A Phase I/II Study of BHQ880, a Novel Osteoblat Activating, Anti-DKK1 Human Monoclonal Antibody, in Relapsed and Refractory Multiple Myeloma (MM) Patients Treated with Zoledronic Acid (Zol) and Anti-Myeloma Therapy (MM Tx).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 750-750 ◽  
Author(s):  
Swaminathan Padmanabhan ◽  
Joseph Thaddeus Beck ◽  
Kevin R. Kelly ◽  
Nikhil C. Munshi ◽  
Andy Dzik-Jurasz ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Phase I ◽  
Bone Disease ◽  
Research Funding ◽  
Human Monoclonal Antibody ◽  
Wnt Signaling Pathway ◽  
Mineral Density ◽  
Employment Equity ◽  
Osteolytic Lesions ◽  
Equity Ownership

Abstract Abstract 750 Background: DKK1 is a negative regulator of the Wnt signaling pathway in bone that is overexpressed in a subset of newly-diagnosed MM patients with osteolytic lesions as well as in refractory and relapsed patients. Expression also correlates with the number of osteolytic lesions in untreated MM patients. BHQ880 is a novel anti-DKK1 human monoclonal antibody. Alleviation of DKK1 inhibition by BHQ880 results in activation of the Wnt signaling pathway, leading to increased bone mass mediated via upregulation of osteoblasts in mice and monkeys. In murine models of MM bone disease; this anabolic activity of BHQ880 increased trabecular and cortical bone density. Lytic bone disease in MM is caused by osteoclast activation and osteoblast inhibition. Current approved therapies for the treatment of MM bone disease are focused on osteoclast inhibition (e.g., bisphosphonates) and BHQ880 therapy may be able to reverse the effects of DKK1-induced osteoblast inhibition. Therefore, dual therapy with zoledronic acid to decrease bone resorption and BHQ880 to increase new bone formation may provide an effective treatment strategy for MM bone disease. Methods: In the phase I portion of this phase I/II study, patients with relapsed or refractory MM with prior skeletal-related event (SRE) were treated with BHQ880 as an IV infusion Q28 days. Patients also received Zol (4 mg) and approved MM Tx (bortezomib not allowed). Bone markers and total DKK1 levels along with bone mineral density are being measured. Full PK profiles were collected during the first and second cycle, after which predose (trough) samples were collected to assess accumulation. Results: Ten pts (6:M, 4:F), median age: 66.5 yrs (range 41- 70), performance status-0(5 pts), 1(4 pts), 2 (1 pts) have been enrolled in the following dose levels (mg/kg) 3 (2 pts), 10 (starting dose level -4 pts), 20 (4 pts) and have been on treatment for 1 day to 5 28-day cycles. No BHQ880-related AE's have been observed to date. Bone mineral density (BMD) data from the first two patients treated at 10 mg show the following: a.) Pt 1 (hip +5.8%, spine N/A due to surgery, wrist -1.8%); b.) Pt 2 (hip -0.2%, spine +6.1%, wrist not done). The biomarker data from these patients show: a.) Pt 1 shows a maximal +98% change over baseline in PINP at day 15 post-treatment, while osteocalcin (OC) changes +17% at day 15, reaching a +56% change over baseline at cycle 4 day 1; uNTx/Cr changes – 43 % at cycle 2 day 15. b) Partial data from Pt 2 suggests a -44 % change in PINP and –73 % change in OC and a +73% change in uNTx/Cr. Baseline total DKK1 levels on 3 patients ranged from 8.8 to 21.5 ng/mL. Preliminary PK analysis is available in 1 out of 3 patients treated at 10mg/kg. The Cmax achieved after the first infusion was 165 ug/mL and 201 ug/mL after the second infusion. Calculated t1/2 was 188 hours after the first infusion and 254 hours after the second infusion. Regarding overall exposure, AUC0-672 hours after first infusion was 36081 hr*ng/mL and 48533 hr*ng/mL after the second infusion. Conclusion: BHQ880 given IV Q28 days appears to be well tolerated in combination with Zol and chosen MM Tx. Once safety of 40 mg/kg BHQ880 or the MTD dose has been determined, pts will be enrolled in the phase II portion to assess activity on a SRE endpoint. Updated safety, efficacy, bone density and biomarker data will be presented on all patients at the upcoming ASH meeting. Disclosures: Padmanabhan: Genentech: Consultancy, Honoraria; GSK: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Off Label Use: BHQ880, a novel osteoblast activating, anti-DKK1 antibody. Dzik-Jurasz:Novartis: Employment, Equity Ownership. Gangolli:Novartis: Employment, Equity Ownership. Ettenberg:Novartis: Employment, Equity Ownership. Miner:Novartis: Employment, Equity Ownership. Bilic:Novartis: Employment, Equity Ownership. Whyte:Novartis: Employment, Equity Ownership. Mehdi:Novartis: Employment, Equity Ownership. Chiang:Novartis: Employment, Equity Ownership. Rae:Novartis: Employment, Equity Ownership. Shah:Novartis: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Millenium: Research Funding, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Elan: Consultancy. Giles:Novartis: Consultancy, Research Funding; BMS: Research Funding; Merck: Research Funding; Clavis: Research Funding. Stewart:Novartis: Consultancy; Amgen: Consultancy; Millenium: Consultancy, Research Funding; Proteolix: Consultancy; Celgene: Honoraria.

Vorinostat in Combination with Decitabine for the Treatment of Relapsed or Newly Diagnosed Acute Myelogenous Leukemia (AML) or Myelodysplastic Syndrome (MDS): A Phase I, Dose-Escalation Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2089-2089 ◽  
Author(s):  
Mark Kirschbaum ◽  
Ivana Gojo ◽  
Stuart L. Goldberg ◽  
Lisa Kujawski ◽  
Ehab Atallah ◽  
...  
Keyword(s):  
Phase I ◽  
Board Of Directors ◽  
Research Funding ◽  
Sequential Therapy ◽  
Employment Equity ◽  
Advisory Committees ◽  
Concurrent Therapy ◽  
Equity Ownership ◽  
Experienced Treatment ◽  
Refractory Aml

Abstract Abstract 2089 Poster Board II-66 Introduction: Although the introduction of epigenetic therapies, such as the DNA methyltransferase inhibitor (DNMT) decitabine, has improved options for the treatment of myeloid malignancies, use is limited by sub-optimal response rates. Therefore, there remains a need for more effective treatment strategies to improve outcomes in AML/MDS. Preclinical and clinical data suggest that broadening epigenetic targeting by adding histone deacetylase (HDAC) inhibitors to DNMTs may improve responses. In addition, it has been reported that outcomes may differ according to the sequence in which HDAC and DNMT inhibitors are combined. Aim: Here we present preliminary data from a Phase I, open-label, multicenter, dose-escalating study, designed to determine the maximum-tolerated dose (MTD) and recommended Phase II dose of the HDAC inhibitor vorinostat combined either concurrently or sequentially with decitabine in patients (pts) with AML/MDS. Other endpoints include tolerability and exploratory assessments of activity. Methods: Pts (≥18 years) with intermediate-high risk MDS, relapsed/refractory AML, or untreated AML (≥60 years; unsuitable for standard chemotherapy), with an ECOG performance status of ≤2, were enrolled into one of six dosing levels (Table) and received treatment for up to 24 months or until disease progression (PD). Results: As of August 3, 2009, 72 pts have entered the study: median age was 68 years (range 18-85) and 58% were male. To date, 69 pts have discontinued due to PD/lack of efficacy (n=37), withdrawal of consent (n=12), adverse events (AEs) (n=16), physician decision (n=3), and protocol deviation (n=1). Of 70 pts evaluable for safety, 69 experienced AEs, the majority of which were Grade 1/2 in severity and included nausea (n=48), diarrhea (n=41), fatigue (n=36), constipation (n=32), and vomiting (n=28). 62 (89%) pts experienced treatment-related AEs and 17 (24%) pts experienced treatment-related serious AEs. 14 deaths occurred during the study, although none were related to study treatment. One dose-limiting toxicity, prolonged QT interval, was documented in dose level 3a. Combinations of vorinostat and decitabine in the schedules in this protocol did not reach MTD. As per protocol, dose levels 3 and 3a were the maximum administered doses and have been expanded. Of the 61 pts evaluable for response, 11 had MDS, 25 had relapsed/refractory AML, and 25 had untreated AML. In pts with MDS receiving concurrent therapy (n=5), complete remission (CR) was achieved in 2 pts, stable disease (SD) in 1 pt, partial remission (PR) in 1 pt, hematologic improvement (HI) in 1 pt; all 6 of the pts who received sequential treatment experienced SD. In pts with relapsed/refractory AML receiving concurrent therapy (n=12), CR was achieved in 1 pt, CR without recovery of counts (CRi) in 1 pt, HI in 1 pt, SD in 6 pts, while 3 pts had PD; in those receiving sequential therapy (n=13), SD was achieved in 9 pts while 4 had PD. In pts with untreated AML receiving concurrent therapy (n=12), CR was achieved in 4 pts, CRi in 1 pt, PR in 1 pt, and SD in 6 pts, and in those receiving sequential therapy (n=13), CR was achieved in 2 pts, CRi in 2 pts, PR in 1 pt, HI in 2 pts, and SD in 5 pts. Overall, CR or CRi was achieved by 18% pts with MDS, 8% with relapsed/refractory AML, and 36% with untreated AML; and HI was reported in 9% pts with MDS, 4% with relapsed/refractory AML, and 8% with untreated AML. Conclusion: These preliminary data indicate that the combination of vorinostat with decitabine, either concurrently or sequentially, is possible without significant toxicity. In addition, the combination shows promising activity in MDS and untreated AML. Disclosures: Kirschbaum: Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celegene: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. 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. Goldberg:Merck: Research Funding. Marks:Merck: Research Funding. Di Gravio:Merck: Employment, Equity Ownership. Pyle:Merck: Employment, Equity Ownership. Rizvi:Merck: Employment, Equity Ownership. Issa:Eisai: Consultancy, Research Funding; Celegene: Research Funding; MGI Pharma: Research Funding.

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.

Ublituximab + TGR-1202 Demonstrates Activity and a Favorable Safety Profile in Relapsed/Refractory B-Cell NHL and High-Risk CLL: Phase I Results

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1538-1538 ◽  
Author(s):  
Matthew A. Lunning ◽  
Julie Vose ◽  
Nathan Fowler ◽  
Loretta Nastoupil ◽  
Jan A. Burger ◽  
...  
Keyword(s):  
High Risk ◽  
Phase I ◽  
Research Funding ◽  
Clinical Activity ◽  
Employment Equity ◽  
Once Daily ◽  
Phase Ib ◽  
Equity Ownership ◽  
Favorable Safety ◽  
Higher Doses

Abstract Introduction: Ublituximab (UTX) is a novel anti-CD20 mAb that has been glycoengineered for enhanced ADCC. TGR-1202 is a novel once daily oral PI3Kδ inhibitor with clinical activity in B-cell lymphoma and a notably differentiated tolerability profile compared to similar agents. The combination of UTX + TGR-1202 showed strong synergistic activity in-vitro (Lugano 2013). Herein we report the results from the Phase 1 (dose-escalation) and updated results from the Phase Ib (dose-expansion) evaluating the safety and efficacy of the combination of UTX + TGR-1202 in patients (pts) with heavily pre-treated rel/ref NHL and CLL. Methods: A 3+3 design was utilized with rel/ref NHL and CLL pts accruing independently and no limit on the number or type of prior therapies. Patients refractory to prior PI3K or BTK inhibitors were eligible. UTX was administered D1, 8, 15 of Cyc 1 & 2, followed by D1 of Cyc 4, 6, 9 & 12. TGR-1202 was administered orally once-daily starting on D1 of Cyc 1. Primary endpoints: Safety and dose limiting toxicities (DLT). Secondary endpoints: Efficacy (ORR, CR rate). Results: 56 patients have been enrolled to date and are evaluable for safety: 16 CLL/SLL, 16 FL, 16 DLBCL, 5 MZL, 2 MCL and 1 Richter's transformation. Med age 64 yo (range 29-86); 37 M/19 F; median # prior treatment regimens = 3 (range 1-9). Day 1 infusion reactions (2% G 3/4), neutropenia (23% G 3/4), diarrhea (2% G 3/4), and nausea (0% G 3/4) were the most commonly reported adverse events considered at least possibly related to either study drug. One patient (CLL cohort 1) with baseline Gr 3 neutropenia at study entry worsened to Gr 4 resulting in a dose delay which necessitated enrollment of an additional 3 pts at that dose level. Dose escalation continued into all planned subsequent NHL and CLL cohorts (up to 1200 mg). No MTD was observed in the Phase I portion and subtype specific expansion cohorts (Phase Ib) with 800 and 1200 mg dose of micronized TGR-1202 followed. Activity was observed at all dose levels; however a possible dose-response relationship was observed with TGR-1202 at higher doses compared to the lower doses. Of the 37 evaluable pts treated at the higher doses of TGR-1202 (1200 mg original formulation or > 600 mg micronized), overall response was as follows: CLL/SLL (5/7); FL/MZL (10/15); DLBCL (5/12); MCL (0/2) and Richter's (1/1). No CLL pts progressed at the first efficacy assessment, despite 4/5 having high-risk cytogenetics. Two CLL pts with SD include a 17p del, ibrutinib refractory patient who eventually progressed on treatment and the other remains on study awaiting future assessments. Of interest, 7 of the DLBCL pts were GCB subtype of which 71% were rituximab refractory, with 3/7 achieving an objective response, 2 remaining in stable disease (4+ and 5+ mos each), and 2 having progressed to date (avg time on study 7 mos, range 2 - 16+ mos). Conclusions: The combination of UTX + TGR-1202 is active and well tolerated in pts with both indolent and aggressive rel/ref NHL and CLL. The Phase I portion is complete and enrollment remains open in expansion cohorts for CLL, FL/MZL and DLBCL pts evaluating TGR-1202 micronized doses at 800 to 1200 mg in combination with UTX. Given the favorable safety profile and clinical activity observed, Phase 3 programs are planned with UTX + TGR-1202. Disclosures Lunning: BMS: Consultancy; Juno: Consultancy; Gilead: Consultancy; Genentech: Consultancy; Spectrum: Consultancy; TG Therapeutics: Consultancy. Vose:Seattle Genetics, Inc.: Honoraria, Research Funding. Nastoupil:Genentech: Honoraria; Celgene: Honoraria; TG Therapeutics: Research Funding; AbbVie: Research Funding; Janssen: Research Funding. Burger:Pharmacyclics LLC, an AbbVie Company: Research Funding. Schreeder:TG Therapeutics, Inc: Research Funding. Siddiqi:Seattle Genetics: Speakers Bureau; Pharmacyclics/Jannsen: Speakers Bureau; Kite pharma: Other: attended advisory board meeting. Flowers:Seattle Genetics: Consultancy; Millennium/Takeda: Research Funding; OptumRx: Consultancy; Millennium/Takeda: Research Funding; Infinity Pharmaceuticals: Research Funding; Onyx Pharmaceuticals: Research Funding; AbbVie: Research Funding; AbbVie: Research Funding; Acerta: Research Funding; Gilead Sciences: Research Funding; Celegene: Other: Unpaid consultant, Research Funding; Pharmacyclics: Research Funding; Spectrum: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; OptumRx: Consultancy; Spectrum: Research Funding; Onyx Pharmaceuticals: Research Funding; Gilead Sciences: Research Funding; Janssen: Research Funding; Genentech: Research Funding; Genentech: Research Funding; Seattle Genetics: Consultancy; Janssen: Research Funding; Infinity Pharmaceuticals: Research Funding; Celegene: Other: Unpaid consultant, Research Funding. Cutter:Clearview Cancer Center: Employment. Pauli:Clearview Cancer Institute: Employment; TG Therapeutics, Inc.: Consultancy, Research Funding. Sportelli:TG Therapeutics, Inc.: Employment, Equity Ownership. Miskin:TG Therapeutics, Inc.: Employment, Equity Ownership. Weiss:TG Therapeutics, Inc.: Employment, Equity Ownership.

scholarly journals Phase I Trial of Targeted Alpha-Particle Therapy Using Actinium-225 (225Ac)-Lintuzumab (Anti-CD33) in Combination with Low-Dose Cytarabine (LDAC) for Older Patients with Untreated Acute Myeloid Leukemia (AML)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5293-5293 ◽  
Author(s):  
Joseph G Jurcic ◽  
Farhad Ravandi ◽  
John M. Pagel ◽  
Jae H Park ◽  
B. Douglas Smith ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase I ◽  
Dose Escalation ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Phase I Trial ◽  
Particle Therapy ◽  
Employment Equity ◽  
Molecular Abnormalities ◽  
Equity Ownership

Abstract Background: Lintuzumab, a humanized anti-CD33 monoclonal antibody, targets myeloid leukemia cells but has only modest activity in AML. To increase the antibody’s potency yet avoid nonspecific cytotoxicity of β-emitting isotopes, 225Ac (t½=10 d), a radiometal that yields 4 α-particles, was conjugated to lintuzumab. A phase I trial showed that 225Ac-lintuzumab is safe at doses ≤ 3 µCi/kg and has anti-leukemic activity across all dose levels studied (Jurcic et al. ASH, 2011). We are conducting a multicenter, phase I dose-escalation trial to determine the maximum tolerated dose (MTD), toxicity, and biological activity of fractionated-dose 225Ac-lintuzumab in combination with LDAC. Patients and Methods: Patients ≥ 60 yrs who had untreated AML with poor prognostic factors, e.g., an antecedent hematologic disorder, unfavorable cytogenetic or molecular abnormalities, and significant comorbidities, were eligible. Patients received LDAC 20 mg twice daily for 10 d every 4-6 wks for up to 12 cycles. During Cycle 1, beginning 4-7 days after completion of LDAC, two doses of 225Ac-lintuzumab were given approximately one week apart. To prevent radiation-induced nephrotoxicity, patients were given furosemide while receiving 225Ac-lintuzumab and spironolactone for one year afterward. Results: Nine patients (median age, 76 yrs; range, 73-81 yrs) were treated. Seven patients (78%) had a history of myelodysplastic syndromes (MDS), for which five (56%) received prior therapy with hypomethylating agents (n=4) or allogeneic hematopoietic cell transplantation (n=1). One patient (11%) had chronic myeloid leukemia in a molecularly undetectable state at the time of AML diagnosis. Six patients (67%) had intermediate-risk cytogenetics, and three (33%) had unfavorable cytogenetics. The median CD33 expression was 76% (range, 45-100%). Patients received 225Ac-lintuzumab at doses of 0.5 (n=3) or 1 (n=6) μCi/kg/fraction. Total administered activity ranged from 68-199 μCi. The median number of cycles administered was 2 (range, 1-4). Dose-limiting toxicity was seen in one patient receiving 1 µCi/kg/fraction who had grade 4 thrombocytopenia with bone marrow aplasia persisting > 6 wks after receiving 225Ac-lintuzumab. Hematologic toxicities included grade 4 neutropenia (n=1) and thrombocytopenia (n=3). Grade 3/4 non-hematologic toxicities included febrile neutropenia (n=6), pneumonia (n=2), bacteremia (n=1), cellulitis (n=1), transient increase in creatinine (n=1), hypokalemia (n=1), and generalized weakness (n=1). Bone marrow blast reductions were seen in 5 of 7 patients (71%) evaluated after Cycle 1. Mean blast reduction was 61% (range, 34-100%). Three of the 7 patients (43%) had marrow blast reductions of ≥ 50%; however, no remissions were observed. Median progression-free survival (PFS) was 2.5 mos (range, 1.7-15.7+ mos). Median overall survival (OS) from study entry was 5.4 mos (range, 2.2-24 mos). For the 7 patients with prior MDS, median OS was 9.1 mos (range 2.3-24 mos). Conclusions: Fractionated-dose 225Ac-linutuzmab in combination with LDAC is feasible, safe, and has anti-leukemic activity. Dose escalation continues to define the MTD, with planned doses up to 2 µCi/kg/fraction. Additional patients will be treated at the MTD in the phase II portion of this trial to determine response rate, PFS, and OS. Disclosures Ravandi: Actinium Pharmaceuticals, Inc.: Research Funding. Pagel:Actinium Pharmaceuticals, Inc.: Equity Ownership, Research Funding. Park:Actinium Pharmaceuticals, Inc.: Research Funding. Wahl:Actinium Pharmaceuticals, Inc.: Research Funding. Earle:Actinium Pharmaceuticals, Inc.: Employment, Equity Ownership. Cicic:Actinium Pharmaceuticals, Inc.: Employment, Equity Ownership. Scheinberg:Actinium Pharmaceuticals, Inc.: Equity Ownership, Research Funding.

TGR-1202 in Combination with Ibrutinib in Patients with Relapsed or Refractory CLL or MCL: Preliminary Results of a Multicenter Phase I/Ib Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 641-641 ◽  
Author(s):  
Matthew S. Davids ◽  
Haesook T. Kim ◽  
Alyssa Nicotra ◽  
Alexandra Savell ◽  
Karen Francoeur ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Phase I ◽  
Dose Reduction ◽  
Median Time ◽  
Research Funding ◽  
Vitreous Hemorrhage ◽  
Employment Equity ◽  
Pi3k Inhibitors ◽  
Preliminary Results ◽  
Equity Ownership

Abstract Introduction The oral BTK inhibitor ibrutinib is highly effective at inducing partial responses (PR) in relapsed or refractory (R/R) CLL and MCL; however, complete responses (CR) are rare, and the durability of response for CLL patients (pts) with complex cytogenetics or del(17p) and for pts with MCL is limited. TGR-1202 is a novel oral PI3K-delta specific inhibitor designed to have less toxicity than other PI3K inhibitors, making it a logical drug to explore in combination regimens. We hypothesized that PI3K/BTK blockade would be tolerable and efficacious in R/R CLL and MCL. Methods This is a phase I/Ib investigator-initiated multicenter trial with primary objectives of determining the RP2D (recommended phase 2 dose) and the safety/tolerability of TGR-1202 plus ibrutinib in pts with R/R CLL or MCL. Secondary objectives are to assess overall response rates (ORR), CR rates, PFS, and OS. Pts receive continuous daily oral dosing of ibrutinib (420 mg CLL, 560 mg MCL) and TGR-1202. In phase I, TGR-1202 dose levels started at 400 mg daily and escalated in a standard 3 + 3 design to 600, then 800 mg daily. CLL and MCL pts were evaluated in separate arms, with a 28 day DLT observation period. Pts continue both drugs until progression or unacceptable toxicity. Eligibility criteria: ≥1 prior therapy, requiring treatment by IW-CLL criteria (CLL arm), ECOG PS ≤2, and adequate hematologic and organ function. Prior BTK or PI3K inhibitors were allowed. CTCAE v4 and IW-CLL or Cheson criteria (MCL) were used to evaluate toxicity and efficacy, with response evaluations after 2 mo., every 3 mo. up to 1 year, and every 6 mo. thereafter. Results As of July 26, 2016, 28 pts were evaluable, including 17 CLL and 11 MCL pts. The median age at enrollment was 67 yrs. (range 48-83). The median number of prior therapies was 2 for CLL (range 1-6, including 2 who started ibrutinib prior to enrollment and 3 with prior PI3Ki who came off prior PI3Ki for reasons other than progressive disease) and 3 for MCL (range 2-5, including 4 with prior autoSCT and 2 with prior ibrutinib). In CLL pts, del(17p) was present in 4/17 (24%), del (11q) in 7/17 (41%), unmutated IGHV in 11/17 (65%), and NOTCH1 or TP53 (without del(17p)) mutation in 2 pts each. In phase I, there were no DLTs in either arm, and the RP2D of TGR-1202 for both CLL and MCL was identified as 800 mg. Hematologic toxicities in CLL include: neutropenia (18%: 6% gr3, 12% gr4), thrombocytopenia (12%, all gr1), and anemia (12%, all gr1/2). All grade non-hematologic toxicities in >20% of CLL pts include: diarrhea (24%: 18% gr1, 6% gr2) and nausea (24%, all gr1). SAEs include gr 3 atrial fibrillation, lipase elevation, and adrenal insufficiency in 1 pt each, 1 pt with CNS aspergillus infection that likely preceded enrollment, and 1 case of sudden death of uncertain cause. Three CLL pts had dose-reduction of ibrutinib (atrial fibrillation, palpitations, vitreous hemorrhage). Hematologic toxicities in MCL include: neutropenia (18%, 6% gr4), thrombocytopenia (18%, 6% gr3), and anemia (18%, 6% gr3). All grade non-hematologic toxicities in >20% of MCL pts include: diarrhea (29%, all gr1), fatigue (29%, all gr1/2), and 24% each for nausea (all gr1/2) and dizziness (all gr1). SAEs included gr3 hypophosphatemia in 2 pts and gr4 lipase elevation in 1 pt. One MCL pt had dose reduction of TGR-1202 (dizziness). Study-wide, 5/28 (18%) pts had transaminitis, all gr1, and bleeding events included gr1 epistaxis, hematuria, and vitreous hemorrhage in 1 CLL pt each. For CLL, the ORR is 82% (14/17), with 35% PR-L (6/17), 41% PR (7/17), and 6% CR (1/17) with bone marrow MRD positivity. 6/8 CLL pts in PR on treatment for ≥6 mo. have residual LN's <2 cm in long axis. All 3 pts with prior PI3Ki exposure responded, and as did 1 of the 2 pts with prior ibrutinib exposure. The median time on study for CLL pts is 9.3 mo. (range 2.5-19.7 mo.). For MCL, the ORR is 67%, with 6/9 pts achieving PR including 1 of the 2 pts with prior ibrutinb. The median time on study for MCL pts is 10.9 mo. (range 1.1-19.8 mo.). Conclusions We report preliminary results of the first dedicated study to look at a PI3Ki plus BTKi doublet in B cell malignancies. TGR-1202 plus ibrutinib is well-tolerated in pts with R/R CLL and MCL, with no DLTs observed. The RP2D of TGR-1202 for both CLL and MCL is 800 mg daily. Preliminary efficacy data suggest a high response rate in both diseases, with several CLL pts close to radiographic CR. Phase Ib expansion cohorts at 800 mg continue to accrue in this ongoing study (NCT 02268851). Disclosures Davids: Infinity: Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Gilead: Honoraria; Abbvie: Consultancy, Honoraria; TG Therapeutics: Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding. Miskin:TG Therapeutics, Inc: Employment, Equity Ownership. Sportelli:TG Therapeutics, Inc.: Employment, Equity Ownership. Arnason:Gilead: Consultancy. Jacobson:Kite: Membership on an entity's Board of Directors or advisory committees. Fisher:Pharmacyclics: Consultancy. Brown:Janssen: Consultancy; Abbvie: Consultancy; Celgene: Consultancy; Infinity: Consultancy; Sun BioPharma: Consultancy; Roche/Genentech: Consultancy; Gilead Sciences: Consultancy; Pfizer: Consultancy.

scholarly journals Changing the Natural History of Fanconi Anemia Complementation Group-A with Gene Therapy: Early Results of U.S. Phase I Study of Lentiviral-Mediated Ex-VivoFANCA Gene Insertion in Human Stem and Progenitor Cells

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3350-3350
Author(s):  
Agnieszka Czechowicz ◽  
Maria Grazia Roncarolo ◽  
Brian C Beard ◽  
Ken Law ◽  
Eileen Nicoletti ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase I ◽  
Peripheral Blood ◽  
Research Funding ◽  
Phase I Study ◽  
Employment Equity ◽  
Hematopoietic Stem ◽  
Early Evidence ◽  
Stem And Progenitor Cells ◽  
Equity Ownership

Background: Fanconi anemia (FA) is a rare genetic disorder characterized by defective cellular deoxyribonucleic acid (DNA) repair, associated with developmental abnormalities, progressive bone marrow failure (BMF), and a predisposition to hematologic malignancies and solid tumors. 80% of FA patients develop BMF. Although allogeneic hematopoietic stem cell transplant (allo-HSCT) is a curative treatment for BMF, its utilization and efficacy is limited by availability of suitable human leukocyte antigen (HLA)-matched donors, risk of graft-versus-host disease (GVHD) and transplant-related toxicities. Ex-vivo insertion of a functional FANCA gene into autologous FA-A CD34+ enriched hematopoietic stem and progenitor cells (HSPCs) has been shown in preclinical studies to provide a survival advantage to the gene-modified stem cells, leading to correction of BMF. Feasibility of this approach was established in the FANCOLEN-1 clinical trial (Spain), although cell doses and transduction levels varied considerably. Modifications to the collection and manufacturing processes were made in the clinical studies to enhance the dose of transduced HSPCs, with the goal of preventing progression of BMF to obviate the need of an allo-HSCT. Design and Methods: RP-L102-0418 (clinicaltrials.gov # NCT03814408) is a U.S. Phase I clinical trial evaluating the feasibility and safety of autologous CD34+ cells transduced with a lentiviral vector (LV) carrying the FANCA gene (PGK-FANCA-WPRE) in two pediatric patients with FA-A. Patients <12 years of age, with early evidence of cytopenias, but with bone marrow (BM) CD34+ count >30/µL were eligible for treatment. Peripheral blood mononuclear cells were collected via leucocytapheresis on two consecutive days after mobilization with granulocyte-colony stimulating factor (G-CSF) and Plerixafor (Mozobil). CD34+ HSPCs were enriched, placed in culture with cytokines, and transduced with PGK-FANCA-WPRE LV. The investigational drug product (DP) (RP-L102) was infused fresh into patients within 4 hours of release, without any prior conditioning regimen. Patients are being followed for 3 years post-infusion for safety assessments (replication competent lentivirus (RCL), insertion site analysis (ISA)) and to ascertain early evidence of efficacy (increasing peripheral blood vector copy number (VCN) and BM mitomycin-C (MMC) resistance), along with stabilization/correction of cytopenias. Results: Two FA-A patients (aged 5 and 6 years) were consented and enrolled on the study at Stanford University. Mobilization and apheresis procedures were performed successfully without any serious adverse events. DP was successfully manufactured using "Process B" optimization including transduction enhancers, commercial-grade vector, and modified cell processing. Because of higher transduced CD34+ and colony forming cell (CFC) doses, we anticipate early development of BM MMC resistance in the current study patients. Safety and efficacy data 4 to 6 months post-treatment, including peripheral blood VCN, blood counts and bone marrow MMC resistance, will be available at the time of presentation. Conclusions: DP has been successfully manufactured in the Phase I study (N=2) to meet the required specifications.Patients are being monitored for early efficacy assessments; 6+ months of follow-up may be required to observe the proliferative advantage of transduced HSPCs.Plans for Phase II portion of the study are in progress. Disclosures Czechowicz: Rocket Pharmaceuticals, Inc.: Research Funding. Beard:Rocket Pharmaceuticals: Employment, Equity Ownership. Law:Rocket Pharmaceuticals: Employment, Equity Ownership. Nicoletti:Rocket Pharmaceuticals, Inc.: Employment, Equity Ownership. Río:Rocket Pharmaceuticals: Equity Ownership, Patents & Royalties, Research Funding. Bueren:Rocket Pharmaceuticals, Inc.: Consultancy, Equity Ownership, Patents & Royalties: Inventor on patents on lentiviral vectors filled by CIEMAT, CIBERER and F.J.D and may be entitled to receive financial benefits from the licensing of such patents, Research Funding. Schwartz:Rocket Pharmaceuticals: Employment, Equity Ownership.

scholarly journals Safety, Clinical Activity, Pharmacokinetics, and Pharmacodynamics from a Phase I Study of PF-06863135, a B-Cell Maturation Antigen (BCMA)-CD3 Bispecific Antibody, in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1869-1869 ◽  
Author(s):  
Noopur S. Raje ◽  
Andrzej Jakubowiak ◽  
Cristina Gasparetto ◽  
Robert F. Cornell ◽  
Heike I. Krupka ◽  
...  
Keyword(s):  
Phase I ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase I Study ◽  
Employment Equity ◽  
Advisory Committees ◽  
Best Response ◽  
Equity Ownership ◽  
Dose Levels

Introduction: PF-06863135 (PF-3135) is a bispecific, humanized, monoclonal antibody (mAb) consisting of BCMA- and CD3-targeting arms paired on an IgG2a backbone by hinge-mutation technology. PF-3135 binds BCMA+ myeloma cells and CD3+ T cells with affinities of 20 pM and ~40 nM, respectively (Panowski et al. Blood 2016). We report here findings from the dose-escalation portion of an ongoing, multi-center, open-label, phase I study (NCT03269136) of PF-3135 in patients with RRMM. Methods: Adult patients (≥18 years of age) with RRMM, previously treated with a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 mAb, received escalating, intravenous (IV) doses of PF-3135, once weekly. Prior BCMA-targeted bispecific T-cell engager or chimeric antigen receptor T-cell (CART) treatment was allowed by protocol. Patients had measurable disease per the International Myeloma Working Group (IMWG) updated criteria 2014. A modified toxicity probability interval method (mTPI), targeting a dose-limiting toxicity (DLT) rate of 25% (equivalence interval ± 5%) was used for dose escalation. The primary study objectives are to assess PF-3135 safety and tolerability, to determine the maximum tolerated dose (MTD) and select the recommended phase II dose (RP2D). Secondary objectives include evaluation of anti-myeloma activity, pharmacokinetics (PK), and immunogenicity of PF-3135. Results: As of April 9, 2019, 17 patients had received once weekly, non-continuous, IV infusion of PF-3135 in 6 dose-escalation groups. The majority were men (71%). The median age was 61 yrs (range, 47-82 yrs) and median disease duration since onset was 7 yrs (range, 1.1-13.3 yrs). Ten (59%) patients had ≥1 chromosomal abnormality and 5 (29%) had a normal karyotype (status not known for 2 [12%] patients). The median number of prior anti-myeloma therapies was 11; 5 (29%) patients had received prior BCMA-targeted therapy. Eight (47%) patients had relapsed MM and 8 (47%) had refractory disease (recurrence type not known for 1 [6%] patient). Ten (59%) patients experienced treatment-related (TR) AEs of any grade. Most TRAEs were grade 1-2, including cytokine release syndrome (CRS, 24%), thrombocytopenia (24%), anemia (18%), and pyrexia (18%). Three (18%) patients had grade 3 TRAEs (increased alanine aminotransferase/aspartate aminotransferase, leukocytopenia, neutropenia, and lymphopenia). One patient treated at the highest dose level, who had received prior BCMA CART therapy, developed treatment-related febrile neutropenia, a DLT, which may have been related to CRS and borderline/low neutrophil count at baseline. None of the patients had grade 4-5 TRAEs or discontinued treatment due to a TRAE. The median duration of treatment was 4 (range, 2-12) actual dosing days. Sixteen of the 17 patients were evaluable for response. At the time of data cut-off, one (6%) patient had a minimal response and 6 (35%) patients had stable disease (SD) across dose levels, as best response by investigator IMWG assessment; 9 (53%) patients experienced disease progression. The clinical benefit rate (defined as best response ≥SD) was 41% (95% CI: 18.4%, 67.1%). Conclusions: Treatment with IV PF-3135 was well tolerated at the dose levels evaluated. The observed CRS events were moderate and dose-dependent. Additional dose cohorts are accruing. The latest clinical, biomarker, and PK data will be presented for this ongoing study. Disclosures Raje: Medscape: Honoraria; Research to Practice: Honoraria; Takeda: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AstraZeneca: Research Funding. Jakubowiak:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SkyLineDx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; KaryoPharm Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Gasparetto:Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Cornell:KaryoPharm: Consultancy; Takeda: Consultancy. Krupka:Pfizer: Employment, Equity Ownership. Navarro:Pfizer: Employment, Equity Ownership. Forgie:Pfizer: Employment, Equity Ownership. Udata:Pfizer: Employment, Equity Ownership. Basu:Pfizer: Employment, Equity Ownership. Chou:Pfizer: Employment, Equity Ownership. Leung:Pfizer: Employment, Equity Ownership. Lesokhin:BMS: Consultancy, Honoraria, Research Funding; Serametrix Inc.: Patents & Royalties; Takeda: Consultancy, Honoraria; Genentech: Research Funding; Juno: Consultancy, Honoraria; GenMab: Consultancy, Honoraria; Janssen: Research Funding. OffLabel Disclosure: PF-06863135, investigational agent

Phase 1 Dose-Escalation Study of Sotatercept (ACE-011) in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed and/or Refractory Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4241-4241 ◽  
Author(s):  
Andrew J. Yee ◽  
Jacob P. Laubach ◽  
Ajay K. Nooka ◽  
Elizabeth K. O'Donnell ◽  
Edie A. Weller ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Multiple Myeloma ◽  
Bone Mineral ◽  
Dose Escalation ◽  
Bone Disease ◽  
Research Funding ◽  
Phase 1 ◽  
Activin A ◽  
Mineral Density ◽  
Grade 3

Abstract Introduction Anemia and bone disease are hallmarks of multiple myeloma (MM). Sotatercept (ACE-011) is a novel, first-in-class activin type IIA receptor fusion protein that binds with high affinity to activin A and GDF11, and it acts during late-stage erythropoiesis to increase the production of mature erythrocytes through a mechanism independent of erythropoietin. Sotatercept has shown promising activity in clinical trials for anemia in myelodysplastic syndromes (Komrokji et al., ASH 2014) and in thalassemia (Cappellini et al., EHA 2015). Additionally, we have shown that targeting activin A through an analog of sotatercept reverses osteoblast inhibition and improves MM bone disease in a mouse model (Vallet et al., PNAS 2010). Lenalidomide increases activin A secretion with consequent inhibition of osteoblastogeneis, and this can be abrogated by treatment with an activin A neutralizing antibody (Scullen et al., Leukemia 2013). Sotatercept has been previously studied with melphalan, prednisolone, and thalidomide in MM (Abdulkadyrov et al., Br J Haematol 2014). Based on these findings, we evaluated sotatercept in combination with lenalidomide and dexamethasone in MM (NCT01562405). Methods Patient with relapsed and/or refractory MM with at least one prior line of therapy, anemia with hemoglobin <13 g/dL, lytic bone disease, and otherwise adequate organ function were eligible to participate. Sotatercept 10, 15, 30, or 45 mg was given s.c. q28 days along with lenalidomide and weekly dexamethasone on a standard 28 day schedule, with dose escalation following a 3 + 3 design. Sotatercept was held for hemoglobin ≥13 g/dL or for ≥ grade 3 hypertension. Bone mineral density by DEXA was assessed after four cycles. Bisphosphonates were not permitted during the study; prior bisphosphonate therapy was allowed. Results Thirteen patients with a median age of 62 years (range 49-77) and a median of 2 prior lines (range 1-5) of therapy have been enrolled to date (July 31, 2015). Median duration of treatment is 8.1 months (range 0.5, 27 months); five patients continue on study. The MTD has not been reached, and the current dosing level is sotatercept 45 mg with lenalidomide 25 mg. Grade 3-4 adverse events included anemia (38%), diarrhea (15%), fatigue (15%), hypophosphatemia (15%), and thrombocytopenia (38%). Grade 3 hypertension occurred in one patient receiving sotatercept 15 mg (hemoglobin at the time, 11.5 g/dL). There was one death on study that was unrelated to treatment. In patients who completed at least two cycles of treatment, there was a significant mean increase in hemoglobin on study of 0.94 g/dL (N = 10, p = 0.0048) from a mean starting hemoglobin 10.27 g/dL (range 8.6, 12.2). Mean maximal increase in hemoglobin was 2.11 g/dL (range 1.1, 4). Bone density by DEXA was assessed after four cycles. In patients who received a cumulative dose of sotatercept over 45 mg (N = 6), total lumbar spine BMD increased by a mean of 2.0% after four cycles; 83% had increase in BMD. ORR for this combination was 60% (CR = 1, VGPR = 1, PR = 4, SD = 4) in patients evaluable for response. Conclusion Sotatercept in combination with lenalidomide and dexamethasone is well tolerated with expected toxicities related to lenalidomide in MM. Preliminary data from this ongoing study suggest that sotatercept leads to early increases in both hemoglobin and bone mineral density, and it is the first agent that may address both of these significant causes of morbidity in MM. Disclosures Laubach: Novartis: Research Funding; Onyx: Research Funding; Celgene: Research Funding; Millennium: Research Funding. Nooka:Onyx Pharmaceuticals: Consultancy; Spectrum Pharmaceuticals: Consultancy. O'Donnell:Millennium: Consultancy. Puccio-Pick:Celgene Corp.: Employment. Laadem:Celgene Corporation: Employment. Sherman:Acceleron Pharma: Employment. Raje:Acetylon: Research Funding; AstraZeneca: Research Funding; Onyx: Consultancy; Takeda: Consultancy; Eli Lilly: Research Funding; Millenium: Consultancy; Novartis: Consultancy; Amgen: Consultancy; BMS: Consultancy; Celgene Corporation: Consultancy.

scholarly journals Sclerostin antibodies as novel anabolic therapy for osteoporosis

2019 ◽  
Vol 21 (3) ◽  
pp. 21-29
Author(s):  
Elizaveta O. Mamedova ◽  
Tatiana A. Grebennikova ◽  
Zhanna E. Belaya ◽  
Liudmila Y. Rozhinskaya
Keyword(s):  
Bone Mineral Density ◽  
Bone Resorption ◽  
Bone Formation ◽  
Bone Mineral ◽  
Human Monoclonal Antibody ◽  
Wnt Signaling Pathway ◽  
Osteoporosis Treatment ◽  
Anabolic Effect ◽  
Mineral Density ◽  
Anabolic Therapy

Osteoporosis medications are divided into two groups: those inhibiting bone resorption and formation (bisphosphonates and denosumab), and those stimulating bone formation i.e. having an anabolic effect. The latter include teriparatide, parathyroid hormone 1-84 and abaloparatide, all of which stimulate bone resorption as well as bone formation, which limits their anabolic effect. The discovery of sclerostin – the key inhibitor of bone formation – has led to development of the concept that inhibition of this protein could stimulate bone formation. Romosozumab is a human monoclonal antibody to sclerostin that binds to sclerostin and enables Wnt-signaling pathway ligands and their co-receptors to interact with each other, which, in turn, leads to increased bone formation and bone mineral density. Unlike classical anabolic drugs in osteoporosis treatment, romosozumab stimulates bone formation and inhibits bone resorption. In clinical trials, romosozumab showed marked increase in lumbar spine and hip bone mineral density. Presented article contains information about pre-clinical and clinical studies of romosozumab.

Final Results of the Phase I Study of Lenalidomide In Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL-001 Study)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1376-1376 ◽  
Author(s):  
Clemens Wendtner ◽  
Peter Hillmen ◽  
Daruka Mahadevan ◽  
Stephan Stilgenbauer ◽  
Lutz Uharek ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Research Funding ◽  
Off Label Use ◽  
Duration Of Treatment ◽  
Employment Equity ◽  
Advisory Committees ◽  
High Risk Disease ◽  
Starting Dose ◽  
Equity Ownership

Abstract Abstract 1376 Introduction: Patients who relapse after fludarabine-based treatments have poor prognosis. These patients have deteriorating immune functions with high infection rates resulting from progressing disease complicated further by ineffective and often immunosuppressive therapies. Two phase II studies in patients with relapsed or refractory (rel/ref) CLL at starting doses of 10 mg or 25 mg daily of lenalidomide (Len) demonstrated promising responses. A phase II/III study was initiated to assess Len 10 mg/d vs 25 mg/d given continuously for 21 days of a 28-day cycle. Four cases of serious tumor lysis syndrome (TLS) prompted an independent data monitoring committee to amend the protocol into a phase I trial (de Parseval et al., JCO 2007) Here we present results from this amended study. Methods: Eligible patients had rel/ref CLL, received prior treatment with an alkylating agent and fludarabine, and progressed during or ≤ 12 months after completing fludarabine-based treatment. Primary objective was to determine whether Len 2.5 mg was a safe starting dose and the maximum tolerated dose escalation level (MTDEL). Prophylaxis with allopurinol and hydration were employed as part of an aggressive monitoring plan for TLS prevention. All patients initiated Len at 2.5 mg/d with subsequent dose escalation to 5 mg/d after 28 days with further dose escalations in 5 mg increments performed every 28 days until MTDEL was defined, or the maximum targeted 20 mg/d dose level attained. The first 6 patients at 10, 15 and 20 mg/d dose levels were considered a cohort and could not escalate beyond that dose level for the duration of treatment. Treatment continued until disease progression or unacceptable toxicity. Results: The redesigned phase I study enrolled 52 patients with a median age of 65 years (range, 37–80) and bulky disease (> 5 cm) in 70%. Cytogenetic data was available for 46 patients, of whom 22 (48%) had high-risk disease: 8 (17%) had del(17p), 12 (26%) had del(11q), 2 had both. Patients were heavily pretreated with a median of 4 prior therapies (range, 1–14); 54% were fludarabine refractory (no-response/relapse ≤ 6 mo), 42% had prior FCR or PCR and 21% had prior alemtuzumab. The TLS prevention strategy resulted in only 2 (3.8%) cases of TLS, both observed at 2.5 mg/d (1 patient with Gr.2 and another with lab TLS). Gr.3/4 tumor flare occurred in 5 (9.6%) patients and was managed with NSAIDs or low-dose steroids. The most common Gr.3/4 adverse events (AEs) included neutropenia (65%) and thrombocytopenia (33%). Febrile neutropenia occurred in 4 (8%) patients. Gr.3/4 infections were observed in 21 (40%) patients; 10 (19%) patients developed pneumonia and 3 developed sepsis; 2 cases of sepsis-related death at day 37 and 94 of therapy were also noted but deemed unrelated to study drug by the investigators. Reasons for study discontinuation included disease progression (37%), AEs (29%), consent withdrawal (15%), death (4%), and other reasons (10%). For 16 (31%) patients, 2.5 mg/d was the maximum dose reached and 22 (42%) patients were unable to escalate beyond 5 mg/d. Gr.4 neutropenia was the primary reason for delay in dose escalation. By intent-to-treat (ITT) analysis, 6 patients (12%) had a partial response (NCI-WG 1996), 30 patients (58%) had stable disease and 13 patients (25%) progressed; 3 patients were non-evaluable. Median duration of treatment was 3.1 months (range, 0.07–18.4) and the median time to response was 4.3 months (range, 2.8–7.4). Responses were observed at 10 mg/d (n=3), at 15 mg/d (n=1), and at 20 mg/d (n=2); Median PFS (ITT) was 5.5 months and median PFS for responders was 12 months. Three patients still remain on therapy. Conclusion: We conclude that a Len starting dose of 2.5 mg/d appears safe, feasible and can be safely titrated to 20 mg/d (maximum intended dose). The MTDEL was not reached at 20 mg/d. Based on the response rate reported in this study, a higher starting dose, such as previously reported by Chanan-Khan et al (JCO 2006) and Ferrajoli et al (Blood 2008), may be needed to achieve clinical efficacy, particularly for patients with high-risk disease. Adequate TLS prophylaxis and monitoring allows for higher starting doses to be investigated. To identify a safe and clinically active starting dose, the CLL-009 study is evaluating Len at starting doses of 5 mg/d, 10 mg/d, and 15 mg/d in the setting of rel/ref CLL. Disclosures: Wendtner: Celgene, BayerSchering, Roche, Mundipharma: Consultancy, Honoraria. Off Label Use: off-label use of lenalidomide. Hillmen:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion Pharmaceuticals: Consultancy; Bayer Schering: Consultancy. Mahadevan:Pfizer, millenium, Amgen: Honoraria. Stilgenbauer:Roche, Bayer, Celgene, GSK, Amgen, Mundipharma: Consultancy, Honoraria, Research Funding. Frankfurt:Bayer, Celgene: Research Funding, Speakers Bureau. Kimby:Roche, Bayer-Schering, Mundipharma: Membership on an entity's Board of Directors or advisory committees, lecturer. Gobbi:Novartis, Jansen Cilag, Roche, Celgene, Amgen: Consultancy, Research Funding, Speakers Bureau. Hurd:Celgene: Research Funding. Sekeres:Celgene: Research Funding, Speakers Bureau. Ferrajoli:Celgene: Honoraria, Research Funding. Shah:Celgene: Employment, Equity Ownership. Zhang:Celgene: Employment. Moutouh de Parseval:Celgene: Employment, Equity Ownership.

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