 patients and by 16 weeks in an additional 4 patients. The median PFS for the entire population was 13 months with a median follow-up of 9 months in patients who have not progressed. 10 patients have died, 5 of disease, 3 of second malignancies, 1 of PML and 1 of SCT complications. The median OS from study entry is 47 months, with 10 patients having undergone subsequent SCT. Following initiation of therapy we observed a >1,700X decrease in the median CD19+5+ cell count in peripheral blood by the start of week 3. Similar rapid depletion of all T and NK cell subsets was also observed, with first signs of recovery at week 28, and more definite recovery at week 40. Preliminary pharmacokinetic data demonstrated lower maximum levels of rituximab (p=0.06) and alemtuzumab (p=0.05) in patients with >80% bone marrow replacement by CLL but not in those with bulky lymphadenopathy. A trend toward higher alemtuzumab levels was observed in those patients with complete bone marrow clearance (p=0.1) but not in those with objective response. In conclusion, we found that administration of alemtuzumab at 90 mg subcutaneously weekly in combination with rituximab was well-tolerated, convenient and resulted in sustained adequate blood levels of both drugs in most patients. Response rates were high although in this relapsed refractory CLL population, abdominal lymphadenopathy was common, resulting in a decreased response rate when CT scans were included in staging. PFS and OS were favorable for this novel combination regimen and many patients went on to SCT. Disclosures: Brown: Genzyme: Research Funding; Celgene: Consultancy, Research Funding; Calistoga: Consultancy; Genentech: Consultancy. Off Label Use: alternative schedule of alemtuzumab. Kipps:GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Genzyme: Research Funding; Memgen: Research Funding; Igenica: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Aventis: Research Funding; Abbott Laboratories: Research Funding.

scholarly journals A Phase II Study of Pomalidomide, Daily Low Dose Oral Cyclophosphamide, and Dexamethasone in Relapsed/Refractory Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4520-4520
Author(s):  
Ajai Chari ◽  
Hearn Jay Cho ◽  
Samir Parekh ◽  
Kenneth Lau ◽  
Gillian Morgan ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Board Of Directors ◽  
Research Funding ◽  
Low Dose ◽  
Advisory Committees ◽  
Common Grade ◽  
Metronomic Therapy ◽  
Grade 3 ◽  
Study Therapy

Abstract Background A treatment option for patients with relapsed/refractory multiple myeloma (RRMM) is pomalidomide(pom) and dexamethasone (dex), with an overall response rate (ORR) of 33% and median progression free survival (PFS) of 4.2 months. Adding the alkylatingagent cyclophosphamide(Cy) to pom and steroids improves ORR and PFS. Baz et al (Blood, 26 May 2016) combined daily pom with weekly dosing ofCy anddex (PCD), with an ORR of 64.7% and a median PFS of 9.5 months, although grade 3/4 neutropenia increased from 31% to 52%. In our experience, compared to weekly Cy, low dose daily oral Cy is better tolerated with less myelosuppression. Palumbo et al (Blood, 17 Oct 2013) in fact combined pom with alternate day dosing ofCy and prednisone, with an ORR of 51% and a median PFS of 10.4 months and a grade 3/4 neutropenia rate of 42%. However, importantly, granulocyte stimulating factor (G-CSF) and platelet transfusion support wereprohibited, resulting in a lower maximum tolerated dose of pom of 2.5 mg (vs 4 mg in the Baz) and therefore, the rates of neutropenia cannot be compared between the two studies. In the present study, we explored PCD at the doses/schedule shown in table 1 with hematologic support even in patients with baselinecytopenias. This type of metronomic therapy has demonstrated efficacy in refractory B cell malignancies, possibly because the anti-angiogenic effects of metronomic therapy may be synergetic with conventional anti-neoplastic agents. Methods This was an open label, single arm, and single center phase 2study. The primary objective was to evaluate the best ORR. Secondary objectives were to evaluate safety, clinical benefit response (CBR), PFS, and overall survival (OS). Inclusion criteria included lenalidomide refractory, pom naïve RRMM patients with at least 2 prior lines of therapy. Patients were required to have measurable disease, adequate performance status, Cr <3 mg/dL, normal hepatic function, and ANC > 1000/uL and platelets > 50,000/uL if bone marrow plasma cells were < 50%, otherwise >30,000/uL. G-CSF and platelet support were permitted during screening and study treatment if needed. Each drug was administered at the doses and schedule shown in Table 1. Results Overall, 28 evaluable patients with progressive disease (PD) at screening have been enrolled. The median age is 66 (57% > 65 yr) with a median of 3 lines of prior therapy over 5 years since diagnosis. 3 (11%) had ANC<1.5 and 2 (7%) hadplts<50,000/µL at study entry.High-risk molecular findings were present in 13 patients (46%), including 3 with del p53 and 6 with gain of 1q21 by FISH (2 with concurrentt(4;14) and 2 with concurrent del p53). With 8 patients still on study therapy, responses include 3 complete responses (CR), 7 very good partial responses (VGPR), 9 partial responses (PR), 3 minor responses (MR), 5 stable disease (SD), and 1 PD, for an ORR of 67%, CBR (i.e. MR or better) of 78% and a median PFS of approximately 14.5 months. The median OS has not been reached. The most common grade 3/4 toxicity (regardless of drug attribution) was neutropenia with 20 (71%) of subjects experienced grade 3/4 neutropenia. Importantly, there was only 1 episode of febrile neutropenia during study therapy. Grade 3/4 thrombocytopenia was seen in 25% of subjects, and 3/4 anemia seen in 18%. The most common grade 3/4 non-hematologic toxicity was pulmonary disease with Grade 3 lung infections occurring in 21% of subjects (3 viral, 2 bacterial, 1 unknown) and 1 additional grade 3 URI. Of note, all of these admissions occurred at local hospitals and none of these occurred in the setting of neutropenia. One additional pt hadpneumonitisattributed to pom requiring study discontinuation. Grade 3rashwas also observed in 14% of subjects leading to pom dose reductions. Correlative data from peripheral blood and bone marrow aspirates taken at baseline, Cycle 3 Day 15, and at disease progression from all patients will be updated at the time of conference. These include PCD-associated changesin gene expression, clonal evolution and immune microenvironment during therapy and on progression. Conclusions With toxicities similar to those in other studies, the ORR of 67% and PFS of 14 months in our study of PCD compares very favorably to pomdexas well as other triplet regimens containingCy. Disclosures Chari: Takeda: Consultancy, Research Funding; Array Biopharma: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics: Research Funding; Amgen Inc.: Honoraria, Research Funding. Cho:Genentech Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Research Funding; Agenus, Inc.: Research Funding; Ludwig Institute for Cancer Research: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding. Catamero:Celgene: Honoraria, Speakers Bureau. Verina:Celgene: Speakers Bureau. Jagannath:Bristol Myer Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

Phase II Trial of Single Agent Panobinostat (LBH589) In Relapsed or Relapsed/Refractory Waldenstrom Macroglobulinemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3952-3952 ◽  
Author(s):  
Irene Ghobrial ◽  
Tiffany Poon ◽  
Meghan Rourke ◽  
Stacey Chuma ◽  
Janet Kunsman ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Stable Disease ◽  
Research Funding ◽  
Bone Marrow Involvement ◽  
Ct Scans ◽  
Advisory Committees ◽  
Bone Marrow Biopsies ◽  
Grade 3

Abstract Abstract 3952 Introduction: This study aimed to determine the safety and activity of panobinostat (LBH589) in patients with relapsed or relapsed/refractory Waldenstrom Macroglobulinemia (WM). This was based on our preclinical studies showing that panobinostat induces significant activity in cell lines and patient samples. Methods: Eligibility criteria include: 1) patients with relapsed or relapsed/refractory WM with any prior lines of therapy, 2) measurable disease and symptomatic disease, 3) off prior chemotherapy> 3 weeks, or biological/novel therapy for WM > 2 weeks. Patients received panobinostat at 30 mg three times a week (Mondays, Wed and Fridays). Patients were assessed after every cycle for the first 6 cycles and then every 3 months thereafter. Subjects who had response or stable disease were allowed to continue on therapy until disease progression or unacceptable toxicity. A planned restaging was performed at the end of cycle 6 including CT scans and bone marrow biopsies. Results: Twenty-seven patients have been enrolled to date. The median age is 62 years (47-80), the median lines of prior therapy is 3 (range, 1–7). All of the patients received prior rituximab. The median hemoglobin at screening is 10.3 g/dL (range 8.2–14.3), the median IgM M-spike by protein electropheresis at study entry is 1.9 g/dL (range, 0.63–5.1), and median serum IgM at baseline is 3610 mg/dL (range, 804- 10, 300). The median bone marrow involvement at enrollment was high for patients with WM, 50%, range (5-95%), with more than 10 patients having 70% or higher bone marrow involvement at baseline. The median number of cycles on therapy is 4 (range 1 – 12). 4 of the patients came off due to toxicity. Minimal response (MR) or better has been achieved in 15 (60%) of patients, with 6 (24%) PR, 9 (36%) MR. In addition, 9 (36%) patients achieved stable disease and 1 (4%) showed progression. The median decrease in IgM is 1020 mg/dL (0- 3970 decrease in IgM) with a median % decrease of 37.13%. Responses were prompt. The median time to first response was 2 cycles (range, 2–4). Bone marrow biopsies at the end of study (or at 6 months follow up) are available on 7 patients, of which 3 showed a significant decrease in bone marrow involvement and 4 showed stable involvement. The 4 patients who had stable bone marrow disease showed 1 PR and 3 MR responses by paraprotein level. Grade 3 and 4 toxicities include 4 (15%) cases of anemia including 1 case of hemolytic anemia, 1 (3%) case of grade 4 leucopenia (but the patient had grade 3 leucopenia at baseline), 7 (26%) of neutropenia, 14 (52%) of thrombocytopenia, 1 (4%) grade 3 GI bleed due to thrombocytopenia, 1 (3%) Grade 4 hyperglycemia and 1 (3%) grade 3 syncope and 3 (27%) grade 3 fatigue. The most common grade 2 toxicities were thrombocytopenia, anemia, and fatigue. There were 5 (20%) cases of asymptomatic pulmonary infiltrates of ground glass opacity observed on routine CT scans in follow up. Of these, 3 came off study for other reasons not related to the pulmonary infiltrates, 1 received a course of corticosteroids and had improvement of infiltrates, and 1 had dose reduction of therapy. All patients except for 2 have been dose reduced due to thrombocytopenia, fatigue, diarrhea, or anemia. Dose reductions include 25 mg three times a week, 20 mg three times a week and 20 mg three times every other week. The protocol was amended to allow a starting dose of 25 mg three times a week, which is better tolerated than 30 mg in this patient population. Conclusions: Panobinostat is an active therapeutic agent in patients with relapsed or refractory WM, with an overall response rate of 60% in patients with relapsed or refractory WM. The dose schedule of 25 mg three times a week is better tolerated in this patient population. Further studies to include this agent in combination with rituximab or bortezomib are being evaluated. Disclosures: Ghobrial: Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Anderson:Millennium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Richardson:Keryx Biopharmaceuticals: Honoraria. Treon:Millennium Pharmaceuticals, Genentech BiOncology, Biogen IDEC, Celgene, Novartis, Cephalon: Consultancy, Honoraria, Research Funding; Celgene Corporation: Research Funding; Novartis Corporation: Research Funding; Genentech: Consultancy, Research Funding.

Final Results of the Phase II Trial of Single Agent Panobinostat (LBH589) in Relapsed or Relapsed/Refractory Waldenstrom Macroglobulinemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2706-2706 ◽  
Author(s):  
Irene M. Ghobrial ◽  
Ranjit Banwait ◽  
Tiffany Poon ◽  
Federico Campigotto ◽  
Erica N Boswell ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Stable Disease ◽  
Research Funding ◽  
Bone Marrow Involvement ◽  
Ct Scans ◽  
Advisory Committees ◽  
Bone Marrow Biopsies ◽  
Grade 3

Abstract Abstract 2706 INTRODUCTION: This study aimed to determine the safety and activity of panobinostat (LBH589) in patients with relapsed or relapsed/refractory Waldenstrom Macroglobulinemia (WM). This was based on our preclinical studies showing that panobinostat induces significant activity in cell lines and patient samples. METHODS: Eligibility criteria include: 1) patients with relapsed or relapsed/refractory WM with any number of prior lines of therapy, 2) measurable disease and symptomatic disease, 3) Not receiving chemotherapy > 3 weeks, or biological/novel therapy for WM > 2 weeks. Patients received panobinostat initially at 30 mg three times a week (Mondays, Wednesdays and Fridays). Patients were assessed after every cycle for the first 6 cycles and then every 3 months thereafter. Subjects who had response or stable disease were allowed to continue on therapy until disease progression or unacceptable toxicity. A planned restaging was performed at the end of cycle 6 including CT scans and bone marrow biopsies. RESULTS: Thirty eight patients have been enrolled on this study from August 2009 to March 2011. Two patients withdrew prior to receiving treatment. Out of the 36 patients that received treatment, 35 patients were evaluable for response. The median age is 62 years (range, 47–67) and the median lines of prior therapy is 2 (range, 1–7). All of the patients had received prior rituximab. The median hemoglobin at screening is 10.7 g/dL, the median IgM M spike by protein electropheresis at study entry is 1.96 g/dL (range, 0.63–5.1), and median serum IgM at baseline is 3610 mg/dL (range, 804–10, 300mg/dL). The median bone marrow involvement at enrollment was high for patients with WM 48% (range, 5–95%), with 14 patients having 70% or higher bone marrow involvement at baseline. The median number of cycles on therapy is 3 (range, 1–12). Minimal response (MR) or better has been achieved in 49% of patients (17/35), with 6/35 PR and 11/35 MR. In addition, 16/35 (46%) patients achieved stable disease and 2/35 (6%) showed progression within the first 60 days of therapy. The median decrease in IgM is 760 mg/dL (range, 0–3970mg/dL decrease in IgM), which is a median decrease in IgM of 32% (range, 0–79%). The median time to first response was 2 cycles (range, 2–4). At 6 months on therapy, bone marrow biopsies are available on 9 patients, of which 5 show a significant decrease in bone marrow involvement, 3 are stable, and 1 show increase in bone marrow involvement. Of the 8 patients showing a decrease or stable bone marrow involvement from baseline, 4 are in PR and 4 are in MR by IgM level. Grade 3 and 4 toxicities include anemia (22%) including 1 case of hemolytic anemia, leukopenia (11%), neutropenia (33%), thrombocytopenia (61%), hypophosphatemia (3%), fatigue (11%), nausea (3%), 1 grade 3 GI bleed, and 2 grade 3 syncope. The most common grade 2 toxicities were anemia, leukopenia, neutropenia, fatigue and GI symptoms. There were 4 cases of asymptomatic pulmonary infiltrates of ground glass opacity observed on routine CT scans in follow up consistent with idiopathic pneumonia/pneumonitis. Of these, 4 came off study and 1 received corticosteroids while on therapy and had improvement in the infiltrates on further follow up. Subsequently, the protocol was amended to allow a starting dose of 25 mg, which proved to be better tolerated than 30 mg in this patient population with less fatigue and cytopenias;14/36 (39%) patients were enrolled on the 25 mg dose. CONCLUSIONS: Panobinostat is an active therapeutic agent in patients with relapsed or refractory WM, with an overall response rate of 49% in patients showing MR or better, and a clinical benefit rate of 95% of stable disease or better. The drug was generally well tolerated but the observation of pulomanary toxicity in some patients warrants further evaluation. The dose schedule of 25 mg three times a week is better tolerated than 30 mg dosing in this patient population. Further studies to include this agent in combination with rituximab and/or bortezomib warrant further evaluation. Disclosures: Ghobrial: Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Noxxon: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Research Funding; Bristol-Myers Squibb: Research Funding; Noxxon: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Off Label Use: panobinostat in WM. Anderson:Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Acetylon: Equity Ownership. Richardson:Millennium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Matous:Celgene: Speakers Bureau; Millenium: Speakers Bureau; Cephalon: Speakers Bureau.

Effect Of Treatment With The JAK2-Selective Inhibitor Fedratinib (SAR302503) On Bone Marrow Histology In Patients With Myeloproliferative Neoplasms With Myelofibrosis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2823-2823 ◽  
Author(s):  
Catriona HM Jamieson ◽  
Robert P Hasserjian ◽  
Jason Gotlib ◽  
Jorge E. Cortes ◽  
Richard M. Stone ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Phase I ◽  
Board Of Directors ◽  
Clinical Benefit ◽  
Research Funding ◽  
Selective Inhibitor ◽  
Advisory Committees ◽  
Grade 3

Abstract Introduction Fedratinib, a JAK2-selective inhibitor, demonstrated clinical benefit through a reduction in splenomegaly and symptoms in patients with myelofibrosis (MF), including post-polycythemia vera MF (post-PV MF), post-essential thrombocythemia MF (post-ET MF) and primary MF (PMF), in Phase I and II studies (J Clin Oncol 2011;29:789; Haematologica 2013;98:S1113). Bone marrow fibrosis (BMF) has been associated with splenomegaly and cytopenias (Ann Hematol 2006;85:226). Hence, stabilization and/or reversal of BMF remain important therapeutic goals. This report represents an exploratory analysis of sequential BMF data from patients with MF in an open-label Phase I/II study to evaluate the long-term effects of orally administered fedratinib (TED12015; NCT00724334). Methods Patients with intermediate or high-risk MF (Mayo Prognostic Scoring System) received fedratinib therapy in consecutive cycles (1 cycle = 28 days) as long as they derived clinical benefit. Bone marrow trephine biopsies were performed at baseline and after every 6 cycles. Hematoxylin and eosin, reticulin, and Masson's trichrome staining of core biopsy slides were used to grade BMF on a scale from 0 to 3 using the 2008 WHO MF grading criteria. BMF was graded independently in a blinded fashion by 3 hematopathologists. BMF grades were established as long as at least 2 of the 3 pathologists agreed independently. Changes in BMF grade from baseline were categorized as improvement (≥1 grade reduction), stabilization (no change), or worsening (≥1 grade increase). Results Of the 43 patients enrolled in the TED12015 study, the median fedratinib dose received was 473 (range 144–683) mg/day and median treatment duration was 32.3 (range 7–61) cycles. Bone marrow biopsies at baseline and at least one other time point were available for 21/43 (49%) patients, whose baseline characteristics were: median age 61 years (range 43–85); 57% male; 38% high-risk MF by WHO 2008 criteria (Leukemia 2008; 22:14); and 90% JAK2V617F positive. A consensus grade was achieved for 96% of the samples. At baseline, 2, 10, and 9 patients had grade 1, 2, and 3 BMF, respectively. Changes in BMF grade from baseline are shown in the figure. BMF improvement with 1 grade reduction was observed in 8/18 (44%) patients at Cycle 6. By Cycle 30, 4/9 (44%) evaluable patients had BMF improvement, including 2 patients with improvement by 2 grades and 2 patients with improvement by 1 grade. Of patients with Grade 3 BMF at baseline, 6/9 (67%) exhibited 1 grade improvement at Cycle 6. Two patients had 2 grades of BMF reduction from baseline during treatment (grade 3 to 1, and grade 2 to 0, both at Cycle 12), and the latter achieved a complete clinical remission at Cycle 30 assessed by IWG-MRT response criteria. The two patients who experienced complete reversal of BMF to grade 0 (one from grade 2 and one from grade 1) had normalization of not only hemoglobin level but also white blood cell and platelet counts at Cycle 18. Conclusions These exploratory analyses suggest that a proportion of patients treated long-term with fedratinib demonstrate stable or improved BMF. The disease modifying impact of fedratinib on BMF changes will be further assessed in a randomized, placebo-controlled Phase III clinical trial (JAKARTA; NCT01437787). This study was sponsored by Sanofi. Disclosures: Jamieson: J&J, Roche: Research Funding; Sanofi: Membership on an entity’s Board of Directors or advisory committees. Hasserjian:Sanofi, Inc: Consultancy. Gotlib:Sanofi: Travel to EHA 2012, Travel to EHA 2012 Other; Sanofi: Membership on an entity’s Board of Directors or advisory committees; Sanofi: Research Funding. Cortes:Incyte, Sanofi: Consultancy; Incyte, Sanofi: Research Funding. Talpaz:Novartis, Bristol-Myers Squibb, Ariad, Deciphera: Research Funding; Novartis, Bristol-Myers Squibb, Ariad, Deciphera: Speakers Bureau. Thiele:AOP Orphan Pharmaceuticals, Incyte, Novartis, Shire, Sanofi: Consultancy; Novartis, Shire: Research Funding; AOP Orphan Pharmaceuticals, Incyte, Novartis, Shire, Sanofi: Honoraria. Rodig:Ventana/Roche Inc.: Research Funding; Daiichi-Sankyo/Arqule Inc., Ventana/Roche Inc., Shape Pharmaceuticals Inc.: Consultancy. Patki:Sanofi: Employment. Wu:Sanofi: Employment. Wu:Sanofi: Employment. Pozdnyakova:Sanofi: Honoraria; Sanofi: Consultancy.

Phase 2 Trial of PRM-151, an Anti-Fibrotic Agent, in Patients with Myelofibrosis: Stage 1 Results

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 713-713 ◽  
Author(s):  
Srdan Verstovsek ◽  
Ruben A. Mesa ◽  
Lynda M Foltz ◽  
Vikas Gupta ◽  
John O Mascarenhas ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Clinical Benefit ◽  
Research Funding ◽  
Overall Response Rate ◽  
Response Rate ◽  
Jak Inhibitor ◽  
Advisory Committees ◽  
Grade 3 ◽  
Stage 1

Abstract PRM-151 (PRM) is a recombinant form of Pentraxin-2, an endogenous human protein that acts at sites of tissue damage, inducing macrophage differentiation to prevent and reverse fibrosis. PRM has broad anti-fibrotic activity in multiple preclinical models of established fibrotic diseases and no dose limiting toxicities in phase 1 trials. Myelofibrosis (MF: primary (PMF), post-essential thrombocythemia (post-ET MF), and post polycythemia vera (Post PV MF)) is a myeloid malignancy characterized by progressive bone marrow (BM) fibrosis with resultant anemia, abnormal platelet and leukocyte counts, extramedullary hematopoiesis, and a well-defined symptom complex. This study investigated the potential of PRM in MF to reduce BM fibrosis and to improve key disease features including abnormal blood counts, symptoms, and splenomegaly. MF patients (pts) with Dynamic International Prognostic Scoring System (DIPSS) intermediate-1, intermediate-2, or high-risk disease and grade ≥ 2 BM fibrosis, either on no current therapy or on a stable dose of ruxolitinib (RUX) for ≥ 12 weeks and no improvement in spleen for ≥ 4 weeks, were eligible for stage 1 of this open-label adaptive trial. Assignment to one of the 4 treatment arms was per investigator and pt choice: PRM 10 mg/kg IV 1-hour infusion days 1, 3, 5, then weekly (QW) or every 4 weeks (Q4W), alone or with RUX, for 24 weeks. Primary endpoint was overall response rate by IWG-MRT (symptoms by MPN-SAF Total Symptom Score (TSS), spleen by palpation) and/or decrease in BM fibrosis by ≥ 1 grade with otherwise stable disease. BM biopsies were obtained at baseline, 3 and 6 months, and were evaluated centrally by two blinded hematopathologists. Pts with clinical benefit were allowed to continue treatment in an extension. At least one response in any arm was required for that regimen to be evaluated in Stage 2. Twenty seven pts were enrolled: 8 PRM QW, 7 PRM Q4W, 6 PRM QW + RUX, 6 PRM Q4W + RUX. Median age 67 years (52-85); 70% DIPSS Int-2 or High Risk; 52% PMF, 15% post-ET MF, 33% post-PV MF; 63% grade 3 BM fibrosis, Hemoglobin (Hgb) < 100 g/L in 56% and < 85 g/L in 26%, platelet count (PLT)< 100 x 109/L in 52% and < 25 x 109/L in 30%; 22% were JAK inhibitor-naive and 52% had received a prior JAK inhibitor (not including ongoing RUX). Twenty pts completed 24 weeks of therapy; 18 continued extension treatment. PRM-151 was well-tolerated alone and with RUX; most adverse events (AEs) were Grade 1/2 and unrelated, with 3 Grade 3 possibly related AEs and 5 possibly related serious AEs. Nine of 26 evaluable pts responded, for an overall response rate (ORR) of 35%, with 4 IWG symptom clinical improvements (CI) and 6 BM fibrosis responses (Table 1), with ≥ 1 response in each arm. One pt had a CI and BM response. Reduction in BM fibrosis was associated with normal erythroid microarchitecture, normal or decreased myeloid:erythroid ratio, and fewer paratrabecular megakaryocytes, all potential surrogates of improved bone marrow microenvironment. IWG stable disease was observed in 77% of pts, with trends of clinical benefit in Hgb, PLT, peripheral blood blasts, spleen, and symptoms (Table 2). In 14 patients (54%), all parameters were stable or improved. Conclusion: PRM-151 was well-tolerated in patients with advanced MF, with no evidence of drug-related myelosuppression and encouraging trends in both clinical and histologic aspects of the disease. Reduction in BM fibrosis, stable to improved hematologic parameters, symptom responses, and stable to reduced spleen size support further development of PRM-151 in MF. Table 1 Two additional subjects had decrease in bone marrow fibrosis but progressive disease. Number of Patients BM Fibrosis Grade at Last Study Timepoint 3 2 1 BM Fibrosis Grade at Baseline 3 8 3 1 2 1 4 2 Abstract 713. Table 2 Outcome Parameter Denominator (n) Clinical Benefit Pts with Improvement (n/%) ORR (primary endpoint) All evaluable pts (26) IWG-MRT CI AND/OR reduction in BM fibrosis by ≥ 1 grade 9 (35%) Hgb Hgb < 100 g/L (15) ≥10 g/L increase from baseline AND no transfusions or 50% reduction in transfusions if transfusion dependent 6 (40%) PLT PLT < 100 x 109/L (13) > 100 x 109/L AND increase of ≥20 x 109/L ; increase of ≥20 x 109/L if baseline < 50, AND/OR increase of ≥ 10 x 109/L with discontinuation of transfusions 8 (62%) Blasts ≥ 1% peripheral blasts (14) No peripheral blasts 3 (21%) Symptoms All evaluable pts (26) ≥ 25% reduction in TSS ≥ 12 weeks 10 (38%) Spleen Palpable spleen (19) ≥ 25% decrease ≥ 4 weeks AND any decrease ≥ 12 weeks 5 (26%) Disclosures Verstovsek: Incyte: Research Funding; Astrazeneca: Research Funding; Lilly Oncology: Research Funding; Roche: Research Funding; Geron: Research Funding; NS Pharma: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Research Funding; Celgene: Research Funding; Gilead: Research Funding; Seattle Genetics: Research Funding; Promedior: Research Funding; Cell Therapeutics: Research Funding. Mesa:Incyte, CTI, NS pharma, Gilead, Celgene: Research Funding; Promedior: Research Funding. Foltz:Janssen: Consultancy; Promedior: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Gupta:Incyte Corporation: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Promedior: Research Funding. Mascarenhas:Novartis Pharmaceuticals Corporation: Research Funding; Incyte Corporation: Consultancy, Research Funding; Promedior: Research Funding. Ritchie:Celgene, Incyte: Speakers Bureau; Promedior: Research Funding. Hoffman:Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; All Cells LLC: Consultancy, Membership on an entity's Board of Directors or advisory committees; Promedior: Research Funding. Pozdnyakova:Sanofi: Consultancy; Incyte: Consultancy; Promedior: Consultancy. Hasserjian:Sanofi: Consultancy; Incyte: Consultancy; Promedior: Consultancy. Trehu:Promedior: Employment, Equity Ownership. Kantarjian:ARIAD, Pfizer, Amgen: Research Funding. Gotlib:Novartis: Research Funding, Travel Reimbursement, Travel Reimbursement Other; Sanofi: Research Funding; Gilead: Research Funding; Incyte: Consultancy, Honoraria, Research Funding, Travel Reimbursement Other; Promedior: Research Funding.

scholarly journals Safety and Efficacy of Venetoclax Combined with Rituximab, Ifosfamide, Carboplatin and Etoposide Chemoimmunotherapy (VICER) for Treatment of Relapsed Diffuse Large B Cell Lymphoma: Results from the Phase 1 Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 397-397 ◽  
Author(s):  
Paolo Caimi ◽  
Deepa Jagadeesh ◽  
Kirsten Marie Boughan ◽  
Robert M. Dean ◽  
Brenda Cooper ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 1 ◽  
B Cell Lymphoma ◽  
Hematologic Toxicity ◽  
Second Line ◽  
Advisory Committees ◽  
Line Therapy ◽  
Grade 3

Abstract Introduction: Diffuse large B cell lymphoma (DLBCL) patients (pts) with relapsed or refractory (r/r) disease after front line chemoimmunotherapy have poor survival. Standard second line therapy for r/r DLBCL consists of platinum-based chemotherapy followed by autologous stem cell transplant (ASCT). Approximately 50% of pts do not respond to second line therapy, highlighting the need for increased efficacy of these regimens. The antiapoptotic protein Bcl-2 is overexpressed in approximately 30% of DLBCL cases. Preclinical and early clinical data suggest that addition of venetoclax (VEN), a potent selective Bcl-2 inhibitor, to chemoimmunotherapy augments response rates and durability in lymphoma. We conducted a phase 1 dose escalation and dose expansion study to evaluate the safety and efficacy of VEN in combination with R-ICE (rituximab, ifosfamide, carboplatin and etoposide) (VICER) r/r DLBCL pts. Here we present the results after completion of VEN dose escalation. Methods: Patients (≥18 years of age) with r/r DLBCL who failed one or two lines of therapy were enrolled. The primary objective was to determine the recommended phase 2 dose (RP2D) of VEN when combined with R-ICE. VEN was given orally on days 1 - 10 of each 21 - day cycle x 3 cycles. Dose escalation was conducted according to a 3+3 design, with 3 dose levels (400, 600 and 800mg). R-ICE was given at standard dose and schedule on days 1 - 3 of each cycle for 3 cycles. No intra-patient dose escalation was allowed. Tumor lysis syndrome (TLS) mitigation included inpatient administration, hydration, allopurinol and frequent laboratory evaluation during cycle 1. All patients received pegfilgrastim; use of prophylactic antibiotics during neutropenia was left at the discretion of the treating physician. Results: As of July 20, 2018, 18 pts with DLBCL (14 male, 4 female) were enrolled (VEN 400mg, n = 3; 600 mg, n = 3; 800 mg, n = 12). Median age of pts was 55.5 years [range 27-78]. All pts received rituximab and anthracycline containing first - line therapy, 4 patients had failed a second line of therapy. One patient experienced dose limiting toxicity (DLT) at 800 mg VEN, with acute renal failure, febrile neutropenia, sepsis and rapid tumor progression and died after cycle 1. No other DLTs were observed. Hematologic toxicity was common, with grade ≥3 anemia in 6 (33%) pts; grade ≥3 neutropenia in 14 (78%) pts and grade ≥3 thrombocytopenia in 10 (55%) pts. Five (28%) pts experienced febrile neutropenia. The most common non-hematologic all-grade treatment emergent adverse events (TEAEs) were fatigue (7 [38%] pts), nausea (6 [33%] pts); diarrhea (6 [33%] pts), anorexia (5 [27%] pts], infection (5 [27%] pts) and sensory neuropathy (5 [27%] pts). Grade ≥3 TEAEs included infection (4 [22%] pts), cholecystitis (2 [11%]) and one case each (5.5%) of peripheral edema, acute renal failure, acute coronary syndrome, atrial fibrillation, hyponatremia and hypokalemia. One case of laboratory TLS occurred, but no clinical TLS was observed. At data cutoff, the intent-to-treat (ITT) population included 13 patients that had at least one cycle of therapy and end of treatment response or had discontinued prior to response assessment; 3 pts did not complete all planned cycles of VICER: one patient died after DLT, one patient proceeded to ASCT in complete remission (CR) after 2 cycles and another withdrew after cycle 1, achieving partial remission (PR) with additional 2 cycles of R-ICE. Nine pts (69%) achieved CR and 2 (15%) achieved PR (overall response rate (ORR): 11/13 [84.6%]) (Tables 2 and 3). Figure 1 depicts tumor response data. Among 11 responding pts, 7 have undergone stem cell collection, with a median CD34 cell count of 3.73x106 cells/kg. Seven pts have completed their ASCT, with hematopoietic engraftment in all cases. Median follow up of patients in CR/PR is 6 months (range 1 - 12), none has experienced progression. Conclusions: In this Phase 1 study, VICER shows encouraging antilymphoma activity in r/r DLBCL, including double hit/double expressor lymphomas, with high rates of complete metabolic response (69% CR by PET), which is higher than historical levels reported with R-ICE alone (CR typically <45%). The RP2D of VEN is 800 mg. Hematologic toxicity - particularly neutropenia - is common, and G-CSF support as well as antibiotic prophylaxis are necessary to prevent infectious complications. Updated safety, progression-free survival and response data will be presented at the meeting. Disclosures Caimi: Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Celgene: Speakers Bureau. Hill:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Phase I/II Study of Escalating Doses of Thalidomide in Conjunction with Bortezomib and High Dose Melphalan As a Conditioning Regimen for Autologous Stem Cell Transplantation in Patients with Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2154-2154
Author(s):  
Noa Biran ◽  
Shijia Zhang ◽  
Scott D. Rowley ◽  
David H. Vesole ◽  
Michele L. Donato ◽  
...  
Keyword(s):  
Phase I ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Conditioning Regimen ◽  
High Dose ◽  
Advisory Committees ◽  
Common Grade ◽  
Grade 3 ◽  
High Dose Melphalan

Abstract Background: A regimen of escalating doses of thalidomide, in combination with bortezomib and high dose melphalan (Mel/Vel/Thal) was evaluated as a conditioning regimen for autologous stem cell transplantation (ASCT) in patients (pts) with multiple myeloma (MM) in a phase I/II study. Methods: Patients received Mel/Vel/Thal as a second of tandem ASCT if they achieved <CR to their first ASCT (tandem), or as conditioning for a salvage ASCT (salvage). Exclusion criteria were dose-intense therapy within 56 days, uncontrolled infections, severe organ dysfunction, Karnofsky score <70%, or painful grade 2 or greater peripheral neuropathy. Conditioning consisted of Vel 1.6 mg/m2 intravenously on days -4 and -1 with Mel 200 mg/m2 on day -2. Thal was given on days -5 through -1 and was administered in a planned step-wise dose escalation of 600, 800 and 1000 mg (in cohorts of 3 pts). Dexamethasone (Dex) 10-20 mg was given prior to Vel and Mel. All pts received G-CSF every other day starting day +3 until engraftment. Serious adverse events (SAEs) were graded according to CTCAE version 3. Results: Twenty-nine pts were enrolled: 9 in the phase 1 dose-escalation phase and an additional 20 pts in phase 2. In the phase I portion, all pts experienced somnolence, with grade 3 occurring in 1 pt at the 800 mg/day dose. Subsequently, Dex 40 mg was given with first dose of Thal at the 1000 mg level with decreased severity of somnolence. No dose limiting toxicities defined as ≥ grade 4 non-hematological SAEs occurred in the phase I portion, allowing full dose escalation with 9 pts enrolled. The maximum tolerated dose for Thal was not reached and the 1000 mg dose was chosen for the phase 2 dose expansion. No regimen related mortality occurred in either phase I or phase II portion of the study. All SAEs except lethargy and dizziness occurred after ASCT and were not attributed to Thal. The most common grade 1 and 2 non-hematologic toxicities included nausea (65.5%), mucositis (51.7%), diarrhea (48.3%), somnolence (48.3%), lethargy (27.6%), and vomiting (17.2%). The most common grade 3 non-hematologic adverse events (AEs) were neutropenic fever (58.6%), mucositis (6.9%), and somnolence (13.8%), which increased risk of falls. SAEs included somnolence (13.8%), tumor lysis syndrome (3.4%), and engraftment syndrome (3.4%). All transplant-related SAEs resolved by day +28 after ASCT. All pts achieved prompt hematological recovery with the median time to ANC >500/uL 10 days (range, 8-14 days), and platelet >20,000 12 days (range 9-26 days). All pts received at least one ASCT prior to enrolling on the study. Seventeen pts (59%) had interim salvage chemotherapy between their upfront and Mel/Vel/Thal ASCT (i.e. received a salvage ASCT), with median time from first to salvage ASCT 29 months. The remaining 12 (41%) went directly from an upfront ASCT Mel-based ASCT to the Mel/Vel/Thal ASCT (tandem ASCT) within 6 months of the first ASCT. Twenty-seven (93%) were Durie-Salmon stage III, and 13 (44%) had >2 prior lines of therapy. Of those who had Mel/Vel/Thal as a salvage ASCT, 70% had ≥3 prior lines of therapy. The overall response rate (ORR) was 69% with 38% complete remission. ORR for Mel/Vel/Thal compared to upfront Mel ASCT was 69% versus 62% with 11 patients achieving CR with Mel/Vel/Thal compared to 5 patients with Mel alone (Figure 1). Ten of 27 evaluable patients (37%) had an upgrade in response in the Mel/Vel/Thal salvage ASCT compared to their upfront ASCT: 2 pts (7%) went from PD to PR, 1 (4%) from SD to CR, 1 (4%) from PR to VGPR; 3 (11%) from PR to CR and 2 (7%) from VGPR to CR. Median PFS and OS were 9.3 and 65.4 months, respectively, with a median follow-up of 17.8 months. Of those who underwent tandem Mel followed by Mel/Vel/Thal ASCT the median PFS was 14.9 months with a median OS not yet reached at time of analysis. For the 17 patients who received a salvage Mel/Vel/Thal ASCT, median PFS from their upfront ASCT was 11.9 months, compared to 9.1 months with the salvage Mel/Vel/Thal ASCT. Conclusions: High-dose Thal up to 1000 mg daily for 5 days can be safely combined with Vel and dose-intense Mel as an ASCT conditioning regimen with acceptable toxicities. Confirmation of potential synergistic effects of this combination regimen will require an appropriately designed phase III study. Figure 1 Figure 1. Disclosures Biran: BMS: Research Funding; Merck: Research Funding; Takeda: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Skarbnik:Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Genentech: Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Speakers Bureau. Siegel:Novartis: Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau.

scholarly journals Blinatumomab in Combination with Pembrolizumab Is Safe for Adults with Relapsed or Refractory B-Lineage Acute Lymphoblastic Leukemia: University of California Hematologic Malignancies Consortium Study 1504

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3880-3880 ◽  
Author(s):  
Marc Schwartz ◽  
Lloyd E. Damon ◽  
Deepa Jeyakumar ◽  
Caitlin L. Costello ◽  
Dimitrios Tzachanis ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Board Of Directors ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Complete Response ◽  
Advisory Committees ◽  
High Bone ◽  
Grade 3 ◽  
Expansion Cohort

Clinical and preclinical findings suggest that PD-L1 overexpression on lymphoblasts and in the bone marrow microenvironment may mediate resistance to blinatumomab by inhibiting T-cell activation. We report preliminary findings from an ongoing phase I/II multicenter trial to evaluate the safety and efficacy of blinatumomab with pembrolizumab in adults with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) and a high bone marrow lymphoblast percentage (NCT 03160079). The primary objective of this Phase I/II trial is to determine overall response rate (ORR = complete response (CR) + complete response with partial hematologic recovery (CRh) rate) after 1-2 cycles of blinatumomab with pembrolizumab, with key secondary endpoints of adverse events (AEs), minimal residual disease (MRD)-negative CR/CRh rate, 2-year disease-free and overall survival, and allogeneic HCT rate. Eligible patients are 18 years of age or older with R/R B-ALL after ≥ 1 prior line of therapy (including Philadelphia chromosome positive (Ph+) B-ALL failing one second or third generation tyrosine kinase inhibitor) and >50% lymphoblasts on screening bone marrow sample. Patients receive blinatumomab by continuous IV at 9 mcg/day on days 1-7 and 28 mcg/day on days 8-28 of cycle 1, then 28 mcg/day on days 1-28 in subsequent cycles. Pembrolizumab 200 mg IV is given on days 15 and 36 of each 42-day cycle. Patients in CR/CRh after 1-2 cycles complete a maximum of 5 cycles. A safety cohort of up to 6 patients assessed safety by 3+3 design. Dose-limiting toxicities (DLTs) were defined as Grade 3 or 4 non-hematologic AEs related to the addition of pembrolizumab to blinatumomab with a DLT monitoring period of 28 days from the first pembrolizumab dose. At the time of this analysis, 5 patients have been enrolled and treated with all 5 completing the DLT monitoring period. Patients had a median age of 60 years (range 22-74) and one had Ph+ disease. Median bone marrow lymphoblast percentage at time of enrollment was 84% (range 53-90). Patients received a median of 1 cycle (range 1-3) of blinatumomab with pembrolizumab. Common AEs included fever, headache, increased bilirubin, nausea, neurotoxicity, and tachycardia. Grade 3-4 non-hematologic AEs included disseminated intravascular coagulation, hyperferritinemia, hypokalemia, subdural hematoma, encephalopathy, hyponatremia, and macrophage activation syndrome in 1 patient (all related to blinatumomab), hyperbilirubinemia and elevated AST in 1 patient, and hypertriglyceridemia in 1 patient. No grade 3 or greater immune-related AEs have occurred. No pembrolizumab-related DLTs occurred in the first 5 patients in the safety cohort and enrollment is now proceeding in the dose-expansion cohort. The ORR was 50% with 2/4 evaluable patients achieving a CR. One patient achieved an MRD-negative CR in cycle 1 and completed 3 cycles before proceeding to allogeneic HCT. One patient discontinued treatment due to subdural hemorrhage and macrophage activation syndrome during cycle 1 and achieved a CR. Both patients remain in CR for over 6 months. Two patients discontinued treatment due to refractory or progressive disease. The one patient not evaluable for response withdrew from study therapy after 1 cycle without ALL progression. Patient, disease, and treatment characteristics as well as outcomes are summarized in the Table. Blinatumomab with pembrolizumab is safe for adults with R/R B-ALL and a high bone marrow lymphoblast percentage. Enrollment continues in the dose-expansion cohort to assess efficacy. Disclosures Damon: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Costello:Celgene: Consultancy, Honoraria, Research Funding; Janssen: Research Funding; Takeda: Honoraria, Research Funding. Schiller:Biomed Valley Discoveries: Research Funding; Astellas: Research Funding; Amgen: Other, Research Funding; Agios: Research Funding, Speakers Bureau; Bristol Myer Squibb: Research Funding; Celgene: Research Funding, Speakers Bureau; Constellation Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding; Eli Lilly and Company: Research Funding; FujiFilm: Research Funding; Genzyme: Research Funding; Gilead: Research Funding; Incyte: Research Funding; J&J: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Karyopharm: Research Funding; Novartis: Research Funding; Onconova: Research Funding; Pfizer Pharmaceuticals: Equity Ownership, Research Funding; Sangamo Therapeutics: Research Funding. Wieduwilt:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen, Leadiant, Merck, Servier: Research Funding; Reata Pharmaceuticals: Equity Ownership; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Pembrolizumab (given off label)to enhance the efficacy of blinatumomab (given on label) for relaped/refractory B-cell acute lymphoblastic leukemia

scholarly journals 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 ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1899-1899 ◽  
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.

scholarly journals Subcutaneous Epcoritamab in Combination with R-CHOP in Patients with Previously Untreated High-Risk Diffuse Large B-Cell Lymphoma: Preliminary Results from a Phase 1/2 Trial

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1413-1413
Author(s):  
David Belada ◽  
Jacob Haaber Christensen ◽  
Kristina Drott ◽  
Sylvia Snauwaert ◽  
Joshua Brody ◽  
...  
Keyword(s):  
High Risk ◽  
B Cell ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Metabolic Response ◽  
Phase 1 ◽  
B Cell Lymphoma ◽  
Advisory Committees ◽  
Grade 3

Abstract Background: In patients (pts) with newly diagnosed diffuse large B-cell lymphoma (DLBCL) that is considered high risk (revised International Prognostic Index [R-IPI]: 3-5), standard treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is associated with a 4-year overall survival rate of 55% (Sehn et al, Blood 2007). Epcoritamab (DuoBody ®-CD3×CD20) is a subcutaneously administered bispecific antibody that simultaneously binds to CD3 on T cells and CD20 on malignant B cells to induce T-cell-mediated killing. Single-agent epcoritamab demonstrated a manageable safety profile and substantial antitumor activity in pts with heavily pretreated B-cell non-Hodgkin lymphoma (NHL) in the first-in-human phase 1/2 trial (EPCORE NHL-1; NCT03625037). Among pts with relapsed/refractory DLBCL treated at the identified recommended phase 2 dose (RP2D) of 48 mg (n=8), the overall response rate was 88% and the complete response rate was 38% (Hutchings, Lancet, in press). These encouraging data supported initiation of the EPCORE NHL-2 phase 1/2 trial (NCT04663347), which is evaluating epcoritamab in combination with various standard of care therapies in pts with B-cell NHL. We present data from arm 1 of this trial, in which epcoritamab in combination with R-CHOP is evaluated in pts with previously untreated high-risk DLBCL. Methods: Adults with previously untreated DLBCL and an R-IPI score ≥3 received flat-dose epcoritamab in combination with standard R-CHOP for 6 cycles followed by epcoritamab monotherapy. The study includes a dose-escalation cohort (epcoritamab doses: dose level 1 = 24 mg; dose level 2 = 48 mg). Step-up dosing of epcoritamab (ie, priming and intermediate doses before first full dose) and corticosteroid prophylaxis were used as previously described (Hutchings, Lancet, in press) to mitigate cytokine release syndrome (CRS). Tumor response was evaluated by positron emission tomography-computed tomography obtained once every 6 weeks for the first 24 weeks. Results: As of July 15, 2021, 9 pts have been treated with the combination of epcoritamab + R-CHOP (4 with epcoritamab 24 mg; 5 with 48 mg). Median age was 66 years (range, 56-78). All pts had stage III-IV disease. At data cutoff, all pts remained on treatment with a median follow-up of 12.2 weeks (range, 2.2-28.2). The most common treatment-emergent adverse events were CRS (56%; all grade 1/2), anemia (56%; grade 1-3), neutropenia (44%; all grade 3/4), fatigue (33%; all grade 1/2), and peripheral neuropathy (33%; all grade 1/2). Notably, no grade ≥3 CRS events or cases of febrile neutropenia were reported. No dose-limiting toxicities have been observed. Four pts have had ≥1 response assessment, with 3 achieving complete metabolic response (CMR; all in the epcoritamab 24 mg dose-escalation cohort) and 1 pt achieving partial metabolic response (epcoritamab 48 mg cohort) by week 6; 2 of the 3 pts with CMR had response assessments at 6 months, and both remained in CMR at that time. Both dose cohorts have been cleared by the Dose Escalation Committee and Safety Committee, and the expansion part has been opened to enroll additional pts. Conclusions: These preliminary data from a small number of pts suggest that epcoritamab in combination with R-CHOP has a manageable safety profile with no new safety signals. Adverse events were similar to those previously reported for epcoritamab and R-CHOP individually. All evaluable pts achieved early responses, and all pts remain on treatment. Updated and additional data from pts treated in the expansion phase will be presented. These findings warrant further evaluation of epcoritamab for the treatment of high-risk, newly diagnosed DLBCL. Disclosures Belada: Genmab: Research Funding. Drott: Roche: Honoraria; Kyowa Kirin: Honoraria; Respiratorius AB: Membership on an entity's Board of Directors or advisory committees. Narkhede: TG Therapeautics: Research Funding; Genmab: Other: Medical writing support, Research Funding; Genentech/Roche: Research Funding; Gilead: Research Funding. Elliot: Genmab: Current Employment, Patents & Royalties: P158-US-PSP3 . Liu: Genmab: Current Employment. Cota Stirner: AbbVie: Current Employment. Abbas: Genmab: Current Employment. Falchi: Abbvie: Consultancy, Research Funding; Genmab: Consultancy, Research Funding; Roche: Research Funding; Genetech: Research Funding. Clausen: Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expences ASH 2019; Gilead: Consultancy, Other: Travel expences 15th ICML ; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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