scholarly journals Safety and Efficacy of Combined Ruxolitinib and Decitabine in Patients with Blast-Phase MPN and Post-MPN AML: Results of a Phase I Study (Myeloproliferative Disorders Research Consortium 109 trial)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1124-1124 ◽  
Author(s):  
Raajit K. Rampal ◽  
John O. Mascarenhas ◽  
Heidi E. Kosiorek ◽  
Dmitriy Berenzon ◽  
Elizabeth Hexner ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Adverse Events ◽  
Phase I ◽  
Peripheral Blood ◽  
Research Funding ◽  
Phase I Trial ◽  
Fixed Dose ◽  
Hematologic Toxicity ◽  
Blast Phase ◽  
Grade 3

Abstract Background: The Philadelphia chromosome negative myeloproliferative neoplasms (MPN) includePolycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF). These stem cell disorders carry a propensity to evolve into acute myeloid leukemia (MPN-blast phase [BP] or post-MPN AML) with a dismal prognosis not meaningfully improved by conventional anti-leukemia therapy. Thus, MPN-BP is an urgent unmet clinical need. Responses in patients with MPN-BP to hypomethylating agents and single agent ruxolitinib have been reported. More recently, combination of ruxolitnib and decitabine has demonstrated synergistic activity in vitro in cells derived from patients with MPN-BP and from a murine model of MPN-BP (Rampal et al PNAS 2014). These observations led us to explore the safety of combined decitabine and dose escalation of ruxolitinib in MPN-BP. Objective: To establish the maximum tolerated dose (MTD) of ruxolitinib in combination with a fixed dose of decitabine (DEC-RUX). Methods: We conducted an open label Phase I trial in patients with MPN acceleration phase (AP) as defined by 10%-19% blasts in the peripheral blood or bone marrow or a diagnosis of MPN-BP as defined by ≥ 20% blasts in the blood or bone marrow, following a previous diagnosis of ET, PV or PMF. Patients were enrolled in a standard 3+3 phase I design with an MTD defined as a dose <33% DLT. Ruxolitinib was administered at doses of 10mg, 15mg, 25mg, or 50mg every 12 hours in combination with concurrent decitabine at a dose of 20mg/m2 daily intravenously over 5 days and repeated every 28 days. Adverse events were assessed using the NCI CTCAE v. 4.0. DLTs were defined as Grade 3 or higher non-hematologic toxicity events not clearly related to disease and grade 4 hematologic events with a bone marrow cellularity of ≤5% and no evidence of leukemia. Response assessment was carried out every cycle using modified Cheson criteria: CR required 0% peripheral blood blasts, WBC ≥4x109/L, hemoglobin ≥10g/L, and platelets ≥100x109/L; CRi required 0% peripheral blood blasts with incomplete count recovery; and PR required ≥50% decrease in peripheral blood blasts regardless of blood counts. Results: A total of 21 patients were accrued to study (Table 1). The median age was 63 years (range 48-88). 52% carried a diagnosis of MPN-AP, and 48% carried a diagnosis of MPN-BP. 29% of patients and 24% of patients had prior exposure to ruxolitinb and decitabine, respectively. The median number of cycles received varied from 10.5 cycles in the 10mg BID cohort to 2 and 2.5 cycles in the 25mg BID and 50mg BID cohorts, respectively (Table 2). The most common Grade 3/4 non-hematologic AEs observed were due to infection in all dosing cohorts. In terms of hematologic toxicity, treatment emergent Grade 3/4 anemia was observed in 1 patient in each of the 10mg BID, 15mg BID, and 50mg BID cohorts. Grade 3/4 leukopenia was observed in only 1 patient at the 50mg BID cohort, and Grade 3/4 thrombocytopenia was observed in 2 patients in the 10mg BID cohort and 1 patient in the 15mg BID cohort. DLT rate was below 33% for all dose levels so the MTD was not reached. The most common reason for ending study treatment was toxicity/adverse events (33%) followed by disease progression (22%). 9 patients died during study or follow-up. Of those, 5 (56%, 2 in 10mg BID cohort, 1 in 15mg BID cohort, 2 in 50mg BID cohort) died of infection, 3 (33%, 1 in each of 10mg, 25mg, and 50mg BID cohorts) of progressive disease, and 1 (11%, 25mg BID cohort) of hemorrhage. The median overall survival for patients on study was 10.4 months (95% CI 3.3 mo - not reached). CR/CRi as best response was observed in 7/21 patients (33%, 95% CI 15-57%; 2 CR, 5 CRi; Table 2). Conclusions: DEC-RUX combination therapy was safely administered to patients with MPN-AP/BP and an MTD was not reached. Based on pre-clinical data, observed safety profile, duration of treatment, and clinical responses in this phase I trial, the Recommended Phase II Dose of RUX was selected as 25mg BID for an induction cycle followed by 10mg BID in all ensuing cycles. Molecular and bone marrow pathology responses will be presented at the meeting. Disclosures Mascarenhas: Promedior: Research Funding; CTI Biopharma: Research Funding; Novartis: Other: DSMB , Research Funding; Janssen: Research Funding; Roche: Research Funding; Incyte: Other: Clinical Trial Steereing Committee, Research Funding. Hexner:Blueprint medicines: Consultancy; Novartis: Research Funding. Abboud:Alexion: Honoraria; Takeda: Honoraria; Novartis: Research Funding; Teva: Research Funding, Speakers Bureau; Pfizer: Research Funding; Merck: Research Funding; Pharmacyclics: Honoraria; Baxalta: Honoraria; Seattle Genetics: Research Funding; Gerson and Lehman Group: Consultancy; Cardinal: Honoraria. Levine:Novartis: Consultancy; Qiagen: Membership on an entity's Board of Directors or advisory committees. Mesa:Promedior: Research Funding; Novartis: Consultancy; Incyte: Research Funding; Celgene: Research Funding; Galena: Consultancy; Ariad: Consultancy; Gilead: Research Funding; CTI: Research Funding.

Plerixafor, G-CSF and Azacitidine For The Treatment Of MDS: Results Of a Phase I Trial

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2816-2816
Author(s):  
Mark A. Schroeder ◽  
Marcus Grillot ◽  
Teresa Reineck ◽  
Meagan A Jacoby ◽  
Rizwan Romee ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Bone Marrow ◽  
Phase I ◽  
Research Funding ◽  
Phase I Trial ◽  
Response Rates ◽  
Response To Treatment ◽  
Hematologic Toxicity ◽  
Oncology Research ◽  
Grade 3

Abstract Azacitidine has been shown to prolong survival and delay progression to leukemia in intermediate-2 and high risk myelodysplastic syndrome (MDS) in a randomized study compared to best supportive care. The combination of G-CSF and plerixafor is synergistic in increasing the release of stem and progenitor cells from the bone marrow through disruption of critical bone marrow stromal interactions including the CXCR4 / CXCL12 axis. The interaction of bone marrow stromal cells with the MDS tumor clone may play a roll in pathogenesis and response to treatment. We hypothesized that resistance of MDS to azacitidine may be related to MDS tumor and BM-stromal cell interactions, and disruption of these interactions by treatment with plerixafor + G-CSF could enhance sensitivity to azacitidine, thus improving complete and partial response rates. We conducted a phase I trial to investigate the safety and tolerability of plerixafor + G-CSF in combination with azacitidine in adult (18 years or older) MDS patients. Secondary objectives included response rates and biologic correlates evaluating: kinetics, phenotype, cell cycle status and kinetics of mobilization of MDS blasts compared to normal stem cells in select patients with informative cytogenetics. Major inclusion criteria included MDS defined by WHO criteria, 5 – 20% blasts on bone marrow aspirate, and at least one cytopenia in one cell lineage. Subjects receiving prior hypomethylating therapy were allowed. A standard 3+3 trial with 3 cohorts (320, 440, and 560 mcg/kg/day SC) was conducted. Dose limiting toxicity was defined as grade 3 or higher non-hematologic toxicity and hematologic toxicity of leukostasis or tumor lysis. Myelosuppression, infection, grade III nausea, fatigue, weight loss and electrolyte abnormalities were not considered dose limiting. Subjects initially received G-CSF 10 mcg/kg subcutaneous (SC) daily D1 – D8, plerixafor SC daily D3 – D8 and azacitidine 75mg/m2 SC D3 – D8, 4 hours after plerixafor administration. The trial was amended after the first 3 subjects to reduce G-CSF dose and administration to 5 days. Results Two of the first three subjects enrolled in cohort 1 (320 mcg/kg/d plerixafor) had leukocytosis. The trial was amended to reduce the G-CSF dose (10 mcg/kg to 5 mcg/kg) and duration (8 days to 5 days) because of this. One subject had symptoms of leukostasis with a WBC reaching nearly 100K/uL and a subsequent subject developed hyperleukocytosis (WBC = 80K/uL) without leukostasis. The trial was amended to reduce the G-CSF to 5 days concurrent with plerixafor and azacitidine along with defining dose holding parameters for G-CSF and plerixafor if the peripheral blood WBC exceeded 40K/uL or if absolute blast count exceeded 10K/uL. Since amendment of the trial, 64 subjects have been screened and 20 subjects have been enrolled and are evaluable. Subjects included 65% males, median age 67, and MDS diagnosis at study entry including 6/18 (33%) RAEB-1 and 12/18 (67%) RAEB-2. 5/18 subjects (28%) had plerixafor and G-CSF held during treatment because of leukocytosis. 9/18 subjects (50%) had received no prior treatment for their MDS. DLTs were experienced in Cohort 1 related to thrombocytosis (n =1) and in Cohort 2 related to atrial fibrillation (n = 1) with near syncope. Major non-hematologic grade 3 or 4 adverse events included epistaxis, hypocalcemia, GI bleed, headache, dyspnea, infection with neutropenia, and bone pain. The MTD was determined to be 560mcg/kg plerixafor SC with no subjects (n = 6) in this cohort experiencing a DLT. The median number of cycles completed was 3. Reasons for stopping treatment included progression to leukemia (n = 6), physician choice (n = 2), withdrawal of consent (n = 1), adverse event (n = 2). Best response in those evaluable after completing 2 cycles of treatment (n = 14) showed marrow CR in 5/14 (36%, 3 in those not previously treated for MDS), stable disease in 5/14 (36%) and progressive disease 4/14 (29%). Conclusion Plerixafor plus G-CSF in combination with azacitidine was well tolerated in the studied MDS patients when given over 5 days and may be associated with encouraging response rates. Correlative studies are ongoing to evaluate changes in cell cycle, apoptosis and preferential mobilization of blasts using this regimen. We are currently enrolling an expanded cohort of 7 subjects at the MTD dose to evaluate preferential mobilization of blasts with plerixafor alone in cases using informative cytogenetics. Disclosures: Schroeder: Celgene: Research Funding; Sanofi Oncology: Research Funding. Off Label Use: Plerixafor and G-CSF for the treatment of MDS. Welch:Eisai: Research Funding. Stockerl-Goldstein:Millennium: Speakers Bureau; Celgene : Speakers Bureau.

A Phase I Study of Ruxolitinib Plus Nilotinib in Chronic Phase CML Patients with Molecular Evidence of Disease

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1892-1892 ◽  
Author(s):  
Kendra L. Sweet ◽  
Lori Hazlehurst ◽  
Eva Sahakian ◽  
John J. Powers ◽  
Lisa Nodzon ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Adverse Events ◽  
Phase I ◽  
Research Funding ◽  
Rt Pcr ◽  
Transcript Levels ◽  
Future Studies ◽  
Fatigue Severity ◽  
Grade 3 ◽  
The Impact

Abstract Background: BCR-ABL tyrosine kinase inhibitors (TKI) are the standard treatment for CP-CML. A subset of patients have profound molecular responses with BCR-ABL transcripts no longer detectable using RT-PCR (MR4.5). The ENESTnd trial compared nilotinib versus imatinib as frontline therapy in CML, and reported an increase in the cumulative incidence of MR4.5 of approximately 11% per year for the first five years in nilotinib treated patients. Discontinuation of TKIs is successful in 40-50% of patients who have a durable MR4.5. The phosphorylation of STAT3-Y705 via the JAK-STAT signaling pathway provides a protective microenvironment for the leukemic stem cells (LSC) and is a well described mechanism of resistance to TKIs. The residual LSCs likely contribute to relapse after TKI discontinuation. Data suggests that by simultaneously blocking JAK2 and TYK2, pSTAT3 is inhibited, thereby eliminating the protective environment in the bone marrow, and sensitizing the LSCs to TKIs. Ruxolitinib is a JAK2 and TYK2 inhibitor. Here we used ruxolitinib in combination with nilotinib in CP-CML patients to establish the maximal tolerated dose (MTD) of ruxolitinib, and obtain preliminary data about the impact of this combination on BCR-ABL transcript levels. Methods: This phase I, dose-escalation study used ruxolitinib plus nilotinib in CP-CML. All subjects were taking nilotinib prior to enrollment. Eligible subjects had a complete cytogenetic response (CCyR), yet had detectable BCR-ABL transcripts by RT-PCR at enrollment. We used a 3+3 design with 3 cohorts. The nilotinib dose remained unchanged, and the three doses of ruxolitinib were 5mg BID, 10mg BID and 15mg BID. Two additional subjects were treated at the MTD. Subjects remained on combination therapy for six months, at which point ruxolitinib was discontinued. RT-PCR was used to measure BCR-ABL transcript levels in the peripheral blood and/or bone marrow at baseline and every 3 months. The primary endpoint was the MTD of ruxolitinib. Secondary endpoints included toxicity assessment, incidence of MR4.5 at six months, change in fatigue severity scores and impact of ruxolitinib on pSTAT3/5 inhibition assessed with a plasma inhibitory assay (PIA) Descriptive statistics were used for baseline demographics, toxicity, MR4.5 and pSTAT3 levels. Subjects completed the fatigue severity index (FSI) questionnaire at baseline and every 3 months. A paired samples t-test was used to measure the difference in fatigue severity over time. Results: A total of 11 patients were enrolled between April 2013 and March 2016. Median age was 41 (25-63). 73% (n=8) were male. 36% (n=4) had received one TKI prior to nilotinib. The nilotinib dose was 300mg (n=8) or 400mg BID (n=3). Median time from diagnosis to enrollment was 11 months (6-135). Each cohort enrolled 3 subjects, and two additional subjects were treated at the MTD. There were no dose limiting toxicities; therefore the MTD/RP2D of ruxolitinib was 15mg PO BID. There were no grade 3/4 adverse events in any cohort, and no clinically significant cytopenias. Grade 1/2 transaminitis occurred in 1 subject in cohorts 1 and 2. No dose reductions were needed. At data cutoff, 9 subjects have completed six months on trial, and 2 remain active. Of those nine, 3 (33%) had ≥1-log reduction in BCR-ABL transcripts from baseline and 4 (44%) achieved MR4.5. One subject in cohort 1 progressed after three months and a kinase domain mutation analysis found a T315I mutation. FSI data available on seven subjects showed a non-significant decline in average fatigue severity from baseline (mean 2.78, SD 1.79) to follow-up (mean 1.86, SD 1.21), p=0.29. Results from the plasma inhibitory assay and updated results of all 11 subjects will be presented at the meeting after all subjects will have completed the trial. Conclusion: Our data suggest that ruxolitinib is safe and tolerable at 15mg PO BID when combined with nilotinib in CP-CML, and with no grade 3/4 adverse events reported, this should be considered the RP2D for future studies. The incidence of MR4.5 after six months was 44% which surpasses that of historical controls, although the sample size is small and a larger study is needed to confirm these results. The combination leads to an improvement in fatigue severity that did not reach statistical significance. This data serves as justification for future studies using ruxolitinib in combination with TKIs to determine the true impact on eradication of MRD in CP-CML. Disclosures Sweet: Karyopharm: Honoraria, Research Funding; Pfizer: Speakers Bureau; Incyte Corporation: Research Funding; Ariad: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Nodzon:Novartis: Speakers Bureau. Pinilla-Ibarz:Janssen: Consultancy, Honoraria; Pharmacyclics: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Novartis: Consultancy; Abbvie: Consultancy, Speakers Bureau.

Phase I Trial of Combination Therapy with 90Y Ibritumomab Tiuxetan and Gemcitabine in Patients with Non-Hodgkin’s Lymphoma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4710-4710
Author(s):  
Hossein Borghaei ◽  
Mitchell Smith ◽  
Michael Millenson ◽  
Danielle Shafer ◽  
Linda Thibodeau ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase I ◽  
B Cell ◽  
Hodgkin’S Lymphoma ◽  
Phase I Trial ◽  
Hodgkin's Lymphoma ◽  
Hematologic Toxicity ◽  
Ibritumomab Tiuxetan ◽  
Non Hodgkin's Lymphoma ◽  
Grade 3

Abstract Y90-ibritumomab tiuxetan, or Zevalin (Z), is an effective therapy against CD20+ lymphomas and is approved for use in patients with relapsed or refractory low grade, follicular, or transformed B-cell non-Hodgkin’s lymphoma (NHL). Gemcitabine also is active against NHL and is a potent radiation sensitizer. We are conducting a phase I trial to assess the safety of concomitant administration of Z and gemcitabine in patients with NHL. Nine patients in three cohorts will be treated with 250 mg/m2 of gemcitabine IV on days 1 and 8 of the Z treatment program of rituximab + In 111-ibritumomab on day 1 and rituximab + Y90 ibritumomab on day 8, with Z at 0.2, 0.3 or 0.4 mCi/kg respectively. The next cohort can only accrue after all patients in the prior cohort have hematologic toxicity that has recovered to grade 0–2 or after 60 days from the date of the last treated patient in the previous cohort. Once it is confirmed that a Z dose of 0.4 mg/kg can be safely administered with gemcitabine 250 mg/m2, Z will remain constant at 0.4 mCi/kg while gemcitabine will be escalated according to a Bayesian based system. Response evaluation is by standard criteria. Eligibility criteria include: any histology of recurrent NHL (not candidates for high dose therapy), platelets ≥ 150,000/ul; &lt; 25% bone marrow involvement by lymphoma; prior radiation to &lt;25% radiation of bone marrow and no prior bone marrow or stem cell transplant. Seven patients have been treated thus far, four with follicular NHL (FL) and three with diffuse large B cell (DLBCL). Median age is 74 (range 55–82). The median number of prior treatments is 3 (range 1–6). The first three patients received Z at 0.2 mCi/kg, next three patients 0.3 mCi/kg and the seventh patient has received standard 0.4 mCi/kg of Z, all with 250 mg/m2 of gemcitabine on days 1 and 8. Toxicity has consisted of: one grade 3 and two grade 2 neutropenia in the first three weeks, three grade 3 leukopenia and one grade 2 in the first 4 weeks of the trial, three grade 2 anemia (one patient has remained with grade 2 anemia for 14 weeks), four grade 2 thrombocytopenia in weeks 6 through 12, and one grade 3 thrombocytopenia in weeks 8&9 resolving to grade 2 (this patient received standard dose of Z). One grade 3 infection occurred, unrelated to the protocol or the study drugs. No grade 3 or 4 non-hematologic toxicity has been seen. In follow up, two patients with FL and one with DLBCL achieved CRu. Two patients with DLBCL and one with FL have progressed. One patient with FL is not yet evaluable. Conclusion: Our preliminary findings suggest that Zevalin can be safely combined with gemcitabine 250 mg/m2 in the treatment of patients with NHL. Accrual to the cohort with full dose Zevalin and gemcitabine is continuing.

Phase I Trial of Combination Therapy with 90y Ibritumomab Tiuxetan and Gemcitabine in Patients with Non-Hodgkin's Lymphoma, Final Report.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2753-2753
Author(s):  
Hossein Borghaei ◽  
Russell J. Schilder ◽  
Samuel Litwin ◽  
Michael Millenson ◽  
Adam D Cohen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase I ◽  
B Cell ◽  
Research Funding ◽  
Phase I Trial ◽  
Hodgkin's Lymphoma ◽  
Low Grade ◽  
Ibritumomab Tiuxetan ◽  
Non Hodgkin's Lymphoma ◽  
Grade 3

Abstract Abstract 2753 Y90-ibritumomab tiuxetan radioimmuotherapy (Y90-RIT) is an effective therapy against CD20+ lymphomas approved for use in patients (pts) with relapsed/refractory low grade, follicular, or transformed B-cell non-Hodgkin's lymphoma (NHL), as well as consolidation of first remission low grade NHL. Gemcitabine (Gem) also is active against NHL and is a potent radiation sensitizer. We conducted a phase I trial to assess the safety of concomitant administration of Y90-RIT and G in patients with NHL. Eligible pts had any histologic subtype of recurrent CD20+ NHL (not candidates for potentially curative options) and met standard Y90-RIT criteria: platelets 150,000/ul; < 25% bone marrow involvement by lymphoma; prior radiation to <25% of bone marrow and no prior bone marrow or stem cell transplant. Initially, nine pts in three cohorts were treated with 250 mg/m2 of Gem IV on days 1 and 8 of the Y90-RIT treatment program (rituximab + 111In-ibritumomab day 1 and rituximab + Y90 ibritumomab day 8), with Y90-RIT at 0.2, 0.3 or 0.4 mCi/kg respectively. We confirmed that a standard Y90-RIT dose of 0.4 mg/kg can be safely administered with Gem at 250 mg/m2. In subsequent cohorts, escalating doses of Gem were used according to a Bayesian based system. Response evaluation was by CT scan criteria (IWG JCO 1999). Between 2004–2012, twenty pts were treated (10 follicular (FL), 3 marginal zone (MZL), 7 diffuse large B-cell (DLBCL) lymphomas). Median age is 71.5 (range 55–82). The median number of prior treatments is 3 (range 1–6). Gem doses ranged from 250 mg/m2 to the maximum planned dose of 800 mg/m2 on days 1 and 8. One DLT occurred (thrombocytopenia) and MTD was not reached. Treatment-related toxicities consisted of grades 3 (N=11) and 4 (N = 2) neutropenia, grade 3 (N=11) leukopenia, grades 3 (N=14) and 4 (N=8) thrombocytopenia. One grade 3 infection occurred, unrelated to study drugs. All pts recovered counts to ≤ grade 1 by week 12. The only grade 3 non-hematologic toxicity was elevated bilirubin in 1 and increased GGT in 2 pts. Best responses seen include: 3 CR/CRu, 7 PR, 4 SD, 4 PD and 2 patients still in follow up. Median PFS for all patients is 192 days. Median PFS for all non-DLBCL histologies (10 FL and 3 MALT) is 202 days and for DLBCL is 77 days. Conclusion: Standard dose Y90-RIT combined with gemcitabine days 1 and 8 is safe and well-tolerated at doses up to 800 mg/m2 in pts with relapsed/refractory NHL. Further investigation with the established doses in non-DLBCL histologies is warranted. Disclosures: Borghaei: Biogen-IDEC: Research Funding. Off Label Use: 90Y Ibritumomab Tiuxetan in relapsed DLBCL. Schilder:Biogen-IDEC: Research Funding. Smith:Biogen-IDEC: Research Funding.

Efficacy of Nilotinib in Patients (Pts) with Newly Diagnosed, Previously Untreated Philadelphia Chromosome (Ph)-Positive Chronic Myelogenous Leukemia in Early Chronic Phase (CML-CP).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 341-341 ◽  
Author(s):  
Jorge Cortes ◽  
Susan O'Brien ◽  
Dan Jones ◽  
Elias Jabbour ◽  
Marina Konopleva ◽  
...  
Keyword(s):  
Adverse Events ◽  
Research Funding ◽  
Philadelphia Chromosome ◽  
Myelogenous Leukemia ◽  
Hematologic Toxicity ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Blast Phase ◽  
Line Therapy ◽  
Grade 3

Abstract Abstract 341 Background: Nilotinib, an oral tyrosine kinase inhibitor with increased selectivity against Bcr-Abl and approximately 30-fold more potent than imatinib, is effective in CML after imatinib failure. We initiated a phase II study to evaluate the efficacy of nilotinib as 1st line therapy in pts with newly diagnosed CML-CP. Aims: To investigate the efficacy and safety of nilotinib as first-line therapy for pts with CML-CP. Methods: The primary objective was to estimate the proportion of pts attaining major molecular response (MMR) at 12 months (mo). Pts with untreated CML-CP within 6 mo from diagnosis were eligible and received nilotinib 400 mg twice daily. A cohort of patients with previously untreated CML in accelerated phase (AP) was also included. Results: Sixty-five pts (61 CP, 4 AP) have been treated for a median of 17 mo (range 1 to 43). The median age was 46 years (range 19 to 86). Among 48 pts who were not in CHR at the start, 47 (98%) achieved CHR (one discontinued after 2 weeks without adverse events). Among 51 pts followed for at least 3 mo, 50 (98%) achieved a complete cytogenetic response (CCyR). MMR has been achieved in 32 (63%) pts, including 12 (24%) with a complete molecular response. The rate of CCyR at different time points (intention-to-treat) for pts in CP compares favorably to that observed in historical controls treated with imatinib 400 mg or 800 mg daily: MMR was achieved by 55% at 12 mo and 53% at 24 mo (corresponding rates with imatinib 400 mg 34 and 55%, and with imatinib 800 mg 58% and 66%, respectively). Grade 3-4 hematologic toxicity (transient) included thrombocytopenia 11%, neutropenia 12%, and anemia 5%. Grade 3-4 non-hematologic adverse events (regardless of causality) included elevation of bilirubin in 8% and lipase in 6%, and non-neutropenic fever in 6%. 24 (37%) pts had transient treatment interruptions and 11 (17%) had dose reductions. The actual median dose is 800 mg daily. Ten pts have discontinued therapy: 4 pts for toxicity, 2 because of transformation to accelerated or blast phase, and 4 for other reasons. 24 mo EFS (event = loss of CHR, loss of MCyR, AP/BP, death, or off because of toxicity) is 90%. All patients are alive. Among pts in AP, 3 achieved CCyR (all of them sustained); one patient progressed to blast phase and died. Conclusion: Nilotinib 400 mg twice daily induces a CCyR in nearly all patients as early as 3 mo after the start of therapy and MMR in more than 50% at 12 months with a favorable toxicity profile. Disclosures: Cortes: BMS: Research Funding; Novartis: Research Funding; Wyeth: Research Funding. Off Label Use: Presentation will include use of nilotinib as initial therapy for CML, and indication for which nilotinib is not approved.. O'Brien:Novartis: Research Funding. Jones:Novartis: Research Funding, Speakers Bureau. Jabbour:Novartis: Speakers Bureau; BMS: Speakers Bureau. Borthakur:Novartis: Speakers Bureau. Kantarjian:Novartis: Research Funding; MGI Pharma (Eisai): Research Funding; Genzyme: Research Funding; BMS: Research Funding.

A Phase I Trial of the Histone Deacetylase (HDAC) Inhibitor, Panobinostat, in Combination with Lenalidomide in Patients with Relapsed/Refractory Hodgkin's Lymphoma (HL)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1644-1644 ◽  
Author(s):  
Beth Christian ◽  
Anne Kopko ◽  
Todd A. Fehniger ◽  
Nancy L. Bartlett ◽  
Kristie A. Blum
Keyword(s):  
Phase I ◽  
Hdac Inhibitor ◽  
Research Funding ◽  
Phase I Trial ◽  
Single Agent ◽  
Hematologic Toxicity ◽  
Phase 2 ◽  
Qtc Prolongation ◽  
Duration Of Response ◽  
Grade 3

Abstract Abstract 1644 Introduction: Previous phase 2 single agent trials with the immunomodulatory agent, lenalidomide, in patients with relapsed or refractory HL demonstrated overall response rates (ORR) of 14–29%, with a median duration of response of 6 months. Likewise, a single agent trial utilizing the orally available HDAC inhibitor, panobinostat, in 127 patients with relapsed/refractory HL after prior autologous stem cell transplant (ASCT) demonstrated an ORR of 27% with a median duration of response of 6.9 months. Based on the encouraging single agent activity of these agents and in vitro synergy of combined panobinostat and lenalidomide in myeloma cell lines, we are conducting a phase I/II trial to determine the dose limiting toxicity (DLT), maximum tolerated dose (MTD), and overall response rate (ORR) with this combination and results of the phase I study are presented. Methods: Patients with relapsed or refractory classical HL (cHL) or lymphocyte predominant HL (LP HL) after at least one prior therapy are eligibile. Measurable disease ≥1 cm in at least one dimension, ejection fraction ≥45%, ECOG PS 0–2, QTc on ECG ≤ 450 msec, ANC ≥1200/mm3, platelets ≥100,000/mm3, AST/ALT ≤ 2.5 × the upper limit of normal (ULN), bilirubin ≤ 1.5 × ULN, and creatinine clearance ≥60 ml/min are required at study entry. Prior ASCT, lenalidomide, and panobinostat are permitted. In the phase I trial, escalating doses of panobinostat (15 or 20 mg) days 1, 3, and 5 weekly are combined with lenalidomide 25 mg days 1–21 utilizing a cohorts of 3 design. DLT is defined during cycle 1 and includes grade 4 neutropenia or thrombocytopenia, grade 4 infection, grade 3 infection for > 7 days, treatment delays > 14 days, and other grade 3–4 non-hematologic toxicity. Six patients will be enrolled at the MTD to ensure patient safety prior to phase 2 enrollment. Twenty-eight days defines a cycle and patients may remain on therapy until disease progression or unacceptable toxicity. Response is assessed after cycles 2, 6, and every 4 cycles thereafter by International Harmonization Criteria (Cheson, JCO 2007). Results: Seven patients (6 males) with cHL (n=6) and LP HL (n=1) and a median age of 31 (range 24–72) have been enrolled. Patients received a median of 3 prior therapies (range 3–5), 1 patient received prior radiotherapy, 3 patients were refractory to their most recent therapy, 3 patients had prior ASCT, 6 patients had received prior brentuximab vedotin, and no patients had prior lenalidomide or panobinostat. Other characteristics included stage III-IV disease in 100% (57% stage IV), bulky adenopathy ≥5 cm in 14%, and bone marrow involvement in 14%. Seven patients have completed one or more cycles of therapy (median 3, range 1–4) with either 15 mg (n=3) or 20 mg (n=4) of panobinostat + 25 mg lenalidomide. Four patients discontinued therapy for progressive disease (PD) after 4 cycles (n=3) and 1 cycle (n=1), respectively. Three patients continue to receive protocol treatment, all receiving panobinostat 20 mg days 1, 3, and 5 weekly. No DLTs have been observed. Grade 3–4 events included neutropenia (43%), lymphopenia (29%), thrombocytopenia (29%), and hypophosphatemia (29%). No QTc prolongation has been observed. Dose reductions from 15 mg panobinostat days 1, 3, and 5 weekly + lenalidomide 25 mg to 15 mg panobinostat days 1, 3, and 5 weeks 1 and 3 only + 20 mg lenalidomide were required in 2 patients for grade 3–4 neutropenia during cycles 3 and 4. ORR is 33% in 6 evaluable patients with a complete response in 1 patient with cHL and partial response in 1 patient with LP HL. One patient has not yet undergone restaging scans. Conclusions: Combined panobinostat and lenalidomide appears to be well tolerated in patients with relapsed/refractory HL without dose limiting myelosuppression, cardiac toxicity, QTc prolongation, or other grade 3–4 non-hematologic toxicity. Study accrual continues, 2 additional patients will be added to the highest dose level (panobinostat 20 mg days 1, 3, and 5 weekly for 4 weeks + lenalidomide 25 mg days 1–21) to complete the phase I trial and will be followed by anticipated enrollment of a maximum of 25 patients to a two-stage phase 2 trial targeting an ORR of 30% or higher. Disclosures: Blum: Celgene: Research Funding; Novartis: Research Funding. Off Label Use: Panobinostat and lenalidomide are not approved for the treatment of HL.

A Phase I Study of Vosaroxin Plus Azacitidine for Patients with Myelodysplastic Syndrome

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1686-1686
Author(s):  
Meagan A. Jacoby ◽  
Camille N. Abboud ◽  
John F Dipersio ◽  
Amanda F. Cashen ◽  
Matthew J. Walter ◽  
...  
Keyword(s):  
Complete Remission ◽  
Febrile Neutropenia ◽  
Phase I ◽  
Stable Disease ◽  
Research Funding ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Fixed Dose ◽  
Hematologic Toxicity ◽  
Grade 3

Abstract Background: Although hypomethylating agents are the mainstay of treatment for myelodysplastic syndromes (MDS), these agents produce remissions in a minority of patients and are not curative. Vosaroxin is a first-in-class quinolone derivative that intercalates DNA and inhibits topoisomerase II activity, which is active and tolerable in acute myeloid leukemia (AML). The novel combination of vosaroxin and azacitidine was found to be synergistic in primary myeloblasts. This phase I/cohort expansion trial was conducted to study the combination of vosaroxin and azacitidine for patients with MDS. Methods: Patients with MDS ≥ 18 years of age with cytopenias requiring transfusions, an IPSS score of intermediate-1 or greater, or CMML were eligible. The primary objective was to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of vosaroxin when given in combination with a fixed dose of azacitidine (75 mg/m2 /day). Vosaroxin was administered on days 1 and 4, and azacitidine on days 1-7 of a 28 day cycle, for up to 6 cycles in a 3+3 design. Results: Thirteen patients were enrolled in the dose escalation phase. No patients received prior hypomethylating therapy. The median age was 65 years (range 38-77) with IPSS scores of intermediate-1 (INT-1), (n=4); intermediate-2 (INT-2), (n=7); and high risk (HR), (n=2). At the initial dose of 50mg/m2 /day vosaroxin, 2 of 6 patients experienced a DLT (grade 4 hyperbilirubinemia, and grade 4 neutropenia >42 days). Additional incidences of ≥ grade 3 non-hematologic toxicity in this cohort included: febrile neutropenia (n=6), dysphagia (n=1), mucositis (n=3), infections (n=9), sepsis (n=3), and bleeding (n=3). The vosaroxin dose was de-escalated to 34 mg/m2 /day, resulting in 1 of 6 patients with a DLT (grade 4 mucositis). Incidences of ≥ grade 3 non-hematologic toxicity in this cohort included febrile neutropenia (n=4) and infection (n=4). No patients died within 30 days of treatment. Twelve patients completed at least one cycle and were evaluable for response, assessed by modified IWG criteria (Table). Best response for each patient was as follows: stable disease, n=3; stable disease with hematologic improvement (HI)-neutrophils, n=1; marrow complete remission (CR), n=3; marrow CR with HI-platelets; n=2; marrow CR with HI-neutrophils, n=1; marrow CR with HI-erythroid, n=1; and marrow CR with HI-platelets and neutrophils, n=1. Of these twelve patients, five (42%) have proceeded on to allogeneic stem cell transplantation. Conclusions: The MTD of vosaroxin in MDS patients was 34 mg/m2 /day when given on days 1 and 4 with a fixed dose of 75 mg/m2 of azacitidine on days 1-7. The major non-hematologic toxicities of febrile neutropenia, infections, and mucositis were expected based on the disease population and prior experiences with vosaroxin. The combination of vosaroxin and azacitidine showed promising activity with responses rates comparable or better than those generally observed with azacitidine alone. Additionally, the transplant rate observed was encouraging in this patient population with a median age of 65 years. A cohort expansion with plans to enroll an additional 20 patients at the MTD to further evaluate the tolerability and activity of the combination of vosaroxin and azacitidine in MDS patients is ongoing. In addition, correlative studies of the DNA damage response to the combination of vosaroxin and azacitidine from primary patient samples are in progress. Table 1.Best responsea, n (%)Evaluable patients (N=12)mCR/ mCR-HI8 (67)mCR3 (25)mCR-HI-erythroid1 (8)mCR-HI-neutrophils1 (8)mCR-HI-platelets2 (17)mCR-HI-neutrophil/platelets1 (8)Stable disease4 (33)mCR, marrow complete remission; HI, hematologic improvement.aResponse categories defined according to the modified IWG criteria (Cheson 2006). Disclosures Jacoby: Sunesis: Research Funding; Novo Nordisk: Consultancy. Off Label Use: Vosaroxin is currently under clinical development for the treatment of AML.. Abboud:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Pfizer: Research Funding; Merck: Research Funding; Teva Pharmaceuticals: Research Funding; Gerson Lehman Group: Consultancy. Uy:Novartis: Research Funding.

Phase I Study of Rituximab, Lenalidomide, and Ibrutinib in Previously Untreated Follicular Lymphoma (Alliance 051103)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 471-471 ◽  
Author(s):  
Chaitra S. Ujjani ◽  
Sin-Ho Jung ◽  
Brandelyn Pitcher ◽  
Peter Martin ◽  
Steven I. Park ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Adverse Events ◽  
Phase I ◽  
Follicular Lymphoma ◽  
Atrial Flutter ◽  
Median Time ◽  
Dose Level ◽  
Research Funding ◽  
Phase I Study ◽  
Grade 3

Abstract Background Chemoimmunotherapy for advanced stage follicular lymphoma (FL) is associated with acute and long-term toxicity; targeted therapy may improve efficacy and tolerability in this incurable, multiply-relapsing disease. The Alliance for Clinical Trials in Oncology previously demonstrated the efficacy of lenalidomide (20 mg D1-21/28) and rituximab (R2) in untreated FL patients (pts): ORR 93%, CR 72%, 2-yr PFS 89% (Martin P, et al. ASCO 2014), which supported the ongoing phase III RELEVANCE study of R2 vs. R-chemo. Attempts at improving R2 include incorporation of other agents. The BTK inhibitor, ibrutinib (I), demonstrated an ORR of 30-55% (Bartlett N et al. ASH 2014, Fowler N et al. ASH 2012) in relapsed/refractory FL. Based on these data, the Alliance designed a multicenter phase I study of this triplet as a front-line regimen for FL. Methods Pts with previously untreated, grade 1-3a FL, Stage III, IV, or bulky stage II disease, performance status < 2, and adequate organ function were eligible. Pts received R 375 mg/m2 on Cycle 1 D 1, 8, 15, 22 and at week 13, 21, 29, and 37 for 8 doses, lenalidomide (L) as per cohort dose on D1-21/28 for 18 months, and I as per cohort dose on D1-28/28 until progression or unacceptable toxicity. Dose escalation used a 3+3 design from a starting level of L 15 mg and I 420 mg (DL0) to DL2 (L 20 mg, I 560 mg). Pts received allopurinol 300 mg daily for tumor lysis prophylaxis. The primary endpoint was the recommended phase II doses (RP2D) of L and I for combination with R in previously untreated FL. The secondary endpoints were toxicity, pharmacokinetics, and preliminary efficacy. Once the MTD was determined, there was a 10-patient expansion cohort. Due to the known incidence of rash with L, grade 3 rash that resolved to < grade 2 in 10 days with supportive care including systemic corticosteroids was prospectively not included as a DLT. The incidence of grade 3/4 rash with R2 and ibrutinib are 8% and 3%, respectively. Results Twenty-two pts were enrolled between June 2013 - May 2015: DL0 (n=3), DL1 (n=3), DL2 (n=16). Median age was 53.5 years (range 36-81); 68% were male, 73% had grade 1/2 disease, 77% had Stage IV disease. By FLIPI, 18% were low risk, 55% were intermediate risk, and 27% were high risk. There were no dose limiting toxicities reported at any dose level. Dose level 2 (L 20 mg, I 560 mg) was found to be the RP2D. Grade 3/4 hematologic toxicities included neutropenia 18.2%, thrombocytopenia 4.5%, and anemia 4.5%. There were no grade 4 non-hematologic toxicities. Rash occurred in 73% of pts (grade 1/2: 41%, grade 3: 32%), typically during C1-4. Grade 3 rash was noted at every dose level: DL 0 (n=1), DL1 (n=1), DL2 (n=6); 4 pts were on allopurinol at time of grade 3 rash. Several pts successfully continued therapy with discontinuation of allopurinol and/or reduction in treatment dose. Other notable grade 3 non-hematologic adverse events included atrial flutter/chest pain (n=1), diarrhea (n=1), and febrile neutropenia (n=1). Other grade 1/2 non-hematologic adverse events included diarrhea 41%, fatigue 36%, nausea 27%, and AST/ALT elevation 18%. Elevenpts required dose reduction, 8 due to rash. The ORR for all pts was 91% (CR/CRu 63%). Seven pts with bone marrow involvement did not undergo a confirmatory bone marrow biopsy to rule out residual disease after achieving a negative PET/CT. The ORR at DL2 was 94% (CR/CRu 63%). Median time to response was 5.6 months (range 1.9-18.4), and median time on treatment was 12.6 months (range 3.4-23.4). At the time of this report, 3 pts have progressed (DL1 (n=1), DL 2 (n=2)). At median follow-up time of 12 months, the 12-month PFS for all pts was 84% (95% CI: 57-94%). The 12-month PFS for the DL2 cohort was 86% (95% CI: 54% - 96%). Twelve pts discontinued therapy: progression (n=2), adverse events [grade 3 rash (n=2), grade 3 atrial flutter (n=1), grade 3 diarrhea (n=1)], patient decision (n=3), new diagnosis of carcinoma (n=2), depression (n=1). Conclusion Although protocol-defined DLT was not observed, the combination of rituximab, lenalidomide, and ibrutinib in previously untreated follicular lymphoma was associated with a significant incidence of rash, which may have been related to allopurinol, the individual study drugs, or drug interactions. Preliminary ORR data of the regimen were comparable to prior reports of the R2 regimen in this population. Efficacy of the combination, including CR rate, may be affected by the reduction in dose intensity. Disclosures Ujjani: Genentech: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Lenalidomide and ibrutinib have activity in follicular lymphoma but are not approved.. Martin:Janssen: Consultancy, Honoraria; Acerta: Consultancy; Gilead: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Bayer: Consultancy. Park:Teva: Research Funding; Seattle Genetics: Research Funding; Janssen: Other: travel. Blum:cephalon: Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding. Smith:Celgene: Consultancy; Pharmacyclics: Consultancy. Czuczman:Celgene: Employment; Morphosys: Consultancy; Boehringer-Ingelheim: Other: ad board; Immunogen: Other: ad board. Davids:Genentech: Other: ad board; Pharmacyclics: Consultancy; Janssen: Consultancy. Leonard:Weill Cornell Medical College: Employment; Genentech: Consultancy; Medimmune: Consultancy; AstraZeneca: Consultancy; Spectrum: Consultancy; Boehringer Ingelheim: Consultancy; Vertex: Consultancy; ProNAI: Consultancy; Biotest: Consultancy; Seattle Genetics: Consultancy; Pfizer: Consultancy; Mirati Therapeutics: Consultancy; Gilead: Consultancy; Novartis: Consultancy. Cheson:Roche/Genentech: Consultancy, Research Funding; Teva: Research Funding; AstraZeneca: Consultancy; Ascenta: Research Funding; Spectrum: Consultancy; Gilead: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Astellas: Consultancy; MedImmune: Research Funding; Pharmacyclics: Consultancy, Research Funding.

Romiplostim in Patients Undergoing Allogeneic Stem Cell Transplantation: Results of a Phase I/II Multicenter Trial

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 65-65 ◽  
Author(s):  
Régis Peffault de Latour ◽  
Sylvie Chevret ◽  
Annalisa Ruggeri ◽  
Felipe Suarez ◽  
Laetitia Souchet ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Septic Shock ◽  
Stem Cell ◽  
Adverse Events ◽  
Stem Cell Transplantation ◽  
Phase I ◽  
Median Time ◽  
Research Funding ◽  
Allogeneic Hsct ◽  
Grade 3

Abstract Background: Delayed platelet (plt) recovery and secondary thrombocytopenia occur in 5-25% of patients (pts) after hematopoietic stem cell transplantation (HSCT) and is of adverse prognostic significance. Plt transfusion to prevent bleeding remains a mainstay of therapy and role of thrombopoietic agents is not known. In this phase I/II multicenter open trial, we investigated the safety and efficacy of romiplostim (Nplate; Amgen, thousand Oaks, CA) for (pts) with transfusion-dependent thrombocytopenia after allogeneic HSCT (NCT01980030). Patients and methods: Adult pts undergoing standard of care allogeneic HSCT for any disease except myelodysplastic syndrome were eligible for this study 45 days or more after transplantation if they had plt count ² 20 x 109/L sustained for 7 days (² 50 x 109/L with a history of bleeding) or if they were plt transfusion dependent. Pts were excluded if they had abnormal liver function tests, serum creatinine ³ 176.8 μmol/L or had prior venous thrombosis. Pts were given weekly romiplostim for 12 weeks with intra-pt weekly dose escalation from 1µg/Kg to a maximum dose of 10 µg/Kg (with a dose reduction schema in case of plt overshoot). The study was composed of a 12-week treatment period. The primarysafety endpoint was the incidence of any grade 3 or 4 adverse events after HSCT, excluding those expected from the HSCT, as well as clinically significant bleeding events. The primary efficacy endpoint was time to reach a plt count above 50 x 109/L free of plt transfusion. Secondary endpoints were the durable plt response defined as a plt count above 50 x 109/L during 8 consecutive weeks independent of plts transfusions, the 1-year cumulative incidence (CumI) after HSCT of Graft versus host disease (GvHD), relapse and non-relapse mortality rates. All pts had a bone marrow biopsy before treatment and at one year. This study was approved by the research review board of the Hospital Saint-Louis (Paris, France). Statistical analysis was based on a modified intent-to-treat basis, excluding pts who did not fulfill the inclusion criteria. CumI were estimated using nonparametric methods, where deaths prior to the event of interest defined competing risks. Results: 25 pts were included in 4 different HSCT French units between April 2013 and November 2015. The analysis was restricted to 24 pts (one pt with plt count > 20x109/L after inclusion). All but one pt have malignant disease (13/24 acute leukemia). Donor type was related for 12 pts. Stem cell source was peripheral blood in 15 pts and bone marrow in 9 pts, myeloablative conditioning regimen was used in 17 pts. Median time between HSCT and romiplostim initiation was 85 days (interquartile range, IQR 63 - 117). Nineteen pts completed the 12 investigational injections of romiplostim, while five did not due to 3 deaths (1 post transplantation EBV-related lymphoproliferative disorder, 1 relapse and 1 septic shock), 1 boost of donor stem cells and one pt with plt count above 50 Giga/L after 8 injections. A total of 21 adverse events (grade 3, n=10; grade 4 n=11) considered possibly related to romiplostim were reported in 6 pts. Hematological complications appeared in 4 pts (2 neutropenia, 1 anemia and 1 pancytopenia) and liver dysfunction was present in 2 pts (mild cytolysis). Overall, romiplostim was well tolerated with a 6 months adverse events CI of 25.2% (95%IC 7.3 - 43.2). No bleeding event as well as no thrombotic complications appeared. None of the pts developed fibrosis 1 year post treatment (2 pts not yet at 1 year). After romiplostim initiation, 20 pts received a plt transfusion. The median time to reach a plt count above 50 x 109/L free of plt transfusion was 36 days (Figure 1), with required doses of 4 mg/Kg (IQR, 3-6). Fifteen pts obtained a durable plt response. A total of 17 and 12 pts experienced aGVHD and cGVHD, respectively, with 100 days CumI of aGVHD of 67% (95%CI, 47-87) and 1-year CumI of cGvHD of 55% (95%CI, 32-78), respectively. Six pts died during the study (1 PTLD, 1 relapse, 1 septic shock, 1 lung aspergillosis and 2 acute distress respiratory syndrome of unknown origin). CumI of non-relapse mortality was thus of 21% (95%CI, 7-42%). Conclusion: Romiplostim can be safely administered and improves plt count in pts with thrombocytopenia after allogeneic HSCT. The required dose to reach plt count above 50 x 109/L is 4 mg/Kg with a median time of 36 days. Research support was provided in part by Amgen. Disclosures Peffault de Latour: Alexion: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Research Funding.

Phase I trial of combination therapy with 90Y ibritumomab tiuxetan and gemcitabine in patients with non-Hodgkin’s lymphoma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 17514-17514
Author(s):  
H. Borghaei ◽  
M. Smith ◽  
M. Millenson ◽  
K. Krieger ◽  
A. Rogatko ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase I ◽  
B Cell ◽  
Hodgkin’S Lymphoma ◽  
Phase I Trial ◽  
Hodgkin's Lymphoma ◽  
Hematologic Toxicity ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma ◽  
Grade 3

17514 Background: Zevalin (Z) is an effective therapy in patients with relapsed or refractory low grade, follicular, or transformed B-cell non-Hodgkin’s lymphoma (NHL). Gemcitabine (gem) also is active against NHL and is a potent radiation sensitizer. We are conducting a phase I trial to assess the safety of concomitant administration of Z and gem in patients with NHL. Methods: The starting gem dose is 250 mg/m2 on days 1 and 8. Nine patients in three cohorts will be treated with 250 mg/m2 of gem with 0.2, 0.3 or 0.4 mCi/kg of Z. The next cohort can accrue after all patients in the prior cohort have hematologic toxicity has recovered to grade 2 or after 60 days from the date of the last treated patient in the previous cohort. Once it is confirmed that a Z dose of 0.4 mg/kg can be safely administered with gem 250 mg/m2, gem will be escalated according to a Bayesian based system. Response evaluation is based on the International Workshop on Standardized Response Criteria for Non-Hodgkin’s lymphomas. Eligibility criteria include: any histology of recurrent NHL (not candidates for high dose therapy), platelets ≥ 150,000/ul; < 25% bone marrow involvement by lymphoma; prior radiation to < 25% radiation of bone marrow and no prior bone marrow or stem cell transplant. Results: Five patients have been treated thus far, two with follicular NHL (FL) and three with diffuse large B cell (DLBCL). Median age is 75 (range 55–82). The median number of prior treatments is 2 (range 1–6). One patient with DLBCL is not evaluable. The first three patients received 0.2 mCi/kg and next two patients 0.3 mCi/kg of Zevalin. Toxicity consists of grades 2 & 3 myelosuppression in the first 3 weeks in 3 pts. due to gem and then of grade 2 in 1 pt. at 6 to 8 weeks as is usually seen with Z. One grade 3 leukopenia and one grade 2 thrombocytopenia have been observed resolving within one week. One grade 3 infection occurred, unrelated to the protocol or the study drugs. No grade 3 or 4 non-hematologic toxicity has been seen. In follow up, two patients with FL and one with DLBCL achieved CRu. One patient with DLBCL has progressed and one is not yet evaluable. Conclusions: Our preliminary findings suggest that Z can be safely combined with gem 250 mg/m2 in the treatment of patients with NHL. Dose escalation to full dose Zevalin and then of gemcitabine is continuing. [Table: see text]

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