A UGT1A1 *28 and *6 genotype-directed phase I study of irinotecan plus infusional leucovorin and 5-fluorouracil (sLV5FU2) in patients with previously untreated metastatic colorectal cancer (mCRC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3592-3592
Author(s):  
Yong Sang Hong ◽  
Kyu-Pyo Kim ◽  
Jae-Lyun Lee ◽  
Kyun Seop Bae ◽  
Ho-Sook Kim ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Maximum Tolerated Dose ◽  
Fixed Dose ◽  
Pharmacokinetic Analysis ◽  
Level 3 ◽  
Defective Allele ◽  
The Mean ◽  
Grade 3 ◽  
Higher Doses

3592 Background: We designed a phase I study to determine maximum tolerated dose (MTD) of irinotecan when combined with sLV5FU2 in mCRC patients (pts). Methods: Pts were genotyped for UGT1A1 *28 and *6, and stratified into 3 groups according to the number of defective allele (DA), designated 0 (*1/*1), 1 (*1/*28, *1/*6), and 2 (*28/*28, *6/*6, *6/*28). Within each group, the dose of irinotecan was escalated (table) in combination with fixed dose of sLV5FU2. Plasma drug levels and dose-limiting toxicity (DLT) were evaluated at cycle 1. Results: A total of 43 pts were accrued: 19 for 0 DA, 20 for 1 DA and 4 for 2 DA group. The MTD was estimated as 300 mg/m2/2-week for the 1 DA group with 2 DLTs in the level 3, and the MTD was not reached for the 0 DA group with 1 DLT in the level 4 (table). The mean relative extents of glucuronidation, AUClast ratio of SN-38G to SN-38, were 9.36, 6.81, and 5.09 for the 0, 1, and 2 DA groups, respectively (P=0.017). Of the 43 pts, five pts showed AUClast, SN38 that exceeded 400 ng·h/mL (1.02 umol·h/L) and DLT was observed in 40% (2/5). The overall response rate was 67.4% (95% CI, 51.5-80.9) with 6 complete responses and 23 partial responses. Median progression-free and overall survival was 8.0 months (95% CI, 7.1-8.9) and 25.6 months (95% CI, 23.4-27.7), respectively. Grade 3 or 4 toxicity during all treatment cycles included neutropenia (79% [0 DA]; 90% [1 DA]; 75% [2 DA]), leucopenia (21%; 30%; 0%), febrile neutropenia (0%; 10%; 0%) and diarrhea (0; 5%; 0) per patient. Conclusions: Dose-normalized exposure of SN38 was significantly higher in the 2 DA UGT1A1 group. Higher doses of irinotecan based on UGT1A1 genotyping are feasible when combined with sLV5FU2 in mCRC pts. The recommended dose of irinotecan was 330, 270, 150 mg/m2/2-week for pts with 0, 1, 2 DA based on pharmacokinetic analysis. [Table: see text]

A Phase I Study of Irinotecan As a 3-Week Schedule in Children With Refractory or Recurrent Solid Tumors

2003 ◽  
Vol 21 (20) ◽  
pp. 3844-3852 ◽  
Author(s):  
Gilles Vassal ◽  
Francois Doz ◽  
Didier Frappaz ◽  
Karima Imadalou ◽  
Evelyne Sicard ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase I Study ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Analysis ◽  
High Dose ◽  
Heavily Pretreated ◽  
Pretreated Patients ◽  
The Mean ◽  
Grade 3

Purpose: A phase I study was performed to determine the maximum-tolerated dose (MTD) and safety profile of irinotecan (CPT-11) administered as a single intravenous infusion every 3 weeks in children with recurrent or refractory solid tumors. Patients and Methods: Eighty-one patients were enrolled, including 48 less heavily, and 33 heavily pretreated patients (cranial irradiation and/or high-dose chemotherapy). Children received CPT-11 as a 120-minute infusion at doses ranging from 200 to 720 mg/m2. The dose-limiting toxicities (DLT) on first cycle were determined in both cohorts. Results: One hundred twenty-two cycles and 81 cycles were administered in less heavily, and heavily pretreated patients, respectively. The primary DLT was delayed diarrhea in less heavily pretreated patients, and neutropenia in heavily pretreated patients. MTD was 600 mg/m2 in both cohorts. Grade 3 to 4 neutropenia occurred in 33% and 38% of cycles in less heavily, and heavily pretreated patients, respectively. Grade 3 to 4 nonhematologic toxicities included nausea/vomiting (7% and 4% of cycles in less heavily, and heavily pretreated patients, respectively), asthenia (7% and 4% of cycles, respectively), and delayed diarrhea (6% and 2.5% of cycles, respectively). Four partial responses at 600 mg/m2 (high-grade glioma, neuroblastoma, medulloblastoma, and rhabdomyosarcoma) and 21 minor responses and stable diseases were observed. Pharmacokinetic analysis of CPT-11 and SN-38 was performed in 77 patients. The mean ± standard deviation (SD) CPT-11 plasma clearance was 20.7 ± 9.5 L/h/m2 (range, 5 to 54). The mean ± SD SN-38 metabolic ratio was 1.5% ± 1.1% (range, 0.15% to 5.55%). Conclusion: The recommended phase II dose of CPT-11 in a 3-week schedule is 600 mg/m2 in less heavily, and heavily pretreated children with solid tumors.

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.

FOLFOX and nab-paclitaxel (nab-P) for advanced pancreatic cancer: A phase I study.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 258-258
Author(s):  
Howard Safran ◽  
Kevin Charpentier ◽  
Kimberly Perez ◽  
Kalyan Mantripragada ◽  
Trevor Clark Austin ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Phase I ◽  
Dose Level ◽  
Phase I Study ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Maximum Tolerated Dose ◽  
Level 3 ◽  
Grade 3 ◽  
Level 2

258 Background: FOLFIRINOX improves survival in advanced pancreatic cancer, however the contribution of irinotecan is uncertain. The addition of irinotecan to gemcitabine was not superior to gemcitabine alone in pancreatic cancer, however nab-P demonstrates a survival benefit. This phase I study was designed to evaluate the maximum tolerated dose (MTD) of the addition of nab-P to fluorouracil, leucovorin, oxaliplatin (FOLFOX-A). Methods: Patients with metastatic or locally advanced pancreatic adenocarcinoma without prior treatment received oxaliplatin, 85 mg/m2, leucovorin 400 mg/m2 and 5-FU 2400 mg/m2 with 3 dose levels of nab-P (125, 150 and 175 mg/m2) every 2 weeks. Pegfilgrastim was required during the first 2 cycles. Dose limiting toxicities (DLTs) were defined in the first 2 cycles of treatment. Results: Fifteen patients were entered: Dose level 1 (n=6), dose level 2 (N=6), dose level 3 (N=3). The median age was 64 (35-81). Ten patients had metastatic and 5 had locally advanced disease. DLTs of nausea and fatigue occurred in 2 of 3 patients at dose level 3. Two patients developed grade 3 neuropathy after >= 10 cycles of treatment. One patient had grade 3/4 neutropenia. Eight of fifteen patients (53%) had a partial response. Conclusions: The MTD of nab-P is 150mg/m2 every 2 weeks with FOLFOX. Cumulative peripheral neuropathy, similar to other FOLFOX regimens, is the most significant toxicity generally occurring after >= 10 cycles of treatment. FOLFOX-A has substantial activity and may represent a promising regimen in pancreatic cancer. Patients are currently being accrued to an expansion phase utilizing dose level 2. Supported by the Davis and Browning families and LIFEcycle. Clinical trial information: NCT01744353.

scholarly journals EPCT-19. A PHASE I STUDY OF RIBOCICLIB AND EVEROLIMUS FOLLOWING RADIATION THERAPY IN CHILDREN WITH NEWLY DIAGNOSED NON-BIOPSIED DIFFUSE PONTINE GLIOMAS (DIPG) AND RB+ BIOPSIED DIPG AND HIGH GRADE GLIOMAS (HGG)

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii307-iii307
Author(s):  
Mariko DeWire ◽  
James Leach ◽  
Christine Fuller ◽  
Peter de Blank ◽  
Trent Hummel ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Studies ◽  
High Grade ◽  
Newly Diagnosed ◽  
High Grade Gliomas ◽  
Grade 3 ◽  
Expansion Cohort

Abstract Genomic aberrations in the cell cycle and mTOR pathways have been reported in diffuse pontine gliomas (DIPG) and high-grade gliomas (HGG). Dual inhibition of CDK4/6 (ribociclib) and mTOR (everolimus) has strong biologic rationale, non-overlapping single-agent toxicities, and adult clinical experience. The maximum tolerated dose (MTD) and/or recommended phase two dose (RP2D) of ribociclib and everolimus administered during maintenance therapy following radiotherapy was determined in the phase I study as a rolling 6 design. Ribociclib and everolimus were administered once daily for 21 days and 28 days, respectively starting two-four weeks post completion of radiotherapy. All HGG patients and any DIPG patient who had undergone biopsy were screened for RB protein by immunohistochemistry. Eighteen eligible patients enrolled (median age 8 years; range: 2–18). Six patients enrolled at dose levels 1,2, and 3 without dose limiting toxicities (DLT). Currently, five patients are enrolled at dose level 3 expansion cohort. The median number of cycles are 4.5 (range: 1–20+). Among the expansion cohort, one dose limiting toxicity included a grade 3 infection and one patient required a dose reduction in course 3 due to grade 3 ALT and grade 4 hypokalemia. The most common grade 3/4 adverse events included neutropenia. Preliminary pharmacokinetic studies on 12 patients suggest an impact of ribociclib on everolimus pharmacokinetics. The MTD/RP2D of ribociclib and everolimus following radiotherapy in newly diagnosed DIPG and HGG is anticipated to be 170 mg/m2/day x 21 days and 1.5 mg/ m2/day every 28 days which is equivalent to the adult RP2D.

Phase I Study of Clofarabine Plus Idarubicin and Clofarabine Plus Idarubicin Plus Cytarabine (ARA-C) in Patients (PTS) with Relapsed and Primary Refractory Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS), and Myeloid Blast Phase of Chronic Myeloid Leukemia (CML).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1809-1809 ◽  
Author(s):  
Stefan Faderl ◽  
Alessandra Ferrajolil ◽  
William Wierda ◽  
Srdan Verstovsek ◽  
Farhad Ravandi-Kashani ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Myeloid Leukemia ◽  
Phase I Study ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Acute Leukemias ◽  
First Remission ◽  
First Relapse ◽  
Grade 3

Abstract Phase I and II clinical studies demonstrated activity of Clofarabine in acute leukemias. In previous studies we have investigated clofarabine, plus ara-C combinations and reported a CR rate of 24% in relapsed AML and 52% in previously untreated AML ≥ 50 years (yrs) with acceptable toxicity profile. Anthracyclines are active in AML. To explore clofarabine further in AML combinations we conducted a phase I study of clofarabine with idarubicin with or without ara-C in pts with relapsed AML, MDS, and CML. Considered as dose-limiting toxicities (DLT) are ≥ grade 3 drug-related toxicities. Maximum tolerated dose (MTD) will be determined by “3+3” dose escalation scheme. On the clofarabine (C)/idarubicin (I) combination (CI), 9 AML pts are enrolled (2 primary refractory, 7 first relapse). Median age: 58 yrs (range 24–71). Median first remission duration (CRD1): 3.1 mos. (0–7.6). For the first dose level, C was given at 22.5mg/m2 i.v. daily x 5d and I at 12mg/m2 i.v. daily x 3d. Among the first 6 pts, 2 ≥ gr. 3 toxicities (diarrhea, rash, ↑ bili) occurred necessitating dose de-escalation of C to 15mg/m2 i.v. daily x 5 and I 8mg/m2 i.v. daily x 3. Among 3 pts, 1 ≥ gr.3 toxicity (↑ bili) was observed. No responses occurred. On the CI + ara-C arm (CIA), 7 AML pts are enrolled (1 primary refractory, 6 first relapse). Median age: 58 yrs. (24–78). Median CRD1: 11.2 mos. (0–13.1). First dose level: C 22.5mg/m2 i.v. daily x 5d, I 8mg/m2 i.v. daily x 3d, A 1g/m2 i.v. daily x 5d. Of 3 pts, 2 developed ≥ gr.3 toxicities (↑ bili, diarrhea) leading to the following de-escalation: C 15mg/m2 i.v. daily x 5d, I 6mg/m2 i.v. daily x 3d, A 0.75g/m2 i.v. daily x 5d. Of 4 pts (1 ≥ gr. 3 rash, ↑ bili), 3 pts achieved CR. The phase I study is ongoing until determination of DLT and MTD for each arm. Our preliminary results indicate clinical activity of CIA even at the low dose level.

Phase I Study of XK469R (NSC 698215), a Quinoxaline Phenoxypropionic Acid Derivative, in Patients with Refractory Hematological Malignancies.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1952-1952
Author(s):  
Wendy Stock ◽  
Samir D. Undevia ◽  
Stefan Faderl ◽  
Olotoyosi Odenike ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Phase I ◽  
Acid Derivative ◽  
Dose Level ◽  
Phase I Study ◽  
Plasma Concentrations ◽  
Hematologic Malignancies ◽  
Median Number ◽  
Fixed Dose ◽  
Pharmacokinetic Analysis ◽  
Clinical Activity

Abstract XK469R is a quinoxaline phenoxypropionic acid derivative which possesses broad activity against murine and human tumors (including leukemia) and high activity against multidrug-resistant tumors. COMPARE analysis of cytotoxicity data from the NCI cell line screen suggested a unique mechanism. Phase I studies in patients with advanced solid tumors indicated that the dose-limiting toxicity (DLT) was myelosuppression, without other significant toxicities noted, at a fixed dose of 1400 mg/dose when given on a day 1,3,5 schedule every 21 days. Therefore, we conducted a phase I study to establish the DLT and maximally tolerated dose (MTD) of XK469R in patients with refractory hematologic malignancies, as well as to study the pharmacokinetics of XK469R in this patient population. XK469R was given as a straight dose as an IV infusion over 30 minutes-1 hour on days 1, 3, and 5 of a 21 day cycle. Because significant interpatient variability in drug clearance (associated with toxicity) was noted in prior studies, each dose cohort included a minimum of six patients. The dose levels studied were 1400 mg (n=6), 1750 mg (n=12), 2200 mg (n=14), and 2750mg (n=14). A total of 46 patients with relapsed/refractory leukemia have been treated and are evaluable for toxicity; 41 patients with AML, 4 ALL, and 1 CML-BC. The group consists of 26 males and 20 females with a median age of 53 (range 20–85). ECOG PS included 0 (n=19), 1 (n=21), and 2 (n=6). Median number of cycles received was 1; 10 patients received 2 cycles and 2 patients received 3 cycles. DLT was defined as any clinically significant grade 3 or 4 adverse nonhematologic toxicity other than prolonged myelosuppression, as defined by NCI criteria specific for leukemia. DLTs of colitis and mucositis were observed at the 2200 mg dose level, and mucositis and elevated bilirubin at the 2750 mg dose level. Other possibly related grade 1 and 2 toxicities noted were SGOT/PT elevations, nausea/vomiting, diarrhea, anorexia, indigestion, rash, and alopecia. The MTD, defined as the dose level at which <2/6 patients experience a DLT, was 2200 mg. Forty-two patients were evaluable for response and include CR (n=1, in 1750 mg cohort), HI (n=5), SD (n=21), and PD (n=15). Preliminary pharmacokinetic analysis revealed that plasma concentrations of XK469R decline in a biphasic manner. Half-life was long with a mean value of 48 h. Mean clearance was 206 ml/h with a coefficient of variation of 32%. Patients with lower clearance did not appear to be at greater risk of DLT. In conclusion, the recommended phase II dose of XK469R in patients with advanced leukemia is 1750 mg (day 1,3,5). Due to its novel mechanism of action, reasonable toxicity profile, and clinical activity in these high-risk patients, further exploration of XK469R, possibly in combination with other established agents, is warranted in patients with relapsed/refractory acute leukemia.

A Q7D phase I study of TPI 287, a novel taxane, in advanced malignancies: Imaging studies, pharmacokinetics (PK) and circulating tumor cell (CTC) quantitation

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 12008-12008 ◽  
Author(s):  
J. J. Hwang ◽  
J. L. Marshall ◽  
S. Malik ◽  
H. Chun ◽  
T. Ahmed ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Phase I ◽  
Dose Escalation ◽  
Phase I Study ◽  
Circulating Tumor Cell ◽  
Median Number ◽  
Maximum Tolerated Dose ◽  
Advanced Malignancies ◽  
Tumor Measurements ◽  
Grade 3

12008 Background: Taxanes have demonstrated activity across a broad range of cancers, but resistance remains an issue. TPI 287 is a third generation taxane designed to overcome issues of resistance secondary to mdr and mutant tubulin. The purpose of this Phase I study was to determine the maximum tolerated dose and pharmacokinetics of IV TPI 287. Methods: Phase I study: TPI 287 is administered IV on days 1, 8, 15 of a 28 day cycle (Q7D) with at least 3 patients treated per dose escalation, in a typical phase I design. Dosing began at 7 mg/m2 and has advanced to the fifth cohort of patients, who are being treated at a dose of 85 mg/m2. Tumor response is assessed after every second cycle via imaging and tumor measurements. Samples are collected for PK analysis and circulating tumor cell (CTC) quantitation. Results: Sixteen pts have been enrolled (9 males, median years = 60.11; 7 females, median years = 50.71: median number of previous chemotherapies = 4). Diagnoses included colorectal (4), prostate (3), breast, kidney, cervical, brain, lung, osteosarcoma, basal cell, endometrial, ovarian cancers. Of 16 pts, 8 and 5 have completed 1, 2 cycles, respectively. Only one drug related grade 3 adverse event (hypersensitivity reaction) occurred, at 14 mg/m2. No other reported toxicities are related to TPI 287. PK and CTC studies are ongoing. Conclusions: These initial results show that TPI 287 is well tolerated at a dose up to 56 mg/m2 administered Q7D, and dose escalation continues. [Table: see text]

Phase I clinical trial of CX-3543, a pro-apoptotic antitumor agent

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3082-3082 ◽  
Author(s):  
R. F. Marschke ◽  
A. D. Ricart ◽  
D. D. Von Hoff ◽  
J. K. Lim ◽  
K. Papadopoulos
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase I Study ◽  
Three Dimensional ◽  
Antitumor Agent ◽  
Maximum Tolerated Dose ◽  
Therapeutic Window ◽  
Disease Response ◽  
Grade 3 ◽  
Xenograft Tumor Growth

3082 Background: CX-3543 is a novel small molecule specifically designed to target three dimensional nucleic acid motifs, and thus induce apoptosis in cancer cells. Preclinically, CX-3543 demonstrated potency in suppressing xenograft tumor growth with a broad therapeutic window. The objectives of this phase I study are: to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLTs), to establish the pharmacokinetics (PKs), and to determine the recommended dose for further clinical development of CX-3543. Methods: Eligible patients with advanced solid tumors or lymphomas whose tumors progressed on standard therapy or for whom there are no standard therapies receive CX-3543 in successive dose cohorts at: 10, 20, 40, 80 and 160 mg/m2. Dosing is by one hour intravenous infusion daily for five consecutive days repeated on a three week cycle. Therapy is continued until the patient shows signs of intolerance to CX-3543 or evidence of advancing disease. Response by RECIST criteria is determined after every 2 cycles. Results: Ten patients with solid tumors (3–4 per cohort) have received intravenous CX-3543. Doses have been well tolerated. Seven grade 3 adverse events have been reported during the study, but none of these are related to CX-3543. To date no objective responses have been observed. One patient with advanced refractory prostate cancer has stable disease of longer than 4 months duration. CX-3543 has demonstrated good linearity in PK parameters between the dose cohorts with a terminal half life of approximately 12 hours following the first dose. Conclusions: To date, CX-3543 has shown no drug related toxicity and has predictable PKs. No DLTs have yet been observed, and the MTD remains to be defined in this Phase I study. Further enrollment to the planned dose escalation cohorts is ongoing. [Table: see text]

A phase I/II study of belinostat (PXD101) in patients with unresectable hepatocellular carcinoma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 15081-15081 ◽  
Author(s):  
W. Yeo ◽  
R. Lim ◽  
B. B. MA ◽  
P. Hui ◽  
L. Chan ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Phase I ◽  
Tumor Regression ◽  
Maximum Tolerated Dose ◽  
Hematological Toxicity ◽  
First Line Therapy ◽  
Level 3 ◽  
Level I ◽  
Grade 3 ◽  
Therapeutic Research

15081 Background: Hepatocellular carcinoma (HCC) is a common cause of cancer morbidity and mortality. It is a highly aggressive tumor with 90% presenting with unresectable disease, resulting in a median survival of 3–6 months. Inhibitors of histone deacetylase (HDAC) have been demonstrated in HCC cell lines and xenografts to induce apoptosis and tumor regression, and have anti-proliferative, anti-metastatic and anti-invasive effects. Belinostat (N-hydroxy-3-[phenylsulphamoylphenyl] acryl amide) is a novel, low molecular weight, HDAC inhibitor. The Cancer Therapeutic Research Group (CTRG) is conducting a phase I/II study of belinostat as the first line therapy for pts with unresectable HCC. The phase I study aims to determine dose limiting toxicity (DLT) and maximum tolerated dose (MTD). Methods: Patient eligibilities include histologically or cytologically confirmed unresectable HCC, ECOG = 2, adequate hematologic, renal and hepatic functions. The dose of belinostat was started at 600 mg/m2/day i.v. on day 1–5 every 3 weeks; with increment of 300 mg/m2/day up to 1200 mg/m2/day. Dose limiting toxicities (DLT) are defined as grade 4 hematological toxicity or grade 3 or 4 nonhematological toxicity during cycle 1 (according to NCI CTC v3), or treatment delay >2 weeks. The MTD is defined as the dose below which ≥ 2 of 3 or ≥ 2 of 6 patients experiencing DLT. After determination of the MTD, 3 additional patients will be treated at this dose to further define toxicity. Results: From June-December 2006, 12 pts were entered; 3 were treated at level I (600 mg/m2/day), 3 at level 2 (900 mg/m2/day), and 6 at level 3 (1200 mg/m2/day). There were no DLTs on level 1, 2 or 3. Therefore, the MTD of belinostat was not reached. Overall toxicities were WBC gr. 0/1/2/3/4: 12/0/0/0/0, ANC gr. 0/1/2/3/4: 12/0/0/0/0; Hb gr. 0/1/2/3/4: 4/7/0/1/0; platelet gr. 0/1/2/3/4: 8/4/0/0/0; lethargy gr. 0/1/2/3: 12/0/0/0/0, phlebitis gr. 0/1/2/3: 10/0/2/0; Cough gr. 0/1/2/3: 9/0/3/0; Nausea gr. 0/1/2/3: 7/3/2/0 and vomiting gr. 0/1/2/3: 9/3/0/0. Conclusions: At the maximum dose of 1200 mg/m2/day (level 3), MTD has not been reached. Belinostat is very well tolerated. Phase II study will be started at dose level 1200 mg/m2/day. Sponsor: The Division of Cancer Treatment and Diagnosis, National Cancer Institute, USA. No significant financial relationships to disclose.

Phase I study of the combination of anti-GD2 antibody 3F8 and barley-derived (1→3,1→4)-β-D-glucan for patients with resistant neuroblastoma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 9566-9566 ◽  
Author(s):  
S. Modak ◽  
B. H. Kushner ◽  
K. Kramer ◽  
A. Vickers ◽  
N. Cheung
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Residual Disease ◽  
Clinical Investigation ◽  
Maximum Tolerated Dose ◽  
Fixed Dose ◽  
Naturally Occurring ◽  
Short Course ◽  
Stage 4 ◽  
Beta Glucans

9566 Background: Beta glucans are complex, naturally occurring polysaccharides that prime leucocyte dectin and CR3 receptors. Based on our preclinical observations that oral barley-derived (1→3,1→4)-β-D-Glucan (BG) synergizes with the murine anti-GD2 antibody 3F8 against neuroblastoma (NB) (Clin Cancer Res 8:1217), we conducted a phase I study to determine the safety of the combination of BG and 3F8 in patients with resistant NB. Methods: Heavily pre-treated patients with recurrent or refractory advanced stage NB were treated with 3F8/BG. Each cycle consisted of intravenous (IV) 3F8 at a fixed dose of 10 mg/m2/day ×10 days, plus oral BG dose escalated from 10 to 80 mg/kg/day ×10 days in 4 cohorts of 6 patients each. Patients without human anti-mouse antibody (HAMA) could be re-treated up to a total of 4 cycles. Results: Twenty-three patients with stage 4 and one with stage 3 NB (M:F = 11:13; median age 8 (range 2–19) years completed 47 cycles of therapy with 3F8/BG. 8 patients had progressive disease (PD) while 16 had stable refractory NB (SD) at enrollment. All patients completed at least one cycle of therapy and were evaluated for toxicity and response. Maximum tolerated dose for BG was not reached. Two patients developed dose-limiting toxicities (DLT). Both had grade 4 thrombocytopenia after completing one cycle of treatment: one at BG dose of 20mg/kg/day and the other at 40 mg/kg/day. Both cases responded to therapy with a short course of ITP (idiopathic thrombocytopenic purpura) therapy; one subsequently developed chronic ITP. There were no other >grade 2 toxicities related to 3F8/BG therapy. 14, 4, 2 and 6 patients completed 1, 2, 3 and 4 cycles respectively. Reasons for withdrawal in patients who did not complete 4 cycles were PD in 10, persistently elevated HAMA in 6 and DLT in 2. Overall 11 patients had SD and 13 PD. 14/23 patients with positive MIBG scans prior to therapy demonstrated improvement after one cycle. Responses did not correlate with BG dose received. 7 patients, all with residual disease survive at a median of 40 (range 24–45) months post-treatment. Conclusions: 3F8/BG is well tolerated and shows activity against resistant NB. Further clinical investigation of this novel combination is warranted. No significant financial relationships to disclose.

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