Gemtuzumab Ozogamicin in Combination with Vorinostat and Azacitidine As Induction and Post-Remission Therapy in Older Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML): A Phase 1 Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1541-1541
Author(s):  
Roland B. Walter ◽  
Bruno C. Medeiros ◽  
Kelda M. Gardner ◽  
Elihu H. Estey
Keyword(s):  
Dna Methyltransferase ◽  
Phase 1 ◽  
Hdac Inhibitors ◽  
Gemtuzumab Ozogamicin ◽  
Hematologic Toxicity ◽  
Phase 1 Study ◽  
First Relapse ◽  
Grade 3 ◽  
Count Recovery

Abstract Abstract 1541 Background: The anti-CD33 immunoconjugate, gemtuzumab ozogamicin (GO), is efficacious in only a minority of AML patients when used alone. Emerging data suggest that epigenetic modifiers may chemosensitize to GO. For example, histone deacetylase (HDAC) inhibitors such as vorinostat increase CD33 expression and lower the apoptotic threshold to GO in vitro, while DNA methyltransferase I inhibitors such as azacitidine enhance GO efficacy in vitro and show promise when combined with GO in early clinical studies. These studies, together with the improved clinical activity when HDAC inhibitors are used with DNA methyltransferase I inhibitors, prompted a phase 1 study (NCT00895934) of GO with vorinostat and azacitidine for primary refractory AML or AML in first relapse (remission duration ≤12 months) requiring 1st salvage therapy. Methods: Patients aged ≥50 years were eligible if they had an ECOG performance status of 0–3 and had adequate organ function. Patients with prior hematopoietic stem cell transplantation were eligible if relapse occurred 6–12 months post-transplant. Excluded were patients with a second active malignancy, prior treatment with any of the study drugs, or central nervous system disease. Hydroxyurea was given to reduce the total white blood cell count to <25,000/μL before treatment. Patients were assigned to therapy according to a “3+3” study design. If there was persistent leukemia (>20% blasts in non-hypoplastic bone marrow) on day 15, the first cycle was repeated, and patients came off study if, after repetition, there was disease progression. In all other patients, a second cycle was begun if peripheral blood counts had recovered (blood count recovery was not required for patients with persistent leukemia) and all toxicities had resolved to ≤grade 2. Patients came off study if a partial remission (PR; >50% decrease of bone marrow blast percentage) was not achieved by the end of cycle #3, or if a complete remission (CR) or CR with incomplete peripheral blood count recovery (CRi) was not achieved by the end of cycle #6. Dose-limiting toxicity (DLT) was defined as: 1) any grade 3 non-hematologic toxicity lasting >48 hours that results in >7 day delay of the subsequent treatment cycle, with the exception of febrile neutropenia or infection; 2) any grade ≥4 non-hematologic toxicity, with the exception of febrile neutropenia/infection or constitutional symptoms if recovery to grade ≤2 within 14 days; and 3) prolonged myelosuppression (platelet count <20,000/μL and/or absolute neutrophil count <500/μL at day 42 after treatment in patients without evidence of persistent leukemia). Results: 15 patients (8 male, 7 female), median age 65.7 (range, 50.2–69.8) years, with either primary refractory disease (n=6) or first relapse (n=9; median duration of first CR: 6 months) were enrolled on this study and received a median of 2 (range, 1–3) cycles of therapy (see Table): One DLT of death due to sepsis and respiratory failure occurred at dose level 4 after cycle 1, defining this level as maximum tolerated dose (MTD). Death within 8 weeks of therapy initiation occurred in 5 patients (33.3%). Besides grade 3–4 cytopenias, the most common grade33 adverse events were: neutropenic fever (n=8) or documented infection (n=5), hypoalbuminemia (n=3), and acute renal failure (n=2). As detailed in the table, 2 patients (13.3%) each achieved either a CR or a CRi for a total CR/CRi rate of 4/15 (26.7%); 2 additional patients (13.3%) met morphological criteria for CRi but had MRD (<5% abnormal blasts) by flow cytometry. Nine patients (60.0%) either had RD (n=8; 53.3%) or experienced DA (n=1; 6.7%). An exact 95% confidence interval about the CR rate is 0–32% compared to an expected CR rate of 15% in 1st salvage patients with CR durations of 0–12 months. Thus, the study is continuing (at dose level 4). Conclusion: The combination of GO, vorinostat, and azacitidine appears feasible and shows anti-AML activity in this cohort of difficult-to-treat patients. Disclosures: Off Label Use: The presentation discusses a phase 1 study using azacitidine, vorinostat, and gemtuzumab ozogamicin for treatment of adults with relapsed/refractory AML; none of these 3 drugs is currently approved for this use in the U.S. Medeiros:Celgene: Honoraria, Research Funding.

Gemtuzumab Ozogamicin In Combination With Vorinostat and Azacitidine In Older Patients With Relapsed Or Refractory Acute Myeloid Leukemia (AML): Final Results From A Phase 1/2 Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3936-3936 ◽  
Author(s):  
Roland B. Walter ◽  
Bruno C. Medeiros ◽  
Kelda M. Gardner ◽  
Kaysey F. Orlowski ◽  
Leonel Gallegos ◽  
...  
Keyword(s):  
Research Funding ◽  
Blood Count ◽  
Treatment Initiation ◽  
Phase 1 ◽  
Gemtuzumab Ozogamicin ◽  
Hematologic Toxicity ◽  
First Relapse ◽  
Grade 3 ◽  
Refractory Aml ◽  
Count Recovery

Abstract Background Epigenetic therapeutics such as the histone deacetylase (HDAC) inhibitor, vorinostat, and the DNA methyltransferase (DNMT) I inhibitor, azacitidine, sensitize AML cells in vitro to the CD33-targeting immunoconjugate, gemtuzumab ozogamicin (GO). This observation, together with the improved clinical activity when HDAC inhibitors are used with DNMT inhibitors, prompted a phase 1/2 study (NCT00895934) of GO with vorinostat and azacitidine for primary refractory AML or AML in first relapse (remission duration ≤12 months) requiring 1stsalvage therapy. Methods Patients aged ≥50 years were eligible if they had an ECOG performance status of 0-3 and had adequate organ function. Patients with prior hematopoietic stem cell transplantation (HCT) were eligible if relapse occurred 6-12 months post-transplant. Excluded were patients with a second active malignancy, prior treatment with any of the study drugs, or central nervous system disease. Hydroxyurea was given to reduce the total white blood cell count to <25,000/μL before treatment. If there was persistent leukemia on day 15, the first cycle was repeated, and patients came off study if, after repetition, there was disease progression. In all other patients, a second cycle was begun if peripheral blood counts had recovered (blood count recovery was not required for patients with persistent leukemia) and all toxicities had resolved to ≤grade 2. Patients came off study if a partial remission was not achieved by the end of cycle 3, or if a complete remission (CR) or CR with incomplete peripheral blood count recovery (CRi) was not achieved by the end of cycle 6. During phase 1, patients were assigned to therapy according to a “3+3” study design; dose-limiting toxicity (DLT) was defined as: 1) any grade 3 non-hematologic toxicity lasting >48 hours that results in >7 day delay of the subsequent treatment cycle, with the exception of febrile neutropenia or infection; 2) any grade ≥4 non-hematologic toxicity, with the exception of febrile neutropenia/infection or constitutional symptoms if recovery to grade ≤2 within 14 days; and 3) prolonged myelosuppression (platelet count <20,000/μL and/or absolute neutrophil count <500/μL at day 42 after treatment in patients without evidence of persistent leukemia). During phase 2, a Simon minimax two-stage design was to monitor whether a response rate of 0.34 was reached, with type I and II errors set at 0.1 and assuming a historical CR rate of 17% in these patients. Results 52 eligible patients, median age 64.8 (range, 50.2-78.9) years, with either primary refractory disease (n=29) or first relapse (n=23; median duration of first CR: 3 months) were enrolled and received a median of 2 (range, 1-4) cycles of therapy. During dose escalation, 1 DLT (death due to sepsis and respiratory failure) occurred at the 4th tested dose level after cycle 1, identifying vorinostat (400 mg/day orally from days 1-9), azacitidine (75 mg/m2/day IV or SC from days 1-7), and GO (3 mg/m2/day IV on days 4 and 8) as the maximum tolerated dose (MTD). A total of 43 patients received therapy at the MTD level. Ten of these achieved CR, while 8 achieved CRi, for a CR/CRi rate of 18/43 (41.9%; exact 95% CI: 27.0-57.9%). Thirteen of the 18 patients that achieved CR/CRi were taken off protocol to receive additional, more intensive consolidative chemotherapy, including HCT (n=12). Of these 18 patients, 5 relapsed after a median of 122 (38-146) days, while 3 died while in remission after a CR duration of 46, 97, and 130 days, and 10 are in ongoing remission after a median of 326 (68- 710) days, respectively. Median overall survival for the 18 patients achieving CR/CRi was significantly longer than for those 21 patients who failed therapy but lived at least 29 days (i.e. did not experience treatment-related mortality) after treatment initiation (224.5 [range 70-798]) vs. 95 [36-900] days, log rank P-value=0.0023). Four patients died within 28 days of treatment initiation. Besides grade 3-4 cytopenias, infectious complications were the most common grade 33 adverse events. Only 1 patient developed possible liver toxicity (abdominal pain/distention and mild ascites) after 4 cycles of therapy, although bilirubin and transaminases were only minimally elevated and doppler studies were unremarkable. Conclusion Our study indicates that GO in combination with vorinostat and azacitidine has encouraging anti-AML activity in older adults with relapsed/refractory AML. Disclosures: Walter: Amgen, Inc: Research Funding; Seattle Genetics, Inc: Consultancy, Research Funding. Off Label Use: Use of vorinostat/azacitidine/gemtuzumab ozogamicin for the treatment of relapsed/refractory AML.

A phase 1 study of daily oral perifosine (P) and weekly gemcitabine (G)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13084-13084 ◽  
Author(s):  
S. Weiss ◽  
J. J. Nemunaitis ◽  
M. Diaz-Lacayo ◽  
R. Birch ◽  
B. Ebrahimi ◽  
...  
Keyword(s):  
Phase 1 ◽  
Performance Status ◽  
State Level ◽  
Unknown Primary ◽  
Hematologic Toxicity ◽  
Phase 1 Study ◽  
Ecog Performance Status ◽  
Phase Ii Studies ◽  
Grade 3

13084 Background: Miltefosine (M) has been shown to be synergistic with gemcitabine (G) in vitro (Georgieva Cancer Letters 182: 163–174, 2002). Perifosine (P) is a derivative of M with less GI toxicity. Methods: Twenty-two patients (pts) were enrolled on a phase 1 study to determine if G could be given at a dose of 1000 mg/m2 on days 1 and 8 of a 21-day cycle with 50 mg of P given orally 1, 2 or 3 times a day on days 1–14. Three pts were entered at each dose and the cohort expanded to 6 if 2 or more experienced a grade 3/4 non-hematologic toxicity (DLT) during the first cycle. A dose was toxic if 4 or more pts experienced a DLT during cycle 1. Ten additional pts were entered at the highest dose achieved. Results: Disease sites: lung 6, pancreas 3, breast 3, renal 2, sarcoma 2, other 5. The median age was 61 (range 29–82); 11 pts were male and median ECOG performance status was 1 (range 0–2). All pts had received prior chemotherapy (median 3, range 1–4) & 6 had received prior G. 10 pts had received prior radiotherapy. The grade 3/4 non hematologic toxicities for each cohort are given in the table below: One pt on cohort 3 died from pneumonia and sepsis unrelated to therapy after cycle 1. A median of 4 cycles (range 1 - 18) were delivered. At each dose 50% of pts had no G dose reductions. P doses were reduced in 7% of cycles (50 mg - 5%, 100 mg - 15%, 150 mg - 7%). Fifteen pts were evaluable & 4 partial responses (lung, breast, pancreas and unknown primary) were seen; 6 pts had stable disease (renal (2), sarcoma (2), liver and head/neck) for a median of 6 (range 3 - 9) months. No responder had received prior G. Pharmacokinetic (PK) studies showed that the steady state level at 150 mg was 9.47 ± 4.56 μM compared to 10.14 ± 2.02 μM in an earlier study (Crul, Eur. J. Cancer 38: 1615–21, 2002) when this dose of perifosine was used alone. Conclusions: It is concluded that full dose G can be safely administered with perifosine doses up to 150 mg with manageable toxicity and without affecting the PK of P. Phase II studies are warranted to further define the activity of the combination and the contribution of P. [Table: see text] [Table: see text]

scholarly journals A Phase 1 Study of the BET-Bromodomain Inhibitor OTX015 in Patients with Advanced Acute Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 117-117 ◽  
Author(s):  
Hervé Dombret ◽  
Claude Preudhomme ◽  
Céline Berthon ◽  
Emmanuel Raffoux ◽  
Xavier Thomas ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Leukemia ◽  
Research Funding ◽  
Phase 1 ◽  
Plasma Concentrations ◽  
Normal Karyotype ◽  
Refractory Anemia ◽  
Phase 1 Study ◽  
Grade 3

Abstract Rationale: BET-bromodomain (BRD) proteins play a major role in the epigenetic regulation of gene transcription, notably of genes with superenhancer promoter regions including many oncogenes, such as MYC. OTX015 is a specific BRD 2, 3 and 4 inhibitor that blocks oncogene transcription, and triggers growth inhibition and apoptosis in acute leukemia cell lines and patient cells in vitro (Braun et al. ASH Annual Meeting 2013). Based on these findings, a Phase 1 study of OTX015 was designed for patients with advanced acute leukemia. Patients & Methods: Patients with various unselected relapsed/refractory leukemia subtypes for which no standard therapy options were available were enrolled in this ongoing Phase 1 study. Patients aged < 60 years had to have failed at least two lines of therapy and those aged >60 years at least one line. At least 5% bone marrow leukemic blasts were required at study entry. OTX015 was given orally, daily for 14 days of 21-day cycles (cy). The dose was escalated from 10 to 160 mg daily (QD) according to a standard 3+3 dose-escalation design, to determine the maximum tolerated dose (MTD) or biologically optimal dose. A BID schedule was tested at dose level (DL) 4 (40 mg x 2) and a continuous schedule at 120 mg. Pharmacokinetics was studied on day 1 and residual concentrations were measured on days 2, 8 and 15. Responses were assessed on blood and bone marrow aspirations at baseline, days 8, 22 and 43. Blasts at baseline and day 8 were stored for pharmacodynamic biomarker evaluation. Cytogenetic and molecular markers were collected based on center practice. Results: From January 2013 to June 2014, 36 patients were treated over 6 dose levels: 33 with acute myeloid leukemia (AML), 2 with acute lymphoblastic leukemia and 1 with refractory anemia with excess blasts. Median age was 70 years (range 19-85), 20 patients were male, 29 patients had ECOG 0-1, and 16 AML patients had normal karyotype. Patients had a median of 2 prior therapy lines (range 1-4). The median number of OTX015 cycles administered was 2 (range 1-14+), including 9 patients with >3 cycles. Among the 28 patients evaluable for dose limiting toxicity (DLT), no DLTs were observed through DL5 (120 mg QD). The MTD was exceeded at DL6 (160 mg QD) with one patient experiencing grade 3 diarrhea and another grade 3 fatigue and anorexia. The main toxicities were non-cumulative grade 1-2 gastrointestinal events (6 patients diarrhea, 3 dysgueusia, 3 abdominal pain, 3 nausea, 1 anorexia), hyperglycemia (3 patients), coagulation factor VII decrease (6 patients) and direct bilirubin increase (3 patients) (two latter AEs asymptomatic). These toxicities were mainly observed at QD doses above 80 mg and with 40 mg BID. Dose proportional plasma concentrations were observed and trough concentrations > 500 nM (in vitro active concentrations) were regularly observed from 80 mg/day. Clinically relevant activity was reported in 5 AML patients treated at 10, 40 and 80 mg, including one sustained CR from cy 4 to cy 12 (40 mg QD) and one CR with incomplete platelet recovery (CRp) from cy 2 to cy 5 (80 mg QD). Two patients (10 mg QD, 40 mg QD) had partial blast clearance (disappearance of peripheral blasts and decrease >50% in bone marrow blast percentage) and the remaining patient (40 mg BID) had gum hypertrophy resolution. Four of these 5 patients had secondary or therapy-related AML, 4 had normal karyotype and 2 had an NPM1 gene mutation. Conclusions: OTX015 single agent exhibits antileukemic activity over a wide range of DLs and plasma concentrations in patients with advanced AML. MTD is exceeded at 160 mg QD. The safe recommended dose and schedule is close to being identified. Central extensive molecular marker analysis is being performed and will be prospectively implemented in an expansion cohort. Updated data will be presented and will include correlations between regimen, pharmacokinetics, clinical activity and molecular profile. Table Dose (Schedule) N pts evaluable Evidence of activity DLT 10 QD (14/21) 3 1 20 QD (14/21) 3 40 QD(14/21) 4 1 (CR) 80 QD(14/21) 3 2 (1 CRp) 40 BID (14/21) 6 1 120 QD (14/21) 3 120 QD (21/21) 3 160 QD (14/21) 3 Diarrhea (1) Anorexia/fatigue (1) Disclosures Dombret: Oncoethix SA: Research Funding. Preudhomme:Oncoethix SA: Research Funding. Berthon:Oncoethix SA: Research Funding. Raffoux:Oncoethix SA: Research Funding. Thomas:Oncoethix SA: Research Funding. Vey:Oncoethix SA: Research Funding. Gomez-Roca:Oncoethix SA: Research Funding. Ethell:Oncoethix SA: Research Funding. Yee:Oncoethix SA: Research Funding. Bourdel:Oncoethix SA: Employee of study CRO Other. Herait:Oncoethix SA: CMO and Shareholder Other. Michallet:Oncoethix SA: Research Funding. Recher:Oncoethix SA: Research Funding. Roumier:Oncoethix SA: Research Funding. Quesnel:Oncoethix SA: Research Funding.

A First-In-Man Phase 1 Study Of CUDC-907, a First-In-Class Chemically-Designed Dual Inhibitor Of PI3K and HDAC In Patients With Refractory Or Relapsed Lymphoma and Multiple Myeloma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4363-4363 ◽  
Author(s):  
Anas Younes ◽  
Ian W. Flinn ◽  
Yasuhiro Oki ◽  
Amanda Copland ◽  
Ali Fattaey ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
B Cell ◽  
Hodgkin’S Lymphoma ◽  
Phase 1 ◽  
Hdac Inhibitors ◽  
Hodgkin's Lymphoma ◽  
Class I ◽  
Phase 1 Study ◽  
Grade 3

Abstract Background PI3K and HDAC inhibitors have demonstrated single agent clinical activity in patients (pts) with a variety of B-cell malignancies, including lymphoma and multiple myeloma (MM). Preclinical experiments indicated synergistic effects between HDAC and PI3K pathway inhibitors. CUDC-907 is a chemically-designed small molecule that combines the active hydroxamate moiety of HDAC inhibitors with a PI3K inhibitor morpholinopyrimidine pharmacophore. CUDC-907 potently inhibits class I PI3K (alpha, beta, and delta) as well as HDACs class I and II enzymes. Preclinical experiments demonstrated that CUDC-907 inhibits the PI3K-AKT-mTOR pathway and compensatory MEK/ERK and STAT3 signaling pathways. CUDC-907 shows greater growth inhibition and proapoptotic activity than single-target PI3K or HDAC inhibitors in both cultured and implanted cancer cells, including human B-cell tumor xenograft models. Here we present the preliminary results of a First-In-Human Phase 1 study of CUDC-907. Methods This is a Phase 1 study using a standard 3+3 dose escalation design. CUDC-907 was orally administered to pts with lymphoma and MM. Patients were eligible if they had relapsed or refractory disease after at least 2 prior regimens and adequate bone marrow and organ functions. The starting dose was 30mg given continuously once daily in 21-day cycles without rest, with planned escalations until the maximum tolerated dose was reached. In the absence of dose limiting toxicities (DLTs), pts were allowed to continue treatment until disease progression. DLTs were defined so as to include ≥ Grade 3 adverse events (AE) or any Grade AE resulting in dose delay ≥7 days. Tumor response was assessed every 2 cycles using standard criteria appropriate for the disease type. Blood samples for pharmacokinetic (PK) and pharmacodynamic analyses were collected during Cycle 1. Results At the time of this abstract, 6 pts were treated on study: 3 each at 30 and 60 mg/day dose. The median age was 70 years (range 61-77) and 2 pts had MM, 3 Non-Hodgkin’s lymphoma and 1 Hodgkin's lymphoma. The median number of prior regimens was 3 (range 2-8) and 3 pts had prior bone marrow transplant. The most common treatment-related AEs were diarrhea (6 pts, Grade 1-3) and thrombocytopenia (5 pts, Grade 1-4). The severity and time to onset of these events appear to be dose-related. In general, thrombocytopenia recovered quickly by withholding treatment and diarrhea was well controlled with loperamide co-administration. However, 1 pt at the 60 mg/day dose level with a history of diabetes and poor co-medication compliance (i.e., loperamide and insulin) developed multiple DLTs including diarrhea (Grade 3), thrombocytopenia (Grade 4) and hyperglycemia (Grade 4). Of the 6 pts, 2 remain on treatment at ≥ 5 cycles with stable disease. CUDC-907 was rapidly transformed to 2 metabolites, M1 and M2, with M2 retaining potent PI3K inhibition activity. While CUDC-907 had low plasma exposure and a short half-life, M2 levels increased during the 24 hour PK sampling period. Conclusion To address AEs and further dose escalate, with consideration of the PK profile of the parent and M2 metabolite, the protocol was modified to include 2 additional dosing schedules: 2x/week and 3x/week administration. In addition, the 30mg continuous daily dose cohort was expanded to further assess the tolerability of this schedule. Updated results from pts treated with the 3 schedules will be presented. Disclosures: Younes: Gilead: Honoraria; Seattle Genetics: Honoraria; Millenium: Honoraria; Celgene: Honoraria; Johnson & Johnson: Honoraria; Pharmacyclics: Honoraria. Fattaey:Curis, Inc.: Employment. Lai:Curis, Inc.: Employment. Laliberte:Curis, Inc.: Employment. Voi:Curis, Inc.: Employment.

A phase 1 study of oral navelbine in patients with advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13095-13095
Author(s):  
L. Rajdev ◽  
Q. Dai ◽  
G. Goldberg ◽  
S. Hoschander ◽  
C. Baker ◽  
...  
Keyword(s):  
Phase I Trial ◽  
Phase 1 ◽  
Antiangiogenic Therapy ◽  
Hematologic Toxicity ◽  
Phase 1 Study ◽  
Frequent Administration ◽  
Psa Response ◽  
Grade 3 ◽  
Recommended Phase Ii Dose ◽  
Dose Limiting Toxicity

13095 Background: Anti-tubulin agents have potent anti-angiogenic effects (Blood 94: 4143–4155, 1999). Recent evidence suggests that “metronomic” drug schedules employing doses sufficient to inhibit angiogenesis yet low enough to allow more frequent administration may enhance the effectiveness of antiangiogenic therapy (J Clin Invest 105: 1045–7, 2000). We therefore performed a phase I trial to determine feasibility and safety of administering and oral navelbine (ON) preparation that is 40% bioavailable thrice weekly (TIW). Methods: ON was given TIW (eg, Monday-Wednesday-Friday) using the dosing escalation schema outlined below with 3–6 patients/cohort. Dose limiting toxicity (DLT) during cycle 1 was defined as a) neutrophil nadir < 500/uL, b) platelet nadir < 50,000/uL, c) febrile neutropenia, or d) grade 3–4 non-hematologic toxicity. One patient was not evaluable (NE) due to urosepsis unrelated to treatment. No patient had a DLT. The most common toxicities were grade 2 nausea (n = 1), dyspepsia (n = 1) and abdominal cramping (n = 2), and grade 3 neutropenia (N = 1). One patient with renal cell carcinoma had stable disease for 19 months; a second with prostate cancer had a greater than 50% PSA response that lasted 18 weeks. Results and Conclusions: The recommended phase II dose of ON is at least 50 mg TIW. Further dose escalation was not possible due to cessation of the drug supply by the manufacturer. Correlative studies of surrogate angiogenesis markers (urine VEGF and serum VCAM-1 and Tie2in serum by ELISA) are currently being analyzed and will be presented. [Table: see text] No significant financial relationships to disclose.

scholarly journals Phase 1 Study of the IDH1m Inhibitor FT-2102 As a Single Agent in Patients with IDH1m Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1453-1453 ◽  
Author(s):  
Justin Watts ◽  
Maria R. Baer ◽  
Jay Yang ◽  
Shira Dinner ◽  
Sangmin Lee ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Human Tissue ◽  
Research Funding ◽  
Phase 1 ◽  
Single Agent ◽  
Phase 2 ◽  
Phase 1 Study ◽  
Grade 3

Abstract Background: Isocitrate dehydrogenase 1 mutations (IDH1m) occur in 7-14% of AML patients and 3% of MDS patients and produce 2-hydroxyglutarate (2-HG), an oncometabolite that impairs differentiation. FT-2102 is an oral, highly potent, selective small molecule inhibitor of mutated IDH1, with the therapeutic potential to restore normal cellular differentiation. Herein, we present preclinical and clinical data from an ongoing Phase 1/2 study of single-agent (SA) FT-2102 in patients with IDH1m AML and MDS (CT.gov: NCT02719574). Methods: Extensive pre-clinical evaluations were performed on FT-2102, including CYP interactions in-vivo in rat and in-vitro in human tissue and in-vivo QTc toxicology in monkeys. The clinical Phase 1 study was initiated to evaluate the safety, PK/PD, and antileukemic activity of FT-2102 in patients with IDH1m AML or MDS and included both dose escalation and expansion phases. FT-2102 was administered daily until disease progression or unacceptable toxicity. Eligibility criteria included: IDH1m AML/MDS [relapsed/refractory (R/R) or treatment naïve (TN) for whom standard therapy was contraindicated], adequate liver and renal function, no prior IDH1 inhibitors, and no restrictions for concomitant non-anticancer medications. Investigator-assessed responses were per modified IWG 2003/2006 criteria. Efficacy was assessed at Cycle 2 Day 1 and as clinically indicated thereafter. Adverse events (AEs) were assessed throughout the study per NCI CTCAE version 4.03. Results: Evaluation of FT-2102 in in-vivo rat and in-vitro human tissue indicated hepatic metabolism by CYP enzymes (CPY3A4, 2C9, 1A1) as the major route of excretion. Animal toxicology studies predicted the threshold for QTc risk occurred at exposures >5.5 fold higher than the murine exposure at which 90% 2-HG reduction was observed. In the clinical study, at the time of the data cutoff, 31 patients (pts) had been treated with SA FT-2102, with a median of 3 mo. on treatment (range: 0.2 to 20 mo.). Of the 31pts treated, 25 had AML (22 R/R; 3 TN) and 6 had MDS (4 R/R; 2 TN). The median number of prior anti-leukemia therapies was 2 (range: 0-9) for AML pts and 1 (range: 0-4) for MDS pts. FT-2102 doses were: 150 mg QD (n=8), 300 mg QD (n=4), 150 mg BID (n=16), and 100 mg QD with food (n=3). Eighteen pts discontinued treatment, most commonly due to death (n=5), progressive disease (n=5), HSCT (n=3), or lack of response (n=3). Severe (≥Grade 3) AEs occurring in >5% of pts included thrombocytopenia (26%), febrile neutropenia (23%), anemia (19%), pneumonia (13%), neutropenia (7%), hypokalemia (7%), pyrexia (7%) and leukocytosis (6%). Three pts had differentiation syndrome (IDH-DS), which resolved with temporary interruption of FT-2102, treatment with dexamethasone, hydroxyurea, and supportive care in all three. One pt had transient QTcF prolongation (Grade 3) which resolved with temporary interruption of FT-2102 and cessation of suspected concomitant medications. Eight pts died on treatment or within 28 days of the last dose, with no deaths considered related to FT-2102. No DLTs were observed during dose escalation. Selection of FT-2102 150 mg BID as the RP2D was supported by PK and PD data. Durable steady-state (Css) achieved by Week 2 was well below the threshold for QTc risk predicted by preclinical studies. The predicted IC90 was confirmed with prompt and durable 2-HG reduction to normal levels by C2D1 at the RP2D. Table 1 shows the Investigator-assessed ORR per IWG. Responses have been observed from 1 to 6 months on treatment, with stable disease observed beyond 6 months; 42% of the patients remain on treatment. Conclusions: FT-2102 preclinical evaluations suggest a low risk of clinically significant CYP-mediated drug-drug interaction and QTc prolongation. SA FT-2102 is well tolerated in AML and MDS, with 150 mg BID selected as the RP2D based on safety, PK and PD (2-HG) response. Significant clinical activity has been observed in heavily pre-treated and in TN patients, both in AML and MDS. FT-2102 continues being investigated at a dose of 150 mg BID in a Phase 2 study. Three SA Phase 2 cohorts are currently open for enrollment in R/R AML, AML/MDS with CR/CRi (i.e., with MRD), and in pts with R/R MDS/AML with prior exposure to an IDH1m inhibitor. Data updates will be available at the time of presentation. Disclosures Lee: LAM Therapeutics: Research Funding; Karyopharm Therapeutics Inc: Consultancy; AstraZeneca: Consultancy; Clinipace: Consultancy; Amgen: Consultancy. Schiller:Celator/Jazz Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding. Ferrell:Incyte: Research Funding. Kelly:Forma Therapeutics Inc.: Employment. Li:Forma Therapeutics Inc.: Employment. Sweeney:Forma Therapeutics Inc.: Employment. Watson:Forma Therapeutics Inc.: Employment. Mohamed:Forma Therapeutics Inc.: Employment. Cortes:Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Arog: Research Funding.

Phase 1 study of picoplatin (pico) in combination with 5-fluorouracil (FU) and leucovorin (LV) as initial therapy in subjects with metastatic colorectal cancer (CRC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14510-14510
Author(s):  
O. Gladkov ◽  
G. Manikhas ◽  
M. Biakhov ◽  
S. Tjulandin ◽  
D. Karlin
Keyword(s):  
Phase 1 ◽  
Standard Of Care ◽  
Maximum Tolerated Dose ◽  
Initial Therapy ◽  
Platinum Resistance ◽  
Phase 1 Study ◽  
Starting Dose ◽  
Clinically Significant ◽  
Grade 3

14510 Background: Pico is a platinum analogue designed to overcome platinum resistance with improved safety and efficacy compared with conventional platinum agents. FOLFOX (FU, LV, oxaliplatin) has emerged as the standard of care in first and second-line therapy of advanced -stage CRC but significant neurotoxicity limits long-term use of oxaliplatin in this regimen. Pico has been well tolerated in >600 patients with rare clinically significant nephro-, oto-, or neurotoxicity (∼2% grade 3 and 0% grade 4), even in platinum pretreated patients. Pico has demonstrated synergy with FU in vitro and is thus an attractive candidate to replace oxaliplatin in the FOLFOX regimen. The objective of this Phase 1 study is to identify the maximum tolerated dose (MTD) of pico administered either every 2 wks or every 4 wks with FU and LV administered every 2 wks. Methods: Each patient receives q 2 wk FU and LV: LV, 400 mg/m2, 2-hr infusion, followed by 5- FU bolus, 400 mg/m2 and then 5-FU, 2,400 mg/m2, 46 hr continuous infusion. Subjects are randomized to pico administered either every 2 or every 4 wks. Starting dose of pico for q 2 weekly regimen was 45 mg/m2 and in subsequent cohorts pico increases by 15 mg/m2. Starting dose of pico for q 4 wk regimen was 60 mg/m2 and in subsequent cohorts pico increases by 30 mg/m2 until dose limiting toxicity (DLT) establishes the MTD. Results: 23 pts have been treated to date, the first have received 32 wks of therapy. Therapy has been well tolerated, with infrequent dose delays from non-cumulative platelet and ANC toxicity and 1 episode of mild diarrhea. No DLT has been seen through the first 3 cohorts, i.e. with picoplatin, 75 mg/m2 with every dose of FU-LV or120 mg/m2 with every other dose of FU-LV. Dose escalation continues. Response assessments for 12 patients in the first 2 cohorts (6 on each pico schedule, all below the MTD) after 16 wks show 4 partial responses, 5 stable disease and 3 progressive disease. Conclusions: Picoplatin can be safely administered with 5FU and LV. A phase 2 study of FU, LV and pico will begin as soon as the MTD is identified and a safe dose and schedule are defined. No significant financial relationships to disclose.

scholarly journals Phase 1 study results of the type II glycoengineered humanized anti-CD20 monoclonal antibody obinutuzumab (GA101) in B-cell lymphoma patients

Blood ◽  
2012 ◽  
Vol 119 (22) ◽  
pp. 5126-5132 ◽  
Author(s):  
Gilles Salles ◽  
Franck Morschhauser ◽  
Thierry Lamy ◽  
Noel Milpied ◽  
Catherine Thieblemont ◽  
...  
Keyword(s):  
B Cell ◽  
Phase 1 ◽  
B Cell Lymphoma ◽  
Type I ◽  
Type Ii ◽  
Phase 1 Study ◽  
Study Results ◽  
Grade 3 ◽  
Anti Cd20

Whereas the chimeric type I anti-CD20 Ab rituximab has improved outcomes for patients with B-cell malignancies significantly, many patients with non-Hodgkin lymphoma (NHL) remain incurable. Obinutuzumab (GA101) is a glycoengineered, humanized anti-CD20 type II Ab that has demonstrated superior activity against type I Abs in vitro and in preclinical studies. In the present study, we evaluated the safety, efficacy, and pharmacokinetics of GA101 in a phase 1 study of 21 patients with heavily pretreated, relapsed, or refractory CD20+ indolent NHL. Patients received GA101 in a dose-escalating fashion (3 per cohort, range 50/100-1200/2000 mg) for 8 × 21-day cycles. The majority of adverse events (AEs) were grades 1 and 2 (114 of 132 total AEs). Seven patients reported a total of 18 grade 3 or 4 AEs. Infusion-related reactions were the most common AE, with most occurring during the first infusion and resolving with appropriate management. Three patients experienced grade 3 or 4 drug-related infusion-related reactions. The best overall response was 43%, with 5 complete responses and 4 partial responses. Data from this study suggest that GA101 was well tolerated and demonstrated encouraging activity in patients with previously treated NHL up to doses of 2000 mg. This trial is registered at www.clinicaltrials.gov as NCT00517530.

A phase 1 study of daily oral perifosine (P) with weekly paclitaxel (T)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13117-13117 ◽  
Author(s):  
B. Ebrahimi ◽  
J. J. Nemunaitis ◽  
R. Shiffman ◽  
R. Birch ◽  
M. Diaz-Lacayo ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Phase 1 ◽  
Single Agent ◽  
Hematologic Toxicity ◽  
Phase 1 Study ◽  
Prior Chemotherapy ◽  
Phase Ii Studies ◽  
Grade 3 ◽  
Tumor Types ◽  
Dose Reductions

13117 Background: P is an oral signal transduction modulator with limited toxicity. P combined with 3-weekly T led to no toxicity beyond that expected with each drug alone. Weekly T is more effective than 3-weekly T in some settings (Seidman, ASCO 2004:512), so this study evaluated whether weekly T altered the tolerance to P. Methods: Twelve patients (pts) were enrolled. T was given at 80 mg/m2 on days 1, 8 and 15 of a 28 day cycle. P, 50 mg, was given 1, 2 or 3 times a day on days 1–21 of each cycle. Results: Tumor types were lung 2, breast 4, endometrium 3 and other 3. Median age was 55 (range 41–82). All pts had received prior chemotherapy (median 2.5, range 1–3 regimens) and 6 a prior taxane. Three pts were entered at each dose and the cohort expanded to 6 pts if 2 or more experienced a grade 3/4 non-hematologic toxicity (DLT) during cycle 1. A dose was toxic if 4 or more pts experienced a DLT during cycle 1. Since toxicity was not dose limiting in any cohort, the 150 dose was expanded to 6 pts. There were no grade 3/4 hematologic toxicities. The grade 3/4 non-hematologic toxicities at least possibly related to perifosine are given in the table below: The high glucose values were 276 and 277. A total of 38 cycles and a median of 2.5 cycles per pt (range 1–10+) were delivered. Full dose T was given in 85% of cycles (50 mg–100%, 100 mg–85%, 150 mg–86%). Dose reductions of T in 3 pts were related to neuropathy, suspected bronchitis and fatigue. One pt treated at 100 mg requested T be stopped after 6 cycles due to neurotoxicity and has received 6 additional cycles of perifosine alone. Perifosine dose reductions were required in 13% of cycles (50 mg - 0%, 100 mg - 21%, 150 mg - 9%). One pt each was reduced due to constipation, nausea and diarrhea. Five of 7 evaluable pts had stable disease (breast 2, cervix, endometrium, thyroid) for at least 3 months. Four remain stable at 3+ to 10+ months. Conclusions: The single agent doses of P (150 mg daily) & T (80 mg/m2 weekly) were given without increasing the toxicities expected from using each drug alone. Phase II studies are warranted to define the activity of the combination. [Table: see text] [Table: see text]

scholarly journals A Novel Regimen for Acute Myeloid Leukemia with MLL Partial Tandem Duplication: Results of a Phase 1 Study NCI 8485

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 900-900 ◽  
Author(s):  
Alice S. Mims ◽  
Rebecca B Klisovic ◽  
Ramiro Garzon ◽  
Alison R. Walker ◽  
Steven M. Devine ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Tandem Duplication ◽  
Phase 1 ◽  
Hdac Inhibitors ◽  
Median Number ◽  
National Institutes Of Health ◽  
Phase 1 Study ◽  
Partial Tandem Duplication ◽  
Acute Myeloid ◽  
Count Recovery

Abstract Background: MLL partial tandem duplication (MLL PTD) occurs in approximately 5-8% of patients with acute myeloid leukemia (AML) and is associated with an adverse prognosis. Our group has published that the MLL wild type (WT) allele is epigenetically silenced in MLL PTD; we showed that re-expression of this gene can be induced with methyltransferase (DNMT) and/or histone deacetylase (HDAC) inhibitors. Further, re-expression of MLL WT following combined decitabine and HDAC inhibitor treatment sensitized MLL PTD myeloid leukemia cells to chemotherapy in vitro. We hypothesized that epigenetic silencing of the MLL WT contributes to MLL PTD-associated leukemogenesis and that its pharmacologic re-expression with DNMT and HDAC inhibitors would activate apoptotic mechanisms important for chemo-response in the clinic. We aimed to develop a regimen to be tested in this unique molecular subset of disease. Because of the relatively low frequency of MLL PTD AML, this dose finding study was conducted in relapsed/refractory (R/R) AML regardless of molecular subtype but was enriched for MLLPTD. Methods:In this phase 1 study, adults aged 18-59 years with R/R AML, ECOG 0-2, and preserved organ function were enrolled. Patients received decitabine 20mg/m2 daily on days 1-10 and vorinostat 400mg daily on days 5-10 for all dose levels. Dose-escalated cytarabine was given on days 12, 14, 16 (six doses) according to the following schedule: dose level (DL) 1, 1.5g/m2/q12hr; DL 2, 2g/m2/q12hr; DL 3, 2.5g/m2/q12hr; and DL 4, 3g/m2/q12hr. Standard method 3+3 phase I design was used with the primary objective to determine the maximum tolerated dose and define specific toxicities with this combination therapy, in order to ultimately develop a regimen for MLLPTD AML. Results:Seventeen adults with R/R AML and median age of 46 years (range, 21-59 years) enrolled. The median number of prior induction therapies was 2 (range, 1-4). European LeukemiaNet (ELN) genetic risk classification frequencies were: favorable (n=2), intermediate-I (n=3), intermediate-II (n=5), and adverse (n=7), respectively. Four patients had MLL PTD. A total of 6 patients were treated at DL 1 with no non-hematologic dose limiting toxicity (DLT). DL 1 was expanded after two patients experienced prolonged but uncomplicated myelosuppression. Since both patients achieved complete remission (CR) shortly after passing the day 42 DLT cut off for hematologic recovery, the protocol was amended to allow further time for count recovery (up to 56 days). Three patients each were treated on DL 2 and 3; 5 patients were treated on DL 4 with no other DLTs observed. Diarrhea, nausea, fatigue, febrile neutropenia, and elevated ALT were the most common toxicities (any grade, regardless of attribution), occurring in 41%, 29%, 29%, 35%, and 35% of patients, respectively, but none were DLTs. In regards to ≥ Grade 3 toxicities, febrile neutropenia and catheter-related infections were most common at 35% and 24%. Significant mucositis was not observed. DL 4 was the recommended phase 2 dose (RP2D). CR or CR with incomplete count recovery (CRi) was observed in 6/17 patients (35%, 5 with CR). Of 6 responders, all (n=4) patients with abnormal karyotype achieved cytogenetic remission. The median number of prior therapies for patients achieving CR/CRi was 2 (range, 1-3). Four patients subsequently received allogeneic transplantation. Of the four patients known to have MLL PTD mutations, two responded (1 with CR and 1 with CRi). It is interesting to note that the two patients with MLL PTD mutations who did not respond to treatment also had FLT3-ITD mutations, while this mutation was absent in the two responding patients who had MLLPTD. Conclusions: We successfully determined the RP2D for this novel treatment regimen. The regimen had modest toxicities beyond uncomplicated (though prolonged) myelosuppression, and we propose that the study provides a framework for larger efficacy studies for AML patients with the uncommon but biologically distinct molecular feature of MLLPTD. Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number U01CA076576. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Also supported by P30 CA016058/CA/NCI. Disclosures No relevant conflicts of interest to declare.

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