Phase I study of BAY 73–4506, a multikinase inhibitor, administered for 21 days on/7 days off in patients with advanced solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3593-3593 ◽  
Author(s):  
S. Hedbom ◽  
S. Steinbild ◽  
A. Frost ◽  
M. Büchert ◽  
C. Unger ◽  
...  
Keyword(s):  
Phase I ◽  
Drug Exposure ◽  
Parent Drug ◽  
Maximum Tolerated Dose ◽  
Exposure Level ◽  
Phase Ii Trials ◽  
Multikinase Inhibitor ◽  
Dce Mri ◽  
Grade 3

3593 Background: BAY 73–4506 is a multikinase inhibitor targeting both the tumor and its vasculature. BAY 73–4506 inhibits VEGFR-2 and -3, and tumor cell signaling kinases (RET, KIT, PDGFR, and Raf). This drug shows potent, oral activity in a wide variety of preclinical xenograft models. Methods: This phase I dose-escalation trial investigated the safety, pharmacokinetic (PK), and pharmacodynamic (PD) profile of BAY 73–4506 given orally in 21 days on/7 days off cycles, until discontinuation due to toxicity or tumor progression. PK was assessed on days 1 and 21 of cycle 1. PD markers included dynamic contrast-enhanced MRI (DCE-MRI) and circulating sVEGFR-2 and VEGF levels assessed at each cycle. Tumor response was evaluated per RECIST criteria. Results: 22 patients (pts) with documented progressive disease were enrolled at doses of 10 mg to 120 mg once daily. Tumor types included CRC (27%), RCC (18%) and pancreatic cancer (14%). Pts had received a median of 3 prior therapies, including anti-VEGF agents in 5 pts. BAY 73–4506 PK appeared linear with dose; the AUC target exposure level of 13 mg*h/L (from preclinical models) was reached at 30 mg. The major metabolite of BAY 73–4506 (active in vitro) reached a similar AUC(0–24)ss as the parent drug at 120 mg. Commonly reported drug-related adverse events (=10% of pts) were hoarseness (7 [32%], all CTC grade 1), hypertension (5 [23%], all CTC grade 1–2), fatigue (3 [14%], CTC grade 3 in 1 pt [5%]), hand-foot-skin reaction (HFSR) (3 [14%], CTC grade 3 in 1 pt [5%], mucositis (3 [14%], all CTC grade 1). Maximum tolerated dose was exceeded at 120 mg with dose-limiting toxicities including fever without documented infection, HFSR, fatigue, and leukopenia. 2 pts (RCC & osteosarcoma) achieved RECIST partial response. 4 pts had stable disease, one of them a cervical cancer pt with extensive tumor cavitation. PD parameters (decrease in sVEGFR-2 levels, decrease in iAUC60s of Gd-DTPA by DCE-MRI) correlated with drug exposure. Conclusions: BAY 73–4506 was well tolerated at 60 mg with report of dose-limiting toxicities at 120 mg. 6 (28%) of 22 pts demonstrated antitumor activity. Optimal dose and regimen are under evaluation in preparation for phase II trials. No significant financial relationships to disclose.

Phase I Assessment of the Pharmacokinetics, Metabolism, and Safety of Emitefur in Patients With Refractory Solid Tumors

2000 ◽  
Vol 18 (19) ◽  
pp. 3423-3434 ◽  
Author(s):  
J. Nemunaitis ◽  
R. Eager ◽  
T. Twaddell ◽  
A. Corey ◽  
K. Sekar ◽  
...  
Keyword(s):  
Steady State ◽  
Phase I ◽  
Solid Tumors ◽  
Prolonged Exposure ◽  
Circadian Variation ◽  
Pharmacokinetic Profile ◽  
Maximum Tolerated Dose ◽  
Minimum Effective Concentration ◽  
Grade 3

PURPOSE: To determine the toxicities, dose-limiting toxicities (DLT), maximum-tolerated dose, and pharmacokinetic profile of emitefur (BOF-A2) in patients with advanced solid tumors. METHODS: This was a phase I dose-escalating trial in which cohorts of patients received BOF-A2 (cohort 1, 300 mg/m2 orally [PO] tid; cohort 2, 200 mg/m2 PO tid; cohort 3, 200 mg/m2 bid; and cohort 4, 250 mg/m2 bid) for 14 consecutive days followed by 1 week of rest (cycle 1). Pharmacokinetics, toxicity, and tumor response were monitored. RESULTS: Nineteen patients received 110 cycles (three patients in cohort 1, three patients in cohort 2, 10 patients in cohort 3, and three patients in cohort 4). DLT (grade 3 stomatitis, diarrhea, leukopenia) was observed in cohorts 1, 2, and 4. Pharmacokinetics indicated that prolonged systemic expression of fluorouracil (5-FU) is maintained after administration of BOF-A2 at a dose of 200 mg bid for 14 days. The mean steady-state concentration of plasma 5-FU was ≥ 24 ng/mL, which was 184-fold greater than the minimum effective cytotoxic concentration in vitro. Lack of variation of 5-FU trough levels within a day at steady-state indicates suppression of circadian variation. One patient in cohort 3 achieved a partial response and five patients maintained stable disease in excess of 6 months. CONCLUSION: BOF-A2 at a dose of 200 mg PO bid for 14 days followed by 7 days of rest is well tolerated. Prolonged exposure to 5-FU above the predicted preclinical minimum effective concentration is maintained, without evidence of circadian variation. Furthermore, evidence of antitumor activity is suggested.

Phase I study of vandetanib (ZD6474) administered during and after irradiation (RT) in children with diffuse intrinsic pontine glioma (DIPG)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 10020-10020
Author(s):  
A. Broniscer ◽  
T. E. Merchant ◽  
C. Hillenbrand ◽  
Z. Patay ◽  
T. K. Chin ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Drug Exposure ◽  
Dosage Level ◽  
Maximum Tolerated Dose ◽  
Volume Of Distribution ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Pharmacokinetic Analysis ◽  
Dismal Prognosis ◽  
Grade 3

10020 Background: Children with DIPG have a dismal prognosis despite use of RT, which is the mainstay of therapy. All chemotherapy regimens used so far demonstrated no benefit. EGFR and VEGFR pathways are considered important in tumorigenesis of DIPG. Methods: We conducted a traditional phase I study combining oral vandetanib (VEGFR-2 and EGFR inhibitor) during and after local RT in children with DIPG. Five dosage levels were tested (50, 65, 85, 110, and 145mg/m2 per day). Vandetanib and RT started on the same day. The first 6 weeks of therapy constituted the dose-limiting toxicity (DLT)-evaluation period. Correlative studies consisted of pharmacokinetic analysis (PK), pharmacodynamic studies in blood, and standard and investigational imaging (before and 1, 3, and 6 weeks after start of therapy). Results: Twenty-one patients were enrolled on study (50 [n = 3], 65 [n = 3], 85 [n = 3], 110 [n = 6], and 145mg/m2 [n = 6]). Two patients experienced DLT consisting of rash/mucositis (level 4) and diarrhea (level 5). The maximum-tolerated dose (MTD) of vandetanib was not reached. Other significant toxicities included lymphopenia grade 3/4 (n = 10), grade 3 neutropenia and hypophosphatemia (one each), grade 2 proteinuria (n = 2), grade 2 hypertension (n = 4), and mild QTc prolongation (n = 7) .Once the phase I component was completed, two extra patients were enrolled at dosage level 5; one of them developed grade 4 seizure secondary to posterior reversible encephalopathy syndrome. PK (n = 21) showed similar drug clearance and volume of distribution compared to adults. However, drug exposure at steady state normalized by dose seemed higher in children. Increased tumor perfusion during the first 6 weeks of therapy was observed in the first 12 patients analyzed. Conclusions: Although MTD was not reached, we recommend administration of vandetanib at a dose of 110mg/m2 per day during and after local RT in children. Further combination studies of vandetanib in children with DIPG are planned. No significant financial relationships to disclose.

A phase I study of mesothelin-targeted immunotoxin LMB-100 in combination with nab-paclitaxel for patients with previously treated advanced pancreatic cancer.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 307-307 ◽  
Author(s):  
Christine Campo Alewine ◽  
Raffit Hassan ◽  
M. Iqra Ahmad ◽  
Jane B Trepel ◽  
Cody Peer ◽  
...  
Keyword(s):  
Phase I ◽  
Drug Exposure ◽  
Bowel Perforation ◽  
Advanced Pancreatic Cancer ◽  
Elongation Factor ◽  
Maximum Tolerated Dose ◽  
Pseudomonas Exotoxin A ◽  
Previously Treated ◽  
Grade 3 ◽  
Anti Tumor Activity

307 Background: LMB-100 is a Pseudomonas exotoxin A-based immunotoxin that targets mesothelin (MSLN). MSLN is expressed by >75% of pancreatic adenocarcinomas (PDAC). LMB-100 kills MSLN-expressing cells by irreversibly modifying elongation factor-2 to halt protein synthesis. Phase I studies of LMB-100 defined the maximum tolerated dose (MTD) of 140 mcg/kg IV given on D1, 3 and 5 of a 21-day cycle. Development of anti-drug antibodies (ADAs) limited patient drug exposure beyond cycle 2. Our pre-clinical data showed that combination of LMB-100 with a taxane resulted in synergistic anti-tumor activity. Methods: We conducted a phase I single center study (standard 3+3 design) to determine the MTD of LMB-100 given with nab-paclitaxel in patients with previously treated advanced PDAC. LMB-100 was given on D1, 3 and 5 of a 21-day cycle, and nab-paclitaxel (125 mg/m2) on D1 and D8. Initial patients could receive a maximum of 4 cycles, but subsequently a 2-cycle maximum was employed. Results: Fourteen patients (median age 58) were enrolled. Two of 6 patients experienced DLTs at the 100 mcg/kg dose of LMB-100 (myalgia- 2 pts, fatigue- 1 pt, hypotension- 1 pt; all grade 3). One of 8 patients had DLT at the 65 mcg/kg dose (edema, urine output decrease- both grade 3). Other toxicities related to LMB-100 included hypoalbuminemia, edema-associated weight gain, hyponatremia, fatigue, drug fever, infusion-related reaction, hypophosphatemia, nausea and anorexia. One patient died on treatment from complications of bowel perforation attributed to cancer. All patients achieved detectable serum levels of LMB-100 during the first cycle, even those with pre-existing ADAs, and 5 of 8 did so during cycle 2. One patient receiving the 65 mcg/kg dose had a confirmed partial response, and CA 19-9 dropped by > 50% in 5 of 8 evaluable patients. Conclusions: MTD of LMB-100 is 65 mcg/kg given with nab-paclitaxel on this schedule. Anti-tumor activity was observed. A phase II cohort is currently being accrued. Clinical trial information: NCT02810418.

ZIO-101 (S-dimethylarsino-glutathione): Phase I/II trials in advanced/progressive multiple myeloma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 8109-8109 ◽  
Author(s):  
J. R. Berenson ◽  
S. Jaganath ◽  
D. Reece ◽  
R. Boccia ◽  
R. Soebel ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Maximum Tolerated Dose ◽  
Oxygen Species ◽  
Low Concentrations ◽  
Anti Cancer ◽  
Organic Arsenic ◽  
Grade 3 ◽  
Dose Limiting Toxicity

8109 Background: ZIO-101(S-dimethylarsino-glutathione), a novel organic arsenic, is active against multiple cancers including myeloma in vitro and in animal models. In vitro, it is active at low concentrations in cancers resistant to arsenic trioxide. Anti-cancer activity is multifaceted and is mediated by disrupted mitochondrial function, increased reactive oxygen species (ROS) production, modified signal transduction and anti-angiogenesis. Methods: (1) Phase I/II study to determine maximum tolerated dose (MTD), dose- limiting toxicity (DLT), safety-profile and preliminary efficacy in patients with advanced/progressive myeloma receiving ZIO-101 daily for 5 consecutive d every 4 w; (2) comparison of this schedule at MTD with a schedule of 420 mg/me2/d twice/w for 3 w every 4 w. Results: (1) phase I/ II: 19 patients have been treated so far. Median age is 61 y (range, 41–84 y). Median N prior therapies was 8 (range, 4–10). ZIO-101 was well-tolerated; MTD was 420 mg/me2/d for the 5 d schedule, and DLT was transient confusion /ataxia. No clinically- important biochemical, bone marrow, or cardiac toxicities were seen and there was neither neuropathy nor QTc-prolongation. Pain during peripheral infusion was reported in some patients. Anemia was the only adverse event = grade-3 in 25% of subjects. 6 of 14 evaluable subjects had stable disease (SD) =8 w and 2, SD > 6 mo. Accrual to the phase II portion continues. Conclusions: ZIO-101 was well- tolerated. In the daily for 5 consecutive d every 4 w schedule, the MTD is 420 mg/me2/d and DLT, transient confusion /ataxia. There was SD in 43% of patients with advanced/progressive myeloma, of whom half are beyond 6 months. Accrual into the phase II part of this study continues. No significant financial relationships to disclose.

Phase I trial of vorinostat in combination with erlotinib in advanced non-small cell lung cancer (NSCLC) patients with EGFR mutations after erlotinib progression

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e19057-e19057 ◽  
Author(s):  
N. Reguart ◽  
A. F. Cardona ◽  
D. Isla ◽  
F. Cardenal ◽  
R. Palmero ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Advanced Nsclc ◽  
Global Analysis ◽  
Maximum Tolerated Dose ◽  
Egfr Mutations ◽  
Combination Regimen ◽  
Duration Of Treatment ◽  
Grade 3

e19057 Background: Vorinostat (SAHA) is a histone deacetylase inhibitor that induces differentiation, growth arrest and apoptosis of malignant cells. In vitro, there is a synergistic interaction of vorinostat in combination with gefitinib in NSCLC cell lines. Moreover, vorinostat increases levels of E-cadherin, p21, and downregulates expression of phospho-AKT and phospho-ERK1/2. These molecular findings could reverse resistance to erlotinib in mutant patients. Methods: We conducted a standard 3+3 Phase I trial of oral erlotinib 150 mg QD in combination with oral vorinostat (dose level 1 [DL1], 300 mg QD on days 1–7 every 21 days; DL2, 400 mg QD on days 1–7 every every 21 days, and; DL3, 400 mg QD on days 1–7 and 15–21 in a 28-day cycle). Cycles were repeated for a maximum of 6 cycles until progressive disease (PD) or intolerable toxicity. Pts with advanced NSCLC with EGFR mutations (Exon 19 and 21) after erlotinib progression and ECOG ≤2 were eligible. The main objectives were to determine the maximum tolerated dose (MTD), drug activity and safety of the combination regimen. Results: Thirteen patients have been enrolled up to date, with 9 patients available for this interim analysis (median age, 59 years; range 41–77). One patient (DL3 cohort) experienced a dose limiting toxicity (Grade 3 diarrhoea). The MTD has not been reached. The most common drug-related toxicities of any grade in the first cycle of treatment were anemia (77.8%), skin alterations (66.7%), diarrhoea (66.7%), xerostomy (55.6%), asymptomatic changes in liver function tests (55.6%), and asthenia (55.6%). There were no Grade ≥3 drug-related adverse events during first cycle of treatment and the global analysis of cycles showed asthenia (11.1%), somnolence (11.1%) and hyporexia (11.1%). Four pts discontinued treatment, all due to PD. Of 9 evaluable pts for efficacy, 6 had stable disease as best response (median duration of treatment 6.0 months, range 4–12). Final data will be presented at ASCO meeting. Conclusions: Although accrual continues to determine the MTD, the combination of vorinostat and erlotinib appears to be well tolerated and effective in this group of advanced NSCLC pts with EGFR mutations after erlotinib progression. No significant financial relationships to disclose.

A phase I trial to determine the maximum tolerated dose and evaluate the safety and pharmacokinetics (PK) of docetaxel-PNP, polymeric nanoparticle formulation of docetaxel, in subjects with advanced solid malignancies.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13104-e13104 ◽  
Author(s):  
Kyung Hae Jung ◽  
Kyu-Pyo Kim ◽  
Dok Hyun Yoon ◽  
Yong Sang Hong ◽  
Chang-Min Choi ◽  
...  
Keyword(s):  
Phase I ◽  
Maximum Tolerated Dose ◽  
Recommended Dose ◽  
Phase Ii Trials ◽  
Polymeric Nanoparticle ◽  
Dose Linearity ◽  
Solid Malignancies ◽  
Heavily Pretreated ◽  
Infusion Reactions ◽  
Grade 3

e13104 Background: The aim of this study was to determine the maximum tolerated dose (MTD) and recommended dose of docetaxel-PNP when administered every 3 weeks in patients with advanced solid malignancies. Methods: Three to six patients received docetaxel at dose levels of 20-75 mg/m2 as 60-min infusions every 3 weeks according to the single dose-escalating 3+3 method. Blood samples at the first dose of docetaxel-PNP were collected for PK analysis. Results: Nineteen pts were treated for a median of two cycles (1-14) in the phase I study. Dose escalation was performed up to 75 mg/m2. The most frequently reported adverse events were grade 4 neutropenia (52.6%, 10/19), grade 1 myalgia (42.1%, 8/19) and grade 1 alopecia (42.1%, 8/19). No acute infusion reactions were noted. Two dose-limiting toxicity was observed at 20 and 60 mg/m2, which were grade 3 hypophosphatemia and death of unknown cause, respectively. Although the MTD was not determined, the recommended dose was determined as 60 mg/m2. This was based on neutropenia and PK parameters which are summarized in the table. PK parameters revealed dose linearity. Partial response was seen in one patient and stable disease in seven patients. Conclusions: Administration of docetaxel-PNP was well tolerated up to 60 mg/m2 every 3 weeks by heavily pretreated patients. Further phase II trials are recommended at this dose level. [Table: see text]

Phase I Trial of the Novel Mammalian Target of Rapamycin Inhibitor Deforolimus (AP23573; MK-8669) Administered Intravenously Daily for 5 Days Every 2 Weeks to Patients With Advanced Malignancies

2008 ◽  
Vol 26 (3) ◽  
pp. 361-367 ◽  
Author(s):  
Monica M. Mita ◽  
Alain C. Mita ◽  
Quincy S. Chu ◽  
Eric K. Rowinsky ◽  
Gerald J. Fetterly ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Mammalian Target Of Rapamycin ◽  
Maximum Tolerated Dose ◽  
Target Of Rapamycin ◽  
Phase Ii Trials ◽  
Solid Malignancies ◽  
Advanced Malignancies ◽  
Grade 3 ◽  
Dose Levels

Purpose This phase I trial was conducted to determine the safety, tolerability, pharmacokinetics, and pharmacodynamics of deforolimus (previously known as AP23573; MK-8669), a nonprodrug rapamycin analog, in patients with advanced solid malignancies. Patients and Methods Patients were treated using an accelerated titration design with sequential escalating flat doses of deforolimus administered as a 30-minute intravenous infusion once daily for 5 consecutive days every 2 weeks (QD×5) in a 28-day cycle. Safety, pharmacokinetic, pharmacodynamic, and tumor response assessments were performed. Results Thirty-two patients received at least one dose of deforolimus (3 to 28 mg/d). Three dose-limiting toxicity events of grade 3 mouth sores were reported. The maximum-tolerated dose (MTD) was 18.75 mg/d. Common treatment-related adverse events included reversible mouth sores and rash. Whole-blood clearance increased with dose. Pharmacodynamic analyses demonstrated mammalian target of rapamycin inhibition at all dose levels. Four patients (one each with non–small-cell lung cancer, mixed müllerian tumor [carcinosarcoma], renal cell carcinoma, and Ewing sarcoma) experienced confirmed partial responses, and three additional patients had minor tumor regressions. Conclusion The MTD of this phase I trial using an accelerated titration design was determined to be 18.75 mg/d. Deforolimus was well tolerated and showed encouraging antitumor activity across a broad range of malignancies when administered intravenously on the QD×5 schedule. On the basis of these overall results, a dose of 12.5 mg/d is being evaluated in phase II trials.

Phase I Study of the Novel Surivin and cdc2/CDK1 Inhibitor Terameprocol in Patients with Advanced Leukemias.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1039-1039 ◽  
Author(s):  
Raoul Tibes ◽  
Kevin T. McDonagh ◽  
Lazaros Lekakis ◽  
Neal Frazer ◽  
Scott Mohrland ◽  
...  
Keyword(s):  
Phase I ◽  
Research Funding ◽  
Drug Exposure ◽  
Hematological Malignancies ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
The Novel ◽  
Regulatory Pathways ◽  
Apoptosis Protein ◽  
Grade 3

Abstract Abstract 1039 Poster Board I-61 Background: The inhibitor of apoptosis protein (IAP) survivin is central in integrating proliferative and cell cycle regulatory networks. In leukemic cells, survivin mediates survival as well as resistance to chemotherapeutics and Flt-3 inhibitors. Experimentally targeting survivin has shown anti-leukemic activity and is a postulated therapeutic approach. Herein we report a clinical trial with the novel survivin and cdc2 (CDK1) inhibitor Terameprocol (EM-1421) in patients (pts) with advanced hematological malignancies. As little is known about in-vivo up- and downstream regulatory pathways of survivin and it's inhibition, specimens from pts were collected for correlative pharmacodynamic (PD) marker analysis. Methods: Open-label, single agent, phase I dose escalation study of Terameprocol (T) in pts with advanced, relapsed or refractory hematological malignancies (AML, ALL, MDS, advanced CLL or CML). Pts age > 18 years with adequate organ function and performance status (ECOG) ≤ 1were treated with 1000, 1500 and 2200 mg of intravenous Terameprocol 3x/week (wk) for 2 of 3 wks in cohorts of 3 pts to establish the safety, maximum tolerated dose (MTD) and to assess pharmacokinetics at the studied dose schedule (primary objectives). Secondary objectives were to select the recommended phase 2 dose (RP2D) and to assess anti-leukemic activity and PD marker regulation (baseline, cycle 1 day 5 and 12, end of study). Results: Between 8/2007 and 3/2009, sixteen pts (4 female, 12 male) with a median age of 68.5 years (range 42-78) and median of 2 prior regimens (range 0-5) were enrolled. Most pts had AML (n=13), 7 pts primary and 6 pts secondary or treatment related AML; one pt each had CML-BP, T-ALL and MDS. Ten pts had unfavorable or complex cytogenetics including 6 pts with 5q/7q and 2 pts with 11q23 aberrations. Four, 5 and 6 pts were treated at the 1000, 1500 and 2200 mg dose cohorts respectively. One pt did not start treatment on study. 15 pts received ≥ 1 dose/cycle, 6 of whom (38%) received ≥ 2 cycles of T (range 1-5). Common possible or probable treatment related adverse events (AE) were grade 1 or 2 headache (n=3, 20%), transaminitis (grade 2 n=2, grade 3 n=2) and pruritus (n=2). Treatment related serious AE's (SAE) was a grade 4 pneumonia in 1 pt. Non-drug related SAE's ≥ grade 3 or 4 included sepsis/febrile neutropenia (n=3), pneumonia (n=2), dyspnea (n=2), cerebral hemorrhage (n=1), confusion/mental status change (n=1), cardiac arrest (n=1) and AML progression (n=3) leading to death in 2 pts. No AE/SAE was felt to constitute a dose limiting toxicity (DLT) per protocol definition. However, due to grade 3 transaminitis observed in 2 pts together with concerns of compromised respiratory status of pts treated at the 2200 mg cohort, the investigators determined the maximum tolerated dose (MTD) to be 1500 mg 3x/week for 2 of 3 weeks, which is also the recommended RP2D. One heavily pretreated pt (3 prior regimens) with CML-BP myeloid, achieved a partial remission (1500 mg) and transfusion independence for 5 cycles prior to disease progression. Hematological improvement (HI-E, HI-P) was seen in 1 pt (1000 mg), and 5 pts had stable disease. Surprisingly, Cmax of T at 1500 mg was higher than at 2200 or 1000 mg. Overall concentrations of T were in the same range as measured in previous studies of T in solid tumors (daily x5), indicating adequate drug exposure at the schedule studied. PD samples at indicated time points were collected and are currently being analyzed to assess the effects of T on survivin, cdc2/CDK1 and survivin associated regulatory genes. Conclusion: The novel small molecule surivin inhibitor Terameprocol can be safely administered to pts with advanced leukemias. Sufficient drug exposure was seen in pts and the MTD and RP2D were established for future studies. Clinical activity was observed in a pt with myeloid CML-BP and potentially in pts with AML. Interestingly, previous work showed an association between progression to advanced stages of CML and survivin expression. Data on correlative PD marker experiments will be presented. Disclosures: Tibes: Erimos Pharmaceuticals : Research Funding. McDonagh:Erimos: Research Funding. Frazer:Erimos Pharmaceuticals: Employment. Mohrland:Erimos Pharmaceuticals: Employment. Von Hoff:Erimos Pharmaceuticals: Consultancy.

Phase I trial of dimethyl fumarate, temozolomide, and radiation therapy in glioblastoma multiforme.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2060-2060 ◽  
Author(s):  
Danielle A. Shafer ◽  
Zhi-jian Chen ◽  
Timothy Harris ◽  
Mary Beth Tombes ◽  
Ellen Shrader ◽  
...  
Keyword(s):  
Phase I ◽  
Disease Progression ◽  
Malignant Gliomas ◽  
Maintenance Phase ◽  
Dimethyl Fumarate ◽  
Maximum Tolerated Dose ◽  
Newly Diagnosed ◽  
Grade 3 ◽  
Dose Levels

2060 Background: Evidence is increasing for altered immune responses in malignant gliomas. Tumor-associated microglia/macrophages infiltrate human glioma tissue and produce cytokines that promote glioma growth, invasion and angiogenesis. Dimethyl fumarate (DMF), approved for relapsing-remitting multiple sclerosis, is toxic to in vitro activated microglial cells. Based on pre-clinical data demonstrating synergism with radiation (RT) and temozolomide (TMZ), we conducted a phase I study of DMF in patients with newly-diagnosed glioblastoma (GBM) in combination with RT and TMZ. Methods: Using a standard 3+3 dose escalation design (3 dose levels: 120 mg bid, 240 mg bid and 240 mg tid), newly-diagnosed GBM patients received daily DMF with RT (60 Gy) and concurrent TMZ 75 mg/m2 daily, followed by adjuvant DMF (continuously) and TMZ for up 6 maintenance cycles (150-200 mg/m2 on days 1-5 of each 28 day cycle). The maximum tolerated dose (MTD) was defined as the dose with ≤ 1/6 dose-limiting toxicities (DLT). The MTD was determined by evaluation of DLTs during the first 6 weeks of therapy. Results: Twelve patients were treated at the three dose levels, and no DLT was identified. There were no unexpected toxicities. The most common toxicities were lymphopenia (11 grade 3/4 events) and thrombocytopenia (2 grade 3/4 events). The only grade 3/4 non-heme toxicity was a grade 3 hemorrhoid event. Of the 12 evaluable patients, one remains on active treatment in maintenance phase. Three patients completed all treatment (concurrent and maintenance) with stable disease. Two patients had a partial response (RANO criteria) but then experienced disease progression during maintenance. Five patients had disease progression during study treatment and one patient chose to withdraw from the study during maintenance. Conclusions: These data suggest that DMF may be safely combined with RT and TMZ in GBM patients. A phase II study is under consideration. Clinical trial information: NCT02337426.

A Phase I Evaluation of TG101348, a Selective JAK2 Inhibitor, in Myelofibrosis: Clinical Response Is Accompanied by Significant Reduction in JAK2V617F Allele Burden.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 755-755 ◽  
Author(s):  
Animesh D. Pardanani ◽  
Jason R Gotlib ◽  
Catriona Jamieson ◽  
Jorge Cortes ◽  
Moshe Talpaz ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Research Funding ◽  
Drug Exposure ◽  
Maximum Tolerated Dose ◽  
Spleen Size ◽  
Allele Burden ◽  
Grade 3 ◽  
Wbc Count

Abstract Abstract 755 Background: TG101348 is a potent, orally bioavailable, JAK2-selective small molecule inhibitor, that is currently being evaluated in a Phase I study for the treatment of myelofibrosis. Data from the dose escalation cohort (n=28; 30-800mg administered as a single daily dose) showed dose-linear plasma exposure, with mean elimination T1/2 at steady state ranging from 20 to 52 hours. The dose-limiting toxicity was asymptomatic grade 3 or 4 amylasemia/lipasemia that was reversible, and the maximum tolerated dose (MTD) was 680mg. The most frequent non-hematological toxicities were mild nausea, vomiting, and/or diarrhea that were easily controlled or resolved spontaneously. Grade 3/4 neutropenia and thrombocytopenia were observed in 14% and 25% of patients, respectively. TG101348 had activity in reducing spleen size, leukocyte count, and JAK2V617F (VF) allele burden. Here, we present updated results with a focus on data from the dose confirmation cohort who initiated treatment at a dose of 680mg/day. Results: Fifty nine patients (median age=66 years; range 43-86) have been treated – 28 in the dose escalation phase, and 31 in the dose confirmation phase. Overall, 44 patients had PMF, 12 post-PV MF, and 3 post-ET MF; 86% were VF-positive. Median palpable spleen size was 18cm and 22 patients were RBC transfusion-requiring at study enrollment. After a median follow-up of 12 weeks (range <1-76), 18 (31%) patients have discontinued treatment due to toxicity (n=7; thrombocytopenia=3, neutropenia=1), comorbidities (n=5), withdrawal of consent (n=4), or non-compliance/lack of response (1 each). The remaining 41 patients are currently at the following dose levels: 680mg (n=14), 520-600mg (n=16), 360-440mg (n=10), and 240mg (n=1). The cumulative drug exposure to date is 362 patient-months; exposure at or above MTD (≥680mg) is 154 patient-months. Forty patients (68%) started treatment at ≥680mg. Toxicity: TG101348 is well tolerated. Of the patients who started at ≥680mg, Gr3/4 neutropenia was observed in 15/0% and Gr3/4 thrombocytopenia in 20/10%. Twenty four (60%) patients did not require RBC transfusions at baseline (median Hgb=9.6g/dL; range 7.4-13.1); of these, 42% and 8% of patients developed Gr3 and Gr4 anemia, respectively. The majority of patients who started at ≥680mg developed mild nausea (1 Gr3), vomiting (1 Gr3), and/or diarrhea (3 Gr3) that were self-limited or easily controlled. Other non-hematological toxicities included Gr1/2 transaminitis (38%), Gr1/2 serum creatinine elevation (38%), and asymptomatic hyperlipasemia (33%). Efficacy: Thirty three patients who started at ≥680mg have completed at least 3 cycles of treatment; at 3 months, reduction in palpable spleen size (baseline median=18cms; range 6-32) was at least 50% in 22 (67%) patients; the spleen became non-palpable in 9 (27%) patients. All 21 patients with leukocytosis at baseline (WBC range 11 to 203 ×109/L) who started at ≥680mg have experienced a marked reduction in their WBC count (range 4 to 90); 70% had a normal WBC count at their last follow-up visit. Overall, 48 of the 51 VF-positive patients completed at least 1 cycle and were evaluable for response in VF allele burden; at last available follow-up, the median decrease in granulocyte mutant allele burden was 48%; 21 (44%) patients have had a ≥50% reduction, and in the group who started treatment at ≥680mg, 48% have had a ≥50% reduction. Of those evaluable, there was clinically significant benefit or resolution of constitutional symptoms, including early satiety, fatigue, cough, pruritus, and night sweats. Conclusions: TG101348 continues to be well tolerated in patients with myelofibrosis. Spleen and leukocyte responses are frequent, observed early, and produce substantial clinical benefit for patients. These responses are associated with significant decrease in VF allele burden and point to activity of TG101348 against the malignant clone in myelofibrosis. Disclosures: Pardanani: TargeGen: Research Funding; Cytopia: Research Funding. Off Label Use: Data from ongoing clinical trial will be presented. Gotlib:TargeGen: Research Funding. Jamieson:Merck: Research Funding; Pfizer: Research Funding; Wintherix: Consultancy; TargeGen: Research Funding; Celgene: Research Funding. Cortes:Targegen: Research Funding. Stone:Cephalon: ad hoc advisory board. Silverman:TargeGen: Consultancy. Shorr:TargeGen: Employment, Equity Ownership. Gilliland:Merck: Employment. Tefferi:TargeGen: Research Funding.

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