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.

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.

scholarly journals Results from Ongoing Phase 1/2 Trial of SL-401 in Combination with Pomalidomide and Dexamethasone in Relapsed or Refractory Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5696-5696 ◽  
Author(s):  
Myo Htut ◽  
Cristina Gasparetto ◽  
Jeffrey Zonder ◽  
Thomas G. Martin ◽  
Emma C. Scott ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Light Chain ◽  
Research Funding ◽  
Phase 1 ◽  
Free Light Chain ◽  
M Protein ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Stage 1

Abstract Background: The bone marrow microenvironment of many multiple myeloma (MM) patients harbors high quantities of plasmacytoid dendritic cells (pDCs), which are specialized immune cells that express the interleukin-3 receptor (CD123). These pDCs have been shown to augment MM growth and contribute to drug resistance, suggesting that targeting pDCs may offer clinical benefit for MM patients. SL-401, a novel targeted therapy directed to CD123, has previously demonstrated potent preclinical in vitro and in vivo activity against MM cell lines and primary tumor samples via both a direct anti-MM effect and an indirect effect by targeting neighboring pDCs. SL-401 has also demonstrated synergy in these systems when used in combination with traditional MM therapies including pomalidomide (POM). Clinically, SL-401 has demonstrated high levels of anti-tumor activity in patients with an aggressive CD123+ malignancy of pDC origin, namely blastic plasmacytoid dendritic cell neoplasm (BPDCN). SL-401 is currently being evaluated in combination with POM and dexamethasone (DEX) in relapsed or refractory (r/r) MM patients. Preliminary results are reported here. Methods and Results: This multicenter, single arm Phase 1/2 trial of patients with r/r MM includes a lead-in (stage 1) and expansion (stage 2). In stage 1, patients receive SL-401 as a daily IV infusion at 7, 9, or 12 ug/kg/day for days 1-5 of a 28 day cycle as a single agent for the initial run-in cycle (cycle 0) and in combination with standard doses/administration of POM+DEX in cycles 1 and beyond, in a 3x3 design. In stage 2, patients receive SL-401 in combination with POM+DEX at the dose and regimen determined in stage 1. Objectives include characterization of the safety profile of SL-401 in combination with POM+DEX, including determination of the maximum tolerated or tested dose, and detection of efficacy signals including evaluation of tumor response based on International Myeloma Working Group criteria, duration of response, progression-free survival, and translational evaluation of changes in BM microenvironmental pDCs. As of 7-25-16, 2 patients with r/r MM received SL-401 at 7 ug/kg in combination with POM+DEX. The median age was 65 years (range: 63-67 years). The most common treatment-related AEs, all grades, were thrombocytopenia (2/2, both grade 1) and hypoalbuminemia (2/2, both grade 2); there has been no DLT. Rapid onset decrease in a set of myeloma-related laboratory values from pre-SL-401 treatment was observed in both patients after the first combination cycle of SL-401 and POM+DEX. In one patient, serum M-protein decreased from 2.34 to 1.19 g/dL (cycle 1), free light chain kappa decreased from 40.1 to 8.27 mg/dL (cycle 1), and free light chain kappa/lambda ratio decreased from 58.12 to 41.35 (cycle 1). In the other patient, serum M-protein decreased from 1.88 to 0.87 (cycle 1) and then was 0.96 (cycle 3) g/dL, free light chain kappa decreased from 134 to 49.4 (cycle 1) and then was 92.5 (cycle 3) mg/dL, and free light chain kappa/lambda ratio decreased from 638.1 to 76 (cycle 1) and then was 111.45 (cycle 3). Both patients remain on study receiving ongoing SL-401 at 2+ and 4+ months. Dose escalation to 9 ug/kg is planned if a third patient clears the 7 ug/kg cohort. Conclusions:This is the first clinical study to evaluate SL-401 in combination with other agents. SL-401 thus far has been well-tolerated in combination with POM+DEX in r/r MM patients, with no unexpected AEs observed. After the first cycle of SL-401 and POM+DEX combination therapy, 2 of 2 patients experienced a rapid decrease in serum M-protein and remain on SL-401 therapy. Given CD123 expression on microenvironmental immune pDCs and the potential synergy of SL-401 with certain current MM agents including POM, SL-401 may offer a novel therapeutic approach in MM. This Phase 1/2 trial continues to enroll and updated data will be presented. Clinical trial information: NCT02661022. Disclosures Zonder: Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria; Prothena: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Pharmacyclics: Other: DSMC membership. Martin:Sanofi: Research Funding; Amgen: Research Funding. Chen:Stemline Therapeutics, Inc.: Employment, Equity Ownership. Shemesh:Stemline Therapeutics: Employment, Equity Ownership. Brooks:Stemline Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties. Chauhan:Stemline Therapeutics: Consultancy. Anderson:Oncopep: Other: Scientific Founder; Acetylon: Other: Scientific Founder; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Sonofi Aventis: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees. Richardson:Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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.

NEOD001 Demonstrates Organ Biomarker Responses in Patients with Light Chain Amyloidosis and Persistent Organ Dysfunction: Results from the Expansion Cohort of a Phase 1/2 Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 644-644 ◽  
Author(s):  
Morie A. Gertz ◽  
Raymond L. Comenzo ◽  
Heather Landau ◽  
Vaishali Sanchorawala ◽  
Brendan M. Weiss ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Organ Dysfunction ◽  
Light Chain ◽  
Research Funding ◽  
Phase 1 ◽  
Al Amyloidosis ◽  
Employment Equity ◽  
Advisory Committees ◽  
Expansion Phase ◽  
Equity Ownership

Abstract Introduction: Systemic amyloidoses are a group of rare disorders characterized by the accumulation of misfolded proteins in tissue, resulting in the dysfunction of vital organs (eg, heart and kidneys). In amyloid light chain (AL) amyloidosis, the most common form of systemic amyloidosis, the amyloidogenic protein is a misfolded light chain (LC) or a fragment of an LC produced by clonal plasma cells. Current therapies used to treat AL amyloidosis limit LC production but do not directly target deposits underlying multiorgan failure. NEOD001, a monoclonal antibody, targets misfolded LC and is thought to neutralize circulating LC aggregates and to clear insoluble deposits. In an interim analysis of a phase 1/2 dose-escalation study in 27 patients with AL amyloidosis and persistent organ dysfunction (NCT01707264; EudraCT2012-002683-27), monthly infusions of NEOD001 were safe, well tolerated, and associated with renal and cardiac responses.1 Here we report updated results from the escalation phase and new results from the expansion phase of this study. Patients and Methods: Inclusion criteria for this trial were that patients complete ≥1 PCD treatment before enrollment, attain partial hematologic response (HR) or better to any previous therapy, and have persistent organ dysfunction. NEOD001 was administered intravenously every 28 days. During the dose-escalation phase, 27 patients received NEOD001 at 0.5, 1, 2, 4, 8, 16, or 24 mg/kg in a 3+3 study design. An additional 42 patients with renal, cardiac, or peripheral nerve involvement were enrolled and treated (24 mg/kg) in the expansion phase. We assessed safety/tolerability, pharmacokinetics, immunogenicity, cardiac and renal responses based on consensus criteria, and neuropathy responses using the Neuropathy Impairment Score-Lower Limb (NIS-LL). Results: The 42 additional patients enrolled in the expansion study included cohorts with renal (16 patients), cardiac (15 patients), and peripheral nerve (11 patients) involvement. In the overall population (n = 69), the median age was 60 years, and 61% of patients were men. Median (range) time since diagnosis was 2.8 (0.4-12.8) years, and 45% of patients underwent ≥3 previous plasma cell-directed regimens. The total number of infusions administered was 913 over a mean of 13.2 (range, 3-35) months. NEOD001 treatment was not associated with dose-limiting toxicities or discontinuations; patients did not develop antidrug antibodies or treatment-related serious adverse events. The most frequent treatment-emergent adverse events, regardless of relationship to study drug, were fatigue, upper respiratory tract infection, nausea, and diarrhea. In a best response analysis, 53% of cardiac-evaluable patients (N = 36) and 63% of renal-evaluable patients (N = 35) met respective criteria for organ response; no patients experienced disease progression. The median time to initial response was 2 months (cardiac) and 4 months (renal). After 9 months of treatment, 82% of patients with measurable peripheral neuropathy at baseline (N = 11) achieved a peripheral neuropathy response based on the NIS-LL score. Conclusions: Our interim results demonstrated that monthly NEOD001 infusions were safe and well tolerated and that organ response rates compared favorably with traditional chemotherapy. These updated results from the escalation phase and these new results from the expansion phase, including results from patients with peripheral nerve involvement, support the design of ongoing late-stage clinical studies. Antibody therapy may allow for effective treatment of patients with AL amyloidosis. Reference: 1. Gertz MA, Landau H, Comenzo RL, et al. First-in-human phase 1/2 study of NEOD001 in patients with light chain amyloidosis and persistent organ dysfunction. J Clin Oncol. 2016;34(10):1097-1103. Disclosures Gertz: Prothena Therapeutics: Research Funding; Novartis: Research Funding; Alnylam Pharmaceuticals: Research Funding; Research to Practice: Honoraria, Speakers Bureau; Med Learning Group: Honoraria, Speakers Bureau; Celgene: Honoraria; NCI Frederick: Honoraria; Sandoz Inc: Honoraria; GSK: Honoraria; Ionis: Research Funding; Annexon Biosciences: Research Funding. Comenzo:Karyopharm: Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Prothena: Consultancy, Research Funding. Landau:Janssen: Consultancy; Spectrum Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx/Amgen: Research Funding. Sanchorawala:Celgene: Research Funding; Takeda: Research Funding; Prothena: Research Funding. Weiss:Prothena: Other: Travel, accommodations, Research Funding; GlaxoSmithKline: Consultancy; Millennium: Consultancy, Other: Travel, accommodations; Janssen: Consultancy, Other: Travel, accommodations, Research Funding; Novartis: Consultancy. Zonder:BMS: Consultancy; Celgene: Consultancy, Research Funding; Prothena: Consultancy; Array Biopharma: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Seattle Genetics: Consultancy. Walling:Stealth: Consultancy; BioMarin: Equity Ownership; Apex: Consultancy; Pharm-Olam: Consultancy; NuMedii: Consultancy; Amgen: Equity Ownership, Patents & Royalties; Crown Bioscience: Consultancy; KaloBios: Consultancy; Exelixis: Consultancy; Newgen: Consultancy; Mateon (was Oxigene): Consultancy; Corcept: Consultancy; Prothena: Consultancy; Aduro: Consultancy; Codexis: Consultancy; Upsher Smith: Consultancy, Patents & Royalties. Kinney:Prothena: Employment, Equity Ownership, Other: Leadership. Koller:Prothena: Employment, Equity Ownership, Other: Travel, accommodations. Schenk:Prothena: Employment, Equity Ownership, Other: Leadership. Guthrie:Prothena: Employment, Equity Ownership, Other: Leadership. Liu:Prothena: Employment, Equity Ownership; Weston Brain Institute: Honoraria. Liedtke:Prothena: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Research Funding; Gilead: Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding.

scholarly journals CC-486 (Oral Azacitidine) in Patients with Hematological Malignancies Who Had Received Prior Treatment with Injectable Hypomethylating Agents (HMAs): Results from Phase 1/2 CC-486 Studies

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 905-905 ◽  
Author(s):  
Guillermo Garcia-Manero ◽  
Michael R. Savona ◽  
Steven D. Gore ◽  
Bart L. Scott ◽  
Christopher R. Cogle ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Phase 1 ◽  
Therapeutic Effects ◽  
Cell Transplant ◽  
Employment Equity ◽  
Advisory Committees ◽  
Hematologic Response ◽  
Equity Ownership ◽  
Grade 3

Abstract Background: Injectable HMAs (azacitidine [AZA], decitabine) are the standard of care in higher-risk myelodysplastic syndromes (HR-MDS) (NCCN, 2016). When other treatment (Tx) options are no longer feasible, HMAs may be used to treat patients (pts) with lower-risk MDS (LR-MDS) and have demonstrated efficacy in older pts with newly diagnosed acute myeloid leukemia (AML) (Dombret, Blood, 2015; Kantarjian, JCO, 2012). Injectable HMAs induce hematologic response or improvement (HI) in ~50% of pts (Grinblatt, Haematologica, 2014; Lyons, JCO, 2009; Silverman, JCO, 2002), but responses may lack durability. There are no standard Tx options indicated for use after HMA failure; the mainstay of Tx in this setting for pts ineligible for stem cell transplant is a clinical trial or supportive care. CC-486, the oral formulation of AZA, was evaluated in 3 phase 1/2 studies that did not exclude pts who had received HMA Tx before study entry. Aim: Determine clinical outcomes for pts with MDS, chronic myelomonocytic leukemia (CMML), or AML, treated with CC-486 monotherapy who had previously failed injectable HMA Tx. Methods: Pts with MDS, CMML, or AML from 3 phase 1/2 CC-486 studies (2 of which included dose-finding periods) who had received HMA Tx before receiving CC-486 are included in these analyses. CC-486 Tx regimens were: 120-600mg x7 days (d) following a single SC AZA cycle (75mg/m2/d x7d), or 300mg QD or 200mg BID x14d or 21d (with no initial SC AZA cycle). All dosing regimens were administered in repeated 28d cycles. Overall response rate (ORR) included complete remission (CR), partial remission (PR), CR with incomplete hematologic recovery (CRi; AML pts only), HI, and transfusion independence (TI). Marrow CR (mCR) was assessed in MDS pts with ≥5% bone marrow blasts at baseline. Results: In all, 40 pts had received prior HMA Tx: 26 pts with MDS, 2 with CMML, and 12 with AML. In the MDS/CMML and AML groups, respectively, median ages were 75 years (range 55-84) and 71 years (60-93) and median times since diagnosis were 28 (2-140) and 4 (0-32) months (Table). Before receiving CC-486, 12 pts (30%) had failed >1 prior injectable HMA course. Most pts (58%) had previously received >4 HMA Tx cycles. Six pts with AML (50%) had received prior HMAs for Tx of antecedent MDS. Of 29 pts for whom outcomes with prior HMAs were known, 16 pts relapsed and 13 pts were refractory to the injectable HMA. The median number of CC-486 Tx cycles was 5 (range 1-52). For all pts treated with CC-486, ORR was 35%. ORR and rates of specific responses were similar between pts with MDS/CMML and pts with AML (Figure). Five of 13 pts (38%) who were refractory to prior HMAs responded, including 1 AML pt who attained CR with CC-486. Six of 16 pts (38%) who had relapsed during or after prior HMA Tx responded. During CC-486 Tx, 32% of pts attained any HI and 31% achieved RBC TI. Of pts who had received ≥6 cycles of prior HMA Tx (n=20), ORR was 35% (7/20). ORR was not statistically different between 7d (n=26) and extended (n=14) CC-486 dosing (P=0.288). The most frequent (≥10%) grade 3-4 hematologic TEAEs were anemia (33%), thrombocytopenia (23%), neutropenia (15%), and febrile neutropenia (10%); the most frequent grade 3-4 gastrointestinal TEAEs were diarrhea and vomiting (10% each). Conclusions: Among pts who were relapsed or refractory to prior HMA Tx, 35% had a hematologic response to CC-486, suggesting that prior HMA failure does not preclude future response to CC-486. Notably, the majority of pts had received >4 prior HMA Tx cycles; thus, prior failures to injectable HMAs were not likely due to inadequate duration of Tx. The ORR with CC-486 in pts who had received ≥6 cycles of the prior injectable HMA was the same as the ORR with CC-486 in all pts. Hypomethylating effects of HMAs are transient; unlike injectable HMAs, oral CC-486 can be administered over extended dosing periods (>7d) of the Tx cycle to produce sustained hypomethylating activity. There was no statistical difference in ORR between CC-486 7d and extended dosing in this small pt group. Nevertheless, given the short half-life and S-phase-restricted DNA incorporation of AZA (Li, Cancer Res, 1970), extending AZA exposure to >7d/cycle with CC-486 could increase the opportunity for cycling cells to incorporate AZA and expose more malignant progenitor cells to AZA, which may optimize therapeutic effects. Extended hypomethylation due to longer exposure to CC-486 may induce pts to respond to CC-486 who had failed prior injectable HMA Tx. Disclosures Savona: TG Therapeutics: Research Funding; Takeda: Research Funding; Sunesis: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Membership on an entity's Board of Directors or advisory committees; Ariad: Membership on an entity's Board of Directors or advisory committees. Gore:Celgene: Consultancy, Honoraria, Research Funding. Scott:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding, Speakers Bureau; Alexion: Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees. Cogle:Celgene: Membership on an entity's Board of Directors or advisory committees. Conkling:USOncology Research: Research Funding; Amgen Inc.: Research Funding. Hetzer:Celgene: Employment, Equity Ownership. Dong:Celgene: Employment, Equity Ownership. Kumar:Celgene: Employment, Equity Ownership. Ukrainskyj:Celgene: Employment, Equity Ownership. Skikne:Celgene: Employment, Equity Ownership.

scholarly journals Current Results of Lentiglobin Gene Therapy in Patients with Severe Sickle Cell Disease Treated Under a Refined Protocol in the Phase 1 Hgb-206 Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1026-1026 ◽  
Author(s):  
John F. Tisdale ◽  
Julie Kanter ◽  
Markus Y. Mapara ◽  
Janet L. Kwiatkowski ◽  
Lakshmanan Krishnamurti ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase 1 ◽  
Employment Equity ◽  
Advisory Committees ◽  
Cd34 Cells ◽  
Equity Ownership ◽  
Grade 3

Abstract Background β-globin gene transfer has the potential for substantial clinical benefit in patients with sickle cell disease (SCD). LentiGlobin Drug Product (DP) contains autologous CD34+ hematopoietic stem cells (HSCs) transduced with the BB305 lentiviral vector (LVV), encoding β-globin with an anti-sickling substitution (T87Q). The safety and efficacy of LentiGlobin gene therapy is being evaluated in the ongoing Phase 1 HGB-206 study (NCT02140554). Results in the initial 7 patients treated with LentiGlobin DP from steady state bone marrow harvested (BMH) HSCs using original DP manufacturing process (Group A) demonstrated stable HbAT87Q production in all patients, but at levels below the anticipated target. The protocol was thus amended to include pre-harvest RBC transfusions, optimize myeloablation by targeting higher busulfan levels, and use a refined DP manufacturing process (Group B); additionally, HSC collection by plerixafor mobilization/apheresis was instituted (Group C). Data from patients in Group C, treated under the modified protocol with DPs manufactured from plerixafor-mobilized HSCs using the refined process, are reported here. Results in patients in Groups A and B are reported separately. Methods Patients with severe SCD (history of recurrent vaso-occlusive crisis, acute chest syndrome, stroke, or tricuspid regurgitant jet velocity of >2.5 m/s) were enrolled. Patients in Group C received ≥2 months of transfusions to reach Hb of 10 - 12 g/dL and <30% HbS before HSC collection. Patients received 240 μg/kg of plerixafor 4 - 6 hours before HSCs were collected by apheresis and CD34+ cells were transduced with the BB305 LVV at a central facility. Following myeloablative conditioning with busulfan, the DP was infused, and patients were monitored for adverse events (AEs), engraftment, peripheral blood (PB) vector copy number (VCN), HbAT87Q expression, and HbS levels. Summary statistics are presented as median (min - max). Results As of 15 May 2018, 11 Group C patients (age 25 [18 - 35] years) had undergone mobilization/apheresis, 9 patients had DP manufactured (median 1 cycle of mobilization [1 - 3]) and 6 patients had been treated. Cell dose, DP VCN and % transduced cells in the 6 treated patients were: 7.1 (3 - 8) x 106 CD34+ cells/kg, 4.0 (2.8 - 5.6) copies/diploid genome (c/dg) and 81 (78 - 88) % transduced cells. The median follow-up was 3.0 (1.2 - 6.0) months. Patients achieved neutrophil engraftment at a median of 19 (18 - 20) days. Platelet engraftment was achieved at a median of 28 (12 - 64) days in 4 patients; platelet engraftment was pending in 2 patients. Two of 11 patients experienced 4 grade ≥3 AEs associated with plerixafor mobilization/HSC collection: 1 had vaso-occlusive pain and hypomagnesaemia, and the other had vaso-occlusive pain and non-cardiac chest pain. The toxicity profile from DP infusion to last follow-up in the 6 treated patients was consistent with myeloablative conditioning. Febrile neutropenia (n=5) and stomatitis (n=4) were the most common non-hematologic grade ≥3 AEs. Serious AEs were reported in 3 patients post-DP infusion: splenic hematoma, non-cardiac chest pain and mucosal inflammation. To date, there have been no DP-related AEs, graft failure, vector-mediated replication competent lentivirus, or clonal dominance. In the 6 treated patients, PB VCN at last visit ranged from 1.4 - 2.9 c/dg. In the 3 patients with 3 months follow-up, total Hb levels were 11.7 g/dL, 9.8 g/dL and 9.2 g/dL, and HbAT87Q levels were 4.7 g/dL, 3.2 g/dL and 3.5 g/dL. One additional patient with 6 months follow-up was off transfusions and had total Hb of 14.2 g/dL, of which 62% (8.8 g/dL) was vector-derived HbAT87Q and 36% (5.1 g/dL) was HbS. All 4 patients had HbAT87Q (median 39%) levels higher than or equal to HbS (median 31%) at the 3-month visit. Summary HGB-206 protocol changes and refined DP manufacturing have improved the LentiGlobin DP characteristics resulting in significantly improved outcomes. In addition, the HbAT87Q expression is comparable to, or exceeds, HbS levels as early as 3 months post DP infusion. These data support the feasibility of plerixafor-mediated CD34+ cell collection in patients with severe SCD and the efficacy of gene therapy. The safety profile of LentiGlobin gene therapy remains consistent with single-agent busulfan conditioning. Additional data and longer follow-up will determine the clinical effect of increased HbAT87Q/HbS ratios. Disclosures Kanter: Global Blood Therapeutics: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; bluebird bio: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Sancilio: Research Funding; NHLBI: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Apopharma: Research Funding; ASH: Membership on an entity's Board of Directors or advisory committees. Mapara:Incyte: Consultancy. Kwiatkowski:Novartis: Research Funding; bluebird bio: Consultancy, Honoraria, Research Funding; Apopharma: Research Funding; Terumo: Research Funding; Agios Pharmaceuticals: Consultancy, Research Funding. Schmidt:GeneWerk GmbH: Employment; German Cancer Research Center: Employment; bluebird bio: Consultancy. Miller:bluebird bio: Employment, Equity Ownership. Pierciey:bluebird bio: Employment, Equity Ownership. Shi:bluebird bio: Employment, Equity Ownership. Ribeil:bluebird bio: Employment, Equity Ownership. Asmal:bluebird bio: Employment, Equity Ownership. Thompson:Amgen: Research Funding; Celgene: Research Funding; Baxalta/Shire: Research Funding; bluebird bio: Consultancy, Research Funding; Novartis: Research Funding; Biomarin: Research Funding; La Jolla Pharmaceutical: Research Funding. Walters:Sangamo Therapeutics: Consultancy; bluebird bio: Research Funding; ViaCord Processing Lab: Other: Medical Director; AllCells Inc.: Other: Medical Director.

A Phase 1, Multicenter Study of Pomalidomide, Bortezomib, and Low-Dose Dexamethasone in Patients with Proteasome Inhibitor Exposed and Lenalidomide-Refractory Myeloma (Trial MM-005)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3036-3036 ◽  
Author(s):  
Paul G. Richardson ◽  
Craig Hofmeister ◽  
Noopur S. Raje ◽  
David Siegel ◽  
Sagar Lonial ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 1 ◽  
Median Number ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Immunomodulatory Drug ◽  
Grade 3

Abstract Background: The combination of an immunomodulatory drug with the proteasome inhibitor (PI), bortezomib (BORT), and low-dose dexamethasone (LoDEX) has demonstrated preclinical synergy and considerable clinical activity in relapsed and refractory multiple myeloma (RRMM; Mitsiades et al Blood, 2002; Richardson et al Blood, 2014). Treatment (Tx) with the immunomodulatory drug pomalidomide (POM) + LoDEX has been shown to delay disease progression and extend survival in patients (pts) with myeloma previously treated with lenalidomide (LEN) and BORT (Richardson et al Blood, 2014; San Miguel et al Lancet Oncol, 2013). This approach was tested using POM + BORT + LoDEX (PVd) in MM-005; preliminary results showed that PVd was effective and well tolerated in LEN-refractory and BORT-exposed pts. Subcutaneous (SC) BORT was shown to be non-inferior to intravenous (IV) BORT and had an improved safety profile in RRMM (Moreau et al Lancet Oncol, 2011). In addition to a cohort of PVd with IV BORT, MM-005 included a cohort of PVd with SC BORT. Methods: In this phase 1 dose-escalation trial, pts must have received 1-4 lines of prior Tx, with ≥ 2 consecutive cycles of LEN plus a PI. Pts had to be PI exposed and refractory to LEN but not to BORT. A 3 + 3 design with 21-day cycles was used to determine the maximum tolerated dose (MTD). Cycles 1-8 of dose-escalation cohorts received POM (1-4 mg/day on days 1-14), IV or SC BORT (1-1.3 mg/m2 on days 1, 4, 8, and 11), and LoDEX (20 mg/day, or 10 mg/day for pts aged > 75 years, on days 1, 2, 4, 5, 8, 9, 11, and 12) until progressive disease (PD) or unacceptable adverse event (AE). After cycle 8, BORT was administered on days 1 and 8, and LoDEX was administered on days 1, 2, 8, and 9. The primary endpoint was MTD, and secondary endpoints included safety, overall response rate (ORR; ≥ partial response [PR]), duration of response (DOR), and time to response. Results: Of the 34 pts enrolled from March 2012 to August 2014, the median age was 58.5 years (range, 36-76 years) and 59% were male. The median number of prior antimyeloma Tx lines (PAMTL) was 2 (range, 1-4), the proportion of pts with ≥ 2 PAMTL was 56%, and the Eastern Cooperative Oncology Group performance status was ≤ 1 for all pts. All pts were refractory to LEN, and all were exposed to prior PI (33 pts [97%] received prior BORT and 2 pts [6%] received prior ixazomib). All pts discontinued Tx, most commonly due to PD (n = 23), but none due to Tx-related AEs. No dose-limiting toxicities were reported in the dose-escalation cohorts or at the maximum planned dose (MPD) of POM 4 mg, BORT 1.3 mg/m2, and LoDEX 20 mg (10 mg for pts aged > 75 years). The median number of Tx cycles received was 9 (range, 2-36) for all pts and was 11 (range, 2-19) vs 8 (range, 3-15) in the MPD with IV BORT (n = 10) vs SC BORT (n = 12) cohorts. The ORR for all pts was 65% (n = 22), with 2 complete responses (CRs), 1 stringent CR, 10 very good PRs (VGPRs), and 9 PRs; all pts achieved at least stable disease. The median DOR for the 22 responders was 7.4 months. Commonly reported grade 3/4 AEs were more frequent at the MPD level with IV BORT vs SC BORT (90% vs 75%), including neutropenia (60% vs 17%), thrombocytopenia (40% vs 8%), and pneumonia (30% vs 8%). There were no reports of grade 3/4 peripheral neuropathy (PN) or deep vein thrombosis (DVT) in any of the cohorts. Conclusions: PVd was effective, with an ORR of 65% in pts with LEN-refractory and PI-exposed myeloma. PVd was well tolerated, with no grade 3/4 PN or DVT and no Tx discontinuation due to Tx-related AE; toxicities were well managed. Moreover, AEs were generally less frequent with SC vs IV BORT. Thus, the favorable tolerability and efficacy of PVd, which could be a highly attractive therapeutic option in pts with RRMM, is under further evaluation in the large ongoing phase 3 trial MM-007. Disclosures Richardson: Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Pomalidomide in combination with bortezomib. Raje:BMS: Consultancy; Takeda: Consultancy; Millenium: Consultancy; Novartis: Consultancy; Celgene Corporation: Consultancy; Onyx: Consultancy; Eli Lilly: Research Funding; Amgen: Consultancy; AstraZeneca: Research Funding; Acetylon: Research Funding. Siegel:Celgene Corporation: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Novartis: Speakers Bureau; Merck: Speakers Bureau. Lonial:Janssen: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Millennium: Consultancy, Research Funding. Laubach:Novartis: Research Funding; Millennium: Research Funding; Onyx: Research Funding; Celgene Corporation: Research Funding. Vesole:Celgene Corporation: Speakers Bureau; Idera Pharmaceuticals: Research Funding. Nooka:Spectrum Pharmaceuticals: Consultancy; Onyx: Consultancy. Zaki:Celgene Corporation: Employment, Equity Ownership. Herring:Celgene Corporation: Employment. Li:Celgene Corporation: Employment, Equity Ownership. Shah:Celgene Corporation: Employment, Equity Ownership. Chen:Celgene Corporation: Employment, Equity Ownership. Anderson:Oncocorp: Equity Ownership; Celgene Corporation: Consultancy; acetylon pharmaceuticals: Equity Ownership; Gilead: Consultancy; BMS: Consultancy; Millennium: Consultancy.

scholarly journals Results from Ongoing Phase 1/2 Clinical Trial of Tagraxofusp (SL-401) in Patients with Intermediate or High Risk Relapsed/Refractory Myelofibrosis

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1773-1773 ◽  
Author(s):  
Naveen Pemmaraju ◽  
Vikas Gupta ◽  
Gary J. Schiller ◽  
Sangmin Lee ◽  
Abdulraheem Yacoub ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Phase 1 ◽  
Optimal Dose ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3 ◽  
Line Setting ◽  
Stage 1

Abstract Background: Patients with myelofibrosis (MF) that have failed or are intolerant to JAK inhibitors (JAKi) have no standard treatment options. Tagraxofusp (Elzonris™; SL-401) is a novel targeted therapy directed to the interleukin-3 receptor-α (CD123), a target expressed on a variety of malignancies, including certain myeloproliferative neoplasms (MPNs) such as MF. CD123 is also expressed on plasmacytoid dendritic cells (pDCs), which reside in the tumor microenvironment and may play a role in promoting growth of MPNs and other malignancies. Therefore, targeting of CD123-expressing malignant cells and/or neighboring pDCs may offer a novel therapeutic approach. Tagraxofusp has demonstrated high levels of clinical activity against blastic plasmacytoid dendritic cell neoplasm (BPDCN), a CD123+ malignancy derived from pDCs. Methods: This multicenter, two-stage Phase 1/2 trial is enrolling patients with MF that were relapsed, refractory, or unable to tolerate JAKi. Primary objectives include assessment of safety, determining optimal dose/regimen, and evaluating efficacy outcomes. In the Stage 1 dose escalation cohort (completed), tagraxofusp was dosed as a daily IV infusion at 7, 9, and 12 mcg/kg/day, on days 1-3 every 21 days (cycle 1-4), every 28 days (cycles 5-7), and every 42 days (cycles 8+). In Stage 2 (ongoing), patients received the optimal dose determined in Stage 1 (12 mcg/kg/day). Results: As of July 2018, 18 patients with MF received tagraxofusp. Five patients were treated in the second line setting and 12 patients were treated in third-line setting, and beyond. Median age was 69 years (range 55-81); 60% patients were female. Of the 18 patients with DIPSS Plus risk group assessment available, 3 patients (17%) were intermediate-1, 10 patients (55%) were intermediate-2, and 5 patients (28%) were high-risk. Median platelet count was 66 K/uL (range 15-579). 70% (14/20) of patients had baseline platelets <100K/uL, of which 6 patients had platelets <50K/uL at study entry. 89% (17/19) of patients had baseline splenomegaly defined as palpable spleen 5 cm or more below costal margin (BCM) by physical exam. Most common treatment-related adverse events (TRAEs) include hypoalbuminemia and thrombocytopenia (each 27%), and alanine aminotransferase increased, anemia, dizziness, fatigue, headache and nausea (each 20%). Most common ≥grade 3 TRAEs include anemia (20%) and thrombocytopenia and fatigue (each 7%). Capillary leak syndrome was reported in 1 patient (5%; grade 3). 50% (6/12) of evaluable patients, with baseline spleen size 5 cm or more BCM, had a spleen response, of which 33% (4/12) had splenomegaly reduction by 33% or more and 25% (3/12) had splenomegaly reduction by 35% or more. 50% (3/6) of patients with spleen response had treatment duration 8+ months, including 8+, 12+ and 14+ months (all 3 ongoing). Four patients with baseline thrombocytopenia had treatment durations 8+ months, 3 of which are ongoing. Conclusions: Tagraxofusp monotherapy demonstrated improvements in splenomegaly, with a manageable safety profile, in patients with relapsed/refractory MF, an area of unmet medical need. Given CD123 expression on myeloid neoplastic cells and pDCs in the tumor microenvironment, tagraxofusp may offer a novel targeted approach for MF patients. Enrollment continues, and updated safety and efficacy data will be presented. Registrational designs are being evaluated. Clinical trial information: NCT02268253. Disclosures Pemmaraju: celgene: Consultancy, Honoraria; abbvie: Research Funding; cellectis: Research Funding; stemline: Consultancy, Honoraria, Research Funding; samus: Research Funding; novartis: Research Funding; Affymetrix: Research Funding; SagerStrong Foundation: Research Funding; plexxikon: Research Funding; daiichi sankyo: Research Funding. Gupta:Incyte: Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Schiller:Pharmacyclics: Research Funding; Celator/Jazz Pharmaceuticals: Research Funding. Lee:LAM Therapeutics: Research Funding; AstraZeneca: Consultancy; Clinipace: Consultancy; Karyopharm Therapeutics Inc: Consultancy; Amgen: Consultancy. Yacoub:Ardelyx, INC.: Equity Ownership; Cara Therapeutics: Equity Ownership; Dynavax: Equity Ownership; Inycte: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Ali:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Sardone:Stemline Therapeutics: Employment, Equity Ownership. Wysowskyj:Stemline Therapeutics: Employment, Equity Ownership. Shemesh:Stemline Therapeutics: Employment, Equity Ownership. Chen:Stemline Therapeutics: Employment, Equity Ownership. Olguin:Stemline Therapeutics: Employment, Equity Ownership. Brooks:Stemline Therapeutics: Employment, Equity Ownership. Dunn:Stemline Therapeutics: Employment, Equity Ownership. Verstovsek:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees. Khoury:Stemline Therapeutics: Research Funding.

scholarly journals A Phase I Trial of Janus Kinase (JAK) Inhibition with INCB039110 in Acute Graft-Versus-Host Disease (aGVHD)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 390-390 ◽  
Author(s):  
Mark A. Schroeder ◽  
H. Jean Khoury ◽  
Madan Jagasia ◽  
Haris Ali ◽  
Gary J. Schiller ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Janus Kinase ◽  
Cell Transplant ◽  
Employment Equity ◽  
Advisory Committees ◽  
Daily Dose ◽  
Equity Ownership ◽  
Grade 3 ◽  
Steroid Refractory

Abstract Background: Corticosteroids are considered standard first-line systemic therapy for patients with aGVHD, but this approach is effective in only approximately half of all cases. For patients who progress or do not respond to corticosteroids, no specific agent has been identified as standard, and regimens are typically selected based on investigator experience and patient co-morbidities. In preclinical models, JAK inhibition has been shown to impair production of cytokines as well as the differentiation and trafficking of T cells implicated in the pathogenesis of aGVHD. Retrospective studies have suggested that JAK1/JAK2 inhibition with ruxolitinib treatment provides clinical benefit in patients with steroid-refractory GVHD (Zeiser et al, Leukemia 2015;29:2062-2068). Herein, we report preliminary safety results from a prospective randomized, parallel-cohort, open-label phase 1 trial evaluating the potent and selective JAK 1 inhibitor INCB039110 in patients with aGVHD. Methods: Male or female patients 18 years or older who underwent their first allo-hematopoietic stem cell transplant (HSCT) from any donor source and developed grades IIB-IVD aGVHD were eligible for the study. Patients were randomized 1:1 to either a 200 or 300 mg oral daily dose of INCB039110 in combination with corticosteroids, and were stratified based on prior treatment status (treatment-naive [TN] versus steroid-refractory [SR]). The primary endpoint of the study was safety and tolerability; secondary endpoints included overall response rate at Days 14, 28, 56, and 100, non-relapse mortality, and pharmacokinetic (PK) evaluations. Patients were assessed through Day 28 for dose-limiting toxicities (DLTs) and response. A Bayesian approach was used for continuous monitoring of DLTs from Days 1-28. Treatment continued until GVHD progression, unacceptable toxicity, or withdrawal from the study. Acute GVHD was graded according to MN-CIBMTR criteria; adverse events (AEs) were graded according to NCICTCAE v 4.03. Results: Between January and June 2016, 31 patients (TN, n=14; SR, n= 17) were randomized. As of July 25, 2016, data were available from 30 patients who received an oral daily dose of 200 mg (n=14) or 300 mg (n=16) INCB039110 in combination with 2 mg/kg methylprednisolone (or equivalent dose of prednisone). The median durations of treatment were 60.8 days and 56.5 days for patients receiving a daily dose of 200 mg and 300 mg INCB039110, respectively. One DLT of Grade 3 thrombocytopenia was reported. The most frequently reported AEs included thrombocytopenia/platelet count decrease (26.7%), diarrhea (23.3%), peripheral edema (20%), fatigue (16.7%), and hyperglycemia (16.7%). Grade 3 or 4 AEs occurred in 77% of patients and with similar frequency across dose groups and included cytomegalovirus infections (n=3), gastrointestinal hemorrhage (n=3), and sepsis (n=3). Five patients had AEs leading to a fatal outcome, including multi-organ failure (n=2), sepsis (n=1), disease progression (n=1), and bibasilar atelectasis, cardiopulmonary arrest, and respiratory distress (n=1); none of the fatal events was attributed to INCB039110. Efficacy and PK evaluations are ongoing and will be updated at the time of presentation. Conclusion: The oral, selective JAK1 inhibitor INCB039110 can be given safely to steroid-naive or steroid-refractory aGVHD patients. The safety profile was generally consistent in both dose groups. Biomarker evaluation, PK, and cellular phenotyping studies are ongoing. The recommended phase 2 dose will be selected and reported based on PK studies and final safety data. Disclosures Schroeder: Incyte Corporation: Honoraria, Research Funding. Khoury:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Jagasia:Incyte Corporation: Research Funding; Therakos: Research Funding; Janssen: Research Funding. Ali:Incyte Corporation: Research Funding. Schiller:Incyte Corporation: Research Funding. Arbushites:Incyte Corporation: Employment, Equity Ownership. Delaite:Incyte Corporation: Employment, Equity Ownership. Yan:Incyte Corporation: Employment, Equity Ownership. Rhein:Incyte Corporation: Employment, Equity Ownership. Perales:Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chen:Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. DiPersio:Incyte Corporation: Research Funding.

scholarly journals Daratumumab (DARA) Maintenance Therapy Improves Depth of Response and Results in Durable Progression-Free Survival (PFS) Following Dara Plus Cyclophosphamide, Bortezomib, and Dexamethasone (CyBorD) Induction Therapy in Multiple Myeloma (MM): Update of the Lyra Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 863-863 ◽  
Author(s):  
Robert M. Rifkin ◽  
Jason M. Melear ◽  
Edward Faber ◽  
William I. Bensinger ◽  
John M Burke ◽  
...  
Keyword(s):  
Stem Cell ◽  
Board Of Directors ◽  
Induction Therapy ◽  
Safety Profile ◽  
Employment Equity ◽  
Advisory Committees ◽  
Depth Of Response ◽  
Equity Ownership ◽  
Grade 3

Background: DARA, a human IgGκ monoclonal antibody targeting CD38, is approved in combination with bortezomib, melphalan, and prednisone (VMP) and bortezomib and dexamethasone (Vd) for newly diagnosed MM (NDMM) and relapsed MM (RMM), respectively. CyBorD is a commonly used immunomodulatory drug-sparing regimen for MM. In the LYRA (NCT02951819) study, DARA plus CyBorD (DARA-CyBorD) demonstrated efficacy and a tolerable safety profile at the end of induction. Here, we present updated findings examining the effect of monthly DARA maintenance on the efficacy and safety of DARA-CyBorD in NDMM and RMM. Methods: LYRA is an ongoing, single-arm, open-label, phase 2 study conducted at US community oncology centers. Patients (pts) were aged ≥18 years with documented MM per IMWG criteria, an ECOG performance score (PS) of 0-2, and ≤1 prior line of therapy. Pts received 4-8 induction cycles of DARA-CyBorD (cyclophosphamide 300 mg/m2 PO on Days 1, 8, 15, and 22; bortezomib 1.5 mg/m2 SC on Days 1, 8, and 15; and dexamethasone 40 mg PO or IV weekly [qw]) every 28 days. DARA was given at 8 mg/kg IV on Days 1 and 2 of C1, 16 mg/kg qw from C1D8 through C2, 16 mg/kg q2w for C3-6, and 16 mg/kg q4w for C7-8. After induction, eligible pts could undergo autologous stem cell transplantation (ASCT). All pts received up to 12 maintenance cycles with DARA 16 mg/kg IV q4w. Results: A total of 101 (87 NDMM, 14 RMM) pts were enrolled; 100 (86 NDMM, 14 RMM) pts received ≥1 treatment dose. Median age was 63 years; most pts were white (81%), male (64%), had ECOG PS 0-1 (94%) and had IgG (57%) MM; 36% of pts had high cytogenetic risk, defined as a del(17p), t(4:14) or t(14;16) abnormality. NDMM and RMM pts received a median of 6 and 8 cycles, respectively, of induction therapy. Thirty-nine NDMM pts and 1 RMM pt underwent ASCT. Fifty percent of pts received plerixafor; median stem cell yield for NDMM pts was 6.2 x 106 (range 2-15 x 106) CD34+ cells/kg. A total of 85 (75 NDMM, 10 RMM) pts received ≥1 dose of maintenance treatment; 63 (56 NDMM, 7 RMM) pts have received all 12 maintenance cycles. In NDMM pts, ORR was 87%, with 64% ≥VGPR and 12% ≥CR, by the end of induction. By the end of maintenance, ORR, ≥VGPR and ≥CR rates were 97%, 82% and 51% in NDMM pts who underwent ASCT and 83%, 70% and 30% in NDMM pts who did not receive ASCT. In RMM pts, ORR, ≥VGPR and ≥CR rates were 79%, 71% and 29% by the end of induction and 86%, 71% and 64% by the end of maintenance. At a median follow up of 24.8 mo in NDMM pts and 26.6 mo in RMM pts, median duration of response was not reached (NR). Median PFS (Figure) was NR in NDMM pts, regardless of transplant status, and was 21.7 mo in RMM pts; median OS was NR in NDMM pts and was 30.1 mo in RMM pts. In NDMM pts the 24-mo PFS rate was 89% in pts who underwent ASCT and 72% in pts who did not receive ASCT. The 24-mo OS rate was 90% for NDMM pts. In RMM pts, the 24-mo PFS and OS rates were 48% and 64%, respectively. All treated pts had ≥1 TEAE. Common TEAEs (≥25%) included fatigue, nausea, cough, diarrhea, upper respiratory tract infection, back pain, vomiting, insomnia, dyspnea, constipation, and headache. Grade 3/4 TEAEs were reported in 62% of pts; the most common (≥10%) was neutropenia (14%). Serious TEAEs occurred in 33% of pts; the most common (&gt;2%) were pneumonia, atrial fibrillation and pulmonary embolism. TEAEs led to permanent treatment discontinuation in 7% of pts, with 2% related to treatment. TEAEs resulted in death in 2 pts (nephrotic syndrome, sudden death); both unrelated to treatment. Infusion reactions (IRs) occurred in 56% of pts including grades 1-2 in 52% of pts, grade 3 in 3% of pts and grade 4 in 1% of pts. Most common (&gt;5%) IRs were chills, cough, dyspnea, nausea, pruritus, flushing and nasal congestion. Conclusion: Maintenance with DARA monotherapy for 12 mo increased the &gt;CR rate in NDMM and RMM pts, consistent with observations in prior studies that longer DARA treatment improves depth of response. Importantly, the increase in ≥CR rate was associated with durable PFS and OS. The 24-mo PFS rates in NDMM and RMM pts compare favorably with results for DARA-VMP and DARA-Vd in NDMM and RRMM, respectively. Safety profile was consistent with previous reports of DARA, with no new safety concerns observed with longer follow-up. These data indicate that DARA-CyBorD is a safe, effective MM treatment and that DARA maintenance increases depth of response and achieves durable remissions. Disclosures Rifkin: Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Melear:Texas Oncology: Employment; DARA: Speakers Bureau. Faber:Cardinal Health: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Bensinger:Amgen, Celgene: Other: Personal Fees, Research Funding, Speakers Bureau; Takeda, Janssen: Speakers Bureau; Sanofi, Seattle Genetics, Merck, Karyopharm: Other: Grant. Burke:Gilead: Consultancy; Celgene: Consultancy; Roche/Genentech: Consultancy. Narang:Celgene: Speakers Bureau. Stevens:Astellas: Consultancy. Gunawardena:Janssen: Employment, Equity Ownership. Lutska:Janssen: Employment. Qi:Janssen: Employment. Ukropec:Janssen: Employment, Equity Ownership. Qi:Janssen: Employment. Lin:Janssen: Employment, Equity Ownership. Yimer:Amgen: Consultancy; Clovis Oncology: Equity Ownership; Puma Biotechnology: Equity Ownership; Celgene: Honoraria; Seattle Genetics: Honoraria; Janssen: Speakers Bureau; AstraZeneca: Speakers Bureau.

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