Phase 2 Trial of Entospletinib (GS-9973), a Selective Syk Inhibitor, in Indolent Non-Hodgkin's Lymphoma (iNHL)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1545-1545 ◽  
Author(s):  
Jeff P. Sharman ◽  
Leonard M. Klein ◽  
Michael Boxer ◽  
Kathryn S. Kolibaba ◽  
Steve Abella ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Median Duration ◽  
Research Funding ◽  
Alkylating Agents ◽  
Response Assessment ◽  
Baseline Risk ◽  
Phase 2 ◽  
Prognostic Features ◽  
Phase 2 Trial ◽  
First Response

Abstract Background: Spleen tyrosine kinase (Syk) is a mediator of B-cell receptor signaling in normal and transformed B-cells. Entospletinib is an orally bioavailable, selective inhibitor of Syk. Methods: This Phase 2 trial is evaluating entospletinib 800 mg BID in a study of 204 patients with previously treated lymphoid malignancies. Tumor imaging was planned at weeks 8, 16, 24 and then every 12. Tumor response was assessed per Cheson 2007 criteria. Results: A cohort of 69 patients with iNHL (41 follicular lymphoma [FL], 11 lymphoplasmacytoid lymphoma [LPL], 17 marginal zone lymphoma [MZL]) are included in this analysis. Median age was 66 years (range 41 - 89). 58% were male. The median number of prior treatments (Rxs) regimens was 3 (range 1- 14). Prior Rxs included anti-CD20 antibodies (rituximab 99%, ofatumumab 4%), alkylating agents (90%; bendamustine 51%) and anthracyclines (35%). Baseline risk factors: Ann Arbor Stg III-IV (70%), Gr 3a FL (29%), FLIPI ≥3 (34%). Median duration of Rx was 16 weeks with 10 patients continuing on Rx. Entospletinib was generally well tolerated. The most common TEAEs (any Grade/≥Gr 3, independent of causality) were fatigue (54%/13%), nausea (49%/4%), diarrhea(36%/0%), vomiting (26%/0%), headache (23%/1%), pyrexia (23%/3%), decreased appetite (22%/0%), constipation (22%/1%) and common laboratory abnormalities were increased AST (33%/15%), increased ALT (41%/19%), increased total bilirubin (32%/16%), anemia (36%/13%) and neutropenia (38%/13%). 4 patients died while on study from progressive disease. At the time of this analysis, 66 of 69 patients have been treated through first response assessment (1 patient ongoing not reaching first response assessment, 1 patient discontinued due to AE and 1 patient withdrew consent prior to it). 38 out of 61 (62%) patients evaluable for SPD experienced reduced tumor burden, with median duration of Rx 28 weeks (range 4-92). 9/61 (15%) achieved a decrease of ≥ 50% in SPD. The ORR was 13.0% (95% CI: 6.1%, 23.3%), with 7 patients achieving a PR, one LPL patient achieving MR and one patient achieving a CR. Forty-one patients (59.4%) had stable disease. The primary end point of 24 weeks PFS was 48.9% (95% CI: 34.6%, 61.7%). Median PFS was 5.5 months (95% CI: 4.4 months, 8.2 months). There were 39 patients (56.5%) with events of disease progression. Conclusions: Entospletinib monotherapy given with this dose and schedule was well tolerated and demonstrated activity in patients with advanced relapsed iNHL, including those with poor prognostic features. Further development of entospletinib in iNHL will focus on the development of combination approaches with chemotherapy and targeted agents. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Sharman: Calistoga: Honoraria; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; TG Therapeutics, Inc.: Research Funding; Celgene Corporation: Consultancy, Research Funding; Roche: Research Funding; Janssen: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding. Off Label Use: Management of CLL/SLL and follicular lymphoma. Kolibaba:Takeda Pharmaceuticals International Co.: Research Funding; Genentech: Research Funding; Seattle Genetics, Inc.: Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; Janssen: Research Funding; GSK: Research Funding; Gilead: Consultancy, Research Funding; TG Therapeutics: Research Funding. Abella:Gilead: Employment. Eng:Gilead: Employment. He:Gilead Sciences: Employment. Hu:gilead: Employment. Yasenchak:Seattle Genetics, Inc.: Research Funding.

scholarly journals Phase 2 Trial of Entospletinib (GS-9973), a Selective SYK Inhibitor, in Follicular Lymphoma (FL)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4419-4419 ◽  
Author(s):  
Jeff P. Sharman ◽  
Leonard M. Klein ◽  
Michael Boxer ◽  
Kathryn S. Kolibaba ◽  
Michael J. Hawkins ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Median Duration ◽  
Research Funding ◽  
Response Assessment ◽  
Phase 2 ◽  
Employment Equity ◽  
Prognostic Features ◽  
Phase 2 Trial ◽  
First Response ◽  
Equity Ownership

Abstract Background: Spleen tyrosine kinase (Syk) is a mediator of B-cell receptor signaling in normal and transformed B-cells. Entospletinib is an orally bioavailable, selective inhibitor of Syk (Kd 7.6 nM, no other kinase < 100 nM). Methods: This Phase 2 trial is evaluating Entospletinib 800 mg BID in a 41 subject cohort with previously treated FL in a study of 165 subjects with lymphoid malignancies. Tumor imaging was planned at weeks 8, 16, 24 and then every 12. Tumor response was assessed per Cheson 2007 criteria. Results: For the subjects with FL included in this analysis, median age was 67 years (range 41 – 89), 49% were male. The median number of prior Rx regimens was 2 (range 1-8). Prior treatments (Rxs) included anti-CD20 antibodies (rituximab 100%, ofatumumab 5%), alkylating agents (95%; bendamustine 51%) and anthracyclines (51%). Baseline risk factors: Ann Arbor Stg III-IV (66%), Gr 3a FL (27%), FLIPI ≥3 (34%). At the time of this analysis, 41 subjects with follicular lymphoma were enrolled and 38 subjects have been treated through first response assessment (1 subject ongoing prior to first response assessment, 1subject discontinued due to AE and 1 subject withdrew consent). Entospletinib was generally well tolerated. The most common TEAEs (any Grade/≥Gr 3, independent of causality) were fatigue (46%/12%), nausea (42%/2%), diarrhea(27%/0%), decreased appetite (22%/0%), vomiting (22%/0%) and common laboratory abnormalities were increased AST (37%/17%), increased ALT (34%/20%), increased total bilirubin (27%/5%), anemia (34%/10%) and neutropenia (22%/10%). Reversible Grade 3 or 4 ALT/AST elevations occurred in 8 (19.5%) FL subjects. 3 subjects died while on study: 2 from progressive disease and 1 from acute renal failure investigator reported as unrelated to study drug. Investigator response assessments are available for 29 subjects, 16/29 (55%) subjects experienced reduced tumor bulk measured by SPD; 3 (10%) achieved a decrease of ≥ 50%. CR has not been observed at this early evaluation. 14/41 subjects continue on Rx. Median duration of Rx for all patients was 15 weeks. Among all patients who experienced reduction in tumor volume, median duration of Rx was 25 weeks (range 4-51). Conclusions: Entospletinib monotherapy given with this dose and schedule was generally well tolerated and demonstrated moderate activity in subjects with advanced relapsed FL, including those with poor prognostic features. Updated data with longer follow-up duration will be presented at the meeting. Disclosures Sharman: Gilead Sciences: Research Funding. Klein:Gilead Sciences: Research Funding. Boxer:Gilead Sciences: Research Funding. Kolibaba:Gilead Sciences: Research Funding. Hawkins:Gilead Sciences: Research Funding. Abella:Gilead Sciences: Employment, Equity Ownership. Wu:Gilead Sciences: Employment, Equity Ownership. Yasenchak:Gilead Sciences: Research Funding.

Phase 2 Trial of Entospletinib (GS-9973), a Selective Syk Inhibitor, in Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4152-4152
Author(s):  
Jeff P. Sharman ◽  
Leonard M. Klein ◽  
Michael Boxer ◽  
Kathryn S. Kolibaba ◽  
Steve Abella ◽  
...  
Keyword(s):  
Research Funding ◽  
Tumor Imaging ◽  
Alkylating Agents ◽  
Response Assessment ◽  
Lymphocytic Leukemia ◽  
Upper Respiratory Tract ◽  
Phase 2 ◽  
Duration Of Treatment ◽  
Prognostic Features ◽  
Phase 2 Trial

Abstract Background: Spleen tyrosine kinase (Syk) is a mediator of B-cell receptor signaling in normal and transformed B-cells. GS-9973 is an orally bioavailable, selective inhibitor of Syk. Methods: This Phase 2 trial enrolled 41 patients with CLL and 15 patients with SLL treated with GS-9973 800 mg BID. Tumor imaging occurred at weeks 8, 16, 24 and then every 12. Response was independently evaluated according to Hallek 2008 as modified by Cheson 2012 for patients with CLL and Cheson 2007 for patients with SLL. Primary endpoint for the study was PFS at 24 weeks. Results: The median ages of CLL and SLL patients were 73 (range 51-89) and 70 (range 57-84), respectively. 68% of CLL subjects and 60% of SLL subjects were male. Ten patients had 17p deletions/TP53 mutations and 17 had SF3B1 or NOTCH1 mutation, or 11q22.3 deletion. The median number of prior regimens for CLL was 2 (range 1-8) and for SLL was 2 (range 1-10). Prior therapies included anti-CD20 antibodies (98%), alkylating agents (86%, [bendamustine 63%]) and fludarabine (66%). 12 CLL and 6 SLL patients are still on treatment; the median duration of treatment for all CLL and SLL patients was 36 weeks The most common treatment emergent AEs (any Grade/≥Gr 3, independent of causality) were fatigue (70%/7%), nausea (54%/2%), diarrhea(48%/0%), cough(34%/0%), dizziness (32%/2%), headache (29%/0%), pyrexia (29%/0%), decreased appetite (27%/2%), upper respiratory tract infection(27%/0%), constipation (23%/0%). Common laboratory abnormalities were increased AST (30%/5%), increased ALT (43%/4%), increased total bilirubin (41%/16%), anemia (50%/7%) and neutropenia (54%/29%). Forty-nine patients were treated for at least 8 weeks and 54 patients had ≥ 1 efficacy assessment, two patients discontinued prior to the first response assessment, one due to AE and one withdrew consent. Per investigator assessment, 51 out of 52 (98%) patients evaluable for SPD experienced reduced tumor bulk; 38 (73%) achieved a decrease of ≥ 50%. The ORR was 62.5% (95% CI: 48.6%, 75.1%), with 35 patients achieving a PR and no subject achieving a CR. Thirteen patients (23.2%) had stable disease. The primary end point of 24 weeks PFS was 72.3% (95% CI: 57.1%, 83.0%). Median PFS was 20.5 months (95% CI: 7.7 months, not reached). There were 24 patients (42.9%) with events, 22 (39%) with disease progression and two deaths (4%) attributed to septic pneumonia and pseudomonal infection which was unrelated to entospletinib by investigator assessment. Among the 35 responding patients, median DOR was 21.3 months (95% CI: 13.2 months, not reached). Results of an independent response assessment are pending and will be presented. Entospletinib was well tolerated and demonstrated substantial activity in patients with CLL, and SLL including those with poor prognostic features. Entospletinib activity seems comparable to that reported by other approved BCR pathway inhibitors with the median PFS reported for Idela of 15.8 months (Blood. 2014;123(22):3390-3397) and Ibrutinib reported 42.6% overall response rate and a PFS of 70-80% @ 12 months (ibrutinib PI) Current studies plans include studying Entospletinib in combination therapy. Figure 1. Figure 1. Figure 2. Figure 2. Figure 3. Figure 3. Disclosures Sharman: Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Research Funding; Calistoga: Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; Celgene Corporation: Consultancy, Research Funding; TG Therapeutics, Inc.: Research Funding; Janssen: Research Funding. Kolibaba:Janssen: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; TG Therapeutics: Research Funding; GSK: Research Funding; Celgene: Research Funding; Acerta: Research Funding; Seattle Genetics, Inc.: Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; Gilead: Consultancy, Research Funding. Abella:Gilead: Employment. Di Paolo:Gilead Sciences: Employment, Equity Ownership. Eng:Gilead: Employment. Hu:gilead: Employment. He:Gilead Sciences: Employment. Reddy:gilead: Employment. Yasenchak:Seattle Genetics, Inc.: Research Funding.

scholarly journals A phase 2 trial of extended induction epratuzumab and rituximab for previously untreated follicular lymphoma: CALGB 50701

Cancer ◽  
2013 ◽  
Vol 119 (21) ◽  
pp. 3797-3804 ◽  
Author(s):  
Barbara W. Grant ◽  
Sin-Ho Jung ◽  
Jeffrey L. Johnson ◽  
Lale Kostakoglu ◽  
Eric Hsi ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Phase 2 ◽  
Phase 2 Trial

A phase 2 trial of CHOP chemotherapy followed by tositumomab/iodine I 131 tositumomab for previously untreated follicular non-Hodgkin lymphoma: Southwest Oncology Group Protocol S9911

Blood ◽  
2003 ◽  
Vol 102 (5) ◽  
pp. 1606-1612 ◽  
Author(s):  
Oliver W. Press ◽  
Joseph M. Unger ◽  
Rita M. Braziel ◽  
David G. Maloney ◽  
Thomas P. Miller ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Progression Free Survival ◽  
Phase 2 ◽  
Oncology Group ◽  
Chop Chemotherapy ◽  
Southwest Oncology Group ◽  
Non Hodgkin Lymphoma ◽  
Phase 2 Trial ◽  
Main Adverse Event ◽  
Anti Cd20

AbstractAdvanced follicular lymphoma is incurable with conventional chemotherapy and radiotherapy. The Southwest Oncology Group (SWOG) conducted a phase 2 trial (S9911) of a novel regimen consisting of 6 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy followed 4 to 8 weeks later by tositumomab/iodine I 131 tositumomab (anti-CD20 antibody) in 90 eligible patients with previously untreated, advanced stage follicular lymphoma. Treatment was well tolerated. Reversible myelosuppression was the main adverse event and was more severe during CHOP chemotherapy than following radioimmunotherapy. The overall response rate to the entire treatment regimen was 90%, including 67% complete remissions (CRs plus unconfirmed CRs [CRu's]) and 23% partial remissions (PRs). Twenty-seven (57%) of the 47 fully evaluable patients who achieved less than a CR with CHOP improved their remission status after tositumomab/iodine I 131 tositumomab. With a median follow-up of 2.3 years, the 2-year progression-free survival (PFS) was estimated to be 81%, with a 2-year overall survival of 97%. This study has established the feasibility, tolerability, and efficacy of this regimen for patients with advanced follicular lymphoma. This novel treatment appears promising compared with the SWOG's historical experience using CHOP alone and is currently being compared with CHOP plus rituximab in a randomized phase 3 trial (S0016).

scholarly journals ATEZOLIZUMAB + OBINUTUZUMAB + VENETOCLAX IN PATIENTS WITH RELAPSED OR REFRACTORY FOLLICULAR LYMPHOMA: PRIMARY ANALYSIS OF A PHASE 2 TRIAL FROM LYSA

2021 ◽  
Vol 39 (S2) ◽  
Author(s):  
G. Cartron ◽  
E. Bachy ◽  
S. Guidez ◽  
E. Gyan ◽  
R. Gressin ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Phase 2 ◽  
Primary Analysis ◽  
Phase 2 Trial

Phase 1b Evaluation of the Safety and Efficacy of a 30-Minute IV Infusion of Carfilzomib In Patients with Relapsed and/or Refractory Multiple Myeloma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3024-3024 ◽  
Author(s):  
Kyriakos Papadopoulos ◽  
David Samuel diCapua Siegel ◽  
Seema B. Singhal ◽  
Jeffrey R. Infante ◽  
Edward A. Sausville ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Peripheral Blood ◽  
Research Funding ◽  
Mononuclear Cells ◽  
Single Agent ◽  
Proteasome Inhibition ◽  
Response Assessment ◽  
Phase 2 ◽  
Peripheral Blood Mononuclear ◽  
Phase 1B

Abstract Abstract 3024 Background: Carfilzomib (CFZ) is a novel, highly selective, epoxyketone proteasome inhibitor. In two separate Phase 2 trials in patients (pts) with relapsed and/or refractory (R/R) multiple myeloma (MM), single-agent CFZ administered as an IV bolus over 1–10 minutes has demonstrated durable activity at 20/27 mg/m2 and is well-tolerated with no clinically significant cumulative toxicity. In rats, significantly improved tolerability of CFZ was obtained following administration as a 30 min infusion as compared to a rapid IV bolus. Notably, a dose of 48 mg/m2 via IV bolus resulted in 50% lethality, compared to minimal toxicity without lethality at the same dose via a 30 min infusion. The reduced toxicity with 30-min infusion may reflect the role of Cmax (45 μM for bolus vs. 1.5 μM for infusion), since proteasome inhibition in blood and tissue was equivalent in both groups. Here we report on the results of administration of CFZ as a 30-minute IV infusion in a Phase 1b study in pts with R/R MM. The goals of this study are to determine the maximum recommended dose for infusion, safety, efficacy, pharmacokinetics (PK), and pharmacodynamic (PD) parameters. Methods: This Phase 1b trial is enrolling pts with R/R MM after ≥2 prior treatment failures. CFZ is given as a 30-minute IV infusion on days (D) 1, 2, 8, 9, 15, and 16 of a 28-day cycle (C) until progression. Dosing in all cohorts is initiated at 20 mg/m2 for the first two doses, with subsequent escalation to 36, 45, 56, or 70 mg/m2. Dose escalation follows standard 3+3 rules. Dexamethasone (4 mg for doses up to 45 mg/m2) is given prior to each infusion, with 8 mg given at higher doses. Responses by IMWG Uniform Response Criteria are measured at every C. Plasma samples for PK analysis and peripheral blood samples for PD analysis were obtained from pts at C1D1 (20 mg/m2) and C2D1 (all dose cohorts). Results: To date, 16 pts with R/R MM have been enrolled in the Phase 1b infusion study (4 at 36 mg/m2; 3 at 45 mg/m2; 7 at 56 mg/m2 and 2 at 70 mg/m2). Pts have remained on study for a median of 4 cycles (range 1–13+). Dose Limiting Toxicity (DLT) was observed in both pts treated at 70 mg/m2: reversible Grade (G) 3 renal failure in one pt within 24-hours following his first dose at 70 mg/m2 (C1D8); reversible G3 fatigue with fevers 4 days following four doses of 70 mg/m2 (C1 D20). Both pts were successfully rechallenged and continue on treatment. Seven patients have started dosing at 56 mg/m2; to date, one DLT (reversible G3 hypoxia with fevers) was observed. Thirteen pts are evaluable for efficacy (2 pts withdrew prior to 1st response assessment; 1 pt is too early to assess). Responses, time on study and prior regimens are detailed in the following table. Preliminary PK analysis demonstrates that the Cmax with 30-minute infusion is lower than obtained with a 5–10 minute IV bolus of the same dose. Inhibition of proteasome activity in red blood cells (RBCs) and peripheral blood mononuclear cells (PBMCs) was >80% at 20 mg/m2 and >90% at 36 mg/m2 and above. Common adverse events (AEs) with CFZ delivered as a 30-minute infusion have included fatigue, fevers, myalgias, diarrhea, nausea, thrombocytopenia, and reversible elevations in serum creatinine. There have been no episodes of worsening of baseline peripheral neuropathy or hepatotoxicity. Conclusions: In pts with R/R MM, single-agent CFZ as 30-minute IV infusion is both active and well-tolerated at doses ≥36 mg/m2; the dose level of 56 mg/m2 is being expanded as the recommended phase 2 dose on this schedule. Responses were seen in 8 out of 13 evaluable MM pts, including three VGPRs in pts who had received 5–7 prior regimens. Similar to animal studies, improved safety outcomes in MM patients can be achieved with near complete proteasome inhibition when CFZ is administered as a 30-minute infusion. An additional schedule of CFZ using weekly dosing (30-minute infusion for 5 weeks out of every 6) will be investigated in this trial. Disclosures: Papadopoulos: Onyx Pharmaceuticals: Consultancy, Research Funding. Siegel:Millenium: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Singhal:Celgene: Speakers Bureau; Takeda/Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Research Funding. Gordon:Onyx Pharmaceuticals: Research Funding. Kauffman:Onyx Pharmaceuticals: Employment. Woo:Onyx Pharmaceuticals: Employment. Lee:Onyx Pharmaceuticals: Employment. Bui:Onyx Pharmaceuticals: Employment. Hannah:Onyx Pharmaceuticals: Consultancy.

Secondary Myelodysplastic Syndrome/Acute Myeloblastic Leukemia During Lenalidomide-Based Regimens in Relapsed and/or Refractory Multiple Myeloma Patients: Single Center Experience

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1867-1867
Author(s):  
Rouslan Kotchetkov ◽  
Esther Masih-Khan ◽  
Chia-Min Chu ◽  
Young Trieu ◽  
Saima Dean ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Myelodysplastic Syndrome ◽  
Median Duration ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Alkylating Agents ◽  
Myelogenous Leukemia ◽  
Median Baseline ◽  
Number Of Patients ◽  
Secondary Myelodysplastic Syndrome

Abstract Abstract 1867 Secondary myelodysplastic syndrome and acute myelogenous leukemia (2° MDS/AML) are well-known complications that can occur after alkylating agent therapy for multiple myeloma (MM) or other cancers. However, until recently, the survival of MM pts was relatively short, a feature which may have contributed to a relatively low reported incidence of this complication in MM. The introduction of novel agents has improved survival rates of MM pts; lenalidomide (len) + dexamethasone–currently approved for MM after one prior therapy– is one of the main regimens that has contributed to this finding. Since alkylating agents, either given orally or as part of high-dose melphalan + ASCT, still remain an important component of MM therapy, more pts may survive to be at risk for 2° MDS/AML. Using the MM database at PMH, we retrospectively reviewed the charts of patients with relapsed/refractory (rel/ref) MM treated with len-based regimens (>1 cycle) to determine the incidence and characteristics of 2° MDS/AML that developed during this therapy. Between 06/2006 and 08/2012 we identified 230 patients having received len-based therapy: len + corticosteroids 222 patients, len alone 8 patients, cyclophosphamide + len + prednisone (CPR) 32 patients. 2° MDS/AML developed in 9 patients (3.9%) at a median of 89.6 months (range 30–188) from the time of diagnosis of MM and 22.4 (2–56.6) months from the time of initiation of len regimens. The median follow-up from start of len was 1.6 years, and from the start of diagnosis 7.5 years. The median duration of len treatment was 9.4 months. The MDS/AML cytogenetic changes were variable, but four patients had deletions of all or part of chromosome 5. None of the 2° MDS/AML had translocation t(4;14), as compared to 5.9% in (−) MDS/AML subgroup. The characteristics of patients at the time of starting len, in those who later developed (+) or did not develop (−) 2° MDS/AML during therapy, are shown in Table 1. Cumulative incidence of 2° AML/MDS from time of diagnosis to time of 2° AML/MDS is 4.5% [95% CI 2.2–9.2%] at 15 years. Cumulative incidence of 2° AML/MDS from starting time of len to time of AML/MDS is 5% [95% CI 2.4–10.4%] at 5 years. The incidence of 2° MDS/AML among those who had prior oral alkylators (OA) and/or concomitant OA was 10.5% (2/19 patients), concomitant cyclophosphamide only 7.6% (1/13), prior OA only 1.9% (3/152), and 6.5% for those who did not receive prior/concomitant OA (3/46). Grade 3–4 neutropenia occurred during len in 44% versus 58% in those with and without 2° MDS/AML, respectively. G-CSF was used in 56% of pts who developed MDS compared with 53% who did not. We conclude: 1) The cumulative incidence of MDS/AML from starting len to time of 2° AML/MDS was 5% at 5 years; 2) patients who developed 2° MDS/AML while on len regimens were slightly older, had slight male predominance, higher beta-2-microglobulin, creatinine and platelet count, less often received prior ASCT, thalidomide, and bortezomib, but had longer exposure to len; 3) the relationship with OA is not entirely certain, but it appears that those with prior and concomitant exposure to OA have the highest incidence of this complication, which is most often seen in prolonged len treatment. Table 1. Patient characteristics (n=230) Feature ALL patients (+) MDS/AML (–) MDS/AML Number of patients 230 9 221 Median age, years 61 (31–80) 68 (53–76) 61 (3–80) Male 134 (58%) 6 (67%) 128 (56%) Median baseline ANC, × 109/L 2.8 (0.9–61.4) 3.0 (1.5–5.1) 2.8 (0.9–61.4) Median baseline β-2 microglobulin (nmol/L) 222 (43–1695) 300 (133–481) 222 (43–1695) Median baseline pl count, × 109/L 156 (5–479) 200 (43–277) 156 (5–479) Median baseline creatinine, μmol/L 87 (39–515) 97 (56–117) 86 (39–515) Median # prior regimens 2 (0–6) 2 (1–5) 2 (0–6) Prior alkylating agents (all) 218 (95%) 9 (100%) 209 (95%) Prior oral alkylators 167 (73%) 6 (67%) 162 (73%) Prior ASCT 187 (81%) 2 (78%) 180 (81%) Prior thalidomide 132 (57%) 3 (33%) 129 (58%) Prior bortezomib 109 (47%) 3 (33%) 106 (48%) Concomitant cyclophosphamide 32 (13.9%) 3 (33%) 29 (13%) G-CSF use 123 (53%) 5 (56%) 118 (53.39%) Median duration of Len (mo, range) 9.4 (0.1–67.2) 22.8 (6.6–56.6) 6.8 (0.1–67.2) Disclosures: Chen: Johnson & Johnson, Lundbeck, Celgene: Consultancy; Roche: Honoraria; Johnson & Johnson, Celgene, GlaxoSmithKline: Research Funding. Kukreti:Roche: Consultancy, Honoraria; Celgene: Honoraria; Janssen: Honoraria. Reece:Janssen: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Millennium Pharmaceuticals: Research Funding.

Efficacy and Safety of Eltrombopag for Treatment of Patients with Myelodysplastic Syndromes after Hypomethylating-Agent Failure: A Phase 2 Clinical Trial

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1691-1691 ◽  
Author(s):  
Maliha Khan ◽  
Bodden Kristy ◽  
Tapan Kadia ◽  
Alessandra Ferrajoli ◽  
Yesid Alvarado ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Bone Marrow ◽  
Myelodysplastic Syndromes ◽  
Research Funding ◽  
Phase 2 ◽  
Open Label ◽  
Bone Marrow Fibrosis ◽  
First Response ◽  
Transfusion Requirements ◽  
Marrow Fibrosis

Abstract Background: Myelodysplastic syndromes (MDS) are malignant clinical disorders characterized by ineffective hematopoiesis, bone marrow dysplasia, peripheral cytopenias and a property to transform into acute myeloid leukemia (AML). Standard of care for MDS includes the hypomethylating agents (HMAs) (i.e. azacitidine, decitabine) to improve quality of life, decrease transfusion requirements and improve clinical outcome. However not all patients (pts) respond to HMAs and even in responding pts, cytopenias may persist. HMA-failure MDS has extremely poor prognosis and currently there are no approved therapeutic options for such pts who are often of advanced age with frequent comorbidities. Objectives: The dual primary objectives of this study evaluate the safety and efficacy of the second-generation thrombopoietin-receptor agonist (TPO-RA) eltrombopag (EPAG) for the treatment of MDS pts at the time of HMA-failure. Secondary objectives include incidence of transformation to AML and evaluation of bone marrow fibrosis during therapy. Methods: Eligible pts for this 2-arm phase 2 open-label clinical trial included adults with MDS after completing >4 HMA cycles with failure to achieve at least a partial response, or the presence of ongoing cytopenias per IWG criteria. Arm A includes eltrombopag monotherapy and Arm B includes eltrombopag with continuation of the HMA at the previous dosing schedule. The starting eltrombopag dose is 200mg orally daily, which can be increased to 300mg in the absence of toxicity. First response is assessed after 2 cycles with each cycle lasting 28 days. The primary efficacy endpoint was overall response rate based on the IWG-2006 criteria. Results: To date, 23 pts with a median age of 72 years (range 42-84 years) have been enrolled. Prior to study entry, pts had received a median of 6 (range 4-25) HMA cycles. Cytogenetics were diploid in 12 (53%), intermediate in 7 (30%), and high risk in 4 (17%) pts by IPSS. Median bone marrow blasts at study start was 3% (range 0-15%). Arm A has enrolled 7 pts with a median age of 74 years; Arm B has enrolled 16 pts with median age of 69 years. In Arm B, ongoing HMA therapy includes azacitidine in 7 (44%) and decitabine in 9 (56%). Nine (39%) pts increased to 300mg EPAG after median of 8 weeks on study. Median total cycles received on study is 5 (1-17); median OS has not been reached. Overall, 16 pts are response-evaluable; 7 pts discontinued prior to the first response assessment at 2 months (4 due to AEs including myalgias/fatigue (n=2), hyperbilirubinemia (n=1), and pneumonia (n=1), 2 per pt request and 1 for pt inability to comply with protocol requirements). Of the 16 response-evaluable pts, 3 (19%) in Arm B demonstrated platelet improvement, including one pt necessitating EPAG dose-reduction to 100mg due to platelet count exceeding 450 x10⁹/L with concomitant ANC recovery at 200mg EPAG dose level. An additional 8 (35%) pts have remained on study for a median of 5 cycles (2-17) with stable disease. Two pts discontinued therapy due to disease progression, including 1 (4%) that progressed to AML. The most common non-hematologic AEs regardless of attribution included hyperbilirubinemia (n=14, 61%), fatigue (n=13, 56%) myalgias (n=11, 48%), fever (7, 30%), dyspnea (7, 30%), nausea (6, 26%) and transaminitis (4, 17%). No significant increase in bone marrow fibrosis has been observed. Conclusion: Eltrombopag orally daily appears to be a safe and beneficial supportive adjunct for pts with MDS while receiving HMA-therapy or after HMA-failure due to persistent cytopenias. Treatment on this study continues and larger prospective clinical trials are needed to confirm these preliminary findings. Disclosures Off Label Use: Eltrombopag for the treatment of MDS-related cytopenias". Pemmaraju:Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Konopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding. DiNardo:Novartis: Research Funding.

Results from Phase 2 Trial Ongoing Expansion Stage of SL-401 in Patients with Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 342-342 ◽  
Author(s):  
Naveen Pemmaraju ◽  
Andrew A. Lane ◽  
Kendra L. Sweet ◽  
Anthony S. Stein ◽  
Sumithira Vasu ◽  
...  
Keyword(s):  
Research Funding ◽  
Plasmacytoid Dendritic Cell ◽  
Phase 2 ◽  
First Line ◽  
Employment Equity ◽  
Phase 2 Trial ◽  
Major Response ◽  
Expansion Stage ◽  
Equity Ownership ◽  
Stage 1

Abstract Background: SL-401 is a targeted therapy directed to the interleukin-3 receptor (CD123), a target overexpressed on blastic plasmacytoid dendritic cell neoplasm (BPDCN) and other hematologic malignancies. BPDCN is an aggressive hematologic malignancy of unmet medical need that often presents in bone marrow and skin, and may also involve lymph nodes and viscera. Long-term outcomes after treatment with chemotherapy have been very poor, with median overall survival from diagnosis of ~12 months, highlighting the need for novel therapies. Results from the Phase 2 trial of SL-401 in patients with BPDCN are reported here. Methods:This multicenter, single-arm Phase 2 trial of patients with BPDCN includes a lead-in (stage 1) and expansion (stage 2). In stage 1, patients with BPDCN or relapsed or refractory (r/r) AML received SL-401 as a daily IV infusion at 7, 9, 12, or 16 ug/kg/day for days 1-5 of a 21 day cycle. In stage 2, patients with BPDCN receive SL-401 at the dose determined in stage 1. Results: As of 7/25/16, 29 patients with BPDCN have received SL-401, including 16 first-line and 10 relapsed/refractory (r/r) adults and 3 pediatric patients (under compassionate use). The 26 adult patients (9+17 in stages 1&2) received SL-401 at 7 ug/kg (n=3 [stage 1]) or 12 ug/kg (n=23 [6+17 in stages 1&2]). The median adult age was 69 years (range: 29-82 years). In stage 1, 12 ug/kg was the highest tested dose for BPDCN; MTD was not reached in BPDCN. Results in AML (r/r) patients will be reported separately. The most common treatment-related AEs, all grades, were transient transaminase elevation (54%) and hypoalbuminemia (38%). Transient thrombocytopenia was also noted (19%). The most common ≥ Grade 3 treatment-related AEs were transient transaminase elevation (42%) and thrombocytopenia (19%). Two stage 1 patients developed capillary leak syndrome (CLS): gr 5 (7 ug/kg) and gr 4 (12 ug/kg). Safety precautions, including monitoring of albumin levels and body weight, were successfully implemented to minimize risk of severe CLS, which has not occurred in patients with BPDCN since adoption. Twenty-one of 26 adult patients were evaluable for response (response assessment from 3 recently treated patients are pending; 1 patient was discontinued for as yet unspecified reasons; and 1 patient treated at 7 ug/kg was not evaluable for response due to AE); median follow-up for evaluable patients was 6.9 months (range: 0.6-17.6 months). An 86% (18/21) ORR was observed in evaluable adult BPDCN patients. ORR in evaluable patients was 100% (14/14) in first-line and 57% (4/7) in r/r BPDCN. Of these, 92% (11/12) of first-line patients treated at 12 ug/kg had a CR (n=8) or clinical CR (CRc: a CR in non-skin organs with gross reduction in cutaneous lesions and residual microscopic skin disease) (n=3). 75% (9/12) of these patients remain progression free for 3+ to 16+ months (ongoing), including 4 patients who remain on SL-401 in remission (for 3+ to 12+ months [up to 16+ cycles], ongoing) and 5 additional patients who experienced a major response on SL-401 (3 CR, 1 CRc, 1 PR) and were then successfully bridged to stem cell transplant (SCT; 3 auto-SCT and 2 allo-SCT) and all remain progression free for 3+ to 16+months (ongoing) since first SL-401 dose. Notably, a patient with r/r BPDCN was recently bridged to allo-SCT following CRc on SL-401. Conclusions: SL-401 demonstrates robust single agent activity in BPDCN, including 86% ORR in all-lines, with multiple CRs, in evaluable patients. Six patients, including 1 r/r patient, have proceeded to SCT after achieving a major response from SL-401, and an additional 7 patients remain on SL-401 for up to 12+ months, ongoing. The SL-401 side effect profile remains manageable, and no unexpected AEs have emerged with increased treatment duration, drug exposure, and patient enrollment. Response duration, progression-free and overall survival data continue to be encouraging and updated data will be presented. Clinical trial information: NCT02113982. Disclosures Lane: N-of-1: Consultancy; Stemline Therapeutics: Research Funding. Sweet:Ariad: Consultancy, Speakers Bureau; Incyte Corporation: Research Funding; Pfizer: Speakers Bureau; Karyopharm: Honoraria, Research Funding; Novartis: Consultancy, Speakers Bureau. Stein:Seattle Genetics: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau; Stemline Therapeutics: Consultancy, Research Funding; Argios: Research Funding; Celgene: Research Funding. Wang:Immunogen: Research Funding; Incyte: Speakers Bureau. Chen:Stemline Therapeutics, Inc.: Employment, Equity Ownership. Shemesh:Stemline Therapeutics: Employment, Equity Ownership. McDonald:Stemline Therapeutics: Employment, Equity Ownership. Brooks:Stemline Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties. Lancet:Quantum First: Consultancy; Pfizer: Research Funding; Seattle Genetics: Consultancy; Novartis: Consultancy; Biopath Holdings: Consultancy; ERYtech: Consultancy; Karyopharm: Consultancy; Baxalta: Consultancy; Kalo Bios: Consultancy; Celgene: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Boehringer-Ingelheim: Consultancy; Amgen: Consultancy. Kantarjian:Bristol-Myers Squibb: Research Funding; Amgen: Research Funding; ARIAD: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding. Konopleva:Reata Pharmaceuticals: Equity Ownership; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Stemline: Consultancy, Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Calithera: Research Funding.

scholarly journals Safety and activity of PD1 blockade by pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma: a single group, open-label, phase 2 trial

2014 ◽  
Vol 15 (1) ◽  
pp. 69-77 ◽  
Author(s):  
Jason R Westin ◽  
Fuliang Chu ◽  
Min Zhang ◽  
Luis E Fayad ◽  
Larry W Kwak ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Phase 2 ◽  
Single Group ◽  
Open Label ◽  
Phase 2 Trial ◽  
Open Label Phase ◽  
Pd1 Blockade
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