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.

A phase I/II study of combination therapy of S-1 and irinotecan in patients with previously untreated metastatic or recurrent colorectal cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15023-e15023
Author(s):  
Y. Choi ◽  
T. Kim ◽  
S. Lee ◽  
J. Lee ◽  
H. Chang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Phase I ◽  
Phase Ii ◽  
Overall Response Rate ◽  
Maximum Tolerated Dose ◽  
Recurrent Colorectal Cancer ◽  
Time To Progression ◽  
Level I ◽  
Grade 3 ◽  
Experienced Grade

e15023 Background: To investigate S-1 and irinotecan (CPT-11) combination as an alternative to infusional 5- fluorouracil/leucovorin plus CPT-11, we performed a phase I/II trial to determine maximum tolerated dose (MTD), efficacy and toxicity in metastatic or recurrent colorectal cancer. In addition, we evaluated the association between genotypes of candidate genes and phenotypes. Methods: S-1 was administered orally at a dose of 70 mg/m2 (level I-III) or 80 (IV and V) from day 1 to 14. CPT-11 was given i.v. on day 1, stepping up to 175 (level I), 200 (II), 225 (III and IV) or 250 (V) mg/m2 . The treatment was repeated every 3 weeks. The association of the UGT1A1 genotypes (*6, *28, and *60) and CYP2A6 genotypes (*4, *7, and *9) with toxicities or efficacy were analyzed in patients who participated in phase II portion. Results: Twenty-three patients entered the phase I and 30 enrolled in phase II study. The MTD of S-1 and CPT-11 was considered to be 80 mg/m2 and 250 mg/m2, respectively. The dose-limiting toxicities (DLTs) were diarrhea and neutropenia. The recommended dose (RD) was determined at a S-1 dose of 80 mg/m2 and a CPT- 11 dose of 225 mg/m2. The overall response rate was 66.7% (95% CI, 48.7–84.6) at the RD level. Median time to progression was 7.6 months (95 % CI, 5.7–9.5). Median survival time was not reached. Grade3–4 neutropenia was observed in 53.4% of the patients. Grade 3–4 nonhematologic toxicities were diarrhea (16.7%) and asthenia (6.7%). The frequencies of UGT1A1*60, *28, and *6 allele were 25.8%, 10.3%, and 15.5%, respectively. Homozygous for *28 or *6 were not observed. All three double heterozygous for *28 and *6 experienced grade 3–4 neutropenia. The allele frequencies of CYP2A6*4, *7, and *9 were 15.5%, 8.6%, and 29.3%, respectively. There were no association between CYP2A6 genotypes and response rates or toxicities. Conclusions: The combination of S-1 and CPT-11 was effective and had manageable toxicities in patients with metastatic or recurrent colorectal cancer. [Table: see text] No significant financial relationships to disclose.

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]

Bortezomib plus modified R-CHOP as initial therapy for indolent B-cell lymphomas: Phase I results

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8577-8577
Author(s):  
C. Flowers ◽  
R. Sinha ◽  
J. Kaufman ◽  
P. Shenoy ◽  
C. Lewis ◽  
...  
Keyword(s):  
Phase I ◽  
Stage Iv ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Initial Therapy ◽  
Hematological Toxicity ◽  
Fiber Density ◽  
Epidermal Nerve Fiber Density ◽  
Stage Iv Disease ◽  
Grade 3

8577 Background: Adding rituximab (R) to chemotherapy improves survival for patients (pts) with follicular lymphoma (FL) and other indolent non-Hodgkin lymphomas (NHL), but not all pts respond. Bortezomib (B) + RCHOP has a high complete response (CR) rate, but higher doses of B with standard vincristine produced severe neuropathy. We developed a phase I/II trial to test if adding B to RCHOP with modified vincristine dosing can be well-tolerated and yield a high CR rate. Methods: Untreated pts with indolent NHL and indications for treatment based on GELF criteria or FLIPI ≥3 received R 375mg/m2, cyclophosphamide 750mg/m2, doxorubicin 50mg/m2, vincristine 1.4mg/m2 (capped at 1.5mg) on day 1, B 1.0- 1.6mg/m2 days 1 and 8, and prednisone 100mg days 1–5 for 6–8 cycles. The maximum tolerated dose (MTD) was defined as the regimen at which <30% grade ≥3 non-hematological or grade ≥4 hematological toxicity (>14 days) occurs. Dose escalation used the Escalation with Overdose Control Bayesian method with upper bound (θ=0.3). This facilitated MTD finding with fewer pts given prior data on B+RCHOP. Functional Assessment of Cancer Therapy (FACT) Neurotoxicity (11-item; 4 point scale), EMG, nerve conduction velocity and epidermal nerve fiber density measures were taken at baseline and after cycle 4. Results: 11 pts with FL (n=6) or other indolent NHL enrolled in phase I. Median age was 59 years (range 29–69). 6 pts (55%) had stage IV disease; 8 (64%) had FLIPI ≥2. Pts received RCHOP + B at 1.0 mg/m2 (n=1), 1.3 mg/m2 (n= 6) or 1.6 mg/m2 (n= 4) and together completed 67 cycles. Treatment was well tolerated. Neuropathy occurred in 4 pts (36%), with 2 grade 1, 1 grade 2 and 1 grade 3 toxicity ( Table ). Grade 4 neutropenia occurred in 4 pts (36%), but none >14 days. Overall response rate was 100% with 5/8 finished pts (63%) achieving CR. 3 continue on treatment. Mean FACT Neurotoxicity after cycle 4 remained < 1 for all items. Conclusions: Adding bortezomib to RCHOP produces limited toxicity when vincristine is capped at 1.5 mg. Phase II will explore the efficacy of this regimen. [Table: see text] [Table: see text]

Phase I study of everolimus (RAD001) with irinotecan (Iri) and cetuximab (C) in second-line metastatic colorectal cancer: Hoosier Oncology Group GI05-102.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 523-523 ◽  
Author(s):  
B. Myre ◽  
M. Yu ◽  
J. Picus ◽  
J. A. Bufill ◽  
W. A. Harb ◽  
...  
Keyword(s):  
Phase I ◽  
Infusion Reaction ◽  
Maximum Tolerated Dose ◽  
Stopping Rules ◽  
First Line Therapy ◽  
Randomized Phase Ii ◽  
Common Grade ◽  
Grade 3 ◽  
Number Of Cycles ◽  
Ecog Ps

523 Background: Preclinically, mTOR and EGFR inhibitors are synergistic. We hypothesize that the mTOR inhibitor RAD001 would enhance efficacy and prevent resistance when added to an anti-EGFR agent. The purpose of the phase I portion of this study was to determine the safety and maximum tolerated dose (MTD) of daily RAD001 combined with weekly Iri and C in mCRC. Methods: Pts who failed first-line therapy, including an Iri-regimen, were treated with Iri 125 mg/m2 weekly x 2 every 3 weeks, C 400 mg/m2 loading dose, then 250 mg/m2 weekly, and escalating doses of RAD001 orally: 5 mg qod, 5 mg qd and 10 mg qd during 21-day cycles, with a “3+3” design. The study was amended after the first 9 pts enrolled, to include stopping rules for excessive toxicity beyond what was expected for diarrhea, nausea/vomiting and febrile neutropenia due to Iri, and skin rash due to C. Enrollment excluded pts with UGT1A1*28, but allowed KRAS mutated mCRC. RAD001 PK was done on C2D1, and archival tumors were analyzed for pharmacodynamic markers. Results: 28 pts were enrolled, median age 61 y (25-77), 15 male, ECOG PS 0/1 (19/9). Reasons for treatment discontinuation were: PD (7), adverse events (AEs) (6), pt withdrawal, symptomatic deterioration and non-compliance (1 each). Prior to study's amendment* (n=9), 3 pts were not evaluable for DLT due to: Iri intolerance after one dose (1), non-compliance (1) and gr 3 C infusion reaction (1). DLTs and number of cycles are listed in Table. Following protocol amendment, 2 pts had DLT in cohort 3 (gr 3 mucositis), thus the MTD was 5 mg RAD001. The most common grade 3/4 AEs were: diarrhea (10), neutropenia (5), fatigue (4), acne-rash (4), mucositis (2), nausea (2), vomiting (1). Among 19 pts evaluable for response, there were 1 CR, 2 PR, (RR 16%), 9 SD (47%), 7 PD (37%). PK and pharmacodynamic data is ongoing. Conclusions: The MTD of RAD001 of 5 mg QD with Iri/C weekly is safe and clinically active. A randomized phase II study is near starting accrual. [Table: see text] [Table: see text]

Phase I study of weekly intraperitoneal paclitaxel combined with S-1 and oxaliplatin for gastric cancer with peritoneal metastasis.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 146-146 ◽  
Author(s):  
Hironori Ishigami ◽  
Shoichi Kaisaki ◽  
Hironori Yamaguchi ◽  
Hiroharu Yamashita ◽  
Shigenobu Emoto ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Peritoneal Metastasis ◽  
Hematological Toxicity ◽  
Phase Ii Studies ◽  
Level 3 ◽  
Grade 3 ◽  
Dose Levels

146 Background: Intraperitoneal (IP) chemotherapy is a promising treatment option for gastric cancer with peritoneal metastasis. We previously verified the safety and efficacy of IP paclitaxel (PTX) combined with S-1 and intravenous PTX in phase I and phase II studies. S-1 plus oxaliplatin (SOX) demonstrated efficacy in a phase II study, and is regarded as a candidate for the next-generation standard regimen for gastric cancer. We designed a new regimen combining weekly IP PTX with SOX in order to maximize systemic effects as well as local effects in the peritoneal cavity. A dose-escalation study of IP PTX in combination with fixed doses of SOX was carried out to determine the maximum-tolerated dose (MTD) and recommended dose (RD). Methods: PTX was administered intraperitoneally on days 1 and 8 with an initial dose of 20 mg/m2 (level 1), stepped up to 30 mg/m2 (level 2) or 40 mg/m2 (level 3) depending on observed toxicity. S-1 was administered orally at a dose of 80 mg/m2/day (b.i.d.) for 14 days followed by a 7-day rest. Oxaliplatin was administered intravenously at a dose of 100 mg/m2 on day 1. This treatment was repeated every 3 weeks. Toxicity was graded according to CTCAE v4.0. Dose-limiting toxicities (DLTs) were defined as grade 4 leukopenia, grade 3 febrile neutropenia, grade 3 thrombocytopenia, and grade 3 non-hematological toxicity. The MTD was defined as the dose level at which 2 or more of 3 or 6 patients developed DLTs during two courses of treatment. The RD was defined as one dose level under the MTD. Results: A total of 12 gastric cancer patients with peritoneal metastasis were enrolled. No DLTs were observed at all dose levels. Neutropenia in one patient at dose level 3 was the only grade 3 toxicity observed. Grade 2/3 leukopenia, neutropenia and thrombocytopenia were observed only in 2 patients at dose level 3. Regarding grade 2 non-hematological toxicities, anorexia, fatigue and nausea were observed in 6, 4 and 2 patients, respectively, independent of dose levels. Consequently, the MTD was not reached, and the RD of IP PTX was determined to be 40 mg/m2 (level 3). Conclusions: Combination chemotherapy of IP PTX with SOX was shown to be a safe regimen that should be further explored in clinical trials.

Phase I/II study of carfilzomib plus melphalan-prednisone (CMP) in elderly patients with de novo multiple myeloma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8009-8009 ◽  
Author(s):  
Brigitte Kolb ◽  
Cyrille Hulin ◽  
Denis Caillot ◽  
Lotfi Benboubker ◽  
Mourad Tiab ◽  
...  
Keyword(s):  
Phase I ◽  
De Novo ◽  
Maximum Tolerated Dose ◽  
Toxicity Assessment ◽  
Hematologic Toxicity ◽  
Effective Combination ◽  
Nonhematologic Toxicity ◽  
Level 3 ◽  
Level 1 ◽  
Grade 3

8009 Background: Melphalan-prednisone + thalidomide (MPT) or bortezomib (MPV) are approved in frontline MM patients (pts) >65 years. Both regimens demonstrated significant benefit over MP alone in terms of PFS and OS but this benefit could be hampered by the risk of peripheral neuropathy (PN). Carfilzomib (Cfz) is a novel proteasome inhibitor that has demonstrated promising activity and favorable toxicity profile, with low rates of PN. This phase I/II study was designed to determine the maximum tolerated dose (MTD) of CMP, to assess safety and evaluate efficacy of this combination in newly diagnosed MM >65. Methods: In Phase I, Cfz was the only escalating agent starting at 20 mg/m2 (level 1) with maximal planned dose 36 mg/m2 (level 3), given IV on days 1, 2, 8, 9, 22, 23, 29, 30 for nine 42-day cycles. Oral melphalan 9 mg/m² and prednisone 60mg/m² were given on days 1 to 4, for all dose levels. Based on toxicity assessment, the study was amended to add dose level 4 (Cfz 45 mg/m2). MTD determination was based on occurrence of Dose limiting toxicities (DLTs) during the first cycle only. DLTs were defined as any grade 4 hematologic toxicity or preventing administration of 2 or more of the 8 Cfz doses of the first treatment cycle except grade 4 thrombocytopenia without bleeding or grade 4 neutropenia lasting ≤ 7 days; or grade ≥ 3 febrile neutropenia; or any other grade ≥ 3 nonhematologic toxicity. Results: As of January 20th 2012, 24 pts have been enrolled in the phase I: 6 pts at level 1 (Cfz 20), 6 at level 2 (Cfz 27), 6 at level 3 (Cfz 36), and 6 at level 4 (Cfz 45). There were 2 DLTs at level 4 (fever and hypotension not related to sepsis) and the MTD was considered to be 36 mg/m². Then, 16 additional pts were included in the phase II at level 3. Overall, 40 pts have been enrolled into the phase I/II study and 26 pts are evaluable for response. The ORR was 92% including 42% at least VGPR. These results compare favorably to those achieved with MPV, MPT, MPR or lenalidomide-dex (ORR 71, 76, 80 and 85%, respectively) in the same population. Conclusions: Frontline carfilzomib (36 mg/m2) + MP is a tolerable and very effective combination in elderly MM pts. Treatment is ongoing, with updated toxicity and efficacy data to be presented at the meeting.

Phase I clinical trial of lenalidomide with temsirolimus in patients with advanced cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2604-2604
Author(s):  
Prasanth Ganesan ◽  
Sarina Anne Piha-Paul ◽  
Aung Naing ◽  
Gerald Steven Falchook ◽  
Jennifer J. Wheler ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Adenoid Cystic Carcinoma ◽  
Advanced Cancer ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Adenoid Cystic ◽  
Level 3 ◽  
Grade 3 ◽  
Antiangiogenic Drug

2604 Background: Lenalidomide (immunomodulatory and antiangiogenic drug) and temsirolimus (mTOR inhibitor) are potentially synergistic (Raje N, Blood 2004;104(13):4188). We conducted a phase I study of the combination in patients with advanced cancers. Methods: During the escalation phase, lenalidomide (PO days 1-21) and temsirolimus (IV, Q weekly) were given at the following respective doses: level 1 (10 mg, 15mg); level 2 (10 mg, 20 mg); level 3 (20 mg, 20 mg); and level 4 (20 mg, 25 mg) (1 cycle = 28 days). A “3+3” study design was used. The maximum tolerated dose, dose-limiting toxicity, and response were assessed. Results: Forty- three patients were treated (median age: 58 (21-80) years; male/female: 26:17). The most common diagnoses were colorectal cancer (N=5), sarcoma (N=5) and adenoid cystic carcinoma (N=4). Overall, 121 cycles (median: 2) were administered. No dose limiting toxicities were observed. The maximum tested dose (level 4) was used for expansion. Grade 3-4 toxicity (all reversible) occurred in 19 (44%) patients: neutropenia (N=12), thrombocytopenia (N=6), and infection (N=1). Of 43 patients, 31 (72%) received anticoagulation prophylaxis. There were no thrombotic events. Of 36 patients who were evaluable for response, PR was noted in 1 (2.7%), and stable disease (SD) was noted in 17 (47%) patients (SD ≥6 months: 17%). Tumors with SD≥6 months were soft tissue sarcoma, 2/5 (40%), adenoid cystic carcinoma, 1/4 (25%), parotid ca, 1/2 (50%), adrenocortical ca 1/3 (33%), and neuroendocrine ca, 1/4 (25%) (Table). The median progression-free survival was 2.2 months (95% CI, 1.5-2.9) and overall survival was 7.8 months (95% CI, 5.1-10.6). Conclusions: Lenalidomide and temsirolimus combination was well tolerated and had antitumor activity in selected participants with advanced cancer. Clinical trial information: NCT01183663. [Table: see text]

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 Phase I Radiation Dose-Escalation Study to Investigate the Dose-Limiting Toxicity of Concurrent Intra-Arterial Chemotherapy for Unresectable Hepatocellular Carcinoma

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1612
Author(s):  
Yeona Cho ◽  
Jun Won Kim ◽  
Ja Kyung Kim ◽  
Kwan Sik Lee ◽  
Jung Il Lee ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Radiation Dose ◽  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
Level 3 ◽  
Level 1 ◽  
Grade 3 ◽  
Dose Limiting Toxicity

Concurrent intra-arterial chemotherapy and radiotherapy (iA-CCRT) can increase the response rate in hepatocellular carcinoma (HCC), but may cause a higher toxicity. We conducted this Phase I study to investigate the dose-limiting toxicity of iA-CCRT for HCC. In total, 52.5 Gy in 25 fractions was prescribed as planning target volume (PTV) 1 at dose level 1. The dose escalation was 0.2 Gy per fraction and up to 2.5 Gy, with 62.5 Gy at level 3. Concurrent intra-arterial 5-fluorouracil was administered during the first and fifth weeks of radiotherapy (RT). Toxicities were graded using the Common Toxicity Criteria for Adverse Events, version 4.0. Results: Seventeen patients with HCC were analyzed: four at dose level 1, 6 at level 2, and 7 at level 3. The mean irradiated dose administered to the uninvolved liver at each dose level was 21.3, 21.6, and 18.2 Gy, respectively. There was no grade ≥3 gastrointestinal toxicity; two patients experienced grade 3 hyperbilirubinemia. All patients had Child-Pugh class A disease, but 3 patients developed class B disease after iA-CCRT. During a median follow-up of 13 months, the median progression-free survival (PFS) and overall survival (OS) were 10 and 22 months, respectively. Patients treated at dose level 3 showed improved PFS and OS. Conclusions: Radiation dose escalation of iA-CCRT did not cause any significant toxicities in patients with advanced HCC. Further large-scale studies with long-term follow-up are needed to determine the efficacy and feasibility of higher doses of iA-CCRT.

A phase I/II study of oxaliplatin, docetaxel, and capecitabine in advanced carcinoma of the esophagus and stomach

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 14046-14046 ◽  
Author(s):  
D. L. Evans ◽  
T. Miner ◽  
T. Ng ◽  
P. Akerman ◽  
D. Harrington ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Phase I ◽  
Dose Level ◽  
Maximum Tolerated Dose ◽  
Carcinoma Of The Esophagus ◽  
Esophagogastric Cancer ◽  
Brown University ◽  
Level 3 ◽  
Grade 3 ◽  
Dose Levels

14046 Background: The Brown University Oncology Group has attempted to modify the regimen of docetaxel, cisplatin and fluorouracil (DCF) to reduce toxicity, simplify administration and maintain efficacy. We have a completed a phase I/II study of weekly doxetaxel, carboplatin and capecitabine for patients with advanced esophagogastric cancer (Safran et al, Am J Clin Oncol, 2006). In this phase I study we have substituted oxaliplatin for carboplatin to determine the maximum tolerated dose (MTD) of weekly docetaxel and oxaliplatin with capecitabine. Methods: Patients with metastatic esophageal and gastric cancers received docetaxel and oxaliplatin on days 1 and 8 and capecitabine in divided doses, twice daily, on days 1–10, with each cycle repeated every 21 days. Patients were treated at 4 dose levels as shown in the table. Results: Fourteen patients have been enrolled. The median age was 58.5 years. Eight patients had esophageal cancer and six had gastric cancer. Grade 3/4 dose limiting toxicities (DLTs) of diarrhea, nausea, and febrile neutropenia occurred in three of four patients at dose level 3. An intermediate dose level was added (2A), reducing the capecitabine dose. Conclusion: Oxaliplatin 50 mg/m2 and docetaxel 35 mg/m2 day 1 and 8 with capecitabine 750 mg/m2 BID × 10 days in 21 day cycles may represent a promising, easily administered regimen for metastatic esophageal and gastric cancer. Enrollment continues at dose level 2A. [Table: see text] [Table: see text]

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