Long-Term Follow Up Of a Randomized Phase II Study Of The JAK2-Selective Inhibitor Fedratinib (SAR302503) In Patients With Myelofibrosis (MF)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4047-4047 ◽  
Author(s):  
Animesh Pardanani ◽  
Ayalew Tefferi ◽  
Catriona HM Jamieson ◽  
Nashat Y Gabrail ◽  
Claudia Lebedinsky ◽  
...  
Keyword(s):  
High Risk ◽  
Disease Progression ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Study ◽  
Hematologic Toxicity ◽  
Costal Margin ◽  
Spleen Volume ◽  
Randomized Phase Ii ◽  
Grade 3

Abstract Background We previously reported that patients with MF enrolled in a randomized Phase II study of fedratinib (SAR302503) (ARD11936; NCT01420770) had clinically meaningful reductions in splenomegaly and improvements in MF-associated constitutional symptoms after 24 weeks of treatment (Haematologica 2013;98:S1113). Here, we report updated efficacy and safety results from this study after 48 weeks of treatment (end of Cycle 12). Methods Patients with intermediate risk-2 or high-risk MF were randomized to receive once-daily fedratinib at doses of 300 mg, 400 mg, or 500 mg, for consecutive 4-weekly cycles, until disease progression or unacceptable toxicity. Eligible patients were aged ≥18 years, with palpable splenomegaly (5 cm below costal margin), and a platelet count ≥50 × 109/L. The primary measure for this study was percent change in spleen volume from baseline at the end of Cycle 3 (Blood 2012:120;Abstract 2837. Haematologica 2013;98:S1113). Endpoints for the current analysis included spleen response (≥35% reduction in spleen volume from baseline, assessed by a blinded independent central review by MRI), safety, and changes in bone marrow fibrosis (BMF). Results A total of 31 patients were randomized and treated: median age 63 years, 52% male, 58% primary MF, 58% high-risk MF, 90% JAK2V617F positive. The median numbers of treatment cycles were 12, 14, and 13 in the 300 mg, 400 mg and 500 mg dose groups, respectively, with median durations of exposure of 48.2, 56.2, and 52.4 weeks. At the cut-off date for this analysis, 21 patients (68%) remained on treatment; the most common reasons for treatment discontinuation were adverse events (AEs) (n=5) and withdrawal of consent (n=2). Overall, 58% (18/31) of patients achieved a spleen response at any time during treatment. The median spleen response duration was >35 weeks at all doses (Table). At Week 48, a spleen response was achieved by 30% (3/10), 80% (8/10), and 45% (5/11) of patients in the 300 mg, 400 mg, and 500 mg groups, respectively. Responses were generally maintained across all treatment groups. From Week 24 to Week 48 two additional patients achieved a spleen response (both in the 400 mg group), while one patient in the 500 mg group did not maintain a response (this patient had a fedratinib dose reduction to 200 mg). Changes in BMF up to Week 48 are being evaluated. The most common non-hematologic AE was diarrhea, with a Grade 3 rate of 13% (4/31 patients) but no Grade 4 cases were recorded. The rates of diarrhea decreased after the first cycle of treatment; from Cycle 2, the incidence of diarrhea (any grade) did not exceed 16% (5/31) at any cycle, and only one case of diarrhea was reported at Week 48 (end of Cycle 12). Anemia was the most-common hematologic toxicity, with a Grade 3 rate of 58% (18/31); no Grade 4 cases were reported. All Grades thrombocytopenia occurred in 55% (17/31) of patients, Grade 3 in three patients, and Grade 4 in two patients. Discontinuation of treatment due to AEs occurred in five patients over the 48 weeks (300 mg [n=2]; 400 mg [n=2]; 500 mg [n=1]), with two cases reported after Week 24 (dyspnea and leukocytosis [400 mg]; anemia and thrombocytopenia [500 mg]). There were 2 deaths (one in the 300 mg group due to unknown reasons [85 days after fedratinib discontinuation] and one in the 500 mg group due to disease progression [36 days after fedratinib discontinuation]). No cases of leukemic transformation were reported. Conclusions This updated analysis of the ARD11936 Phase II trial shows that treatment with fedratinib results in durable reductions in splenomegaly in patients with MF. No additional safety signals were observed with prolonged exposure to fedratinib. This study was sponsored by Sanofi. Disclosures: Pardanani: Sanofi, Bristol Myers Squibb, PharmaMar and JW Pharma: Clinical trial support Other. Jamieson:J&J, Roche: Research Funding; Sanofi: Membership on an entity’s Board of Directors or advisory committees. Lebedinsky:Sanofi: Employment. Gao:Sanofi: Employment. Talpaz:Novartis, Bristol-Myers Squibb, Ariad, Deciphera: Research Funding; Novartis, Bristol-Myers Squibb, Ariad, Deciphera: Speakers Bureau.

Association of Azacitidine and Lenalidomide (Combined vs Sequential Treatment) in High-Risk Myelodysplastic Syndromes. Final Results of a Randomized Phase II Multicenter Study

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2871-2871
Author(s):  
Carlo Finelli ◽  
Cristina Clissa ◽  
Matilde Follo ◽  
Marta Stanzani ◽  
Sarah Parisi ◽  
...  
Keyword(s):  
High Risk ◽  
Complete Remission ◽  
Disease Progression ◽  
Phase Ii ◽  
Myelodysplastic Syndromes ◽  
Research Funding ◽  
Response To Treatment ◽  
Hematologic Toxicity ◽  
Efficacy And Safety ◽  
Randomized Phase Ii

Abstract Introduction. Azacitidine (AZA) is able to induce hematologic responses in 50-60 % of patients (pts) with Myelodysplastic Syndromes (MDS) and moreover to prolong survival in higher risk MDS pts. Recently, several studies have evaluated the efficacy and safety of combining, in high-risk MDS pts, AZA with Lenalidomide (LEN), either administered concurrently (Sekeres, 2010; 2012), or sequentially (Platzbecker, 2013), in both cases showing promising results, although in a limited number of pts. The aim of this study was to evaluate the efficacy and safety of the combination vs the sequential use of AZA and LEN in high-risk MDS pts (IPSS score risk: High or INT-2). Primary endpoint: ORR, defined as the Rate of Complete Remission (CR), Partial Remission (PR), Marrow Complete Remission (mCR), and Hematological Improvement (HI), following the International Working Group (IWG) criteria (Cheson, 2006). Methods. This is a randomized, phase II, multicenter, open label study, including pts with MDS (WHO 2008 classification) with International Prognostic Scoring System (IPSS) risk High or Intermediate-2, without previous treatment with AZA or LEN. ARM 1 (combined treatment): AZA: 75 mg/m2/day (days 1-5) I.C. + LEN: 10 mg/day (days 1-21), orally, every 4 weeks. ARM 2 (sequential treatment): AZA: 75 mg/m2/day (days 1-5) I.C. + LEN: 10 mg/day (days 6-21), orally, every 4 weeks. The induction treatment was planned for 8 cycles (32 weeks). For responder patients (CR, PR, mCR, or HI) the same treatment was continued until disease progression or unacceptable toxicity. A sample size of 44 pts was planned. Results. From March 2013, 44 pts (27 males), with a median age of 72 (48-83 yrs) were enrolled, from 13 hematologic italian Centers. At baseline, WHO diagnosis was: RCMD: 2 pts; RCMD-RS: 1 pt ; RAEB-1: 11 pts; RAEB-2: 30 pts; IPSS risk was: Intermediate-2: 31 pts; High: 9 pts; not determined (N.D.) (because of lack of cytogenetic data): 2 pts. (all with RAEB-2). In 2 pts IPSS risk was Intermediate-1, but they were enrolled because of severe thrombocytopenia and neutropenia, respectively. IPSS-R risk was: intermediate: 8 pts; High: 16 pts; Very-High: 18 pts; N.D.: 2 pts; IPSS cytogenetic risk was: Good: 17 pts; Intermediate: 11 pts; Poor: 14 pts; N.D.: 2 pts. 21 pts were randomly assigned to ARM 1, and 23 pts to ARM 2. At the time of this analysis, enrolment of the planned 44 pts was completed. 34/44 pts (77.3%) completed ≥ 6 cycles of treatment, and are evaluable for response. The remaining 10 pts (4 in ARM 1 and 6 in ARM 2) are not evaluable for response, as they discontinued treatment before completing the 6th cycle because of adverse events (6 pts, 13.6%), consent withdrawal (2 pts, 4.5%) or medical decision (2 pts, 4.5%), respectively. Treatment was given for a median of 8 (1-28) cycles; in ARM 1: 9 (1-22) cycles, in ARM 2: 8 (1-28) cycles, respectively. Among the 34 pts evaluable for response, 26/34 pts (ORR: 76.5 %) showed a favourable response to treatment. The Best Response achieved was: CR: 8 pts (23.5%), PR: 1 pt (2.9%), mCR: 3 pts (8.8%), HI: 8 pts (23.5%), mCR+HI: 6 pts (17.6%). The remaining 8 pts showed either Stable Disease (SD) (6 pts, 17.6%) or Disease Progression (DP) (2 pts, 5.9%). First Response was detected after a median of 2 (1-8) cycles. Responder pts were: 13/17 (ORR: 76.5 %) in ARM 1 (3 CR; 1 PR; 1 mCR; 4 HI, 4 mCR+HI), and 13/17 (ORR: 76.5 %) in ARM 2 (5 CR; 2 mCR; 4 HI; 2 mCR+HI), respectively. Overall, the median duration of response was 8.5 (2-23) months: 6 (2-19) months in ARM 1; 16 (2-23) months in ARM 2. A grade > 2 non hematologic toxicity was observed in 24/44 (54.5 %) pts (ARM 1: 66.7%; ARM 2: 43.5%). 27/44 pts (61.4 %) (ARM 1: 61.9%; ARM 2: 60.9%) had a dose reduction of LEN because of hematologic or non-hematologic toxicity. 22 pts (50%) died (ARM 1: 47.6%; ARM 2: 52.2%). 14 pts (31.8%) (ARM 1: 23.8%; ARM 2: 39.1%) showed progression to AML. Overall, median survival was 13 (1-28) months; ARM 1: 13 (1-25) months; ARM 2: 14 (2-28) months. Conclusions. Our results confirm the efficacy of both AZA + LEN treatment regimens in high-risk MDS pts. Moreover, at a molecular level, a significant increase of phosphoinositide-specific phospholipase C (PI-PLC) beta1 and/or PI-PLCgamma1 expression was associated with a favourable clinical response to treatment. Responder cases also showed an increase of Beta-globin expression, hinting at a specific contribution of LEN on erythroid activation Disclosures Finelli: Janssen: Other: Speaker; Novartis: Other: Speaker; Celgene: Other: Speaker, Research Funding. Visani:Celgene: Research Funding. Cavo:Janssen-Cilag, Celgene, Amgen, BMS: Honoraria.

Azacitidine and Lenalidomide (Combined vs Sequential Treatment) in Higher-Risk Myelodysplastic Syndromes. Long-Term Results of a Randomized Phase II Multicenter Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3169-3169
Author(s):  
Carlo Finelli ◽  
Cristina Clissa ◽  
Matilde Follo ◽  
Marta Stanzani ◽  
Sarah Parisi ◽  
...  
Keyword(s):  
Complete Remission ◽  
Disease Progression ◽  
Phase Ii ◽  
Median Duration ◽  
Myelodysplastic Syndromes ◽  
Research Funding ◽  
Hematologic Toxicity ◽  
Efficacy And Safety ◽  
Randomized Phase Ii ◽  
Microrna Profile

Abstract Introduction. Azacitidine (AZA) is the standard of care of higher-risk myelodysplastic syndromes (MDS), but the duration of clinical response is limited, and outcome after AZA failure is dismal. Several studies have demonstrated the efficacy and safety of combining AZA with Lenalidomide (LEN), either administered concurrently or sequentially, however the optimum dose and schedule for this combination remains unknown. The aim of this study was to evaluate the efficacy and safety of the combination vs the sequential use of AZA and LEN in higher-risk MDS pts (IPSS score risk: High or INT-2), and to look for possible biomarkers able to predict response. Primary endpoint: ORR, defined as the Rate of Complete Remission (CR), Partial Remission (PR), Marrow Complete Remission (mCR), and Hematological Improvement (HI), following the International Working Group (IWG) criteria (Cheson, 2006). Methods. This is a randomized, phase II, multicenter, open label study, including pts with MDS (WHO 2008 classification) with International Prognostic Scoring System (IPSS) risk High or Intermediate-2, without previous treatment with AZA or LEN. ARM 1 (combined treatment): AZA: 75 mg/m2/day (days 1-5) I.C. + LEN: 10 mg/day (days 1-21), orally, every 4 weeks. ARM 2 (sequential treatment): AZA: 75 mg/m2/day (days 1-5) I.C. + LEN: 10 mg/day (days 6-21), orally, every 4 weeks. The induction treatment was planned for 8 cycles (32 weeks). For responder patients (CR, PR, mCR, or HI) the same treatment was continued until disease progression or unacceptable toxicity. A sample size of 44 pts was planned. Results. From March 2013, 44 pts (27 males), with a median age of 72 (48-83 yrs) were enrolled, from 13 hematologic italian Centers. At baseline, IPSS risk was: Intermediate-2: 31 pts; High: 9 pts; not determined (N.D.) (because of lack of cytogenetic data): 2 pts. (all with RAEB-2). In 2 pts IPSS risk was Intermediate-1, but they were enrolled because of severe thrombocytopenia and neutropenia, respectively. IPSS-R risk was: intermediate: 8 pts; High: 16 pts; Very-High: 18 pts; N.D.: 2 pts. In 5 pts (11.4%) del(5q) was present. 21 pts were randomly assigned to ARM 1, and 23 pts to ARM 2. 34/44 pts (77.3%) completed ≥ 6 cycles of treatment, and are evaluable for response. The remaining 10 pts (4 in ARM 1 and 6 in ARM 2) are not evaluable for response, as they discontinued treatment before completing the 6th cycle because of adverse events (6 pts, 13.6%), consent withdrawal (2 pts, 4.5%) or medical decision (2 pts, 4.5%), respectively. Treatment was given for a median of 8.5 (1-37) cycles; in ARM 1: 9 (1-32) cycles, in ARM 2: 8 (1-37) cycles, respectively. 6 pts (ARM 1: 2; ARM 2: 4) are still on treatment. Pts have been followed for a median of 15 (2-37) months for all subjects, for a median of 32 (18-37) months for survivors. Among the 34 pts evaluable for response, 26/34 pts (ORR: 76.5 %) showed a favourable response to treatment. The Best Response achieved was: CR: 8 pts (23.5%), PR: 1 pt (2.9%), mCR: 3 pts (8.8%), HI: 8 pts (23.5%), mCR+HI: 6 pts (17.6%). The remaining 8 pts showed either Stable Disease (SD) (6 pts, 17.6%) or Disease Progression (DP) (2 pts, 5.9%). First Response was detected after a median of 2 (1-8) cycles. The median duration of hematologic response was 10.5 months. A grade > 2 non hematologic toxicity was observed in 54.5 % of pts, and an emerging (from grade 0-2 to > 2) hematologic toxicity in 27.3% of pts. In 61.4% of pts LEN dose was reduced because of hematologic or non-hematologic toxicity. 32 pts (72.7%) died , and 17 pts (38.6%) showed progression to AML. Median overall survival (OS) was 15 months. No significant differences between the 2 arms were observed, in terms of ORR, CR rate, toxicity, AML incidence and OS, but there was a trend (although still not significant) towards a longer median duration of response in the sequential arm: ARM 1: 6 months; ARM 2: 18 months (p=0.0847). MDS cells showed alterations of the inositide-dependent signalling as well as an altered microRNA profile. In particular, responder cases showed a frequent downregulation of miR-3613 and mir-4668, that were upregulated in non responder cases. Further analyses are ongoing. Conclusions. Our results confirm the efficacy of both AZA+LEN treatment regimens in higher-risk MDS pts, in terms of ORR, although the sequential schedule seems to induce more durable responses. Moreover, possible relationships with signal transduction pathways and microRNA profile are under evaluation. Disclosures Finelli: Novartis: Other: Speaker fees; Celgene: Other: Speaker fees; Celgene: Research Funding. Gobbi:Janssen: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; Roche: Honoraria; Takeda: Consultancy; Gilead: Honoraria; Celgene: Consultancy; Mundipharma: Consultancy, Research Funding. Cavo:Bristol-Myers Squibb: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria.

Phase II Trial of Initial Safety and Toxicity Prior to the Phase III Trial of Lenalidomide Versus Observation Alone in Patients with Asymptomatic High-Risk Smoldering Multiple Myeloma (E3A06): A Trial Coordinated by the Eastern Cooperative Oncology Group

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4079-4079 ◽  
Author(s):  
Sagar Lonial ◽  
Susanna Jacobus ◽  
Matthias Weiss ◽  
Rafael Fonseca ◽  
Madhav V. Dhodapkar ◽  
...  
Keyword(s):  
High Risk ◽  
Phase Ii ◽  
Research Funding ◽  
Plasma Cells ◽  
Phase Ii Trial ◽  
Phase Iii ◽  
Hematologic Toxicity ◽  
Trial Testing ◽  
Grade 3 ◽  
Smoldering Myeloma

Abstract Abstract 4079 The treatment and natural history of asymptomatic or smoldering myeloma has been an area of intense preclinical and clinical study. Historical attempts to treat these patients have not demonstrated significant benefit, likely as a consequence of limited therapeutic options as well lack of attention to the vast heterogeneity contained within the diagnosis of smoldering myeloma. More recent risk criteria from both US and Spanish investigators have identified a cohort of smoldering myeloma patients at high risk for progression to myeloma in a short time. Recently the PETHEMA group has conducted a randomized clinical trial testing lenalidomide and dexamethasone vs observation among high risk smoldering patients and has demonstrated a clear benefit in terms of progression free survival and hints towards improvement in overall survival favoring early intervention. To further evaluate the potential benefit of early intervention in a high risk smoldering cohort, the ECOG myeloma group designed a phase II trial testing the safety and efficacy of single agent lenalidomide with the intent of broadening to a randomized phase III trial if toxicity was acceptable. We report here on the safety portion of the phase II trial. The phase II group of patients received lenalidomide at a dose of 25 mg days 1–21 every 28 days to evaluate the early toxicity and tolerance of this dosing. The dose of lenalidomide could be adjusted based on toxicity using a defined dose-modification guideline in the protocol. The primary endpoint for the safety study was the rate of any treatment-related grade 4–5 non-hematologic toxicity plus grade 3 non-hematologic toxicity that affects vital organ function (such as cardiac, hepatic, or thromboembolic events) observed within 6 cycles of treatment. The goal was to enroll 34 patients; if 9 or more patients experience toxicity as defined, then the study would not continue. In terms of eligibility, patients were to be diagnosed with asymptomatic high-risk smoldering multiple myeloma (SMM) within the past 12 months, as confirmed by both of the following: bone marrow plasmacytosis with >= 10% plasma cells or sheets of plasma cells and an abnormal serum free light chain ratio (<0.125 or >8.0) by serum FLC assay. Further, patients must have measurable levels of monoclonal protein (M-protein): >=1g/dL on serum protein electrophoresis or >=200 mg of monoclonal protein on a 24 hour urine protein electrophoresis. Patients must have no lytic lesions on skeletal surveys and no hypercalcemia. Among the 36 patients enrolled in the phase II study, 56% were female, and 44% were 65 years and older. Treatment and toxicity data at a minimum through cycle 6 is complete as of August 2, 2102. The last patient enrolled completed cycle 6 treatment on June 7, 2012. The median treatment duration of the entire cohort is 9 cycles (range 1–18 cycles), with 86% of patients completing at least 6 cycles of treatment. Ten patients are off treatment for the following reasons: disease progression (n=1), AE/complication (n=5), death (n=1) and patient withdrawal/refusal (n=3); 5 of the 10 patients ended treatment before completing 6 cycles. Of 36 patients assessed for toxicity, 8 patients [22.2%, 90% CI: (11.6%-36.5%)] experienced worst grade treatment-related non-hematologic toxicity of grade 3 or higher. Separately, 6 patients experienced unrelated non-hematologic toxicity of grade 3 or higher. Three patients [8.3%, 90% CI: (2.3%-20.2%)] experienced a serious adverse event as defined for the purposes of the phase II toxicity analysis (treatment-related grade 4–5 non-hematologic toxicity or grade 3 non-hematologic toxicity that affects vital organ function (such as cardiac, hepatic, or thromboembolic events). Based upon this analysis of the study, the phase II portion of the trial met the prespecified safety benchmark established to allow for phase III expansion, and accrual to the phase III portion of this study will begin. Efficacy data will be presented at the time of presentation. Disclosures: Lonial: Novartis: Consultancy; Millennium: Consultancy; Onyx: Consultancy; BMS: Consultancy; Celgene Corp: Consultancy; Merck: Consultancy. Off Label Use: Lenalidomide is not approved for treatment of smoldering MM. Fonseca:Medtronic: Consultancy; Otsuka: Consultancy; Celgene: Consultancy; Genzyme: Consultancy; BMS: Consultancy; Lilly: Consultancy; Onyx: Consultancy; Binding site: Consultancy; Millenium: Consultancy; AMGEN: Consultancy; Celgene : Research Funding; Onyx: Research Funding; prognostication of MM based on genetic categorization of the disease: Prognostication of MM based on genetic categorization of the disease, Prognostication of MM based on genetic categorization of the disease Patents & Royalties. Dhodapkar:Celgene: Research Funding; KHK: Research Funding.

Ofatumumab Added To Dexamethasone In Patients With Relapsed Or Refractory Chronic Lymphocytic Leukemia. Results From a Phase II Study Of The Czech Leukemia Study Group For Life

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2877-2877 ◽  
Author(s):  
Michael Doubek ◽  
Yvona Brychtova ◽  
Anna Panovska ◽  
Jakub Trizuljak ◽  
Ludmila Sebejova ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Disease Progression ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Study ◽  
Lymphocytic Leukemia ◽  
High Dose ◽  
In Vitro Testing ◽  
Grade 3

Abstract The treatment of relapsed/refractory chronic lymphocytic leukemia (CLL) remains a challenging clinical issue despite remarkable improvements in prognostication and therapy. One emerging treatment option for relapsed/refractory CLL is the use of high-dose corticosteroids. High-dose methylprednisolone or dexamethasone combined with rituximab are active in relapsed/refractory CLL, but serious infections are frequent and progression-free survival (PFS) is short. The purpose of this clinical trial was to determine the efficacy and toxicity of ofatumumab-dexamethason (O-dex) combination in relapsed or refractory CLL population. The trial was an open-label, multi-center, non-randomized, phase II study. The O-dex regimen consisted of intravenous ofatumumab (Cycle 1: 300mg on day 1, 2000mg on days 8, 15, 22; Cycles 2-6: 1000mg on days 1, 8, 15, 22) and oral dexamethasone (40mg on days 1-4 and 15-18; Cycles 1-6). Premedication consisted of glucocorticoid, paracetamol, and antihistamine before each ofatumumab infusion. All patients received allopurinol, omeprazol, co-trimoxazole, and fluconazole for prophylaxis of tumor lysis syndrome and infections. The O-dex regimen was given for a minimum of 3 cycles, until best response, or a maximum of 6 cycles. Between July 2010 and December 2012, 32 patients (pts.) were recruited at 3 centers. Basic patient characteristics at the start of O-dex therapy were as follows: median age 66 years (range, 50-77); 24 males, 8 females; median CIRS score 7 (0-15); median previous treatment lines 3 (1-10); 30 (94%) pts. were pretreated with fludarabine and 12 (38%) with alemtuzumab; Rai III/IV stage was present in 20 (63%) pts.; 6 (19%) pts. had bulky lymphadenopathy; IgVH genes were unmutated in 30 (94%) pts.; del 11q was present in 6 (19%) and p53 defects (del 17p and/or TP53 mutation) in 8 (25%) pts. The median number of O-dex cycles administered was 6 (1-6). Twenty two (69%) pts. completed at least 3 cycles of therapy. The remaining 9 patients were prematurely discontinued due to CTCAE grade 3/4 infections (7 pts.), disease progression (1 pt.), or uncontrollable diabetes mellitus (1 pt.). Overall responses/complete remissions (ORR/CR) were achieved in 22/5 pts. (69/16%). One patient achieved minimal residual disease negativity (measured by 4-color flow cytometry) at the end of therapy. Median PFS was 10 months. In patients with p53 defects, ORR/CR were achieved in 5/2 pts. (63/25%). The Median PFS was 10.5 months for this subgroup. Median overall survival (OS) has not yet been reached. During therapy, CTCAE grade 3/4 toxicity consisted of bacterial infections (25%), ofatumumab infusion-related side-effects (9%), neutropenia (9%), hyperglycemia (6%), and anemia (3%). No reactivation of herpetic viral infection was observed during the course of therapy. Nine patients died during the follow-up as a result of disease progression (6 pts.), infections (2 pts.), or complications after allogeneic stem cell transplantation (1 relapsed pt.). The median CD20 antigen density in CLL cells was 4766 (881-18515) MESF (molecules of equivalent soluble fluorochrome) units at baseline. At the end of therapy, CD20 density had significantly decreased (median 821 MESF; 443-2637); nevertheless, it was high once more at relapse (median 6619 MESF; 628-21359). In vitro testing of malignant pts. cells sensitivity to dexamethasone and ofatumumab did not show synergistic or additive effect of these compounds in majority of patients. Also, in vitro testing did not clearly predict the outcome of O-dex therapy. Conclusions The O-dex regimen shows relatively high ORR and CR, with promising findings for PFS and OS (including pts. harboring p53 defects), as compared to published data on rituximab plus dexamethasone regimen or ofatumumab in monotherapy. The infectious toxicity in 1/4 of pts. represents the most frequent side effect for this regimen. The study was registered at www.clinicaltrials.gov (NCT01310101). Disclosures: Doubek: GlaxoSmithKline: Research Funding. Mayer:Roche: Consultancy, Research Funding; Glaxo: Consultancy, Research Funding.

A Phase II Randomized Dose-Ranging Study of the JAK2-Selective Inhibitor SAR302503 in Patients with Intermediate-2 or High-Risk Primary Myelofibrosis (MF), Post-Polycythemia Vera (PV) MF, or Post-Essential Thrombocythemia (ET) MF.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2837-2837 ◽  
Author(s):  
Moshe Talpaz ◽  
Catriona Jamieson ◽  
Nashat Y Gabrail ◽  
Claudia Lebedinsky ◽  
Guozhi Gao ◽  
...  
Keyword(s):  
Clinical Trial ◽  
High Risk ◽  
Phase Ii ◽  
Research Funding ◽  
Jak2 V617f ◽  
Spleen Volume ◽  
Employment Equity ◽  
Symptom Response ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 2837 Introduction: Treatment with the JAK2 selective inhibitor SAR302503 reduced spleen size, disease-related symptoms, and the JAK2 V617F allele burden, with an acceptable safety profile in patients with primary MF, post-PV MF, or post-ET MF in a Phase I/II study (J Clin Oncol 2011;29:789, ASH 2011; Abs 3838). The objective of this Phase II study is to assess the efficacy, safety, pharmacokinetics (PK), and pharmacodynamics (PD) of 3 doses of SAR302503. Methods: Patients with intermediate-2 or high-risk primary MF, post-PV MF, or post-ET MF were randomized to 1 of 3 dose groups of SAR302503 (300, 400, or 500 mg per day). Eligibility criteria included age ≥18 years, ECOG PS 0–2, and an enlarged spleen (length ≥5 cm). SAR302503 was taken orally, once a day, in consecutive 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint is the absolute change in spleen volume at the end of cycle 3 assessed by MRI with independent central review. Secondary endpoints include spleen response (≥35% reduction in spleen volume vs baseline), safety, symptom response (MPN-SAF), PK, and PD (changes in leukocyte pSTAT3). Results: From August–December 2011, at total of 31 patients were enrolled (n=10 in the 300 and 400 mg groups; n=11 to 500 mg). Risk status (intermediate-2 vs high) was balanced in the 400 mg and 500 mg groups (∼50%), whereas the 300 mg group had more high-risk patients (70%). The majority of patients (88% to 91%) had the JAK2 V617F mutation and most (∼80%) were blood transfusion independent. Mean (median) percentage reductions in spleen volume vs baseline at the end of cycle 3 were 30% (26%) in the 300 mg group, 33% (31%) with 400 mg, and 42% (38%) with 500 mg. A spleen response at the end of cycle 3 was seen in 30% of patients (3/10) in the 300 mg group, 50% (5/10) in the 400 mg group, and 64% (7/11) in the 500 mg group. Patients with constitutional symptoms at baseline in all groups reported a symptom response at the end of cycle 3, with at least a 2-point improvement in or resolution of night sweats in 93% (14/15) of patients, itching in 71% (10/14), early satiety in 56% (10/18), abdominal pain in 56% (10/18), and abdominal discomfort in 50% (10/20). Safety was evaluated in all patients. The most common grade 3–4 hematological adverse event (laboratory) was anemia, with rates across the 300, 400, and 500 mg doses of 33%, 30%, and 55%, respectively. Rates of grade 3–4 thrombocytopenia were 20%, 0, and 9%. There was no grade 3–4 neutropenia. Most common grade 3–4 nonhematological events were diarrhea (10%, 20%, 0), nausea (10%, 10%, 0), and vomiting (10%, 10%, 0). Adverse events in the 300 mg group led to discontinuation in 2 patients: 1 patient had grade 3 anemia, and 1 patient with pre-existing intermittent mild transaminase elevations and polyarthritis had hepatic failure, but completely recovered after discontinuation. No other grade 3–4 increases of AST, ALT, or bilirubin were observed. No deaths were due to an adverse event. Following repeated once-daily oral doses, SAR302503 exposure increased in a dose-dependent manner, with a median time to maximum plasma concentration of 2 to 3 hours. Steady state was achieved by cycle 1 day 15 (C1D15), with a 2.95- to 3.88-fold accumulation of drug. Time-dependent pSTAT3 inhibition was observed at all doses, with the highest mean percentage decreases from baseline (range) occurring at C1D15 (44% to 52%) and C2D1 (40% to 51%). The relationship between PK and PD pSTAT3 suppression can be described by an Emax model. There was also a correlation between percentage of pSTAT3 inhibition and spleen response rate at C1D15 and C2D1 and evidence of a steady state exposure-response relationship for spleen volume reduction at the end of cycle 3. Conclusions: In this Phase II trial, treatment with SAR302503 was associated with clinically meaningful reductions in splenomegaly and improvements in constitutional symptoms. SAR302503 was generally well tolerated in this trial and adverse events were consistent with the known safety profile. Time-dependent decreases in pSTAT3 and exposure-response correlations can be demonstrated across the three doses tested. Sponsored by Sanofi (NCT01420770) Disclosures: Talpaz: Novartis: Research Funding, Speakers Bureau; BMS: Research Funding; ARIAD: Research Funding; Deciphera: Research Funding. Gabrail:Sanofi: Research Funding. Lebedinsky:Sanofi: Employment, Equity Ownership. Gao:Sanofi: Employment, Equity Ownership. Liu:Sanofi: Employment, Equity Ownership. Pardanani:YM BioSciences: Clinical trial support, Clinical trial support Other; BMS: Clinical trial support, Clinical trial support Other; Sanofi: Clinical trial support Other.

A randomized phase II study of continuous versus intermittent S-1 plus oxaliplatin in first-line treatment of patients with metastatic gastric carcinoma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4028-4028 ◽  
Author(s):  
Sook Ryun Park ◽  
Young-Iee Park ◽  
Jiyoung Rhee ◽  
Byung-Ho Nam ◽  
Sun-Young Kong ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Progression Free Survival ◽  
Metastatic Gastric Cancer ◽  
Induction Treatment ◽  
Hematologic Toxicity ◽  
Randomized Phase Ii ◽  
Significant Difference ◽  
Grade 3 ◽  
Ecog Ps

4028 Background: We conducted a randomized phase II study to compare continuous vs. intermittent S-1 + oxaliplatin (SOX) after induction of 6 cycles of SOX in patients (pts) with metastatic gastric cancer (MGC). Methods: Pts >18 yrs with chemo-naive MGC, normal organ function, ECOG PS 0-2, and measurable or evaluable lesion(s) were initially given an induction treatment of 6 cycles of SOX (S-1 40 mg/m2 bid on D1-14 + oxaliplatin 130 mg/m2 on D1 q 3 wks). Pts with CR/PR or SD were randomized to continue SOX (arm A) until progression/intolerable toxicity or discontinue until progression when SOX was re-administered (arm B). The primary endpoint was overall survival (OS), and secondary endpoints included progression-free survival (PFS), response rate, safety, quality of life, and biomarker correlative studies. Results: From July 2007 to Dec 2010, a total of 250 pts entered into the study. Median age was 53 yrs (range, 24-69); PS 0/1/2=13/219/18; M/F=162/88. Three pts did not receive treatment and 126 (50.4%) discontinued treatment before or at the completion of 6 cycles of SOX due to progression (45.6%), pt refusal (2.8%), or adverse events (2.0%). A total of 121 pts were randomized: 59 (48.8%) to arm A and 62 (51.2%) to arm B. Clinical characteristics were well balanced between arms. SOX continuation resulted in a significant reduction in the risk of progression (median PFS, 10.5 months for arm A vs. 7.2 months for arm B; HR=0.57, 95% CI 0.39-0.84, p=0.005). With a median follow-up of 34.0 months (range, 10.5-53.3 months), there was no significant difference in OS (median OS, 22.6 months for arm A vs. 22.7 months for arm B; HR, 0.79, 95% CI 0.51-1.25, p=0.31). Arm A had higher rates of grade 3/4 fatigue (28.8% vs. 8.1%, p=0.004) and neuropathy (25.4% vs. 8.1%, p=0.014) but other grade 3/4 hematologic (neutropenia, 35.6% vs. 32.3%; thrombocytopenia, 23.7% vs. 21.0%; anemia, 15.3% vs. 6.5%) or non-hematologic toxicity rates were not significantly different. Conclusions: Continuous chemotherapy with SOX after induction therapy improved PFS but not OS. Supported by NCC Grant 1010180 (S-1 and oxaliplatin was provided by JEIL Pharm. Co., Ltd. and sanofi-aventis Korea Co., Ltd., respectively).

Randomized Multicenter Phase II Study Comparing a Combination of Fluorouracil and Folinic Acid and Alternating Irinotecan and Oxaliplatin With Oxaliplatin and Irinotecan in Fluorouracil-Pretreated Metastatic Colorectal Cancer Patients

2001 ◽  
Vol 19 (22) ◽  
pp. 4195-4201 ◽  
Author(s):  
Yves Bécouarn ◽  
Erick Gamelin ◽  
Bruno Coudert ◽  
Sylvie Négrier ◽  
Jean-Yves Pierga ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Folinic Acid ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Survival Times ◽  
Activity Data ◽  
Randomized Phase Ii ◽  
Grade 3 ◽  
Intent To Treat ◽  
Colorectal Cancer Patients

PURPOSE: To assess antitumor activity and safety of two regimens in advanced colorectal cancer (CRC) patients with proven fluorouracil (5-FU) resistance in a randomized phase II study: 5-FU/folinic acid (FA) combined with alternating irinotecan (also called CPT-11) and oxaliplatin (FC/FO tritherapy), and an oxaliplatin/irinotecan (OC) combination. PATIENTS AND METHODS: Sixty-two patients were treated: arm FC/FO (32 patients) received, every 4 weeks, FA 200 mg/m2 followed by a 400-mg/m2 5-FU bolus injection, then a 600-mg/m2 continuous infusion of 5-FU on days 1 and 2 every 2 weeks administered alternately with irinotecan (180 mg/m2 on day 1) and oxaliplatin (85 mg/m2 on day 15). Arm OC (30 patients) received oxaliplatin 85 mg/m2 and irinotecan 200 mg/m2 every 3 weeks. RESULTS: In an intent-to-treat analysis, two partial responses lasting 10.7 and 16 months were observed with the tritherapy regimen, and seven (median duration, 11 months; range, 10.6 to 11.4 months) were observed with the bitherapy regimen. Median progression-free and overall survival times were 8.2 and 9.8 months, respectively, in the FC/FO arm and 8.5 and 12.3 months, respectively, in the OC arm. Main grade 3/4 toxicities were, respectively, neutropenia, 53% and 47%; febrile neutropenia, 13% and 3%; diarrhea, 19% and 10%; vomiting, 6% and 13%; and neurosensory toxicity, 3% and 3%. No treatment-related deaths occurred. CONCLUSION: The every-3-weeks OC combination is safe and active in advanced 5-FU–resistant CRC patients. The lower activity data seen with the tritherapy regimen may be related to the lower dose intensities of irinotecan and oxaliplatin in this schedule.

A Phase II Study of Temsirolimus (CCI-779) in Patients with Advanced Leukemias.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4523-4523 ◽  
Author(s):  
Karen W.L. Yee ◽  
Guillermo Garcia-Manero ◽  
Deborah Thomas ◽  
Farhad Ravandi-Kashani ◽  
Srdan Verstovsek ◽  
...  
Keyword(s):  
Disease Progression ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Blast Crisis ◽  
Single Agent ◽  
Mammalian Target Of Rapamycin ◽  
Median Number ◽  
Prior Therapy ◽  
Flat Dose ◽  
Grade 3

Abstract Temsirolimus (CCI-779, Wyeth Pharmaceuticals) has been shown to inhibit proliferation of a variety of tumors and induce G1 cell cycle arrest by preventing activation of the serine/threonine kinase, mTOR (mammalian target of rapamycin), a downstream effector of the PI3K/Akt pathway. Several lines of evidence implicate the PI3K/Akt/mTOR pathway in hematological malignancies. Interim results of a phase II study evaluating the efficacy and toxicity of single-agent temsirolimus in patients with advanced malignancies are presented. Temsirolimus was administered weekly, at a flat dose of 25 mg, as a 30-minute intravenous infusion. Treatment was continued until evidence of disease progression or unacceptable toxicity. To date, 8 patients have been enrolled and 7 are evaluable for efficacy and toxicity (one patient did not receive temsirolimus). Of these 7 patients, 5 had AML, 1 CML-myeloid blast crisis, and 1 ALL. Median age was 68 years (range, 21 to 87 years) and 5 were male. All patients had received prior therapy, median 2 regimens (range, 1 to 3 regimens). The median number of temsirolimus doses administered was 3 (range, 1 to 10) with a median time on study of 18 days (range, 3 to 89+ days). The most common temsirolimus-related adverse events were grade ≤ 2 and consisted of anorexia, nausea and/or vomiting and diarrhea, mucositis, dermatitis, hypertriglyceridemia, hyperglycemia, hypomagnesemia, hypocalcemia, hypokalemia, hypophosphatemia, and fatigue/asthenia. No patient developed nonspecific pneumonitis. Grade 3 toxicities included fatigue/asthenia (2), hyperglycemia (1), painful mucositis with dehydration and electrolyte abnormalities (1), diarrhea with hypokalemia (1), and hypophosphatemia (1). No patient experienced grade 4 toxicities or death from temsirolimus. No patient required dose reductions, but 2 did have dose delays due to grade 3 mucositis (1) and out-of-state hospitalization for pneumonia and atrial fibrillation (1). No patient achieved a complete remission. One patient with heavily pre-treated Philadelphia-negative precursor B-cell ALL had a transient 79% to 91% reduction in peripheral blood blasts 4 days after the first dose of temsirolimus that was maintained for 12 days prior to disease progression with involvement of the synovial fluid in bilateral knees. At the time of analysis, 6 of the 7 patients have discontinued treatment due to disease progression (4), patient refusal (1), or physician decision (1). Preliminary findings indicate that temsirolimus is relatively well-tolerated at a dose of 25 mg per week and may have biologic activity in ALL. Accrual onto the study is currently ongoing.

Rituximab for Graft-Versus-Host-Disease-Prophylaxis after Allogeneic Stem Cell Transplantation Given as Treatment of High Risk Relapse of Aggressive Lymphoma: Results of a Randomized Phase II Study.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1974-1974 ◽  
Author(s):  
Bertram Glass ◽  
Justin Hasenkamp ◽  
Anke Görlitz ◽  
Peter Dreger ◽  
Jörg Schubert ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
B Cell ◽  
Phase Ii ◽  
Progressive Disease ◽  
Phase Ii Study ◽  
Cell Lymphoma ◽  
Randomized Phase Ii ◽  
Gvhd Prophylaxis ◽  
Unrelated Donors

Abstract Background: High dose therapy (HDT) followed by autologous stem cell support has poor outcome in patients with primary progressive lymphoma or relapse after primary HDT. Allogeneic SCT may help these patients by exerting an GVL effect. Its use however is hampered by high incidence of severe GVHD and non-relapse mortality in this population. Rituximab has been claimed to reduce the incidene of GVHD without negative impact on the relapse rate. Patients and Methods : We initiated a randomized phase II study using intermediate conditioning (Fludarabine 125 mg/m2, Busulfan 12 mg/kg and cyclophosphamide 120 mg/kg) followed by GVHD prophylaxis with short term mycophenolat mofetil plus tacrolimus. Anti-thymozyte globulin (ATG) was given due to center decision. Patients were randomized to receive two times four doses of rituximab (375 mg/m2) post transplant starting day +21 and day +175 or no additional GVHD prophylaxis. From June 2004 to July 2007 sixty five patients with aggressive NHL were enrolled and 59 were eligible for analysis. Thirty one pts had diffuse large B cell NHL, 3 patients follicular lymphoma grade 3, 7 pts blastic mantle cell lymphoma, 2 pts aggressive marginal zone lymphoma, 2 patients lymphoblastic B cell lymphoma, and 12 T cell lymphoma. 42 (71%) pts received at least one cycle of HDT and autologous SCT prior to alloSCT; 78% had early relapse ( &lt; 12 months) or primary progressive disease, 59% chemo-refractory disease and 48% had progressive disease with high or high intermediate age adjusted IPI immediately prior to conditioning. Results: Allo-PBPC were obtained from HLA-identical siblings in 17 pts, from matched unrelated donors in 32 pts and from one locus mismatched unrelated donors in 10 pts. 33 patients did receive ATG. Median observation time of surviving patients is 1,8 years. 30 pts died, in 19 patients death was attributed to treatment related causes. After one year, estimated overall survival is 49%, progression free survival is 39%, relapse rate is 28 % and incidence of GVHD &gt; grade 1 is 73%. The last documented lymphoma progress occurred at day 288 after alloSCT. There are no significant differences in OS, PFS and GvHD in relationship to the application of Rituximab. Conclusion: Intermediate intensity conditioning followed by allogeneic SCT is a valuable treatment option in patients with high-risk relapse of aggressive NHL. The incidence of GVHD and non-relapse mortality is high. On the background of this very high basic incidence of GVHD, we did not find a significant impact of post transplant rituximab on GVHD, relapse rates or survival, respectively. Therefore, ATG will be added as an obligatory part of the conditioning regimen in the next study phase in additional 30 patients

The VcR-CVAD Regimen Produces a High Complete Response Rate in Untreated Mantle Cell Lymphoma (MCL): First Analysis of E1405 – A Phase II Study of VcR-CVAD with Maintenance Rituximab for MCL.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1661-1661 ◽  
Author(s):  
Brad S Kahl ◽  
Hailun Li ◽  
Mitchell R Smith ◽  
Randy D. Gascoyne ◽  
Elisabeth Paietta ◽  
...  
Keyword(s):  
Phase Ii ◽  
Research Funding ◽  
Response Rate ◽  
Complete Response Rate ◽  
Phase Ii Study ◽  
Cell Lymphoma ◽  
Complete Response ◽  
Mantle Cell ◽  
Grade 3

Abstract Abstract 1661 Poster Board I-687 Introduction One approach to improving outcomes in Mantle Cell Lymphoma (MCL) is to incorporate newer targeted agents into standard chemotherapy regimens. As the proteasome inhibitor bortezomib (Velcade‘) achieved a 33% response rate in relapsed MCL, we hypothesized that the incorporation of Velcade (Vc) into a modified R-hyperCVAD chemotherapy backbone would result in a high complete response rate (CR). The new regimen, VcR-CVAD, was tested for safety and efficacy in a phase II study within the Wisconsin Oncology Network (UW) and demonstrated a CR rate of 77% (Kahl, ASH 2008). To determine the safety and efficacy of this regimen in a cooperative group setting, we initiated E1405: a phase II study of VcR-CVAD with maintenance rituximab (MR) for untreated MCL. Methods Eligible patients had histologically confirmed, previously untreated MCL, PS 0-2, and adequate end organ function. The treatment plan included: Velcade 1.3 mg/m2 days 1 and 4, rituximab 375 mg/m2 IV day 1, cyclophosphamide 300 mg/m2 IV over 3 hrs q 12 hrs X 6 doses days 1-3, doxorubicin 50 mg/m2 continuous infusion over 48 hrs days 1-2, vincristine 1 mg IV day 3, dexamethasone 40 mg po days 1-4. Cycles were repeated every 21 days for 6 cycles and all patients received G-CSF support. Patients achieving SD, PR, or CR received MR administered as 4 weekly treatments every 6 months for 2 years (protocol therapy). Patients had an option to receive high dose chemotherapy and autologous stem cell transplantation (off protocol) rather than MR. The primary endpoint of the trial was the CR rate, incorporating PET imaging, to VcR-CVAD induction therapy. Results Seventy-six eligible patients were enrolled between 5/07 and 10/08. Baseline characteristics include median age 62 (40-76), 59M:17F, 91% stage III/IV, and 39% with elevated LDH. Sixty-four patients (84%) completed VcR-CVAD induction therapy. Reasons for treatment discontinuation included PD (1), toxicity (4), patient preference (2), and other/unknown (5). Response information is available on 74 patients while data is outstanding on 2 patients. The ORR was 96% (73/76; 95% CI, 89%-99%), CR rate 75% (57/76; 95% CI, 64%-84%) and the PR rate 21% (16/76; 95% CI, 13%-32%). Six of the PR patients were coded as such because of protocol violations in which a post-treatment bone marrow biopsy or PET scan was not obtained. The CR rate in the 68 completely restaged patients was 84%. Forty-four patients proceeded to planned MR while 21 patients went off protocol to SCT consolidation. Median follow up is currently too short (9 months) to assess PFS and OS. The major toxicity of the treatment regimen was expected myelosuppression. Grade 3-4 non hematologic toxicities were rare. No patients developed grade 3-4 neuropathy. There were no treatment related deaths. Conclusion The VcR-CVAD induction produced high overall response (96%) and CR rate (75%) in a representative MCL patient population treated on a cooperative group protocol. The CR rate was high and comparable to the UW pilot study (77%). No episodes of severe painful peripheral neuropathy were reported using the reduced vincristine dosage and the overall toxicity profile was very acceptable. Longer follow up is needed to determine if the high CR rate will translate into improved PFS and OS. Disclosures Kahl: Genentech: Consultancy, Research Funding; Millennium: Consultancy, Research Funding. Off Label Use: Bortezomib as front line treatment in MCL. Smith:Genentech: Research Funding; Millennium: Research Funding. Advani:Seattle Genetics, Inc.: Research Funding. Horning:Genentech: Honoraria, Research Funding.

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