Phase 1 Dose-Ranging Study of Oral Ezatiostat Hydrochloride (Telintra®, TLK199) in Combination with Lenalidomide (Revlimid®) in Patients with Non-Deletion(5q) Low to Intermediate-1 Risk Myelodysplastic Syndrome (MDS)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2778-2778
Author(s):  
Azra Raza ◽  
Naomi Galili ◽  
Deborah Mulford ◽  
Scott E. Smith ◽  
Gail Brown ◽  
...  
Keyword(s):  
Research Funding ◽  
Platelet Transfusion ◽  
Phase 1 ◽  
Employment Equity ◽  
Off Label ◽  
Transfusion Independence ◽  
Dose Ranging ◽  
Equity Ownership ◽  
Grade 3 ◽  
Rbc Transfusion

Abstract Abstract 2778 Introduction: Lenalidomide is approved for the treatment of del(5q) MDS in US and Japan. In Low to Intermediate-1 (Int-1) risk non-del(5q) MDS, lenalidomide treatment is less effective with a lower response rate (25%) and shorter response duration [Raza A. et al, Blood, 2008.111,1]. Ezatiostat, a glutathione S-transferase P1-1 (GST P1-1) inhibitor, activates Jun kinase, promoting the growth and maturation of hematopoietic progenitors while inducing apoptosis in malignant cells. Based on the novel mechanism of action, response rates, non-overlapping toxicities, and tolerability observed in a single agent ezatiostat Phase 2 study in MDS, a study of the combination of ezatiostat and lenalidomide was conducted to determine the safety and efficacy of ezatiostat with lenalidomide in non-del(5q) Low to Int-1 risk MDS. Methods: In this multicenter Phase 1 dose-ranging study, ezatiostat was given at a starting dose of 2000 mg in combination with lenalidomide at 10 mg, days 1–21 of a 28-day cycle. In stage 1, 3–6 patients in a standard 3+3 design were treated before escalation to the ezatiostat/lenalidomide 2500/10 mg dose level. Treatment was given until lack of MDS response or unacceptable toxicity. Hematologic improvement-erythroid (HI-E) rates were determined by the MDS International Working Group (IWG; 2006) criteria. Results: Eighteen pts (median age 73 yrs; range 57–82; 72% male), with World Health Organization classifications: 4 refractory anemia (RA), 2 RA with excess blasts-1, 4 refractory cytopenia with multilineage dysplasia (RCMD), 5 RCMD with ring sideroblasts, 2 MDS-unclassified, 1 MDS/myeloproliferative disorder-U were enrolled. Thirteen pts (72%) were Int-1 risk, 5 (28%) Low risk; 4 pts (22%) had abnormal cytogenetics. Twelve RBC transfusion-dependent pts (67%) required a median of 6 units (range 4–10)/8-weeks. Two pts (11%) were platelet transfusion dependent. A total of 67 treatment cycles were given (median 3.5 cycles/pt [range 1–11]) and only 6 cycles (9%) required dose reductions and 8 (12%) dose delays. Two of 6 pts reported DLTs (Grade 3 diarrhea and Grade 3 rash) at 2500/10 mg, with 9 additional pts receiving the recommended combination dose of 2000/10 mg. Eleven of 18 pts were evaluable (4 at 2500/10 mg and 7 at 2000/10 mg), and 3 pts are still on therapy with insufficient treatment duration to be evaluable. The HI-E rate was 43% (3/7; 95% CI, 10%–82%) for pts at the recommended 2000/10 mg dose and 6 pts are continuing therapy at the time of analysis. Three of 8 (38%; 95% CI, 9%–76%) RBC transfusion-dependent evaluable pts achieved transfusion independence including 1 responder who did not respond to prior lenalidomide. In responders, the median increase in hemoglobin level was 3.4 g/dL (from 7.9 g/dL). In 2 of 4 thrombocytopenic pts, a HI-platelet (HI-P) response was observed. A bilineage (HI-E and HI-P) response in 2 of 4 pts with anemia and thrombocytopenia was reported. One RBC and platelet transfusion-dependent pt who had a poor response to prior anti-thymocyte globulin treatment achieved complete RBC and platelet transfusion independence. The combination was generally well tolerated with no unexpected toxicities. Most common treatment-related non-hematologic adverse events (AEs) were Grades 1 and 2 including: fatigue (6%, 28%), swelling (0%, 11%), anorexia (11%, 6%), rash (0%, 6%), skin odor (11%, 6%), nausea (39%, 11%), diarrhea (22%,17%), vomiting (28%,17%), upper abdominal pain (5.6%, 5.6%), and constipation (11%, 0%). Grade 3 events were rash (11%), nausea (6%), diarrhea (17%), and vomiting (6%). Most common hematologic-related AEs were Grades 1 and 2 thrombocytopenia (11%, 6%) and neutropenia (0%, 11%). Grade 3–4 AEs were thrombocytopenia (11%, 17%), neutropenia (17%, 11%), anemia (6%, 6%), and febrile neutropenia (11%, 0%). Conclusions: Ezatiostat is the first GST P1-1 inhibitor to cause clinically significant reductions in RBC and platelet transfusions, including RBC and platelet transfusion independence. Since ezatiostat is non-myelosuppressive, it is a good candidate for combination with lenalidomide and in this study, the combination was well tolerated. Interestingly, ezatiostat may also have the potential to enhance lenalidomide's efficacy. The recommended doses of this combination regimen for future studies is the ezatiostat/lenalidomide 2000/10 mg. Disclosures: Off Label Use: Lenalidomide was used off-label in patients with non-del5q MDS. Mulford:Celgene: Speakers Bureau. Brown:Telik, Inc.: Employment, Equity Ownership. Meng:Telik, Inc.: Employment, Equity Ownership. Lyons:Incyte: Research Funding; Telik: Research Funding; Alexion: Consultancy, Honoraria; Novartis: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Sekeres:Celgene: Consultancy, Honoraria, Speakers Bureau. Mesa:NS Pharma: Research Funding; Astra Zeneca: Research Funding; SBio: Research Funding; Lilly: Research Funding; Incyte: Research Funding; Celgene: Research Funding.

scholarly journals Imetelstat Treatment Leads to Durable Transfusion Independence (TI) in RBC Transfusion-Dependent (TD), Non-Del(5q) Lower Risk MDS Relapsed/Refractory to Erythropoiesis-Stimulating Agent (ESA) Who Are Lenalidomide (LEN) and HMA Naive

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 463-463 ◽  
Author(s):  
David P. Steensma ◽  
Uwe Platzbecker ◽  
Koen Van Eygen ◽  
Azra Raza ◽  
Valeria Santini ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Lower Risk ◽  
Research Funding ◽  
Employment Equity ◽  
Advisory Committees ◽  
Transfusion Independence ◽  
Equity Ownership ◽  
Grade 3 ◽  
Rbc Transfusion

Abstract BACKGROUND: Patients with TD lower-risk (LR)-MDS relapsed or refractory to ESA have limited treatment options. Imetelstat is a first-in-class telomerase inhibitor that targets cells with short telomere lengths and active telomerase, characteristics observed in some MDS patients. IMerge is an ongoing global study of imetelstat in RBC TD patients with LR-MDS (IPSS Low or Int-1). In the first 32 patients enrolled, 8-week TI rate was 34%, with 24-week TI of 16%, and HI-E of 59%. The most frequently reported adverse events were reversible grade ≥3 cytopenias (Fenaux et al EHA 2018 Abstr S1157). Higher response rates were observed in patients (n=13) who were LEN and HMA naïve without del(5q). We report here results in an additional 25 LEN and HMA naïve patients without del(5q), with longer term follow-up of the 13 initial patients meeting the same criteria. METHODS: IMerge is a phase 2/3 trial (NCT02598661) that includes LR-MDS patients with a high transfusion burden (≥4 units / 8 weeks) who are relapsed/refractory to ESA or have sEPO >500 mU/mL. The additional 25 were required to be LEN and HMA naïve and lack del(5q). Imetelstat 7.5 mg/kg was administered IV every 4 weeks. In addition to the key endpoints noted above, secondary endpoints include safety, time to and duration of TI. Biomarkers are also being explored, including telomerase activity, hTERT, telomere length, and genetic mutations. RESULTS: Overall, for the 38 LEN/HMA naïve and non-del(5q) patients, median age was 71.5 years and 66% were men. 63% of patients were IPSS Low and 37% Int-1. Median prior RBC transfusion burden was 8.0 (range 4-14) U, and 71% had WHO 2008 RARS or RCMD-RS. 9/37 (24%) patients with evaluable sEPO levels had baseline level >500 mU/mL. As of July 2018, with a median follow-up of 25.8 months for the initial 13 patients, and 5.2 months for the 25 recently included patients, the 8-week RBC-TI rate was 37% (14/38). Durability of 24-week TI responses was demonstrated, with a median duration of 10 months and the longest ongoing response now >2 years. Among the patients achieving durable TI, all showed a Hb rise of ≥3.0 g/dL compared to baseline during the transfusion-free interval. Response rates were similar in RARS/RCMD-RS (33% [9/27]) and other patients (27% [3/11]), and those with baseline EPO levels >500 mU/mL (33% [3/9]) and ≤500 mU/mL (32% [9/28]). Reversible grade ≥3 neutropenia and thrombocytopenia were each reported in 58% of the patients. Liver function test (LFT) elevations were mostly grade 1/2. Reversible grade 3 LFTelevations were observed in 3 (8%) patients on study. An independent Hepatic Review Committee deemed the observed LFT elevations were not imetelstat-related hepatic toxicities. SUMMARY / CONCLUSIONS: In this cohort of 38 non-del(5q) LR-MDS patients with a high RBC transfusion burden who were ESA relapsed/refractory and naïve to LEN/HMA, single-agent imetelstat yielded a TI rate of 37%, with a median duration of 10 months and limited side effects. Durable responses were characterized by transfusion independence >24 weeks and accompanied by Hb rise. Updated data will be presented. Disclosures Steensma: Takeda: Consultancy; Syros: Research Funding; Otsuka: Membership on an entity's Board of Directors or advisory committees; Onconova: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Kura: Research Funding; Janssen: Consultancy, Research Funding; H3 Biosciences: Research Funding; Celgene: Research Funding; Amphivena: Membership on an entity's Board of Directors or advisory committees; Acceleron: Consultancy. Platzbecker:Celgene: Research Funding. Van Eygen:Janssen: Consultancy, Research Funding; Roche: Research Funding; Amgen: Research Funding. Raza:Kura Oncology: Research Funding; Onconova: Research Funding, Speakers Bureau; Celgene: Research Funding; Novartis: Speakers Bureau; Geoptix: Speakers Bureau; Janssen: Research Funding; Syros: Research Funding. Santini:Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; AbbVie: Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Research Funding. Germing:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Novartis: Honoraria, Research Funding. Font:Celgene: Membership on an entity's Board of Directors or advisory committees. Samarina:Janssen: Research Funding. Díez-Campelo:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Bussolari:Janssen: Employment, Equity Ownership. Sherman:Janssen: Employment, Equity Ownership. Sun:Janssen: Employment, Equity Ownership. Varsos:Janssen: Employment, Equity Ownership. Rose:Janssen: Employment, Equity Ownership. Fenaux:Roche: Honoraria; Otsuka: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

A Phase I/II Study of Lenalidomide in Combination with Rituximab in Relapsed/Refractory Mantle Cell Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2719-2719 ◽  
Author(s):  
Luhua Wang ◽  
Luis Fayad ◽  
Fredrick B. Hagemeister ◽  
Sattva Neelapu ◽  
Felipe Samaniego ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Phase 2 ◽  
Employment Equity ◽  
Mantle Cell ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 2719 Poster Board II-695 Background: Rituximab directly targets CD20 positive lymphoma cells while lenalidomide targets the microenvironment. This combination was proven effective in vitro and in vivo in mantle cell lymphoma (Wu et al, Clin Cancer Res 2008; Zhang et al, Am J Hematol 2009). Clinically, lenalidomide (Habermann et al, Br J Haematol 2009) and rituximab have single-agent activity in mantle cell lymphoma (MCL) and may be an effective combination. The goal of our study was to determine the maximum tolerated dose (MTD) in phase 1 and evaluate the efficacy and safety of lenalidomide plus rituximab in patients with relapsed/refractory MCL in phase 2. Methods: Patients with relapsed/refractory MCL received lenalidomide on days 1–21 of every 28-day cycle, and rituximab (375 mg/m2) weekly during cycle 1. Dose escalation was used to determine the MTD with lenalidomide (10 mg, 15 mg, 20 mg, and 25 mg). Dose-limiting toxicity (DLT) was defined as grade 3 or 4 non-hematologic, or grade 4 hematologic adverse events in cycle 1. Phase 2 has reached targeted enrolment with 45 patients treated at MTD. Kaplan-Meier method was used to estimate progression free survival rate and response duration. Median time to event in months with 95% confidence interval was calculated. Of 45 patients treated at the MTD, the median age was 66 (46–85), 91% were males. All patients had received prior rituximab and were enrolled regardless of prior rituximab sensitivity or resistance. Results: The median follow-up time for the censored observations was 11.4 months. Two DLTs occurred at 25 mg in phase 1 (hypercalcemia, non-neutropenic fever); therefore, the MTD was 20 mg. The grade 3–4 non-hematologic events included elevated AST, elevated ALT, fatigue, myalgia, tremors, ataxia, cough, deep vein thrombosis, dyspnea, edema (facial), infection, neuropathy sensory, rash, and respiratory failure. Grade 3–4 hematologic adverse events included neutropenia (37 events), neutropenic fever (4 events), and thrombocytopenia (16 events). There were no responses in patients treated at 10 mg or 15 mg. Thirty six patients (36) were evaluable for response. Nine (9) patients are too early in their treatment and are not yet eligible for response evaluation. Among the 36 evaluable patients, 11 (31%) patients achieved CR, 8 (22%) patients achieved PR, 3 (8%) patients had minor response, 6 (17%) patients had stable disease and 8 (22%) patients had progressive mantle cell lymphoma. The overall response rate (CR + PR) was 53%. Seventy eight (78%) patients achieved stable disease or better and benefited from oral Lenalidomide plus 4 doses of rituximab. The median time to response was 2 months (2–8), and the median duration of response for the 19 patients with CR or PR was 18 months (95% CI: 10.6, NA) (range1–30 months). The median progression free survival for all patients on phase 2 was 14 months (95% CI: 9.8, NA) (ranging from 1–32 months). Conclusion: Oral lenalidomide plus rituximab resulted in durable responses in relapsed/refractory MCL with a favourable toxicity profile. Disclosures: Wang: Celgene: Honoraria, Research Funding. Hagemeister:Celgene Corporation: Consultancy. Samaniego:Celgene Corporation: Research Funding. Yi:Celgene Corporation: Research Funding. Shah:Celgene Corporation: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Elan: Consultancy; Millennium: Research Funding, Speakers Bureau. Bell:Celgene Corporation: Employment, Equity Ownership. Knight:Celgene Corporation: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Zeldis:Celgene: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Evaluation of Oral Azacitidine Using Extended Treatment Schedules: A Phase I Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 603-603 ◽  
Author(s):  
Guillermo Garcia-Manero ◽  
Steven D. Gore ◽  
Christopher R. Cogle ◽  
Elias J. Jabbour ◽  
M. Renee Ward ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Phase I ◽  
Research Funding ◽  
Phase I Study ◽  
Treatment Schedule ◽  
Employment Equity ◽  
Transfusion Independence ◽  
Clinical Responses ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 603 Parenteral azacitidine (AZA) is approved for administration on days 1–7 of a 28-day treatment schedule. Based on the short plasma half-life of AZA, S-phase restricted incorporation into DNA, and rapid re-methylation of DNA, it is possible that chronic daily exposure could enhanced its clinical activity. An oral formulation would be convenient and allow evaluation of lower doses administered on extended schedules. The initial phase I study of oral AZA, administered daily on a 7-day schedule demonstrated that it was bioavailable, safe, and clinically active in patients with MDS and AML (Garcia-Manero G, et al. Blood 2009;114:A117). Here, we report the results of a multicenter phase I exploration of extended oral AZA schedules, including dose-limiting toxicities (DLTs), safety, pharmacokinetic (PK), pharmacodynamic (PD), and preliminary response data. Patients aged ≥ 18 years with MDS, CMML or AML (not candidates for other therapies) were enrolled in the study. Inclusion criteria were a hemoglobin level of ≤ 9.0 g/dL, and/or platelet count of ≤ 50 × 109/L, and/or be RBC transfusion-dependent; prior azanucleoside therapy was not permitted. Patients received oral AZA daily (QD) or twice daily (BID) on 14- or 21-days schedules, with starting at a dose of 300 mg for QD dosing and 200 mg for BID dosing. Patients were enrolled into cohorts of 6 and evaluated for DLTs at the end of Cycle 1. Patients were monitored continuously for adverse events (AEs) and assessed for disease response at the end of every second cycle. During Cycle 1, on the first and last day of treatment, PK parameters were derived from AZA concentrations in the plasma after the first dose of the day. PD samples were collected during the first 2 cycles and DNA methylation changes were evaluated using a LINE-1 assay. To date, 25 patients (median age 68 years [range 44–87]; 14 male and 11 female) with MDS (n = 13), AML (n = 7 de novo and n = 3 transformed), and CMML (n = 2) have received oral AZA on extended treatment schedules. Two DLTs, grade 3 nausea and grade 3 vomiting, occurred in 1 of 6 DLT-evaluable patients treated at 14-days QD (n = 7). No DLTs were observed on the 21-day QD (n = 6) or 14-day BID (n = 6) schedules; safety evaluation for the 21-day BID schedule is ongoing (n = 6). The maximum tolerated dose has not been reached on these schedules; no patient has received > 300 mg per dose. Overall rates of all grades nausea, vomiting, diarrhea, constipation, and abdominal pain with the extended schedules were similar to those observed with the oral 7-day schedule. The rate of febrile neutropenia (all grades) was higher in the 21-day QD cohort. This was observed in 4 patients with baseline ANC < 500 and/or AML diagnosis. Most common grade 3/4 AEs in the QD schedules were febrile neutropenia (14-day, 1/7; 21-day, 4/6), anemia (14-day, 1/7; 21-day, 0/6), thrombocytopenia (14-day, 1/7; 21-day, 1/6), diarrhea (14-day, 0/7; 21-day, 1/6), nausea (14-day, 1/7; 21-day, 0/6), and vomiting (14-day, 1/7; 21-day, 0/6). Extended BID schedules are under evaluation. PK data have been generated for 19 of 25 patients. For the 300 mg 14-day QD, 300 mg 21-day QD, and 200 mg 14-day BID schedules, using mean AUC (first and last day) results, extrapolated cumulative exposures per cycle were ~28%, 42% and 26%, respectively, compared with historical exposure observed following subcutaneous administration. AZA exposure increased with increasing dose, but was not dose-proportional. Clinical responses were observed for MDS/CMML patients on both extended QD schedules, with assessment ongoing for BID schedules (Table). In summary, extended (14- and 21-day) dosing of oral AZA is generally well tolerated, with no AZA accumulation, and promising clinical responses were observed, including complete remission (CR), marrow CR (mCR), and hematologic improvement (HI). Table. Parameter, n (%) Oral AZA Treatment Schedule MDS/CMML Responders/Evaluable patients, (%) 14-day QD 21-day QD Overall response* (CR, mCR, any HI) 5/6 (83) 3/3 (100) CR 0/6 2/3 (67) mCR 0/6 3/3 (100) HI 5/6 (83) 3/3 (100) HI-erythroid 3/5 (60) 1/1 (100) HI-platelet† 2/5 (40) 3/3 (100) HI-neutrophil 0/1 0/1 Transfusion independence 3/4 (75) 1/2 (50) RBC 1/2 (50) 1/1 (100) Platelet 2/2 (100) 0/1 * International Working Group 2006 criteria, patients only counted once for overall response, but may be counted more than once in individual response categories. † Includes patients achieving partial (≥ 50%) or complete platelet transfusion independence. Disclosures: Gore: Celgene: Consultancy, Equity Ownership, Research Funding. Cogle:Celgene: Research Funding, Speakers Bureau. Ward:Celgene: Equity Ownership. MacBeth:Celgene: Employment, Equity Ownership. Laille:Celgene: Employment. Giordano:Celgene: Employment, Equity Ownership. Kantarjian:Celgene: Research Funding. Skikne:Celgene: Employment.

Phase II Study of the Pan-Deacetylase Inhibitor Panobinostat in Combination with Bortezomib and Dexamethasone in Relapsed and Bortezomib-Refractory Multiple Myeloma (PANORAMA 2)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 814-814 ◽  
Author(s):  
Paul G. Richardson ◽  
Melissa Alsina ◽  
Donna M. Weber ◽  
Steven E. Coutre ◽  
Sagar Lonial ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Phase 1 ◽  
Treatment Phase ◽  
Employment Equity ◽  
Advisory Committees ◽  
Overall Response ◽  
Equity Ownership ◽  
Grade 3 ◽  
Stage 1

Abstract Abstract 814FN2 Background: Patients with refractory multiple myeloma (MM) have limited treatment options and an extremely poor prognosis. A recent study of patients who were refractory to bortezomib and were relapsed following, refractory to or ineligible to receive an immunomodulatory drug (IMiD, thalidomide or lenalidomide) demonstrated a median event-free survival of only 5 months (Kumar S et al, Leukemia, 2011). Panobinostat is an oral pan-deacetylase inhibitor (pan-DACi) that increases acetylation of proteins involved in multiple oncogenic pathways. Preclinical studies have demonstrated synergistic anti-myeloma activity of the combination of panobinostat and bortezomib through dual inhibition of the aggresome and proteasome pathways. In a phase I study (B2207) of patients with relapsed or relapsed/refractory MM treated with panobinostat + bortezomib, clinical responses (≥ minimal response [MR]) were observed in 65% of patients, including in patients with bortezomib-refractory disease. PANORAMA 2 seeks to expand upon these preliminary results and seeks to determine whether panobinostat can sensitize resistant patients to a bortezomib-containing therapeutic regimen. Methods: PANORAMA 2 is a single arm, phase II study of panobinostat + bortezomib + dexamethasone in patients with bortezomib-refractory MM. Patients with relapsed and bortezomib-refractory MM (≥ 2 prior lines of therapy including an IMiD and who had progressed on or within 60 days of the last bortezomib-based therapy) are treated in 2 phases. Treatment phase 1 consists of 8 three-week cycles of oral panobinostat (20 mg days 1, 3, 5, 8, 10, 12) + intravenous bortezomib (1.3 mg/m2 days 1, 4, 8, 11) + oral dexamethasone (20 mg on day of and after bortezomib). Patients demonstrating clinical benefit (≥ stable disease) can proceed to treatment phase 2, consisting of 4 six-week cycles of panobinostat (20 mg TIW 2 weeks on 1 week off, and repeat) + bortezomib (1.3 mg/m2 days 1, 8, 22, 29) + dexamethasone (20 mg on day of and after bortezomib). The primary endpoint is overall response (≥ partial response [PR]), as defined by the European Group of Blood and Marrow Transplantation 1998 criteria, in the first 8 cycles of treatment phase 1. A Simon 2-stage design is used to test the primary endpoint where ≥ 4 responses (≥ PR) in 24 patients are needed in stage 1 in order to proceed to stage 2, where ≥ 9 responses in all patients (N = 47) are required to reject the null hypothesis (overall response rate ≤ 10%). Results: A sufficient number of responses ≥ PR were observed in stage 1 to allow for enrollment to continue to stage 2. As of 15 July 2011, 53 patients with bortezomib-refractory MM were enrolled. Safety and demographic data were available for 48 patients. The median age was 61 (41–88) years. Patients were heavily pretreated, with a median of 4 (2–14) prior regimens, and most patients (69%) received prior autologous stem cell transplant. Efficacy data were available for 44 patients. At the time of this analysis, 9 patients achieved ≥ PR (2 near CR [nCR] and 7 PR) as best overall response, and an additional 7 patients achieved an MR. Responders exhibited a long duration on therapy, and, to date, 8 patients have proceeded to treatment phase 2. The 2 patients with nCR have received ≥ 10 cycles of treatment (duration of therapy 190 and 253 days). Four patients who achieved PR have received ≥ 9 cycles (duration of therapy 155–225 days). Updated response data will be presented. Common adverse events (AEs) of any grade included, fatigue (52%), diarrhea (41%), thrombocytopenia (38%), nausea (38%), and anemia (21%). Gastrointestinal AEs were generally mild, with a relatively low incidence of grade 3/4 events. Grade 3/4 AEs were generally hematologic in nature, with grade 3/4 thrombocytopenia, anemia, and neutropenia reported in 38%, 12%, and 10% of patients, respectively. Other common nonhematologic grade 3/4 AEs included fatigue (10%) and pneumonia (10%). Of note, to date, a relatively low rate of peripheral neuropathy (17%) has been observed. No grade 3/4 peripheral neuropathy has been observed. Conclusions: The combination of panobinostat and bortezomib is a promising treatment for patients with bortezomib-refractory MM. These data, along with forthcoming data from the phase III study of panobinostat/placebo + bortezomib + dexamethasone in patients with relapsed MM (PANORAMA 1), will further define the potential role of panobinostat in the treatment of patients with MM. Disclosures: Richardson: Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Alsina:Novartis: Research Funding; Celgene: Research Funding; Ortho Biotech: Research Funding; Onyx: Research Funding; Millennium: Consultancy, Research Funding. Weber:Millennium: Honoraria; Celgene: Honoraria, Research Funding; Novartis: Research Funding. Lonial:Millennium: Consultancy; Celgene: Consultancy; Merck: Consultancy; Onyx: Consultancy; BMS: Consultancy; Novartis: Consultancy. Gasparetto:Millennium: Speakers Bureau. Warsi:Novartis: Employment, Equity Ownership. Ondovik:Novartis: Employment, Equity Ownership. Mukhopadhyay:Novartis: Employment, Equity Ownership. Snodgrass:Novartis: Employment, Equity Ownership.

An Open-Label, Phase 1 Study of R-CVP in Combination with Inotuzumab Ozogamicin in Patients with CD22-Positive B-Cell Non-Hodgkin's Lymphoma: Preliminary Safety and Efficacy Data

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1633-1633
Author(s):  
Michinori Ogura ◽  
Kiyohiko Hatake ◽  
Andrew Davies ◽  
Michael Crump ◽  
Kensei Tobinai ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Phase 1 ◽  
Employment Equity ◽  
Efficacy Data ◽  
Inotuzumab Ozogamicin ◽  
Advisory Committees ◽  
Common Grade ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 1633 Background: Inotuzumab ozogamicin (INO) is a humanized anti-CD22 antibody conjugated to calicheamicin, a potent antitumor antibiotic. CD22 is expressed on the majority of B-cell non-Hodgkin's lymphomas (NHL). This phase 1 study was conducted to identify the maximum tolerated dose (MTD) of INO when given in combination with R-CVP (rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, and vincristine 1.4 mg/m2 all on Day 1 and prednisone 40 mg/m2on Days 1–5) every 21 days, and to obtain preliminary safety and efficacy data for this regimen. Patients and methods: The study enrolled patients with relapsed/refractory CD22+ B-cell NHL. The dose-escalation part (Part 1; previously presented) identified the MTD as INO 0.8 mg/m2 given on Day 2 with R-CVP q3wks [Blood. 2011;118:3715]. Subsequent cohorts included the MTD confirmation cohort (Part 2) and MTD expansion cohort (Part 3), for collection of additional safety and preliminary efficacy data. Untreated patients who were not candidates for anthracyclines were allowed in Part 2 and Part 3 of the study. In Part 2 (n = 10), confirmation of the MTD required a dose-limiting toxicity (DLT) rate of <33% in Cycle 1 and fewer than 1/3 of patients discontinuing prior to Cycle 3 due to an adverse event (AE). In Part 3 (n = 22), additional patients were enrolled to explore preliminary signs of activity of INO when given in combination with R-CVP. Results: In Parts 2 and 3, a total of 32 patients with follicular lymphoma (FL; n = 15), diffuse large B-cell lymphoma (DLBCL; n = 16), or mantle cell lymphoma (n = 1) were enrolled. CD22 expression was confirmed by immunohistochemistry or flow cytometry prior to enrollment. The median age was 65 years (range, 44–81 years); 34% of patients had 1 prior anti-lymphoma regimen, 34% had 2, 28% had ≥3, and 3% (n = 1) had no previous therapy (median, 2; range, 0–6). The median number of cycles received was 5 (range, 1–6). In Part 2, the MTD was confirmed as standard-dose R-CVP plus INO 0.8 mg/m2, with 2 of 10 patients presenting with a DLT (grade 3 increase in alanine/aspartate aminotransferases [ALT/AST] and grade 4 neutropenia requiring granulocyte-colony stimulating factor). Four patients discontinued due to AEs after 2 cycles (n = 1), 3 cycles (n = 2), and 5 cycles (n = 1), respectively. Across Parts 2 and 3, the most common treatment-related AEs (all grades) were thrombocytopenia (78%), neutropenia (66%), fatigue (53%), constipation (50%), leukopenia (50%), and nausea (41%); the most common grade 3/4 AEs included neutropenia (63%), thrombocytopenia (53%), leukopenia (38%), lymphopenia (31%), increased ALT (9%), increased AST (6%), and febrile neutropenia (6%). There was 1 case of treatment-related fatal pneumonia associated with grade 4 neutropenia. Ten patients discontinued study treatment due to AEs, with thrombocytopenia or delayed recovery from thrombocytopenia being the leading AE causing study drug discontinuation (n = 9 [grade 1/2, n = 6; grade 3/4, n = 3]). The best overall response (ORR; partial + complete response [CR]) from Part 2 and 3 (31 evaluable patients) was 77% (n = 24/31), including 29% (n = 9/31) with CR. Of patients with FL, the ORR was 100% (n = 15/15), including 53% (n = 8/15) with CR. Of patients with DLBCL, the ORR was 60% (n = 9/16), including 7% (n = 1/16) with CR. Conclusions: Results from this phase I study showed that R-CVP in combination with INO 0.8 mg/m2 may have acceptable toxicity and promising activity in patients with relapsed or refractory CD22+ B-cell NHL, based on the response rates in FL and DLBCL. The most common grade 3/4 AEs were hematological toxicities, notably thrombocytopenia and neutropenia. Follow-up for progression-free survival and overall survival is currently ongoing; however, the observed results warrant additional study in both indolent and aggressive B-cell NHL. Disclosures: Ogura: Pfizer Inc: Research Funding. Hatake:Pfizer Inc: Research Funding. Davies:Pfizer Inc: Research Funding. Crump:Pfizer, Celgene, Roche, Millennium, Seattle Genetic: Membership on an entity's Board of Directors or advisory committees. Tobinai:Merck, Zenyaku, Symbio, Biomedics, Pfizer, GSK, Chugai/Roche: Research Funding. Smith:Pfizer Inc: Research Funding. Offner:Pfizer Inc: Research Funding. Wang:Pfizer Inc: Employment, Equity Ownership. Ishibashi:Pfizer Inc: Employment, Equity Ownership. Paccagnella:Pfizer Inc: Employment, Equity Ownership. Vandendries:Pfizer Inc: Employment, Equity Ownership. MacDonald:Roche Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding.

MM-008: A Phase 1 Trial Evaluating Pharmacokinetics and Tolerability of Pomalidomide + Low-Dose Dexamethasone in Patients with Relapsed or Refractory and Refractory Multiple Myeloma and Renal Impairment

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4730-4730 ◽  
Author(s):  
Jeffrey Matous ◽  
David S Siegel ◽  
Sagar Lonial ◽  
R. Donald Harvey ◽  
Claudia Kasserra ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Renal Impairment ◽  
Creatinine Clearance ◽  
Research Funding ◽  
Platelet Transfusion ◽  
Low Dose ◽  
Phase 1 ◽  
Employment Equity ◽  
Refractory Multiple Myeloma ◽  
Equity Ownership

Abstract Background: Pomalidomide (POM) is indicated for patients (pts) with relapsed or refractory multiple myeloma (RRMM) who received ≥ 2 prior therapies including lenalidomide and bortezomib and demonstrated progression on or within 60 days of completion of the last treatment (Tx). Renal impairment (RI) is a common comorbidity of multiple myeloma (MM) occurring in 20% to 40% of pts (Eleutherakis-Papaikovou, et al. Leuk Lymphom, 2007; Knudsen, et al., Eur J Haematol, 2000). POM is extensively metabolized, with < 5% eliminated renally as the parent drug (Hoffmann, et al., Cancer Chemother Pharmacol, 2013). POM in combination with low-dose dexamethasone (LoDEX) has shown efficacy in pts with RRMM and moderate RI (creatinine clearance [CrCl] < 30-44 mL/min), but pts with severe RI (CrCl < 30 mL/min; serum creatinine> 3 mg/dL) were excluded from most trials (Siegel, et al., Blood. 2012; Weisel, et al., J Clin Oncol, 2013). MM-008 is a multicenter, open-label, phase 1 study assessing the pharmacokinetics (PK) and safety of POM + LoDEX in pts with RRMM and normal or severely impaired renal function. Methods: Pts withRRMM (≥ 1 prior Tx) and normal kidney function or mild RI (creatinine clearance [CrCl] ≥ 60 mL/min; Cohort A—control arm), severe RI (CrCl < 30 mL/min) not requiring dialysis (Cohort B), and severe RI requiring dialysis (Cohort C) were eligible. Cohort A received POM 4 mg, and Cohort B received POM 2 or 4 mg on days 1-21 of a 28-day cycle, following a 3 + 3 dose-escalation design. Cohort B results informed the 4 mg dosing of Cohort C. All cohorts received DEX 40 mg (20 mg for pts aged > 75 yrs) on days 1, 8, 15, and 22. Tx continued until progression or unacceptable toxicity. Dose-limiting toxicities (DLTs) were defined as any of the following: grade (Gr) 4 neutropenia, febrile neutropenia, Gr 4 thrombocytopenia that is a ≥ 30% decrease in platelets from baseline and requires > 1 platelet transfusion, Gr 3 thrombocytopenia with significant bleeding (requiring hospitalization and/or platelet transfusion), Gr 4 infection, or ≥ Gr 3 other non-hematologic toxicity related to POM. Serial plasma samples were analyzed to generate PK parameters. Updated PK and AE data for all cohorts will be presented. Results: As of July 17, 2014, updated data for 16 treated pts were available (8 in Cohort A; 3 in Cohort B at 2 mg; 4 in Cohort B at 4 mg; and 1 in Cohort C). Median age was 67 yrs (range, 46-76 yrs), 56% were male, all had Eastern Cooperative Oncology Group performance status 0 or 1, and a median time from diagnosis of 3.8 yrs (range, 0.6-12.5). No DLTs in cycle 1 were reported for any cohort. The most common Gr ≥ 3 adverse events (AEs) were neutropenia, anemia, infection, and fatigue (Table). Median relative dose intensity was consistent across cohorts: 90% (Cohort A), 90% (Cohort B; 2 mg), 100% (Cohort B; 4 mg) and 100% (Cohort C). Three pts discontinued due to AEs (2 in Cohort A and 1 in Cohort B 4 mg); no deaths have occurred during treatment phase. Conclusion: MM-008 is an ongoing trial prospectively evaluating the PK and safety of POM + LoDEX in pts with RRMM and severe RI. Preliminary PK data support mean dose-normalized exposure in pts with RRMM being similar between those with severe RI and those with no or mild RI at the clinical dose of 4 mg; early tolerability data (after one cycle) are encouraging. Table Cohort A(n = 8) Cohort B(n = 3) Cohort B(n = 4) Cohort C(n = 1) Cohort Characteristics POM dose 4 mg 2 mg 4 mg 4 mg CrCl (mL/min) ≥ 60 mL/min < 30 mL/min without dialysis < 30 mL/min without dialysis < 30 mL/min with dialysis Safety Dose-limiting toxicities (n) N/A 0 0 0 Grade 3/4 AEs (n) Neutropenia 4 2 1 0 Anemia 3 1 2 0 Infection 3 2 0 0 Fatigue 2 0 0 0 N/A: Not applicable (4 mg POM is approved dose for population) Disclosures Matous: Celgene Corp: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Siegel:Celgene Corp: Honoraria, Speakers Bureau; Onyx: Honoraria, Speakers Bureau; Millennium: Honoraria, Speakers Bureau. Lonial:Onyx: Consultancy; BMS: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Millennium: Consultancy. Harvey:Celgene Corp: Research Funding. Kasserra:Celgene Corp: Employment, Equity Ownership. Li:Celgene Corp: Employment, Equity Ownership. Chen:Celgene Corp: Employment. Doerr:Celgene Corporation: Employment. Sternas:Celgene Corp: Employment, Equity Ownership. Zaki:Celgene : Employment, Equity Ownership. Jacques:Celgene Corp: Employment, Equity Ownership. Shah:Celgene Corp: Consultancy, Research Funding.

The Safety and Activity of BMS-906024, a Gamma Secretase Inhibitor (GSI) with Anti-Notch Activity, in Patients with Relapsed T-Cell Acute Lymphoblastic Leukemia (T-ALL): Initial Results of a Phase 1 Trial

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 968-968 ◽  
Author(s):  
Patrick A. Zweidler-McKay ◽  
Daniel J. DeAngelo ◽  
Dan Douer ◽  
Hervé Dombret ◽  
Oliver G. Ottmann ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Research Funding ◽  
Phase 1 ◽  
Employment Equity ◽  
Mutation Status ◽  
Response Data ◽  
Notch Receptors ◽  
Equity Ownership ◽  
Grade 3 ◽  
Count Recovery

Abstract Background: Activating mutations in Notch receptors are found in multiple hematopoietic malignancies, including > 50% of patients with T-ALL, making it the most common genetic abnormality in this disease. GSIs block activation of Notch receptors and limit growth and survival in pre-clinical T-ALL models. However, various GSIs evaluated in clinical trials have had on target toxicities and have not been reported to show significant responses. CA216002 is a multicenter phase 1 trial designed to assess the safety of a novel intravenous GSI BMS-906024 in patients with relapsed or refractory T-ALL and T-cell lymphoblastic lymphoma (T-LL). We are presenting the initial toxicity profile and response data on this trial. Methods: Adults with relapsed/refractory T-ALL or T-LL were enrolled and received BMS-906024 intravenously weekly at doses of 0.6 mg, 4 mg, and 6 mg. Due to the rapid progression of T-ALL in many cases, administration of glucocorticoids or other agents was permitted and dosing guidelines for dexamethasone were provided in the protocol. Results: As of July 2, 2014, safety and response data are available on 25 patients (age 18-74 yrs) with relapsed/refractory T-ALL/T-LL that received at least one dose of BMS-906024, at doses of 0.6 mg (n=1), 4 mg (n=10), and 6 mg (n=14). Seven patients did not complete the first 4-week cycle due to rapid disease progression or disease-related death (n=5), infusion reaction (n=1), or an unrelated adverse event (n=1). Safety: The drug-related grade 3-5 adverse events included grade 4 events of anemia, hypophosphatemia, and thrombocytopenia, and grade 3 events of diarrhea, febrile bone marrow aplasia, hepatotoxicity, hypophosphatemia, pancytopenia, and tumor lysis syndrome (n=1 each). Drug-related diarrhea was common (n=11, 44%), consistent with expectations for Notch inhibition, but was generally grade 1-2 with only one grade 3 event. One dose-limiting toxicity involving grade 3 elevations of ALT and AST without bilirubin elevation (reported as grade 3 hepatotoxicity) occurred at the 4 mg dose level. One death not related to disease progression occurred, due to GI and post-surgical hemorrhage associated with pancytopenia; hemorrhage was considered not related, but pancytopenia was considered related to study drug. Responses: Eight patients (32%; 4 at 4 mg and 4 at 6 mg) had at least 50% reduction in bone marrow (BM) blasts, including one formal CR and one PR (both at 6 mg), and three of these eight had 98-100% clearance of BM blasts. (One patient, marked “*” below, began the study with 0.1% BM blasts and is not included in the eight.) The patient who achieved a CR began the study with 85% BM blasts and an absolute peripheral blood (PB) blast count of 38 k/mcL. By the end of the first cycle the BM and PB were cleared of blasts, and by the end of the second cycle there was count recovery. This patient received dexamethasone during the first cycle only, and left the study after 3 cycles in CR for an allogeneic transplant. The patient who achieved a PR began with 32% BM blasts, and by the end of the first cycle the BM blasts had decreased to 7% with improvement in ANC. The additional six patients with 50-100% decreases in BM blasts had residual lymphadenopathy, had incomplete count recovery or failed to meet other criteria which prevented them from being considered CR or PR based on the protocol definitions. One of these six patients also received hydroxyurea beginning on study day 16. Biomarkers: The figure shows change in BM blasts in 12 patients with paired BM assessments and Notch mutation status available. BM responses occurred in both Notch mutant and wildtype patients. Conclusions: Overall 8 of the 25 patients (32%) showed at least 50% reduction in BM blasts including one CR and one PR. Although the contribution of concurrent glucocorticoid therapy to the improvement in some patients is not clearly defined, the multiple responses on this trial suggest anti-leukemia activity of BMS-906024. This represents the first Notch targeting trial leading to multiple responses in relapsed/refractory T-ALL. BMS-906024 was relatively well tolerated, with minimal diarrhea in this population. The weekly dosing of this long-acting GSI shows promise for targeting Notch in T-ALL. Pharmacokinetic and additional biomarker data will be presented. Figure 1 Figure 1. Maximum Percent Reduction from Baseline of BM Blasts in Patients with Paired BM Assessments and Known Mutation Status Disclosures Zweidler-McKay: BMS: Research Funding. Off Label Use: BMS-906024 is in early Phase I clinical trials, and does not yet have an FDA-approved indication.. Douer:BMS: Research Funding. Ottmann:BMS: Consultancy, Honoraria, Research Funding. Vey:BMS: Honoraria. Thomas:BMS: Research Funding. Zhu:BMS: Employment. Huang:BMS: Employment, Equity Ownership. Bajaj:BMS: Employment. Fischer:BMS: Employment, Equity Ownership.

scholarly journals Interim Analysis of a Phase 1 Study of the Antibody-Drug Conjugate SGN-CD19A in Relapsed or Refractory B-Lineage Non-Hodgkin Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1741-1741 ◽  
Author(s):  
Craig H. Moskowitz ◽  
Andres Forero-Torres ◽  
Bijal D. Shah ◽  
Ranjana Advani ◽  
Paul Hamlin ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Phase 1 ◽  
Objective Response ◽  
Antibody Drug Conjugate ◽  
Employment Equity ◽  
Non Hodgkin Lymphoma ◽  
Equity Ownership ◽  
Grade 3

Abstract Background CD19, a B-cell specific marker, is expressed in the majority of patients with B-cell non-Hodgkin lymphoma (NHL). SGN-CD19A is a novel antibody-drug conjugate (ADC) composed of a humanized anti-CD19 monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin F (MMAF) via a maleimidocaproyl linker. Methods This ongoing phase 1, open-label, dose-escalation study investigates the safety, tolerability, pharmacokinetics, and antitumor activity of SGN-CD19A in patients with relapsed or refractory B-cell NHL (NCT 01786135). Eligible patients are ≥12 years of age and must have a confirmed diagnosis of diffuse large B-cell lymphoma (DLBCL), including transformed follicular histology; mantle cell lymphoma (MCL); follicular lymphoma grade 3 (FL3); Burkitt lymphoma; or B-cell lymphoblastic lymphoma. Patients must be relapsed or refractory to at least 1 prior systemic regimen. Patients with DLBCL or FL3 must have also received intensive salvage therapy with or without autologous stem cell transplant (SCT), unless they refused or were deemed ineligible. A modified continual reassessment method is used for dose allocation and maximum tolerated dose (MTD) estimation. SGN-CD19A is administered IV on Day 1 of 21-day cycles (0.5–6 mg/kg). Response is assessed with CT and PET scans according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Results To date, 44 patients have been treated: 39 patients (89%) with DLBCL (including 10 with transformed DLBCL), 4 (9%) with MCL, and 1 (2%) with FL3. Median age was 65 years (range, 33–81). Patients had a median of 2 prior systemic therapies (range, 1–7), and 10 patients (23%) had autologous SCT. Twenty-six patients (59%) were refractory to their most recent prior therapy, and 18 (41%) were relapsed. Patients received a median of 3 cycles of treatment (range, 1–12) at doses from 0.5–6 mg/kg. Eleven patients (25%) remain on treatment, and 33 have discontinued treatment (18 due to progressive disease [PD], 5 for investigator decision, 5 for adverse events [AE], 4 because of patient decision/non-AE, and 1 for SCT). No dose-limiting toxicity (DLT) in Cycle 1 has been reported. Treatment-emergent AEs reported in ≥20% of patients were blurred vision (59%), dry eye (39%), fatigue (39%), constipation (32%), keratopathy (23%), and pyrexia (20%). Corneal exam findings consistent with superficial microcystic keratopathy were observed in 25 patients (57%) and were mostly Grade 1/2. Grade 3/4 corneal AEs were observed in 4 patients at the higher doses; the majority resolved or improved to Grade 1/2 at last follow-up. Corneal AEs were treated with ophthalmic steroids, and during the trial steroid eye drop prophylaxis was instituted with each dose of study drug. SGN-CD19A ADC plasma exposures were approximately dose-proportional. Accumulation was observed following multiple dose administrations, consistent with a mean terminal half-life of about 2 weeks, suggesting less frequent dosing might be possible. In the 43 efficacy-evaluable patients, the objective response rate (ORR) is 30% (95% CI [17, 46]), including 7 complete responses (CRs; 16%) and 6 partial responses (PRs; 14%). Of the 13 patients with an objective response, 8 are still on study with follow-up times of 0.1–31 weeks; 2 are no longer on study; and 3 had subsequent PD or death with response durations of 14, 19, and 31 weeks. Table Best Clinical Response by Disease Status Relative to Most Recent Therapy, n (%) Relapsed N=17 Refractory N=26 Total N=43 CR 5 (29) 2 (8) 7 (16) PR 4 (24) 2 (8) 6(14) SD 4 (24) 9 (35) 13 (30) PD 4 (24) 13 (50) 17 (40) ORR (CR + PR), (95% CI) 53 (28, 77) 15 (4, 35) 30 (17, 46) Conclusions To date, SGN-CD19A has shown evidence of clinical activity with an ORR of 30% and CR rate of 16%. Enrollment in the trial is ongoing to further refine optimal dose and schedule. SGN-CD19A is generally well-tolerated. No DLTs have been observed in tested dose levels. Observed ocular AEs are manageable with steroid eye drops and dose modifications. The high response rate (53%) in relapsed patients and low rate of bone marrow suppression or neuropathy suggest that SGN-CD19A could be incorporated into novel combination regimens in earlier lines of therapy. Disclosures Moskowitz: Merck: Research Funding; Genentech: Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding. Off Label Use: SGN-CD19A is an investigational agent being studied in patients with B-cell malignancies. SGN-CD19A is not approved for use. . Forero-Torres:Seattle Genetics, Inc.: Research Funding, Speakers Bureau. Shah:Pharmacyclics: Speakers Bureau; SWOG: Consultancy; Celgene: Consultancy, Speakers Bureau; NCCN: Consultancy; Seattle Genetics, Inc.: Research Funding; Janssen: Speakers Bureau. Advani:Janssen Pharmaceuticals: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Takeda International Pharmaceuticals Co.: Research Funding; Seattle Genetics, Inc.: Research Funding, Travel expenses Other. Hamlin:Seattle Genetics, Inc.: Consultancy, Research Funding. Kim:Bayer: Consultancy; Eli Lily: Consultancy; Seattle Genetics, Inc.: Consultancy, Research Funding. Kostic:Seattle Genetics, Inc.: Employment, Equity Ownership. Sandalic:Seattle Genetics, Inc.: Employment, Equity Ownership. Zhao:Seattle Genetics, Inc.: Employment, Equity Ownership. Fanale:Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding, Travel expenses Other.

Phase 1 Clinical Trial of the Novel Structure Proteasome Inhibitor NPI-0052 in Patients with Relapsed and Relapsed/Refractory Multiple Myeloma (MM).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 431-431 ◽  
Author(s):  
Paul Richardson ◽  
Craig Hofmeister ◽  
Andrzej Jakubowiak ◽  
Todd M. Zimmerman ◽  
Matthew A. Spear ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Light Chain ◽  
Safety Profile ◽  
Research Funding ◽  
Phase 1 ◽  
Proteasome Inhibition ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 431 Background: NPI-0052 has a novel, non-peptide based, bicyclic structure resulting in a unique proteasome inhibition and safety profile. In contrast to other proteasome inhibitors, NPI-0052 produces rapid, broad and prolonged inhibition of all 3 catalytic activities. Preclinical data subsequently suggested improvements in toxicology and efficacy, including activity MM resistant to bortezomib (BZ) and other agents (Chauhan et al, Cancer Cell 2005), thus this Phase 1 dose escalation trial in patients (pts) with relapsed/refractory MM was initiated. Materials and Methods: Patients (pts) were treated with NPI-0052 IV weekly for 3 weeks in 4-week cycles. Measurable disease by EBMT criteria was not required. The dose of NPI-0052 was escalated using a combination of accelerated titration and 3+3 design. PK and proteasome inhibition (blood and PBMCs) were assayed after the first and third doses. Preliminary Results: 27 pts have been treated at doses ranging from 0.025 to 0.7 mg/m2; median age is 62; 18 males/9 females; IgG/IgA/light chain/non-secretory 14/4/2/6; median of 4 prior regimens and 27% refractory to prior bortezomib. Reversible DLT was observed in two out of eight patients treated at 0.7 mg/m2 (Grade 3 fatigue; Grade 3 mental status changes and loss of balance), with 2 additional pts undergoing dose reductions in Cycle 1 (nausea and vomiting; vertigo and confusion/word-finding difficulties). Prophylactic anti-emetics have been instituted with a decrease in infusion-related nausea; similarly, pts with dizziness/vertigo have been administered meclizine with symptomatic improvement. Other drug-related adverse events have consisted principally of mild-to-moderate fatigue, nausea, vomiting, dizziness, headache and diarrhea; interestingly, myelosuppression, neuropathy and thrombosis do not appear to be elicited by NPI-0052. PK assessment demonstrates a rapid elimination half-life (<20 minutes) and relatively large Vz. NPI-0052 produces dose dependent proteasome inhibitions. At 0.7 mg/m2, Day 1/Day 15 inhibition of chymotrypsin-like activity in whole blood is 73% and 99%, respectively (the value for bortezomib at 1.3 mg/m2 is 65%). One patient with IgA MM (4 prior regimens plus ASCT; relapsed after prior BZ, not refractory) had a 71% decrease in M-protein (unconfirmed PR; off study after 3 cycles). A second pt with non-secretory disease (4 prior regimens;relapsed after prior BZ, not refractory) had a nearly 50% reduction in involved light chain; this pt remains active on study at 5+ months. In addition, 8 pts with relapsed/refractory MM remained on study for between 6-15 months (3 pts were on-study for over one year) with stable disease and no significant toxicity; 2 of these pts were BZ-refractory. Conclusions: Tolerability of 0.7 mg/m2 continues to be investigated in pts with MM, with prophylactic antiemetics and meclizine to reduce common drug-related toxicities of nausea and dizziness. The safety profile of NPI-0052 is importantly different from bortezomib in spite of higher and more durable proteasome inhibition; peripheral neuropathy and thrombocytopenia were not seen. Accrual continues to expand upon these results and assess the new lyophile formulation of NPI-0052. Disclosures: Richardson: Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keryx: Membership on an entity's Board of Directors or advisory committees; Gentium: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Vorinostat is a histone deacetylase (HDAC) inhibitor that was approved in the FDA in October 2006 for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma (CTCL) who have progressive, persistent, or recurrent disease on or following two systemic therapies. Jakubowiak:Celgene: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Centocor Ortho Biotech: Consultancy, Honoraria; Exelixis: Consultancy, Honoraria; Bristol-Myers-Squibb: Consultancy, Honoraria. Spear:Nereus Pharmaceuticals: Employment, Equity Ownership. Palladino:Nereus Pharmaceuticals: Employment, Equity Ownership. Longenecker:Nereus Pharmaceuticals: Employment, Equity Ownership. Neuteboom:Nereus Pharmaceuticals: Employment, Equity Ownership. Cropp:Nereus Pharmaceuticals: Consultancy. Lloyd:Nereus Pharmaceuticals: Employment, Equity Ownership. Hannah:Nereus Pharmaceuticals: Consultancy. Anderson:Nereus Pharmaceuticals: Consultancy, Research Funding.

Initial Findings From the PACE Trial: A Pivotal Phase 2 Study of Ponatinib in Patients with CML and Ph+ ALL Resistant or Intolerant to Dasatinib or Nilotinib, or with the T315I Mutation

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 109-109 ◽  
Author(s):  
Jorge E. Cortes ◽  
Dong-Wook Kim ◽  
Javier Pinilla-Ibarz ◽  
Philipp D. Le Coutre ◽  
Charles Chuah ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Phase 1 ◽  
Initial Response ◽  
Employment Equity ◽  
Advisory Committees ◽  
Primary Endpoints ◽  
T315i Mutation ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 109 Background: Despite progress in chronic myeloid leukemia (CML) therapy with tyrosine kinase inhibitors (TKIs), patients (pts) who fail dasatinib or nilotinib or pts with T315I mutation have no treatment options. Ponatinib is a potent, oral, pan-BCR-ABL inhibitor active against the native enzyme and all tested resistant mutants, including the uniformly resistant T315I mutation. Methods: The PACE trial (Ponatinib Ph+ALL and CML Evaluation) was initiated in September 2010. The objective of this international, single-arm, open-label, phase 2 trial is to establish the efficacy and safety of ponatinib. Pts with refractory CML in chronic, accelerated or blast phase (CP, AP or BP), or Ph+ acute lymphoblastic leukemia (ALL), resistant or intolerant (R/I) to dasatinib or nilotinib or with the resistant T315I mutation received 45 mg ponatinib orally once daily in one of 6 cohorts: CP R/I; CP T315I; AP R/I; AP T315I; BP/ALL R/I; BP/ALL T315I. The primary endpoints are major cytogenetic response (MCyR) for CP and major hematologic response (MaHR) for AP, BP or ALL. The trial is ongoing; projected enrollment is approximately 450. Data as of 18 July 2011 are reported. Results: At analysis, 403 pts were enrolled; 397 were treated and eligible. The median age was 59 (range, 18–94) years, 52% were male. Diagnoses were: CP R/I, n=188; CP T315I, 48; AP R/I, 52; AP T315I, 15; BP/ALL R/I, 51; BP/ALL T315I, 43. Median time from initial diagnosis to start of ponatinib was 6.2 years. Prior TKIs included imatinib (93%), dasatinib (85%), nilotinib (66%), and bosutinib (8%); 94% failed >2 prior TKIs, and 57% failed >3 prior TKIs. Overall, 88% had a history of resistance to dasatinib or nilotinib, and 12% were purely intolerant. Mutation status was determined centrally by MolecularMD. Overall, 106 pts had the T315I mutation. Of 291 R/I pts, 110 (38%) had non-T315I BCR-ABL mutations, most frequently F317L (10%), F359V (5%), E255K (4%), and G250E (4%). To date, 343 (85%) pts remain on therapy, 60 (15%) have discontinued (42 BP/ALL): 24 (6%) progressive disease (20 BP/ALL); 11 (3%) AE (3 pain, 3 thrombocytopenia, 1 each haemorrhage, loss of consciousness, enterocolitis, cytokine release syndrome, hepatotoxicity/pleuro-pericardial effusion after overdose); 8 (2%) died (3 related; 7 BP/ALL); 17 (4%) other. The most common drug-related AEs (≥10% any grade) were thrombocytopenia (19%; 15% grade 3/4), rash (18%), dry skin (13%), myalgia (12%), abdominal pain (11%; 3% grade 3/4), headache (11%), arthralgia (11%). Overall, 67 (17%) pts experienced at least 1 related SAE. The most common related SAEs (>5 cases) were pancreatitis 15 cases (3.7%), 5 cases each (1.2%) diarrhea, anemia, febrile neutropenia, and pyrexia. At the time of reporting, 159/397 eligible pts were evaluable for the primary endpoints. Median follow-up was 57 days. Of CP pts, 83 had an assessment at 3 months (10 at 6 months) or discontinued. In CP R/I, 25/60 (42%) attained MCyR (15 CCyR). In CP T315I, 13/23 (57%) had MCyR (11 CCyR). The overall CP MCyR rate was 38/83 (46%) (26 CCyR). Of AP, BP/ALL pts, 76 had an assessment at 1 month or later or discontinued. In AP, 17/23 (74%) R/I and 1/1 T315I pts achieved MaHR. In BP/ALL, 11/30 (37%) R/I and 6/22 (27%) T315I pts had MaHR. Conclusion: In this first analysis of the pivotal PACE trial, ponatinib has a favorable early safety profile, similar to that observed in phase 1, but with a lower incidence of pancreatitis. Initial response data after short follow-up indicate ponatinib has substantial anti-leukemic activity in this heavily pretreated population, and in pts with refractory T315I. These early efficacy signals replicate initial response results reported in the phase 1 setting. Updated data will be presented at the annual meeting. Disclosures: Cortes: Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding. Kim:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; ARIAD: Research Funding. Pinilla-Ibarz:ARIAD: Membership on an entity's Board of Directors or advisory committees, Research Funding. Le Coutre:Novartis: Honoraria, Research Funding, Speakers Bureau; ARIAD: Research Funding. Paquette:ARIAD: Membership on an entity's Board of Directors or advisory committees. Apperley:Novartis: Honoraria, Research Funding; Bristol Myers Sqibb: Honoraria; Ariad: Honoraria; Chemgenex: Honoraria; Genzyme: Honoraria. DiPersio:Genzyme: Honoraria. Rea:Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Talpaz:ARIAD: Research Funding. Abruzzese:Novartis: Consultancy; BMS: Consultancy. Baccarani:Pfizer Oncology: Consultancy; Novartis: Consultancy; BMS: Consultancy; Ariad: Consultancy; Novartis: Research Funding; Pfizer Oncology: Honoraria; Novartis: Honoraria; BMS: Honoraria; Ariad: Honoraria; Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Ariad: Membership on an entity's Board of Directors or advisory committees. Wong:MolecularMD: Employment, Equity Ownership. Lustgarten:ARIAD: Employment. Turner:ARIAD: Employment, Equity Ownership. Rivera:ARIAD: Employment, Equity Ownership. Clackson:ARIAD: Employment, Equity Ownership. Haluska:ARIAD: Employment, Equity Ownership. Kantarjian:Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; ARIAD: Research Funding.

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