A phase I trial of AVN944 in patients with advanced hematologic malignancies

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14026-14026 ◽  
Author(s):  
R. B. Klisovic ◽  
G. Tricot ◽  
S. Coutre ◽  
T. Kovacsovics ◽  
F. Giles ◽  
...  
Keyword(s):  
Gene Expression ◽  
Phase I ◽  
Hematologic Malignancies ◽  
Guanine Nucleotide ◽  
Inosine Monophosphate Dehydrogenase ◽  
Open Label ◽  
Serious Adverse Events ◽  
Peripheral Blood Mononuclear ◽  
Nucleotide Synthesis

14026 Background: AVN-944 is an inhibitor of inosine monophosphate dehydrogenase (IMPDH), an enzyme that catalyzes the rate- limiting step in guanine nucleotide synthesis, and induces apoptosis in malignant hematopoietic cell lines in vitro. Methods: This phase I study employed open-label dose escalations in patients (pts) with relapsed, refractory hematologic cancers with safety, pharmacokinetic (PK), pharmacodynamic, & efficacy endpoints. Between 12/05 and 1/07 a total of 70 cycles of AVN944 at 25 (7pts), 50 (6pts), 75 (7pts), 100 (7pts) or 125 mg (3pts) b.i.d. orally X 21d every 28d were administered to 30 pts with AML (12), ALL (2), CLL (3), and multiple myeloma (13). Peripheral blood mononuclear cell (PBMC) or leukemic blast samples were obtained from all pts pre and post-receiving AVN944 to determine effects on GTP pools, IMPDH activity, and to correlate these changes to response in a 32-gene set that relates directly to cellular pathways dependent upon guanine nucleotide biosynthesis. Results: Pharmacokinetics were dose proportional with mean Tmax=1 hour, T1/2=1.5 hours, Cmax=2800 ng/ml and AUC=7228 hr.ng/ml at the 100 mg b.i.d. dose. Toxicities were generally mild-moderate and/or not attributed to AVN944. Twelve serious adverse events (SAEs) occurred in 8 pts; 7 of 8 had AML. No SAEs was attributed to AVN944. DLT was not seen. No protocol defined responses were seen. Twelve of 24 assessable pts had stable disease of 2 to 10 months duration. Changes in the gene expression set correlated with disease stability. Conclusions: AVN944 is well tolerated with oral b.i.d. dosing. Stabilization of disease was observed in half of the pts. Gene expression correlated with stable versus progressive disease. [Table: see text]

scholarly journals In vitro assessment and phase I randomized clinical trial of anfibatide a snake venom derived anti-thrombotic agent targeting human platelet GPIbα

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Benjamin Xiaoyi Li ◽  
Xiangrong Dai ◽  
Xiaohong Ruby Xu ◽  
Reheman Adili ◽  
Miguel Antonio Dias Neves ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Platelet Aggregation ◽  
Phase I ◽  
Human Platelet ◽  
Open Label ◽  
Serious Adverse Events ◽  
Open Label Phase ◽  
Deinagkistrodon Acutus

AbstractThe interaction of platelet GPIbα with von Willebrand factor (VWF) is essential to initiate platelet adhesion and thrombosis, particularly under high shear stress conditions. However, no drug targeting GPIbα has been developed for clinical practice. Here we characterized anfibatide, a GPIbα antagonist purified from snake (Deinagkistrodon acutus) venom, and evaluated its interaction with GPIbα by surface plasmon resonance and in silico modeling. We demonstrated that anfibatide interferds with both VWF and thrombin binding, inhibited ristocetin/botrocetin- and low-dose thrombin-induced human platelet aggregation, and decreased thrombus volume and stability in blood flowing over collagen. In a single-center, randomized, and open-label phase I clinical trial, anfibatide was administered intravenously to 94 healthy volunteers either as a single dose bolus, or a bolus followed by a constant rate infusion of anfibatide for 24 h. Anfibatide inhibited VWF-mediated platelet aggregation without significantly altering bleeding time or coagulation. The inhibitory effects disappeared within 8 h after drug withdrawal. No thrombocytopenia or anti-anfibatide antibodies were detected, and no serious adverse events or allergic reactions were observed during the studies. Therefore, anfibatide was well-tolerated among healthy subjects. Interestingly, anfibatide exhibited pharmacologic effects in vivo at concentrations thousand-fold lower than in vitro, a phenomenon which deserves further investigation.Trial registration: Clinicaltrials.gov NCT01588132.

scholarly journals PC3 - 154 Phase I/II Study of VAL-083 in Patients with Recurrent Glioblastoma

2016 ◽  
Vol 43 (S4) ◽  
pp. S18-S18
Author(s):  
K.C. Shih ◽  
M.R. Patel ◽  
N. Butowski ◽  
G.S. Falchook ◽  
S.H. Kizilbash ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Dna Methyltransferase ◽  
Phase Iii ◽  
Cancer Resistance ◽  
Open Label ◽  
Serious Adverse Events ◽  
Dose Escalation Study ◽  
Recurrent Gbm

Glioblastoma (GBM) is the most common brain cancer. Resistance to front-line systemic therapy with temozolomide (TMZ) is correlated with O6-methylguanine-DNA-methyltransferase (MGMT) expression. Second-line treatment with bevacizumab has not improved overall survival. Dianhydrogalactitol (VAL-083) is a bi-functional alkylating agent that has MGMT-independent cell-kill activity against GBM cell-lines and cancer stem cells in vitro. VAL-083 crosses the blood-brain barrier and showed promise against CNS tumors in prior NCI-sponsored clinical trials. The goal of this clinical trial is to determine appropriate VAL-083 dosing for advancement to Phase III trials as a new treatment for recurrent GBM. METHODS: Patients must have recurrent GBM following surgery, radiation, TMZ and bevacizumab. Phase I: Open-label, single-arm, dose-escalation study. Patients received VAL-083 on days 1,2,3 of a 21-day cycle, until reaching MTD. Phase II: Additional patients enrolled at MTD to further assess safety and outcomes. RESULTS: Phase I: 29 patients were enrolled across 9 dose cohorts (1.5-50 mg/m2/d). 40mg/m2/d was confirmed as MTD. Myelosuppression was mild; no drug-related serious adverse events were reported at doses up to 40mg/m2/d. Dose limiting G4 thrombocytopenia was observed at higher doses. Platelet nadir occurred around day 20 and resolved rapidly and spontaneously. A dose-related survival improvement was observed. Pharmacokinetic analyses show 1-2h plasma terminal half-life; average Cmax 781ng/mL at 40mg/m2/d. Phase II: 14 patients were enrolled at 40mg/m2/d. To date, safety observations in Phase II are consistent with Phase I. CONCLUSIONS: VAL-083 at 40mg/m2/d exhibits a favorable safety profile and dose-related trend toward clinically meaningful improved survival in refractory GBM patient

Effects of Ofloxacin Administration on the Reliability of Urine Glucose Testing

1996 ◽  
Vol 30 (5) ◽  
pp. 469-472
Author(s):  
Tsong-Mei Tsai ◽  
Brian F Shea ◽  
Paul F Souney ◽  
Fred G Volinsky ◽  
Joseph M Scavone ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Tertiary Care ◽  
Urine Samples ◽  
Care Hospital ◽  
Open Label ◽  
Urine Glucose ◽  
Glucose Testing

OBJECTIVE: TO study the effects of ofloxacin on the reliability of urine glucose testing. DESIGN: Open-label, nonrandomized. SETTING: A university-affiliated tertiary care hospital, ambulatory clinic. PARTICIPANTS: Ten healthy volunteers (8 men and 2 women) aged 22-39 years. MAIN OUTCOME MEASURES: Phase I (in vitro) involved the addition of selected amounts of ofloxacin to a set of standard 50-mL urine samples prepared to simulate glycosuria. Phase II (in vivo) involved the oral administration of ofloxacin 400 mg to 10 subjects. Urine was collected: (1) immediately predose, (2) pooled 0–4 hours postdose, and (3) pooled 4–8 hours postdose. Known glucose concentrations were then added to these samples. Clinitest and Diastix tests were performed on all samples. The accuracy of these tests in determining glucose concentrations was compared among urine samples taken before and after ofloxacin dosing. RESULTS: None of the ofloxacin concentrations in phase I (0,25,50, 100, 200,400, and 800 μg/mL) influenced these testing methods at the urine glucose concentrations of 0.0%, 0.5%, 1%, and 2%. Likewise, the accuracy of these two tests was unaffected by ofloxacin administration in phase II. CONCLUSIONS: In single-dose administration, ofloxacin does not interfere with Clinitest or Diastix for determining urine glucose concentrations. Supported by a grant from the RW Johnson Pharmaceutical Research Institute. Presented in abstract form at the American College of Clinical Pharmacy 1994 Winter Practice and Research Forum, February 6–9, 1994, San Diego. CA.

scholarly journals A phase I study of a dual PI3-kinase/mTOR inhibitor BEZ235 in adult patients with relapsed or refractory acute leukemia

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Fabian Lang ◽  
Lydia Wunderle ◽  
Susanne Badura ◽  
Eberhard Schleyer ◽  
Monika Brüggemann ◽  
...  
Keyword(s):  
Adverse Events ◽  
Acute Leukemia ◽  
Phase I ◽  
Mtor Inhibitor ◽  
Prolonged Treatment ◽  
Small Subset ◽  
Open Label ◽  
Serious Adverse Events ◽  
Efficient Treatment ◽  
Link Type

Abstract Background Combined inhibition of phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) complexes may be an efficient treatment for acute leukemia. The primary objective of this phase I single center open label study was to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of the dual pan-class I PI3K and mTOR inhibitor BEZ235 in patients with advanced leukemia. Methods Herein patients > 18 years of age who had relapsed or showed refractory leukemia were treated with BEZ235 (orally at 300–400 mg BID (cohort − 1/1)) to assess safety, tolerability, preliminary efficacy and pharmacokinetic (PK). Adverse events data and serious adverse events were analyzed and haematological and clinical biochemistry toxicities were assessed from laboratory test parameters. Response was assessed for the first time at the end of cycle 1 (day 29) and after every subsequent cycle. Pharmacokinetic and pharmacodynamic analyses of BEZ235 were also included (BEZ235 plasma levels, phosphorylation of AKT, S6 and 4EBP1). On statistics this trial is a multiple ascending dose study in which a following variant of the 3 + 3 rule (“Rolling Six”), a minimum of 6 and a maximum of 12 patients was recruited for the dose escalation and another 5 were planned for the expansion phase. Results Twenty-four patients with ALL (n = 11) or AML (n = 12) or CML-BP (n = 1) were enrolled. All patients had failed one (n = 5) or more lines of therapy (n = 5) and 14 patients were in refractory / refractory relapse. No formal MTD was defined, stomatitis and gastrointestinal toxicity at 400 mg BID dose was considered incompatible with prolonged treatment. The RP2D of BEZ235 was defined as 300 mg BID. Four of 24 patients showed clinical benefit. Twenty-two of 24 patients discontinued because of progression, (median time to progression 27 days (4d-112d). There was no association between PK parameters and efficacy or tolerability. Conclusions Combined inhibition of PI3K and mTOR inhibits a clinically meaningful driver pathway in a small subset of patients with ALL, with no benefit in patients with AML. Trial registration ClinicalTrials.gov, identifier NCT01756118. retrospectively registered 19th December 2012, https://clinicaltrials.gov/ct2/show/NCT01756118.

scholarly journals ACTR-59. A PHASE 1 STUDY OF BPM31510 PLUS VITAMIN K IN SUBJECTS WITH HIGH-GRADE GLIOMA THAT HAS RECURRED ON A BEVACIZUMAB-CONTAINING REGIMEN

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi27-vi27
Author(s):  
Lawrence Recht ◽  
Reena Thomas ◽  
Sophie Bertrand ◽  
Priya Yerballa ◽  
Gordon Li ◽  
...  
Keyword(s):  
Phase I ◽  
Vitamin K ◽  
Phase I Study ◽  
Phase 1 ◽  
High Grade Glioma ◽  
High Grade ◽  
Open Label ◽  
Open Label Phase ◽  
Grade 3

Abstract BACKGROUND High-grade gliomas (HGG) are characterized by dysregulated metabolism, utilizing glycolysis for energy production to support unrestricted growth. BPM 31510, an ubidecarenone (coenzyme Q10) containing lipid nanodispersion, causes a switch in cancer energy sourcing from glycolysis towards mitochondrial oxidative phosphorylation in vitro, reversing the Warburg effect and suggesting potential as an anti-tumor agent. The current study is a phase I study of BPM31510 + vitamin K in GB with tumor growth after bevacizumab (BEV). METHODS This is an open-label phase I study of BPM31510 continuous infusion with weekly vitamin K (10mg IM) in HGG patients using an mTPI design, starting at 110mg/kg, allowing for a single dose de-escalation and 2 dose-escalations. Patients had received first-line ChemoRadiation and were in recurrence following a BEV containing regimen. RESULTS 9 eligible and evaluable patients completed the 28 day DLT period. 8 patients had primary GB, 1 had anaplastic astrocytoma with confirmed pathologic transformation to GB. Median age was 55 years (27–67) and median KPS 70 (60–90) at enrollment. 4 patients were treated at the highest dose 171mg/kg, where there was a single DLT: Grade 3 AST & ALT. The most common grade 1–2 AEs possibly, probably or definitely related to drug were elevated AST, rash, and fatigue, each occurring in 3 patients. Median OS for 9 eligible/evaluable patients was 128 days (95% CI: 48–209) while PFS was 34 days (CI of mean 8.9). 3 patients are currently alive; 2 patients have survived >1 year. PK/PD data are being processed and will be presented. CONCLUSION This study confirms that BPM 31510 + vitamin K is safe and feasible in treatment-refractory HGG patients. Though this study demonstrates safety at 171mg/kg, the proposed dose for future studies in GB, based on additional pre-clinical and non-GB clinical data is 88mg/kg.

NE-180, a Novel glycoPEGylated Erythropoietin Demonstrates Dose-Dependent Activity in a Phase 1 Single Dose, Dose Escalating Study in Normal Human Volunteers (NHV).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1149-1149
Author(s):  
Bruce A. Wallin ◽  
Denise Ramjit ◽  
Michael Seiberling ◽  
David Zopf
Keyword(s):  
Adverse Events ◽  
Animal Studies ◽  
Phase 1 ◽  
Stopping Rules ◽  
Open Label ◽  
Serious Adverse Events ◽  
Maximal Increase ◽  
The Mean ◽  
Dose Dependent

Abstract NE-180 is a glycoPEGylated recombinant human erythropoietin that binds to and activates the erythropoietin (EPO) receptor. It has demonstrated in vitro activities comparable to EPO and an extended serum half-life in animal studies. This may allow less frequent dosing in patients being treated with chronic anemia. METHODS: A single center, open-label study of NE-180, administered as single escalating doses given by the SC or IV route, was conducted to assess the safety, tolerability, PK and PD. Subjects (male or female NHV) were planned to be assigned to one of 4 dose groups, 10 subjects per dose with 5 SC and 5 IV subjects per group: 0.5, 1.5, 3, or 4.5 mg/kg. Each dose group was planned to be initiated in an ascending, sequential fashion unless or until stopping rules were met. RESULTS: 25 NHV (16 females) were enrolled in the first two dose cohorts and have completed 56 day follow-up. The 1.5 mg/kg IV cohort met the protocol-specified Hb rate of rise stopping rule (change in Hb greater than 1 g/dL during any 14 day period). Injections were generally well tolerated with no discontinuations for adverse events or serious adverse events. Reticulocyte increases were dose proportional. Average reticulocyte count at baseline was 1.0±0.3%. The maximal increase occurred at day 7. The mean change from baseline for the 0.5 and 1.5 mg/kg SC group was: 0.9±0.4% and 2.2±0.9%, respectively. The mean change from baseline for the 0.5 and 1.5 mg/kg IV group was: 1.7±0.8% and 2.3±0.8%, respectively. PK data will be presented. CONCLUSIONS: Single doses up to 1.5 mg/kg of NE-180 administered to NHV were generally well tolerated and demonstrated potent dose-dependent erythropoietic activity.

Phase I study of intravenous CCI-779 in combination with bryostatin-1 in solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3067-3067 ◽  
Author(s):  
N. B. Haas ◽  
N. Lewis ◽  
R. B. Cohen ◽  
L. Malizzia ◽  
M. B. Einarson ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Messenger Rna ◽  
Bryostatin 1 ◽  
Naive Patient ◽  
Peripheral Blood Mononuclear ◽  
Mtor Inhibition ◽  
Resistant Disease ◽  
Grade 3

3067 Background: mTOR regulates translation of messenger RNA critical for angiogenesis and cell growth. CCI-779 inhibits mTOR signaling through p70S6 kinase (S6K), which phosphorylates the ribosomal S6 protein (S6). CCI-779 is active in renal carcinoma (RCC) and other solid tumors. Based on our finding that bryostatin-1 (bryo) inhibits S6K, and that CCI-779 + Bryo additively inhibit S6K and RCC growth in vitro, we initiated a phase I trial to determine the maximum tolerable (MTD) doses and dose-limiting toxicities of this novel combination in patients with solid tumors. Methods: Bryo (20 μg/m2) was administered over 60 minutes IV followed by CCI-779 (10 and 15 mg, planned escalation to 75 mg) IV over 30 minutes, both weekly for 3 of 4 weeks. Serum and peripheral blood mononuclear cell (PBMC) samples were collected for analysis of pharmacokinetics and markers of mTOR inhibition (phospho-S6 and p21waf1). Results: Nine patients (median age 57, 6 RCC, 2 sarcoma and 1 neuroendocrine) are evaluable for toxicity (total cycles=27 cycles, median 4, range 1–7) at the initial 2 dose levels (Bryo 20 μg/m2, CCI-779 10 mg and 15 mg). Cycle 1 toxicity includes grade 3 hypophosphatemia and myelosuppression in one patient each and grade 2 fatigue, stomatitis, and anemia. One patient developed reversible grade 3 pneumonitis after 7 cycles. Of 7 patients with therapy-resistant disease, 5 (4 RCC and 1 sarcoma) had stable disease lasting up to 7 months. A therapy-naive patient with RCC has 23% tumor reduction after 2 cycles at dose level 2 (CCI-779=15 mg). PBMC proteins from 5 patients show consistent decreases in phospho-S6 at 2–6 hours-post treatment compared with pre-treatment baseline measurement, with recovery by 24–72 hours after dosing. In parallel with inhibition of phosphorylation of S6, PBMC levels of p21waf1 were completely inhibited in all 5 patients. Conclusions: The combination of bryo and CCI-779 is feasible, with antitumor activity in RCC and mTOR pathway inhibition observed at submaximal doses. Dose escalation is continuing. No significant financial relationships to disclose.

Combination of 5-azacytidine (5-AZA) and valproic acid (VPA) in advanced solid cancers: A phase I study

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3547-3547 ◽  
Author(s):  
A. O. Soriano ◽  
F. Braiteh ◽  
G. Garcia-Manero ◽  
L. H. Camacho ◽  
D. Hong ◽  
...  
Keyword(s):  
Phase I ◽  
Histone Acetylation ◽  
Phase I Study ◽  
Mononuclear Cells ◽  
Neutropenic Fever ◽  
Dna Hypomethylation ◽  
Peripheral Blood Mononuclear ◽  
Western Blots

3547 Background: 5-AZA is a DNA hypomethylating agent. VPA is a histone deacetylase inhibitor (HDACI). The combination of hypomethylating agents and HDACI has synergistic anticancer activity in vitro and in vivo. Based on this, we conducted a phase I study of the combination of 5-AZA and VPA in patients with advanced solid cancers. Methods: 5-AZA was administered SQ daily for 10 days. VPA was given orally daily titrated to 75–100 mcg/ml. Cycles were 28 days long. 5-AZA was started at 20 mg/m2 and escalated using an adaptive algorithm based on toxicity in the prior cohort. Each cohort included 6 patients (pts). Global DNA methylation was estimated with the LINE pyrosequencing assay in peripheral blood mononuclear cells on days 1 and 10 of each cycle. Histone H3 and H4 acetylation was assessed with western blots. Results: Forty seven patients were evaluable. Median age was 60 years (15–77). 5- AZA dose levels included 20, 25, 37.5, 47, 59, 75 and 94 mg/m2. One DLT occurred at 37.5 (Neutropenic fever (NF)). At 75 mg/m2, 1 grade 3 NF and at 94 mg/m2, 3 DLTs (2 NF and 1 thrombocytopenia) were observed. The MTD was 75 mg/m2 SQ daily for 10 days. Other toxicities included drowsiness (N=6), tremor (N=6), hypomagnesemia (N=1), anemia (N=2) and vomiting (N=1). Stable disease (SD) was observed in 16 pts (34%). One pt with rapidly progressive renal cell carcinoma had SD for 6 months (mos). Two pts with leiomyosarcoma of the uterus had SD for 8 and 6 mos. One pt with melanoma and two pts with uveal melanoma had SD for 4 mos. One pt with sinus adenoid cystic carcinoma and 1 with thymic carcinoma had SD for 4 mos. SD was also observed in pts with colon (N=3), sarcoma (N=2), papillary thyroid (N=2) and breast cancer (N=1). Global DNA hypomethylation was demonstrated in all of the doses of 5- AZA. Median LINE methylation pretreatment was 65% (59–70%), it declined to 61% (53–63%) by day 10 (p=0.001) and returned to baseline by day 0 of the next cycle. Histone acetylation was observed in 53% of the pts. Conclusions: The combination of 5-AZA and VPA in patients with advanced solid tumors is safe. The MTD of 5-AZA in combination with VPA was 75 mg/m2 SQ daily for 10 days. DLTs were neutropenic fever and thrombocytopenia. Clinical benefit (SD) was observed in 16 pts (34%). Transient global hypomethylation and histone acetylation were demonstrated. No significant financial relationships to disclose.

Results of a phase I study to evaluate the feasibility, safety, and biological effects of intravenous administration of wild-type reovirus with docetaxel to patients with advanced malignancies

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e13524-e13524
Author(s):  
S. M. Rudman ◽  
C. Comins ◽  
D. Mukherji ◽  
M. Coffey ◽  
K. Mettinger ◽  
...  
Keyword(s):  
Phase I ◽  
Biological Effects ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Wild Type ◽  
Systemic Delivery ◽  
Open Label ◽  
Phase Ii Studies

e13524 Background: Reovirus has minimal pathogenicity in humans but selectively replicates in cells with activated Ras. Wild- type reovirus serotype 3 Dearing strain (Reolysin) has selective antitumor activity in vitro, in murine models, and after systemic delivery in humans in phase 1 trials. Synergistic tumour kill has been observed combining reovirus with taxanes in a range of cancer cell lines and in vivo. Methods: Patients were treated in an open-label, dose-escalating, phase I trial and received 3- weekly 75mg/m2 docetaxel i.v. and reovirus i.v. (day 1–5 of first week inclusive). Reovirus was administered at a starting dose of 3x109 tissue culture infectious dose (TCID50) and then increased to 1 x 1010 and 3 x 1010 TCID50. Primary endpoints were to determine the maximum tolerated dose (MTD), dose limiting toxicity (DLT) and to recommend a dose and schedule for future investigation. Secondary endpoints were to evaluate pharmacokinetics, neutralizing antibody development, cell- mediated immune response and anti-tumour activity. Results: 17 patients were treated (15 males, median age 60 years). No MTD has been reached. DLT's observed were G4 neutropenia (and a recurrent perianal abcess) and G3 rise in AST. Other toxicities observed were fatigue, hypotension and neutropenic sepsis. At present, 5 patients remain on treatment. We have observed 2 partial responses (breast and gastric carcinoma) and 10 patients had stable disease as best response. Conclusions: Reovirus is well tolerated when administered in combination with intravenous docetaxel, with predictable toxicity observed. The recommended dose has been defined at 3x1010 TCID50 and phase II studies are planned. Objective radiological evidence of anticancer activity for this combination has been observed. [Table: see text]

Phase I dose escalation of ibrutinib and buparlisib in relapsed/refractory diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and follicular lymphoma (FL).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 7544-7544 ◽  
Author(s):  
Connie Lee Batlevi ◽  
Paul A. Hamlin ◽  
Matthew J. Matasar ◽  
Steven M. Horwitz ◽  
John F. Gerecitano ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Dose Escalation ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Serious Adverse Events ◽  
Pi3k Inhibitors ◽  
Grade 3 ◽  
Dose Reductions

7544 Background: In vitro studies of BTK and PI3K inhibitors demonstrate synergy in non-Hodgkin lymphoma (NHL). We embarked on a phase I/Ib investigator-initiated clinical trial evaluating the combination of ibrutinib (BTK inhibitor) and buparlisib (pan-PI3K inhibitor) in relapsed/refractory (R/R) NHL. The completed dose escalation is reported. Methods: Patients (pts) were eligible if they had R/R DLBCL, MCL, or FL with ECOG≤2 and adequate organ function. Ibrutinib and buparlisib were given daily by mouth on a 28-day cycle. Dose reductions were permitted after cycle 1. Tumor response was based on Lugano Classification however CR required both PET resolution and ≥ PR by CT. Results: As of Dec 16, 2016, 13 pts were enrolled and evaluated for toxicity (DLBCL 5, FL 2, MCL 6). Dose levels and DLT per table. Six pts discontinued treatment for disease progression (DLBCL 4, FL 2). Hematologic AE ≥ grade 3 are anemia (2), leukocytosis (2), and leukopenia (4). Relevant non-hematologic AEs of any grade ≥ 20% across all pts were fatigue (77%), diarrhea (62%), anorexia (54%), rash (46%), hyperbilirubinemia (46%), gastric reflux (46%), CMV reactivation (31%), mood change (31%), and hypertension (23%). Most common related grade 3/4 toxicity is rash (N = 3). No grade 5 toxicities noted. Serious adverse events (SAE) include: grade 2 pleural effusion and grade 2 nausea (N = 1), grade 1 fever with hospitalization (N = 1), grade 2 confusion and grade 4 hyponatremia (N = 1) were unrelated to therapy. Responses noted in 13 pts: MCL (N = 6: CR 4, PR 2), FL (N = 2: SD 2), DLBCL (N = 5: SD 1). One CR was a MCL pt with CR after 2 cycles on combination therapy and continues in remission on ibrutinib alone because of buparlisib toxicity. Conclusions: Combination of ibrutinib and buparlisib while generally well tolerated has predicted toxicities of both BTK and PI3K inhibitors. The recommended phase 2 dose is ibrutinib 560 mg and buparlisib 100 mg though dose reductions for tolerability may be needed for long term oral therapies. Promising efficacy is observed in MCL. Clinical trial information: NCT02756247. [Table: see text]

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