Thioguanine Combined with Decitabine Can Overcome Resistance to Hypomethylating Agents: Final Results of a Phase I Trial of a Pharmacodynamically-Conceived Thioguanine/Decitabine Combination in Patients with Advanced Myeloid Malignancies

Abstract Background: Outcomes are poor for older patients with acute myeloid leukemia (AML), high-risk myelodysplastic syndromes (MDS), or relapsed/refractory disease, and new therapies are needed. Using a chemosensitivity screening assay, we previously demonstrated that combination treatment with thioguanine and decitabine can restore therapeutic efficacy in primary leukemia cells isolated from patients with relapsed/refractory AML. To test the safety and synergistic efficacy of this combination in patients with advanced myeloid malignancies, we performed a Phase I dose-escalation trial of thioguanine given with decitabine. Patients and Methods: Patients with untreated AML ≥60 years of age and ineligible for standard induction, relapsed/refractory AML, and high-risk or relapsed MDS were eligible. Two thioguanine dose levels were evaluated: 80 and 120 mg/m2/day, given on Days 1-12 of induction and Days 1-7 of maintenance. Decitabine at 20mg/m2 was administered on Days 3-12 during induction and on Days 3-7 during maintenance. The primary objective was to determine the maximum tolerated dose (MTD) of thioguanine when given with decitabine. Key secondary objectives were to evaluate the overall response rate (ORR) and progression-free survival (PFS). Patient-specific pharmacodynamic measures to assess the biologic activity of thioguanine-decitabine were also performed. These included an in vitro chemosensitivity assay, BH3 profiling to measure the degree to which the leukemic blasts were primed for apoptosis, and genome-wide analysis of DNA methylation changes. Results: Twelve patients (median age 67; range 56-83) with de novo AML (n=1), secondary AML (n=6), relapsed/refractory AML (n=4), and chronic myelomonocytic leukemia (CMML) (n=1) were treated. Three patients experienced dose-limiting toxicity (DLT), which were acute renal failure requiring hemodialysis (80 mg/m2), persistent grade 4 leukopenia and thrombocytopenia (120 mg/m2), and grade 4 sepsis preventing continued treatment (120 mg/m2). Thioguanine at 80 mg/m2 was determined to be the MTD. Eleven of the 12 patients completed the first induction cycle, and 6 patients completed a second, identical induction cycle. The median number of cycles administered was 3 (range 1-8). One patient experienced a DLT prior to the first response assessment and was removed from study. The ORR in this intent-to-treat study was 67% (8/12). Six patients achieved a CR or CRi, one obtained a morphologic leukemia-free state, and one patient had a PR. Responses were observed in all disease types. Five of the 8 responses, including 4 CR/CRi, were achieved with thioguanine at 80 mg/m2, suggesting no loss of efficacy at the MTD compared with the higher dose level. All 11 evaluable patients had ≥50% reduction in bone marrow blast percentages after induction therapy. Six patients had previously received single-agent hypomethylating therapy, and 5 (83%) of these patients responded, demonstrating that thioguanine-decitabine can rescue prior hypomethylating agent failure. Out of the 8 responders, four (50%) proceeded to allogeneic stem cell transplantation (SCT), two relapsed after CR or CRi, one had a CNS-only relapse after achieving a CR, and one patient experienced DLT and was removed from the study. Of the four patients who proceeded to allogeneic SCT, two patients died in CR from transplant-related toxicity, one relapsed, and one patient remains alive and in remission greater than 2 years. Median PFS in responding patients was 42 weeks (range, 10-not reached, weeks). In vitro pharmacodynamic studies currently have been completed on samples from the first 6 patients treated on this trial. The chemosensitivity assay results on pre-treatment mononuclear cells directly correlated with initial response. In addition, significant apoptotic priming of the blasts, as suggested from BH3 profiling, also corresponded to initial clinical response. Conclusions: Thioguanine-decitabine can be administered safely and induce remission, even among patients who had previously been treated with hypomethylating agents. Intriguingly, preliminary results from the chemosensitivity screening assay and BH3 profiling correlated well with clinical responses. Additional correlative studies including DNA methylation analysis are ongoing to better understand the mechanism of synergy between thioguanine and decitabine. A multi-center Phase II trial is planned. Disclosures Jurcic: Astellas: Research Funding. Letai:Astra-Zeneca: Consultancy, Research Funding; Tetralogic: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding.

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A Phase I Trial of a Pharmacodynamically-Conceived Decitabine and Thioguanine Combination in Patients with Advanced Myeloid Malignancies

Blood ◽

10.1182/blood.v124.21.974.974 ◽

2014 ◽

Vol 124 (21) ◽

pp. 974-974

Author(s):

Todd Rosenblat ◽

Mark L. Heaney ◽

Joseph G Jurcic ◽

Azra Raza ◽

John G. Mears ◽

...

Keyword(s):

Dna Methylation ◽

Research Funding ◽

Single Agent ◽

Newly Diagnosed ◽

Chemosensitivity Assay ◽

Pre Treatment ◽

Grade 3 ◽

Dose Levels ◽

Refractory Aml

Abstract Background: Using a chemosensitivity screening assay, we previously demonstrated that decitabine and thioguanine combinations can rescue therapeutic efficacy in primary leukemia cells isolated from patients with relapsed and refractory acute myeloid leukemia (AML). Although both decitabine and thioguanine have single-agent anti-leukemic activity, they have not previously been used concurrently. To test the safety and preliminarily assess possible additive/synergistic activity of this combination, we are performing a Phase I dose escalation trial of thioguanine given with decitabine. Patients and Methods: Patients with untreated AML over 60 years who are not suitable candidates for standard induction therapy, as well as those with relapsed/refractory AML, advanced myelodysplastic syndrome, and chronic myelomonocytic leukemia (CMML) are eligible. Three thioguanine dose levels are being evaluated: 80, 120, and 160 mg/m2/day, given in two divided doses on Days 1-12 of each induction course for up to two cycles and Days 1-7 of maintenance cycles. Decitabine 20 mg/m2 is administered IV on Days 3-12 during induction cycles and on Days 3-7 during maintenance cycles. In addition to standard safety measures and clinical outcomes, the biologic activity of the combination is assessed by patient specific pharmacodynamic measures. These measures include an in vitro chemosensitivity assay, genome-wide analysis of DNA methylation changes, and BH3 profiling in order to measure the degree to which samples are primed to undergo apoptotic cell death. Results: Six patients (median age, 69 yrs; range, 66–83 yrs) with newly diagnosed AML (n=2), relapsed/refractory AML (n=3), and newly diagnosed CMML (n=1) have been treated to date with thioguanine at the 80 mg/m2 dose. Dose-limiting toxicity was seen in one patient who developed acute renal failure (ARF) requiring hemodialysis. Infectious complications were the most common toxicity and included two episodes of grade 3 neutropenic colitis in one patient, grade 3 pseudomonal bacteremia, grade 3 staphylococcal bacteremia, and a dental infection requiring extraction. No other grade 3–4 non-hematologic toxicities were observed. Three patients remain on active treatment three to seven months from the initiation of therapy. Two patients were removed from study due to disease progression (n=1) and grade 4 ARF noted above (n=1). A patient with CMML was removed to undergo allogeneic hematopoietic stem cell transplantation after achieving a hematologic remission with red cell transfusion independence and platelet count normalization. The median number of cycles administered was 3 (range, 1-5). Bone marrow blast reductions to less than 5% were seen in all 4 evaluable patients with AML and included 1 CR and 1 CRi. The overall response rate in this high risk patient population was 67% (4 of 6 patients). Importantly, the patient who achieved a CR was 83 years old with relapsed disease following 4 previous cycles of single-agent decitabine therapy, demonstrating that this regimen can rescue previous hypomethylating agent failures. Clinical activity was well-correlated with the in vitro cytotoxicity assays. The chemosensitivity assay results for thioguanine on pre-treatment mononuclear cells directly correlated with clinical outcome in both response to therapy and clinical resistance. BH3 profiling was also performed on pre-treatment myeloblasts. Significant apoptotic priming corresponded to good initial clinical response. In addition, in the single patient who responded and subsequently relapsed, decreased apoptotic priming was observed in the relapsed sample, suggesting that the thioguanine/decitabine regimen applies selective pressure for reduction in apoptotic priming. Detailed analysis of treatment-related changes in DNA methylation will be presented and compared to prior work showing decitabine-induced hypomethylation in CD34+ leukemic cells during single agent therapy with decitabine. Conclusions: Combination decitabine and thioguanine has been well-tolerated and has shown surprising anti-leukemic activity at the lowest dose level studied. Importantly, the in vitro chemosensitivity testing and BH3 profiling accurately predicted the observed clinical responses while also confirming the etiology of the loss of therapeutic response. Accrual to this trial continues at higher dose levels to determine the maximum tolerated dose. Disclosures Letai: AbbVie, Inc: Consultancy, Research Funding; Tetralogic: Consultancy, Research Funding.

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A Phase 1a/b Dose Escalation Study of the MYC Repressor Apto-253 in Patients with Relapsed or Refractory AML or High-Risk MDS

Blood ◽

10.1182/blood-2021-150049 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3411-3411

Author(s):

Maro Ohanian ◽

Martha L. Arellano ◽

Moshe Y. Levy ◽

Kristen O'Dwyer ◽

Hani Babiker ◽

...

Keyword(s):

Clinical Trial ◽

High Risk ◽

Adverse Events ◽

Board Of Directors ◽

Research Funding ◽

Publicly Traded ◽

Advisory Committees ◽

Grade 3 ◽

Refractory Aml

Abstract INTRODUCTION: APTO-253 represses expression of the MYC oncogene by targeting a conserved G-quadruplex structure in its promoter, down-regulates MYC mRNA and protein levels and induces apoptosis in AML cell lines and marrow samples from patients with AML, MDS, and MPN in vitro. After injection, a large fraction of APTO-253 binds iron and transforms to the Fe(253) 3 complex which retains full activity. APTO-253 has been granted orphan drug designation for AML by the US FDA and is being studied in a Phase 1a/b clinical trial in patients with relapsed or refractory AML (R/R AML) or high-risk myelodysplasias (high-risk MDS) (NCT02267863). AIMS: Primary objectives are to determine the safety and tolerability of APTO-253, MTD, dose limiting toxicities (DLT), and the RP2D. Key secondary objectives are to assess the pharmacokinetic (PK) profile, pharmacodynamic (PD) activity, and preliminary evidence of antitumor activity. METHODS: Eligible patients have R/R AML or high-risk MDS for which either standard treatment has failed, is no longer effective, or can no longer be administered safely. Treatment- emergent adverse events (TEAEs) and tumor responses are evaluated using International Working Group criteria. APTO-253 is administered by IV infusion once weekly on days 1, 8, 15, and 22 of each 28-day cycle; ascending dose cohorts were enrolled at a starting dose of 20 mg/m 2 with planned escalation to 403 mg/m 2. RESULTS: As of June 7, 2021, a total of 18 patients (median age 64.0 years, 16 AML and 2 high-risk MDS) with a median of 2.5 prior treatments (range of 1 - 9) have been treated with APTO-253 at doses of 20 (n=1), 40 (n=1), 66 (n=4), 100 (n=4) and 150 mg/m 2 (n=8). Most patients were RBC (87.5% of AML and 100% of MDS) and/or platelet (75% of AML and 50% MDS) transfusion-dependent. No DLTs or drug-related serious adverse events have been reported. Only 1 patient had a drug-related TEAE of grade 3 or greater (fatigue, Grade 3, probably related). Preliminary PK analysis (Figure 1) showed that serum levels of APTO-253 were dose proportional. C max and AUC 0-72h for C1D1 dosing were 0.06, 0.02, 0.36 ± 0.37, 0.44 ± 0.41 and 0.72 ± 0.70 µM and 0.11, 0.15, 3.98 ± 1.77, 4.79 ± 0.87 and 2.51 ± 1.73 µM*h for dose levels of 20, 40, 66, 100 and 150 mg/m 2, respectively. Plasma levels for Fe(253) 3 were significantly higher than those for the APTO-253 monomer. For example, C max and AUC 0-72h of Fe(253) 3 for C1D1 dosing of patients in Cohort 150 mg/m 2 were 2- and 20- fold higher than the ATPO-253 monomer at 15.09 ± 0.42 µM and 51.52 ± 28.26 µM*h, respectively. Following dosing at 150 mg/m 2, serum concentrations of Fe(253) 3 were above 0.5 µM for > 48 h, which approaches the therapeutic range based on in vitro studies. CONCLUSIONS: APTO-253 has been well-tolerated at doses of 20, 40, 66, 100 and 150 mg/m 2 over multiple cycles and escalated to 210 mg/m 2 (Cohort 6). PK analysis revealed that APTO-253 is rapidly transformed to and co-exists with the Fe(253) 3 in serum from R/R AML and high-risk MDS patients. Enrollment of patients at the 210 mg/m 2 dose level is ongoing and updated clinical data will be presented at the meeting. Figure 1 Figure 1. Disclosures Arellano: KITE Pharma, Inc: Consultancy; Syndax Pharmaceuticals, Inc: Consultancy. Levy: AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Other: Promotional speaker; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Morphosys: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Epizyme: Consultancy, Other: Promotional speaker; Takeda: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Dova: Consultancy, Other: Promotional speaker; Novartis: Consultancy, Other: Promotional speaker; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Speakers Bureau; Beigene: Consultancy, Honoraria, Speakers Bureau; Amgen Inc.: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau. Mahadevan: caris: Speakers Bureau; Guardanthealt: Speakers Bureau; PFIZER: Other: Clinical trial Adverse events committee; TG Therapeuticals: Other: Clinical trial Adverse events committee. Zhang: Aptose Biosciences, Inc.: Current Employment. Rastgoo: Aptose Biosciences, Inc.: Current Employment. Jin: Aptose Biosciences, Inc.: Current Employment. Marango: Aptose Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Howell: Aptose Biosciences, Inc.: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Research Funding. Rice: Aptose Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties; Oncolytics Biotech Inc.: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Bejar: Aptose Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company; Takeda: Research Funding; BMS: Consultancy, Research Funding; Gilead: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Astex: Consultancy; Silence Therapeutics: Consultancy.

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GSK1120212, a MEK1/MEK2 Inhibitor, Demonstrates Acceptable Tolerability and Preliminary Activity In a Dose Rising Trial In Subjects with AML and Other Hematologic Malignancies

Blood ◽

10.1182/blood.v116.21.3281.3281 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3281-3281 ◽

Cited By ~ 1

Author(s):

Gautam Borthakur ◽

James M. Foran ◽

Tapan Kadia ◽

Elias Jabbour ◽

Paul Wissel ◽

...

Keyword(s):

Bone Marrow ◽

Phase I ◽

Cell Lines ◽

Research Funding ◽

Loading Dose ◽

Bone Marrow Blast ◽

Blast Count ◽

Visual Changes ◽

Refractory Aml

Abstract Abstract 3281 Background: MEK (mitogen-activated extracellular signal-related kinase) is downstream of the RAS/RAF pathway and is activated by many upstream oncogenic drivers. GSK1120212 is a potent and selective allosteric inhibitor of MEK 1 and 2 kinases. In vitro, GSK1120212 inhibited proliferation of myeloid cell lines selectively as compared to lymphoid cell lines. This 2 part study of a single daily oral dosing regimen was conducted to define the recommended Phase 2 dose, evaluate pharmacokinetics, and assess preliminary activity in patients with relapsed or refractory AML, MDS, ALL or CMML. Methods: Subjects with WBC< 30,000/uL who met hepatic, renal and cardiac function criteria were eligible for participation. GSK1120212 was given orally, once daily in the following dose cohorts: 3mg loading dose followed by 1mg/day (n=3), 1mg/day without loading dose (n=1), and 2mg/day without loading dose (n=9). The loading dose was discontinued after cohort 1, based on findings in the phase I solid tumor study (J Clin Oncol 28:15s, 2010 (suppl, abstr 2503). Results: Fourteen subjects (10 with AML, 2 MDS transformed to AML, 1 MDS, 1 ALL) entered the trial. Eight were male, and median age was 65 years (range 33 to 85). Pharmacokinetic analysis showed that, upon repeat dosing, GSK1120212 exposure increased in a dose-proportional manner, had a small peak:trough ratio of approximately 4 and an effective half-life of approximately 7.7 days. Steady state concentrations were reached by day 15. Both single and repeat dose pharmacokinetics of GSK1120212 appeared to be similar to a phase I study in patients with solid tumors. Systemic exposure exceeded concentrations that inhibited in vitro leukemic cell proliferation. At the 2mg/day dose level (n=9), drug-related adverse events were diarrhea (7 overall; 6-Grade 1/2, 1-Grade 3), rash (3-Grade 1/2), fatigue (4-Grade 1/2), visual changes (3 Grade 1/2). One subject experienced a Grade 2 reversible serous retinopathy associated visual changes which resolved after drug discontinuation. One dose limiting toxicity was seen in a subject with disease-related Grade 4 thrombocytopenia and pneumonia who experienced a Grade 5 cerebrovascular accident possibly related to drug. One subject in the 2mg/day cohort achieved a CR; peripheral blast count was reduced from 30% at baseline to 0% and bone marrow blast count was reduced from 50% at baseline to 3%. During this time, platelet count increased from 48K to a maximum of 276K. Initial salutary effect was seen after 2 weeks on therapy and duration of CR was 4 weeks bone marrow blast count was 3% and 5%, respectively, at the beginning and end of the 4 week CR duration. Conclusion: GSK1120212 administered at 2mg/day orally was tolerable in subjects with relapsed or refractory AML and other leukemias. This dose regimen achieved plasma concentrations sufficient for target inhibition and showed preliminary anti-leukemic clinical activity. Based on these results, a phase II study in AML, MDS and CMML has been initiated. Disclosures: Borthakur: GlaxoSmithKline: Research Funding. Foran:GlaxoSmithKline: Research Funding. Kadia:GlaxoSmithKline: Research Funding. Jabbour:GlaxoSmithKline: Research Funding. Wissel:GlaxoSmithKline: Employment. Cox:GlaxoSmithKline: Employment. Xu:GlaxoSmithKline: Employment. Bauman:GlaxoSmithKline: Employment. Baccus:GlaxoSmithKline: Research Funding. Connor:GlaxoSmithKline: Research Funding. Cortes:GlaxoSmithKline: Research Funding. Kantarjian:GlaxoSmithKline: Research Funding.

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Results of a Phase I Trial of Lenalidomide, Rituximab (R2) and Ixazomib for Frontline Treatment of High Risk Follicular and Indolent Non-Hodgkin Lymphoma

Blood ◽

10.1182/blood-2020-136370 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 1-2

Author(s):

Brian T. Hill ◽

Deepa Jagadeesh ◽

Alex V. Mejia Garcia ◽

Robert M. Dean ◽

Omer N. Koc ◽

...

Keyword(s):

High Risk ◽

Phase I ◽

Board Of Directors ◽

Research Funding ◽

Marginal Zone ◽

Proteasome Inhibitors ◽

Marginal Zone Lymphoma ◽

Aggressive Lymphoma ◽

Advisory Committees ◽

Frontline Treatment

INTRODUCTION: Lenalidomide and Rituximab (R2) is an effective frontline treatment regimen for patients (pts) with indolent B-cell lymphoma including follicular lymphoma (FL). Recent phase III data from the RELEVANCE trial comparing R2 to traditional chemoimmunotherapy showed that this regimen is generally well-tolerated and has favorable clinical efficacy [61% overall response, 53% CR rate, 77% 3-year progression free survival (PFS) (Morschhauser, et al)]. Proteasome inhibitors such as bortezomib disrupt NF-KB signaling and have shown clinical activity in indolent NHL. Although randomized trials have failed to demonstrate clinical benefit of adding bortezomib to standard chemoimmunotherapy regimen bendamustine + rituximab (BR) for frontline treatment of FL, the addition of proteasome inhibitors to lenalidomide is a mainstay of treatment for plasma cell neoplasms due to synergistic antitumor effect. The oral proteasome inhibitor ixazomib has less potential for dose-limiting neuropathy than bortezomib, making it an attractive option to incorporate into the R2 regimen. We sought to investigate the safety and efficacy of the addition of ixazomib to R2 for FL and indolent B-cell NHL through a phase I clinical trial of this combination for patients with high risk disease. METHODS: Adult (age ≥ 18) pts with untreated FL or other indolent lymphoma, adequate organ function and performance status were enrolled. To be enrolled, FL patients were required to have stage 2, 3 or 4 disease, with high tumor burden by GELF criteria and/or FLIPI score of 3-5. During 3 x 3 dose escalation, ixazomib was given at a dose of 2 mg (n=3), 3 mg (n=3) or 4 mg (n=12) PO on days 1, 8, and 15 with lenalidomide 20 mg PO on days 1-21 every 28 days. Rituximab was administered at standard dosing on days 1,8,15,21 for cycle 1, once every 28 days for cycles 2-6 and then once every 2 months for cycles 7-12. Treatment was continued for 12 cycles and no maintenance therapy was specified per protocol. All pts received low dose aspirin for venous thromboembolism prophylaxis and acyclovir for prevention of VZV reactivation. Response assessments by CT were performed after cycle 3 and 6 and by PET/CT at the end-of-treatment (cycle 12). RESULTS: 20 pts were enrolled and 18 were eligible for treatment [15 FL (14 grade 1-2, 1 grade 3A), 2 splenic marginal zone lymphoma and 1 nodal marginal zone lymphoma].The median age of treated pts was 61 (range 40-83) years old. 55% of patients were female. Stage at diagnosis was II (n =2), III (n = 4) and IV (n = 12). For FL pts, FLIPI scores at enrollment were low (n=2), intermediate (n = 5) and high risk (n=8) and FLIPI-2 scores were low (n=3), intermediate (n = 2) and high risk (n=10). There were no dose limiting toxicities during 3 x 3 dose escalation. Grade (G) 1/2 and G3/4 treatment-related hematologic adverse events (AEs) included neutropenia (6%, 28%), thrombocytopenia (16.7%, 5.6%) and anemia (16.7%, 0%). The most common treatment-related AEs included nausea/vomiting (44% G1, 11% G2), diarrhea, (50% G1, 22% G2, 5% G3), rash (33% G1, 6% G2, 11%G3), peripheral neuropathy (22% G1, 6% G2), myalgia/arthralgia (17% G1, 17% G2), and infection (33% G2, 17% G3). There was one pulmonary embolism and no cases of febrile neutropenia. As of June, 2020, median follow-up among living pts was 21 months. 4 pts discontinued treatment due to disease progression; 2 with transformation to aggressive lymphoma. Of the transformed cases, one subject died on study due to progression disease and one developed CNS disease on study treatment but proceeded to autologous stem cell transplant. The best overall response rate was 61.2% [55.6% CR, 5.6% PR): 22.2% had stable disease and 16.7% had disease progression. 18-month Kaplan-Meier estimates of PFS and overall survival were 71% and 94%, respectively (Figure). CONCLUSION: R2 can safely be combined with at the target dose of 4 mg of ixazomib for treatment-naïve indolent NHL patients. Non-hematologic AEs were generally consistent with known toxicity of each component of therapy. CR rate and PFS were was similar to the outcomes reported in the RELEVANCE trial despite enrolling high risk patient. R2 may serve as backbone for future studies of novel treatment combinations for high risk FL after thorough evaluation for occult transformation to aggressive lymphoma. Disclosures Hill: Abbvie: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding. Jagadeesh:MEI Pharma: Research Funding; Regeneron: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Debiopharm Group: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees. Caimi:Celgene Corp: Other: Incyte Corporation - Ownership - Pharmacyclics, Inc. - Ownership - Celgene Corp. - Other, Speakers Bureau; ADC Therapeutics: Research Funding; Genentech: Research Funding. Smith:Takeda: Research Funding; Celgene: Research Funding. OffLabel Disclosure: Ixazomib is off-label for treatment of NHL

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Phase I Study of a Liposomal Carrier (CPX-351) Containing a Synergistic, Fixed Molar Ratio of Cytarabine (Ara-C) and Daunorubicin (DNR) in Advanced Leukemias

Blood ◽

10.1182/blood.v112.11.2984.2984 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2984-2984 ◽

Cited By ~ 2

Author(s):

Eric J. Feldman ◽

Jeffrey Lancet ◽

Jonathan E. Kolitz ◽

Ellen Ritchie ◽

Alan F. List ◽

...

Keyword(s):

Bone Marrow ◽

Phase I ◽

Dose Escalation ◽

Phase I Study ◽

Molar Ratio ◽

Phase 2 ◽

Phase 2 Study ◽

Grade 3 ◽

Refractory Aml

Abstract Background: CPX-351 is a liposomal formulation of Ara-C and DNR which fixes the synergistic 5:1 molar ratio found to enhance efficacy in both in vitro and in vivo preclinical leukemia models. CPX-351 overcomes the pharmacokinetic (PK) differences of each drug, enabling the maintenance of the 5:1 molar ratio for extended periods of time after IV administration and the delivery of this ratio to bone marrow. Preclinical data from in vitro models show that CPX-351 is actively internalized by leukemic cells within vacuoles and subsequently releases DNR intracellularly. A Phase I study was performed with CPX-351 in patients with acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), and myelodysplastic syndrome (MDS). Objectives: to determine safety, tolerability, and pharmacokinetics of a 90 min IV infusion of CPX-351 given on days 1, 3, 5 to patients with advanced leukemia and MDS, and to seek preliminary evidence of antitumor activity. Methods: Patients with relapsed/refractory AML/ALL and MDS were eligible. A second induction course was permitted if the day 14 bone marrow showed evidence of antileukemic effect and persistent leukemia. Dosing started at 3 units/m2 (1 u = 1 mg Ara-C and 0.44 mg DNR) using single patient cohorts and dose doublings. Three patient cohorts and 33% dose increments began after evidence of antileukemic activity and continued until limiting toxicities (DLTs) completed dose escalation. PK samples were collected after each dose. Results: Forty-seven subjects received 69 courses of CPX-351: Male/Female = 31/16, median age = 62 years (range 23–81); 44 patients had AML and 3 patients had ALL; median number of prior regimens = 2 (1–7). Thirty-seven patients entered the escalation phase of the study and ten subjects, most in first relapse, were treated after completion of dose escalation to confirm safety. At 24 u/m2 antileukemic effects were observed leading to increased cohort size to 3 and decreased escalation rate to 33%. The MTD and recommended Phase 2 dose was 101 u (101 mg Ara-C + 44 mg DNR)/m2 after observing 3 DLTs (decreased LVEF, hypertensive crisis, prolonged aplasia) at 134 u/m2. Adverse events data are available for 36 of 37 patients from the escalation phase of the study. Nonhematologic grade 3–5 toxicities occurring in more than one patient included: infections (58%), dyspnea (11%), fever (11%), hypophosphatemia (8%), hypokalemia (6%), renal failure (6%), skin rash (6%), headache (6%) hyperglycemia (6%) hypoxia (6%) and respiratory failure (6%). Mucositis of any grade was observed in 42% of patients with 3% having grade 3 mucositis. Diarrhea of grade 1 and 2 severity occurred in 39% of patients. Interim analysis of PK data demonstrates maintenance of the 5:1 molar ratio and detectable encapsulated drug persisting up to 24 hours. The average half-lives were 35 hr for total Ara-C and 23 hr for DNR, significantly longer than reported for the conventional drugs. Overall, 11 patients achieved CR/CRp. Among the 19 patients treated at the MTD, 5 of the 13 patients evaluable for response achieved CR. Six patients were treated above the MTD (134 u/m2) and 2 achieved CR. Median time to CR was 43 days. Conclusions: The recommended phase 2 dose is 101 u/m2. CPX-351 was well tolerated, with no unexpected toxicities noted up to the MTD. GI toxicities and mucositis were transient and nearly always of mild to moderate severity. Reduced LV function was observed in two patients both with substantial prior anthracycline exposure. CRs were observed in heavily pre-treated patients with relapsed/refractory AML. Future plans include a randomized Phase 2 study comparing CPX-351 versus Cytarabine + Daunorubicin (“7 + 3”) in older (>60 yo) subjects with previously untreated AML, and a phase 2 study in patients with AML in 1st relapse.

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Vorinostat in Combination with Decitabine for the Treatment of Relapsed or Newly Diagnosed Acute Myelogenous Leukemia (AML) or Myelodysplastic Syndrome (MDS): A Phase I, Dose-Escalation Study.

Blood ◽

10.1182/blood.v114.22.2089.2089 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2089-2089 ◽

Cited By ~ 8

Author(s):

Mark Kirschbaum ◽

Ivana Gojo ◽

Stuart L. Goldberg ◽

Lisa Kujawski ◽

Ehab Atallah ◽

...

Keyword(s):

Phase I ◽

Board Of Directors ◽

Research Funding ◽

Sequential Therapy ◽

Employment Equity ◽

Advisory Committees ◽

Concurrent Therapy ◽

Equity Ownership ◽

Experienced Treatment ◽

Refractory Aml

Abstract Abstract 2089 Poster Board II-66 Introduction: Although the introduction of epigenetic therapies, such as the DNA methyltransferase inhibitor (DNMT) decitabine, has improved options for the treatment of myeloid malignancies, use is limited by sub-optimal response rates. Therefore, there remains a need for more effective treatment strategies to improve outcomes in AML/MDS. Preclinical and clinical data suggest that broadening epigenetic targeting by adding histone deacetylase (HDAC) inhibitors to DNMTs may improve responses. In addition, it has been reported that outcomes may differ according to the sequence in which HDAC and DNMT inhibitors are combined. Aim: Here we present preliminary data from a Phase I, open-label, multicenter, dose-escalating study, designed to determine the maximum-tolerated dose (MTD) and recommended Phase II dose of the HDAC inhibitor vorinostat combined either concurrently or sequentially with decitabine in patients (pts) with AML/MDS. Other endpoints include tolerability and exploratory assessments of activity. Methods: Pts (≥18 years) with intermediate-high risk MDS, relapsed/refractory AML, or untreated AML (≥60 years; unsuitable for standard chemotherapy), with an ECOG performance status of ≤2, were enrolled into one of six dosing levels (Table) and received treatment for up to 24 months or until disease progression (PD). Results: As of August 3, 2009, 72 pts have entered the study: median age was 68 years (range 18-85) and 58% were male. To date, 69 pts have discontinued due to PD/lack of efficacy (n=37), withdrawal of consent (n=12), adverse events (AEs) (n=16), physician decision (n=3), and protocol deviation (n=1). Of 70 pts evaluable for safety, 69 experienced AEs, the majority of which were Grade 1/2 in severity and included nausea (n=48), diarrhea (n=41), fatigue (n=36), constipation (n=32), and vomiting (n=28). 62 (89%) pts experienced treatment-related AEs and 17 (24%) pts experienced treatment-related serious AEs. 14 deaths occurred during the study, although none were related to study treatment. One dose-limiting toxicity, prolonged QT interval, was documented in dose level 3a. Combinations of vorinostat and decitabine in the schedules in this protocol did not reach MTD. As per protocol, dose levels 3 and 3a were the maximum administered doses and have been expanded. Of the 61 pts evaluable for response, 11 had MDS, 25 had relapsed/refractory AML, and 25 had untreated AML. In pts with MDS receiving concurrent therapy (n=5), complete remission (CR) was achieved in 2 pts, stable disease (SD) in 1 pt, partial remission (PR) in 1 pt, hematologic improvement (HI) in 1 pt; all 6 of the pts who received sequential treatment experienced SD. In pts with relapsed/refractory AML receiving concurrent therapy (n=12), CR was achieved in 1 pt, CR without recovery of counts (CRi) in 1 pt, HI in 1 pt, SD in 6 pts, while 3 pts had PD; in those receiving sequential therapy (n=13), SD was achieved in 9 pts while 4 had PD. In pts with untreated AML receiving concurrent therapy (n=12), CR was achieved in 4 pts, CRi in 1 pt, PR in 1 pt, and SD in 6 pts, and in those receiving sequential therapy (n=13), CR was achieved in 2 pts, CRi in 2 pts, PR in 1 pt, HI in 2 pts, and SD in 5 pts. Overall, CR or CRi was achieved by 18% pts with MDS, 8% with relapsed/refractory AML, and 36% with untreated AML; and HI was reported in 9% pts with MDS, 4% with relapsed/refractory AML, and 8% with untreated AML. Conclusion: These preliminary data indicate that the combination of vorinostat with decitabine, either concurrently or sequentially, is possible without significant toxicity. In addition, the combination shows promising activity in MDS and untreated AML. Disclosures: Kirschbaum: Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celegene: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Off Label Use: Vorinostat is a histone deacetylase (HDAC) inhibitor that was approved in the FDA in October 2006 for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma (CTCL) who have progressive, persistent, or recurrent disease on or following two systemic therapies. Goldberg:Merck: Research Funding. Marks:Merck: Research Funding. Di Gravio:Merck: Employment, Equity Ownership. Pyle:Merck: Employment, Equity Ownership. Rizvi:Merck: Employment, Equity Ownership. Issa:Eisai: Consultancy, Research Funding; Celegene: Research Funding; MGI Pharma: Research Funding.

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Phase I Study of Bortezomib(Bz), Pegylated Doxorubicin(DOX) and Dexamethasone(dex); ( VDD) with Escalating Doses of Cyclophosphamide(Cy) in Patients with Newly Diagnosed Myeloma.

Blood ◽

10.1182/blood.v114.22.617.617 ◽

2009 ◽

Vol 114 (22) ◽

pp. 617-617

Author(s):

Melissa Alsina ◽

Rachid Baz ◽

Jose L Ochoa ◽

Jyotishankar Raychaudhuri ◽

Kara Kosakowski ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Phase I ◽

Research Funding ◽

Stem Cell Mobilization ◽

Cell Transplant ◽

Newly Diagnosed ◽

Long Term Outcome ◽

Cell Mobilization ◽

Grade 3

Abstract Abstract 617 Background: The VDD treatment regimen has been shown to be highly effective as initial therapy for multiple myeloma. Given the established synergy between bortezomib and alkylating agents, incorporating an alkylator to VDD may increase the depth of response and may improve long term outcome. We report the results from a Phase I trial combining VDD with escalating doses of cyclophosphamide ( CVDD) in patients (Pts) with newly diagnosed myeloma. Methods: Pts received Bz 1.0–1.3 mg/m2 on days 1, 4, 8, 11, DOX 30mg/m2 on day 4, Dex 20 mg on days 1, 2, 4, 5, 8, 9, 11, 12 and Cy 250-750 mg/m2 on day 1, for up to eight 21-day cycles, at four planned dose levels (Cy/Bz: 250/1.0, 500/1.0, 750/1.0, 750/1.3). Dose-escalation proceeded (three-pt cohorts) depending on dose-limiting toxicities (DLTs) grade 3 non-hematologic toxicity; thrombocytopenia with platelets <10,000/mm3 on >1 occasion despite transfusion support; Grade 4 neutropenia for >5 days and/or resulting in neutropenic fever; inability to receive cycle 2/day 1 dose due to drug-related toxicity). Pts with Grade 2 peripheral neuropathy (PNY) were excluded. Responses were assessed by International Working Group criteria. Pts with at least partial response ( PR) and standard risk cytogenetics could proceed to autologous stem cell transplant (ASCT) after 6 cycles. Responsive pts with high risk cytogenetics defined as the presence of one of the following at diagnosis; deletion of chromosome 13 by cytogenetics, hypodiploidy, or t (4;14), t(14;16) or deletion of 17 p by FISH, completed 8 cycles of therapy. Results: 26 pts have been enrolled to date: 12 in phase l, and 14 additional pts at the maximum planned dose (MPD). Median age 60 yrs, 62% men, 50% IgG MM, 81% with ISS stage II/III. Pts have received a median of 6 cycles; 17 have completed all 6-8 cycles, 1 has discontinued therapy. No DLTs were observed in the phase I portion of study. Dose reductions in cycle 2 and beyond have occurred in 31% of patients. Toxicities to date have been manageable, including all Grade 3/4 hematological toxicities (4-35%), Grade 3 hand foot syndrome( 15%), Grade 3 pneumonia (8%), Grade 3 UTI (8%), and Grade 3/4 metabolic (19%). There were no grade 3/4 PNY. There was 1 treatment-related mortality secondary to infection. The overall response rate in patients that have completed at least 4 cycles of therapy (ORR; ≥PR) is 90%, including 57% ≥VGPR, and 24% CR. ORR and VGPR rates were similar in patients with standard or high risk cytogenetics. Nine patients have proceeded to transplant and all have had successful stem cell mobilization with G-CSF alone. Conclusions: CVDD produces high quality responses and is well tolerated in newly diagnosed MM pts, regardless of their cytogenetic status or ISS stage. MPD has been reached at CY 750 mg/m2, Bz 1.3 mg/m2, DOX 30 mg/m2, and Dex 20 mg, with phase II enrollment ongoing. Stem cell mobilization has been successful in all pts, with transplant course in pts otherwise unremarkable. Updated efficacy will be presented at the meeting. Disclosures: Alsina: Millenium: Research Funding, Speakers Bureau; Ortho Biotech: Research Funding, Speakers Bureau.

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Inhibition of Lymphocyte Trafficking Using a CCR5 Antagonist – Final Results of a Phase I/II Study

Blood ◽

10.1182/blood.v118.21.1011.1011 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1011-1011 ◽

Cited By ~ 2

Author(s):

Ran Reshef ◽

Selina M. Luger ◽

Elizabeth O. Hexner ◽

Alison W. Loren ◽

Noelle V. Frey ◽

...

Keyword(s):

T Cell ◽

Hiv Infection ◽

Phase I ◽

Research Funding ◽

Acute Gvhd ◽

Lymphocyte Trafficking ◽

Comparator Group ◽

Gvhd Prophylaxis ◽

Grade Iii

Abstract Abstract 1011 Inhibition of lymphocyte trafficking early after allogeneic stem cell transplantation (SCT) may prevent GvHD without interfering with GvL activity. Animal models and genomic data in humans indicate that the interaction between CCR5 and its ligands CCL3, CCL4 and RANTES is pivotal in the pathogenesis of GvHD. Maraviroc (MVC; Selzentry®, Pfizer) is the first oral CCR5 antagonist in clinical use. The antiviral properties of MVC in HIV infection are known, but its effects on chemotaxis and immune function in patients without HIV infection have not been explored. We hypothesized that CCR5 inhibition early after allogeneic SCT would reduce lymphocyte chemotaxis and result in low rates of acute GvHD without impairing engraftment or antitumor activity. In vitro, MVC effectively and specifically inhibited CCR5 internalization and reduced RANTES-induced chemotaxis in concentrations achievable in humans, recapitulating a defect observed in homozygotes for the del32-CCR5 polymorphism. MVC had no effect on hematopoietic colony formation, T-cell mediated cytotoxicity and T-cell proliferation. Between May 2009 and March 2011, we enrolled 38 pts in a phase I/II study of reduced intensity conditioned (RIC) allogeneic SCT. Patients had high-risk features by age (median=62, range 21–74), donor source (matched related 34%, matched unrelated 50%, single-antigen mismatch 16%) and comorbidities (comorbidity index: low 55%, intermediate 34%, high 11%). Underlying diseases were AML (15), MDS (6), NHL (8), myelofibrosis (4), aplastic anemia, myeloma, CLL, Hodgkin, CML (1 each). Pts received fludarabine 120mg/m2 and IV busulfan 6.4 mg/kg followed by peripheral blood stem cells. In addition to standard GvHD prophylaxis with tacrolimus and methotrexate, MVC was given from day −2 to +30. Pharmacokinetic analysis on the first 13 pts identified 300 mg bid as the appropriate dose (Reshef, ASH 2010). MVC was well tolerated, and adverse events were similar to the expected toxicity observed in patients undergoing RIC SCT. The median time to ANC>500/μL was 15 d (range 10–27) and to platelets>20k/μL was 19 d (range 9–84). The median whole blood and T-cell donor chimerism at day 100 was 96.5% (range 0–100%) and 85% (range 0–100%) respectively. Median follow-up was 200 days (range 12–760). Among 35 evaluable patients, the cumulative incidences of any acute GvHD and grade III–IV acute GvHD at day 100 were 14.7 ± 6.2% and 2.9 ± 2.9%, respectively. Importantly, in the first 100 days, there were no cases of acute GvHD involving the liver or gut. At day 180, the rate of acute GvHD was 20.7 ± 7.1%, largely confined to the skin with low rates of GvHD in the liver (3 ± 3%) and gut (7.4 ± 5.3%). In evaluable pts who received a graft from their HLA-matched sibling (11), there was no GvHD before day 100 and only two cases of acute GvHD before day 180. We compared these results to a cohort of 38 well-matched consecutive patients treated at our institution with RIC SCT using an identical regimen but without MVC between 2009 and 2011. We observed a similar incidence of acute GvHD (all grades) at day 100 (14.7 ± 6.2 vs. 16 ± 6.1%; P=0.88), but a 64% decrease in the MVC group at day 180 (20.7 ± 7.1 vs. 45.4 ± 9%; P=0.03). The incidence rates of severe GvHD (grade III–IV) were 2.9 ± 2.9% in the MVC group vs. 5.5 ± 3.8% in the comparator group at day 100 (P=0.59) and 6.5 ± 4.5% vs. 18.1 ± 6.8% at day 180 (P=0.15). Treatment-related mortality in pts receiving MVC was low. At 1 year, non-relapse mortality rate was 7.6 ± 5.5% (control group: 15.7 ± 6.6%; P=0.35). Infectious complications were seen at a rate that is expected with RIC SCT. Recovery of lymphocyte counts and lymphocyte subsets was not impaired by MVC. We evaluated whether a protective effect against GvHD was associated with an increase in relapse. In the MVC group, the incidence of relapse was 34.2 ± 8.8% at day 180; this was not significantly different from the comparator group (43.9 ± 8.8%, P=0.44), implying preservation of the graft-versus-tumor effect with MVC. Rates of overall survival and relapse-free survival were similar in both groups. Pharmacodynamic testing revealed that sera from patients taking MVC prevented CCR5 internalization by RANTES and blocked T-cell chemotaxis in vitro, providing evidence for in vivo biological activity and supporting the hypothesized mechanism of action. In summary, inhibition of lymphocyte trafficking is a novel, specific and potentially effective strategy to reduce the incidence of acute GvHD. Disclosures: Off Label Use: Use of maraviroc in GvHD prophylaxis will be discussed. Frey:Pfizer: Speakers Bureau. Vonderheide:Pfizer: Research Funding. Porter:Pfizer: Research Funding.

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A Phase I Study of Myeloablative I-131-Anti CD-20 (Tositumomab) Radioimmunotherapy with Escalating Doses of Fludarabine Followed by Autologous Hematopoietic Stem Cell Transplantation (ASCT) for Adults ≥ 60 Years of Age with High-Risk or Relapsed/Refractory B-Cell Lymphoma

Blood ◽

10.1182/blood.v118.21.663.663 ◽

2011 ◽

Vol 118 (21) ◽

pp. 663-663

Author(s):

Ajay K. Gopal ◽

Ted Gooley ◽

Joseph Rajendran ◽

John M. Pagel ◽

Darrell R. Fisher ◽

...

Keyword(s):

High Risk ◽

Phase I ◽

B Cell ◽

Radiation Exposure ◽

Research Funding ◽

Cell Lymphoma ◽

Nucleoside Analogs ◽

B Cell Lymphoma ◽

High Dose ◽

Hematopoietic Stem

Abstract Abstract 663 Background: The majority of patients with relapsed or refractory B-cell, non-Hodgkin's lymphoma (NHL) are over 60 years of age, yet many are denied potentially curative high-dose regimens due to concerns of excessive toxicity. We have shown that myeloablative anti-CD20 radioimmunotherapy (RIT) can safely deliver effective radiation doses to tumor sites while limiting exposure to normal organs in older adults requiring high-dose therapy, however, not all patients in this series remained progression-free (Gopal, JCO 2007). Preclinical data suggest that improved anti-tumor activity may be attained by the concurrent administration of nucleoside analogs (fludarabine, cytarabine) which synergize with RIT (Johnson, Int J Cancer; Gopal, BBMT, 2006). We hypothesized that a prolonged regimen of fludarabine could be administered concurrently with myeloablative RIT and ASCT to safely augment the efficacy of this approach. We present the phase I data evaluating this strategy. Methods: Patients were eligible if they were 60 years of age or older, had mantle cell lymphoma (MCL) in first remission or relapsed/refractory B-NHL, an ECOG PS of 0–1, acceptable organ function, >2×106 autologous CD34+ peripheral blood stem cells/kg collected, <20 Gy prior radiation to critical organs, and no human-anti-mouse-antibodies (HAMA). All patients underwent outpatient biodistribution studies for dosimetry using tositumomab (1.7 mg/kg, n=3 or 485mg flat dose, n=33) labeled with ∼10mCi I-131 followed by serial quantitative gamma camera imaging to calculate individualized organ-specific absorbed dose estimates. Patients then received therapeutic infusions of I-131-tositumomab to deliver 27Gy to the critical normal organ receiving the highest radiation exposure. Forty-eight hours later fludarabine was administered in escalating doses to patients (Table) to define a regimen associated with a dose limiting toxicity (DLT = grade III/IV Bearman toxicity) rate of <25%. ASCT occurred when radiation exposure was estimated to be <2mR/hr at 1meter. Filgrastim at 5μg/kg/day or pegfilgrastim at 6mg × 1 was started on day 1. Response was scored using standard criteria. Results: Between July 2005 and May 2011 36 patients were treated. Baseline characteristics included: median age 65 yrs (range 60–76), stage III/IV = 34 (94%), median number of prior regimens = 2 (range 1–9), chemoresistant disease (defined as < a partial response [PR] to the most recent regimen) = 12 (33%), >1 extranodal site = 14 (39%), elevated LDH at treatment = 13 (36%), IPI score at transplant 3–5 = 53%. Histology: MCL = 23, diffuse large B-cell = 8 (with 5 transformed from follicular lymphoma [FL]), FL=3, and marginal zone = 1, Waldenstrom's = 1. Dose limiting organs receiving up to 27Gy included lung (30), kidney (4), and liver (2) with a median administered I-131 activity of 471 mCi (range 260–1620). Fludarabine was escalated from 10 mg/m2/day × 5 days to 30 mg/m2 × 7 days without observation of a DLT (Table). The median CD34 dose was 5.42 ×106/kg with neutrophil (ANC>500μl) and platelet (>20 K/μl) engraftment occurring a median on 10 and 12 days after ASCT, respectively. Only 2 patients developed grade 4 NCI-CTC grade 4 non-hematologic toxicities (hypokalemia/hypophosphatemia, depression), 25 (69%) remained outpatients after discharge from radiation isolation, and there were no non-relapse deaths in the first 100 days after transplant. Responses to therapy were as follows: CR/CRu = 26 (79%), PR = 2 (6%), SD = 4 (11%), and PD = 4 (11%). Currently, 23 (64%) patients are alive with 22 (61%) progression free. The estimated 3 yr overall survival, progression-free survival, relapse, and non-relapse mortality are 54%, 53%, 41%, and 7%, respectively (median follow up of 2.5yrs after ASCT, Figure). Improved survival was associated with <2 prior regimens (HR=.08, p=.02) and chemosensitive disease (HR=.35, p=.07). Conclusions: High-dose (27 Gy) I-131 tositumomab can safely be administered concurrently with up to 210 mg/m2 fludarabine in an older, high-risk patient population. This strategy warrants further investigation as a method to safely augment the antitumor activity of myeloablative RIT. Disclosures: Gopal: GSK: Research Funding; Spectrum: Research Funding; Seattle Genetics: Consultancy, Research Funding; Merck: Research Funding; Piramal: Research Funding; Cephalon: Research Funding; Millenium: Speakers Bureau; Abbott: Research Funding; Pfizer: Research Funding; SBio: Research Funding; Bio Marin: Research Funding; Biogen-Idec: Research Funding. Off Label Use: High-dose use of I-131-tositumomab. Maloney:GSK: Consultancy, Honoraria.

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Initial Results of the Phase I/II Panobidara Study of Panobinostat in Combination with Idarubicin and Cytarabine in Patients Aged 65 Years or Older with Newly Diagnosed Acute Myeloblastic Leukaemia (AML)

Blood ◽

10.1182/blood.v120.21.1512.1512 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1512-1512

Author(s):

Enrique M Ocio ◽

Pilar Herrera ◽

Teresa Olave ◽

Salut Brunet ◽

Albert Oriol ◽

...

Keyword(s):

Overall Survival ◽

Elderly Patients ◽

Phase I ◽

Research Funding ◽

Maintenance Phase ◽

Newly Diagnosed ◽

Term Survival ◽

Deacetylase Inhibitor

Abstract Abstract 1512 Introduction: Acute Myeloblastic Leukemia (AML) in elderly patients remains an unmet medical need with a long term survival rate inferior to 10% despite the use of novel drugs. Therefore, there is a need for new agents that could induce higher CR rates and, most importantly, that could prolong the relapse free survival (RFS) and the overall survival (OS) of these poor-prognosis patients. Agents targeting epigenetics such as the hypomethylating drug 5-Azacitidine, have emerged as a promising strategy for elderly patients with AML or MDS. A second group of drugs targeting the epigenome are deacetylase inhibitors. Panobinostat is a pan-deacetylase inhibitor, with clear in vitro activity in AML and which is synergistic with anthracyclines (Maiso et al. Leukemia 2009). Based on these data we designed a phase I/II trial of panobinostat in combination with idarubicine and cytarabine followed by panobinostat maintenance in newly diagnosed AML patients older than 65 years. Methods: The initial schema included one or two induction cycles with idarubicine (8 mg/m2 days 1–3) + cytarabine (100 mg/m2 days 1–7) followed by escalating doses of panobinostat three days per week, per 3 weeks starting at 20 mg. Patients achieving CR/CRi received a consolidation cycle with the same schema. Those patients remaining in CR/CRi started a maintenance phase with 40 mg oral panobinostat in monotherapy three days per week, for 3 weeks in 28-days cycles. This schedule was amended after the six first patients, to reduce the weeks of administration of panobinostat to two weeks in the cycles in combination and to every other week in the maintenance phase. Initially a dose-escalating phase I with the classical 3+3 schema was carried out to define the maximum tolerated dose (MTD) of panobinostat in this combination; and then a phase 2 expansion phase was started to determine the efficacy of this combination in terms of CR rate and RFS. Results: 21 patients have been included after the amendment. Median age was 71 (range 66–83). Median % blasts was 40 (20–93). 35% of patients had AML with dysplastic features while adverse cytogenetics were present in 24%. Two out of 6 evaluable patients in the first cohort developed DLTs with panobinostat 20 mg (G3 hyperbilirrubinaemia in both, and one of them also G3 oedema), accordingly the dose of panobinostat was reduced to 10 mg. No DLTs were observed at this dose level, so 10 mg panobinostat was defined as the MTD in this combination. Treatment was well tolerated in the intensive cycles with the toxicity proper of standard induction chemotherapy. The most common non-hematologic toxicities (occurring in ≥20% of patients) included: fever (90%), infections (62%), mucositis (52%), diarrhoea (62%), constipation (43%), vomiting (57%), skin rash (38%), hepatotoxicity (38%) and hypokalaemia (24%). Grade 3/4 AEs were fever, infection, diarrhoea and hepatotoxicity in 2 patients each (10%) and hypokalaemia in 5 (24%). The median duration of the aplasia was 32 days (range 26–51). Regarding the maintenance phase with panobinostat monotherapy, the most frequent AEs were gastrointestinal: diarrhoea (62%), vomiting (62%) or abdominal pain (25%); as well as asthenia (50%. One of them being G3) and hyporexia (25%). In terms of efficacy, 11 patients (52%) achieved CR plus 2 more (10%) achieving CR with incomplete blood recovery (CRi) (overall 62%). There were 2 deaths in induction (10%), one due to a tumoral lysis syndrome before starting panobinostat and the other secondary to a respiratory infection. From the remaining 6 patients, 2 achieved partial response (10%) and 4 showed refractory disease (19%). With a median follow up of 6 months (range 2–14), among the 11 patients that achieved CR, 10 of them remain in CR and only 1 has progressed (in the 9th maintenance cycle). Both patients that achieved CRi have progressed in the 2nd and 6thmaintenance cycles. The median overall survival for the whole population is 13 months (2.3–23.6), and has not been reached for patients achieving CR. Conclusion: To the best of our knowledge, this is the first report of the use of a histone deacetylase inhibitor with chemotherapy in elderly AML patients. This combination was shown to be safe at the MTD. Although preliminary results are encouraging, particularly for the potential benefit of the maintenance phase, longer follow up is needed to evaluate if panobinostat maintenance is able to prolong RFS and subsequently OS in this poor prognostic population. Disclosures: Ocio: Novartis: Consultancy, Research Funding. Off Label Use: Panobinostat in newly diagnosed AML. Aliseda:Novartis: Employment. Winiger:Novartis: Employment. Hardikar:Novartis: Employment. Mateos:Novartis: Consultancy. San-Miguel:Novartis: Consultancy, Research Funding.

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