Vorinostat (V) In Combination With Bortezomib (B), Doxorubicin (D) and Dexamethasone (D) (VBDD) In Patients With Refractory Or Relapsed Multiple Myeloma: An Interim Phase I/II Analysis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3202-3202
Author(s):  
Martina Kleber ◽  
Dagmar Wider ◽  
Kristina Keller ◽  
Barbara Groß ◽  
Heike Reinhardt ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Level ◽  
Research Funding ◽  
Off Label Use ◽  
Hdac Activity ◽  
Deacetylase Inhibitor ◽  
Level 1 ◽  
Level 2 ◽  
Label Use

Abstract Introduction The combination of bortezomib, doxorubicin and dexamethasone (BDD) is well tolerated and induces a high overall response rate (ORR). Preclinical studies have demonstrated that vorinostat, a histone deacetylase inhibitor, is synergistic with bortezomib and doxorubicin. The aim of this phase I/II study was to determine the tolerability and activity of the combination of BDD with vorinostat (VBDD) in relapsed/refractory multiple myeloma (MM). Methods Patients received escalated vorinostat-doses (provided by MSD) at 100mg (dose level 0), 200mg (dose level +1) and 300mg (dose level+2) on days 1-4, 8-11, 15-18, combined with bortezomib 1.3mg/m2 day 1,8,15 (provided by Janssen), dexamethasone 40mg day 1,8,15,22 and doxorubicin on 9mg/m2 day 1+8. The primary objective was the maximum tolerated dose (MTD; 3+3 dose escalation design). Secondary objectives were safety, response assessed by EBMT and IMWG criteria, progression-free survival and overall survival. Correlative endpoints include prognostic MM-parameters, organ function, QoL-, comorbidity-assessments and translational studies (e.g. HDAC-activity in PB MNCs, Figure 1). Dose limiting toxicities (DLTs) were defined as any possibly drug related adverse events (AEs) ≥grade 3 (CTCAE) within the 1st cycle. After completion of 6 cycles, patients could continue with bortezomib maintenance therapy or proceed to (most often 2nd) ASCT. Results To date, 18/30 patients have been enrolled (median age 63 years [range 54-75], 55% men). The median Karnofsky Performance Status was 90% (range 70-100%). Median prior therapy lines were substantial with 3 (range 1-8): bortezomib, thalidomide or lenalidomide were given in 88% and 24% each, respectively; 94% of patients had undergone prior SCTs. Cytogenetic abnormalities included del(17p) (n=2), t(4;14) (n=2), gain(1q) (n=2), t(11;14) (n=4) and hyperdiploidy (n=7). No DLTs have been observed to date; with 3 patients each being included in dose level 0 and dose level +1 and the following patients safely proceeding to dose level +2. Six SAEs occurred in 4/18 patients (22%): bacteraemia (n=1) and herpes zoster reactivation (n=1) were suspected to be related to all VBDD-drugs. No causal relationship to study drugs was suspected for pneumonia (n=2), 1 syncope and 1 death due to PD with persisting plasma cell leukemia. The ORR (>PR) and clinical benefit rate (SD, PR, CR) was 65% and 89%, respectively. At a median follow-up of 8 months (range 3-23), there have been only 2 patients with PD (refractory MM + plasma cell leukemia). The analysis of HDAC activity after VBDD initiation demonstrated downregulation in 6/8 (75%) patients (Figure 1). Further analyses will determine, whether HDAC activity and treatment response may correlate and whether this HDAC downregulation may precede and/or indicate depth of response Conclusions VBDD is a well tolerated and effective regimen in heavily pretreated relapsed/refractory MM patients. There have been no observed DLT and the MTD of vorinostat was set at 300mg, with all reported SAEs being in line with the known safety profile of the investigated drugs. Our alternative vorinostat-schedule (dosing of 4 days on and 4 days off) induced excellent tolerability and seems to enhance the antimyeloma response, warranting completion of this study. Disclosures: Kleber: MSD, Janssen-Cilag: Research Funding. Off Label Use: Preclinical studies have demonstrated that vorinostat, a histone deacetylase inhibitor, is synergistic with bortezomib and doxorubicin. The aim of this phase I/II study was to determine the tolerability and activity of the combination of BDD with vorinostat (VBDD) in relapsed/refractory multiple myeloma. Vorinostat is off-label use for MM patients, all other drugs are in label use. Waesch:MSD, Janssen-Cilag: Research Funding. Engelhardt:MSD, Janssen-Cilag: Research Funding.

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.

scholarly journals A Multicenter, Open Label Phase I/II Study of Carfilzomib, Pomalidomide and Dexamethasone in Relapsed and/or Refractory Multiple Myeloma (MM) Patients

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1145-1145 ◽  
Author(s):  
Sara Bringhen ◽  
Valeria Magarotto ◽  
Anna Marina Liberati ◽  
Angelo Belotti ◽  
Alessandra Larocca ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Level ◽  
Research Funding ◽  
Low Dose ◽  
Response Rate ◽  
Primary Objective ◽  
Advisory Board ◽  
Level 1

Abstract Background: Survival rates of multiple myeloma (MM) patients (pts) has improved over the past few years, but patients inevitably relapse and become more resistant to subsequent treatments. Carfilzomib and Pomalidomide were both approved for the treatment of relapsed/refractory MM (RRMM). Combinations including a proteasome inhibitor (PI) plus an immunomodulator (IMiD), such as Bortezomib-Lenalidomide-Dexamethasone (VRD) or Carfilzomib-Lenalidomide-Dexamethasone (CRD), showed a very high response rate with an acceptable toxicity. Moreover, in the CHAMPION1 study (Berenson et al Blood 2016), the weekly infusion of Carfilzomib showed to be as effective as the twice schedule. In this phase I/II study we assessed for the first time weekly Carfilzomib plus Pomalidomide and low dose Dexamethasone (wKPd) for the treatment of RRMM. Here we report preliminary results. Methods: the primary objective of the phase I part of the trial was to determine the maximum tolerated dose (MTD) of wKPd combination. The primary objective of the phase II was to determine the rate of partial response (PR). Patients with RRMM, who received 1-3 prior lines of treatments and were refractory to Lenalidomide were eligible. Treatment consisted of 28-day cycles of oral Pomalidomide at fixed dose of 4 mg on days 1-21 (1 week off), oral or intravenous (iv) Dexamethasone 40 mg on days 1,8,15,22 and iv Carfilzomib at escalating doses on days 1,8,15. Escalation started at the dose of 36 mg/m2 (0 level) and used a standard 3+3 schema based on dose-limiting toxicities (DLTs) occurring in cycle 1. Treatment was continued until relapse or intolerance. Results: A total of 57 patients were enrolled in 6 Italian centers. Fifty-two patients could be evaluated for this analysis (5 patients did not complete the first cycle yet). The median age was 62 years with a median time from diagnosis of 4 years. 17/39 (44%) of patients were considered high risk according to cytogenetic abnormalities [at least one among t (4;14) t (14;16) and deletion chromosome 17 (del17) detected by FISH]. In the phase I of the trial 15 patients were enrolled. The first 3 patients at the dose level 0 of Carfilzomib did not experience any DLT. In the next cohort with Carfilzomib 20/45 mg/m2 a G3 hypertension and a sudden death occurred. According to the protocol, 3 more patients were enrolled at dose level 0: 1 patient experienced G3 atrial fibrillation, 2 patients ≥ G3 hypertension. Considering the serious adverse events (SAEs) occurred, the trial was temporary stopped to evaluate the benefit of continuing the study. All the DLTs were cardiologic and occurred in patients with a prior history of cardiac disease. As per protocol, they were evaluated with ECG and echocardiogram before the enrolment and were considered eligible for the study. The safety committee established new procedures for the evaluation of cardiac function of potentially eligible patients, including 24 h continuing pressure monitoring before the enrolment and serial measurement of blood pressure during and after Carfilzomib infusions. Six more patients were enrolled at dose level -1 (Carfilzomib 20/27 mg/m2) and none experienced a DLT. The MTD was established at dose level -1 with Carfilzomib 20/27 mg/m2, Pomalidomide 4 mg and Dexamethasone 40 mg. In the phase II portion of the trial, 42 patients were enrolled. Considering both phase I and II portions of the study, the most frequent drug related, grade ≥ 3 AEs were hematologic (65% of neutropenia and 13% of thrombocytopenia) and cardiologic (17%, mainly hypertension). We recorded only 4% of infection and ≥ G3 peripheral neuropathy. The overall response rate (ORR) of phase I/II portions was 58% (30/52) including 25% (13/52) of ≥ very good partial remission (VGPR). The ORR of high risk patients was 44% (7/16) including 19% (3/16) of ≥ VGPR. With a median follow-up of 10 months, median progression free survival (PFS) was 9.5 months and the median overall survival was not reached. Conclusions: This is the first phase I/II trial that combined weekly Carfilzomib with Pomalidomide and Dexamethasone. This combination was highly effective in RRMM. After a median follow-up of 10 months, wKRd showed a double median PFS in comparison with Pomalidomide-low dose dexamethasone (Sanmiguel et al Lancet Oncology 2013): 9.5 vs 4 months respectively, confirming the efficacy of combining a PI with an IMiD. An updated analysis will be presented at the meeting. Disclosures Bringhen: BMS: Honoraria; Celgene: Honoraria; Janssen-Cilag: Honoraria; Amgen: Other: ADVISORY BOARD; Mundipharma: Other: ADVISORY BOARD; Karyopharm: Other: ADVISORY BOARD. Larocca:Celgene: Honoraria; Janssen-Cilag: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria. Gaidano:Karyopharm: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Morphosys: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau. Oliva:Amgen: Honoraria; Celgene: Honoraria; Takeda: Honoraria. Sonneveld:Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding. Palumbo:Janssen Cilag: Honoraria; Takeda: Employment, Honoraria. Boccadoro:Janssen: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Abbivie: Honoraria; Mundipharma: Research Funding; SANOFI: Honoraria, Research Funding; CELGENE: Honoraria, Research Funding.

Results of an Open, Non-Comparative, Phase I/II Investigator Initiated Trial (IIT) in Relapsed or Refractory Multiple Myeloma Patients Using Vorinostat, Bortezomib, Doxorubicin and Dexamethasone (VBDD)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4260-4260
Author(s):  
Alexander Keller ◽  
Johannes M. Waldschmidt ◽  
Dagmar Wider ◽  
Dorothee Jakobs ◽  
Mandy Möller ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Level ◽  
Research Funding ◽  
Comprehensive Cancer Center ◽  
Cancer Center ◽  
Moderate Activity ◽  
Allogenic Stem Cell Transplantation ◽  
Hdac Activity ◽  
Refractory Multiple Myeloma

Abstract Introduction: Multiple myeloma (MM) relapse is common and may eventually lead to highly refractory/relapsed MM (RRMM). Therefore, novel treatment combinations are crucially needed for this highly challenging subgroup of patients (pts). The aim of the here presented phase I/II IIT was to test the tolerability and activity of a novel, so-called VBDD schedule within an outpatient regimen for extensively pretreated RRMM pts. In addition to Bortezomib, Doxorubicin and Dexamethason, which are all active and approved drugs in RRMM, Vorinostat has shown promising anti-tumor effects as a histone deacetylase inhibitor (HDACi). It inhibits the enzyme activity of HDAC 1, 2, 3 and 6, thereby allowing the activation of tumor suppressor genes. MM cells have been shown to escape from bortezomib treatment by formation of aggrosomes which desensitize cells to proteasome inhibitors and by microtubule mediated protein shuttling to lysosomes, where proteins are degradaded in order to prevent cytotoxic stress and ultimately escape from apoptosis (Fig.A). Albeit vorinostat has shown moderate activity when given alone, it has promising additive effects when combined with other antimyeloma agents, and was therefore used as an add-on agent within this RRMM regimen as it blocks microtubule coppling and aggrosome building and thereby may antagonize escape mechanisms in bortezomib-refractory pts. Methods: Vorinostat was escalated from 100mg (dose level 0), to 200mg (+1) and 300mg (+2). Primary objectives (MTD; 3+3 dose escalation), secondary objectives (safety, IMWG responses, PFS, OS) and supplementary endpoints (organ function, prognostic factors, QoL, comorbidity and HDAC-activity in PBMCs/BM) were assessed throughout the trial. Dose limiting toxicities (DLTs) were defined as any possibly drug-related adverse event (AEs) ≥grade 3 (CTCAE) during the 1st cycle. After completing 6 cycles, patients could receive either a bortezomib maintenance therapy or next-line treatment (e.g. 2nd ASCT). Results: 34 pts with RRMM with a median age of 63 years (47-78) and KPS of 90% (70-100%) have been enrolled, of which 33 received therapy according to the study protocol (1 pt deceased prior to study start due to aggressive MM progression and was therefore not included in the evaluation). The number of prior therapy lines was substantial with a median of 3 (1-8; with prior bortezomib, SCT and IMiDs in 88%, 94% and 42%, respectively). 3 pts each were treated in dose levels 0 and +1, and the remaining 27 pts in dose level +2. No DLTs were observed. In our current analysis, SAEs amounted to 15 and occurred in 9/33 pts (27%): Amongst them, 2 nonfatal SAEs were judged to be related to the investigational therapy (1 bacteraemia, 1 herpes zoster), for the others, no causal relationship to VBDD was found. The response according to IMWG criteria was rewarding with best ORR (>PR) and clinical benefit rate (CBR; >SD) of 42% and 94% (Fig. B), and end of treatment (EoT) ORREoT and CBREoT of 36% and 88%, respectively (Fig.C). Our data also revealed that the response was independent of the presence or absence of unfavorable cytogenetics. Comorbidity assessments assured no decline in pts' mental or physical condition and pts reported preserved or improved QoL with this well-tolerated 4-agent treatment regimen. Pharmacodynamic analyses in peripheral blood (PB) MCs showed substantial and early HDAC downregulation between VBDD cycles 1 and 2 in 11/16 pts (69%): median HDAC activity decreased to 52% of pre-treatment levels. Thereby, we were able to distinguish 3 groups of pts with substantial, more subtle or no PB HDAC decreases in 8, 3 and 5 pts, respectively. Of note, these HDAC changes correlated well with pts' serological and clinical responses, except in 2 pts. These intriguing results are currently further assessed and will be presented at the meeting. Conclusions: VBDD demonstrated to be an effective and well-tolerated outpatient regimen with promising response rates in heavily pretreated RRMM pts. The employed VBDD regimen, with a continuous, rather than pulsed vorinostat-schedule, constitutes a promising treatment option, expands current standard therapies and, similarly to other HDACi (i.e. panobinostat), suggests HDACi as a valuable add-on within this combination schedule in order to stabilize the disease and/or bridge RRMM patients to next-line treatments (i.e. autologous/allogenic stem cell transplantation) or novel clinical trial drugs. *AK and JW contributed equally Figure 1. Figure 1. Disclosures Off Label Use: We report on results of an Phase I/II IIT, in which the HDACi Vorinostat is used to treat relapsed or refractory Multiple Myeloma pts . Engelhardt:MSD: Research Funding; Janssen-Cilag: Research Funding; Comprehensive Cancer Center Freiburg: Research Funding; German Cancer Aid: Research Funding. Wäsch:German Cancer Aid: Research Funding; Janssen-Cilag: Research Funding; Comprehensiv Cancer Center Freiburg: Research Funding; MSD: Research Funding.

scholarly journals Phase I Trial of Systemic Administration of Vesicular Stomatitis Virus Genetically Engineered to Express NIS and Human Interferon, in Patients with Relapsed or Refractory Multiple Myeloma (MM), Acute Myeloid Leukemia (AML), and T-Cell Neoplasms (TCL)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3268-3268
Author(s):  
Martha Q. Lacy ◽  
Kah-Whye Peng ◽  
Stephen J. Russell ◽  
Amylou C. Dueck ◽  
Mrinal M. Patnaik ◽  
...  
Keyword(s):  
Phase I ◽  
Board Of Directors ◽  
Dose Level ◽  
Research Funding ◽  
Tumor Burden ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

Abstract Background: We previously reported successful treatment of myeloma with an oncolytic virus, MMV-NIS. Preexisting immunity against measles made use of that virus unsatisfactory. The Indiana strain of Vesicular Stomatitis Viruses (VSV) are being developed as anticancer drugs for the treatment of a variety of malignancies. To ensure tumor selective replication and spread, we designed the VSV to encode interferon beta. Expression of IFNβ also serves as a STING agonist to activate host immunity against the cancer. The sodium iodide symporter (NIS) is inserted as a reporter gene into the viral genome to enable noninvasive monitoring of viral spread using PET/CT imaging. We report a Phase I clinical trial of intravenous administration of VSV-IFNβ-NIS for relapsed hematological malignancies including MM, AML, and TCL. Methods: Arm A consisted of patients with low tumor burden. Arm B included patients with high tumor burden. Both arms consisted of a classical 3+3 phase I trial, starting at 5x10^9 TCID50 (dose level 1) through 5x10^11 TCID50 (dose level 4), given as a single IV dose. In order to obviate potential toxicity from high interferon levels, Arm B received ruxolitinib 15 mg twice daily for 10 days beginning on day -1. The primary objective was determining the maximum tolerated dose (MTD) of VSV-IFNβ-NIS alone and in combination with ruxolitinib; secondary objectives include estimating the safety profile and preliminary efficacy. Correlative objectives include monitoring the pharmacodynamics of viral replication through SPECT/CT imaging with NIS gene, viremia, virus shedding, changes in the immune profile of peripheral blood leukocytes, and immunohistochemistry for immune cell infiltrates in tumors. Adverse events (AEs) are reported herein based on CTCAE v4 with the exception of cytokine release syndrome (CRS) which is based on Lee (Blood 2014; 124(2):188-195) criteria. Results: To date, 10 patients have received IV VSV-IFNβ-NIS; 8 in Arm A and 2 in Arm B. In Arm A, 3 patients were treated at dose level 1, 3 at dose level 2 and 2 at dose level 3. At dose level 1, there were three grade 3 hematologic AEs (neutropenia [1], lymphopenia [2]), and no grade 3+ non-hematologic AEs. At dose level 2, there were two grade 3 hematologic AEs (anemia [1], lymphopenia [1]), and two grade 3 non-hematologic AEs (nausea [1], dehydration [1]). A grade 2 CRS by Lee criteria was also observed. At dose level 3, 2 patients have been enrolled and data are maturing for DLT evaluation. In Arm B (VSV + rux), 2 patients have been enrolled and data are maturing for dose limiting toxicity (DLT) evaluation. Other grade 1 and 2 toxicities have included fever, hypertension, headache, electrolyte abnormalities, nausea, vomiting, transient elevation of liver function tests and creatinine. All grade 1 and 2 toxicities resolved within 72 hours. Among the 6 patients evaluable for response, there was one partial remission (TCL patient treated at dose level 2), and 5 with progressive disease. Multiple cytokines increased at 4h post infusion of virus, but most returned to baseline levels by 24h.Viremia was detectable in all patients at the end of infusion, and to varying levels at 30 mins, 1, 2, 4, 24, 48h or 72 hours post virus infusion. No persistent viremia was observed. No infectious virus was recovered in buccal swabs or urine and neutralizing anti-VSV antibodies were present by day 29. Extensive immune phenotyping and ELIspot assays for shared antigens are ongoing. Conclusion: In the lowest dose levels tested to date, VSV-IFNβ-NIS has not led to any observed dose limiting toxicity. Dose escalation is ongoing and updated results will be reported. Disclosures Lacy: Celgene: Research Funding. Peng:Vyriad: Equity Ownership. Russell:Vyriad: Equity Ownership. Dueck:Bayer: Employment; Phytogine: Employment; Pfizer: Honoraria. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Gertz:spectrum: Consultancy, Honoraria; Physicians Education Resource: Consultancy; Ionis: Honoraria; janssen: Consultancy; Medscape: Consultancy; celgene: Consultancy; Apellis: Consultancy; Prothena: Honoraria; Amgen: Consultancy; annexon: Consultancy; Abbvie: Consultancy; Research to Practice: Consultancy; Teva: Consultancy; Alnylam: Honoraria. Dingli:Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding. Kapoor:Celgene: Research Funding; Takeda: Research Funding. Al-Kali:Novartis: Research Funding. Naik:Vyriad: Equity Ownership. Kumar:AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Combination of Bendamustine, Lenalidomide, and Dexamethasone In Patients with Refractory or Relapsed Multiple Myeloma Is Safe and Highly Effective: Results of a Phase I Clinical Trial

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 989-989
Author(s):  
Suzanne Lentzsch ◽  
Amy O'Sullivan ◽  
Ryan Kennedy ◽  
Navkiranjit Gill ◽  
Carrie Andreas ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Phase I ◽  
Dose Level ◽  
Research Funding ◽  
Phase I Trial ◽  
Clinical Activity ◽  
Grade 3 ◽  
Expansion Cohort ◽  
Level 2

Abstract Abstract 989 Background: Lenalidomide is an analog of thalidomide that has significant clinical activity in combination with dexamethasone in patients with relapsed or refractory multiple myeloma (MM). Bendamustine is a bifunctional alkylating agent that is approved for the treatment of chronic lymphocytic leukemia and indolent non-Hodgkin's lymphoma that has progressed during or relapsed within 6 months following a rituximab-containing regimen. This multicenter phase I trial is the first to investigate the combination of bendamustine, lenalidomide, and dexamethasone. Our primary objective was to determine the maximum tolerated dose (MTD) and safety profile of bendamustine and lenalidomide when administered with dexamethasone for patients with relapsed or refractory MM. Methods: Patients aged ≥18 years with confirmed, measurable symptomatic MM that was refractory to or progressed after 1 or more prior therapies were treated with bendamustine by intravenous infusion on days 1 and 2, oral lenalidomide on days 1–21, and oral dexamethasone on days 1, 8, 15, and 22 of each 28-day cycle. Treatment was continued until a plateau or best response, as determined by the International Myeloma Working Group uniform response criteria, was reached. Study drug doses were escalated through 3 levels (Table 1) in a 3+3 dose-escalation scheme. The MTD was defined as the dose level at which ≤1 of 6 patients experienced dose-limiting toxicity (DLT) during the first cycle of therapy when the next higher dose level is associated with DLTs in ≥2 patients. After determining the MTD, an expansion cohort of 12 additional patients at the MTD will be treated to better evaluate toxicity and clinical activity. Secondary endpoints included preliminary efficacy as evidenced by objective response, time to disease progression, and overall survival. Results: Twenty-six patients with a median age of 63 years (range, 38 to 81 years) were enrolled. The mean number of prior therapies was 3 (range, 2–7); 81% of the patients had prior lenalidomide, 48% had prior thalidomide, and 29% had both. The MTD was identified at dose level 2: 75 mg/m2 bendamustine and 10 mg lenalidomide. Four DLTs were recorded: at dose level 2 (n = 6), 1 patient with grade 4 neutropenia; at dose level 3 (n = 6), 2 patients with grade 4 neutropenia and another with delayed platelet recovery from grade 3 thrombocytopenia. Currently 9 patients have been enrolled in the expansion cohort. Twenty-one of 26 patients received at least 2 cycles and were included in the response assessment. A partial response (PR) or better was observed in 63% (n = 12) of the patients, including 16% (n = 3) achieving a very good PR (VGPR). In addition to these 12 patients, another 3 (15%) had a minor response (25%-49% reduction in M-protein). Stable disease was observed in 32% (n = 6), and only 5% (n = 1) had disease progression. The median time to next treatment was 8.1 months (range, 1.9–27.3 months). Other grade 3/4 adverse events occurring after the first cycles of treatment included prolonged QTc in 1 patient. Conclusions: This is the first phase I trial testing the combination of bendamustine, lenalidomide, and dexamethasone for relapsed and refractory MM. This regimen is well tolerated even in older patients up to 81 years. With a PR/VGPR rate of 63%, this combination is a highly active regimen even in heavily pretreated MM patients, and its side effect profile makes it an attractive treatment option for MM patients especially with pre-existing therapy-related peripheral sensory neuropathy. Final data on response and overall survival will be available at the time of presentation. Disclosures: Lentzsch: Celgene Corp: Research Funding. Roodman:Amgen, Novartis, Celgene, Acceleron: Consultancy. Zonder:Amgen, Celgene, Cephalon: Consultancy; Millennium: Research Funding; Millennium: CME only, no promotional work.

scholarly journals Biological and Clinical Impact of JAK2/mTOR Blockade in Gvhd Prevention: Preclinical and Phase I Trial Results

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 48-49
Author(s):  
Joseph Pidala ◽  
Kelly Walton ◽  
Hany Elmariah ◽  
Jongphil Kim ◽  
Asmita Mishra ◽  
...  
Keyword(s):  
T Cells ◽  
Phase I ◽  
Board Of Directors ◽  
Dose Level ◽  
Research Funding ◽  
Acute Gvhd ◽  
Advisory Committees ◽  
Mtor Inhibition ◽  
Level 1 ◽  
Level 2

Background: Distinct from broadly acting graft-versus-host disease (GVHD) prophylaxis, JAK2 inhibition suppresses alloreactive T cells, while sparing regulatory T cells (Tregs) and graft-versus-leukemia (GVL). Early IL-6 activity via JAK2 and phosphorylated STAT3 in CD4+ T cells is associated with acute GVHD onset. In mice, we show combined JAK2/mTOR blockade synergistically prevents xenogeneic GVHD. In this first-in-human phase I/II GVHD prevention trial we combine pacritinib, a JAK2 inhibitor, with sirolimus to concurrently reduce T-cell costimulation via mTOR and IL-6 activity. With phase I complete, we demonstrate that dual JAK2/mTOR inhibition is safe, suppresses pathogenic Th1 and Th17 cells, spares Tregs and key GVL effector cells, and exhibits preliminary activity in preventing GVHD. The primary aim of phase I was to identify the lowest biologically active dose of pacritinib (defined as < 35% of CD4+ pSTAT3+ T cells at day +21) that is safe when combined with sirolimus-based immune suppression. The preliminary activity of JAK2/mTOR inhibition in GVHD prevention was also investigated. Materials and Methods: This single-arm phase I/II trial (NCT02891603) tested the safety of pacritinib when administered with sirolimus plus low-dose tacrolimus (PAC/SIR/TAC) after allogeneic hematopoietic cell transplantation (alloHCT). A 3+3 dose escalation design was followed, including dose level 1 (PAC 100mg daily), level 2 (PAC 100mg twice daily), and level 3 (PAC 200mg twice daily). Clinical safety, pharmacodynamic assessments, and pharmacokinetic (PK) studies were followed during the study. Acute GVHD was scored through day +100. Patient characteristics are described in Table 1 (n=12). Allowed donor types were HLA-A, -B, -C, and -DRB1 matched-related or unrelated donors. Adequate vital organ function and Karnofsky performance status (KPS ≥ 80%) were required. Results: Dose level 2, PAC 100mg twice a day, was the lowest biologically active and safe dose, and thus the recommended phase II dose. Blood samples acquired at day +21 showed that PAC 100mg twice a day reduced the mean frequency and geometric MFI of CD4+ pSTAT3+ T cells (Figure 1A, B). Consistent with suppressed pSTAT3, PAC 100mg twice a day decreased pathogenic Th1 and Th17 cells (Figure 1C, D). pSTAT5 is critical for Tregs and effectors of GVL. PAC 100mg twice a day favored STAT5 phosphorylation in CD4+ T cells, preserved Tregs and increased the ratio of Tregs to pathogenic T helper cells, and supported CD3+ T cell and NK cell effectors (Figure 1E-J). Patients treated on dose level 2 of PAC exhibited a robust increase in Th2 cells at day +21 (29.5% v 4.87% level 1 or 4.5% baseline, P<0.001 ANOVA). Additionally, neutrophil and platelet engraftment occurred without delay (Figure 1K, L). A single dose limiting toxicity was observed in dose level I only, and consisted of angioedema possibly related to PAC. CMV reactivation or disease were not observed among patients treated at dose level 2, with only a single case of CMV reactivation among dose level 1 (8 of 12 recipients were CMV seropositive). A single patient treated on dose level 2 developed grade 4 acute GVHD and died, after prematurely discontinuing TAC for acute kidney injury and electively stopping PAC. A patient died of relapsed disease in dose level 1. To test the efficacy of dual JAK2/mTOR inhibition in vivo, NSG mice were transplanted with human peripheral blood mononuclear cells (PBMCs) and treated with either vehicle, PAC, STAT3 inhibitor S3I-201, SIR, PAC/SIR, or S3I/SIR. The combination of JAK2 or downstream STAT3 inhibition plus SIR significantly reduced xenogeneic GVHD in mice (Figure 1M) and maintained donor anti-tumor activity by CD8+ T cells (data not shown). Further, dual JAK2 or STAT3 inhibition with mTOR blockade significantly increased the induction of Tregs in mice transplanted with Treg-depleted human PBMCs (62.3% PAC/SIR or 74% S3I/SIR v 29.9-38% with vehicle or inhibitors alone, P<0.01 ANOVA). Conclusions: We demonstrate that PAC/SIR/TAC (RP2D: PAC 100mg twice a day) is safe and effectively reduces IL-6 signal transduction, pathogenic Th1 and Th17 cells, and preserves Tregs and effectors necessary for GVL and antiviral immunity. Preliminarily, adding pacritinib limits acute GVHD, preserves donor CMV immunity, and permits timely engraftment. The efficacy of PAC/SIR/TAC will be tested in our ongoing phase II GVHD prevention trial. Disclosures Pidala: Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Takeda: Research Funding; Janssen: Research Funding; Johnson and Johnson: Research Funding; Pharmacyclics: Research Funding; Abbvie: Research Funding; BMS: Research Funding. Bejanyan:Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees. Nishihori:Karyopharm: Other: Research support to institution; Novartis: Other: Research support to institution. Lawrence:Patent Pending: Patents & Royalties: Dr. Lawrence has a patent WO2014070859A1: Stat3 dimerization inhibitors. . Lawrence:Patent Pending: Patents & Royalties: Dr. Lawrence has a patent WO2014070859A1: Stat3 dimerization inhibitors. . Sebti:Patent Pending: Patents & Royalties: Dr. Sebti has a patent WO2014070859A1: Stat3 dimerization inhibitors. . Betts:Patent Pending: Patents & Royalties: Dr. Betts has a pending patent WO2017058950A1: Methods of treating transplant rejection. This includes the use of JAK inhibitors. Neither he nor his institution have received payment related to claims described in the patent.. OffLabel Disclosure: Pacritinib and its use in GVHD prevention as part of a phase I trial

A Multicenter Phase I/II Trial Evaluating the Safety and Efficacy of Lenalidomide [Revlimidä (R), CC-5013] in Combination with Doxorubicin and Dexamethasone (RAD) in Patients with Relapsed or Refractory Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5136-5136 ◽  
Author(s):  
C. Gerecke ◽  
S. Knop ◽  
M.S. Topp ◽  
S. Kotkiewitz ◽  
H. Gollasch ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Level ◽  
Fixed Dose ◽  
Severe Toxicity ◽  
Refractory Multiple Myeloma ◽  
Dose Levels ◽  
Anti Tumor Activity ◽  
Level 2 ◽  
Dose Limiting Toxicity

Abstract Introdution: Lenalidomide (Revlimid™) is Celgene’s lead clinical compound in a new group of drugs called IMiDs, which have immunomodularory properties. The drug has been evaluated in phase-I, II, and III clinical trials for the treatment of multiple myeloma (MM). Lenalidomide shows substantial anti-tumor activity in patients with refractory or relapsed MM and significantly prolongs time to tumor progression (TTP) compared to standard therapy in these patients. Lenalidomide was well tolerated in these trials, the only dose limiting toxicity in a phase-I trial was myelosuppression. In order to further improve therapeutic efficacy and to overcome drug resistance we are currently evaluating Lenalidomide (Revlimid™) in combination with doxorubicin and dexamethasone (RAD) for the treatment of patients with refracrory or relapsed MM in a phase-I/II trial. Methods: Patients with relapsed or refractory multiple myeloma recieve a fixed dose of either 10 mg or 15 mg Revlimid Revlimid™ given daily for 21 days (d 1–21) in combination with doxorubicin (adriamycin) and dexamethasone, to be repeated on day 29. Three dose levels of doxorubicin (adramycin) are planned: 4 mg/m2 day 1–4, 6 mg/m2 day 1–4 and 9 mg/m2 day 1–4. 40 mg dexamethasone is given orally day 1–4 and day 17–20 at a fixed dose. 3– 6 cycles are applicated unless severe toxicity or disease progression occurs. Results: RAD treatment was well tolerated at dose level 1 and dose level 2. Therefore, current dose escalation is continued. All patients treated at the first two dose levels (6/6) responded to RAD treatment. Further updated results on this trial will be presented.

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.

A Phase I Study of the HDAC Inhibitor LBH589 in Combination with Imatinib for Patients with CML in Cytogenetic Remission with Residual Disease Detectable by Q-PCR.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2194-2194 ◽  
Author(s):  
Ravi Bhatia ◽  
David S. Snyder ◽  
Allen Lin ◽  
Jennifer Arceo ◽  
Linda Seymour ◽  
...  
Keyword(s):  
Stem Cells ◽  
Phase I ◽  
Research Funding ◽  
Residual Disease ◽  
Leukemia Stem Cells ◽  
Gi Symptoms ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2 ◽  
Dose Limiting Toxicity

Abstract Abstract 2194 Poster Board II-171 Imatinib mesylate (IM) is effective in inducing remission and improving survival in CML patients. However IM-treated patients continue to harbor residual leukemia stem cells (Blood 101:4701, 2003). Most patients relapse if treatment is discontinued, and it is generally recommended that treatment with IM be continued indefinitely. The inability of IM to cure CML, the potential for side effects and the financial burden of life-long treatment provide an impetus to develop approaches to eliminate residual leukemia stem cells. We have shown in preclinical studies that treatment with the HDAC inhibitor LBH589 (LBH) combined with IM effectively eliminates CML stem cells resistant to IM alone. The safety and MTD of LBH589 in combination with Imatinib has not been previously evaluated. We have initiated a phase I, open label clinical trial to determine the safety and tolerability of LBH589 given in combination with IM in CML patients, and to determine the MTD and dose-limiting toxicity (DLT). CML patients in chronic phase (CP) treated with IM 400mg/d for >1 year with major or complete cytogenetic response and residual disease on Q-PCR are eligible. LBH589 is administered in combination with IM 400mg PO daily in 28 day cycles, with successive cohorts of patients receiving escalating doses of LBH 3 times a week (level 1: 10mg; level 2: 15mg; level 3: 20mg). Treatment is scheduled for 6 cycles of 28 days each. Five patients have been enrolled thus far (Table). No dose limiting toxicity (DLT), defined as Grade 3 hematological or non-hematological toxicity in the first 28 days, was observed in 3 patients enrolled at dose level 1. DLT (Grade 3 thrombocytopenia) was observed in 1 of the 2 patients enrolled at dose level 2. Other toxicities included thrombocytopenia (Grade 3 [n=2]; Grade 1-2 [n=4]), hypophosphatemia (Grade 3 [n=1]; Grade 2 [n=2]), fatigue (Grade 1 [n=3]), hypocalcemia (Grade 1 [n=2] and Grade 1-2 GI symptoms (diarrhea [n=2]; nausea [n=3]; anorexia [n=2]; vomiting [n=3]; constipation [n=1]). Of note, significant QTc prolongation was not observed on intensive EKG monitoring. IM did not require to be held for any of these toxicities. Two patients have completed 6 cycles of treatment, with one opting to receive an additional 3 cycles, 2 are currently receiving treatment, and one withdrew after 1.5 cycles because of fatigue and GI symptoms. Bone marrow aspirates for assessment of BCR-ABL status were performed at the end of cycles 3 and 6 of treatment. Q-PCR analyses showed reduction in BCR-ABL levels in patient #2 (LBH 10mg) after 3 months, which was not sustained at 6 months. Patient #4 (LBH 15mg), followed for 5 months so far, had undetectable BCR-ABL after 3 months of treatment. These results suggest that LBH589 can be safely administered in combination with IM. Reduction in BCR-ABL levels was seen in two patients but the durability is unclear as yet. We are continuing accrual of patients to define the MTD and safety of this combination. Disclosures: Bhatia: Novartis: Consultancy, Research Funding. Snyder:Novartis: Consultancy, Honoraria, Speakers Bureau. Deininger:Novartis: Consultancy. Radich:Novartis: Consultancy, Honoraria, Research Funding.

Final Report of a Phase I Study of Clofarabine Plus High Dose Melphalan as a Conditioning Regimen for Allogeneic Transplantation

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 528-528
Author(s):  
Mark Kirschbaum ◽  
Anthony Selwyn Stein ◽  
Paul Frankel ◽  
Leslie Popplewell ◽  
Robert w Chen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Phase I ◽  
Dose Level ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Level 3 ◽  
Level 1 ◽  
Level 2 ◽  
Reduced Intensity

Abstract Abstract 528 Background: Allogeneic Stem Cell transplantation remains the only curative treatment modality for hematologic malignancies such as AML, ALL, and MDS. Reduced intensity regimens were designed which replaced the alkylating agent cyclophosphamide with the purine nucleoside antimetabolite, fludarabine, a potent immunosuppressive with a substantially milder toxicity profile. Clofarabine is a purine nucleoside analogue designed to exploit a double halogen strategy which confers resistance to adenosine deaminase, increases stability and bioavailability and makes the drug more efficient than fludarabine at inhibiting ribonucleotide reductase (RNR) and disrupting mitochondrial function, leading to apoptosis. Clofarabine is potentially a superior antileukemic agent as compared with fludarabine, thus enhancing the activity of the conditioning regimen. Aims: To evaluate a novel clofarabine containing regimen as conditioning for adult fully matched allogeneic stem cell transplant. Methods: phase I dose escalation: clofarabine (dose level 1 = 30 mg/m2, dose level 2 and 3 =40 mg/m2) IV daily days –7 to day –3 infused over 30 minutes IV, plus Melphalan (dose level 1 and 2, 100mg/m2, dose level 3, 140 mg/m2) administered over 30 minutes IV on day –2. Related or unrelated allogeneic stem cells were infused on day 0. GVHD prophylaxis: initially cyclosporine plus mycophenolate, then tacrolimus plus sirolimus was adopted as per City of Hope standard of care. Patients (pts) age ≥ 18 years with AML, ALL, MDS in either CR1, CR2 or in relapse (up to 50% marrow blasts), not deemed eligible for standard transplant regimens by the attending physician, or at high risk for relapse, are eligible. Results: 16 eligible pts, all with AML, have been treated thus far, 7,males, 9 females, with a median age of 63 years (30 – 66). Seven pts were in CR1, 2 pts were in CR2, 4 pts where induction failures, and 3 pts were in first relapse. Grade 3 non-hematologic toxicities included elevation of transaminases, diarrhea, and hyponatremia. No dose limiting toxicities (DLT) were seen in the 3 pts treated at dose level 1. One patient in dose level 2 died prior to engraftment due to hepatic, renal, and infectious toxicities; that dose level has been expanded to 12 patients and no further DLTs were seen. The first patient treated at dose level 3 developed multiorgan failure and died prior to engraftment. Given the excellent results seen in the two previous cohorts we opted not to dose escalate any further patients beyond clofarabine 40 mg/m2 and melphalan 100 mg/m2. Three patients with primary induction failure received an unrelated donor graft and had complete engraftment and obtained remission. The median time to ANC recovery is 14 days and to platelet recovery is 16 days (see table). Mild acute skin graft versus host disease (GvHD) was seen in five patients, mild chronic GvHD in four patients, one patient developed severe chronic GVHD of the liver and died at day 201 from CNS bleed due to tacrolimus-sirolimus related TTP-HUS. Of the 14 patients that successfully completed transplant (no DLT or engraftment difficulty), only one patient has relapsed, with median follow-up of 10.5 months (range 4–24). Conclusion: The combination of clofarabine and melphalan is a well tolerated reduced intensity conditioning regimen with enhanced anti-leukemia activity leading to complete engraftment of related and unrelated fully matched allogeneic stem cells. Complete engraftment with prolonged disease free survival was seen at both dose levels 1 and 2. Disclosures: Off Label Use: clofarabine as a component of the conditioning regimen for allogeneic transplant.

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