Efficacy and Safety of YM155 in Relapsed/Refractory Non-Hodgkin’s Lymphoma Patients Enrolled in a Phase I Study.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3422-3422 ◽  
Author(s):  
Kyriakos Papadopoulos ◽  
Alain Mita ◽  
Scott Antonio ◽  
Lionel D. Lewis ◽  
N.J. Reddy ◽  
...  
Keyword(s):  
Stem Cell ◽  
Adverse Events ◽  
Phase I ◽  
Tumor Cells ◽  
Phase I Study ◽  
Stem Cell Transplant ◽  
Cell Lymphoma ◽  
Large Cell ◽  
Cell Transplant ◽  
To Receive

Abstract Background: YM155 is a member of a novel class of compounds called survivin suppressants that target survivin. Survivin is a member of the inhibitor of apoptosis proteins (IAPs) family which is responsible for preservation of cell viability and regulation of mitosis in tumor cells. Survivin over-expression has been reported in a variety of tumor cells including lymphoma. A Phase I dose escalation study of YM155 was conducted to evaluate safety, tolerability and antitumor activity in patients with solid tumors or non-Hodgkin’s lymphoma (NHL). Methods: Patients with solid tumors or NHL with no other treatments options were eligible for this Phase I study and received YM155 in escalating doses ranging from 1.8 – 6 mg/m2/day as a 168 hour (7 day) continuous infusion in a 21 day cycle. Patients could continue to receive YM155 until either disease progression or toxicity. 41 patients were enrolled into the study including 5 patients with NHL (2 diffuse large B-cell lymphoma [DLBCL], 1 each small lymphocytic B-cell, follicular [FL] and anaplastic large cell lymphoma). This report focuses solely on the patients with NHL. All 5 NHL patients had at least 2 prior treatment regimens (range: 2 – 7) including stem cell transplant in two patients (DLBCL, FL) and one patient who received 2 investigational therapies. Three patients were considered refractory to the treatment regimen given just prior to study entry (DLBCL, anaplastic large cell, FL). Results: All 5 NHL patients were male with a mean age of 56 (range: 46 – 64). They were all dosed at the maximum tolerated dose (MTD) of 4.8 mg/m2/day. The most common adverse events reported, regardless of relationship to YM155, were URI (3/5) and arthralgia, fever, hypomagnesemia, mucositis peripheral edema and rash (2/5). The majority of adverse events were Grade 1 or 2 with 3 events reported as Grade 4: Klebsiella bacteremia, neutropenia and hypokalemia. Three patients (60%) (2 DLBCL and FL) had partial response (PR) to YM155 as assessed by independent review using both RECIST and 1999 Cheson criteria. One responder (DLBCL) had a PR after 2 cycles, completed a total of 5 cycles and proceeded to stem cell transplant. This patient has no evidence of disease at 3 years. A second responder (DLBCL) had a PR after 12 cycles and received a total of 26 cycles (∼ 1.5yrs) before disease progression. The third responder (FL) had a PR after 14 cycles, has maintained a prolonged PR for ∼ 2 years and continues to receive YM155 in a long-term extension study. Conclusion: Based upon the objective responses, the tolerability and safety profile observed in this Phase I study in 5 NHL patients, a Phase II study in refractory DLBCL has been initiated.

Allogeneic NK Cell Therapy After Autologous Stem Cell Transplant: Results of a Phase I Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4299-4299
Author(s):  
Hans-Georg Klingemann ◽  
Carrie Grodman ◽  
Andreas K. Klein ◽  
Kellie Sprague ◽  
Kenneth B. Miller ◽  
...  
Keyword(s):  
Stem Cell ◽  
Phase I ◽  
Phase I Study ◽  
Stem Cell Transplant ◽  
Nk Cell ◽  
Autologous Stem Cell Transplant ◽  
Cell Transplant ◽  
University Of Minnesota ◽  
Processing Facility ◽  
Autologous Hsct

Abstract Abstract 4299 Previous reports have shown that infusion of NK cells from a MHC mismatched donor can mediate an anti-leukemic effect in the recipient of an allogeneic hematopoietic stem cell transplant (HSCT). In this phase I study, we infused increasing numbers of allogeneic NK-cell enriched mononuclear cells (NK-MNC) from a MHC haplo-mismatched relative into patients who had recently undergone autologous stem cell transplant. We sought to determine whether infusion of mismatched, allogeneic NK-MNC cells was safe without concern for GvHD or graft rejection, and also whether cell collection, processing and patient treatment could feasibly be performed at different cities across the US. MNC were obtained by apheresis from healthy haploidentical relatives by one steady-state leukapheresis of 2–4 hours on day 1, and were sent by air courier to the PACT* cell processing facility (University of Minnesota) where immunomagnetic depletion of CD3 cells (Miltenyi CliniMACS) was performed. The CD3-depleted cells were then cultured in X-VIVO 15, without gentamicin and phenol red (Cambrex BioScience, Walkersville, Maryland), supplemented with 1000 U/mL IL-2 (Chiron Corporation, Emeryville, CA) and 10% human heat-inactivated AB serum (Valley Biomedical Products and Services, Inc., Winchester, VA) in VueLife™Teflon® (FEP) bags (American Fluoroseal Corporation, Gaithersburg, MD). The resulting NK-MNC products were then returned by air courier at approximately body temperature to Boston for infusion on day 3. Twelve patients (age range: 27–63) within 49–191 days (median 106 days) after autologous HSCT were treated at four different dose levels of NK-MNC: 105, 106, 107 and 2×107 NK-MNC/kg. No logistical transport issues between Boston and the processing facility in Minnesota occurred. Release criteria (< 5 × 105 CD3+ cells/kg, > 20% CD3-/CD56+ cells, viability >70%, Gram stain – no organisms) were met in all but one case. Side effects after infusion occurred only at the higher dose level of NK-MNC infusion: rigors (n=2) and muscle aches (n=1), responsive to meperidine. None of the patients required discontinuation of NK-MNC infusion. No GvHD or marrow suppression occurred. Chimerism analysis (STR-PCR) from leukocytes on peripheral blood samples collected 24 hours after the NK-MSC infusion failed to detect donor-derived NK-MNC in the recipients (sensitivity: 3 %). Given these results, we conclude that long-distance transport of manipulated NK-MNC products between treatment and processing centers is feasible and reliable, clearly supporting the premise of PACT, and that CD3-depleted allogeneic NK-MNC from a MHC-mismatched relative can be safely administered to recipients of a recent autologous HSCT. This project has been funded in part by the National Heart, Lung, and Blood Institute, National Institutes of Health, under the University of Minnesota Contract [] N01-HB-37164 and HHSN268201000008C *PACT: Production Assistance for Cellular Therapies Disclosures: No relevant conflicts of interest to declare.

Phase I Study of Decitabine and Rapamycin in Relapsed/Refractory Acute Myelogenous Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3549-3549
Author(s):  
Jane L. Liesveld ◽  
Kristen O'Dwyer ◽  
Michael W. Becker ◽  
Deborah Mulford ◽  
Alison Walker ◽  
...  
Keyword(s):  
Stem Cell ◽  
Phase I ◽  
Phase I Study ◽  
Stem Cell Transplant ◽  
Single Agent ◽  
Myelogenous Leukemia ◽  
Akt Pathway ◽  
Cell Transplant ◽  
Allogeneic Stem Cell Transplant ◽  
Acute Myelogenous

Abstract Abstract 3549 Introduction: Decitabine (5-aza-2'-deoxyctiidine) has demonstrated single agent activity in newly diagnosed acute myelogenous leukemia (AML). Complete response rates are low, however, and this agent has not been extensively studied in settings of relapsed or refractory disease where treatment responses are generally short in the absence of allogeneic stem cell transplantation. Most AML cases have activation of the mTOR pathway as evidenced by expression of phosphorylated p70S6 kinase or phopho-4EBP1. Since inhibitors of the mTOR pathway such as the tuberous sclerosis genes (TSC1 and TSC2) are hypermethylated in some cases of AML and there is evidence that decitabine may inhibit the PI3K/Akt pathway often activated after mTOR inhibition, we conducted a phase I study utilizing decitabine (DAC) followed by the mTOR inhibitor rapamycin in patients with relapsed/refractory AML to assess safety and feasibility. Methods: Patients ≥ 18 years of age with non-M3 AML with relapsed or refractory disease were eligible for this protocol. Patients who had relapsed after allogeneic stem cell transplant were eligible if they did not have active graft vs. host disease >grade 1 of skin. Patients received DAC 20 mg/m2 intravenously daily for 5 days followed by rapamycin from day 6 to 25 at doses of 2mg, 4mg, and 6 mg/day in a 3+3 dose escalation design. Cycles were 28 days in duration, and in the absence of overt progression of disease, patients could receive up to 6 cycles of therapy. A marrow aspirate was performed at day 5 to assess effects of single agent decitabine on mTOR and Akt pathway mediators. Bone marrow responses were assessed after cycles 1 and 3. Results: Thirteen patients were treated, and 12 are available for safety evaluation. The median age of patients is 64 years (range 46–78). Median marrow blast percentage at enrollment was 35% (range 6–83%). In the 2 mg dose cohort, 1 patient had disease progression before completion of cycle 1 and another patient in the first cohort had a history of prolonged neutropenia at the time of enrollment and experienced reversible grade 3 mucositis, which was deemed a DLT. Three more patients enrolled at this dose, and no further DLTs were observed, allowing dose escalation to the 4 mg and 6 mg cohorts. The MTD has not yet been reached. Reversible grade 2–3 mucositis occurred in 7 patients, but no other recurrent non-hematologic toxicities were seen. On the 2 mg cohort, all patients achieved therapeutic rapamycin levels (5–15 ng/ml) during the first cycle, and in 5/7 patients, the therapeutic level was achieved within 4 days of beginning rapamycin. In the 2 mg cohort, no cumulative increase in rapamycin levels occurred over subsequent cycles (4/7 completed >1 cycle). In the 4 mg cohort, one patient had an elevated level at day 9, and one patient on concomitant voriconazole had supra-therapeutic levels at day 16 and day 23. At the end of one cycle, 4 patients demonstrated disease progression, 5 had stable marrow blasts, and 4 demonstrated a decline in marrow blast percentage. Median survival to date is 6 months (range 1 to 15+ months). Two patients proceeded to allogeneic stem cell transplant, and one patient who relapsed shortly after stem cell transplant survived 4 months and demonstrated stable donor chimerism during that time. As assessed by Western blotting in 9 patients with evaluable samples at baseline, 87% of these cases expressed phospho (p)-4EBP1 at diagnosis, 56% p70S6K, 67% peIF4E, and 44% pAKT. In the 7 patients with Western blot samples evaluable at the end of cycle 1, 3 had decreases in p4EBP1 after the first cycle, and 4 had increased expression. Of the 7 evaluable patients, only 3 expressed baseline p70S6K, and this decreased in 2 and was unchanged in 1 patient. Conclusion: The combination of decitabine and rapamycin can be safely administered to patients with relapsed/refractory AML. Based on this phase I data, a phase II cohort to define efficacy can be conducted at the 2 mg rapamycin dosing given the therapeutic rapamycin levels demonstrated at this dose. Effects on mTOR mediators and on AKT can be serially assessed and are variable. Correlation with clinical response will require a phase II study. This trial is registered at clinical trials.gov as NCT00861874. Disclosures: Liesveld: Eisai: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Ariad: Honoraria. Off Label Use: This is a phase 1 study to see if rapamycin is safe in AML.

scholarly journals Phase I Study of Topotecan, Ifosfamide, and Etoposide (TIME) with Autologous Stem Cell Transplant in Refractory Cancer: Pharmacokinetic and Pharmacodynamic Correlates

2011 ◽  
Vol 17 (24) ◽  
pp. 7743-7753 ◽  
Author(s):  
Janelle B. Perkins ◽  
Steven C. Goldstein ◽  
Jana L. Dawson ◽  
Jongphil Kim ◽  
Teresa L. Field ◽  
...  
Keyword(s):  
Stem Cell ◽  
Phase I ◽  
Phase I Study ◽  
Stem Cell Transplant ◽  
Autologous Stem Cell Transplant ◽  
Cell Transplant

High Response Rate to Lenalidomide in Relapsed/Refractory Aggressive Non-Hodgkin’s Lymphoma with Prior Stem Cell Transplant.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2570-2570 ◽  
Author(s):  
Julie M. Vose ◽  
Joseph M. Tuscano ◽  
Glen Justice ◽  
Izidore S. Lossos ◽  
Annette Ervin-Haynes ◽  
...  
Keyword(s):  
Stem Cell ◽  
Adverse Events ◽  
Dose Reduction ◽  
Median Time ◽  
Stem Cell Transplant ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Tumor Burden ◽  
Cell Transplant ◽  
Grade 3

Abstract Background: High dose chemotherapy with stem cell transplant is currently employed in relapsed/refractory aggressive Non-Hodgkin’s Lymphoma (NHL). Lenalidomide (Revlimid®), an immunomodulatory drug, has shown activity in hematological malignancies including relapsed/refractory multiple myeloma, chronic lymphocytic leukemia and cutaneous T-cell lymphoma. Aim: To determine the activity and safety of lenalidomide monotherapy in relapsed/refractory aggressive NHL following stem cell transplant (SCT). Methods: Patients with relapsed/refractory aggressive NHL with measurable disease ≥ 2 cm after at least 1 prior treatment regimen were eligible. Patients received 25 mg lenalidomide orally once daily on Days 1–21 every 28 days and continued therapy for 52 weeks as tolerated or until disease progression. Response and progression were evaluated using the IWLRC methodology. Results: Fourteen (29%) of the 49 patients enrolled into the study had a prior SCT. Median age was 61 (23–76) and 5 were female. Histology was diffuse large B-cell lymphoma [DLBCL] (n=5), follicular center lymphoma grade 3 [FL] (n=2), mantle cell lymphoma [MCL] (n=5) and transformed [TSF] (n=2). Median time from diagnosis to lenalidomide was 3.9 (1.1–31.4) years and median time from SCT to study entry was 1.9 (0.5–11.7) years. The median number of prior treatment regimens was 5 (2–8). Seven patients (50%) exhibited an objective response (1 complete response unconfirmed (CRu), and 6 partial responses (PR)), 5 had stable disease (SD) and 2 patients had progressive disease (PD). Six responses were in eight patients having a tumor burden &lt; 50 cm2 and a time since last rituximab therapy of ≥ 230 days. One response was achieved in six patients having a tumor burden ≥ 50 cm2 or a time since last rituximab therapy of &lt; 230 days. Four of 6 (67%) patients who had SCT as their last treatment prior to lenalidomide [median time from SCT to lenalidomide = 0.8 (0.5–4.8) years] responded. Progression free survival [PFS] is 4.5 months and ongoing. Six patients (43%) required at least one dose reduction with a median time to first dose reduction of 1.6 months (0.4–4.9). Two patients each (14%) had Grade 4 adverse events of neutropenia and thrombocytopenia. The most common Grade 3 adverse events were neutropenia (36%), thrombocytopenia (21%), and leukopenia (14%). Conclusion: Lenalidomide produced a 50% response rate with manageable side effects in relapsed/refractory aggressive NHL following stem cell transplant.

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