Final Results of a Phase I/II Trial of the Combination of Concurrent Lenalidomide, Thalidomide and Dexamethasone in Patients with Relapsed and/or Refractory Myeloma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 75-75 ◽  
Author(s):  
Jatin J. Shah ◽  
Robert Z. Orlowski ◽  
Sheeba K. Thomas ◽  
Raymond Alexanian ◽  
Michael Wang ◽  
...  
Keyword(s):  
Research Funding ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Refractory Disease ◽  
Concurrent Administration ◽  
Advisory Committees ◽  
Minor Response ◽  
Elevated Creatinine ◽  
A Minor

Abstract Abstract 75 Background: The combination of lenalidomide (Len) and dexamethasone (Dex) has demonstrated overall response rates (ORR) of 60% in relapsed and/or refractory multiple myeloma (RRMM). Preclinical studies have demonstrated Len resistance is mediated via the Wnt/β-catenin pathway, which can be reversed by thalidomide (Thal). The concurrent administration of Len, Thal and Dex has not previously been evaluated in RRMM. Our hypothesis proposed that the concurrent administration of Len, Thal and Dex may overcome Len resistance and improve response rates in patients with relapsed and/or refractory myeloma. The aim of this study was to determine the maximum tolerated dose (MTD) of the combination of Len/Thal/Dex and evaluate efficacy of the combination. Methods: The primary objective of the phase 1 portion was to determine the MTD, and the primary objective of the phase 2 was to determine the overall response rate. Patients (pts) with relapsed and/or refractory myeloma with ≥1 line of therapy were eligible, and received dexamethasone in pulse dose fashion in cycles 1–2, and weekly Dex in cycles 3 and beyond. The protocol was amended to enroll an additional 10 patient cohort who were Len refractory and received Dex on days 1, 8, 15 and 22 starting with cycle 1. All patients received anticoagulation with warfarin or low molecular weight heparin. Phase 1 data has been previously presented, and herein we present the final data from the phase 1/2. Adverse events (AEs) were graded by NCI-CTCAE v4, and responses were assessed by the modified International Uniform Response Criteria. Results: 64 patients were enrolled who had a median of 4 prior lines of therapy (range: 1–12), a median age of 65 (range: 36–86), and 40/64 (63%) were males. 60/64 patients had available cytogenetic data; and 52% (31/60) had high risk cytogenetics, including 40% (24/60) with deletion 13; 13% (8/60) with deletion 17p; 5% (3/60) with t(4:14); and 12% (7/60) with t(11:14). These patients were heavily pretreated, with 66% (42/64) having Len refractory disease; 56% (36/64) had prior Thal; and 77% (49/64) had prior autologous transplantation. The maximum tolerated dose used for phase 2 was Len 25 mg/Thal 100 mg/Dex 40 mg. Among the 64 patients, 59/64 patients were evaluable for efficacy, excluding 5 who withdrew consent during cycle 1. Among the 59 evaluable patients, 56% (34/59) had a partial remission (PR) or greater, and 73% (43/59) had at least a minor response (MR). 13% (8/60) achieved a complete remission (CR/near CR (nCR)), 7% (4/60) had a very good partial remission (VGPR), 37% (22/60) had a PR, 15% (9/60) had MR, 15% had stable disease (SD), and 12% (7/60) had progressive disease (PD).Among the 42 patients who were Len refractory, 38 were efficacy evaluable. The ORR (≥MR) was 63% (24/38) and ≥PR was 39% (15/38), and achieved at least a minor response. 2/38 had a CR/nCR, 1/38 a VGPR, 12/38 a PR, 9/38 a, MR, 8/38 had SD, and 6/38 had PD.Grade 1–4 AEs regardless of causality occurring in >20% of patients included anemia (26/56), thrombocytopenia (29/56), neutropenia (21/56), diarrhea (24/56), constipation (32/56), nausea (15/56), dizziness (32/56), memory changes (21/56), blurred vision (24/56), fatigue (41/56), elevated creatinine (16/56), dyspnea (32/56), transaminitis (11/56), pneumonia (14/56), upper respiratory infection (16/56), hyperglycemia (18/56), hypomagnesemia (23/56), hypokalemia (16/56), hyponatermia (14/56), and hypophosphatemia (15/56). Grade ≥3 AEs regardless of causality included anemia (10/56), thrombocytopenia (12/56), neutropenia (15/56), diarrhea (2/56), dizziness (5/56), fatigue (17/56), elevated creatinine (5/56), and pneumonia (10/56).One venous thromboembolic (VTE) event was observed. No treatment emergent G3/4 peripheral neuropathy was seen. 1 patient died on study with cardiac arrest at home. Conclusions: The recommended dose for this regimen is Len 25 mg/Thal 100 mg/Dex 40 mg. The combination is well tolerated with an expected side effect profile and, importantly, limited incidence of VTE and treatment emergent neuropathy. The ORR of 73% was higher than would be expected of the two-drug regimen of Len/Dex. The preserved activity in Len-refractory disease, with a response rate of 63%, supports the hypothesis that the combination of Len and Thal can overcome lenalidomide resistance, and provides a new treatment option for patients with Len-refractory disease. Disclosures: Shah: Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Off Label Use: This presentation will include information about panobinostat, which is not yet approved for use in patients with multiple myeloma. Orlowski:Celgene: Honoraria, Research Funding. Thomas:celgene: Research Funding.

scholarly journals Deep and Durable Responses with Selinexor, Daratumumab, and Dexamethasome (SDd) in Patients with Multiple Myeloma (MM) Previously Exposed to Proteasome Inhibitors and Immunomodulatory Drugs: Results of Phase 1b Study of SDd

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 599-599 ◽  
Author(s):  
Cristina J Gasparetto ◽  
Suzanne Lentzsch ◽  
Gary J. Schiller ◽  
William Bensinger ◽  
Nizar Bahlis ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Nuclear Export ◽  
Research Funding ◽  
Phase 1 ◽  
Proteasome Inhibitors ◽  
Maximum Tolerated Dose ◽  
Immunomodulatory Drugs ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Introduction - Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound that binds and inactivates Exportin 1 (XPO1). Selinexor with low dose dexamethasone (Sd) or in with protesome inhibitors (PIs) or immunomodulatory drugs (IMiDs), has shown anti-MM activity in patients (pts) with relapsed or refractory MM. Daratumumab (Dara), an anti-CD38 mAb, is approved for the treatment of heavily pretreated MM is limited by short PFS and an ORR of ~21% in quad-refractory MM. Selinexor in combiniation with dara have shown preclinical synergistic killing of MM cells. Methods - Pts were eligible if they had received ≥ 3 prior lines of anti-myeloma therapy, including a PI and an IMiD. Selinexor was dose-escalated in 2 concurrent cohorts: once-weekly (QW, at 100 mg) or twice-weekly (BIW, at 60 mg). Dara was 16 mg/kg IV (recommended schedule) and dexamethasone (dex) was 40 mg QW or 20 mg BIW. The objectives were to determine the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), safety, tolerability and preliminary efficacy of the combination of this SDd combination in pts with PI/IMiD refractory MM Results - As of Jul 20th2018, 25 pts (11 males / 14 females) have been enrolled. Three pts have been enrolled into the 60 mg BIW and 22 pts in the 100 mg QW cohorts. Pts have a median age of 68 years and a median of 3 (range, 2 - 10) prior treatment regimens. Common SDd treatment related adverse events included (all grades, grades 3/4): thrombocytopenia (58%, 42%), leukopenia (54%, 38%), anemia (46%, 29%), nausea (50%, 0%) and fatigue (46%, 8%). Two dose limiting toxicities (DLTs) were reported in the 60 mg BIW cohort: G3 thrombocytopenia and G2 fatigue requiring dose reduction in selinexor to 100 mg QW. In the 100 mg QW escalation cohort, 6 pts enrolled, 5 evaluable, with no DLTs. This cohort was expanded and enrollment is ongoing. A total of 21 pts were evaluable for response. In 19 dara-naïve pts, the ORR was 74% (5 VGPR, 9 PR, 2 MR, 2 SD, 1 PD), including 3 unconfirmed PRs, 1 unconfirmed MR. In the 2 pts with dara refractory MM, there was one PD and one SD. The longest duration of therapy is 13 months. Based on tolerability and efficacy, the RP2D of SDd is selinexor 100 mg, daratumumab 16 mg/kg and dex 40 mg, administered QW. Conclusions - Selinexor 100 mg QW can be combined safely with dara (per approved dosing) and dex. The preliminary ORR of 74% with SDd in patients with PI/IMiD refractory MM who are dara naïve is promising and compares favorably to 21% ORR of Dara and Sd in quad refractory myeloma. This once weekly regimen is well tolerated with no major organ toxicities to date. Data from the full phase 1 dose expansion will be presented. Disclosures Gasparetto: Takeda: Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel; Janssen: Consultancy, Honoraria, Other: Travel; Celgene: Consultancy, Honoraria, Other: Travel, Research Funding. Schiller:Celator/Jazz Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding. Bensinger:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; amgen: Speakers Bureau; Takeda: Speakers Bureau. Bahlis:Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria. White:Amgen, Celgene, Janssen, Takeda: Honoraria. Sebag:Amgen Canada: Membership on an entity's Board of Directors or advisory committees; Takeda Canada: Membership on an entity's Board of Directors or advisory committees; Janssen Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene Canada: Membership on an entity's Board of Directors or advisory committees. Venner:Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria; Takeda: Honoraria. Leblanc:Janssen Inc.: Membership on an entity's Board of Directors or advisory committees; Amgen Canada: Membership on an entity's Board of Directors or advisory committees; Celgene Canada: Membership on an entity's Board of Directors or advisory committees; Takeda Canada: Membership on an entity's Board of Directors or advisory committees. Chen:Amgen: Honoraria. Shah:Karyopharm Therapeutics: Employment. Jeha:Karyopharm Therapeutics: Employment. Saint-Martin:Karyopharm Therapeutics: Employment. Kauffman:Karyopharm Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Shacham:Karyopharm Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Lipe:Celgene: Consultancy.

Phase II Trial of Weekly Bortezomib in Combination with Rituximab in Untreated Patients with Waldenstrom's Macroglobulinemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3752-3752
Author(s):  
Irene M. Ghobrial ◽  
Swaminathan Padmanabhan ◽  
Ashraf Z. Badros ◽  
Renee Leduc ◽  
Meghan Rourke ◽  
...  
Keyword(s):  
Herpes Zoster ◽  
Board Of Directors ◽  
Research Funding ◽  
Waldenström’S Macroglobulinemia ◽  
Advisory Committees ◽  
Minor Response ◽  
Waldenstrom's Macroglobulinemia ◽  
A Minor ◽  
Waldenström's Macroglobulinemia

Abstract Abstract 3752 Poster Board III-688 INTRODUCTION This study aimed to determine activity and safety of weekly bortezomib and rituximab in patients with untreated Waldenstrom's Macroglobulinemia (WM). Prior studies using twice a week bortezomib in this population showed high responses, but significant neuropathy. METHODS Patients who had symptomatic WM and were not previously treated were eligible. All patients received bortezomib IV weekly at 1.6 mg/m2 on days 1, 8, 15, q 28 days x 6 cycles, and rituximab 375 mg/m2 weekly on cycles 1 and 4. Dexamethasone was not added. Primary endpoint was the percent of patients with at least a minor response. Patients were encouraged to receive herpes zoster prophylaxis but it was not mandated. RESULTS Twenty-six patients were treated. At least minimal response or better was observed, assessed using serum protein electropheresis, in 24/26 cases (92%) with 2 patients (8%) in complete remission (CR)/near CR, 15 (54%) in partial response (PR), and 7(27%) in minimal response (MR). Two patients (8%) had stable disease. By using IgM by nephlometry, all 26 patients (100%) had at least a minor response, with 2 (8%) CR, 15 (58%) in PR and 9 (35%) with minor response. The median time of follow up is 11.2 months (range, 3-18.6). To date, six (23%) patients have developed progressive disease or required a new therapy. A single patient has died due to disease progression. The median progression-free survival and overall survival have not been reached. The most common grade 3 and 4 therapy related adverse events included anemia in 3 patients, lymphopenia in 2 patients; neutropenia, leucopenia, thrombocytopenia, pneumonia, fatigue, allergic reaction and nausea and vomiting in 1 patient for each. Five patients developed grade 2 peripheral neuropathy including 4 did who did not have neuropathy at baseline. It required dose reductions in cycles 4 and 5 and these neuropathies resolved to grade 1 or less with follow up. One case developed grade 1 herpes zoster reactivation in cycle 1. CONCLUSIONS The combination of weekly bortezomib and rituximab showed significant activity and minimal neurological toxicity in patients with untreated WM. Disclosures: Ghobrial: Millennium: Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Anderson:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Richardson:Keryx Biopharmaceuticals: Honoraria. Treon:Millennium: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Genentech: Honoraria, Research Funding, Speakers Bureau. Matous:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cephalon: Membership on an entity's Board of Directors or advisory committees.

Insulin Growth Factor 1 Receptor (IGF-1R) Inhibitor, Linsitinib (OSI-906) in Combination with Bortezomib and Dexamethasone Demonstrates Favorable Safety Prolife and Clinical Activity in Patients with Relapsed/Refractory Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4234-4234
Author(s):  
Suzanne Trudel ◽  
Darrell White ◽  
Martin Gyger ◽  
Jonahtan Kaufmann ◽  
Andrzej Jakubowiak ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Progressive Disease ◽  
Predictive Biomarkers ◽  
Optimal Dose ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Clinical Activity ◽  
Advisory Committees

Abstract Background: Preclinical studies have demonstrated anti-myeloma activity of IGF-1R inhibition against myeloma cell lines, primary patient samples and myeloma xenograft models. Further, it has previously been reported that IGF-1R inhibition enhances the in vitro activity of bortezomib (BTZ), suggesting that IGF-1R inhibitors may improve the clinical efficacy of proteosome inhibitors (PIs). Based upon these observations, we initiated a phase I trial combining linsitinib (a selective IGF-IR an IR inhibitor) with BTZ and dexamethasone (Dex) to clinically evaluate the tolerance and efficacy of this combination. Methods: This study investigates BTZ 1.3 mg/m2 and dex 20 mg given on days 1, 4, 8, and 11 together with escalating doses of oral linsitinib (75-150mg bid) given daily on a 21-day cycle. Continued daily linsitinib and BTZ dosing on days 1, 8, 15 and 22 of a 35-day cycle is allowed after 8 cycles for those benefitting and tolerating treatment. The primary objective is to determine the maximum tolerated dose (MTD) of the combination using a modified 3+3 design with 4 dose cohorts. The secondary objectives are to assess tolerability, pharmacokinetics (PKs), predictive biomarkers and clinical activity. Responses per dosing cohort are assessed by IMWG criteria (plus MRs as per the EBMT). Results: 18 patients (pts) have been enrolled to date into dose levels 75 mg (n=3), 100 mg (n=6), 125 mg (n=5) and 150 mg (n=4). All pts had refractory and/or progressive disease (PD); with a median number of 3 prior lines of treatment (range 1- 4). 67% of pts had received prior immunomodulatory drugs (IMiDs), 78% had prior PI exposure of which 3 were were confirmed refractory, and 50% had received both an IMiD and a PI. Two dose limiting toxicities (DLT) consisting of Gr 4 thrombocytopenia without bleeding (100 mg dose) and a grade 4 ALT (150 mg dose) were observed. All DLTs were reversible. The most common (>20%) adverse events (AEs) were anemia (41%), nausea (35%), fatigue (41%), creatinine increase (47%), thrombocytopenia (88%), cough (35%) and increase in ALT (24%). Most were grade 1-2. The most frequent Gr 3-4 AEs (>10%) regardless of causality were diarrhea (17.6%), back pain (11.8%), thrombocytopenia (47.1%), anemia (17.6%) and neutropenia (11.8%). Additional Gr 3 toxicities included renal insufficiency due to progressive disease (PD), pneumonia, altered mental state (not drug-related) and weight loss. Two deaths occurred; one due to PD, the other due to a cardiac event possibly related to BTZ. IGF-1R expression on CD138 positive cells was confirmed by flow cytometry in 8 pts. Analysis of substrate phosphorylation downstream of IGF-1R at baseline, are ongoing. PK analysis will also be reported. Of 18 pts assessable for response we observed 1 sCR, 1 VGPR, 7 PRs and 2 MR, for an overall response rate (ORR) of 50% and a clinical benefit rate of 61% (PR+MR). 5 pts achieved SD and 2 pts had PD. Of the 2 pts that had PD, neither expressed IGF-1R and of the 3 pts that were progressing on a PI-based regimen immediately prior to starting linistinib and BTZ, one achieved a PR, one an MR and one had SD. The median PFS is 7.3 months. Pts have received a median of 5 cycles of treatment (range 1-22). Dose escalation of linistinib at the 150 mg cohort is currently ongoing. Conclusions: The combination of BTZ and linsitinib is supported by preclinical rationale and has produced stable disease or better in 88% of advanced myeloma patients and appears to be safe and well tolerated. The optimal dose of linsitinib combined with BTZ however, has yet to be defined and data from the complete cohort of pts in addition to studies correlating response to tumor expression of IGF-1R and CD45 will be presented. Disclosures White: Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Jakubowiak:SkylineDx: Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SkylineDx: Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: institutional funding for support of clinical trial conduct, Speakers Bureau. Reece:Amgen: Honoraria; Bristol-Myers Squibb: Research Funding; Onyx: Consultancy; Otsuka: Research Funding; Millennium Takeda: Research Funding; Lundbeck: Honoraria; Merck: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding. Kukreti:Celgene: Honoraria; Amgen: Honoraria; Lundbeck: Honoraria; Roche: Honoraria; Janssen Ortho: Honoraria.

Final Results of Phase 1 MMRC Trial of Selinexor, Carfilzomib, and Dexamethasone in Relapsed/Refractory Multiple Myeloma (RRMM)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 973-973 ◽  
Author(s):  
Andrzej Jakubowiak ◽  
Jagoda Jasielec ◽  
Cara A. Rosenbaum ◽  
Craig E. Cole ◽  
Ajai Chari ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Dose Level ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Advisory Committees ◽  
Treatment Regimens ◽  
Line Of Therapy

Abstract Background There are an increasing number of multiple myeloma (MM) patients (pts) refractory to currently available drugs, including the proteasome inhibitors bortezomib and carfilzomib (CFZ), necessitating development of novel therapeutics. Pre-clinical evaluation of selinexor (SEL), an orally available Selective Inhibitor of Nuclear Export (SINE) compound, demonstrated synergistic myeloma cell death with CFZ and mechanistic rationale for overcoming resistance to CFZ (Rosebeck et al., 2016), providing support for this phase 1 trial. Aims The primary objectives were to assess the maximum tolerated dose (MTD) of a SEL, CFZ and dexamethasone (DEX) combination and to obtain preliminary efficacy data for this novel regimen in RRMM pts. Methods Pts with RRMM who progressed after at least two prior treatment regimens of myeloma therapy were eligible for enrollment. Dose escalation followed the 3+3 design with pts receiving 30 mg/m2 - 40 mg/m2 SEL PO on days (D) 1, 3, 8, 10, 15, 17; 20 mg/m2 - 56 mg/m2 CFZ IV on D 1, 2, 8, 9, 15, 16, and DEX PO (20mg cycles 1-4/ 10mg cycles 5+) in 28-day cycles (C) in up to 5 dose levels. An expansion cohort has enrolled additional pts to a total of 12 CFZ-refractory pts treated at the recommended Phase 2 dose (RP2D). Dose Limiting Toxicities (DLTs) were evaluated through C2D1. Responses were assessed by IMWG criteria plus near complete response (nCR). Results As of July 1st, 2016, the study has completed dose escalation and enrolled a total of 18 pts; 5 at dose level 1 (30 mg/m2 SEL, 20/27 mg/m2 CFZ, 20/10 mg DEX), 3 at dose level 2a (30 mg/m2 SEL, 20/36 mg/m2 CFZ, 20/10 mg DEX), and a total of 10 (7 in dose escalation, 3 in cohort expansion) at dose level 2b (60mg flat dose SEL, 20/27 mg/m2 CFZ and 20/10 DEX). Pts age ranged between 55 to 74 years with a median of 63.5 years; and had a median of 4 prior treatment regimens (range 2-10). Sixteen pts were evaluable for response, all refractory to their last line of therapy. All 16 response evaluable pts were refractory to CFZ, of which 11 were refractory to CFZ combinations as their last line of therapy, including 8 to a KPd combination of CFZ, pomalidomide, and DEX. Fifteen pts were evaluable for DLT and 3 of 18 pts required replacement for DLT evaluation (1 had DEX reduced not due to DLT; 2 did not receive all scheduled C1 doses). In the dose escalation phase, there was one DLT of cardiac amyloidosis (CA) in a pt with history of prior congestive heart failure and CA at baseline. While the maximum tolerated dose (MTD) has not been reached, the RP2D was identified at dose level 2b based on tolerability. Grade 3/4 adverse events (AEs) included: thrombocytopenia (67%), neutropenia (33%), anemia (17%), fatigue (17%), and infections (11%). The most common all grade AEs included: gastrointestinal disorders (78%), thrombocytopenia (73%), fatigue (72%), anemia (47%), dyspnea (33%), and elevated liver and pancreatic enzymes (28%). There were 2 (11%) serious AEs, 1 upper respiratory infection and 1 lower gastrointestinal bleeding. All adverse events were manageable with concomitant medications. Response rates for all evaluable pts were 75% ≥MR (12 of 16), 63% ≥PR, and 25% ≥VGPR. Response rates in CFZ-refractory pts at last line of treatment were 73%, 64%, and 18% respectively. Responses occurred rapidly; after C1 with 75% ≥MR. As of the data cutoff date, 15 pts progressed (between 1 and 14 months on study) and 3 pts remained on treatment (1 - 4 months). Conclusions The combination of SEL, CFZ, and DEX demonstrates encouraging activity and safety in heavily pretreated, mostly CFZ-refractory myeloma. In addition, with 64% PR or better for pts progressing on CFZ, these results provide early clinical evidence that selinexor has the ability to overcome CFZ resistance, warranting further investigation of this regimen in RRMM. Disclosures Jakubowiak: Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SkylineDx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Rosenbaum:Celgene: Speakers Bureau. Chari:Novartis: Consultancy, Research Funding; Amgen Inc.: Honoraria, Research Funding; Pharmacyclics: Research Funding; Array Biopharma: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Zonder:Pharmacyclics: Other: DSMC membership; Celgene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Prothena: Consultancy, Honoraria.

scholarly journals Weekly Carfilzomib with Dexamethasone for Patients with Relapsed or Refractory Multiple Myeloma: Updated Results from the Phase 1/2 Study Champion-1 (NCT01677858)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 373-373 ◽  
Author(s):  
James Berenson ◽  
Alan Cartmell ◽  
Roger Lyons ◽  
Wael Harb ◽  
Dimitrios Tzachanis ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase 1 ◽  
The United States ◽  
Primary Objective ◽  
Phase 2 ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Introduction: Carfilzomib is an irreversible proteasome inhibitor that is approved as a single agent in the United States and other countries for the treatment of relapsed and refractory multiple myeloma (MM); carfilzomib in combination with lenalidomide (LEN) and dexamethasone is also approved in the United States for the treatment of relapsed MM. The approved dose and schedule of carfilzomib is a twice-weekly, 10-min intravenous (IV) infusion on days 1, 2, 8, 9, 15, and 16 of 28-day cycles (starting dose: 20 mg/m2 [days 1 and 2 of cycle 1]; escalated to a target dose of 27 mg/m2 thereafter). Here we present updated results from the multicenter, phase 1/2 study CHAMPION-1 (NCT01677858), which evaluated the safety and efficacy of once-weekly carfilzomib with dexamethasone (Kd) in patients with relapsed or refractory MM. Methods: Patients with relapsed or refractory MM (1-3 prior lines of therapy) were eligible. Patients received carfilzomib as a 30-min IV infusion on days 1, 8, and 15 of 28-day cycles. The phase 1 portion of the study utilized a standard 3+3 dose-escalation scheme. All patients received carfilzomib at 20 mg/m2 on day 1 of cycle 1; patients received 45, 56, 70, or 88 mg/m2 beginning on day 8 of cycle 1 in successive dose-level cohorts until the maximum tolerated dose (MTD) was reached. All patients received dexamethasone 40 mg (IV or oral administration) on days 1, 8, 15, and 22 of cycles 1-8; dexamethasone was omitted on day 22 in cycles ≥ 9. In the phase 2 portion, patients received carfilzomib at the MTD (carfilzomib dose of 20 mg/m2 on cycle 1, day 1; escalating to the MTD for subsequent doses) and dexamethasone at the same dose and schedule. Kd was administered until unacceptable toxicity or disease progression. The primary objective of the phase 1 portion was to determine the MTD of carfilzomib in the Kd regimen; the primary objective of the phase 2 portion was to determine the overall response rate (ORR [≥partial response]). Blood samples were collected for pharmacokinetic and pharmacodynamic analyses. Results: A total of 27 patients were enrolled in phase 1; the MTD of carfilzomib was determined to be 70 mg/m2. Results are presented for all patients treated with Kd at the carfilzomib MTD in both the phase 1b (n=15) and phase 2 (n=89) portions of the study. Among these 104 patients, median patient age was 68.5 years (range, 41-88). Patients received a median of 1 prior line of therapy (range, 1-3); 83% of patients had received prior bortezomib (BTZ), 49% of patients were BTZ-refractory, 27% were LEN-refractory, and 16% were refractory to both BTZ and LEN. Median carfilzomib treatment duration was 7.7 months (range, 0.03-24.2). The ORR was 77% (95% confidence interval [CI]: 68%-85%); the clinical benefit rate (≥minimal response) was 84% (95% CI: 75%-90%). Kaplan-Meier median progression-free survival was 12.6 months (95% CI: 9.0-not estimable). Twelve patients (12%) discontinued treatment due to an adverse event. The most common adverse events of any grade and of grade ≥3 are shown in the Table. Five patients died on study: 1 patient each had cause of death reported as disease progression, acute respiratory distress syndrome, acute respiratory failure, acute kidney injury, and cardiopulmonary arrest. The mean area under the curve and maximum concentration following a 70-mg/m2 carfilzomib dose was 1050 ng×h/mL and 2510 ng/mL, respectively. At 1 hour post dosing of carfilzomib 70 mg/m2, the activity of the predominant chymotrypsin-like proteasome catalytic subunit in peripheral blood mononuclear cells (ie, low molecular mass polypeptide 7) was strongly inhibited (97% inhibition as determined by an enzyme-linked immunosorbent assay [ProCISE]; 93% inhibition as determined by a fluorogenic substrate assay). Conclusions: CHAMPION-1 is the first clinical study to evaluate carfilzomib on a weekly dosing schedule. Once-weekly carfilzomib (70 mg/m2) with dexamethasone demonstrated acceptable safety and tolerability with promising efficacy for patients with relapsed or refractory MM. The dose and schedule of carfilzomib used in the CHAMPION-1 study (20/70 mg/m2) is currently being compared with the regulatory-approved carfilzomib dose and schedule (20/27 mg/m2 administered twice-weekly) in the ongoing, phase 3, superiority study ARROW (NCT02412878). Disclosures Lyons: Amgen: Consultancy, Honoraria; Insyte: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Harb:Onyx Pharmaceuticals: Consultancy. Boccia:Incyte Corporation: Honoraria. Moss:Onyx: Honoraria, Research Funding. Rifkin:Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: 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. Schupp:Amgen: Employment, Equity Ownership. Dixon:Onyx/Amgen: Employment, Equity Ownership. Ou:Onyx/Amgen: Employment, Equity Ownership. Anderl:Onyx/Amgen: Employment, Equity Ownership. Berdeja:Abbvie: Research Funding; BMS: Research Funding; Acetylon: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Onyx: Research Funding; Janssen: Research Funding; Novartis: Research Funding; MEI: Research Funding; Array: Research Funding; Curis: Research Funding.

Phase 1 Study of a Hepcidin Antagonist, LY2787106, in Cancer-Associated Anemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 537-537 ◽  
Author(s):  
Saroj Vadhan-Raj ◽  
Rafat Abonour ◽  
Jonathan W. Goldman ◽  
David A. Smith ◽  
Christopher A. Slapak ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Half Life ◽  
Research Funding ◽  
Serum Iron ◽  
Reticulocyte Count ◽  
Phase 1 ◽  
Primary Objective ◽  
Phase 1 Study ◽  
Advisory Committees ◽  
Post Dose

Abstract BACKGROUND: Hepcidin is a 25-amino-acid peptide that binds to ferroportin and causes internalization and degradation of the hepcidin-ferroportin complex, leading to decreased iron absorption and reduced iron export from reticuloendothelial cells. High hepcidin levels are found in cancer patients (pts) and implicated in anemia pathogenesis. It is hypothesized that neutralizing hepcidin with a monoclonal antibody (mAb) will prevent internalization of ferroportin, restore iron efflux from cells, and allow transferrin-mediated iron transport to the bone marrow to support erythropoiesis. LY2787106 is a fully humanized mAb with high affinity for human hepcidin. This phase 1 study evaluated the safety, PK/PD, and efficacy (effects on serum iron panel [iron, ferritin, transferrin saturation (TSAT), soluble transferrin receptor, reticulocyte hemoglobin], reticulocytosis, and hemoglobin [Hb]) of LY2787106 in cancer pts with anemia. METHODS: A 3+3 design was used in the dose-escalation phase to determine the recommended phase 2 dose of LY2787106. Eligible pts were ≥18 years old with previously treated metastatic/incurable nonmyeloid cancer, Hb <11 g/dL, serum hepcidin ≥5 ng/mL, and ECOG performance status ≤2. The primary objective of Part A was to assess the safety of LY2787106 over a range of doses (0.3-10 mg/kg IV every 3 weeks [Q3W]); the primary objective of Part B was to assess mean change in Hb from baseline to end of Cycle 4 following LY2787106 treatment (10 mg/kg IV weekly) with (Cohort B1) or without (Cohort B2) oral iron supplementation. RESULTS: A total of 33 pts were enrolled (Part A, n=19; Part B, B1, n =7; B2, n=7). Overall, most pts had multiple myeloma (n=14 [42.4%]). Mean age was 65 years (range, 44-88 years). There were 20 females and 13 males. Patients had received a median of 4.5 prior oncology treatments. Mean (SD) Hb level at baseline was 9.2 (0.95) g/dL. The median number of cycles given and completed was 3. No DLTs were seen in Part A, so the MTD was not reached. Data from Part A showed that LY2787106 was well tolerated when given Q3W, had a short half-life (~7 days), and transiently increased serum iron. This supported more frequent weekly dosing in Part B. Treatment-emergent AEs related to LY2787106 occurred in 4 pts (12.1%): increased creatine phosphokinase (grade 2), cardiac failure (grade 3), QT prolongation (grade 1), and neutropenia (grade 2) (1 pt each). Eight pts generated antibodies to LY2787106, but none had hypersensitivity reactions. The LY2787106 PK profile was consistent with reported PK characteristics of a mAb; the profile included a small clearance of ~0.032 L/h associated with limited volume of distribution, resulting in a terminal half-life of ~7 days. LY2787106 PK was independent of time and dose and exposure linear in the 0.3-10 mg/kg dose range. PD data indicated that LY2787106 administration led to a mean maximum 3.48-fold increase (90% CI, 2.5-4.8) from baseline in serum iron at the highest dose (10 mg/kg) in Parts A and B. Serum iron increase was maximal ~24-48 hours post dose, but returned to baseline within a week after dosing. The increase in serum iron paralleled a transient increase in TSAT at dose levels of 1, 3, and 10 mg/kg. This translated to a transient increase in mean ratio of reticulocyte count relative to baseline at 2 weeks post dose in pts who received 10 mg/kg Q3W, but Hb levels remained relatively unchanged. In Part B, a ≥0.5 g/dL increase in Hb from baseline, albeit transient, was seen in 4 pts at Week 12 (2 pts each cohort). No consistent increase in reticulocytes or changes in iron profiles were seen in these pts. Factors that may have confounded the limited change in Hb and reticulocyte profiles included the myelosuppressive effects of chemotherapy concomitantly given during the study, comorbidities, and study-related blood draws. As expected, LY2787106 administration led to increased hepcidin concentrations secondary to hepcidin binding/neutralization by LY2787106 and hepcidin release in response to iron increase. CONCLUSIONS: This is the first clinical trial of a fully humanized mAb against hepcidin. LY2787106 was well tolerated in cancer pts with anemia. Targeting the hepcidin-ferroportin pathway by neutralizing hepcidin resulted in transient iron mobilization and reticulocyte count relative to baseline, thus supporting the role of hepcidin in iron regulation and anemia pathogenesis. Disclosures Vadhan-Raj: Eli Lilly & company: Research Funding. Goldman:Eli LIlly and Company: Research Funding. Slapak:Eli Lilly and Company: Employment. Tiu:Eli Lilly and Company: Employment. Wang:Eli Lilly and Company: Employment. Callies:Eli Lilly and Company: Employment. Cox:Eli Lilly and Company: Employment. Tuttle:Eli Lilly and Company: Employment. Lau:Eli Lilly and Company: Employment. Roeland:Cellceutix: Other: DSMB; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Helsinn: Membership on an entity's Board of Directors or advisory committees; Inform Genomics: Membership on an entity's Board of Directors or advisory committees; TEVA: Speakers Bureau.

scholarly journals A first-in-human, phase 1 study of the NEDD8 activating enzyme E1 inhibitor TAS4464 in patients with advanced solid tumors

2021 ◽  
Author(s):  
Noboru Yamamoto ◽  
Toshio Shimizu ◽  
Kan Yonemori ◽  
Shigehisa Kitano ◽  
Shunsuke Kondo ◽  
...  
Keyword(s):  
Liver Function ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Enzyme Inhibitor ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Open Label ◽  
Phase 1 Study ◽  
Open Label Phase

SummaryBackground This open-label, phase 1 study investigated TAS4464, a potent NEDD8-activating enzyme inhibitor, in patients with advanced/metastatic solid tumors (JapicCTI-173,488; registered 13/01/2017). The primary objective was dose-limiting toxicities (DLTs). Maximum-tolerated dose (MTD) was investigated using an accelerated titration design. Methods The starting 10-mg/m2 dose was followed by an initial accelerated stage (weekly dosing; n = 11). Based on liver function test (LFT) results, a 14-day, 20-mg/m2 dose lead-in period was implemented (weekly dosing with lead-in; n = 6). Results Abnormal LFT changes and gastrointestinal effects were the most common treatment-related adverse events (AEs). DLTs with 56-mg/m2 weekly dosing occurred in 1/5 patients; five patients had grade ≥ 2 abnormal LFT changes at 40- and 56-mg/m2 weekly doses. Further dose escalation ceased because of the possibility of severe abnormal LFT changes occurring. DLTs with weekly dosing with lead-in occurred in 1/5 patients at a 56-mg/m2 dose; MTD could not be determined because discontinuation criteria for additional enrollment at that particular dose level were met. As no further enrollment at lower doses occurred, dose escalation assessment was discontinued. Serious treatment-related AEs, AEs leading to treatment discontinuation, and DLTs were all related to abnormal LFT changes, suggesting that TAS4464 administration could affect liver function. This effect was dose-dependent but considered reversible. Complete or partial responses to TAS4464 were not observed; one patient achieved prolonged stable disease. Conclusions MTD could not be determined due to TAS4464 effects on liver function. Further evaluation of the mechanism of NEDD8-activating enzyme inhibitor-induced abnormal liver function is required. Trial registration number JapicCTI-173,488 (registered with Japan Pharmaceutical Information Center). Registration date 13 January 2017

scholarly journals Aspacytarabine (BST-236) Is Safe and Efficacious As a Single-Agent, First-Line Therapy for Patients with Acute Myeloid Leukemia Unfit for Standard Chemotherapy. Integrated Results from a Phase 1/2a and an Ongoing Phase 2b

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 179-179
Author(s):  
Jessica K. Altman ◽  
Tsila Zuckerman ◽  
Olga Frankfurt ◽  
Selina M. Luger ◽  
Dale L. Bixby ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Standard Therapy ◽  
Research Funding ◽  
Phase 1 ◽  
Single Agent ◽  
Prior Exposure ◽  
Efficacy And Safety ◽  
First Line ◽  
Advisory Committees ◽  
Ongoing Phase

Introduction: Aspacytarabine (BST-236) is a prodrug of cytarabine, a backbone of acute myeloid leukemia (AML) therapy. Due to its unique pharmacokinetics and metabolism, treatment with aspacytarabine evades peak exposure to free cytarabine, which reduces non-hematological toxicity and enables delivery of high-dose cytarabine also to patients unfit for standard therapy. Data from a completed phase 1/2a and an ongoing phase 2b studies in AML patients unfit for standard therapy, including patients with AML secondary to therapy and myelodysplastic syndrome (MDS) with prior exposure to hypomethylating agents (HMA), demonstrate promising single-agent efficacy and safety of aspacytarabine as a potential first-line AML treatment for this challenging population. Aims: To evaluate the efficacy and safety of aspacytarabine in AML patients unfit for standard induction therapy. Methods: A completed phase 1/2a study and an ongoing phase 2b study evaluate the efficacy and safety of aspacytarabine as a single-agent therapeutic for AML. The phase 1/2a, dose-escalation study enrolled newly-diagnosed patients unfit for standard therapy and patients with relapsed/refractory AML. Patients were treated with 0.3-6 g/m2/d aspacytarabine in 6 dose-escalating cohorts. The ongoing multi-center phase 2b study expands the subgroup of newly-diagnosed AML patients unfit for standard therapy, to evaluate the efficacy and safety of aspacytarabine as a first-line therapy for this population. Secondary AML patients, treated with HMA, chemotherapy, or radiotherapy for a prior condition, are allowed. Patients in the phase 2b study are treated with the selected aspacytarabine dose of 4.5 g/m2/d, containing approximately 3 g/m2/d of cytarabine. Each aspacytarabine treatment course (induction and consolidation) consists of 6 1-hour daily intravenous infusions. Results: To date, 34 AML patients, median age 76 years, received at least 1 dose of aspacytarabine, including 30 patients unfit for standard induction therapy due to age or comorbidities. Overall, 25 patients completed 1 course of aspacytarabine, 4 patients completed 2 courses, 1 patient completed 3 courses, and 1 patient completed 4 courses of aspacytarabine. Three patients (in the phase 1/2a study) did not complete the first course. Aspacytarabine was safe and well-tolerated in repeated-course administration, including in older and unfit patients. Adverse events included mainly hematological "on-target" events with no drug-related mucositis or cerebellar toxicity. Twenty-one patients were newly-diagnosed with AML, either de novo or secondary to MDS or therapy. The patient population was characterized by older age (median 76 years, range 67-88 years), and the majority (67%) of patients had secondary AML, including 10 patients (48%) who were previously treated with HMA (median of 10 courses) or radiotherapy. The median baseline bone marrow blast percentage of this population was 75, and 43% and 48% had intermediate or adverse European LeukemiaNet (ELN) cytogenetic score, respectively. Despite these poor-prognostic characteristics, the 30-day mortality rate in the group of patients receiving ≥4.5 g/m2/d aspacytarabine was 7%. The combined complete remission (CR) rate of all doses was 33%, including 1 patient reaching a CR with partial platelet recovery (CRp). The CR rate in patients treated with at least 4.5 g/m2/d aspacytarabine is 36%, with median time for complete hematological recovery of 27 days (range 21-30) following induction and consolidation. Notably, among the 7 patients who reached a CR/CRp (median age 77), 3 secondary AML patients reached a CR, including 2 patients with prior exposure to HMA (5 and 10 courses) and 1 with prior exposure to radiotherapy (Table 1). Duration of response and overall survival follow up is ongoing and will be presented at the meeting. Conclusions: The accumulating clinical data suggest that aspacytarabine is safe and efficacious for the treatment of AML patients who are unfit for standard induction therapy, including patients with prior exposure to HMA, which may establish aspacytarabine as a new therapeutic backbone for AML, either as a single agent or in combination with targeted therapy. Disclosures Altman: Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Consultancy, Honoraria, Other: Data Safety and Monitoring Committee; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Biosight: Other: US Lead; Novartis: Consultancy; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Cancer Expert Now: Consultancy; France Foundation: Speakers Bureau; prIME Oncology: Speakers Bureau; PeerView: Speakers Bureau; Theradex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Luger:Seattle Genetics: Research Funding; Pfizer: Honoraria; Onconova: Research Funding; Kura: Research Funding; Jazz: Honoraria; Genetech: Research Funding; Daichi Sankyo: Honoraria; Cyslacel: Research Funding; Celgene: Research Funding; Biosight: Research Funding; Ariad: Research Funding; Agios: Honoraria. Kota:Takeda: Honoraria; Xcenda: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Pfizer: Honoraria. Flaishon:BioSight Ltd.: Employment. Tessler:BioSight Ltd.: Employment. Gengrinovitch:BioSight Ltd.: Employment. Ben Yakar:BioSight Ltd.: Employment. Rowe:BioSight: Consultancy.

scholarly journals A Phase II Single Arm Study of Nivolumab As Maintenance Therapy after Autologous Stem Cell Transplantation in Patients with Hodgkin Lymphoma at Risk of Relapse or Progression

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2455-2455
Author(s):  
Carlos Bachier ◽  
Henning Schade ◽  
Behyar Zoghi ◽  
Aravind Ramakrishnan ◽  
Nirav N. Shah
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Maintenance Therapy ◽  
Board Of Directors ◽  
Hodgkin Lymphoma ◽  
Research Funding ◽  
Residual Disease ◽  
Refractory Disease ◽  
Advisory Committees ◽  
Extranodal Disease

Abstract Introduction: Autologous stem cell transplants (ASCT) are standard of care for patients with primary refractory or recurrent Hodgkin lymphoma (HL). While transplant results in cure for some patients, others relapse and succumb from their disease. Studies have found high expression of programmed death ligand 1 (PD-L1) in HL cells. The anti-PD-1 monoclonal antibody, nivolumab, has been safe and efficacious in the treatment of relapsed, refractory HL (Ansell et al. 2015). We evaluated the safety and efficacy of nivolumab maintenance therapy post-ASCT in high risk for relapse Hodgkin disease. Methods: Patients with HL with high risk of residual disease following ASCT ( high risk defined as refractory disease, relapse &lt;12 months, or relapse ≥12 months with extranodal disease after frontline therapy) received nivolumab (240 mg IV every 2 weeks) starting 45-180 days post-transplant for a maximum of 6 months of treatment. Patients were followed for AEs through 100 days after the last dose of drug. PET-CT response assessments were performed 1-3 month, 6 month, and 12 month post-ASCT. The primary objective was to evaluate the safety and tolerability of nivolumab as maintenance therapy early after ASCT. The secondary objective was to evaluate progression-free survival (PFS) at 12 months post-transplant. Results: To date, 37 patients were enrolled; median age 36 years; 25 patients (68%) male. The median number of prior systemic regimens was 2 (range 2-4). 25 patients (68%) had relapsed disease, and 12 patients (32%) had primary refractory disease. 18 patients (49%) had extranodal disease at relapse, 6 patients (16%) had B-symptoms at relapse, and 11 patients (30%) had residual disease after salvage, including 10 patients (27%) of whom had 2-3 prior salvage therapies. 22 patients (60%) had received prior brentuximab, and 3 patients (8%) had received prior nivolumab or pembrolizumab. 36 patients received ASCT and 1 patient received tandem ASCT. At the time of data cutoff, 28 patients (76%) had discontinued nivolumab treatment, 22 patients (60%) because they had completed the 6-month treatment course, 4 patients (11%) due to an adverse event (AE) (1 patient each with pain, pneumonitis, rhabdomyolysis, or hypothyroidism), and 2 patients (5%) due to disease progression. The median duration of treatment was 22.1 weeks. 17 patients (46%) experienced a treatment-related AE (TRAE), of which 5 patients (14%) experienced a ≥Grade 3 TRAE. The most common (≥5%) TRAEs were diarrhea, fatigue, bone pain, neutrophil count decreased, pruritus, rash, and vomiting. 2 patients experienced a treatment-related serious AE (pneumonitis, rhabdomyolysis). There were no treatment-related deaths. With a median follow up of 9.2 months, the median PFS and overall survival (OS) have not been reached. The 6 month PFS is 92.1% and the 12-month OS is 100%. There were no differences in OS when stratified based on prior treatment. Conclusions: The use of nivolumab maintenance early after ASCT is safe and tolerable in this high risk patient population. Early efficacy data is promising, but data need to mature to determine the 12 month PFS. Figure 1 Figure 1. Disclosures Bachier: CRISPR: Membership on an entity's Board of Directors or advisory committees; Autolus: Membership on an entity's Board of Directors or advisory committees; Nkarta: Membership on an entity's Board of Directors or advisory committees; Mana: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Shah: Umoja: Consultancy; Incyte: Consultancy; Legend: Consultancy; Kite: Consultancy; Miltenyi Biotec: Consultancy, Honoraria, Research Funding; Lily: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy.

scholarly journals Venetoclax and Azacitidine for Older Newly Diagnosed Patients with Acute Myeloid Leukemia: A Single-Institution Pilot Study Using Measurable Residual Disease to Guide Therapy

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2638-2638 ◽  
Author(s):  
Amanda Winters ◽  
Jonathan A Gutman ◽  
Enkhtsetseg Purev ◽  
Brett M. Stevens ◽  
Shanshan Pei ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Residual Disease ◽  
Refractory Disease ◽  
Advisory Committees ◽  
Ras Pathway ◽  
Measurable Residual Disease ◽  
Count Recovery

Background: Venetoclax (ven) was approved for older untreated acute myeloid leukemia (AML) patients due to high response rates and durable remissions. As a participating site in the dose escalation study, we observed deeper/more durable responses in some who received >400mg ven. We also noted 16/33 discontinued azacitidine (aza) after achieving a response; 9 relapsed and 7 remained in long term remission on ven only. Based on these observations, we designed a study that hypothesized: A)Higher initial doses of ven would allow deeper/more durable responses, and B)Multi modality high sensitivity measurable residual disease (MRD) testing could identify patients able to discontinue aza and remain on maintenance ven. Methods: This is an ongoing phase 2 study (NCT03466294) of 42 untreated AML patients ≥60 who decline/are ineligible for induction. Patients have adequate organ function and white blood cell counts <25x109/L (hydrea permitted). In cycle 1, patients receive aza 75mg/m2 on days (d) 1-7 and ven, escalated from 100 to 200 to 400 to 600mg on d 1-4. Ven continues at 600mg d 5-28 and bone marrow biopsies (BMBXs) are performed on d 8 and 28. Patients who achieve morphologic remission without count recovery have up to 14 days off therapy before subsequent cycles, with growth factor support; "upgraded" responses are recorded if count recovery occurs. Non responders discontinue or receive up to two additional cycles of aza and ven 600mg. Responders who remain MRD+ by multiparameter flow cytometry (MPFC, Hematologics) and/or digital droplet PCR (ddPCR) for as many identifiable diagnostic genes as possible also receive up to 2 additional cycles of aza and ven 600mg. MRD+ responders after 3 cycles continue aza and ven 400mg until toxicity/progression. Patients who experience MRD- responses at any time stop aza and continue ven 400mg daily (Fig 1). Results: 30 patients enrolled between May 2018 and July 2019; median age is 71 (60-88), 10% evolved from MDS and 10% and 73% had intermediate and unfavorable risk disease by ELN, respectively (Table 1). 732 adverse events (AEs) occurred; 46 (6%) were serious, the most common were neutropenic fever (37%) and pneumonia (13%). The most common >grade 2 related AEs were leukopenia (53%), thrombocytopenia (44%) and neutropenia (35%); there were no related grade 5 AEs. The overall response rate was 70% (21/30; CR=19, MLFS=2). Median number of cycles to achieve best response was 1. Significant blast reductions were seen on day 8; of the 28 with interpretable day 8 BMBXs, 10 achieved MLFS on day 8. 4 completed ≥1 cycle and were refractory. An additional 4 did not complete cycle 1: 1 died of disease and 3 elected to come off therapy (all subsequently died of disease). Four (19%) responders relapsed, after a median 180 days (27-279). With median follow up of 214 days, median response duration has not been reached. 10 patients died, after a median 65 days (29-256); 1/30 died within 30 days. Median overall survival has not been reached. Of the 26 who completed ≥1 cycle, 19 were MRD- by MPFC, including 18/19 who achieved CR. Of these 26, 3 were not monitored by ddPCR: for 2 patients this was due to the absence of detectable baseline mutations and for 1 patient it was due to refractory disease. The remaining 23 had ddPCR monitoring; 3 became MRD- by this modality (Fig 2). All 3 were also MRD- by MPFC and per protocol discontinued aza and initiated ven maintenance (Fig 1). MRD negativity by both parameters occurred after cycles 1, 2 and 3, respectively. One MRD- patient relapsed after 216 days; two remain in remission after 301 and 124 days. An additional 4 who achieved MRD+ responses discontinued aza at their insistence (and in violation of the protocol); 1 relapsed after 279 days, and 3 remain in ongoing remission. Univariate predictors of refractory disease were FAB M0/M1 (OR 0.070, p=0.02) and RAS pathway mutations (OR 14.25, p=0.02). Conclusions: Higher initial doses of ven are tolerated in this population. Blast reduction occurs quickly in many patients (day 8), for this low intensity regimen. Response rates are consistent with lower doses of ven. Very deep responses, as measured by highly sensitive MRD methods (MPFC and ddPCR are capable of sensitivity up to 0.02%), are attainable. Longer follow up time will determine if higher ven doses and MRD-driven decisions related to continuation of aza result in more durable responses. Increased maturation of blasts and RAS pathway mutations are predictors for refractory disease. Disclosures Lyle: Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo Incyte: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Pollyea:Agios: 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; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Diachii Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forty-Seven: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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