Dose-Response Analyses Of Momelotinib (CYT387), a JAK1 and JAK2 Inhibitor, From a Phase I/II Study (CCL09101) In Treatment Of Myelofibrosis

Abstract Background Momelotinib (MMB, previously CYT387) is a selective small molecule inhibitor of JAK 1 and JAK 2 currently under investigation for the treatment of myelofibrosis (MF). Study CCL09101 is a Phase I/II, open-label, dose-escalation study of oral MMB in MF subjects. Following an initial dose escalation phase, subjects were assigned to 150 mg once-daily (QD), 300 mg QD or 150 mg twice-daily (BID) MMB capsules, in a 9 month (mos) dose expansion phase. The safety and tolerability of MMB, based on assigned dose, was previously reported with a maximum tolerated dose of 300 mg QD and dose limiting toxicities of elevated lipase and headache at 400 mg QD. Clinical efficacy included spleen response rate of 37% based on IWG criteria and suggested improvement in anemia related endpoints. As the study allowed intra-subject dose adjustments for tolerability, additional analyses based on average daily dose administered were performed. In a subset of patients, pharmacokinetics (PK) was assessed. Methods Dose-efficacy analyses were conducted using the average daily dose received over 6 mos for spleen response and 9 mos for transfusion (txn) independence response. Subjects were grouped based on tertiles of average daily dose < 200 mg, 200 to < 300 mg, > 300 mg. Spleen response at 6 mos required a ≥ 50% reduction in palpable splenomegaly. Txn response required maintaining transfusion independence for ≥12 weeks (wks) for subjects who were txn dependent at baseline and completed ≥ 12 wks on study. The incidence of hgb and platelet (plt) decline was also analyzed as a function of average daily dose received over 6 mos. Subjects evaluated for hgb decline were txn independent with hgb ≥ 8 g/dL at baseline. Hgb decline was defined as the incidence of hgb < 8 g/dL and at least a 1 g/dL decrease compared to baseline. Subjects evaluated for plt decline had baseline platelet count ≥ 100 x 109/L. Plt count decline was defined as the incidence of plt count < 100 x 109 /L and ≥ 50 x 109/L decrease compared to baseline at any point during the 6 mos. In the PK subset, dose-exposure relationship was explored. Results Spleen response rates were comparable across MMB average daily dose tertiles, indicating a relatively flat dose-efficacy relationship. A trend towards a higher txn response was observed at the highest MMB average daily dose. No dose dependent increase in hgb or plt decline was noted across average daily dose tertiles. 60 subjects (41%) reported peripheral neuropathy as an adverse event during the 9 mos study; 92% grade 1, 8% grade 2. Incidence was comparable across average daily dose tertiles (see table). In the PK subset of subjects, MMB exposures were generally dose proportional between 150 mg QD and 300 mg QD (mean AUCtau: 2114 and 4424 h×ng/ml, respectively; steady state Cmax: 339 and 660 ng/ml, respectively) with limited data from the other dose levels (n ≤ 5). Of subjects receiving 300 mg total daily starting dose, > 60% of subjects maintained this dose level throughout the study; > 75% of subjects had an average daily dose of ∼250 mg to 280 mg (following 300 mg QD or 150 mg BID dosing, respectively), and the median average daily dose was 300 mg, suggesting 300 mg QD was well tolerated. Conclusion No relationships were observed between average daily doses of MMB vs clinically relevant endpoints of spleen response rate or plt count decline compared to baseline. There was a suggested trend, albeit with limited sample size, towards improved anemia-related endpoints at MMB dose ≥ 300 mg QD. Analyses suggest no need to adjust dose based on baseline plt count. In conjunction with the previously reported primary endpoints of safety and efficacy, these analyses support selection of the 300 mg QD capsule formulation as the starting dose for all subjects in the planned Phase 3 study. Disclosures: Xin: Gilead Sciences: Employment, Equity Ownership. Shao:Gilead Sciences: Employment, Equity Ownership. Deng:Gilead Sciences: Employment, Equity Ownership. Niforos:Gilead Sciences: Employment. Kowalski:Gilead Sciences: Employment. Bavisotto:YM Biosciences: Consultancy. Kawashima:Gilead Sciences: Employment. Jun:Gilead Sciences: Employment. Collins:Gilead Sciences: Employment, Equity Ownership. Ramanathan:Gilead Sciences: Employment, Equity Ownership.

Download Full-text

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

Blood ◽

10.1182/blood.v116.21.1376.1376 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1376-1376 ◽

Cited By ~ 1

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.

Download Full-text

A Multicenter Phase I/II Dose Escalation Study of Lenalidomide in Combination with Melphalan and Dexamethasone in Subjects with Newly-Diagnosed Light-Chain (AL)-Amyloidosis.

Blood ◽

10.1182/blood.v112.11.1732.1732 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1732-1732

Author(s):

Philippe Moreau ◽

Arnaud Jaccard ◽

Lotfi Benboubker ◽

Bruno Royer ◽

Valerie Coiteux ◽

...

Keyword(s):

Phase I ◽

Dose Escalation ◽

Response Rate ◽

Standard Dose ◽

High Dose ◽

Al Amyloidosis ◽

Hematologic Toxicity ◽

Newly Diagnosed ◽

Open Label ◽

Dose Escalation Study

Abstract A recent prospective randomized trial comparing standard-dose to high-dose melphalan in patients presenting with newly diagnosed AL-amyloidosis showed that oral melphalan-dexamethasone (M-dex) given monthly could be considered the current standard of care, with a median survival of 56 months (Jaccard, N Engl J Med 2007). The use of a combination of lenalidomide and dexamethasone has also been tested in patients with symptomatic AL-amyloidosis. The initial dose of lenalidomide at 25 mg/day was poorly tolerated. However, a 15 mg/day dose regimen was well tolerated and effective, with both hematologic and organ responses (Dispenzieri, Blood 2007 & Sanchorawala, Blood 2007). Combining M-dex with lenalidomide (M-dex-rev) could increase the response rate but the toxicity of this regimen is still unknown. Thus we have initiated a multicenter single-arm open-label phase I/II dose escalation study of lenalidomide administered in combination with M-dex. The primary endpoint was the incidence of dose limiting toxicities (DLT) during the first cycle of lenalidomide at a given dose level in order to determine the maximum tolerated dose (MTD). In addition to melphalan 0.18mg/kg/day from day 1–4 of each 28 day cycle and dexamethasone 40mg/day from day 1– 4 of each 28 day cycle, 3 cohorts of 3 subjects were successively exposed to escalating doses of lenalidomide (5, 10 and 15mg once daily on days 1–21 of a 28 day cycle). DLT was defined using National Cancer Institute (NCI) common toxicity criteria during the first 4 weeks of treatment (one cycle) as the following: at least grade 2 cardiac arrhythmia, at least grade 3 non hematologic toxicity, grade 4 neutropenia lasting >7 days or any other Grade 4 hematologic toxicity, or treatment delay due to toxicity that occurred during the first cycle. No DLT was observed among the first 3 patients treated at 5, 10 and 15 mg lenalidomide/day. 9 additional subjects will be enrolled at 15 mg/day to better define the safety profile and estimate the hematologic and organ response rate. Final results regarding both toxicity and efficacy will be presented during the meeting.

Download Full-text

A Phase I/II Study of CYT387, An Oral JAK-1/2 Inhibitor, In Myelofibrosis: Significant Response Rates In Anemia, Splenomegaly, and Constitutional Symptoms

Blood ◽

10.1182/blood.v116.21.460.460 ◽

2010 ◽

Vol 116 (21) ◽

pp. 460-460 ◽

Cited By ~ 14

Author(s):

Animesh Pardanani ◽

Geeta George ◽

Terra Lasho ◽

William J. Hogan ◽

Mark R. Litzow ◽

...

Keyword(s):

Phase I ◽

Response Rate ◽

Red Cell ◽

Spleen Size ◽

Jak Inhibitors ◽

Employment Equity ◽

Previously Treated ◽

Equity Ownership ◽

Red Cell Transfusion ◽

Grade 3

Abstract Abstract 460 Background: CYT387 is a potent JAK-1/2 inhibitor that suppresses the in vitro growth of cells harboring JAK2V617F (Leukemia 2009;23:1441) and was effective in a murine model of myeloproliferative neoplasms (MPN) (Blood 2010;115:5232). Aims/Methods: To assess the safety, tolerability, and pharmacokinetic behavior of CYT387 in a Phase I dose-escalation study in patients with high- or intermediate-risk primary myelofibrosis (PMF) and post-PV or post-essential thrombocythemia (ET) myelofibrosis. The secondary objective was evaluation of preliminary efficacy. CYT387 was administered orally once daily in 28-day cycles. Once dose-limiting toxicity (DLT) was identified, a dose-confirmation cohort initiated treatment at the maximum tolerated dose (MTD) or lower. Result: Thirty six subjects (median age 64 years) have been enrolled (targeted accrual 120); 18 each in the dose escalation and dose confirmation phases. Twenty-three subjects had PMF, 8 post-PV MF, and 5 post-ET MF; 81% were JAK2V617F-positive. Median palpable spleen size was 18 cm and 20 subjects (56%) were red cell transfusion-dependent at study entry. Prior treatment included JAK inhibitors (9 and 1 subjects with INCB018424 and TG101348, respectively) and pomalidomide in 9 patients. The median treatment duration to date is 15 weeks (range 4–38). Dose-linear plasma exposures were observed up to 300 mg/day, with mean elimination T1/2 at steady state ranging from 3.9 to 5 hours across doses. Toxicity: All 36 subjects were evaluable for toxicity. At 400 mg/day, 2 of 6 subjects experienced DLT (1 each with asymptomatic grade 3 hyperlipasemia and grade 3 headache that were reversible upon holding drug); consequently, the MTD was declared at 300 mg/day. In the dose-confirmation phase, subjects were started at one of 2 dose levels that were deemed clinically effective: 150 mg/day (n=15) and 300 mg/day (n=3). Thirty-five subjects are currently on active therapy: 100 mg/day (n=2), 150 mg/day (n=20), 300 mg/day (n=10), and 400 mg/day (n=3). CYT387 was well tolerated. No grade 4 non-hematological toxicities were observed. Grade 3 non-hematologic adverse events were infrequent and included increased transaminases (n=2), increased alkaline phosphatase (n=2), headache/head pressure (n=2), increased lipase (n=1), and QTc prolongation (n=1). Thirteen (36%) subjects experienced “first-dose effect” characterized by grade 1 lightheadedness and hypotension; this phenomenon was self-limited and generally resolved within 3–4 hours with rare recurrence. Grade 3/4 thrombocytopenia was seen in 8 (22%) subjects, and treatment-emergent grade 3 anemia was seen in 1 subject only (3%). Treatment-emergent grade 3/4 neutropenia was not observed. Efficacy: Thirty two of 36 subjects who completed at least 1 cycle were eligible for response assessment: Anemia: Twenty two subjects were evaluable for anemia response (baseline Hgb <10 g/dL or red cell transfusion-dependent). Of these, 9 subjects (41%) achieved the threshold of response for “Clinical Improvement (CI)” per the International Working Group for MPN Research and Treatment (IWG-MRT) criteria, including 2 of 4 subjects who were previously treated with INCB018424. An additional 5 subjects experienced a >50% reduction in transfusion requirement, thus increasing the total anemia response rate to 63%. Splenomegaly: Thirty of 32 evaluable subjects had splenomegaly at baseline: median 20 cm; range 10–32 cm. Twenty nine subjects (97%) had some degree of spleen size reduction (median 9 cm; range 2–18 cm): 11 (37%) patients have achieved a minimum 50% decrease in palpable spleen size, thus qualifying them for a CI, including 3 of 8 subjects (38%) who were previously treated with INCB018424. Constitutional symptoms: The proportion of patients with the following symptoms at baseline, are: fatigue (97%), pruritus (22%), night sweats (38%), cough (13%), bone pain (28%), and fever (16%). At last follow up, improvement (complete resolution) in these symptoms was reported by 68% (16%), 86% (57%), 83% (75%), 75% (50%), 78% (44%), and 100% (100%), respectively. Conclusion: CYT387 is first-in-class of the JAK inhibitors with a significant response rate in anemia in myelofibrosis patients. The drug also shows substantial activity in reducing spleen size and controlling constitutional symptoms. CYT387 is well tolerated, and treatment responses have been seen both at (300 mg/day) and below (150 mg/day) the MTD. Disclosures: Pardanani: Cytopia Inc.: Research Funding. Off Label Use: Clinical trial data for CYT387 use in Myelofibrosis. Fida:YM Biosciences Australia: Employment, Equity Ownership. Burns:YM Biosciences Australia: Employment, Equity Ownership. Smith: YM Biosciences Australia: Employment, Equity Ownership.

Download Full-text

Ruxolitinib Provides Reductions in Splenomegaly Across Subgroups: An Analysis of Spleen Response in the COMFORT-II Study

Blood ◽

10.1182/blood.v118.21.279.279 ◽

2011 ◽

Vol 118 (21) ◽

pp. 279-279 ◽

Cited By ~ 6

Author(s):

Claire N. Harrison ◽

Jean-Jacques Kiladjian ◽

Heinz Gisslinger ◽

Dietger Niederwieser ◽

Francesco Passamonti ◽

...

Keyword(s):

Board Of Directors ◽

Response Rate ◽

Response Rates ◽

Risk Category ◽

Spleen Volume ◽

Employment Equity ◽

Advisory Committees ◽

Starting Dose ◽

Secondary Endpoints ◽

Equity Ownership

Abstract Abstract 279 Background: COMFORT-II is a randomized, open-label, phase 3 study evaluating the safety and efficacy of ruxolitinib, a potent and selective oral inhibitor of JAK1 and JAK2, in patients with primary myelofibrosis (PMF), post-polycythemia vera-MF (PPV-MF), or post-essential thrombocythemia-MF (PET-MF). Patients who received ruxolitinib had significantly greater reductions in spleen volume compared with those who received best available therapy (BAT). The primary and key secondary endpoints of the study were both met: the proportion of patients achieving ≥35% reduction in spleen volume at week 48 (28.5%, ruxolitinib; 0%, BAT; P <.0001) and week 24 (31.9%, ruxolitinib; 0%, BAT; P <.0001), respectively. Subgroup analysis was performed on both the 48- and 24-week endpoints. Methods: In the COMFORT-II study, 219 patients were randomized (2:1) to receive ruxolitinib (15 or 20 mg twice daily [bid] based on the baseline platelet count [100– 200 × 109/L or >200 × 109/L, respectively]) or BAT of the investigator's choice. The proportions of ruxolitinib-treated patients achieving the primary and key secondary endpoints were analyzed by subgroup for gender (male or female), age (≤65 or >65 years), starting dose (15 or 20 mg bid), baseline MF type (PMF, PPV-MF, or PET-MF), previous hydroxyurea (hydroxycarbamide) use (yes or no), baseline palpable spleen length (≤10 or >10 cm), baseline spleen volume (>median or ≤median), JAK2V617F mutation (presence or absence), and International Prognostic Scoring System (IPSS) risk category (intermediate-2 or high) (Cervantes F, et al, Blood, 2009;113(13):2895–2901). In addition, the relationships between these factors and spleen volume reduction were investigated by multivariate logistic regression. Results: The proportion of patients in each subgroup with ≥ 35% reduction in spleen volume from baseline at week 48 is shown below (Figure). BL, baseline; HU, hydroxyurea. The response rate was higher in patients receiving ruxolitinib than in patients receiving BAT in all subgroups; no patients in the BAT group reached a ≥35% reduction in spleen volume at week 48. All subgroups receiving ruxolitinib responded and all subgroup comparisons had overlapping 95% confidence intervals. At week 24, a trend for a higher response rate was observed in patients who received a starting dose of 20 mg bid compared with those who received a starting dose of 15 mg bid; however, the response rates among these patients at week 48 were not different. No significant difference in response rates was observed between patients with the JAK2V617F mutation compared with those without the mutation. Results of the subgroup analysis were confirmed by the multivariate models. A significant effect of the ruxolitinib starting dose was seen when response rates were modeled at week 24 but not when modeled at week 48. Conclusions: Recent findings from the COMFORT-II study show that patients who received ruxolitinib had significantly greater reductions in splenomegaly than did patients who received BAT. In this analysis, ruxolitinib was shown to be more effective than BAT at reducing spleen volume in all patient subgroups regardless of gender, age, mutation status, IPSS risk category, baseline spleen size, MF subtype, or ruxolitinib starting dose. Disclosures: Harrison: Novartis: Honoraria; Incyte: Honoraria; S*Bio: Honoraria; Celgene: Honoraria; Sanofi Aventis: Honoraria. Kiladjian:Novartis: Honoraria; Celgene: Honoraria. Gisslinger:Novartis: Speakers Bureau; Celgene Austria: Research Funding, Speakers Bureau; Aop-Orphan: Speakers Bureau. Niederwieser:Novartis: Speakers Bureau. Passamonti:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Waltzman:Novartis: Employment. Hollaender:Novartis Pharma AG: Employment. Hunter:Incyte Corporation: Employment, Equity Ownership. Levy:Incyte Corporation: Employment, Equity Ownership. Knoops:Novartis: Consultancy. Cervantes:Bristol-Myers-Squibb: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Vannucchi:Novartis: Honoraria. Barosi:Novartis: Consultancy.

Download Full-text

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 ◽

10.1182/blood.v124.21.5293.5293 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5293-5293 ◽

Cited By ~ 2

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.

Download Full-text

A Phase I Dose Escalation Study of Oxaliplatin, Cisplatin and Doxorubicin Applied as PIPAC in Patients with Peritoneal Carcinomatosis

Cancers ◽

10.3390/cancers13051060 ◽

2021 ◽

Vol 13 (5) ◽

pp. 1060

Author(s):

Manuela Robella ◽

Michele De Simone ◽

Paola Berchialla ◽

Monica Argenziano ◽

Alice Borsano ◽

...

Keyword(s):

Adverse Events ◽

Phase I ◽

Dose Escalation ◽

Serum Levels ◽

Maximum Tolerable Dose ◽

Tissue Penetration ◽

Dose Escalation Study ◽

Starting Dose ◽

Intraperitoneal Dose ◽

Tolerable Dose

Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) is an innovative laparoscopic intraperitoneal chemotherapy approach with the advantage of a deeper tissue penetration. Thus far, oxaliplatin has been administered at an arbitrary dose of 92 mg/m2, cisplatin at 7.5 mg/m2 and doxorubicin 1.5 mg/m2. This is a model-based approach phase I dose escalation study with the aim of identifying the maximum tolerable dose of the three different drugs. The starting dose of oxaliplatin was 100 mg/m2; cisplatin was used in association with doxorubicin: 15 mg/m2 and 3 mg/m2 were the respective starting doses. Safety was assessed according to Common Terminology Criteria for Adverse Events (CTCAE version 4.03). Thirteen patients were submitted to one PIPAC procedure. Seven patients were treated with cisplatin and doxorubicin and 6 patients with oxaliplatin; no dose limiting toxicities and major side effects were found. Common adverse events included postoperative abdominal pain and nausea. The maximum tolerable dose was not reached. The highest dose treated cohort (oxaliplatin 135 mg/m2; cisplatin 30 mg/m2 and doxorubicin 6 mg/m2) tolerated PIPAC well. Serological analyses revealed no trace of doxorubicin at any dose level. Serum levels of cis- and oxaliplatin reached a peak at 60–120 min after PIPAC and were still measurable in the circulation 24 h after the procedure. Cisplatin and doxorubicin may be safely used as PIPAC at a dose of 30 mg/m2 and 6 mg/m2, respectively; oxaliplatin can be used at an intraperitoneal dose of 135 mg/m2. The dosages achieved to date are the highest ever used in PIPAC.

Download Full-text

Ivosidenib (AG-120) Induced Durable Remissions and Transfusion Independence in Patients with IDH1-Mutant Relapsed or Refractory Myelodysplastic Syndrome: Results from a Phase 1 Dose Escalation and Expansion Study

Blood ◽

10.1182/blood-2018-99-111264 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1812-1812 ◽

Cited By ~ 10

Author(s):

Courtney D. DiNardo ◽

Justin M. Watts ◽

Eytan M. Stein ◽

Stephane de Botton ◽

Amir T. Fathi ◽

...

Keyword(s):

Dose Escalation ◽

Research Funding ◽

Phase 1 ◽

Hematologic Malignancies ◽

Advisory Board ◽

Employment Equity ◽

Transfusion Independence ◽

Starting Dose ◽

Equity Ownership ◽

Advisory Role

Abstract BACKGROUND: Recurrent mutations in isocitrate dehydrogenase 1 (IDH1) are observed in approximately 4% of patients with myelodysplastic syndrome (MDS) and have been linked with increased transformation to acute myeloid leukemia. Ivosidenib (AG-120), an oral, potent, targeted, small-molecule inhibitor of the mutant IDH1 protein (mIDH1), is a therapeutic candidate for the treatment of patients with mIDH1 MDS. Through inhibition of mIDH1, ivosidenib suppresses the production of the oncometabolite 2-hydroxyglutarate (2-HG), leading to clinical responses via differentiation of malignant cells. AIM: To report safety and efficacy data from patients with relapsed or refractory (R/R) MDS enrolled in the first-in-human, phase 1, dose escalation and expansion study of ivosidenib in patients with mIDH1 advanced hematologic malignancies (NCT02074839). METHODS: This ongoing study is evaluating the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and clinical activity of ivosidenib. Trial enrollment was completed on 08May2017. In dose escalation, patients received single-agent ivosidenib orally once daily (QD) or twice daily in 28-day cycles. The MTD was not reached and 500 mg QD was selected as the dose to be tested in expansion. Expansion Arm 3 enrolled patients with mIDH1 advanced hematologic malignancies, including MDS. The overall response rate (ORR) for MDS was defined as complete remission (CR) + partial remission + marrow CR. Exploratory biomarker assessments included baseline co-occurring mutations (next-generation sequencing panel for hematologic malignancies) and mIDH1 variant allele frequency (VAF) in bone marrow mononuclear cells (BEAMing Digital PCR; lower limit of detection for mIDH1, 0.02-0.04%). Here, we present safety and efficacy data for patients with MDS in expansion Arm 3 and in dose escalation whose starting dose was 500 mg QD. RESULTS: In all, 258 patients (78 in dose escalation, 180 in expansion) received ivosidenib, including 12 patients with MDS (9 from expansion and 3 from escalation) whose starting dose was 500 mg QD. Baseline characteristics for these 12 patients were: 9 men/3 women; median age, 72.5 years (range, 52-78) and 42% were ≥75 years of age; median number of prior therapies, 1 (range, 1-3). As of 10Nov2017, 7 of 12 (58.3%) patients remained on treatment and 5 (41.7%) had discontinued (one for allogeneic stem cell transplantation). The median duration of exposure to ivosidenib was 11.0 months (range, 3.3-31.1). The most common adverse events (AEs) of any grade, irrespective of causality, occurring in ≥20% of the 12 patients were back pain (n=4, 33.3%) and anemia, decreased appetite, diarrhea, dyspnea, fatigue, hypokalemia, pruritus, and rash (n=3, 25.0% each). The majority of these AEs were grade 1-2 and reported as unrelated to treatment. No AEs led to permanent discontinuation of treatment. IDH differentiation syndrome (IDH-DS) was observed in 2 of 12 (16.7%) patients; the events were grade 1 and 2, respectively. Of the 12 patients with MDS receiving ivosidenib 500 mg QD, 5 achieved CR (41.7%; 95% CI 15.2%, 72.3%) and 6 achieved marrow CR (50.0%), resulting in an ORR of 91.7% (95% CI 61.5%, 99.8%). The median durations of CR and overall response were not estimable at the time of the data cutoff. The percentages of patients who remained in CR and response at 12 months were 60.0% and 61.4%, respectively. Among 5 patients who were transfusion dependent at baseline, 4 became transfusion independent for at least 56 days on treatment. Baseline co-occurring mutations and changes in mIDH1 VAF levels on ivosidenib therapy will be presented. CONCLUSION: In patients with mIDH1 R/R MDS, ivosidenib monotherapy was well tolerated and induced durable remissions and transfusion independence. These findings support the role of ivosidenib as an effective, oral, targeted treatment for patients with mIDH1 R/R MDS. Disclosures DiNardo: Karyopharm: Other: Advisory role; Medimmune: Other: Advisory role; Celgene: Other: Advisory role; Bayer: Other: Advisory role; Agios: Consultancy, Other: Advisory role; AbbVie: Consultancy, Other: Advisory role. Watts:Jazz Pharma: Consultancy, Speakers Bureau; Takeda: Research Funding. Stein:Celgene: Consultancy; Daiichi Sankyo: Consultancy; Agios: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Bayer: Consultancy. de Botton:Agios: Research Funding; Celgene: Honoraria, Research Funding. Fathi:Takeda: Consultancy, Honoraria; Jazz: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Boston Biomedical: Consultancy, Honoraria; Astellas: Honoraria; Seattle Genetics: Consultancy, Honoraria; Agios: Honoraria, Research Funding. Stein:Amgen: Speakers Bureau; Celgene: Speakers Bureau. Foran:Agios: Research Funding; Xencor, Inc.: Research Funding. Stone:AbbVie: Consultancy; Agios: Consultancy, Research Funding; Cornerstone: Consultancy; Orsenix: Consultancy; Fujifilm: Consultancy; Sumitomo: Consultancy; Pfizer: Consultancy; Celgene: Consultancy, Other: Data and Safety Monitoring Board, Steering Committee; Ono: Consultancy; Novartis: Consultancy, Research Funding; Otsuka: Consultancy; Jazz: Consultancy; Merck: Consultancy; Astellas: Consultancy; Arog: Consultancy, Research Funding; Argenx: Other: Data and Safety Monitoring Board; Amgen: Consultancy. Patel:France Foundation: Honoraria; Dava Oncology: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tallman:Cellerant: Research Funding; BioSight: Other: Advisory board; ADC Therapeutics: Research Funding; AbbVie: Research Funding; Daiichi-Sankyo: Other: Advisory board; AROG: Research Funding; Orsenix: Other: Advisory board. Choe:Agios: Employment, Equity Ownership. Wang:Agios: Employment, Equity Ownership. Zhang:Agios: Employment, Equity Ownership. Dai:Agios: Employment, Equity Ownership. Fan:Agios: Employment, Equity Ownership. Yen:Agios: Employment, Equity Ownership. Kapsalis:Agios: Employment, Equity Ownership. Hickman:Agios: Employment, Equity Ownership. Agresta:Agios: Employment, Equity Ownership. Liu:Agios: Employment, Equity Ownership. Wu:Agios: Employment, Equity Ownership, Patents & Royalties. Attar:Agios: Employment, Equity Ownership.

Download Full-text

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 ◽

10.1182/blood-2019-121805 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1869-1869 ◽

Cited By ~ 13

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

Download Full-text

A Phase 1, Open-Label, Dose-Escalation Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of Oral Azacitidine in Patients with Myelodysplastic Syndromes (MDS) or Acute Myelogenous Leukemia (AML).

Blood ◽

10.1182/blood.v114.22.117.117 ◽

2009 ◽

Vol 114 (22) ◽

pp. 117-117 ◽

Cited By ~ 3

Author(s):

Guillermo Garcia-Manero ◽

Steven D. Gore ◽

Barry Skikne ◽

Christopher R. Cogle ◽

Yuhong Ning ◽

...

Keyword(s):

Dna Methylation ◽

Dose Escalation ◽

Research Funding ◽

Oral Therapy ◽

Phase 1 ◽

Employment Equity ◽

Dose Escalation Study ◽

Platelet Counts ◽

Equity Ownership ◽

Grade 3

Abstract Abstract 117 Background: Parenteral azacitidine significantly improves overall survival of subjects with higher-risk MDS and WHO AML (20–30% blasts) compared to conventional care (Fenaux, Lancet Oncol 2009; 10:223). An oral formulation would be a more convenient administration route for patients and allow the evaluation of extended low-dose regimens, which could in turn lead to better treatment efficacy and lower toxicity profiles. The aim of this phase 1 study is to determine the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), safety, pharmacokinetic (PK) and pharmacodynamic (PD) profiles of increasing doses of orally-administered azacitidine in subjects with MDS or AML. Methods: Subjects aged ≥ 18 years with a diagnosis of MDS or AML (not candidates for other therapies) by WHO criteria were enrolled into this multicenter, Phase 1, dose escalation study. Prior treatment with azacitidine or other demethylating agent was permitted. To allow PD/PK analyses of oral vs. subcutaneous (SC) administration, azacitidine was administered SC (75 mg/m2/day x 7 days) in Cycle 1, then orally in Cycle 2 starting at a dose of 120 mg/day x 7 days of every 28-day cycle. A standard “3+3” dose escalation design was used and an expansion cohort at the MTD was planned. Subjects were evaluated for DLT during the first cycle of oral azacitidine therapy. Azacitidine levels in plasma and urine were measured. DNA methylation was assayed using Illumina's Infinium Human Methylation27 BeadArrays. Response was assessed according to International Working Group (IWG) criteria for MDS (2006) and AML (2003). Results: To date, 45 subjects have enrolled into the study. Forty subjects received both SC and oral azacitidine; 5 subjects received SC azacitidine only. Median age is 70 years (range 31–91). Thirty-four subjects had MDS, 9 AML, and 2 CMML. Median pretreatment WBC and platelet counts of MDS subjects were 2.5 × 109/L (range 0.8–39.4) and 55.0 × 109/L (range 4.0–234.0) respectively. For subjects with AML, the median pretreatment WBC and platelet counts were 1.8 × 109/L (range 0.5–3.4) and 42.8 × 109/L (range 10.0–82.0) respectively. Baseline cytogenetics for subjects with MDS were as follows: 12 complex karyotype; 10 diploid; 1 with −7; 1 with t(11q23) and 10 whose karyotype was unknown. Doses of oral azacitidine evaluated were 120, 180, 240, 300, 360, 480 and 600 mg. The MTD of oral azacitidine on a 7-day QD treatment schedule was 480 mg. The DLT was grade 3 or 4 diarrhea in 2 of 3 subjects enrolled in the 600 mg cohort. Other grade 3 or 4 AEs reported include febrile neutropenia (6 subjects), infection (6 subjects), nausea (2 subjects), vomiting (2 subjects), fatigue (2 subjects), and thrombocytopenia (2 subjects). The bioavailability of oral azacitidine ranged from 5% to 35%. The exposure (AUCinf) of oral azacitidine was highly variable compared to SC exposure, ranging from 15% to 74% (except for one subject whose PK exposure following oral therapy was 167% of his SC exposure). Median duration of oral azacitidine was 5+ cycles (range 1–19+) for subjects with MDS and 2.5+ cycles (range 1–6+) for subjects with AML. Responses were evaluated following 6 cycles of oral therapy. To date, 14 subjects have received ≥ 6 cycles of oral azacitidine: 4 (29%) had complete response (CR), 6 (43%) had stable disease (SD), 3 (21%) had disease progression, and 1 subject (7%) was not evaluated. Among subjects with CR or SD, hematologic improvement by disease-specific IWG criteria included erythroid response (n = 5), platelet response (n = 5) and neutrophil response (n = 3). Fourteen subjects are ongoing, but have not completed 6 cycles of oral therapy; 17 subjects discontinued prior to completing 6 cycles. Changes in DNA methylation were observed in the blood of MDS and AML subjects following SC and oral azacitidine treatment, and a set of CpG loci were identified for which these changes were associated with azacitidine AUCinf and/or Cmax.. In addition, approximately 260 hypomethylated loci were common to both SC and oral therapy. Conclusions: Results to date indicate that a 7-day dosing regimen of oral azacitidine is active and well tolerated, with a manageable side effect profile in subjects with MDS or AML. Oral azacitidine exposure was highly variable and lower than that of SC azacitidine. Changes in DNA methylation were observed in the blood of MDS and AML subjects following SC and oral therapy. Evaluation of prolonged and BID treatment schedules is planned. Disclosures: Garcia-Manero: Celgene: Research Funding. Gore:Celgene: Consultancy, Equity Ownership, Research Funding; Johnson & Johnson: Research Funding. Skikne:Celgene: Employment. Cogle:Celgene: Research Funding, Speakers Bureau; Eisai: Speakers Bureau. Ning:Celgene: Employment, Equity Ownership. MacBeth:Celgene Corporation: Employment, Equity Ownership. Laille:Celgene: Employment, Equity Ownership. Ward:Celgene: Employment, Equity Ownership.

Download Full-text

A Dose-Escalation Study of Venetoclax (ABT-199/GDC-0199) in Combination with Bendamustine and Rituximab in Patients with Relapsed or Refractory Non-Hodgkin's Lymphoma

Blood ◽

10.1182/blood.v126.23.255.255 ◽

2015 ◽

Vol 126 (23) ◽

pp. 255-255 ◽

Cited By ~ 28

Author(s):

Sven de Vos ◽

Lode Swinnen ◽

Mark Kozloff ◽

Ding Wang ◽

Erin Reid ◽

...

Keyword(s):

Combination Therapy ◽

Febrile Neutropenia ◽

Dose Escalation ◽

Lymphocyte Count ◽

Research Funding ◽

Hodgkin's Lymphoma ◽

Employment Equity ◽

Dose Escalation Study ◽

Heavily Pretreated ◽

Equity Ownership

Abstract Introduction: Bcl-2 is an antiapoptotic protein commonly overexpressed in hematologic malignancies, including non-Hodgkin's lymphoma (NHL). Venetoclax (VEN) is a selective, potent, orally bioavailable BCL-2 inhibitor that has demonstrated single-agent activity in patients with relapsed or refractory (R/R) NHL. Data in NHL xenograft models indicate that VEN enhances the efficacy of bendamustine (B) and rituximab (R). Methods: This ongoing phase 1, open-label, dose-escalation study with a safety expansion portion evaluates VEN in combination with BR in patients with R/R NHL (NCT01594229). Patients (≥18 years) with ECOG PS ≤1 are treated with oral VEN (50-800 mg) for 3, 7, or 28 consecutive days of each 28-day cycle. Patients with refractory diffuse large B-cell lymphoma (DLBCL) who progressed during or within 2 months of completion of their last planned course of chemotherapy were excluded. Dose escalation follows a 3+3 design. The BR regimen is administrated for 6 cycles: B (90 mg/m2; 2 days/cycle) and R (375 mg/m2; 1 day/cycle). Patients who complete VEN + BR treatment can continue VEN monotherapy for up to 2 years following the date of the last subject enrolled, in the absence of disease progression or toxicity. Primary objectives are to assess safety, pharmacokinetics (PK) profile, and to determine the maximum tolerated dose (MTD) and the recommended phase 2 dose of VEN in combination with BR. Secondary objectives include preliminary efficacy evaluations. Dose-limiting toxicities (DLTs) are assessed during cycle 1. Disease responses were evaluated on day 1 of cycles 3, 5, 7, 11, 14, 17, 23, and every 6 cycles thereafter. Results: As of June 17, 2015, 47 patients (64% male; median age 63 years) have been enrolled in 10 escalation cohorts. Twenty-seven patients (57%) had been diagnosed with follicular lymphoma, 15 (32%) with DLBCL, and 5 (11%) with marginal zone lymphoma. Patients had a median of 3 (range: 1-8) prior therapies. All patients had prior R or R-combination, of whom 44 (94%) had R-based chemotherapy. Eleven patients (23%) had prior B or BR therapy. Median time on study is 128 days (range: 3-1066). As of June 2015, 25 patients (53%) are active and 22 (47%) discontinued (13 progressive disease, 4 adverse events [AEs; Table 1], 3 consent withdrawal, 1 noncompliance, and 1 completion of BR regimen per protocol). For the 17 patients who completed 6 cycles of combination therapy, 14 have continued to monotherapy and 11 active patients have not reached 6 cycles. Most common AEs (≥25%) in the combination therapy portion of the study (≤6 cycles) were nausea (51%), thrombocytopenia (45%), neutropenia (40%), constipation (36%), anemia (34%), diarrhea (30%), fatigue (30%), hyperglycemia (30%), lymphocyte count decrease (28%), and hypokalemia (28%). Most common grade 3/4 AEs (≥10%) during combination therapy were neutropenia (32%), lymphocyte count decrease (26%), thrombocytopenia (21%), anemia (15%), and leukopenia (13%). The most frequent serious AE was febrile neutropenia (9%). Three deaths occurred; none were drug-related AEs. Four patients experienced a DLT during cycle 1 (Table 1). Following 2 DLTs (febrile neutropenia and thrombocytopenia) in Cohort 5 (200 mg; 28/28d), a protocol amendment was filed in order to strongly encourage granulocyte colony-stimulating factor prophylaxis during VEN administration, particularly in heavily pretreated patients, and to refine the DLT definition in the context of known BR toxicities. Escalation continues with only 2 observed DLTs: Stevens-Johnson syndrome (400 mg 28/28d; primary reasonable possibility due to allopurinol; patient discontinued) and thrombocytopenia (600 mg 28/28d). Coadministration of BR did not significantly impact the PK of VEN. A total of 38 patients were evaluable for disease response. Overall, 29 patients had an objective response: 10 complete responses, 19 partial responses, and 4 patients had stable disease. Objective responses were observed across dose cohorts. Responses by NHL histology subgroups are shown in Table 1. Enrolling in Cohort 11 (1200 mg 28/28d) is currently ongoing. Conclusions: Combination therapy with VEN and BR demonstrated a tolerable safety profile. Responses were observed across dose cohorts in this heavily pretreated population. The MTD has not been reached and dose escalation is ongoing. Disclosures Off Label Use: Venetoclax is an investigational drug that is not yet approved in this indication.. Kozloff:Genentech: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; AbbVie: Consultancy. Nastoupil:AbbVie: Research Funding; Celgene: Honoraria; TG Therapeutics: Research Funding; Janssen: Research Funding; Genentech: Honoraria. Cordero:AbbVie: Employment, Equity Ownership. D'Amico:AbbVie: Employment, Equity Ownership. Diehl:AbbVie: Employment, Equity Ownership. Dunbar:AbbVie: Employment, Equity Ownership. Zhu:AbbVie: Employment, Equity Ownership. Wong:AbbVie: Employment, Equity Ownership. Heitner Enschede:AbbVie: Employment, Equity Ownership. Chien:AbbVie: Employment, Equity Ownership. Humerickhouse:AbbVie: Employment, Equity Ownership. Flowers:Millennium/Takeda: Research Funding; Gilead Sciences: Research Funding; AbbVie: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Millennium/Takeda: Research Funding; Onyx Pharmaceuticals: Research Funding; OptumRx: Consultancy; Janssen: Research Funding; AbbVie: Research Funding; Seattle Genetics: Consultancy; Gilead Sciences: Research Funding; Janssen: Research Funding; Onyx Pharmaceuticals: Research Funding; Spectrum: Research Funding; Spectrum: Research Funding; Acerta: Research Funding; Celegene: Other: Unpaid consultant, Research Funding; Acerta: Research Funding; Infinity Pharmaceuticals: Research Funding; OptumRx: Consultancy; Seattle Genetics: Consultancy; Pharmacyclics: Research Funding; Infinity Pharmaceuticals: Research Funding; Genentech: Research Funding; Celegene: Other: Unpaid consultant, Research Funding.

Download Full-text