Phase 1 Results of FF-10501-01, a Novel Inosine 5'-Monophosphate Dehydrogenase Inhibitor, in Advanced Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS), Including Hypomethylating Agent (HMA) Failures

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1640-1640 ◽  
Author(s):  
Guillermo Garcia-Manero ◽  
Hui Yang ◽  
Zhihong Fang ◽  
Hagop M. Kantarjian ◽  
Courtney D. DiNardo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Disease Progression ◽  
Cell Lines ◽  
Dose Level ◽  
Research Funding ◽  
De Novo ◽  
Phase 1 ◽  
Clinical Activity ◽  
Guanine Nucleotide ◽  
Bone Marrow Blast

Abstract Inosine 5'- monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme that catalyzes de novo synthesis of the guanine nucleotide and is overexpressed in both hematologic and solid tumors. FF-10501-01 is a potent new competitive IMPDH inhibitor. We investigated the anti-leukemia effect of FF-10501-01 in a Phase 1 clinical study in advanced AML and MDS, including HMA failures. Previous preclinical studies demonstrated potent anti-proliferative and apoptotic effects of FF-10501-01 on AML cell lines, including HMA-resistant derivatives, through inhibition of de novo guanine nucleotide synthesis. Therefore, we performed a standard 3+3 dose-escalation Phase 1 trial to access the safety and clinical activity of FF-10501-01 in patients with advanced AML, MDS and chronic myelomonocytic leukemia (CMML). Eligibility criteria: age ≥ 18 years, high risk MDS/CMML, AML with documented PD following previous therapy, AML ≥ 60 years of age and not a candidate for other therapy, adequate renal and hepatic function, and no known history of significant cardiac disease. A total of 29 patients, 15M and 14F (23 AML, 6 MDS) have been treated in 7 dose cohorts (50 - 500 mg/m2 PO BID) for 14 days on and 14 days off, and 400 mg/m2 for 21 days on and 7 days off, each 28-day cycle. Median (range) values: age 75 yrs (59 - 88); baseline bone marrow blast counts for AML 34% (12 - 82), for MDS 10% (5 - 16), and overall 30% (5 - 82); and prior treatment regimens 2 (1 - 7). All patients relapsed from, or progressed on, prior HMAs. At baseline, mutations in FLT3, NPM1, GATA2, TET2, ASXL1, DNMT3A, NOTCH1, JAK2, IDH2, PTPN11, KRA, TP53, RUNX1, EZH2 and/or MDM2 were present in 13 of 29 (45%) of patients. Atrial fibrillation (Gr 2) was reported in 2 subjects at a dose of 500 mg/m2 BID. This met the definition of dose-limiting toxicity (DLT) and no further enrollment was made at this dose level. The maximally tolerated dose (MTD) was declared at 1 dose level lower, 400 mg/m2 BID, and this cohort was expanded to 6 subjects. No DLTs have been observed in N=7 total subjects treated at 400 mg/m2 BID x 14 days. FF-10501-01 has been very well tolerated through 24 cycles. The most frequent drug-related AEs have been Gr 1-2 nausea, diarrhea and fatigue. Drug-related thrombocytopenia, neutropenia and bone marrow aplasia (all Gr 4) were reported in 1 patient at 200 mg/m2 BID. The median number of FF-10501-01 cycles received to date is 2 (range 1 - 24). Partial remissions have occurred in 2 AML patients (50 and 100 mg/m2 BID) after 3 cycles, lasting for 5 and 24 cycles, respectively, with the higher dose patient still on study after 24 cycles. A total of 8/23 (34.8%) AML patients, including the 2 PRs, have attained stable disease (SD) control with no disease progression over 3 - 24 cycles. Three AML patients remain on study through 3, 23 and 24 cycles, respectively. A bone marrow complete response was achieved in 1 MDS patient treated at 400 mg/m2 BID after 1 cycle. Although the bone marrow blast counts have increased since, this patient remains stable and is still on therapy through 14 cycles. Three of 6 MDS patients (50%), including the marrow CR, attained SD control with no disease progression over 3, 14 and 14 cycles, and 2 remain on study through 3 and 14 cycles, respectively. FF-10501-01 was rapidly absorbed with mean Tmax of 2.74 hours and mean t1/2 of 4.05 hours. Drug exposure (AUC0-24 and AUCcourse) increased with dose in a near linear manner. Potent suppression of circulating xanthine monophosphate (XMP), a marker of IMPDH activity, has been observed following FF-10501-01 administration on Day 1 of Cycles 1 and 2 at dose levels of 50 mg/m2 BID and above. FF-10501-01 is a promising new agent for the treatment of advanced AML and MDS in patients who have failed or progressed on HMAs and with one or more baseline mutations in pathways known to be affected in AML and MDS. Preclinical activity was seen in multiple leukemia cell lines, including HMA-resistant derivatives. In a Phase 1 trial, clinical activity with a marrow CR, PRs, long-term disease stabilization (≥ 5 cycles) and a highly tolerable safety profile were observed. The Phase 2a expansion phase of the study is soon to begin. Disclosures DiNardo: Agios: Research Funding; Daiichi Sankyo: Research Funding; Celgene: Research Funding; Novartis: Research Funding; Abbvie: Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Daver:BMS: Research Funding; Kiromic: Research Funding; Pfizer: Consultancy, Research Funding; Otsuka: Consultancy, Honoraria; Ariad: Research Funding; Karyopharm: Honoraria, Research Funding; Sunesis: Consultancy, Research Funding. Denton:Westat Corporation: Employment. Smith:Westat Corporation: Employment. Tiefenwerth:Westat Corporation: Employment. Iwamura:FUJIFILM Corporation: Employment. Gipson:Strategia Therapeutics, Inc.: Employment. Rosner:Strategia Therapeutics, Inc.: Employment. Myers:Strategia Therapeutics, Inc.: Employment. Paradiso:Strategia Therapeutics, Inc.: Employment.

scholarly journals Anti-Leukemia Effect of FF-10501-01, a Novel Inosine 5'-Monophosphate Dehydrogenase Inhibitor, in Advanced Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS), Including Hypomethylating Agent (HMA) Failures

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3800-3800 ◽  
Author(s):  
Guillermo Garcia-Manero ◽  
Hui Yang ◽  
Zhihong Fang ◽  
Courtney DiNardo ◽  
Elias Jabbour ◽  
...  
Keyword(s):  
Cell Line ◽  
Cell Lines ◽  
Research Funding ◽  
De Novo ◽  
Phase 1 ◽  
Leukemia Cell ◽  
Clinical Activity ◽  
Guanine Nucleotide ◽  
Leukemia Cell Lines ◽  
Induced Apoptosis

Abstract Inosine 5'- monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme that catalyzes de novo synthesis of the guanine nucleotide and is overexpressed in both hematologic and solid tumors. FF-10501-01 is a potent new competitive IMPDH inhibitor. We investigated the anti-leukemia effect of FF-10501-01 in AML cell lines and in a Phase 1 clinical study in advanced AML and MDS, including HMA failures. Thirteen leukemia cell lines were studied, including 5 parental AML cell lines and their HMA-resistant derivatives (MOLM13, SKM1, HL60, TF1, and U937), and 3 other AML cell lines (KG1, HEL, and OCI-AML3). Cell proliferation was determined using trypan blue analysis. Flow cytometry was performed to detect drug-induced apoptosis and cell cycle analysis. High-performance liquid chromatography (HPLC) was performed to detect the intracellular concentrations of guanine nucleotides. Mycophenolic acid-treated cells were used as positive control. Effect of guanosine supplement on FF-10501-01 treatment was evaluated. Within 72 hours of treatment, FF-10501-01 inhibited proliferation of all 13 AML cell lines. The IC50 of FF-10501-01 ranged between 4.3 and 144.5 µM. MOLM13 was the most sensitive leukemia cell line, whereas the decitabine-resistant TF1 cell line was the most resistant. FF-10501-01-induced apoptosis was observed in all cell lines. Increased numbers of cells in G1 phase and decreased numbers in S phase were observed in MOLM13, SKM1 and TF1 cell lines treated with <100 µM FF-10501-01. Decreased intracellular concentrations of guanine nucleotides were observed in MOLM13 and SKM1 cell lines treated with 3 to 30 µM of FF-10501-01 for 24 hours. Proliferation was partially rescued after 72 hours of treatment with 3 µM guanosine and FF-10501-01 in MOLM-13, HL60 cells and their HMA-resistant derivatives. No treatment synergy was observed with the combination of FF-10501-01 with HMAs in MOLM-14 and HL-60 or their HMA-resistant cell lines. In summary, FF-10501-01 produced potent anti-proliferative and apoptotic effects on AML cell lines through inhibition of de novo guanine nucleotide synthesis. In view of these pre-clinical findings, we performed a standard 3+3 dose-escalation Phase 1 trial to access the safety and clinical activity of FF-10501-01 in patients with advanced AML, MDS and chronic myelomonocytic leukemia (CMML). Eligibility criteria: age ³ 18 years, high risk MDS/CMML, AML with documented PD following previous therapy, AML ≥ 60 years of age and not a candidate for other therapy, adequate renal and hepatic function, and no known history of significant cardiac disease. Sixteen patients (12 AML, 4 MDS) have been enrolled in 5 dose cohorts (50 - 400 mg/m2 PO BID) for 14 days on/14 days off each 28-day cycle, including 8 M and 8 F. Median (range) values: age 75.3 yrs (59.1 - 88.6); bone marrow blasts for AML patients 40.5% (12 - 71), for MDS patients 10% (6 - 13), or 30% overall (6 - 71); and prior treatment regimens 2.5 (1 - 6). All patients relapsed from, or progressed on, prior HMAs. Mutations in FLT3, NPM1, GATA2, TET2, ASXL1, DNMT3A and/or MDM2 were present in 4/16 (25%) patients. The median number of FF-10501-01 cycles received to date is 1.5 (range 1 - 10). No DLTs or drug-related serious adverse events (AEs) have been observed and FF-10501-01 has been very well tolerated through 5 - 10 cycles. The most frequent drug-related AEs have been Gr 1-2 nausea, diarrhea and fatigue. Drug-related Gr 4 prolonged thrombocytopenia and Gr 4 prolonged neutropenia were reported in one patient at 200 mg/m2 BID. Two partial responses (PRs) have been achieved in 1 patient each at 50 and 100 mg/m2 BID after 3 cycles, 7 (50%) patients demonstrated long-term stable disease over 2 - 10 cycles, and 4 patients have remained on study drug through 5 - 10 cycles and are still ongoing. Updated safety and efficacy data, including PK/PD, will be presented at the meeting. FF-10501-01 is a promising new agent for the treatment of advanced AML and MDS. Preclinical activity was seen in multiple leukemia cell lines. In a Phase 1 trial, clinical activity with PRs, prolonged disease stabilization and a highly tolerable safety profile were observed. The Phase 2 expansion phase will be initiated soon. Disclosures DiNardo: Novartis: Research Funding. Pemmaraju:Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Smith:Westat Corporation: Employment. Iwamura:FUJIFILM Corporation: Employment. Gipson:Strategia Therapeutics, Inc.: Employment. Rosner:Strategia Therapeutic, Inc.: Employment. Madden:Strategia Therapeutics, Inc.: Employment. Myers:Strategia Therapeutics, Inc.: Employment. Paradiso:Strategia Therapeutics, Inc.: Employment.

Combined Autophagy and Proteasome Inhibition for Multiple Myeloma: Final Results of a Phase 1 Trial of Hydroxychloroquine and Standard Dose Bortezomib for Patients with Relapsed or Refractory Myeloma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1869-1869 ◽  
Author(s):  
Dan T. Vogl ◽  
Edward A. Stadtmauer ◽  
James Bradner ◽  
Lisa Davis ◽  
Thomas M. Paul ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Disease Progression ◽  
Dose Level ◽  
Stable Disease ◽  
Peripheral Blood ◽  
Research Funding ◽  
Plasma Cells ◽  
Proteasome Inhibition ◽  
Bone Marrow Plasma ◽  
Grade 3

Abstract Abstract 1869 BACKGROUND: The aggresome/autophagy pathway is the primary mechanism for disposal of ubiquitinated proteins for cells exposed to proteasome inhibition. Preclinical evidence shows that combining inhibition of the proteasome with bortezomib (Bz) and inhibition of autophagy with the anti-malarial drug hydroxychloroquine (HCQ) leads to enhanced cytotoxicity in myeloma cells. METHODS: Patients with relapsed or refractory myeloma enrolled on a standard 3+3 dose escalation design. Patients received 2-weeks of single-agent oral HCQ, followed by the addition of Bz on days 1, 4, 8, and 11 of 21-day cycles. HCQ and Bz doses were determined by dose level: (1) 200 mg qod / 1.0 mg/m2, (2) 200 qod / 1.3, (3) 200 qd / 1.3, (4) 200 bid / 1.3, (5) 400 bid / 1.3, (6) 600 bid / 1.3. Dose-limiting toxicity (DLT) was defined as grade ≥3 toxicity probably related to study therapy and occurring during the first 5 weeks, with the exception of any anemia or lymphopenia, neutropenia responsive to growth factor, platelets >10,000/mm3 not associated with bleeding, or gastrointestinal complaints relieved by symptomatic therapy. We used electron microscopy to characterize changes in autophagic vesicles in serial samples of peripheral blood mononuclear cells and CD138-selected bone marrow plasma cells. RESULTS: We enrolled 25 patients between 1/2008 and 2/2011, of which 21 patients completed at least 1 cycle of combined therapy and were evaluable for toxicity. The median duration of study participation was 14 weeks (range 1–77). Reasons for study discontinuation were side effects of therapy (6), lack of response (7), disease progression (11), and non-compliance (1). No protocol-defined dose limiting toxicities occurred, and the maximum tolerated dose was determined to be the top dose level of Bz 1.3 mg/m2 and HCQ 600 mg twice daily. Hematologic abnormalities were generally more attributable to disease progression than to treatment toxicity, but at the top dose level one patient had grade 3 thrombocytopenia and neutropenia after starting with a normal platelet count and ANC, without evidence of progression through therapy. At the top dose level, gastrointestinal toxicities predominated, including 5 out of 6 evaluable patients with some form of grade 3 GI toxicity. Treatment emergent neuropathy occurred in 7 patients but was restricted to grade 1 or 2 and was easily managed with dose reduction of the Velcade. Three patients came off study before receiving the combined regimen and were not evaluable for response. The best responses for the remaining 22 patients included 3 near complete responses (nCR), 3 minor responses (MR), 9 stable disease (SD), and 7 progression (PD). The 3 nCRs occurred in Bz-naïve patients receiving HCQ at 400 mg/d (1 pt) and 1200 mg/d (2 pts). Two patients who had previously progressed while receiving weekly maintenance Bz had MRs on study, including one who maintained a MR for over 7 months. Three additional Bz-refractory patients initially achieved stable disease during study treatment, with on study TTP of 8 weeks (at HCQ 1200 mg/d), 15 weeks (100 mg/d), and 17 weeks (200 mg/d). Preliminary analyses of vesicle counts at HCQ doses up to 800 mg/d identify individual patients with increases in autophagic vesicles in either peripheral blood or bone marrow plasma cells, but these are not consistent, nor is there any evident correlation with response. CONCLUSION: Combined Bz and HCQ is tolerable, with a phase 2 dose of Bz 1.3 mg/m2 and HCQ 1200 mg/d and likely hematologic and gastrointestinal DLTs. There is a suggestion of improved efficacy over Bz alone, with minor responses and long periods of stable disease in Bz-refractory patients. Final analysis of autophagy inhibition in correlative specimens, including the top dose cohort, will be available for the meeting. Disclosures: Vogl: Millennium Pharmaceuticals: Honoraria, Research Funding. Off Label Use: Hydroxychloroquine is FDA approved for treatment of malaria and rheumatoid arthritis. This paper discusses its use in treatment of myeloma. Carroll:Agios Pharmaceuticals: Research Funding; TetraLogic Pharmaceuticals: Research Funding; Sanofi Aventis Corporation: Research Funding; Glaxo Smith Kline, Inc.: Research Funding. Amaravadi:Millennium Pharmaceuticals: Honoraria, Research Funding.

scholarly journals Phase 1/2 Study of Nexi-001 Donor-Derived Multi-Antigen Specific CD8+ T Cells for the Treatment of Relapsed Acute Myeloid Leukemia (AML) after Allogeneic Hematopoietic Transplantation

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4819-4819
Author(s):  
Monzr M. Al Malki ◽  
Sumithira Vasu ◽  
Dipenkumar Modi ◽  
Miguel-Angel Perales ◽  
Lucy Y Ghoda ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Board Of Directors ◽  
Cd8 T Cells ◽  
Research Funding ◽  
Phase 1 ◽  
Clinical Activity ◽  
Advisory Committees ◽  
Over Time

Abstract Patients who relapse after allogeneic HCT have a poor prognosis and few effective treatment options. Responses to salvage therapy with donor lymphocyte infusions (DLI) are driven by a graft versus leukemia (GvL) effect. However, relapses and moderate to severe graft versus host disease (GVHD) are common. Therapies that increase the GvL effect without inducing GVHD are needed. The NEXI-001 study is a prospective, multicenter, open-label phase 1/2 trial designed to characterize the safety, immunogenic, and antitumor activity of the NEXI-001 antigen specific T-cell product. This product is a donor-derived non-genetically engineered therapy that consists of populations of CD8+ T cells that recognize HLA 02.01-restricted peptides from the WT1, PRAME, and Cyclin A1 antigens. These T cells consist of populations with key memory phenotypes, including stem-like memory, central memory, and effector memory cells, with a low proportion (&lt;5%) of potentially allogeneic-reactive T-naïve cells. Patients enrolled into the first cohort of the dose escalation phase received a single infusion of 50 million (M) to 100M cells of the NEXI-001 product. Bridging anti-AML treatment was permitted during the manufacture of the cellular product with a wash-out period of at least 14 days prior to lymphodepletion (LD) chemotherapy (intravenous fludarabine 30 mg/m 2 and cyclophosphamide 300 mg/m 2) that was administered on Days -5, -4, and -3 prior to the infusion of the NEXI-001 product up to 72 hours later (Day1). Lymphocyte recovery to baseline levels occurred as early as three days after the NEXI-001 product infusion with robust CD4 and CD8 T cell reconstitution after LD chemotherapy. NEXI-001 antigen specific T cells were detectable in peripheral blood (PB) by multimer staining and were found to proliferate over time and to traffic to bone marrow. The phenotype composition of detectable antigen specific T cells at both sites was that of the infused product. T-cell receptor (TCR) sequencing assays revealed T cell clones in the NEXI-001 product that were not detected in PB of patients tested at baseline. These unique clones subsequently expanded in PB and bone marrow (BM) and persisted over time. Neutrophil recovery, decreased transfusion burden of platelets and red blood cells, and increased donor chimerism were observed. Decreases in myeloblasts and reduction in the size of an extramedullary myeloid sarcoma were suggestive of clinical activity. One patient, a 23-year- old with MRD+ disease at baseline, received two doses of 200M NEXI-001 cells separated by approximately 2 months. Following the first infusion, antigen specific CD8+ T cells increased gradually in PB to 9% of the total CD3+ T cell population just prior to the second infusion and were found to have trafficked to bone marrow. By Day 2 following the second infusion, which was not preceded by LD chemotherapy, the antigen specific CD8+ T cells again increased to 9% of the total CD3+ T cell population in PB and remained at ≥5% until the end of study visit a month later. The absolute lymphocyte count increased by 50% highlighting continued expansion of the NEXI-001 T cells. These cells also maintained significant Tscm populations. Treatment related adverse events, including infusion reactions, GVHD, CRS, and neurotoxicity (ICANS), have not developed in these patients who have received 50M to 200M T cells of the NEXI-001 product either as single or repeat infusions. In conclusion, these results show that infusion of the NEXI-001 product is safe and capable of generating a cell-mediated immune response with early signs of clinical activity. A second infusion is associated with increasing the level of antigen specific CD8+ T cells and their persistence in PB and BM. TCR sequencing and RNA Seq transcriptional profiling of the CD8+ T cells are planned, and these data will be available for presentation during the ASH conference. At least two cycles of 200M NEXI-001 cells weekly x 3 weeks of a 4-week cycle is planned for the next dose-escalation cohort. Early data suggest that the NEXI-001 product has the potential to enhance a GvL effect with minimal GVHD-associated toxicities. Disclosures Al Malki: Jazz Pharmaceuticals, Inc.: Consultancy; Neximmune: Consultancy; Hansa Biopharma: Consultancy; CareDx: Consultancy; Rigel Pharma: Consultancy. Vasu: Boehringer Ingelheim: Other: Travel support; Seattle Genetics: Other: travel support; Kiadis, Inc.: Research Funding; Omeros, Inc.: Membership on an entity's Board of Directors or advisory committees. Modi: MorphoSys: Membership on an entity's Board of Directors or advisory committees; Seagen: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding. Perales: Sellas Life Sciences: Honoraria; Novartis: Honoraria, Other; Omeros: Honoraria; Merck: Honoraria; Takeda: Honoraria; Karyopharm: Honoraria; Incyte: Honoraria, Other; Equilium: Honoraria; MorphoSys: Honoraria; Kite/Gilead: Honoraria, Other; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Medigene: Honoraria; NexImmune: Honoraria; Cidara: Honoraria; Nektar Therapeutics: Honoraria, Other; Servier: Honoraria; Miltenyi Biotec: Honoraria, Other. Edavana: Neximmune, Inc: Current Employment. Lu: Neximmune, Inc: Current Employment. Kim: Neximmune, Inc: Current Employment. Suarez: Neximmune, Inc: Current Employment. Oelke: Neximmune, Inc: Current Employment. Bednarik: Neximmune, Inc: Current Employment. Knight: Neximmune, Inc: Current Employment. Varela: Kite: Speakers Bureau; Nexlmmune: Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Hematologic Malignancies Exhibit Selective Vulnerability to Inhibition of De Novo Pyrimidine Biosynthesis By AG-636, a Novel Inhibitor of Dihydroorotate Dehydrogenase in Phase 1 Clinical Trials

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1570-1570
Author(s):  
Danielle Ulanet ◽  
Victor Chubukov ◽  
John Coco ◽  
Gabrielle McDonald ◽  
Mya Steadman ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Solid Tumor ◽  
Research Funding ◽  
De Novo ◽  
Phase 1 ◽  
Cancer Cell Lines ◽  
Pyrimidine Biosynthesis ◽  
Employment Equity ◽  
Equity Ownership

Rapidly proliferating cells reprogram metabolism to support increased biosynthetic demands, a feature that can expose targetable vulnerabilities for therapeutic intervention. A chemical biology screen was performed in an effort to identify metabolic vulnerabilities in particular tumor subtypes, and revealed potent and selective activity of a novel dihydroorotate dehydrogenase (DHODH) inhibitor, AG-636, in cancer cell lines of hematologic origin. In contrast, cancer cell lines of solid tumor origin exhibited comparatively poor sensitivity. Evaluation of a lymphoma cell line panel demonstrated broad responsiveness to DHODH inhibition, independent of clinical subtype (e.g. ABC, GCB, double-hit). The on-target cellular activity of AG-636 was evaluated by examining the metabolic effects of AG-636 on cells and by evaluating the ability of extracellular uridine to rescue the effects of AG-636 on proliferation and viability. The metabolic changes incurred upon treatment of cells with AG-636 were consistent with a mechanism of action driven by inhibition of DHODH and de novo pyrimidine biosynthesis. Supraphysiologic concentrations of extracellular uridine rescued the effects of AG-636 on growth and viability as well as the effects on metabolism, further confirming on-target activity. The mechanistic basis for differential sensitivity to AG-636 was assessed by comparing the activity of the de novo pyrimidine biosynthesis and uridine salvage pathways in cancer cell lines of hematologic or solid tumor origin with similar proliferative rates. Differential response to AG-636 could not be attributed to varying abilities to utilize the de novo pyrimidine biosynthesis pathway or to salvage extracellular uridine. Real-time imaging of cells treated with AG-636, along with monitoring of extracellular uridine concentrations, demonstrated immediate effects on the viability of lymphoma cell lines in the setting of depleted extracellular uridine. In contrast, solid tumor cell lines were able to maintain growth for an additional period of time, suggestive of adaptive mechanisms to supply pyrimidine pools and/or to cope with nucleotide stress. The high in vitro activity of AG-636 in cancer cells of hematologic origin translated to xenograft models, including an aggressive, patient-derived xenograft model of triple-hit lymphoma and an ibrutinib-resistant model of mantle cell lymphoma in which complete tumor regression occurred. These studies support the development of AG-636 for the treatment of hematologic malignancies. A phase 1 study has been initiated in patients with relapsed/refractory lymphoma (NCT03834584). Disclosures Ulanet: Agios: Employment, Equity Ownership. Chubukov:Agios: Employment, Equity Ownership. Coco:Agios: Employment, Equity Ownership. McDonald:Agios: Employment, Equity Ownership. Steadman:Agios: Employment, Equity Ownership. Narayanaswamy:Agios: Employment, Equity Ownership. Ronseaux:Agios: Employment, Equity Ownership. Choe:Agios: Employment, Equity Ownership. Truskowski:Agios: Employment, Equity Ownership. Nellore:Aurigene Discovery Technologies: Employment. Rao:Firmus Laboratories: Employment, Equity Ownership. Lenz:Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Agios: Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy; AstraZeneca: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Employment, Honoraria, Research Funding, Speakers Bureau. Cooper:Agios: Employment, Equity Ownership. Murtie:Agios: Employment. Marks:Agios: Employment, Equity Ownership.

Phase I Trial of the Targeted Alpha-Particle Nano-Generator Actinium-225 (225Ac)-Lintuzumab (Anti-CD33; HuM195) in Acute Myeloid Leukemia (AML)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 768-768 ◽  
Author(s):  
Joseph G. Jurcic ◽  
Todd L. Rosenblat ◽  
Michael R. McDevitt ◽  
Neeta Pandit-Taskar ◽  
Jorge A. Carrasquillo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase I ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Clinical Activity ◽  
Bone Marrow Blast ◽  
Elimination Kinetics ◽  
Advisory Committees ◽  
Dose Levels

Abstract Abstract 768 Background: Lintuzumab, a humanized anti-CD33 antibody, targets myeloid leukemia cells and has modest activity against AML. To increase the antibody's potency yet avoid nonspecific cytotoxicity seen with β-emitting isotopes, the α-emitter bismuth-213 (213Bi) was conjugated to lintuzumab. Substantial clinical activity was seen in phase I and II trials, but the use of 213Bi is limited by its 46-min half-life. The isotope generator, 225Ac (t½=10 days), yields 4 α-emitting isotopes and can be conjugated to a variety of antibodies using DOTA-SCN. 225Ac-labeled immunoconjugates kill in vitro at radioactivity doses at least 1,000 times lower than 213Bi analogs and prolong survival in mouse xenograft models of several cancers (McDevitt et al. Science 2001). Methods: We are conducting a first-in-man phase I dose escalation trial to determine the safety, pharmacology, and biological activity of 225Ac-lintuzumab in AML. Results: Fifteen patients (median age, 62 yrs; range, 45–80 yrs) with relapsed (n=10) or refractory (n=5) AML were treated to date. Patients received a single infusion of 225Ac-lintuzumab at doses of 0.5 (n=3), 1 (n=4), 2 (n=3), 3 (n=3), or 4 (n=2) μCi/kg (total administered activity, 23–402 μCi). No acute toxicities were seen. Myelosuppression was the most common toxicity; the median time to resolution of grade 4 leukopenia was 26 days (range, 0–71 days). DLT was seen in 3 patients, including myelosuppression lasting >35 days in 1 patient receiving 4 μCi/kg and death due to sepsis in 2 patients treated at the 3 and 4 μCi/kg dose levels. Febrile neutropenia was seen in 4 patients, and 4 patients had grade 3/4 bacteremia. Extramedullary toxicities were limited to transient grade 2/3 liver function abnormalities in 4 patients. With a median follow-up of 2 mos (range, 1–24 mos), no evidence of radiation nephritis was seen. We analyzed plasma pharmacokinetics by gamma counting at energy windows for 2 daughters of 225Ac, francium-221 (221Fr) and 213Bi. Two-phase elimination kinetics were seen with mean plasma t½-α and t½-β of 1.9 and 35 hours, respectively. These results are similar to other lintuzumab constructs labeled with long-lived radioisotopes. Peripheral blood blasts were eliminated in 9 of 14 evaluable patients (64%), but only at doses of ≥1 μCi/kg. Bone marrow blast reductions were seen in 8 of 12 evaluable patients (67%) at 4 weeks, including 6 patients (50%) who had a blast reduction of ≥50%. Three patients treated with 1, 3, and 4 μCi/kg achieved bone marrow blast reductions to ≤5%. Conclusions: This is the first study to show that therapy with a targeted α-particle generator is feasible in humans. 225Ac-lintuzumab has antileukemic activity across all dose levels. Accrual to this trial continues to define the MTD. Disclosures: Jurcic: Actinium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. McDevitt:Actinium Pharmaceuticals, Inc.: Consultancy, Research Funding. Cicic:Actinium Pharmaceuticals, Inc.: Employment, Equity Ownership, Patents & Royalties. Scheinberg:Actinium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.

Pharmacokinetic (PK) and Pharmacodynamic (PD) Results of a Novel, First-in-Class Modulator of Eukaryotic Translation Initiation Factor 5A (eIF5A) in Patients (pts) with Relapsed or Refractory B-Cell Malignancies: Data from a Phase 1-2 Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2121-2121
Author(s):  
Alice S Bexon ◽  
Michael Craig ◽  
David S. Siegel ◽  
William Bensinger ◽  
Nicolas Novitzky ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Death ◽  
B Cell ◽  
Dose Level ◽  
Plasmid Dna ◽  
Research Funding ◽  
Phase 1 ◽  
Serum Concentrations ◽  
Tnf Α ◽  
Dose Levels

Abstract Introduction eIF5A is the only known protein to be modified by hypusination and is highly conserved across species. Hypusinated eIF5A, the predominant form in normal and cancer cells, is involved in cell survival and inflammatory pathway activation. siRNAs targeting eIF5A inhibit NF-kB activation and reduce pro-inflammatory cytokine production. Accumulation of the unhypusinated lysine form of eIF5A is associated with apoptosis. Mutants of eIF5A that cannot be hypusinated (e.g. eIF5AK50R) are pro-apoptotic in vitro and have anti-tumoral activity in vivo in multiple cancer types including melanoma and lung cancer. SNS01-T is a novel therapeutic with a dual mechanism of eIF5A modulation: inducing cell death via siRNA-mediated inhibition of hypusinated eIF5A while simultaneously causing over-expression of pro-apoptotic eIF5AK50R via a DNA plasmid with a B-cell promoter to induce tumor cell death. SNS01-T significantly inhibited tumor growth and increased survival in mouse models of myeloma (MM), mantle cell and diffuse large B-cell lymphoma. The phase 1-2 study of SNS01-T has completed 4 planned dosing cohorts 0.0125, 0.05, 0.2 and 0.375 mg/kg twice weekly IV for 6 weeks in pts with refractory B-cell cancers. Methods PK and PD secondary endpoints included characterization of PK by measuring pExp5A plasmid DNA and eIF5A siRNA in blood and bone marrow (BM), assessing potential immunogenicity of SNS01-T by measuring serum concentrations of antibodies against SNS01-T nanoparticles, and measuring serum concentrations of select proinflammatory cytokines by enzyme-linked immunosorbent assay in serum and plasma samples. Blood PK timepoints were 30 minutes before the first infusion and at 30 minutes, 2, 6, and 24 hours after the first infusions on Week 1, Week 3, and Week 6 and at the 4, 8, and 12 week visits after the last infusion; BM samples were collected 1 day after the final infusion. Serum and plasma PD sampling timepoints were 30 minutes before and at 2, 6, and 24 hours after the first infusion on Week 1, Week 3, and Week 6, and at 4 weeks after the final infusion. Cytokines assayed included TNF-α, IFN-α, IFN-ß, IFN-g, CXCL1, IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-10, and IL-12. Results Table 1 shows data available for interpretation as of August 2014. The remaining samples are under analysis and will be presented. Abstract 2121. Table 1:Data available for interpretation (number of patients)SNS01-T DoseOverall(n=18)0.0125 mg/kg(n=6)0.05 mg/kg(n=4)0.2 mg/kg(n=4)0.375 mg/kg(n=4)Blood PK DNA and RNA156441Bone marrow PK82321Serum antibodies to SNS01-T nanoparticles186444Serum and plasma cytokines156441 Plasmid and siRNA blood levels generally peaked 30 minutes post-dosing at weeks 1, 3 and 6 of dosing. Both plasmid and siRNA exhibited rapid clearance from the blood, with levels dropping to near pre-dosing levels within 24 hours of administration. pExp5A plasmid DNA was detectable in the bone marrow of 2 pts at cohort 1, 2 at cohort 2, 1 at cohort 3 and 1 at cohort 4. eIF5A siRNA was not detectable in bone marrow. No antibodies to SNS01-T nanoparticles were detected at any timepoint at any dose level. Cytokines remained within the expected range of inter-patient variability, similar to baseline across all timepoints at the first 2 dose levels. At dose level 3, levels of IL-6, IL-8 and TNF-α in particular increased at the 2 and 6 hour timepoints but had recovered to baseline levels 24-hours post dosing. This effect was more pronounced at the first infusion. Conclusions PCR analysis demonstrated the presence of both plasmid DNA and siRNA components of SNS01-T in blood at all dose levels, with a dose-dependent increase in plasmid copy number. Plasmid DNA was also detected in bone marrow collected 24 hours after the final infusion of SNS01-T. Pro-inflammatory cytokines did increase within hours of infusion but returned to baseline within 24 hours, synchronous with the clinical infusion reactions (see Abstract 70148). No evidence of an anti-SNS01-T antibody response was observed in any subject. Phase 2 trials are planned. Disclosures Bexon: Senesco: Consultancy. Craig:Senesco: PI Other. Siegel:Senesco: PI Other. Bensinger:Senesco: PI Other. Novitzky:Senesco: PI Other. McDonald:Senesco: PI Other. Gutierrez:Senesco: PI Other. Libby:Senesco: PI Other. van Rhee:Senesco: PI Other. Heidel:Senesco: Consultancy. Thompson:Senesco: Consultancy, Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Barranco:Senesco: Consultancy. Taylor:Senesco: Research Funding. Browne:Senesco: Employment. Kurman:Senesco: Consultancy. Lust:Senesco: PI Other. Dondero:Senesco: Employment.

KB004, a Novel Non-Fucosylated Humaneered® Antibody, Targeting EphA3, Is Active and Well Tolerated in a Phase I/II Study of Advanced Hematologic Malignancies

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3756-3756 ◽  
Author(s):  
Ronan T Swords ◽  
Andrew H Wei ◽  
Simon Durrant ◽  
Anjali S. Advani ◽  
Mark S Hertzberg ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase I ◽  
Dose Level ◽  
Research Funding ◽  
Hematologic Malignancies ◽  
Clinical Activity ◽  
Bone Marrow Biopsies ◽  
Infusion Reactions ◽  
Equity Ownership ◽  
Dose Levels

Abstract Background: EphA3 is a novel drug target involved in cell positioning in fetal development. In adults it is an oncofetal antigen, that is re-expressed in hematologic malignancies (blood and bone marrow, leukemic stem cells) and solid tumors. It is also upregulated in diseases characterized by abnormal proliferation and fibrosis, such as idiopathic pulmonary fibrosis and diabetic kidney disease. KB004 is a Humaneered® high affinity antibody (KD = 610 pM) targeting EphA3 with at least 3 possible mechanisms of action: direct apoptosis in tumor cells, activation of ADCC and disruption of tumor vasculature. Objectives: The primary objectives of the Phase I study component are to determine safety and MTD for KB004 in patients with hematologic malignancies, refractory to or unfit for chemotherapy. Secondary objectives are to characterize PK, immunogenicity, and preliminary clinical activity of KB004. Exploratory objectives include evaluation of EphA3 expression on tumor, stromal, and endothelial cells. Methods: Multicenter Phase I/II study. Key eligibility criteria: unsuitable for standard of care or relapsed or refractory hematologic malignancy, ECOG PS 0-1, adequate organ function, platelets ≥ 10,000/uL (untransfused for 7 days) and normal coagulation times. KB004 was administered as a 1-2 hr intravenous infusion on days 1, 8, and 15 of each 21-day cycle, at incremental doses of 20, 40, 70, 100, 140, 190, 250 and 330 mg. At 70 mg and above infusion reaction prophylaxis included H1 and H2 blockers, acetaminophen and IV steroids. Safety and activity by IWG response criteria were assessed. Peripheral blood and bone marrow biopsies for PK analysis and EphA3 expression were also collected. Results: A total of 50 patients (AML 39, MDS 7, DLBCL 1, MF 3) received KB004 in the phase I/dose finding component of the study, which has been completed. The most common toxicities were transient grade 1 and grade 2 transient infusion reactions (IRs) in 79% of patients. IRs were characterized by chills, elevated temperature, fever, rigors, back pain, nausea, vomiting, hypotension, hypertension and transient hypoxia (in 2 cases). No other significant KB004 related toxicity was observed. Two patients discontinued KB004 due to an IR. One of these (grade 3) defined a DLT at the 330mg dose level. A second patient at 330mg had grade 2 infusion reactions associated with multiple infusion delays. These observations prompted expansion of the next lowest dose cohort, 250mg. Six evaluable patients were treated at this dose level. No clinically significant IRs or DLTs were observed. This is therefore the recommended phase 2 dose (RP2D). At all dose levels observed Cmax for KB004 was approximately dose proportional. Sustained exposure above the predicted effective concentration (1ug/mL) to cover the 7-day interval between doses was achieved above 190mg. Responses according to IWG criteria were observed in patients with AML, MF and MDS at the 20 mg, 140g and 250mg dose levels, respectively. At 20mg, a 78 yr-old patient with relapsed AML achieved CRp. Remission was sustained for over 18 months and relapse was preceded by a rise in EphA3 expression. Serial bone marrow biopsies with KB004 treatment show decreased reticulin and collagen fibrosis. At 140mg, a 67 yr old patient with JAK2 V617F mutant previously untreated myelofibrosis whose predominant clinical problem at diagnosis was anemia achieved Clinical Improvement [CI]. Transfusion independency (both RBC and platelets) has been sustained for 8+ months with improvement in constitutional symptoms and improved splenomegaly. At 250 mg an 84 yr-old patient with MDS/MPN (intermediate risk) achieved a Hematologic Improvement [HI, erythroid]. A > 50% reduction in marrow blast percentage was seen in 8 patients. Bone marrow biopsies positive for EphA3 expression with a cut-off of 10% of nucleated cells were obtained in greater than 70% of AML patients. Of 20 patients for whom EphA3 expression data exists with time, 7 (35%) had at least a 50% reduction in expression with treatment. Conclusion: KB004 is a novel agent targeted against EphA3 that is well tolerated when given as a weekly 2 hour infusion. The promising clinical activity profile is postulated to be consistent with the antifibrotic mechanism. The Phase II component of the study is ongoing in which the activity of KB004 will be characterized in disease specific cohorts including AML, MDS and MF at the RP2D of 250mg. Disclosures Durrant: KaloBios: Research Funding. Advani:KaloBios: Research Funding. Greenberg:Celgene: Research Funding; Novartis: Research Funding; GSK: Research Funding; Onconova: Research Funding; KaloBios: Research Funding. Cortes:KaloBios: Research Funding. Yarranton:KaloBios: Employment; Glaxo: Equity Ownership; EnGen: Equity Ownership, Science Advisor, Science Advisor Other; Stemline Therapeutics: Equity Ownership. Walling:KaloBios, Corcept Therapeutics, Prothena, NewGen Therapeutics, Valent Technologies, LBC Pharmaceuticals: Consultancy, Equity Ownership; Amgen, BioMarin: Equity Ownership; Crown BioScience: Membership on an entity's Board of Directors or advisory committees.

A Phase II Study of the Combination of Oral Rigosertib and Azacitidine in Patients with Myelodysplastic Syndromes (MDS)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 910-910 ◽  
Author(s):  
Shyamala C. Navada ◽  
Lewis R. Silverman ◽  
Katherine P. Hearn ◽  
Rosalie Odchimar-Reissig ◽  
Erin P. Demakos ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase I ◽  
Phase Ii ◽  
Research Funding ◽  
De Novo ◽  
Standard Dose ◽  
Single Agent ◽  
Leukemic Cells ◽  
Bone Marrow Blast ◽  
Recommended Phase Ii Dose

Background: Rigosertib (RIG) is a Ras-mimetic that inhibits the PI3K and PLK cellular signaling pathways by binding directly to the Ras-binding Domain found in Ras effector proteins. It has been tested as a single agent in patients (pts) after failure of hypomethylating agents (HMAs). In vitro, the combination of RIG with azacitidine (AZA) inhibits growth and induces apoptosis of leukemic cells in a sequence-dependent fashion (RIG administered prior to AZA) (Skidan et al 2006). Phase I results of this study in pts with MDS or AML showed combination of oral RIG and standard-dose AZA to be well-tolerated with evidence of efficacy (Navada et al, Blood 2014). Phase II was initiated to further study the combination in pts with MDS. Methods: Results from pts in Phase II with MDS previously untreated with an HMA, or who had failed to respond to or progressed on a prior HMA, are presented, while response data from Phase I MDS pts are updated. Pts with CMML are analyzed separately. Oral RIG was administered twice daily on Day 1-21 of a 28-day cycle at the recommended Phase II dose (RPTD: 560 mg qAM and 280 mg qPM). AZA 75 mg/m2/d SC or IV was administered for 7 days starting on Day 8. A CBC was performed weekly and a bone marrow aspirate and/or biopsy was performed at baseline, day 29, and then every 8 weeks thereafter. Results: The combination of oral RIG and AZA has been administered to a total of 45 pts within Phase I (N=18) and Phase II (N=27). Pts were classified into the following MDS risk categories per the IPSS (Greenberg et al, Blood 1997): intermediate-1 (4), intermediate-2 (10), high-risk (14), and IPSS classification pending (4). Five pts had CMML and 8 had AML. Median age was 66 years; 69% of pts were male; and ECOG performance status was 0, 1, and 2 in 27%, 67%, and 6%, respectively. Twelve pts [MDS (9), CMML (3)] received prior HMA therapy: AZA (11 pts), decitabine (1 pts). Patients have received 1-21+ cycles of treatment to date (median, 3 cycles), with median duration of treatment of 14 weeks. Among 15 evaluable MDS pts treated with the RPTD (1 pt in Phase I, 14 pts in Phase II), marrow responses were observed in 10: marrow CR (mCR) (8), marrow PR (mPR) (2). Responses according to IWG criteria were observed in 10 pts: complete remission (CR) (1), mCR (7), hematologic improvement (HI) (2). Table 1. Responses for MDS Patients Treated at the Recommended Phase II Dose Pt Prior HMA Best BMBL at Nadir1 IWG Response2 Hematologic Improvement 102-008 None mCR mCR Platelet 101-010 None mCR CR Erythroid & Neutrophil 101-011 None mCR mCR None 101-013 None mCR mCR Erythroid 102-010 None SD SD None 101-014 AZA PD PD None 102-011 AZA mPR HI Erythroid & Platelet 101-016 AZA SD SD None 101-017 AZA mCR mCR None 102-013 None NE NE NE 101-019 None SD SD None 101-021 None PD PD None 101-024 None mCR mCR None 101-022 AZA mCR mCR None 101-025 None mCR mCR None 101-026 AZA NE NE NE 101-027 None NE NE NE 102-016 None mPR HI Platelet 1 Silverman et al, Hematol Oncol 2014 2 IWG = International Working Group (Cheson et al, Blood 2006) NE = not evaluable BMBL = bone marrow blast Overall, in pts with MDS treated on Phase I and Phase II, marrow responses were observed in 15 out of 20 evaluable pts: mCR (13), mPR (2). Responses according to IWG 2006 criteria were observed in 14 out of 19 evaluable MDS pts: CR (2), mCR (10), HI (2). Among the 7 evaluable pts with MDS in both the Phase I and Phase II who had failed to respond or progressed on prior treatment with an HMA, 5 had a response after RIG was added: CR (1), mCR (3), HI (1). Analyzed as a separate subgroup, 2 out of 5 (40%) pts with CMML had a mCR. The most frequent adverse events (AEs) in Cycle 1 included nausea (21%) and fatigue (15%), which were also the most frequent AEs in all cycles (fatigue, 28%; nausea, 26%). Six deaths have been observed so far. Three pts were treated for more than 1 year and continue on study. Conclusions: The combination oforalrigosertib and standard-dose AZA was well tolerated in repetitive cycles in pts with MDS. Marrow CR was observed in 65% of pts, both with de novo MDS and after failure of prior HMA therapy. In pts who received the RPTD, 67% of pts with MDS had a bone marrow blast and IWG response. These results suggest potential synergistic interaction of the combination and support continued study of this unique combination in patients with MDS. Disclosures Silverman: Onconova Therapeutics Inc: Honoraria, Patents & Royalties: co-patent holder on combination of rigosertib and azacitdine, Research Funding. Daver:ImmunoGen: Other: clinical trial, Research Funding. DiNardo:Novartis: Research Funding. Konopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding. Pemmaraju:Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Fenaux:CELGENE: Honoraria, Research Funding; JANSSEN: Honoraria, Research Funding; AMGEN: Honoraria, Research Funding; NOVARTIS: Honoraria, Research Funding. Fruchtman:Onconova Therapeutics Inc: Employment. Azarnia:Onconova Therapeutics Inc: Employment.

Phase 1 Trial of Sorafenib and Everolimus In Patients with Lymphoma or Multiple Myeloma.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2802-2802 ◽  
Author(s):  
Shaji Kumar ◽  
Luis F Porrata ◽  
Stephen M. Ansell ◽  
Joseph P Colgan ◽  
Betsy LaPlant ◽  
...  
Keyword(s):  
Disease Progression ◽  
Dose Level ◽  
Research Funding ◽  
Phase 1 ◽  
Hematologic Toxicity ◽  
Phase 2 ◽  
Level 3 ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

Abstract Abstract 2802 Background: Redundancy of pro-survival signaling pathways promotes survival and drug resistance in lymphoid and plasma cell malignancies. In particular, the PI3K-Akt and the MEK-ERK pathways have been shown to play an important role in the proliferation and survival of these malignant cells induced by various cytokines in the tumor microenvironment. Sorafenib, a Raf kinase and VEGF receptor inhibitor, and everolimus, an mTOR inhibitor, have synergistic cytotoxicity in myeloma and lymphoma cells due to inhibition of multiple signaling pathways. Methods: We designed a Phase 1/2 clinical trial to identify the maximum tolerated doses of the two drugs used in combination and the efficacy of the combination. Patients (Pts) with relapsed myeloma or lymphoma were eligible for enrollment. Pts were required to have an absolute neutrophil count ≥1500 × 10(6)/L, a platelet count ≥75,000, and a serum creatinine 21.5 mg/dL. The study utilized the classic 3+3 design. Extensive pharmacokinetic studies were performed to better delineate potential drug interactions. Results: Twenty-six pts were accrued from August 2007 to February 2009. Four pts discontinued sorafenib during cycle 1 for various reasons (2 patient refusal, 1 unrelated medical condition and 1 physician discretion) and were excluded from MTD determination. An additional pt did not have measurable disease and was ineligible, leaving 19 pts with lymphoma (including 6 with Hodgkin lymphoma) and 2 with myeloma for phase I analysis. The pts had a median age of 56 years (range, 22, 69) and were heavily pretreated with a median of 4 prior therapies (range, 1–10). Eighteen (86%) had received a prior stem cell transplant. Four dose limiting toxicities were seen across all dose levels (Table). These included grade 3 vomiting (level 1), grade 4 thrombocytopenia (level 2 and 3, one each) and grade 2 hand and foot rash leading to treatment delay (level 3). Overall, 13 pts experienced a grade 3 or 4 hematologic toxicity. Grade 3 or 4 anemia, neutropenia, and thrombocytopenia occurred in 19%, 43%, and 38% of pts, respectively. Four pts have experienced a grade 3 non-hematologic toxicity; no grade 4 non-hematologic toxicities were seen. Grade 3 non-hematologic toxicities included hypokalemia, weight loss, vomiting, hand-foot skin reaction, fatigue, and elevated alkaline phosphatase. Dose level 1 (sorafenib 200 mg and everolimus 5 mg daily) was best tolerated and was selected for phase 2 evaluation. The ORR was 33% (7/21;95% CI: 15–57%, Table) with 3 pts at dose level 0 (2 PR, 1 CR), one at level 2 (1 PR) and three at level 3 (2 PR, 1 CR) responding. The responders included 5 pts with Hodgkin's disease and one each with an NK cell and T-cell lymphoma. Pts have received a median of 6 cycles (range: 1–19) of treatment. 16 pts have discontinued treatment due to disease progression (13 pts), non-resolution of cytopenias (1 pt), physician discretion (1 pt), and death on study due to lymphoma (1 pt). Disease progression has been seen in 16 pts; 9 pts have died. Median follow-up for pts still alive is 18.7 months (range: 11.5–29.4). 6 pts died from disease progression, one each due to sepsis unlikely related to treatment, cholecystitis, and unknown causes. Sorafenib is metabolized by the cytochrome P450 CYP3A enzyme and RAD-001 mainly by the CYP3A4 system in the liver, hence there is a potential for interactions. The detailed PK analyses performed as part of this trial showed a decrease in the RAD001 levels following initiation of sorafenib on day 8 of cycle 1 (Figure). Conclusion: The combination of sorafenib and everolimus is safe at a recommended phase 2 dose of sorafenib 200 mg and everolimus 5 mg daily. There is no significant drug interaction seen. Activity has been observed, especially in the setting of Hodgkins Disease. Disclosures: Kumar: Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Off Label Use: Lenalidomide for treatment of newly diagnosed myeloma. Witzig:Novartis and Celgene: Patents & Royalties, Research Funding, Served on advisory boards with Novartis and Celgene – both uncompensated with compensation to Mayo Clinic.

scholarly journals Clinical Heterogeneity of AML Is Associated with Mutational Heterogeneity

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5240-5240
Author(s):  
Mahesh Swaminathan ◽  
Kiyomi Morita ◽  
Yan Yuanqing ◽  
Feng Wang ◽  
Jared K Burks ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dna Sequencing ◽  
Research Funding ◽  
Clinical Presentation ◽  
De Novo ◽  
Hot Spot ◽  
Bone Marrow Blast ◽  
Trisomy 8 ◽  
Immunological Parameters ◽  
Exon 2

Abstract BACKGROUND: AML is a group of clinically heterogeneous diseases. We hypothesized that heterogeneous presentation of AML is a reflection of equally heterogeneous genetic process during the leukemogenesis. METHODS: 536 AML patients (pts) bone marrow samples were analyzed by targeted capture exome sequencing of 295 genes. Extensive clinical-genotype correlation was performed using well annotated clinical data. RESULTS: The median age of the cohort was 62 years (IQR: 51-72) including 297 (55%) elderly (age ≥60), and 239 (45%) young (age <60) pts. Of the 536 pts, 308 (57%) pts had de novo AML (dnAML), and 103 (19%) had secondary or therapy-related AML (stAML). DNA sequencing revealed 1,586 high-confidence somatic mutations (922 SNVs and 664 indels) in 79 genes in 493 (92%) pts [median 3 (IQR 2-4) mutations/patient]. Cytogenetics were favorable in 10 (2%), intermediate in 326 (61%), and adverse in 177 (33%) (All defined by ELN 2017criteria); 23 (4%) pts had no cytogenetics data. Elderly pts and young pts had distinct mutational landscape. (1.3-9.6), p = 0.0079] were significantly more enriched in elderly AML, whereas young AML pts were enriched with mutations in FLT3 [OR 0.6 (0.4-0.9), p = 0.0089], NPM1 [OR 0.5 (0.3-0.9), p = 0.0113], PTPN11 [OR 0.2 (0.2-0.7), p = 0.0033], and WT1 [OR 0.4 (0.2-0.7), p = 0.0033]. Some of the mutations enriched in elderly pts are frequently observed in pts with clonal hematopoiesis with indeterminate potential. Based on the ontogeny of AML, PTPN11 [OR 7.6 (1-57.2), p=0.0210], NPM1 [OR 3.0 (1.5-6.1), p = 0.0007], WT1 [OR 2.9 (1.1-7.4), p=0.0279] mutations were significantly enriched in dnAML, while SF3B1 [OR 0.4 (0.18-0.89), p=0.0376], SRSF2 [OR 0.5 (0.3-0.85), p = 0.0109], TP53 [OR 0.5 (0.3-0.8), p = 0.0131], ASXL1 [OR 0.6 (0.36-0.95), p=0.0451] mutations were more enriched in stAML (Figure A). We then correlated mutation data with clinical and immunological parameters that are routinely tested in AML. Mutations in NPM1, FLT3, PTPN11 and NRAS were associated with significantly higher white blood cell (WBC) counts, bone marrow blast and LDH, which is consistent with their hyperproliferative activity as class 1 genes. In contrast, pts with mutations in TP53, STAG2 and ASXL1 presented with significantly low bone marrow blast, circulating blast, and WBC. Mutations in BCOR and ASXL1 was associated with significantly low LDH. Interestingly, pts with IDH2 mutations presented with significantly higher platelet, which is consistent with anecdotal report (DiNardo et al. Am J Hematology). Not surprisingly, TP53 mutations were associated with complex cytogenetics, whereas SRSF2, NPM1, IDH2, FLT3, and CEBPA mutations were associated with good and intermediate cytogenetics by ELN classification (Figure B). Pts with NPM1, IDH2, and IDH1 mutations were associated with less HLA-DR and CD34 expression in blast by flow cytometry. This is consistent with the frequent presentation of these AML sub-types with cuplike nuclei (Rakheja et al. BJH). DNA sequencing of a large cohort also allowed us to detect mutations that have not been as commonly reported in AML. We detected hot-spot mutations in exon 2 of MYC and MYCN genes in 9 (2%) AML pts. Additionally, internal tandem duplication (ITD) in MYC was also detected in one patient. Immunohistochemical staining showed that MYC expression was significantly elevated in patients with MYC mutations than in patients without the mutations (median H score 22 vs. 15 in MYC mutated vs. normal karyotype control, p < 0.001, 22 vs. 13.5 in MYC mutated vs. trisomy 8 control). These data suggest that a subset of AML is driven by the strong MYC signaling, consistent with a prior study (Ohanian et al. Leuk Lymphoma). CONCLUSION: Heterogeneous clinical presentation of AML has significant association with genetic heterogeneity, which suggest that distinct genetic basis of leukemogenic process has strong role in defining clinical presentation of AML. These data also help stratifying the patients for the likely target of precision medicine. Disclosures DiNardo: Medimmune: Honoraria; Celgene: Honoraria; Agios: Consultancy; Abbvie: Honoraria; Karyopharm: Honoraria; Bayer: Honoraria. Kadia:Celgene: Research Funding; Pfizer: Consultancy, Research Funding; BMS: Research Funding; Jazz: Consultancy, Research Funding; Abbvie: Consultancy; Abbvie: Consultancy; Amgen: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Takeda: Consultancy; Amgen: Consultancy, Research Funding; Takeda: Consultancy; Novartis: Consultancy; Celgene: Research Funding; Novartis: Consultancy. Cortes:novartis: Research Funding. Daver:Daiichi-Sankyo: Research Funding; Pfizer: Consultancy; Alexion: Consultancy; ARIAD: Research Funding; Karyopharm: Consultancy; ImmunoGen: Consultancy; Kiromic: Research Funding; Otsuka: Consultancy; Sunesis: Consultancy; Novartis: Research Funding; BMS: Research Funding; Incyte: Consultancy; Novartis: Consultancy; Sunesis: Research Funding; Karyopharm: Research Funding; Pfizer: Research Funding; Incyte: Research Funding. Pemmaraju:SagerStrong Foundation: Research Funding; celgene: Consultancy, Honoraria; cellectis: Research Funding; samus: Research Funding; daiichi sankyo: Research Funding; Affymetrix: Research Funding; stemline: Consultancy, Honoraria, Research Funding; plexxikon: Research Funding; novartis: Research Funding; abbvie: Research Funding.

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