Combination of Sorafenib, Idarubicin, and Cytarabine Has a High Response Rate in Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) Younger Than 65 Years

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 768-768 ◽  
Author(s):  
Farhad Ravandi ◽  
Jorge Cortes ◽  
Stefan Faderl ◽  
Guillermo Garcia-Manero ◽  
Susan O’Brien ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Phase I ◽  
Cell Lines ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Single Agent ◽  
High Response Rate ◽  
Clinical Activity ◽  
Mutation Burden

Abstract Background: Sorafenib is an orally active multi-kinase inhibitor with potent activity against the Raf/ERK/MEK pathway, VEGFR, PDGFR-β, and c-KIT. In vitro, it has growth-inhibitory effects in several AML cell lines with or without constitutive activation of ERK signaling. Sorafenib selectively induces cell growth arrest and apoptosis in FLT3-mutant human AML cell lines at nM concentrations. In a phase I study of single agent sorafenib in patients (pts) with AML escalating doses were well tolerated with no myelosuppression and with significant clinical activity predominantly (but not exclusively) in FLT3 mutated pts. Methods: This study was conducted to determine the tolerability and efficacy of combination of sorafenib with cytarabine 1.5 g/m2 iv over 24 hours daily × 4 (× 3 for pts over 60) and idarubicin 12 mg/m2 iv daily × 3. In the phase I portion of study, pts with relapsed AML were treated with escalating doses of sorafenib po (400 mg qod, 400 mg daily and 400 mg bid) for 7 days during induction, and 400 mg bid was established as a safe dose for phase II evaluation. Pts achieving CR receive up to 5 courses of consolidation with idarubicin 8 mg/m2 iv daily × 2 and cytarabine 0.75 g/m2 iv daily × 3 in addition to continuous sorafenib 400 mg po bid for up to 28 days per cycle. Maintenance with sorafenib 400 mg bid would continue for up to a year after consolidation. Results: Ten pts (median age 34 years, range 21–58) with relapsed AML (median prior therapy 2, range 1–6) were treated on the phase I portion. Seven had FLT3-ITD mutation (5 with high mutation burden, 2 with low), and 3 were negative. Four achieved CR, and 6 failed. In the phase II portion, 30 pts (including 8 with FLT3-ITD and 2 with FLT3-TKD) have been treated. Median age is 53 years (range 18 – 65) Cytogenetics were diploid in 13, +8 in 3, −5/−7 in 3, t(9;11) in 1, miscellaneous in 6, and unavailable in 4. The median presentation WBC was 4.6 × 109/L (range 1.5 –122.7 × 109/L). FLT3 mutation burden was low in blasts from 4 pts, and high in 6). Five pts were FLT3-ITD+/NPM1-. Among 25 evaluable pts, 22 (88%) have achieved CR (n=19), or CRi (n=3); 1 achieved PR, 1 died at induction from pneumonia, 1 was resistant; 5 pts are too early. The regimen is well tolerated and grade 3 adverse events thought to be possibly related to the study combination have included elevation of transaminases (3), hyperbilirubinemia (4), small bowel obstruction (1), diarrhea (2), rash (2), pericarditis (1), elevated creatinine (1), and atrial fibrillation (1). Median follow-up is 8 weeks (range, 1 – 28) with the probability of survival at 6 months of 87%; 2 pts have relapsed with CR durations of 2 and 3 months. Samples from 8 pts were studied prior to and 24–48 hours post sorafenib administration, and prior to chemotherapy. In six pts (75%), sorafenib alone induced apoptosis in peripheral blood blasts and in CD33/CD34 positive leukemia progenitor cells as determined by flow cytometry. Expression of phospho-ERK (pERK) was detectable by flow cytometry in 5 out of 7 samples tested at baseline; 24-hour exposure to sorafenib resulted in >50% downregulation of pERK in 3 of the 5 samples. Plasma inhibitory assay was performed using day 7 samples from 10 pts; mutant FLT3 was suppressed by all samples with 5-fold more potent suppression against mutant versus wildtype FLT3. Conclusions: Combination of sorafenib with idarubicin and cytarabine is safe and has a high CR rate in frontline therapy of younger pts with AML. Correlative studies confirm potent activity of sorafenib against ERK and FLT3 signaling.

Phase I study of a novel, pharmacokinetically derived schedule of flavopiridol in acute leukemias: Clinical efficacy including hyperacute tumor lysis, pharmacokinetics, and pharmacodynamics

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6568-6568
Author(s):  
W. Blum ◽  
R. B. Klisovic ◽  
C. Kefauver ◽  
A. Johnson ◽  
M. Phelps ◽  
...  
Keyword(s):  
Phase I ◽  
Kinase Inhibitor ◽  
Single Agent ◽  
Calf Serum ◽  
Clinical Activity ◽  
Acute Leukemias ◽  
Tumor Lysis ◽  
Optimal Dosing ◽  
Dose Levels

6568 Background: Flavopiridol is a cyclin dependent kinase inhibitor with in vitro activity in many cancer cell lines. However, phase I/II studies of either 24 or 72-hour continuous infusion schedules demonstrated no significant clinical activity. Discordant binding of flavopiridol to human plasma proteins as compared to fetal calf serum prompted us to perform pharmacokinetic modeling studies which suggested that optimal dosing would be a 30 min IV bolus followed by 4 hr IV infusion. With this schedule, our group has observed impressive clinical activity in refractory CLL. Methods: We intensified this schedule for relapsed or refractory adult AML and ALL patients (pts) to administer an IV bolus over 30 min followed by an infusion over 4 hrs on 3 consecutive days in a phase I trial. Results: To date, 10 pts have been treated at 2 dose levels. Pts had relapsed/refractory AML (N=6) or ALL (N=4) and were 25–77 yrs old. 4 pts received flavopiridol at 20 mg/m2 IV bolus and 30 mg/m2 infusion; 6 received 30 mg/m2 bolus followed by 35 mg/m2 infusion. The most significant toxicity was tumor lysis; treatment was well tolerated, and toxicities were similar to those previously reported by our group with the single day dosing schedule used in CLL. Plasma levels were 1–2 μM during the infusion (N=7) and declined with a terminal half life comparable to that previously reported with a 72 hr infusion. Significant anti-leukemic activity was seen in 5/7 evaluable pts at both dose levels. Tumor lysis was seen in both ALL and AML (see table ). Downregulation of Mcl-1 protein by immunoblotting was seen in 2/3 pts tested to date. Conclusions: Single agent flavopiridol given with this novel, pharmacologically modeled schedule has clinical activity in pts with relapsed/refractory ALL and AML. Further study in acute leukemia using this schedule is warranted; dose escalation to the current trial is ongoing. (NCI U01 CA 76576–05) [Table: see text] No significant financial relationships to disclose.

A phase I study of nilotinib alone and in combination with imatinib (IM) in patients (pts) with imatinib-resistant gastrointestinal stromal tumors (GIST) - Study update

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 10023-10023 ◽  
Author(s):  
M. Von Mehren ◽  
P. Reichardt ◽  
P. G. Casali ◽  
J. Blay ◽  
M. Debiec-Rychter ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Kinase Inhibitor ◽  
Progression Free Survival ◽  
Skin Toxicity ◽  
Clinical Activity ◽  
Imatinib Resistant ◽  
Exon 9 ◽  
Exon 11

10023 Background: Nilotinib is a novel tyrosine kinase inhibitor (TKI) targeting KIT, PDGFR, and Bcr-Abl and inhibiting the proliferation of both IM-sensitive and -resistant cells in vitro. We report the results of a phase I study in GIST pts resistant to IM and other TKIs. Methods: Pts with progressive disease received nilotinib alone (400 mg p.o. bid) or escalating doses of nilotinib (200 mg qd, 400 mg qd, or 400 mg bid) in combination with IM (400 mg p.o. bid), or nilotinib 400 mg bid plus IM 400 mg qd. Pharmacokinetic (PK) analyses were performed. Tumor assessments (RECIST) were done every 8 weeks. Baseline samples of 18 GISTs were analyzed for KIT and PDGFR mutations. Results: 53 pts received nilotinib, alone (n=18) or in combination with IM (n=35), for a median of 134 days (range 8 to 430 days). Thirty-nine pts (74%) had failed second-line therapies including sunitinib, AMG-706, dasatinib or RAD001. Most frequent adverse events were grade 1 (17% of pts) or 2 (51% of pts) including: skin toxicity, fatigue, myalgia, headache, abdominal pain, nausea, vomiting, diarrhea, constipation, hyperbilirubinemia and edema. Six pts experienced dose limiting hyperbilirubinemia or skin rash. One pt on nilotinib alone achieved partial response (PR) for > 6 months and 36 pts (68%)-13 on nilotinib alone-, had SD ranging from 6 weeks to > 6 months. Median progression-free survival was 134 days overall and 178 days for pts on nilotinib alone. Genotyping revealed mutations in KIT exon 9 (n=4) or 11 (n=11), and KIT WT (n=3). The single PR occurred in KIT exon 11 mutant GIST following previous adjuvant imatinib and intolerance to imatinib 800 mg. KIT was WT in 2 out of 8 pts with SD > 6 months. Conclusions: Nilotinib, alone and in combination with IM has promising clinical activity in pts with GIST resistant to prior TKIs. Tolerability is acceptable for both nilotinib 400 mg bid, alone and in combination with IM 400 mg qd, which are the recommended doses for future studies. No significant financial relationships to disclose.

Phase I Study of Aurora Kinase Inhibitor MLN8237 and Bortezomib in Relapsed or Refractory Multiple Myeloma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1859-1859
Author(s):  
A. Keith Stewart ◽  
Ravi Vij ◽  
Jacob P. Laubach ◽  
Craig C. Hofmeister ◽  
Rachel Hagerty ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Single Agent ◽  
Aurora Kinase ◽  
Cell Transplant ◽  
Days Of Therapy

Abstract Abstract 1859 Genome wide RNA interference studies identified Aurora Kinase (AURK) A and B as lethal targets in Multiple Myeloma (MM) while suppression of these genes also sensitized MM to bortezomib (BTZ). MLN8237 is an oral inhibitor of AURKA. We therefore conducted a Phase I clinical trial of MLN8237 in combination with BTZ. The study enrolled a total of 19 patients at 5 institutions. 9 patients are still receiving active treatment as of the date of this report. Study Design: The phase I portion of this study uses a standard 3+3 design to determine the maximum tolerated dose (MTD) of MLN8237 and BTZ in patients with relapsed/refractory MM. Eligibility required a minimum of 1 and maximum of 4 lines of prior therapy. Patients who have received prior BTZ therapy were allowed on trial as long as they did not progress during prior BTZ or ≤ 60 days of therapy discontinuation. The following laboratory values were required £7 days prior to registration. ANC3 1000/mL, Hgb ≥9 g/dl, PLT3 100,000/mL, Total bilirubin £1.5 × upper limit of normal (ULN), Creatinine £ 2.5 × ULN, a baseline LVEF ≥45%. Patients were required to be able to take oral medication and to maintain a fast as required for 2 hours before and 1 hour after MLN8237 administration. Treatment Overview: The first 3 patients received MLN8237 at 25 mg po days 1–14 and BTZ at 1.3 mg/m2/dose iv. days 1, 4, 8, 11 on a 28 day schedule. Based on data from other concurrent trials an amendment changed dosing of MLN8237 to 20, 30, 40 or 50 mg po twice daily on days 1–7 and BTZ was given at 1.5mg/m2 iv weekly on a 28 day schedule. Results: Median age of patients was 64, 63% were male, 31% had high risk genetics, 84% had prior stem cell transplant, 53% of patients were relapsed and 47% were relapsed and refractory to therapy. No DLTs were observed even at the highest dose level tested. However, one patient at the highest dose level required a platelet transfusion in order to initiate treatment on time in Cycle 2. Thus, a further 3 patients accrued at the highest dose level before declaring the MTD and proceeding to phase II. The highest dose level (Dose Level 3: MLN8237 50 mg po twice daily on days 1–7; BTZ 1.5 mg/m2 iv. given on days 1, 8, 15, 22) was the final dose level tested (the MTD of single agent MLN8237 is 50mg as defined in other Phase I trials). The ORR was 26% (1 CR, 4 PR); when minor responses are included the ORR was 52%. Median follow up was 4.3 months (range 0.9–23.4) and PFS was 5.5 months. At last follow up 12 patients showed no progression and 7 had progressed. Toxicity: 63% of patients experienced a grade 3AE and 5% a grade 4 AE. Grade 3 or 4 toxicity seen in more than one patient was all hematologic with thrombocytopenia and neutropenia being common. Other toxicity of any grade regardless of attribution occurring in more than 20% of patients included neuropathy 63%, fatigue 63%, diarrhea 53%, nausea 47%,vomiting 26%, infection 32%, alopecia 21%, Conclusions: The MTD of the combination is MLN8237 50 mg po twice daily on days 1–7 and BTZ at 1.5mg/m2 iv weekly. Phase II testing is underway and updated results will be presented. Disclosures: Stewart: Millenium: Consultancy, Honoraria, Research Funding; Onyx: Consultancy; Celgene: Consultancy. Vij:Millennium: Speakers Bureau. Hofmeister:Celgene: Advisory board Other, Honoraria.

scholarly journals The novel MET inhibitor, HQP8361, possesses single agent activity and enhances therapeutic efficacy of osimertinib, against NSCLC cells with acquired resistance to osimertinib due to MET amplification

2020 ◽  
Author(s):  
Danlei Yu ◽  
Yiting Li ◽  
Kevin D-H Sun ◽  
Jiajia Gu ◽  
Zhen Chen ◽  
...  
Keyword(s):  
Cell Lines ◽  
Kinase Inhibitor ◽  
Single Agent ◽  
Acquired Resistance ◽  
Met Amplification ◽  
Egfr Mutant ◽  
Egfr Tkis ◽  
Human Nsclc

Abstract Background The oncogenic protein, MET (or c-MET), is involved in the positive regulation of cell survival and proliferation and in mediating acquired resistance to EGFR-TKIs including AZD9291 (osimertinib). Thus, MET inhibition is a promising strategy for overcoming acquired EGFR-TKI resistance due to MET amplification. HQP8361 (MK8033) is a novel and selective MET kinase inhibitor that has completed a phase I clinical trial. The current study focuses on determining the activity and mechanism of action of HQP8361 as a single agent and in combination with AZD9291 against human NSCLC cells, particularly EGFR-mutant NSCLCs with acquired resistance to AZD9291. Methods Drug effects on cell growth in vitro were evaluated by measuring cell number alterations and colony formation and in vivo with mouse xenogtaft models, respectively. Apoptosis was assessed with annexin V/flow cytomentry and protein cleavage. Protein alterations were detected with Western blotting. Protein degradation was determined by comparing protein half-lives and inhibiting proteasome. Gene overexpression and knockout were achieved with lentiviral infection and CRISPR/Cas9, respectively. Significance of differences between two tested groups was analyzed with two-sided unpaired Student's t tests. Results The majority of human NSCLC cell lines tested, including those harboring EGFR-activating mutations with acquired resistance to AZD9291, had very low or undetectable levels of MET and p-MET and were insensitive to HQP8361. However, AZD9291-resistant (AR) cell lines derived from the EGFR-mutant HCC827 cell line possessed high levels of MET and p-MET and responded to HQP8361 single agent and particularly to the combination of HQP8361 and AZD9291. The HQP8361 and AZD9291 combination synergistically decreased the survival of these HCC827/AR cell lines with enhanced induction of apoptosis that involved alteration of Bim and Mcl-1 levels via modulating their degradation. Moreover, the combination also very effectively inhibited the growth of HCC827/AR xenografts in nude mice. Conclusions These preclinical findings support the potential of HQP8361 in the treatment of NSCLCs with MET amplification or highly activated MET protein and, when combined with AZD9291, in overcoming acquired resistance to EGFR-TKIs due to MET amplification.

Phase I Trial of the Oral Antiangiogenesis Agent AG-013736 in Patients With Advanced Solid Tumors: Pharmacokinetic and Clinical Results

2005 ◽  
Vol 23 (24) ◽  
pp. 5474-5483 ◽  
Author(s):  
Hope S. Rugo ◽  
Roy S. Herbst ◽  
Glenn Liu ◽  
John W. Park ◽  
Merrill S. Kies ◽  
...  
Keyword(s):  
Growth Factor ◽  
Phase I ◽  
Solid Tumors ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Peak Plasma ◽  
Plasma Concentrations ◽  
Vascular Endothelial Cell ◽  
Clinical Activity ◽  
Advanced Solid Tumors

Purpose We studied the safety, clinical activity, and pharmacokinetics (PK) of AG-013736, an oral receptor tyrosine kinase inhibitor of vascular endothelial cell growth factor, platelet-derived growth factor, and c-Kit, in patients with advanced cancer. Patients and Methods Patients received fixed doses of AG-013736 orally in 28-day cycles. In the first cohort, patients initially received two single test doses of AG-013736 (10 and 30 mg); subsequent dosing was determined by individual PK parameters. Doses in subsequent cohorts were assigned by using a traditional dose-escalation/de-escalation rule based on observed toxicities in the current and previous cohorts. PK analysis included evaluation of the effect of food and antacid. Results Thirty-six patients received AG-013736 at doses ranging from 5 to 30 mg by mouth twice daily. The dose-limiting toxicities observed included hypertension, hemoptysis, and stomatitis and were seen primarily at the higher dose levels. The observed hypertension was manageable with medication. Stomatitis was generally tolerable and managed by dose reduction or drug holidays. AG-013736 was absorbed rapidly, with peak plasma concentrations observed within 2 to 6 hours after dosing. The maximum-tolerated dose and recommended phase II dose of AG-013736 is 5 mg, twice daily, administered in the fasted state. No significant drug interaction with antacid was seen. There were three confirmed partial responses and other evidence of clinical activity. Conclusion In this study, we have demonstrated clinical activity and safety of AG-013736 in patients with advanced solid tumors and identified the dose for phase II testing. The unique phase I study design allowed early identification of important absorption and metabolic issues critical to phase II testing of this agent.

Phase I/II Results of a Multicenter Trial of Perifosine (KRX-0401) + Bortezomib in Patients with Relapsed or Relapsed/Refractory Multiple Myeloma Who Were Previously Relapsed from or Refractory to Bortezomib

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 870-870 ◽  
Author(s):  
Paul Richardson ◽  
Jeffrey Wolf ◽  
Andrzej Jakubowiak ◽  
Jeffrey Zonder ◽  
Sagar Lonial ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Phase Ii ◽  
Phase 1 ◽  
Multicenter Trial ◽  
Toxicity Assessment ◽  
Clinical Activity ◽  
Hematologic Toxicity ◽  
Refractory Multiple Myeloma

Abstract INTRODUCTION: Perifosine (Peri) is an orally -bioavailable, novel signal transduction modulator with multiple pathway effects including inhibition of Akt and activation of JNK. Peri first demonstrated activity in combination with dexamethasone (dex) in patients (pts) with advanced, relapsed/refractory multiple myeloma (MM) (ASH 2007 #1164). Of interest were experiments conducted combining Peri with bortezomib (Velcade®, Vel). In vitro, Peri + Vel shows at least additive cytotoxicity against MM cells with Peri inhibiting Vel induced Akt activation (Hideshima et. al, BLOOD 2006). We conducted a phase I/II study with encouraging safety and clinical activity of the combination seen in the phase I portion of the trial, including a 56% ORR (ASH 2007 # 1170). Herein, we report on the combined phase I/II results (n=76) which determined the safety and activity of Peri + Vel 322 PATTerNS of CAre 2008 ASH ANNUAl MeeTiNG ABSTrACTS, VolUMe 112, iSSUe 11, NoVeMBer 16, 2008 (+/− dex), in pts with relapsed and relapsed/refractory MM, who were previously relapsed from or refractory to Vel. METHODS: The phase I stage of the study enrolled a total of 18 pts in 4 cohorts (≥3 pts each) with dosing of Peri 50 mg or 100 mg (daily) and Vel 1.0 or 1.3 mg/m2 (d 1, 4, 8, 11) in 21-d cycles. The selected dose for phase II was Peri 50 mg qd + Vel 1.3 mg/m2 (d 1, 4, 8, 11) in 21-d cycles, with a planned enrollment of 64 pts. Dex 20mg (on day of and after each Vel dose) could be added in pts with progressive disease (PD). NCI CTCAE v3.0 was used for toxicity assessment. For the phase I portion, DLT was defined as any grade (G) 3 non-hematologic toxicity, G4 neutropenia for 5 d and/or neutropenic fever, or platelets <10,000/mm3 on >1 occasion despite transfusion. Response was assessed by modified EBMT and Uniform criteria. RESULTS: A total of 76 pts have been enrolled (18 pts in phase I and 58 in phase II) comprised of 45 men and 31 women, median age 63 y, (range 41 – 89). 84% of pts had relapsed/refractory MM, with a median of 6 lines of prior treatment (range 2–13). Prior therapy included Vel (100%), dex (95%), thalidomide (79%), lenalidomide (71%) and SCT (57%). 63 pts have completed at least one cycle and were evaluable for safety (13 pts are currently not evaluable; 3 were removed in cycle 1 and 10 are too early in their treatment). Most common (□ 10%) grade 1/2 events were nausea, diarrhea, fatigue and myelosuppression, which were manageable with supportive care and growth factors. Grade 3/4 adverse events 5% included thrombocytopenia (40%); lymphopenia (36%); neutropenia (21%); anemia (14%); hyponatremia (13%); leukopenia (11%); proteinuria (8%), and upper respiratory infection (6%). No DVT has been seen, and only 1 worsening peripheral neuropathy from grade 1 to 3 has been reported to date: 2 pts had Peri reduced to 50 mg (nausea, fatigue) in the phase 1 cohort, and 7 pts had Vel dose reductions primarily due to hematologic toxicity. 57 pts have completed at least 2 cycles and are evaluable for response, with best response to Peri + Vel (+/− dex) as follows: CR PR MR ORR SD All Patients:Best Response N=57 2 4% 7 12% 14 25% 23 40% 23 40% Peri + Vel 57 1 2% 5 9% 8 14% 14 24% 17 30% With dex added* 31 1 2% 2 3% 6 11% 9 16% 6 11% (* as a subset of the evaluable population) 9 of 76 pts (12%) rapidly progressed without response or stable disease, including 6 pts in whom dex was also added. As of August 2008, the median time to progression (TTP) for pts achieving PR is 34 wks, and for all pts achieving MR is 33 wks. The median TTP for all study pts is 19 wks (range 3 – 103 wks). The median TTP for responders and for all pts has not been met. In a subset analysis of Vel refractory pts (35/57), the reported ORR (□ MR), and median TTP were as follows: Vel Refractory:N= 35 CR PR MR ORR SD Peri + Vel (+/− dex) 1 3% 4 11% 8 23% 13 37% 12 34% Median TTP (wks/range): Responders (n=13) 103 17 (11 – 24) 40 (19 – 76) 37 (11 – 103) 21 (9 – 32) Median TTP (wks/range): All pts (n=35) 23 wks (3 – 103 wks) CONCLUSIONS: Peri in combination with Vel (+/− dex) was generally well tolerated and is remarkably active in a heavily pre-treated, Vel-exposed pt population, with an ORR of 40%, including an ORR of 37% and a median TTP of 9.25 months in responding but previously Vel –refractory pts. Responses have been durable overall with clinical benefit seen, as reflected by an encouraging TTP in this setting. Additional analysis will be reported at the meeting and further trials, including randomized studies earlier in relapsed disease, are planned.

scholarly journals SL-401, a Targeted Therapy Directed to the Interleukin-3 Receptor (CD123), and SL-801, a Reversible Inhibitor of Exportin-1 (XPO1), Display Synergistic Anti-Tumor Activity Against Hematologic Malignancies in Vitro

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4724-4724 ◽  
Author(s):  
John Gionco ◽  
Janice Chen ◽  
Ross Lindsay ◽  
Vince Macri ◽  
Christopher L. Brooks
Keyword(s):  
Cell Line ◽  
Cell Lines ◽  
Single Agent ◽  
Hematologic Malignancies ◽  
Clinical Activity ◽  
Employment Equity ◽  
Equity Ownership ◽  
Rpmi 8226 ◽  
Anti Tumor Activity

Abstract Background: Novel combination therapies have shown success in combating tumor heterogeneity and drug resistance. SL-401 is a targeted therapy directed to the interleukin-3 receptor (CD123), which is overexpressed on numerous hematologic malignancies. SL-401 has demonstrated high single agent response rates in an ongoing Phase 2 trial of blastic plasmacytoid dendritic cell neoplasm (BPDCN) and is also being evaluated in the clinic for additional cancers, including acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPNs) as a single agent, and multiple myeloma (MM) in combination with other agents. While SL-401 has demonstrated robust single agent clinical activity in patients with BPDCN, its unique mechanism of action and non-overlapping side effect profile with other agents may lend itself to combination therapy as well. Another class of drugs that has demonstrated clinical activity against several hematologic and solid malignancies is Exportin-1 (XPO1) inhibitors. SL-801 is a novel oral small molecule that reversibly inhibits XPO1 and has shown potent in vitro and in vivo anti-tumor activity against a broad range of hematologic and solid malignancies. SL-801 is currently being evaluated in a Phase 1 trial of patients with advanced solid tumors, and a Phase 1 trial in advanced hematologic cancers is planned. Here, we investigated the in vitro effect of combination treatment of SL-401 and SL-801 against cell lines of chronic myeloid leukemia (CML), AML, MM, and Hodgkin's lymphoma (HL). Methods: The human K562 CML cell line, MV4-11 AML cell line, RPMI-8226 MM cell line, and L-428 HL cell line were treated with varying concentrations of SL-401 and SL-801 alone or in combination for 48 hours. Cell viability was assessed by the CellTiter Glo in vitro cytotoxicity assay. Combination index (CI) values were calculated using CompuSyn software by the method of Chou and Talalay, and treatment was considered to be synergistic when CI < 1. Caspase activation was measured using the Caspase-Glo 3/7 assay, and lactate dehydrogenase (LDH) release was measured using the CytoTox 96 Non-Radioactive Cytotoxicity Assay. Results: As single agents, SL-401 and SL-801 demonstrated anti-tumor activity in all four cell lines tested. MV4-11 cells were the most sensitive to both drugs, with an IC50 of 34 pM for SL-401 and 21 nM for SL-801. In the other cell lines, the IC50s for SL-401 were 17 nM in K562 cells, 25 nM in RPMI-8226 cells, and 100 nM in L-428 cells, and the IC50s for SL-801 were 99 nM in K562 cells, 51 nM in RPMI-8226 cells, and 494 nM in L-428 cells. When combined with each other, SL-401 and SL-801 potently inhibited cell growth in all cell lines, and CI calculations indicated that the interaction between the two drugs was synergistic at most dose combinations. Notably, CI values < 0.3 were observed in MV4-11 and L-428 cells, indicative of strong synergy. Consistent with these observations, the combination of SL-401 and SL-801 also induced higher levels of caspase activation and LDH release in MV4-11 and L-428 cells than either drug alone. Conclusion: These findings demonstrate that SL-401 and SL-801, when combined, act synergistically in their in vitro anti-tumor activity against CML, AML, MM, and HL cells. Investigations into the molecular mechanisms underlying the observed synergy are in progress. These promising results provide rationale for further development of SL-401 and SL-801 combination therapy in the treatment of a broad range of hematologic malignancies. Disclosures Gionco: Stemline Therapeutics, Inc.: Employment. Chen:Stemline Therapeutics, Inc.: Employment, Equity Ownership. Lindsay:Stemline Therapeutics, Inc.: Employment, Equity Ownership. Macri:Stemline Therapeutics, Inc.: Employment, Equity Ownership. Brooks:Stemline Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties.

Pre-Clinical In Vitro Evaluation of BCL-2 Antisense Compound GenasenseTM (G3139; Genta, Inc.) as a Targeted Pro-Apoptotic Agent for Leukemias with t(4;11)(q21;q23) Translocations.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3360-3360 ◽  
Author(s):  
Blaine W. Robinson ◽  
Kathyrn C. Behling ◽  
Jeffrey S. Barrett ◽  
Manish Gupta ◽  
Jessicca M. Rege ◽  
...  
Keyword(s):  
Response Surface ◽  
Cell Lines ◽  
Caspase 3 ◽  
Single Agent ◽  
Chemotherapy Resistance ◽  
Surface Modeling ◽  
Clinical Activity ◽  
Response Surface Modeling ◽  
Cd34 Cells

Abstract Background: Chemotherapy resistance from reduced apoptosis may contribute to poor outcome in infant leukemias with t(4;11). G3139 has clinical activity against refractory adult leukemias with minimal toxicity. Methods: We quantified anti-apoptotic BCL-2 and pro-apoptotic BAX mRNAs in 56 leukemias cases (55/56 from infants; 41 ALL, 15 AML; 24 t(4;11), 32 non-MLL), the ALL cell lines RS4:11 and SEM-K2, the AML cell line MV4-11, all of which have t(4;11), and normal CD34+ cells. BCL-2 and BAX mRNA levels were normalized to β-actin and examined by the comparative CT method. The in vitro cytotoxicity and pro-apoptotic activity of G3139 was investigated in the cell lines. Cytotoxicity was assessed by MTT after exposing log phase cells for 6 days to single agent G3139, or to fixed-concentration G3139 combined with anti-leukemia cytotoxic drugs over a range of concentrations; transfection reagent was not used for G3139 delivery. Pharmacostatistical response surface modeling was performed to determine synergy. Apoptosis was assessed by flow cytometry analysis of Caspase-3 activation and a FACS TUNEL assay. Results: BCL-2 and BAX mRNAs were abundant in the leukemias and cell lines with t(4;11), whereas CD34+ cells showed lower BCL-2 expression. The difference in normalized expression ratios of BCL-2:BAX relative to CD34+ cells approached significance when t(4;11) leukemias and cell lines were compared to non-MLL leukemias (p=0.07). The approximate IC50 of single agent G3139 was 10 μM in RS4:11 cells, 100 μM in MV4-11, and 180 μM in SEM-K2. Low, biologically achievable G3139 concentrations (5 μM, 1 μM) sensitized RS4:11 cells to the cytotoxicity of doxorubicin, 6-thioguanine, etoposide and cytosine arabinoside, but not methotrexate or dexamethasone. Despite the higher IC50 of G3139 alone in MV4-11 cells, synergy also was suggested when G3139 (50 μM, 10 μM) was combined with etoposide and 6-thioguanine since response surface modeling showed ability to achieve lower effective doses than projected from either single agent. When RS4:11 cells were assayed for proof of principle that the observed cytotoxicity was due to apoptosis, exposure to G3139 and doxorubicin together increased active Caspase-3 and TUNEL staining in a time and dose dependent manner. Conclusions: The imbalanced BCL-2/BAX expression suggests that an anti-apoptotic genotype forms the basis for the chemotherapy resistance in infant leukemias with t(4;11). These in vitro studies indicate that G3139 has pre-clinical activity, that select G3139-cytotoxic agent combinations are synergistic against cell lines with t(4;11), and that the observed activity occurs through apoptosis. Further studies are warranted to determine the pre-clinical in vivo effects of similar combinations against leukemias with t(4;11), with the goal of advancement to the clinic if results are promising.

A Phase I Trial of the Small Molecule Pan-Bcl-2 Family Inhibitor Obatoclax Mesylate (GX15-070) Administered by 24 Hour Infusion Every 2 Weeks to Patients with Myeloid Malignancies and Chronic Lymphocytic Leukemia (CLL).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2654-2654 ◽  
Author(s):  
Gautam Borthakur ◽  
Susan O’Brien ◽  
Farhad Ravandi-Kashani ◽  
Francis Giles ◽  
Aaron D. Schimmer ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Phase I Trial ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Ambulatory Setting ◽  
Clinical Activity ◽  
Qtc Prolongation ◽  
Grade 3

Obatoclax is an antagonist of the BH3-binding groove of the bcl-2 family of anti apoptotic proteins. It activates apoptosis and has clinical activity in CLL (O’Brien et al, ASH 2005) with a recommended phase II dose of 28 mg/m2 every 3 weeks with DLT of grade 3 infusional CNS toxicities. This Phase I trial was designed to evaluate the potential of prolonged infusions to minimize these toxicities while maintaining biological and clinical activity. We enrolled 14 patients at doses ranging from 7–40 mg/m2 over 24 hours every 2 weeks utilizing a modified accelerated titration design with 3–6 patients per cohort and doubling of the dose until 28 mg/m2. Cycle 1 was administered in a clinical research unit to accommodate PK sampling but subsequent cycles were administered in the ambulatory setting using portable infusion pumps. Median age was 62 (range 56–82) and 10 patients were male. The following diagnoses were included: myelodysplatic syndromes (MDS; 8, 4 secondary), refractory acute myelogenous leukemia (AML; 5) and CLL (1). A total of 51 infusions were administered. At doses ≤28 mg/m2, adverse events (AE) of Grade 1 dizziness (2/9), headache (2/9), euphoric mood (2/9) and Grade 2 somnolence (2/9) were of lesser frequency and intensity then at equivalent dose levels previously administered with a 3 hour infusion. At the 40 mg/m2 dose level, dose-limiting toxicities of Grade 3 QTc prolongation with no accompanying arrythmias were reported in 2/5 patients who both had QTc prolongation at baseline. Other toxicities included Grade 2 somnolence (4/5), Grade 1 euphoric mood (3/5), Grade 1 anxiety (2/5) and single reports of Grade 1 dizziness, dysarthria, dysphasia, confusion, hallucination and disorientation. The pharmacokinetics (PK) of obatoclax following a 24-hr IV infusion is dose proportional for both Cmax and AUC24h. Induction of apoptosis was monitored quantitatively with serial determinations of plasma concentration of histone-oligonucleosomal DNA (ODNA) complexes. An early release of ODNA greater than 4-fold occurred in 10/14 patients by the midpoint of the infusion and was sustained to the end of the infusion. The rapid elimination of the plasma obatoclax concentration immediately following the end of infusion was associated with a decline of the plasma oligonucleosomal DNA level; however multiple additional peaks of oligonucleosomal DNA concentrations occurring over days following the infusion were still detected in 9 of 14 patients. 3/8 patients with MDS showed hematological improvement with red blood cell or platelet transfusion independence. Bone marrow blasts were reduced from 14% to 4% in another patient with secondary MDS. Conclusions: Single agent obatoclax is well tolerated when administered as a 24 hour continuous infusion, with abrogation of previously noted infusional CNS toxicities. Biological and clinical activity are retained. Further prolongation of the infusion may lead to more robust activity and will be explored. Phase II single agent trials using 28 mg/m2 over 24 hours every 2 weeks have been initiated in patients with myelofibrosis and previously untreated MDS with anemia and/or thrombocytopenia to further evaluate the potential for hematological improvement in response to obatoclax.

Phase I/II Study of MGCD0103, an Oral Isotype-Selective Histone Deacetylase (HDAC) Inhibitor, in Combination with 5-Azacitidine in Higher-Risk Myelodysplastic Syndrome (MDS) and Acute Myelogenous Leukemia (AML).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 444-444 ◽  
Author(s):  
Guillermo Garcia-Manero ◽  
Allen S. Yang ◽  
Virginia Klimek ◽  
Jorge Cortes ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Hdac Inhibitor ◽  
Response Rate ◽  
Single Agent ◽  
Substantial Reduction ◽  
Myelogenous Leukemia ◽  
Clinical Activity ◽  
Flat Dose ◽  
Dose Levels

Abstract Epigenetic alterations are common in leukemia. MGCD0103 in an oral isotype-selective HDAC inhibitor that synergizes in vitro with the DNA methyltransferase inhibitor 5-azacitidine (Vidaza, Pharmion). Both agents have single-agent clinical activity in MDS and AML (Garcia-Manero, ASCO, 2006 & Silverman, JCO, 2002). We have developed a Phase I/II study of 5-azacitidine in combination with MGCD0103 in patients with AML and MDS. Patients with MDS (≥10% marrow blasts), relapsed/refractory AML, or untreated elderly patients with AML were eligible. Adequate performance status, renal and hepatic functions were required. 5-azacitidine was administered at its approved dose/schedule: 75 mg/m2 SC daily for the first 7 days of a 28 day cycle. MGCD0103 was administered as a flat dose orally three-times a week starting on the 5th day of 5-azacitidine administration. The phase I portion of the study design followed a classic “3+3” model and only MGCD0103 was dose escalated. The phase II portion targeted a 30% response rate. Final data from the Phase I and II portions of the study will be presented at the Meeting. Five dose levels of MGCD0103 have been evaluated: 35, 60, 90, 110 and 135 mg. At current data cut-off, 37 patients registered in the study were fully evaluable: median age was 67 (range 27–85); 31 patients had AML and 6 MDS. A total of 97 cycles were administered to date, mean = 2.6 (range 1–12). Dose limiting toxicities included nausea, vomiting, anorexia, diarrhea and dehydration which appear similar to dose limiting toxicities for MGCD0103 alone. The MTD of MGCD0103 was initially determined to be 110 mg, however, upon cohort expansion, this dose level was associated with excess toxicity and the starting dose was decreased to 90 mg. Eleven (30%) patients have achieved response: 4 CR, 5 CR-i, and 2 PR. Of these 11 patients, 6 continue on study with mean duration on study of 7 cycles. Of the 5 patients discontinued, 3 discontinued due to SAEs, 1 due to progressive disease and 1 to undergo transplantation. Of the 27 patients at the phase II dose levels of 90 and 110mg, 10 achieved a response (37%; same rate at both doses). Preliminary response data are available at the time of abstract preparation for 13 additional patients, revealing 4 with CR (one of which had 1% residual peripheral blast) and 3 with CR-I for a response rate of 53% in this subset. MGCD0103 pharmacokinetics were not affected by 5-azacitidine. Likewise, co-administration of MGCD0103 had no impact on the pharmacokinetics of 5-azacitidine. A majority of patients exhibited a substantial reduction in PBMC HDAC activity during treatment with the combination. Analysis of DNA methylation is ongoing. In conclusion, the combination of 5-azacitidine with MGCD0103 is safe in patients with advanced AML/MDS and has clinical activity potentially superior to that expected with 5-azacitidine alone in this patient population. These results form the bases of a planned randomized study of 5-azacitidine with or without MGCD0103 in AML and MDS.

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