A Phase 2 Study of Lenalidomide to Repair Immune Synapse Response and Humoral Immunity in Early-Stage, Asymptomatic Chronic Llmphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) with High-Risk Genomic Features

Abstract BACKGROUND: Patients (pts) with CLL/SLL are at high risk for infections, and pts with genetically high-risk disease are at increased risk for early disease progression and death. Lenalidomide, an oral immunomodulatory agent with demonstrated activity in treatment-naïve CLL/SLL, can potentially restore immune system dysfunction associated with CLL/SLL. We present results from an NCI/CTEP-sponsored, randomized phase 2 study (NCI 8834) of low-dose lenalidomide designed to assess the ability of lenalidomide to restore immune synapse response and humoral immunity, as well as delay progression of asymptomatic, genetically high-risk, early-stage CLL/SLL. METHODS: Pts with genetically high-risk CLL/SLL (unmutated IGHV, deletion(17p)/(11q), and/or complex abnormal karyotype) were eligible if they were treatment-naïve, did not meet IWCLL 2008 criteria for initiating therapy, age ≥ 18 but < 80 years, ECOG ≤ 2, no history of autoimmune cytopenia, no venous thromboembolic event ≤6 months prior, and adequate end-organ function. Pts were randomized to receive lenalidomide either concurrent with (Arm A) or sequential to (Arm B) 2 doses of 13-valent protein-conjugated pneumococcal vaccine (Prevnar-13) administered 2 months apart (see figure). Lenalidomide was dosed at 2.5 mg/day during the first 28-day cycle to reduce risk for tumor flare and increased to 5 mg/day for the second and subsequent cycles as tolerated. Treatment continued for at least 24 cycles in the absence of disease progression or irreversible Grade ≥ 3 adverse event (AE). Anti-pneumococcal antibody titers, the primary endpoint of the study, were measured in each arm at 1 and 2 months after the second dose of vaccine and every 6 months thereafter. Secondary endpoints included clinical response, IWCLL 2008 response after 24 cycles, and progression-free survival (PFS). RESULTS: 49 pts were randomized. Median age at enrollment was 59 (range 40-70) years, median time from diagnosis 1.26 (range 0.15-9) years, and ECOG = 0 in 96%. Baseline clinical and genetic risk factors were similar between the 2 arms (see table). In general, AE were mild and manageable. Gr ≥3 AE were uncommon and included (in ≥10% pts): neutropenia in 10 (20%) and hypophosphatemia in 6 (12%). The most common treatment-emergent Gr 1/2 AEs included neutropenia in 27 pts (55%), diarrhea in 26 (53%), rash in 25 (51%), and thrombocytopenia in 23 (47%). Gr 1/2 infections were reported in 17 (35%), but only 1 Gr 3 infection (pneumonia) was observed. Gr 1/2 tumor flare was observed in 2 pts (4%). There were no thromboembolic events. Seroprotection against 7 pneumococcal serotypes (1, 3, 4, 5, 14, 19F, and 23F) was measured 4 weeks after the second dose of vaccine. All but 4 pts (3 in Arm A, 1 in Arm B) achieved seroprotection against ≥1 serotype, and the median number against which seroprotection was achieved was 3 (range: 0-7) in both arms. Mean IgG/IgM/IgA levels at baseline were 722/109/49, and improved to 820/136/51 and 947/197/59 after 12 and 24 cycles of treatment, respectively. Disposition of study patients and treatment responses are summarized in the table; after median 31 cycles received, 59% of patients remain on treatment. 75% of patients achieved a clinically assessed disease response, and of the 34 patients that completed IWCLL response assessment after 24 cycles of therapy (including CT scans and bone marrow biopsy), 9 achieved a PR, 23 SD, and 2 PD. Median PFS has not yet been reached; 1 year PFS was 88% (95%CI 74-94), 2 year PFS was 78% (63-88), and estimated 3 year is PFS 72% (95%CI 56-83). CONCLUSIONS: Low-dose lenalidomide can be administered to asymptomatic, genetically high-risk, early-stage CLL patients with modest toxicity and high rates of durable clinical response. Some anti-pneumococcal vaccine response was achieved by nearly all treated patients on both schedules. Lenalidomide effectively prevented and/or reversed the expected progression of hypogammaglublinemia, which may explain the low incidence of infection, and near absence of severe infection, observed here. Figure Figure. Disclosures Jones: Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; 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. Awan:Novartis Oncology: Consultancy; Innate Pharma: Research Funding; Pharmacyclics: Consultancy. Andritsos:Hairy Cell Leukemia Foundation: Research Funding. Woyach:Morphosys: Research Funding; Karyopharm: Research Funding; Acerta: Research Funding. Lozanski:Stemline Therapeutics Inc.: Research Funding; Genentech: Research Funding; Beckman Coulter: Research Funding; Boehringer Ingelheim: Research Funding.

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

Blood ◽

10.1182/blood.v114.22.3866.3866 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3866-3866 ◽

Cited By ~ 2

Author(s):

Maria Teresa Petrucci ◽

Igor W. Blau ◽

Paolo Corradini ◽

Meletios A. Dimopoulos ◽

Johannes Drach ◽

...

Keyword(s):

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Phase 2 ◽

Efficacy And Safety ◽

Advisory Committees ◽

Bortezomib Treatment ◽

Best Response ◽

Phase 2 Study ◽

Grade 3

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

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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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The Eatl-001 Trial: Results of a Phase 2 Study of Brentuximab Vedotin and CHP Followed By Consolidation with High-Dose Therapy - Autologous Stem-Cell Transplantation (HDT-ASCT) in the Frontline Treatment of Patients with Enteropathy-Associated T-Cell Lymphoma

Blood ◽

10.1182/blood-2021-153709 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 136-136

Author(s):

David Sibon ◽

Sherine Khater ◽

Julie Bruneau ◽

Chantal Brouzes ◽

Ludovic Lhermitte ◽

...

Keyword(s):

T Cell ◽

High Risk ◽

Board Of Directors ◽

Gene Rearrangement ◽

Cell Lymphoma ◽

Brentuximab Vedotin ◽

Phase 2 ◽

Advisory Committees ◽

Phase 2 Study ◽

Frontline Treatment

Abstract Background Enteropathy-associated T-cell lymphoma (EATL), previously designated type 1 EATL, is a neoplasm of intraepithelial T cells that occurs in individuals with celiac disease (CD). It is a rare lymphoma, accounting for approximately 3% of all peripheral T-cell lymphomas (PTCLs). EATL may be preceded by refractory CD (RCD), defined as persistent or recurrent symptoms and signs of malabsorption with villous atrophy despite a strict gluten-free diet for more than 12 months. Currently, RCD is categorized into 2 types, based on immunophenotypic and molecular criteria. In RCD-II, intraepithelial lymphocytes (IELs) have an aberrant phenotype and a clonal TCR gene rearrangement. RCD-II is considered a low-grade lymphoma of intraepithelial T cells, with a high risk of transformation into EATL. CD or RCD may be diagnosed prior to or concomitant with EATL. EATL has a poor prognosis due to perforation or obstruction of the bowel, sepsis, malnutrition and treatment resistance, with 2-year OS of 20% (de Baaij, CCR 2015). An EATL prognostic index (EPI) has been developed, that can distinguish 3 risk groups (de Baaij, CCR 2015). Optimal treatment of EATL is an unmet need, and novel therapeutic approaches are required. Most EATLs are CD30+ and could be targeted by brentuximab vedotin (BV). Based on the encouraging activity and manageable safety profile of BV and CHP (cyclophosphamide, doxorubicin and prednisone) combination in CD30+ PTCLs, the EATL-001 phase 2 trial was initiated to assess the efficacy and safety of BV-CHP followed by HDT-ASCT for the frontline treatment of patients (pts) with EATL (ClinicalTrials.gov No. NCT03217643). Here we report the first results of the EATL-001 trial. Methods EATL-001 is an Investigator Initiated-Sponsored Research phase 2 study, on behalf of the CELAC (French NCI-labeled network of Centers of Expertise for Lymphomas Associated with Celiac disease). Key inclusion criteria were as follows: Newly diagnosed CD30+ (≥10% of neoplastic cells by central review) EATL (WHO 2016 criteria), 18-65 years, PS 0-3. Response was assessed according to the Lugano classification. Pts were scheduled to receive 4 cycles of BV+CHP as induction. Responding pts received 2 cycles of Etoposide (200 mg/m2) + Methotrexate (3 g/m2) followed by HDT-ASCT (BEAM conditioning regimen). The primary endpoint was 2-year PFS per investigator. Underlying CD/RCD diagnosis was based on uninvolved duodenal histology (including CMF and TCR gene rearrangement analysis of IEL), serology and HLA typing. Results A total of 14 pts were included between February 2018 and February 2021. The median age was 54 years (range, 34-65) and 64% were male. 11 pts (79%) had initial surgery for bowel obstruction (n=6) or jejunal perforation (n=5). All pts had CD, diagnosed prior to (n=4) or concomitant with (n=10) EATL. 9 pts (64%) had RCD-II. CD30 expression ranged from 10% to 100%, nine cases having 100% positivity. EPI was high-risk in 4 pts (29%), intermediate-risk in 6 pts (43%), and low-risk in 4 pts (29%). Preliminary results by investigator assessment show an overall response rate following completion of the induction of 79% (11/14) with 64% (9/14) achieving a complete response. 3 pts had primary progressive disease (all had high-risk EPI), of which 2 died of the lymphoma. The 11 responding pts, still in response before intensification, underwent HDT-ASCT. 2 pts died of septic shock during HDT-ASCT. With a median follow-up of 2.1 years, there was no relapse and the 2-year PFS and OS for all pts were 63% and 68%, respectively. The incidence of AEs was consistent with the known safety profiles of BV-CHP regimen. Conclusions EATL-001 is the first prospective phase 2 study dedicated to EATL. BV-CHP was well tolerated and induced high response rates, allowing the majority of patients to be transplanted. This novel therapeutic approach shows promising efficacy compared to historical controls. Disclosures Sibon: Takeda: Consultancy; Roche: Consultancy; Janssen: Consultancy; Abbvie: Consultancy; iQone: Consultancy. Cartron: Roche, Celgene-BMS: Consultancy; Danofi, Gilead, Novartis, Jansen, Roche, Celgene-BMS, Abbvie, Takeda: Honoraria. Morschhauser: Incyte: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria; AstraZenenca: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy; Janssen: Honoraria; Roche: Consultancy, Speakers Bureau; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genmab: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy. Hermine: Takeda: Consultancy. OffLabel Disclosure: Brentuximab vedotin is not approved in Europe for EATL.

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A Prospective Phase 2 Study of Venetoclax and Low Dose Ara-C (VALDAC) to Target Rising Molecular Measurable Residual Disease and Early Relapse in Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2021-152583 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1261-1261

Author(s):

Ing S Tiong ◽

Sun Loo ◽

Emad Uddin Abro ◽

Devendra Hiwase ◽

Shaun Fleming ◽

...

Keyword(s):

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Residual Disease ◽

Phase 2 ◽

Advisory Committees ◽

Early Relapse ◽

Phase 2 Study ◽

Measurable Residual Disease ◽

Acute Myeloid

Abstract Introduction Rising molecular measurable residual disease (MRD) is an arbiter of clinical relapse in acute myeloid leukemia (AML). Venetoclax (VEN) is active against IDH and NPM1 mutant (mt) AML as monotherapy (Konopleva et al, 2016 and Chua et al, 2020) and can yield MRD negative remission when combined with low dose ara-C (LDAC) in patients unfit for intensive chemotherapy (DiNardo and Tiong et al, 2020). In a retrospective study, we showed that VEN in combination with hypomethylating agents or LDAC could erase rising NPM1mt MRD in 6/7 cases (Tiong et al, 2020). We now present a prospective phase 2 study of VEN and LDAC in patients with molecular MRD failure or oligoblastic AML relapse. Methods This multicenter phase 2 study stratified patients into oligoblastic relapse (marrow blasts 5-15%; Group A), or molecular MRD failure (Group B) as defined by the European LeukemiaNet (ELN) recommendations (failure confirmed by 2 interval samples) (Schuurhuis et al, 2018). Patients received VEN 600 mg (days 1-28) and LDAC 20 mg/m 2 (days 1-10). Primary objectives were morphologic or MRD response (≥1 log reduction) in groups A and B, respectively. Key secondary objectives were allogeneic hematopoietic cell transplantation (allo-HCT) realization and relapse-free (RFS) and overall survival (OS). The study had Alfred Health ethics approval (196/19). NPM1mt and other fusion transcript levels (per 10 5 ABL) from bone marrow were analyzed by RT-qPCR, IDH1 and IDH2 by Bio-Rad TM droplet digital PCR. Results The study enrolled 32 patients, with 29 evaluable (cut-off date 15/7/21). The median age of the study population was 62 years; 79% had intermediate cytogenetic risk, 66% NPM1mt, 11% FLT3-ITD and 37% IDH1/IDH2 mt. Most received prior intensive chemotherapy (93%) and 2 (7%) allo-HCT in first remission. Median interval from AML diagnosis to study entry was 12.6 months (Table 1). After a median follow-up of 7.9 months, patients had received a median of 3 cycles (range 1-14) of VEN-LDAC, with 13 patients ongoing. The main reasons for treatment cessation were allo-HCT (n=10; 34%) or donor lymphocyte infusion (n=2; 7%), treatment failure (n=3) or an adverse event (n=1). Hematologic complete/incomplete response (CR/CRi) among 11 patients with oligoblastic relapse (group A) was 73% and included: CR (n=5, 45%) or CRi (n=3, 27%), with an additional patient with morphologic leukemia-free state and 2 patients with stable disease. Overall, across both groups, median RFS and OS were not reached, estimated at 78% and 91% at 1 year, respectively. Among 18 patients with molecular MRD failure (group B) treated with VEN+LDAC, molecular response (≥1 log reduction) was achieved in 72%, and the RFS and OS were estimated at 83% and 87% at 1 year, respectively. Analysis of a sub-group of patients with NPM1mt (n=18); 6 and 12 from Groups A and B, respectively revealed the median NPM1mt transcript level at study entry to be 8985 copies (IQR 826, 94,431). A molecular response was achieved in 14 (78%) patients, including 9 (50%) with complete molecular remission (CR MRD-), with most responses achieved within 2 cycles of therapy (Figure B). Treatment with VEN-LDAC was generally well tolerated, with 15 serious adverse events reported within the first 2 cycles, including infection (n=6; 19%) and febrile neutropenia (n=3; 9%). Only one subject discontinued treatment due to stroke. Conclusions In this prospective study, in patients with first oligoblastic relapse or MRD failure, VEN in combination with LDAC induced a high rate of molecular MRD remission that was rapidly achieved, resulting in a high rate of survival at 12-months (>90%) and with low toxicity. Follow-up is ongoing to determine the durability of response. Treatment of patients with MRD or early clinical failure may represent an attractive clinical trial setting for investigation of novel, non-intensive AML therapies. This approach will be investigated in a future multi-arm, precision-based platform trial called INTERCEPT (Investigating Novel Therapy to Target Early Relapse and Clonal Evolution as Pre-emptive Therapy in AML). Figure 1 Figure 1. Disclosures Tiong: Servier: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; Pfizer: Consultancy. Hiwase: Novartis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Fleming: Amgen Inc: Research Funding. Bajel: Amgen: Speakers Bureau; Abbvie, Amgen, Novartis, Pfizer: Honoraria. Fong: Amgen, BMS: Speakers Bureau; Amgen: Research Funding; AbbVie, Amgen, Novartis, Pfizer, Astellas: Honoraria. Wei: Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Macrogenics: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: This presentation will discuss the use of venetoclax in targeting measurable residual disease and early relapse of acute myeloid leukemia.

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A Laboratory Based Scoring System Predicts Early Treatment in Rai 0/Binet a CLL

Blood ◽

10.1182/blood-2018-99-112162 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4399-4399

Author(s):

Jared A Cohen ◽

Francesca Maria Rossi ◽

Riccardo Bomben ◽

Lodovico Terzi-di-Bergamo ◽

Pietro Bulian ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Scoring System ◽

Research Funding ◽

Early Stage ◽

Recursive Partitioning ◽

Risk Groups ◽

Advisory Committees ◽

Early Stage Disease ◽

Training Cohort

Abstract Introduction: Observation is the standard of care for asymptomatic early stage chronic lymphocytic leukemia (CLL) however these cases follow a heterogenous course. Recent studies show novel biomarkers can delineate indolent from aggressive early stage disease and current clinical trials are exploring the role of early intervention in high risk cases. Although several scoring systems have been established in CLL, most are designed for overall survival, do not circumscribe early stage disease, and require cumbersome calculations relying on extensive laboratory and clinical information. Aim: We propose a novel laboratory-based prognostic calculator to risk stratify time to first treatment (TTFT) in early stage CLL and guide candidate selection for early intervention. Methods: We included 1574 cases of early stage CLL in an international cohort from Italy, the United Kingdom and the United States using a training-validation model. Patient information was obtained from participating centers in accordance with the Declaration of Helsinki. The training cohort included 478 Rai 0 cases from a multicenter Italian cohort, all referred to a single center (Clinical and Experimental Onco-Hematology Unit of the Centro Riferimento Oncologico in Aviano, IT) for immunocytogenetic lab analyses. Considering TTFT as an endpoint, we evaluated 8 variables (age>65, WBC>32K, 17p-, 11q-, +12, IGHV status, CD49d+, gender) with univariate and multivariate Cox regression internally validated using bootstrapping procedures. FISH thresholds were 5% for 11q-, and +12 and 10% for 17p-. Cases were categorized according to the hierarchical model proposed by Dohner. IGHV status was considered unmutated at ≥98%. CD49d+ was set at >30%. WBC cutoff of >32K was established by maximally selected log rank analysis. Variables were weighted based on the proportion of their normalized hazard ratios rounded to the nearest whole integer. We used recursive partitioning for risk-category determination and Kaplan-Meier analysis to generate survival curves. We compared the concordance index (C-index) of our model with the CLL international prognostic index (CLL-IPI) for 381/478 cases in the training cohort with available beta-2-microglobulin data and for all validation cohorts. We used 3 independent single-center cohorts for external validation. Results: The training cohort had 478 cases of Rai 0 CLL with a median (95% CI) TTFT of 124 months (m) (104-183m). Five prognostic variables emerged with respect to TTFT, and each assigned a point value of 1 or 2 according to their respective normalized HR values as follows: 17p-, and UM IGHV (2 pts); 11q-, +12, and WBC>32K (1 pt). We identified three risk groups, based on point cut-offs of 0, 1-2, and 3-5 established by recursive partitioning analysis with a median (95% CI) TTFT of 216m (216-216m), 104m (93-140m) and 58m (44-68m) (p<0.0001, C-index 0.75) for the low, intermediate, and high-risk groups, respectively (figure 1). A comparison with the CLL-IPI was possible in 381 cases with available beta-2-microglobulin data. In this subset, the C-index was 0.75 compared to 0.68 when patient risk groups were split according to the CLL-IPI. The scoring system was then validated in 3 independent cohorts of early stage CLL: i) Gemelli Hospital in Rome, IT provided 144 Rai 0 cases. Median (95% CI) TTFT was 86m (80-94m, 95% CI). Median (95% CI) TTFT for the low, intermediate and high-risk groups was 239m (239-239m), 98m (92-132m) and 85m (60-109m) respectively (p=0.002 between low and intermediate groups, p=0.09 between intermediate and high groups; C-index 0.64 v 0.60 for CLL-IPI). ii) Cardiff University Hospital in Wales, UK provided 395 Binet A cases. Median (95% CI) TTFT was 74 m (67-81m) overall and NR, 111m (97-146m) and 70m (29-114m) for the low, intermediate and high-risk groups respectively (p<0.001 between low and intermediate groups, p=0.009 between intermediate and high groups; C-index 0.63 v 0.63 for CLL-IPI). iii) Mayo Clinic in Rochester, MN provided 557 Rai 0 cases. Median (95% CI) TTFT was 127m (96m-NR) overall and NR, 76m (64m-NR) and 36m (31-59m) for the low, intermediate and high-risk groups respectively (p<0.0001; C-index 0.72 v 0.68 for CLL-IPI). Conclusion: We present a novel laboratory-based scoring system for Rai 0/Binet A CLL to aid case selection in risk-adapted treatment for early disease. Further comparison to existing indices is needed to verify its utility in the clinical setting. Disclosures Zaja: Novartis: Honoraria, Research Funding; Takeda: Honoraria; Abbvie: Honoraria; Celgene: Honoraria, Research Funding; Amgen: Honoraria; Janssen: Honoraria; Sandoz: Honoraria. Fegan:Roche: Honoraria; Napp: Honoraria; Janssen: Honoraria; Gilead Sciences, Inc.: Honoraria; Abbvie: Honoraria. Pepper:Cardiff University: Patents & Royalties: Telomere measurement patents. Parikh:AstraZeneca: Honoraria, Research Funding; Janssen: Research Funding; MorphoSys: Research Funding; Abbvie: Honoraria, Research Funding; Gilead: Honoraria; Pharmacyclics: Honoraria, Research Funding. Kay:Janssen: Membership on an entity's Board of Directors or advisory committees; Acerta: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity Pharm: Membership on an entity's Board of Directors or advisory committees; Cytomx Therapeutics: Membership on an entity's Board of Directors or advisory committees; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Agios Pharm: Membership on an entity's Board of Directors or advisory committees.

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

Blood ◽

10.1182/blood-2018-99-120155 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3011-3011 ◽

Cited By ~ 1

Author(s):

Lucia Masarova ◽

Jorge E. Cortes ◽

Keyur P. Patel ◽

Susan M. O'Brien ◽

Graciela M. Nogueras González ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Phase 2 ◽

Advisory Committees ◽

Free Survival ◽

Genetics Research ◽

Phase 2 Study ◽

Grade 3

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

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

Blood ◽

10.1182/blood-2019-129827 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1899-1899 ◽

Cited By ~ 2

Author(s):

Norbert Grząśko ◽

Stefan Knop ◽

Hartmut Goldschmidt ◽

Marc S Raab ◽

Jan Dürig ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Board Of Directors ◽

Research Funding ◽

Proteasome Inhibitors ◽

Immunomodulatory Drugs ◽

Phase 2 ◽

Advisory Committees ◽

Phase 2 Study ◽

Grade 3

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

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Final Results of a Phase 1/2a, Dose Escalation Study of Pvx-410 Multi-Peptide Cancer Vaccine in Patients with Smoldering Multiple Myeloma (SMM)

Blood ◽

10.1182/blood.v128.22.2124.2124 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2124-2124 ◽

Cited By ~ 2

Author(s):

Ajay K Nooka ◽

Michael Wang ◽

Andrew J. Yee ◽

Sheeba K. Thomas ◽

Elizabeth K. O'Donnell ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Cell Population ◽

Research Funding ◽

Low Dose ◽

Memory Cell ◽

Fold Increase ◽

Post Treatment ◽

Target Dose ◽

Advisory Committees

Abstract Introduction: PVX-410 Multi-Peptide Vaccine (OncoPep, Inc.) is being developed for the treatment of SMM. PVX-410 consists of 4 human leukocyte antigen-A2 (HLA-A2), synthetic 9-mer peptides from unique regions of 3 multiple myeloma (MM)-associated antigens (XBP1 US184-192; XBP1 SP367-375; CD138260-268; and CS1239-247) emulsified in Montanide® ISA-720 VG (Seppic). Adults with SMM at high risk of progression to active MM who were HLA-A2-positive were eligible. The primary objective was to determine the tolerability of PVX-410, initially as monotherapy and then in combination with lenalidomide (len). Immune and disease response also were assessed. Methods: All patients received 6 bi-weekly subcutaneous injections of PVX-410, initially at the low-dose of 0.4 mg (0.1 mg/peptide or 0.4 mg total) and then at the target dose of 0.8 mg (0.2 mg/peptide or 0.8 mg total). In the PVX-410+len cohort, patients received 3 standard cycles of len (25 mg orally on Days 1-21 every 28 days, without dexamethasone). All patients also received 0.5 mL (1 mg) Hiltonol® (poly-ICLC) (2 mg/mL) via intramuscular injection at the time of PVX-410 administration. Patients were followed for 12 months post-treatment. Blood samples for immune response evaluation were collected at Week 0 (Baseline; pre-dose), 2, 4, and 8 weeks during treatment and at Months 1, 3, 6, 9, and 12 post-treatment. Disease response was assessed at the same time points, except Weeks 0 and 2, using International Myeloma Working Group and modified European Group for Blood and Bone Marrow Transplant criteria. Results: Overall, 22 patients with high-risk SMM were enrolled (age range 39 to 82 years), of whom 12 received PVX-410 monotherapy (3 low-dose; 9 target dose) and 10 received PVX-410 (target dose) + len. All 22 patients have either completed the study through post-treatment Month 12 (N=15) or discontinued before that time (N=7). PVX-410 was well-tolerated, with a treatment-emergent adverse event (TEAE) profile consistent with that expected, based on previous clinical studies with peptide vaccines. All (100%) 22 patients experienced at least 1 TEAE. Among monotherapy patients, the most common TEAEs were injection site pain (50%); fatigue (33%); and injection site erythema, pyrexia, and rash (each 25%). The TEAE profile of PVX-410+len was generally similar to that see with PVX-410 alone, although the incidence of commonly reported TEAEs was higher with the combination than with PVX-410 alone. The majority of TEAEs were Grade 1 in intensity and occurred within 2 days after study vaccine injection. No deaths or study drug-related serious adverse events were reported. PVX-410 was immunogenic as monotherapy (10/11 patients) and in combination with len (9/9), as demonstrated by an increase in the percentage of tetramer+ cells (≥1.5-fold increase over baseline) and interferon-gamma+ (IFN-γ) cells (≥2.0-fold increase over baseline) in the CD3+CD8+ cell population. This increase was statistically higher for IFN-γ+ cells after 2 vaccinations in the combination group. The CD8+ T-lymphocyte response was also characterized by increases from baseline in interleukin-2-, tumor necrosis factor-alpha-, and CD137-positive cells in both treatment groups. Furthermore, decreases in the naïve memory cell population and increases in the effector memory cell population were seen post-vaccination; this response was enhanced by the addition of len. Among the 12 monotherapy patients, 5 (2 low-dose; 3 target-dose) experienced progression to active disease within 9 months post-treatment, and 7 had stable disease (SD) at follow-up Month 12. Among the 9 evaluable PVX-410+len patients, 5 achieved at least a minimal response, with 1 patient achieving a partial response; 1 of these 5 patients then progressed to MM by Month 5 post-treatment. Four patients had SD at follow-up Month 12. Conclusions: Six doses of PVX-410 were well tolerated in 22 patients with high-risk SMM, with an expected AE profile both as monotherapy and in combination with len. An immune response to PVX-410 was seen with PVX-410 alone, which was enhanced by the addition of len. Based on these promising findings to date, investigation of PVX-410 in combination with immunogenic agents is continuing. Disclosures Nooka: Spectrum, Novartis, Onyx pharmaceuticals: Consultancy. Wang:Acerta: Consultancy, Research Funding; Asana biosciences, Beigene, Celgene, Juno, Kite, Onyx, Pharmacyclics: Research Funding; BeiGene: Research Funding; Juno Therapeutics: Research Funding; Kite Pharma: Research Funding; Dava Oncology: Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Asana BioSciences: Research Funding. Kaufman:Incyte: Consultancy; Pharmacyclics: Consultancy; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Peterkin:OncoPep: Employment. Lonial:Celgene: Consultancy; Onyx: Consultancy; Janssen: Consultancy; BMS: Consultancy; Onyx: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Novartis: Consultancy; BMS: Consultancy; Janssen: Consultancy; Merck: Consultancy; Millenium: Consultancy. Richardson:Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Raje:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Eli Lilly: Research Funding.

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Pmd-107: Marizomib, Pomalidomide and Low Dose-Dexamethasone Combination Study in Relapsed/Refractory Multiple Myeloma (NCT02103335): Full Enrollment Results from a Phase-1 Multicenter, Open Label Study

Blood ◽

10.1182/blood.v128.22.3326.3326 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3326-3326 ◽

Cited By ~ 4

Author(s):

Andrew Spencer ◽

Simon Harrison ◽

Jacob P. Laubach ◽

Jeffrey Zonder ◽

Ashraf Z Badros ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Low Dose ◽

Employment Equity ◽

Advisory Committees ◽

Refractory Multiple Myeloma ◽

Heavily Pretreated ◽

Equity Ownership

Abstract Marizomib (MRZ) is a novel, irreversible, pan subunit proteasome inhibitor (PI) with preclinical evidence demonstrating in vitro and in vivo activity in multiple myeloma (MM). This study was designed to evaluate the safety and antimyeloma activity of pomalidomide (POM), MRZ and low dose dexamethasone (Lo-DEX) (PMD) in patients with relapsed and refractory multiple myeloma (RRMM). Thirty-eight heavily pretreated patients with RRMM were enrolled [dose-escalation cohort (n=14); recommended Phase 2 dose (RP2D) cohort (n=24)]. IV MRZ (0.3 to 0.5 mg/m2) was administered on Days (D) 1, 4, 8, 11; POM (3 or 4 mg) on D1 through 21; and Lo-DEX (5 or 10 mg) on D1, 2, 4, 5, 8, 9, 11, 12, 15, 16, 22, 23 of every 28-D cycle. Patients received a median of 4 (range 1-9) prior lines of therapy; 100% received prior lenalidomide (LEN) and bortezomib (BTZ), 34% carfilzomib (CFZ), and 50% thalidomide. 53% of patients were refractory to both LEN and BTZ and 21% were refractory to LEN, BTZ, and CFZ. There were no dose limiting toxicities during the study. The most common study treatment related ≥Grade 3 adverse events (AEs) were neutropenia (11/38 pts: 29%), pneumonia (4/38 pts 11%), anemia (4/38 pts; 11%), thrombocytopenia (4/38 pts; 11%), and febrile neutropenia (2/38 pts; 5%), with two grade 4 AEs (neutropenia related to POM and viral infection related to DEX), and one grade 5 AE (cardio-respiratory arrest from a suspected PE related to POM). Overall, MRZ was well tolerated, did not add to the incidence or severity of POM/Lo-DEX AEs and the regimen may have fewer hematological and infectious AEs compared to that observed with POM/Lo-DEX. MRZ pharmacokinetic analysis revealed that it was rapidly cleared with a short T1/2 (6.2-11mins) and a large volume of distribution (41-86L) suggesting extensive tissue distribution. Pharmacodynamic analysis demonstrated rapid and robust inhibition of chymotrypsin-like activity in both packed whole blood (PWB) and peripheral blood mononuclear cells (PMBCs), reflecting the irreversible binding nature of MRZ. Evolving inhibition of trypsin-like and caspase-like proteasome activity was also observed in PWB and PBMC with continued dosing. The overall response rate (ORR) and clinical benefit rate (CBR) for the 36 response evaluable patients was 53% (19/36) and 64% (23/36), respectively (Table 1). Subpopulation analysis demonstrated an ORR of 50% (5/10) in high risk cytogenetic patients, 56% (10/18) in LEN/BTZ refractory patients, 71% (5/7) in LEN/BTZ/CFZ refractory patients and 80% (8/10) in CFZ refractory patients. These data compare favorably against POM/Lo-Dex with a near doubling of ORR in both the total patient population and the double refractory patients. Substantial activity in high-risk patients that are triple refractory and in patients that are refractory to CFZ in prior last regimen was observed. MRZ activity in RRMM patients exposed and/or refractory to multiple PIs is likely a consequence of its unique pan proteasome subunit inhibitory actions. In conclusion, MRZ in combination with POM and Lo-DEX was well tolerated and demonstrated promising activity in heavily pretreated, high-risk RRMM patients. Table 1 Table 1. Disclosures Harrison: Janssen-Cilag: Research Funding, Speakers Bureau; Celgene: Honoraria. Zonder:Prothena: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Pharmacyclics: Other: DSMC membership. Khot:Amgen: Honoraria; Janssen: Consultancy; Pfizer: Speakers Bureau. Anderson:C4 Therapeutics: Equity Ownership; Millennuim: Membership on an entity's Board of Directors or advisory committees; Oncoprep: Equity Ownership; C4 Therapeutics: Equity Ownership; Gilead: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Acetylon: Equity Ownership; Acetylon: Equity Ownership; Oncoprep: Equity Ownership; Millennuim: 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; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. MacLaren:Triphase Accelerator: Employment, Equity Ownership. Reich:Triphase Accelerator: Consultancy. Trikha:Encycle Therapeutics: Consultancy, Equity Ownership; Triphase Accelerator: Employment, Equity Ownership. Richardson:Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Phase 2 Study of Tirabrutinib (ONO/GS-4059), a Second-Generation Bruton's Tyrosine Kinase Inhibitor, Monotherapy in Patients with Treatment-Naïve or Relapsed/Refractory Waldenström Macroglobulinemia

Blood ◽

10.1182/blood-2019-124614 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 345-345 ◽

Cited By ~ 10

Author(s):

Wataru Munakata ◽

Naohiro Sekiguchi ◽

Rai Shinya ◽

Kenshi Suzuki ◽

Hiroshi Handa ◽

...

Keyword(s):

Research Funding ◽

Kinase Inhibitor ◽

Performance Status ◽

Phase 2 ◽

Ecog Performance Status ◽

Advisory Committees ◽

Waldenström Macroglobulinemia ◽

Waldenstrom Macroglobulinemia ◽

Phase 2 Study ◽

Treatment Naïve

BACKGROUND Waldenström macroglobulinemia (WM) is a lymphoplasmacytic lymphoma in which bone marrow is infiltrated by immunoglobulin M (IgM)-producing clonal lymphoplasmacytic cells. Tirabrutinib (ONO/GS-4059) is a second-generation Bruton's tyrosine kinase inhibitor with greater selectivity than ibrutinib. We performed a prospective, multicenter phase 2 study of tirabrutinib in patients with treatment-naïve (TN) or relapsed/refractory (R/R) WM. METHODS Patients with TN or R/R WM, serum IgM ≥500 mg/dL, ECOG performance status ≥1, and normal end-organ function were treated with tirabrutinib 480 mg once daily. The primary endpoint was major response rate (MRR, ≥ partial response [PR]) assessed by an independent review committee (IRC) according to the criteria of the VIth International Workshop on Waldenström Macroglobulinemia (IWWM) (Owen RG et al. Br J Haematol. 2013). Secondary endpoints included overall response rate (ORR, ≥ minor response [MR]), time to major response (TTMR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS Twenty seven patients (18 TN and 9 R/R) were treated as of July 3, 2019, and the median follow-up duration was 6 months. The median age of patients was 71 years (range 50-83), and 20 patients (74.1%) had ECOG performance status 0. Median serum IgM was 3600 mg/dL (range 730-6930). Median number of prior therapies among R/R patients was 2 (range 1-7), and 8 patients had received prior rituximab monotherapy or rituximab-containing chemotherapy. IRC-assessed MRR was 77.8% (95%CI: 52.4-93.6) in TN and 88.9% (95%CI: 51.8-99.7) in R/R. IRC-assessed ORR was 94.4% (95%CI: 72.7-99.9) in TN and 100% (95%CI: 66.4-100.0) in R/R. Median TTMR was 1.9 months (range 1.0-5.7) in TN and 2.1 months (range 1.0-3.7) in R/R. Median DOR, PFS, and OS were not reached. The most common adverse events (AEs) at any grade were rash (41%), neutropenia (22%), and leukopenia (15%), of which most were grade 1 or 2. Grade ≥3 AEs were neutropenia (7.4%), leukopenia, lymphopenia, atypical mycobacterial infection, rash erythematous, and erythema multiforme (3.7% each); there was no grade 4 or 5 AE. There were 4 bleeding events and all events were grade 1: mouth hemorrhage, petechiae, anal hemorrhage, and hematoma (3.7% each). Rash-related events occurred in 56% of patients and 2 events were grade 3: erythema multiforme and rash erythematous (3.7% each) which were manageable. CONCLUSION Although the follow-up time was relatively short, the results of this phase 2 study showed that tirabrutinib monotherapy is a highly effective treatment option for patients with TN and R/R WM, with a manageable safety profile. Disclosures Munakata: Ono: Research Funding. Sekiguchi:Ono, A2 Healthcare, Astellas, Janssen, Merck Sharp & Dohme. Otsuka, Pfizer, PPD SNBL, Sumitomo Dainippon Pharma, Daiichi Sankyo Company, Bristol-Myers Squibb: Research Funding. Shinya:Chugai Pharmaceutical Co., Ltd: Membership on an entity's Board of Directors or advisory committees. Suzuki:Ono: Research Funding; BMS: Honoraria, Research Funding; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Handa:Ono: Research Funding. Shibayama:Astellas, Teijin, MSD, Shionogi, Eisai, Sumitomo Dainippon, Taiho, Nippon Shinyaku: Research Funding; Takeda, Novartis, Janssen, Chugai, Eisai, Mundi Pharma, Ono, Otsuka, Kyowa Kirin, Sumitomo Dainippon, AstraZeneca, Avvie, DaiichiSankyo, Fujimoto, Nippon Shinyaku, Sanofi, Bristol-Myers Squibb, Pfizer: Honoraria; Celgene, Chugai, Eisai, AstraZeneca: Membership on an entity's Board of Directors or advisory committees. Endo:Ono: Research Funding. Terui:Bristol-Myers Squibb K.K.: Research Funding; Bristol-Myers Squibb, Celgene, Janssen, Takeda, MSD, Eisai, Ono, and Chugai-Roche Pharmaceuticals Co.,Ltd.: Honoraria. Iwaki:Ono: Research Funding. Fukuhara:AbbVie: Research Funding; Ono Pharmaceutical Co., Ltd.: Honoraria; Nippon Shinkyaku: Honoraria; Mundi: Honoraria; Celgene Corporation: Honoraria, Research Funding; Takeda Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Zenyaku: Honoraria; Gilead: Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria; Eisai: Honoraria, Research Funding; Janssen Pharma: Honoraria; Kyowa-Hakko Kirin: Honoraria; Mochida: Honoraria; Bayer: Research Funding; Solasia Pharma: Research Funding. Tatetsu:Ono: Research Funding. Iida:Astellas: Research Funding; Abbvie: Research Funding; Gilead: Research Funding; Daichi Sankyo: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; MSD: Research Funding; Teijin Pharma: Research Funding; Kyowa Kirin: Research Funding; Chugai: Research Funding; Sanofi: Research Funding; Celgene: Honoraria, Research Funding. Shiibashi:Ono: Employment. Izutsu:Chugai, Celgene, Daiichi Sankyo, Astra Zeneca, Eisai, Symbio, Ono, Bayer, Solasia, Zenyaku, Incyte, Novartis, Sanofi, HUYA Bioscience, MSD, Astellas Amgen, Abbvie, ARIAD, Takeda, Pfizer: Research Funding; Eisai, Symbio, Chugai, Zenyaku: Research Funding; Eisai, Chugai, Zenyaku: Honoraria; Celgene: Consultancy; Kyowa Kirin, Eisai, Takeda, MSD, Chugai, Nihon Medi-physics, Janssen, Ono, Abbvie, Dainihon Sumitomo, Bayer, Astra Zeneca, HUYA Japan, Novartis, Bristol-Byers Squibb, Mundi, Otsuka, Daiichi Sankyo, Astellas, Asahi Kasei: Honoraria. OffLabel Disclosure: Tirabrutinib. Clinical trial for WM/LPL.

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