Oral Formulation of Rigosertib (ON 01910.Na) in Patients with Myelodysplastic Syndrome (MDS) – Phase I Study Results,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3797-3797
Author(s):  
Rami S. Komrokji ◽  
Alan F. List ◽  
Francois Wilhelm ◽  
Jeffrey E. Lancet ◽  
Azra Raza
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
Research Funding ◽  
Oral Formulation ◽  
Refractory Anemia ◽  
Absolute Bioavailability ◽  
History Of ◽  
Grade 3 ◽  
Dose Levels

Abstract Abstract 3797 Background: Rigosertib (ON 01910.Na) is a multi-kinase inhibitor that selectively induces mitotic arrest leading to apoptosis in cancer cells and myeloblasts, while non-toxic to normal cells. Biological activity of the intravenous formulation has been demonstrated in myelodysplastic syndromes (MDS), including an ongoing randomized clinical trial in patients with refractory anemia and excess blasts failing azanucleosides. We report the preliminary results of a safety and efficacy study of a novel oral formulation of rigosertib. Methods: The trial is a 3 part phase I dose escalation study. The first part addressed bioavailability and tolerability of single oral dosing administered on a weekly basis for 5 weeks, the second included dose escalation, the third represented a dose expansion of the recommended phase 2 dose (RP2D) with absolute biavailability and food/fasting bioavailability studies. Eligibility included any International prognostic Scoring System (IPSS) MDS risk group with at least one cytopenia, failure to respond to at least one prior standard treatment, good performance status (ECOG≤ 2), adequate kidney and liver functions. Key exclusions included hypoplastic MDS (< 10% cellularity), ascites, history of seizures, uncontrolled hypertension, and history of HIV. Dose limiting toxicity (DLT) was defined as grade 3 or greater non-hematological drug related toxicity or delay in blood count recovery for more than 30 days in the absence of response. Rigosertib dose was escalated based on a defined escalation dose schema (70, 140, 280, 560, and 700 mg). The drug was administered orally twice a day for 14 days of a 21 day cycle. Results: Between January 2010 and July 2011, 33 MDS patients were enrolled in an ongoing phase I dose escalating study. Pharmacokinetic dose proportionality was established in the 70–700 mg single dose range in the first 3 patients, and pharmacodynamically active concentrations were reached. A subsequent escalation phase enrolled 15 patients who were treated with 70 to 700 mg doses of rigosertib capsules bid for 2 weeks of a 3 week cycle (70mg: N=3; 140 mg: N=2; 280mg: N=2; 560: N=2; 700mg: N=6). The formulation was well tolerated. One patient experienced DLT at the 700mg dose level during the first 3-week cycle (dysuria and shortness of breath). Another patient at this dose level had grade 3 dysuria during cycle 2. The RP2D was identified as 560 mg bid and 18 patients were enrolled in the expansion cohort (part 3). Up to 12 patients in this cohort are undergoing full pharmacokinetic evaluation (absolute bioavailability vs. the IV formulation and food effect). Encouraging signs of activity have been observed, including two marrow CR responses at the 140 and 560 mg dose levels; erythroid response (reduction of at least 4 units of RBC transfusions over 56 days) in four Low/Int-1 risk transfusion dependent MDS patients (3 at 560mg and 1 at 700 mg dose levels). Full PK results as well as clinical activity and tolerability at the RP2D dose level will be presented. Conclusion: Oral rigosertib is bioavailable and well tolerated. The RP2D was 560 mg bid for 2 weeks of a 3 week with a DLT of dysuria. Early encouraging responses are being confirmed in the expansion phase of the study. Disclosures: Komrokji: Onconova Therapeutics: Research Funding. List:Onconova Therapeutics: Research Funding. Wilhelm:Onconova Therapeutics: Employment, Equity Ownership. Lancet:Onconova Therapeutics: Research Funding. Raza:Onconova Therapeutics: Research Funding.

scholarly journals Updated Results of a Phase I Study of Ibrutinib and Lenalidomide in Patients with Relapsed and Refractory B-Cell Non-Hodgkin's Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3983-3983 ◽  
Author(s):  
Beth A Christian ◽  
John G. Kuruvilla ◽  
Sonali M. Smith ◽  
Pierluigi Porcu ◽  
Kami J. Maddocks ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Disease Progression ◽  
Dose Level ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase I Study ◽  
Hematologic Toxicity ◽  
Off Label ◽  
Grade 3

Abstract Introduction: Lenalidomide, an immunomodulatory agent, and ibrutinib, a selective and covalent inhibitor of Bruton's tyrosine kinase, are orally bioavailable agents with single-agent activity in several histologic subtypes of relapsed/refractory B-cell non-Hodgkin lymphoma (NHL). We are conducting a phase I study of the combination of ibrutinib and lenalidomide to determine the maximum tolerated dose, dose limiting toxicities (DLT), and preliminary efficacy in pts with relapsed/refractory NHL and updated results are presented. Methods: Patients (pts) with relapsed/refractory B-cell NHL including diffuse large B-cell (DLBCL), transformed, mantle cell (MCL), marginal zone (MZL), lymphoplasmacytic (LPL), and follicular (FL) lymphoma who have received at least one prior therapy were eligible. Prior autologous but not allogeneic stem cell transplant and prior lenalidomide were permitted. Prior ibrutinib, CNS involvement, and pts requiring anticoagulation were not permitted. ANC > 1000/mm3, platelets > 50,000/mm3, and creatinine < 2.0 mg/dL, ALT/AST ≤ 2.5 x ULN, bilirubin ≤ 1.5 x ULN, and ECOG PS 0-2 were required at study entry. Treatment consisted of escalating doses of lenalidomide days 1-21 and ibrutinib days 1-28 of a 28 day cycle. A standard 3+3 dose escalation schema was followed. DLTs included: treatment delays > 14 days for toxicity; grade 5 toxicity; tumor lysis syndrome requiring dialysis; tumor flare reaction nonresponsive to corticosteroids; ANC < 500/mm3 or platelets <25, 000/mm3 persisting > 7 days; grade 3 or 4 febrile neutropenia or infection; and any grade 3 or 4 non-hematologic toxicity with the following exceptions: DVT, diarrhea, nausea or vomiting amenable to medical therapy, correctable electrolyte abnormalities; grade 3 fatigue, or grade 3 maculopapular rash that resolved within 7 days. Pts without significant toxicity could continue treatment until disease progression. Response was assessed every 3 months for 12 months and then every 6 months until disease progression. Results: Twenty-five pts have been treated. Median age is 67 years (range 45-85) with 16 males. Histologies include DLBCL/transformed lymphoma (n=9), MCL (n=7), FL (n=4), MZL (n=2), and LPL (n=3). Four pts were treated at dose level (DL) 1 (lenalidomide 15 mg/ibrutinib 420 mg). One pt was replaced for rapid disease progression and 1 pt experienced DLT consisting of a grade 2 ischemic stroke. As a result of this DLT, DL 1 was expanded to 6 evaluable pts. A second DLT was observed, a grade 3 rash that resolved within 7 days but recurred on day 22. A total of 6 pts were then treated at DL-1 (lenalidomide 10 mg/ibrutinib 280 mg), and no DLTs were encountered. The protocol was amended to include additional dose levels. Pts enrolled on dose level -1A with lenalidomide 10 mg and ibrutinib 420 mg. One DLT occurred at this dose level, a grade 3 rash that failed to resolve within 7 days. The dose level was expanded to 6 pts without further DLT. DL-1B includes an intra-pt dose escalation of the lenalidomide from 10 mg in cycle 1 to 15 mg in cycle 2 with ibrutinib 420 mg. Six pts have been enrolled on this dose level. Three pts have been replaced including 2 with cytopenias not meeting DLT criteria but precluding dose escalation and one with progressive disease. Three pts at DL-1B remain on treatment. Related grade 3-4 toxicities occurred in 16/24 currently evaluated pts (67%), including primarily hematologic toxicity, rash, increased LFTs, pneumonia, hypokalemia, and syncope. Pts have received a median of 3 cycles of therapy to date (range 1-19) and 9 remain on therapy. At DL 1, a pt with DLBCL achieved a complete response (CR) and a pt with transformed follicular achieved a partial response (PR). At DL-1, a pt with DLBCL achieved a CR and 1 pt each with MCL and FL achieved PR. At DL -1A, 1 pt each with MCL and MZL achieved a PR. Overall response rate for 18 assessable pts is 39%. Five pts had best response of stable disease. Sixteen pts have discontinued the study including 3 pts with DLTs, 2 for alternative treatment, 2 for toxicity, and 9 pts with progression. Conclusions: Combined therapy with lenalidomide and ibrutinib in pts with relapsed NHL is well-tolerated, although DLTs of recurrent rash and stroke were encountered. Lenalidomide 10 mg and ibrutinib 420 mg was tolerated and pts are currently enrolling in an intra-pt dose escalation cohort. Preliminary efficacy has been observed in pts with relapsed/refractory DLBCL, MCL, FL, MZL, and transformed NHL. Disclosures Christian: Pharmacyclics: Research Funding; Acerta: Research Funding; Immunomedics: Research Funding; Celgene: Consultancy; Novartis: Other: IDSM; Seattle Genetics: Consultancy, Research Funding; Janssen: Research Funding. Off Label Use: The use of ibrutnib and lenalidomide in combination in relapsed/refractory non-Hodgkin's lymphoma is off-label. Kuruvilla:Karyopharm: Honoraria, Research Funding; Roche Canada: Honoraria; Seattle Genetics: Honoraria, Research Funding. Smith:Celgene: Consultancy; Pharmacyclics: Consultancy. Porcu:Cell Medica: Research Funding; Infinity: Research Funding; Seattle Genetics: Research Funding; Celgene: Research Funding; Shape: Research Funding. Maddocks:Acerta: Research Funding; Pharamcyclics: Research Funding; Novartis: Research Funding. Byrd:Pharmacyclics: Research Funding. Blum:Celgene: Research Funding; cephalon: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding.

scholarly journals A Phase I Study of Ibrutinib and Lenalidomide in Patients with Relapsed and Refractory B-Cell Non-Hodgkin's Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4476-4476 ◽  
Author(s):  
Beth Christian ◽  
John Kuruvilla ◽  
Sonali Smith ◽  
Pierluigi Porcu ◽  
Amy S. Ruppert ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Disease Progression ◽  
Dose Level ◽  
Dose Escalation ◽  
Stable Disease ◽  
Research Funding ◽  
Phase I Study ◽  
Mantle Cell ◽  
Grade 3

Abstract Introduction: Lenalidomide, an immunomodulatory agent, and ibrutinib, a selective and covalent inhibitor of Bruton’s tyrosine kinase, are orally bioavailable agents with promising single agent activity in relapsed/refractory B-cell NHL. We are conducting a phase I study of the combination of ibrutinib and lenalidomide to determine the maximum tolerated dose, dose limiting toxicities (DLT), and preliminary efficacy in patients with relapsed/refractory NHL. Methods: Patients with relapsed/refractory B-cell NHL including diffuse large B-cell (DLBCL), transformed, mantle cell, marginal zone, lymphoplasmacytic, and follicular lymphoma who have received at least one prior therapy were eligible. Prior autologous but not allogeneic stem cell transplant and prior lenalidomide were permitted. Prior ibrutinib, CNS involvement, and patients requiring anticoagulation were not permitted. ANC > 1000/mm3, platelets > 50,000/mm3, and creatinine < 2.0 mg/dL, ALT/AST ≤ 2.5 x ULN, bilirubin ≤ 1.5 x ULN, and ECOG PS 0-2 were required at study entry. Treatment consisted of escalating doses of lenalidomide days 1-21 and ibrutinib days 1-28 of a 28 day cycle. A standard 3+3 dose escalation schema was followed. DLTs were assessed during cycle 1 and included: treatment delays > 14 days for toxicity; grade 5 toxicity; tumor lysis syndrome requiring dialysis; tumor flare reaction nonresponsive to corticosteroids; ANC < 500 / mm3 or platelets <25, 000 / mm3 persisting > 7 days; grade 3 or 4 febrile neutropenia or infection; and any grade 3 or 4 non-hematologic toxicity with the exception of DVT, diarrhea, nausea, or vomiting amenable to medical therapy, correctable electrolyte abnormalities; grade 3 fatigue, or grade 3 maculopapular rash that resolved within 7 days. Patients without significant toxicity could continue treatment until disease progression. Response was assessed every 3 months for 12 months and then every 6 months until disease progression. Results: From September 2013 until July 2014, 13 patients have been treated. Median age is 68 years (range 45-85) with 9 males. Histologies include DLBCL (4), transformed (4), follicular (2), mantle cell (2), and lymphoplasmacyctic (1) lymphoma. Median number of prior therapies is 3 (range 2-9) with 4 patients having undergone prior autologous transplant. Four patients were treated at dose level (DL) 1 (lenalidomide 15 mg and ibrutinib 420 mg). One patient was replaced for rapid disease progression and 1 patient experienced DLT consisting of a grade 2 ischemic stroke while on aspirin with no history of cardiovascular disease that resulted in discontinuation of study therapy. As a result of this DLT, dose level 1 was expanded to 6 patients. A second DLT was observed, a grade 3 rash that resolved within 7 days with interruption of therapy but recurred with diffuse erythroderma within 4 hours of ibrutinib resumption on day 22 at 280 mg. A total of 6 patients were then treated at DL -1 (lenalidomide 10 mg and ibrutinib 280 mg), and no DLTs were encountered. Related grade 3-4 toxicities occurred in 4/13 patients (31%), including one patient with hypokalemia, neutropenia, thrombocytopenia, and pneumonia, two others with neutropenia and one with maculapapular rash. Patients have received a median of 3 cycles of therapy to date (range 1-5) and 5 remain on therapy. At DL 1, a patient with DLBCL achieved a complete response (CR) and patient with transformed follicular achieved a partial response (PR). At DL -1, a patient with DLBCL achieved a CR and a patient with mantle cell lymphoma achieved a PR. Four patients achieved stable disease. Reasons for study discontinuation include two patients with DLTs who were not evaluated for response, one patient with stable disease who went off study for alternative treatment, and five patients who have progressed. Conclusions: Combined therapy with lenalidomide and ibrutinib in patients with relapsed NHL has been well tolerated at doses of 10 mg and 280 mg respectively, although DLTs of recurrent rash and stroke were encountered with 15 mg lenalidomide and 420 mg ibrutinib. Dose escalation to an intermediate dose level with lenalidomide 10 mg and ibrutinib 420 mg is planned. If this dose level is deemed safe, intra-patient dose escalation of the lenalidomide from 10 mg in cycle 1 to 15 mg in cycle 2 with ibrutinib 420 mg continuously will be tested. Preliminary efficacy has been observed in patients with relapsed/refractory DLCL, MCL, and transformed NHL. Disclosures Christian: Janssen Research & Development, LLC: Research Funding; Celgene: Consultancy. Off Label Use: Use of lenalidomide and ibrutinib in B-cell non-Hodgkin's lymphoma. Smith:Celgene: Consultancy, Research Funding; Pharmacyclics/Janssen: Consultancy, Speakers Bureau. Porcu:Celgene: Honoraria. Byrd:Phamacyclics: Research Funding. Blum:Janssen, Pharmacyclics: Research Funding.

scholarly journals Weekly Carfilzomib, Cyclophosphamide and Dexamethasone (wCCd) in Newly Diagnosed Multiple Myeloma Patients: A Phase I- II Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 175-175 ◽  
Author(s):  
Antonio Palumbo ◽  
Davide Rossi ◽  
Sara Bringhen ◽  
Alessandra Larocca ◽  
Fabiana Gentilini ◽  
...  
Keyword(s):  
Partial Response ◽  
Phase I ◽  
Board Of Directors ◽  
Dose Level ◽  
Dose Escalation ◽  
Research Funding ◽  
Maximum Tolerated Dose ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Grade 3

Abstract Background Carfilzomib is a novel second generation proteasome-inhibitor with significant anti MM activity and favorable toxicity profile, including very limited neurotoxicity and neutropenia. This Phase I/II study was designed to determine the maximum tolerated dose (MTD) of once weekly carfilzomib combined with cyclophosphamide-dexamethasone (wCCd) and to assess safety and efficacy of this combination in elderly patients with newly diagnosed MM. Here we report the first findings from the Phase I dose-escalation and expansion portions. Enrolment in the phase II portion is ongoing. Methods In the Phase I, the standard 3+3 dose-escalation scheme was adopted, with Carfilzomib as the only escalating agent starting at 45 mg/m2 (level 0), maximal planned dose 70 mg/m2 (level 2), and 36 mg/m2, if needed (level -1), given IV on days 1, 8, 15 in 28-day cycles. Oral cyclophosphamide was administered at 300 mg/m2 on days 1, 8, 15 and oral dexamethasone at 40 mg on days 1, 8, 15, 22 for all dose levels. Dose escalation of Carfilzomib was based on dose-limiting toxicities (DLTs) occurring in cycle 1. After completion of 9 cycles, patients receive 28-day maintenance cycles with Carfilzomib (days 1, 8, 15) at the maximum tolerated dose (MTD) defined by the Phase I study until disease progression or intolerance. The objectives were to determine the MTD and assess activity and safety. Results As of June 15, 2014, 28 newly diagnosed MM patients were enrolled. Median age was 74 years, 29% of patients were older than 75 years, 36% had ISS stage III, 24% had unfavorable FISH profile [t(4;14) or t (14;16) or del17p]. Twelve patients were enrolled in the Phase I portion of the study. At dose level 0 (Carfilzomib 45 mg/m2) no DLT was reported; at dose level 1 (Carfilzomib 56 mg/m2), 1 of 6 patients experienced DLT, consisting of grade 3 creatinine increase; at dose level 2 (Carfilzomib 70 mg/m2) no DLT occurred. The MTD of weekly Carfilzomib was thus established as 70 mg/m2. Toxicity and response data are available for 25 patients, who have completed at least the first cycle; 3 patients are currently receiving their first cycle of treatment. Grade 3-4 drug-related adverse events occurred in less than 15% of patients and included neutropenia (12%, 3 patients), anemia (12%, 3 patients), acute pulmonary edema (8%, 2 patients), pulmonary embolism (4%, 1 patient), creatinine increase (4%, 1 patient), nausea (4%, 1 patient), and fatigue (4%, 1 patient). No peripheral neuropathy was observed. Overall, the wCCd regimen was well tolerated, 3 patients (12%) required Carfilzomib dose reduction (grade 3 creatinine increase, grade 3 transaminase increase and grade 2 fever) and 3 patients (12%) required drug discontinuation due to adverse events (2 acute pulmonary edemas and 1 creatinine increase). Patients received a median of 5 cycles (range 1-9). After 4 induction cycles, 83% of patients achieved at least partial response, 39% at least very good partial response, and 22% complete response. Responses improved over time, as shown in table 1. During the study, only 2 patients progressed and 1 patient died, due to acute pulmonary edema considered probably related to treatment. Conclusions This is the first prospective study evaluating once weekly carfilzomib in treatment-naïve MM. wCCd therapy appears safe and effective in newly diagnosed MM patients. Responses became deeper with subsequent cycles and toxicities were manageable. The response rate observed with weekly carfilzomib compares favorably with similar studies with standard twice weekly carfilzomib infusion. Updated results will be presented at the meeting. Table 1 2nd cycle 4th cycle 6th cycle Complete Response 5% 22% 27% At least Very Good Partial Response 9% 39% 63% At least Partial Response 73% 83% 91% Disclosures Palumbo: Celgene: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria; Onyx Pharmaceuticals: Consultancy, Honoraria; Array BioPharma: Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Honoraria; Genmab A/S: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Off Label Use: Use off-label of Carfilzomib (proteasome inhibitor).. Bringhen:Merck Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Janssen and Cilag: Honoraria; Celgene: Honoraria; Onyx: Consultancy. Larocca:Janssen Cilag: Honoraria; Celgene: Honoraria. Cavallo:Onyx: Honoraria; Janssen-Cilag: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Boccadoro:Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Gaidano:Onyx: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Sonneveld:Millenium: Honoraria, Research Funding; Onyx: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

Phase I study of topotecan and cisplatin in patients with advanced solid tumors: a cancer and leukemia group B study.

1994 ◽  
Vol 12 (12) ◽  
pp. 2743-2750 ◽  
Author(s):  
A A Miller ◽  
J B Hargis ◽  
R C Lilenbaum ◽  
S Z Fields ◽  
G L Rosner ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Phase Ii ◽  
Dose Escalation ◽  
Topoisomerase I ◽  
Advanced Solid Tumors ◽  
Phase Ii Trials ◽  
Grade 3 ◽  
Dose Levels

PURPOSE The objectives of this phase I trial were to determine the dose-limiting toxicities (DLTs) of the novel topoisomerase I inhibitor topotecan combined with cisplatin, to define the maximum-tolerated doses (MTDs) of the combination without and with the use of filgrastim, and to define recommended doses for phase II trials. PATIENTS AND METHODS Patients with advanced solid tumors were eligible if they had normal bone marrow, renal, and hepatic function and had not previously been treated with platinum compounds. Topotecan was administered intravenously on days 1 through 5 and cisplatin was administered intravenously on day 1 of a 21-day cycle. The topotecan dose was fixed at 1.0 mg/m2/d on the first four dose levels, and cisplatin was escalated in 25-mg/m2 increments from 25 to 100 mg/m2 without filgrastim. After encountering DLT, the dose of cisplatin was decreased by one level and topotecan dose escalation was attempted. After defining the MTD without growth factor, the study proceeded with escalating cisplatin doses to define the MTD with filgrastim 5 micrograms/kg subcutaneously (SC) daily starting on day 6 of treatment. Priming with filgrastim 5 micrograms/kg SC on days -6 to -2 before the first course was explored last. RESULTS Of 38 patients entered, 37 were eligible, 35 assessable for toxicity in the first course, and 28 assessable for response. The principal toxicity was grade 4 neutropenia, which had to last more than 7 days to be considered dose-limiting. No DLT was observed at the starting cisplatin dose of 25 mg/m2 (dose level 1). On level 2 (cisplatin 50 mg/m2, one patient had dose-limiting neutropenia and one patient had grade 3 renal toxicity. On level 3 (cisplatin 75 mg/m2), two patients had dose-limiting neutropenia. Therefore, cisplatin dose escalation was stopped. On dose level 5 (cisplatin 50 mg/m2 and topotecan 1.25 mg/m2/d), one patient had grade 4 neutropenia that lasted more than 7 days and one patient died of neutropenic sepsis. The remaining dose levels used topotecan 1.0 mg/m2/d plus cisplatin 75 mg/m2 (level 6) and 100 mg/m2 (levels 7 and 8) with filgrastim. No DLT was observed on level 6. On level 7, two patients had dose-limiting neutropenia and one patient had grade 3 hyperbilirubinemia. Priming with filgrastim on level 8 demonstrated no obvious advantage over level 7, and one patient had grade 4 thrombocytopenia that lasted more than 7 days. Three patients with non-small-cell lung cancer achieved a partial response and one patient with breast cancer had a complete response. CONCLUSION Topotecan and cisplatin in combination cause more neutropenia than expected from either drug given alone at the same dosage. The recommended phase II doses are topotecan 1.0 mg/m2/d for 5 days in combination with cisplatin 50 mg/m2 on day 1 without filgrastim or cisplatin 75 mg/m2 on day 1 with filgrastim support.

A Phase I Dose-Escalation Trial of Oral Clofarabine for Relapsed/Refractory Non-Hodgkin Lymphoma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1775-1775
Author(s):  
Jeremy S Abramson ◽  
Tak Takvorian ◽  
Eric D Jacobsen ◽  
Jennifer R Brown ◽  
Jeffrey A. Barnes ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Dose Level ◽  
Dose Escalation ◽  
Median Number ◽  
Hematologic Toxicity ◽  
Low Grade ◽  
Non Hodgkin Lymphoma ◽  
Grade 3 ◽  
Dose Levels

Abstract Abstract 1775 Background: Clofarabine is a second-generation purine analogue currently FDA-approved for intravenous use for relapsed/refractory pediatric ALL. Purine analogues demonstrate significant clinical activity in non-Hodgkin lymphomas (NHL), though clofarabine offers potential pharmacologic advantages over existing agents. Clofarabine is a more efficient substrate for deoxycytidine kinase, more completely inhibits ribonucleotide reductase and DNA polymerase α, and demonstrates improved activity in cells that are non-dividing or have a low proliferation rate. This phase I trial is the first evaluation of an oral formulation of clofarabine in relapsed or refractory non-Hodgkin lymphoma. Patients and Methods: The primary objective was to determine the maximum tolerated dose (MTD) and define dose-limiting toxicities (DLT). Efficacy was a secondary objective. Patients (pts) were eligible if they had relapsed or refractory B-cell or T-cell NHL without prior stem cell transplant. All pts were required to have adequate organ function and performance status ≤2 as well as absence of both CNS involvement and HIV infection. No routine infectious prophylaxis was given. Patients were treated at 4 dose levels (1mg, 2mg, 4mg and ultimately 3mg) with oral clofarabine administered once daily on days 1–21 of a 28 day cycle for up to 6 cycles. Three to 6 pts were treated at each dose level in a traditional 3+3 design. Response assessment occurred after cycles 2 and 6. DLT was assessed during cycle 1 and was defined as Grade 4 neutropenia or thrombocytopenia occurring for ≥5 days, any grade 3–4 non-hematologic toxicity, and grade 2 non-hematologic toxicity that did not recover prior to the subsequent cycle of therapy. Results: Twenty-one pts were enrolled on the dose-escalation phase of the study. The median age was 63 years (range 51–85). The median number of prior regimens was 2 (range 1–7). Histologies included follicular lymphomas (FL; 5 pts), small lymphocytic lymphomas (SLL; 5 pts), diffuse large B-cell lymphomas (DLBCL; 4 pts), marginal zone lymphomas (MZL; 4 pts), mantle cell lymphomas (MCL. 2 pts) and lymphoplasmacytic lymphoma (LPL; 1 pt). Median number of cycles administered was 5.5. No DLTs were observed at the 1mg or 2mg dose levels. Three pts were accrued at 4mg with 1 patient experiencing DLT of persistent grade 3 thrombocytopenia and grade 4 neutropenia. No additional DLTs occurred in the cohort, but the majority of pts required late dose reductions due to grade 3–4 hematologic toxicity. The dose was therefore de-escalated to 3mg and 6 additional pts were accrued. No DLTs were observed at the 3mg dose level with a median of 6 cycles administered (range 5–6); 3mg was declared the recommended phase 2 dose. Grade 3–4 hematologic toxicity included neutropenia (7 pts), thrombocytopenia (4 pts), and anemia (2 pts). Grade 1–2 non-hematologic toxicities were uncommon, and included fatigue, diarrhea, cough, and dizziness. There were no grade 3–4 non-hematologic toxicities. Seventeen pts completed one cycle of therapy and were evaluable for response. Radiographic disease reduction was observed in 11 of 17 pts (65%). The overall response rate (ORR) was 35% (6 of 17), all partial responses (PR). Responders included FL (2 pts), MZL (2 pts), SLL and LPL (1 pt ea.). ORR among low grade histologies (FL, MZL, SLL) was 43% in this phase 1 trial. Seven pts had stable disease, including 5 pts with reduction in tumor size that did not reach threshold for PR. Of the 4 pts with progressive disease, 2 had DLBCL, 1 had MCL and 1 had FL with biopsy following relapse identifying ALK-negative anaplastic large T-cell lymphoma. Of the 4 pts not evaluable for response, 1 pt died of progressive DLBCL during cycle 1 on dose level 1 and was replaced, 1 pt was the DLT pt on the 4mg dose level and was removed due to prolonged cytopenias, and 2 pts withdrew consent (1pt at 4mg, 1pt at 3mg), and were replaced. The 3mg dose level has been expanded in a 10-patient dose-expansion cohort limited to low-grade NHL and MCL. Conclusions: Oral clofarabine demonstrates encouraging tolerability and efficacy in relapsed B-cell NHL, particularly in low-grade histologies, warranting further investigation. Disclosures: Abramson: Genzyme: Consultancy. Off Label Use: Clofarabine is not FDA approved for NHL.

Oral Weekly Cyclophosphamide in Combination with Pomalidomide and Dexamethasone for Relapsed and Refractory Myeloma: Report of the Dose Escalation Cohort

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4062-4062 ◽  
Author(s):  
Rachid Baz ◽  
Kenneth H. Shain ◽  
Melissa Alsina ◽  
Lisa A Nardelli ◽  
Taiga Nishihori ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Dose Escalation ◽  
Partial Remission ◽  
History Of ◽  
Grade 3 ◽  
Recommended Phase Ii Dose ◽  
Level 2 ◽  
Dose Reductions

Abstract Abstract 4062 Introduction: The response rate (partial remission and better) of pomalidomide and low dose dexamethasone in myeloma patients who received prior lenalidomide and bortezomib was 34% (Richardson P, Blood 2011, 118; abs 634). In order to augment the response rate of a pomalidomide based therapy, we conducted a phase I trial to evaluate the safety of the addition of oral weekly cyclophosphamide to pomalidomide and a more frequent dose of dexamethasone and plan a phase II randomized trial to assess the efficacy of this strategy in relapsed and refractory myeloma. Patients/Methods: Eligible patients had relapsed and refractory myeloma after at least 2 prior therapies and were lenalidomide refractory. Patients received pomalidomide 4mg PO D1–21, dexamethasone 40 mg PO D1–4; 15–19 (20mg if older than 75 years) and oral cyclophosphamide on D1, 8, 15 of a 28 days cycle. Three cyclophosphamide dose levels (300 mg, 400mg and 500mg) were planned in this dose escalation. A dose limiting toxicity (DLT) was defined as one of the following toxicities occurring in cycle 1: febrile neutropenia, grade 3/4 non hematologic toxicity at least possibly related to pomalidomide or cyclophosphamide, grade 4 thrombocytopenia or neutropenia lasting more than 7 days or more than 7 days delay in starting cycle 2 for toxicities. Given the significant tumor burden and/or multiple prior therapies these patients were exposed to, Granulocyte colony stimulating factor support was allowed and encouraged during the phase I portion of the trial including the DLT period consistent with routine medical care. Responses were assessed per the IMWG criteria with the addition of minimal remission (>25% decrease in serum component). This study was approved by the institutional review board. Results: Between 12/2011 and 6/2012, ten patients were enrolled in the phase I portion. The median age was 69 (range 48–73) years, and 7 were males (70%). The median time from diagnosis to current therapy was 6 years (range 6 months – 15 years). The median number of prior therapies was 5 (range 3–10) and 9/10 patients were bortezomib refractory and all were lenalidomide refractory. In dose level 1, no DLT was noted and 1 patient achieved a very good partial remission (VGPR) and 1 a MR. In dose level 2, 1 patient developed an upper extremity DVT (DLT) and 1 patient developed diverticular rupture in cycle 2. Another patient with a history of colitis had a flare of his colitis which required IV antibiotics during cycle 1 but that was not felt to be related to study drugs. In dose level 2, 1 patient had a VGPR, 2 a partial remission (PR), 1 a MR and 2 stable disease (SD). 6/10 patients had dexamethasone dose reductions and none had pomalidomide or cyclophosphamide dose reductions. Grade 3/4 neutropenia, and thrombocytopenia occurred in 5 (50%), 3 (30%) patients. 1 patient had febrile neutropenia. Based on the above, further dose escalation of cyclophosphamide was not planned and the recommended phase II dose (RP2D) of cyclophosphamide was 400 mg PO D1, 8, 15 in combination with pomalidomide and low dose dexamethasone. Conclusion: The recommended phase II dose of cyclophosphamide in combination with pomalidomide and dexamethasone was 400 mg PO D1, 8, 15. Toxicities are manageable and the regimen has evidence of preliminary efficacy. Enrollment on the randomized phase II study is ongoing and updated safety data will be presented at the meeting. [a] 1 patient was not evaluable for DLT in the first cycle and was replaced because she took 50 mg of oral cyclophosphamide instead of 300 mg weekly in error. [b] 1 patient developed an upper extremity DVT which was considered a DLT. In addition, 1 patient with a history of colitis had a flare of his colitis which was not felt to be treatment related. 1 patient developed diverticular rupture in cycle 2. Disclosures: Baz: Celgene, Millennium, Bristol Myers Squibb, Novartis: Research Funding. Off Label Use: Pomalidomide for relapsed multiple myeloma. Alsina:Millenium: Consultancy, Research Funding. Martin:celgene: Consultancy.

scholarly journals A Safety Study of the Addition of Omacetaxine to the Standard-of-Care Induction Regimen of Cytarabine and Idarubicin in Newly-Diagnosed AML Patients

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5218-5218
Author(s):  
Sonia Christian ◽  
Kelley E. Kozma ◽  
Stephanie Barath ◽  
Ardaman Shergill ◽  
Damiano Rondelli ◽  
...  
Keyword(s):  
High Risk ◽  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
De Novo ◽  
Standard Of Care ◽  
Hematologic Toxicity ◽  
Newly Diagnosed ◽  
Induction Regimen ◽  
Dose Levels

Abstract Background: Omacetaxine mepesuccinate (OM) is a semi-synthetic form of Homoharringtonine (HH), a cephalotaxine alkaloid. OM induces cell apoptosis by inhibiting peptide bond formation during mRNA translation, with rapid loss of short-lived proteins, such as MCL-1, c-MYC, and Cyclin D1 (Lu, J Hematol Oncol. 2014, 7: 2). Notably, cytarabine synergizes with HH in causing apoptosis of leukemia cells in vitro. A phase III RCT in China of 620 patients with de novo AML demonstrated superior CR and 3-yr survival rates upon addition of HH to a standard 2-drug AML induction therapy ('7 + 3'; Jin, Lancet Oncol. 2013, 14:599). Thus, we hypothesized that OM, at an appropriate dose, would similarly enhance the efficacy of a 7 + 3 regimen. OM is FDA-approved for the treatment of TKI-resistant CML. The MTD of 1.25 mg/m2/d SQ for 14 days every 28 days, as determined in a phase I/II CML trial of OM (Quintás-Cardama, Cancer 2007, 109: 248), served as a basis for the dose escalation used in this study. Methods: The primary endpoint of this phase I safety trial was to determine the optimally safe and active dose (OD) of OM when added to a standard 7 + 3 induction regimen, cytarabine and idarubicin. OM was administered SQ q12h d1-7 with cytarabine (100mg/m2 CIV) d1-7 and idarubicin (12mg/m2 IV) d1-3. Four dose levels were tested, starting with OM 0.625 mg/m2 q12h (further dose levels: 1.25, 2.0, 3.0, and 4.2 mg/m2 q12h). All newly diagnosed, untreated de novo or secondary AML patients, aged 18-70y with ECOG PS of 0-3 were eligible for this study. Secondary endpoints included overall response rate (ORR) and overall and event free survival (OS, EFS). Hematologic toxicity (HT) was defined as incomplete hematologic recovery; ANC < 1.0 x 109/L or platelet count < 100 x 109/L present at d49, with the bone marrow documented to be free of leukemic infiltration. Dose escalation was based on the EffTox design (Biometrics 2004, 60:684), a Bayesian adaptive design which considers the trade-off between efficacy and toxicity in determining the OD for Phase II trials. Results: Twenty-two patients, median age 58 (range 25-69) years were enrolled from June 2015 to June 2018. 12 patients (54.5%) had adverse cytogenetics, 6 (27%) intermediate risk, 3 (13.7%) favorable risk and 1 patient's cytogenetic risk was unknown (fibrotic BM). Eight patients demonstrated disease evolution from myelodysplastic syndrome (MDS). Altogether 16 of the 22 patients (73%) were deemed high risk based on cytogenetics or MDS-AML evolution. The EffTox design was implemented until cohort 4 (3 mg/m2 q12h), where 2 of 3 patients experienced a grade 5 non-hematologic toxicity (NHT), resulting in a dose-limiting toxicity (DLT). Since no DLTs were observed in cohort 3, an additional 5 patients were thus enrolled at this dose level to ensure safety. The OD was determined to be the dose level used in cohort 3: OM 2 mg/m2. No HTs were observed in 21 of 22 patients, (one patient not evaluable). The most common non-hematologic treatment emergent adverse events (TEAEs) of any grade were fever (68%), nausea (64%), vomiting (55%), hyperglycemia (41%), diarrhea (41%), mucositis (36%), headache (36%), sinus tachycardia (32%), rash/dermatitis (32%), and abdominal pain (32%). The most prevalent non-hematologic grade 3/4 TEAEs were febrile neutropenia (23%), hypoxia (18%), hyperglycemia (18%), and dyspnea (18%). ORR (CR and CRi) was 45.5%. Median OS was 605 days and EFS was 100 days. Conclusion: In this population with predominantly high-risk AML, the combination of OM with a standard 7 + 3 regimen demonstrates a manageable safety profile with acceptable efficacy. As ~ 25% of patients achieving CR with '7 + 3' do so after a second induction (based on meta-analysis of 6 trials, n = 1980, see Cancer 2010, 116: 5012), the ORR here is comparable to those receiving a single standard of care induction. The results in this high-risk group are therefore promising and warrant further investigation in a phase II trial. At present, we are assessing leukemic blast MCL protein expression in stored pre-treatment samples to determine if this predicts OM efficacy. NCT02440568. Teva has performed a Medical Accuracy Review of this abstract. Figure. Figure. Disclosures Khan: Teva: Speakers Bureau. Patel:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Honoraria.

Phase I-II Trial of Oral Cyclophosphamide, Prednisone and Lenalidomide (Revlimid®) (CPR) for the Treatment of Patients with Relapsed and Refractory Multiple Myeloma.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1723-1723
Author(s):  
Donna E. Reece ◽  
Esther Masih-Khan ◽  
Arooj Khan ◽  
Peter Anglin ◽  
Christine Chen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Level ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Oral Cyclophosphamide ◽  
Varicella Zoster ◽  
Refractory Multiple Myeloma ◽  
Grade 3 ◽  
Dose Levels

Abstract Oral cyclophosphamide and prednisone is a convenient regimen in relapsed and refractory multiple myeloma (MM), with a partial response (PR) rate of 40% and median progression-free survival of 19 months in our retrospective analysis of patients in first or second relapse after autologous stem cell transplantation (ASCT) (Trieu Y, et al, Mayo Clin Proc2005; 80: 1582). We sought to enhance the efficacy of this regimen by adding oral lenalidomide (Revlimid®), a potent anti-myeloma agent, in a phase I-II trial. The CPR regimen consisted of cyclophosphamide on days 1, 8 and 15, lenalidomide on days 1–21, and prednisone 100 mg every other day in a 28-day cycle. ASA 81 mg/day was given to all patients (pts) as prophylaxis for DVT. Three dose levels were evaluated using a 3 by 3 dose escalation design. Between 11/2007–07/2008, 15 pts with relapsed/refractory MM were entered onto study. Median age was 60 (45–78) years and 60% were male. Immunoglobulin subtype was IgGκ:λ in 10:1; IgA κ:λ in 2:1 and κ light chain in 1. Median number of prior regimens was 2 (1–3) and 14 had undergone previous ASCT, including double transplants in 2 pts. Prior therapy also included thalidomide in 3 (20%) and bortezomib in 6 (40%). FISH cytogenetics were available in 9, but none had 13q deletion, t(4;14) or p53 deletion. At the time of protocol entry, median β2-microglobulin level was 222 (92–325) nm/L, albumin 38 (35–46) g/L, creatinine 78 (50–100) μmol/L, platelet count 230 (93–318) x 109/L and ANC 2.5 (1.9–9.0) x 109/L. Protocol treatment is summarized in Table 1. Dose level N Cyclophosphamide dose (mg/m2) Lenalidomide dose (mg) Prednisone dose (mg) Median # cycles given 1 3 150 15 100 9 2 3 150 25 100 6 3 6 300 25 100 4 3 (expanded) 3 300 25 100 1 Dose limiting toxicity was not observed during cycle 1 at any of the dose levels and the maximum tolerated dose of this regimen has not yet been reached at the highest dose level planned; all pts remain on active therapy. Grade 3/4 thrombocytopenia was seen in 1 pt (cohort 2) and neutropenia in 4 pts (1 in cohort 1, 1 in cohort 2 and 2 in cohort 3) and were managed with dose reduction and/or growth factor support. No episodes of febrile neutropenia occurred in any pt. Only 1 pt experienced varicella zoster; routine antiviral prophylaxis was not used. Other grade 3/4 non-hematologic toxicities were uncommon and included abdominal pain/bacteremia in 1 pt in cohort 1, hypokalemia in 1 pt in cohort 2, and DVT in 1 pt in cohort 3. Mild grade 1/2 constipation (47%), muscle cramps (33%) and fatigue (33%) were also noted. To date, best response includes the following: dose level 1 (1 near complete remission [nCR], 2 PR); dose level 2 (3 PR); dose level 3 (4 PR, 2 minimal response [MR]); expanded cohort 3 (1 MR, 2 too early). We conclude: 1) the combination of full doses of the agents in CPR can be given in a 28-day cycle with minimal toxicity; 2) the overall response rate (nCR + PR + MR) in 13 evaluable pts to date is 87%; 3) no pts have progressed in this preliminary analysis; 4) longer follow-up is required to assess the long-term efficacy of this regimen.

Phase I-II Trial of Oral Cyclophosphamide, Prednisone and Lenalidomide (Revlimid®) (CPR) for the Treatment of Patients with Relapsed and Refractory Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1874-1874 ◽  
Author(s):  
Donna E. Reece ◽  
Esther Masih-Khan ◽  
Arooj Khan ◽  
Saima Dean ◽  
Peter Anglin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Level ◽  
Research Funding ◽  
Overall Response Rate ◽  
Response Rate ◽  
Oral Cyclophosphamide ◽  
Refractory Multiple Myeloma ◽  
Grade 3

Abstract Abstract 1874 Poster Board I-899 Lenalidomide (Revlimid®) and dexamethasone is an effective regimen in relapsed/refractory multiple myeloma (MM) patients (pts), with an overall response rate of 60.6% and median time to progression (TTP) of 13.4 months (Dimopoulos MA, et al, Leukemia 2009 Jul 23 [Epub ahead of print]). Oral cyclophosphamide and prednisone is an older regimen with excellent patient tolerance, and we sought to enhance the efficacy of lenalidomide by adding oral cyclophosphamide and prednisone in this phase I-II trial. The CPR regimen consisted of cyclophosphamide on days 1, 8 and 15; lenalidomide on days 1–21; and prednisone 100 mg every other day in a 28 day cycle. ASA 81 mg/day was given to all pts as DVT prophylaxis. Three dose levels were evaluated using a 3 by 3 dose escalation design. Between 11/2007–07/2009, 31 pts with relapsed/refractory MM who had not previously received lenalidomide were entered onto study. Median age was 61 (40–78) years and 61% were male. Immunoglobulin subtype was IgG in 19 pts (61%), IgA in 8 pts (26%) and light chain only in 4 pts (13%). Median number of prior regimens was 2 (1–5) and 28 pts had undergone previous ASCT, including double transplants in 6 pts. Prior therapy included thalidomide in 9 (29%) and bortezomib in 15 (48%). FISH cytogenetics were available in 13 pts; one had 13q deletion but none had t(4;14) or p53 deletion. At the time of protocol entry, median β 2-microglobulin level was 246 (92–767) nm/L, albumin 39 (34–48) g/L, creatinine 83 (50–126) μmol/L, platelet count 230 (75–337) × 109/L and ANC 2.5 (1.1–6.1) x 109/L. Protocol treatment is summarized in Table 1. Dose limiting toxicity was not observed during cycle 1 at any dose level. Grade 3–4 toxicities included thrombocytopenia in 5 pts (16%) and neutropenia in 9 pts (29%). These were managed with dose reduction and/or growth factor support. Four episodes of febrile neutropenia occurred. Other grade 3–4 non-hematologic toxicities included abdominal pain/bacteremia in 1 pt in cohort 1; hypokalemia in 1 pt in cohort 2; and DVT in 2 pts, dizziness in 2 pts and fatigue in 1 pt in cohort 3. Using the International uniform response criteria (Durie BG, et al, Leukemia 2006; 20:1467–1473), the best response was documented at a median of 6 (1–5) cycles and included the following: dose level 1 (1 CR, 2 PR); dose level 2 (1 VGPR, 2 PR); dose level 3 (5 CR, 9 VGPR, 9 PR, 1 MR and 1 stable disease). At a median follow-up (F/U) of 12 (8–21) months, 20 pts remain on study, 2 have withdrawn and 9 pts have progressed at a median of 9 (4–13) months; only 1 one has died (due to MM). We conclude: 1) the combination of full doses of the agents in CPR can be given in a 28 day cycle with minimal toxicity; 2) the overall response rate (CR + VGPR + PR) in 31 pts to date is 93%; 3) at a median F/U of 1 year, only 9 pts (29%) have progressed; 4) longer follow-up is required to assess the TTP and survival of the CPR regimen. Disclosures: Reece: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: Lenalidomide in combination with drugs other than dexamethasone. Anglin:Celgene: Honoraria. Chen:Celgene: Honoraria, Research Funding. Kukreti:Celgene: Honoraria. Mikhael:Celgene: Honoraria. Trudel:Celgene: Honoraria.

Oxaliplatin, Fludarabine, Cytarabine, and Rituximab Combination Therapy Induces High Response Rates in Agressive Chronic Lymphocytic Leukemia (CLL) and Richter's Syndrome (RS).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3443-3443 ◽  
Author(s):  
Apostolia-Maria Tsimberidou ◽  
William Wierda ◽  
William Plunkett ◽  
Susan O'Brien ◽  
Thomas J. Kipps ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Research Funding ◽  
Response Rates ◽  
Off Label ◽  
Level 3 ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

Abstract Abstract 3443 Poster Board III-331 Introduction The first Phase I-II clinical trial of oxaliplatin, fluradabine, cytarabine (Ara-C), and rituximab (OFAR1) demonstrated significant activity in refractory CLL and RS (Tsimberidou et al, J Clin Oncol, 2008;26:196). To enhance the response rate and decrease myelosuppression, the dose of oxaliplatin was increased to 30mg daily, the dose of Ara-C was decreased to 0.5g/m2 daily and the optimal number of days of fluradabine and Ara-C administration was explored (OFAR2). Methods In a Phase I-II study of OFAR2, patients were treated with oxaliplatin 30mg/m2, D1-4; fludarabine 30mg/m2, Ara-C 0.5g/m2; rituximab 375mg/m2, D3; and pelfigrastim 6mg, D6. Fludarabine and Ara-C were given on D2-3 (dose level 1) D2-4 (dose level 2) or D2-5 (dose level 3); courses were repeated every 4 weeks. Patients received prophylaxis for tumor lysis, DNA viruses, and PCP. A “3+3” design was used and the planned number of patients in the Phase II was 90 (CLL, 60; RS, 30). Results Ninety-one patients (CLL, 67; RS, 24) have been treated to date: Phase I, 12 patients (by dose level: 1, n=3; 2, n=6; and 3, n=3). DLTs were noted in 2 of 3 patients on dose level 3 (G4 diarrhea, 1; G4 neutropenic sepsis, 1); thus, dose level 2 was the MTD. Seventy-nine patients (relapsed CLL, 58; RS, 19) have been treated in the Phase II portion of the study. Patient characteristics were as follows: age > 60 years, 65%; 17p deletion, 38%; 11q deletion, 13%; 13q deletion, 16%; trisomy 12, 21%; no findings, 12%; unmutated IgVH, 80%; ZAP70-positive, 75%; and CD38 ≥30%, 58%. Response in patients treated in the Phase II recommended dose is shown in Table (evaluable, 67). The overall response rates in patients with 17p and 11q deletions were 48% and 55%, respectively. The median survival duration was 21 months (CLL, 21 months; RS, 9.5 months). At 18 months, the survival rates in patients with 17p and 11q deletions were 66% and 76%, respectively. Twelve patients underwent stem cell transplantation after OFAR2 (as post-remission therapy, n=10; as salvage, n=2). Overall, 196 cycles were administered. Grade 3-4 neutropenia, thrombocytopenia, and anemia were noted in 63%, 72%, and 39% of patients and in 57%, 70%, and 25% of cycles and Grade 3-4 infections in 19% of patients. Conclusion Preliminary results demonstrated that OFAR2 induced response in 40% of patients with RS and 63% of patients with relapsed/refractory CLL. OFAR2 had antileukemic activity in patients with 17p deletion. Clinical outcomes appeared to be superior to those of OFAR1 in refractory CLL, whereas results of OFAR1 appeared to be superior to those of OFAR2 in RS. Accrual is ongoing. Disclosures Tsimberidou: ASCO: ASCO Career Development Award; Sanofi: Research Funding. Off Label Use: Oxaliplatin is used off-label. Wierda:Genentech: Honoraria; Bayer, Sanofi-Aventis, Abbott, GSK: Research Funding; GSK, Trubion, Ligand, Genentech, Medimmune, Abbot: Consultancy; Celgene: Speakers Bureau. Plunkett:Sanofi-Aventis: Research Funding. O'Brien:Genentech: Research Funding; Sanofi: Consultancy. Kipps:NCI: Grant P01CA-81534.

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