Phase Ⅰ study of postoperative radiotherapy combined with capecitabine for gastric cancer

AIM:To determine the maximum tolerated dose(MTD)and dose-limiting toxicity(DLT)of capecitabine combined with postoperative radiotherapy for gastric cancer.METHODS:We enrolled patients with any T stage and node-positive gastroesophageal or gastric adenocarcinoma after complete resection with negative margins(R0)or microscopic(R1)or macroscopic(R2)resection.Intensity modulated radiotherapy(IMRT)using a fiveto-seven-field,coplanar,sliding window technique was delivered to the tumor bed(T4b),anastomosis site,duodenal stump and regional lymph nodes(LNs)to a total dose of 45 Gy(1.8 Gy/fraction,5 d/wk).Patients with R1 or R2 resection received 10.8 Gy as a boost.Capecitabine was administered twice daily on every radiotherapy treatment day in a dose-escalation schedule (mg/m2)of 625(levelⅠ,n=6),700(levelⅡ,n=6),800(levelⅢ,n=6),900(levelⅣ,n=0)and 1000(levelⅤ,n=0).DLT was defined as grade 4 leukopenia or neutropenia,grade 3-4 thrombocytopenia or anemia and grade 3-4 non-hematological toxicity.RESULTS:Between October 2007 and August 2009,18 patients(12 men,6 women;median age,54 years)were enrolled in the study.The median number of positive LNs was 6,and total number of resected LNs was19.Twelve patients underwent R0 resection(66.7%).Fifteen patients received adjuvant chemotherapy under the leucovorin,fluorouracil and oxaliplatin(FOLFOX4)regimen.Six patients each were enrolled at dose levelsⅠ,ⅡandⅢ.Grade 1-3 leukopenia(16 patients,88.9%),anorexia(15,83.3%)and nausea(15,83.3%)were the most common toxicities.Grade 3 anorexia/nausea and grade 4 vomiting occurred in one level-Ⅰpatient.Grade 3 anorexia and nausea occurred in one level-Ⅱpatient.One level-Ⅲpatient developed grade 4neutropenia,while another developed grade 3 radiation esophagitis.No abnormal liver or renal function examinations were observed.Three patients did not finish chemoradiotherapy because of DLTs and two without DLTs received sequential boosts(total dose,55.8 Gy).CONCLUSION:The MTD of capecitabine was 800 mg/m2twice daily concurrent with IMRT for gastric cancer after surgery.The DLTs were anorexia/nausea,vomiting,neutropenia and radiation esophagitis.     

High-dose mitoxantrone and cyclophosphamide without stem cell support in high-risk and advanced solid tumors: a phase I trial

This phase I study was designed to develop a high-dose combination of two cycles of mitoxantrone and cyclophosphamide in patients with solid tumors, as an alternative to single-cycle high-dose regimens that use only alkylating agents. Treatment was delivered with granulocyte colony-stimulating factor (G-CSF), but without stem cell support, in order to avoid potential tumor cell reinfusion. Thirty-one patients with advanced solid tumors received two cycles of high-dose mitoxantrone (20-30 mg/m2) plus high-dose cyclophosphamide (3000-4000 mg/m2). All patients received G-CSF until hematologic recovery. Dose-escalation was performed when less than 50% of cycles per level had dose-limiting toxicity (DLT). The maximum tolerated dose (MTD) achieved was mitoxantrone 25 mg/m2 and cyclophosphamide 4000 mg/m2. Main dose-limiting toxicities (DLTs) were hematological: grade IV neutropenia lasting more than 7 days and thrombopenia below 20 x 10(9)/l requiring more than one platelet transfusion. Non-hematological DLT consisted predominantly of grade III emesis and asthenia. Follow-up after each cycle was performed in an outpatient setting and there were no toxic deaths. In conclusion, the administration of two cycles of high-dose mitoxantrone and cyclophosphamide with G-CSF support is safe and feasible. MTD was mitoxantrone 25 mg/m2 and cyclophosphamide 4000 mg/m2. Evaluation of this regimen is being done in a phase II trial.     

Phase I-II trial of weekly gemcitabine plus high-dose 5-fluorouracil and leucovorin in advanced pancreatic cancer

BACKGROUND: Pancreatic cancer is a dismal disease. Few drugs, including gemcitabine and 5-fluorouracil (5-FU), have notable antitumor effects against advanced pancreatic cancer. The purpose of the present study was to determine the maximum tolerated dose (MTD) of 5-FU and the efficacy and toxicity profile of weekly gemcitabine plus infusional 5-FU/leucovorin in advanced pancreatic cancer. METHODS: Patients with histo-/cytologically confirmed, advanced pancreatic cancer were eligible. Treatment consisted of a 30-min infusion of gemcitabine (800 mg/m2), followed by a 24-h infusion of 5-FU and leucovorin (300 mg/m2) at day 1, day 8 and day 15 every 28 days, and was termed the GemFL24 regimen. The dose of 5-FU was escalated from 1600, 2000, to 2600 mg/m2 in the phase I study, and fixed MTD for subsequent enrolled patients. RESULTS: Eighteen patients were enrolled in the phase I study, and 24 in phase II. The MTD of 5-FU was 2000 mg/m2, with major dose-limiting toxicities being febrile neutropenia and delayed recovery from neutropenia. The dose intensity of gemcitabine of the 35 patients with 5-FU dosage set at MTD was 593 mg/m2 per week. In the entire series of 42 patients, myelosuppression was the main toxicity, with grade 3 neutropenia in eight patients, and grade 3/4 thrombocytopenia in six. On an intention-to-treat analysis, the overall and clinical benefit response rates were 22% and 46%, respectively; with median progression-free and overall survival of 4.1 and 6.9 months, respectively. CONCLUSIONS: The GemFL24 regimen is a feasible and moderately active treatment with manageable toxicities for advanced pancreatic cancer, and could be a basis for further combination with other anticancer drugs.     

Phase I study of paclitaxel and cisplatin for patients with advanced or recurrent gastric cancer

BACKGROUND/AIMS: The present phase I study was planned to define the toxicities, maximum tolerated dose (MTD), and pharmacokinetics of the combination of paclitaxel and cisplatin in patients with advanced or recurrent gastric cancer, and to recommend a dose for the phase II study. METHODOLOGY: Patients were required to have performance status of 0 to 1, to be between 15 and 74 years of age, and to have adequate organ function. The cisplatin was administered at a fixed dose of 25mg/m2 and paclitaxel was administered at four dose levels (60, 70, 80, and 90mg/m2). Plasma sampling was performed to characterize the pharmacokinetics and pharacodynamics of paclitaxel. RESULTS: All of the 15 patients entered were assessable for toxicity and response and were subject to analysis of dose-limiting toxicity (DLT) and MTD. Neutropenia (grade 4, for 3 days or more; n=2) indicated DLT at dose level 4 (90mg/m2). The MTD for this regimen was 90mg/m2/week of paclitaxel for 3 weeks. Tumor response occurred in 7 of the 15 patients and the overall response rate was 57.1%. The pharmacokinetic profiles of paclitaxel were similar to those observed after the administration of each dose as a single agent. CONCLUSIONS: Our study demonstrated that the level 3 dosage (80mg/m2 of paclitaxel and 25mg/m2 of cisplatin) is recommended for this combination chemotherapy. This phase I study showed favorable antitumor activity and fewer adverse reactions relative to other types of chemotherapy.     

Phase?I?trial of combination chemotherapy with gemcitabine,cisplatin, and S-1 in patients with advanced biliary tract cancer

AIM: To evaluate the dose-limiting toxicities (DLTs) and determine the maximum-tolerated dose (MTD) and recommended dose (RD) of combination chemotherapy with gemcitabine, cisplatin and S-1 which is an oral fluoropyrimidine pro-drug in patients with advanced biliary tract cancer.METHODS: Patients with histologically or cytologically confirmed unresectable or recurrent biliary tract cancer were enrolled. The planned dose levels of gemcitabine (mg/m²), cisplatin (mg/m²), and S-1 (mg/m² per day) were as follows: level -1, 800/20/60; level 0, 800/25/60; level 1, 1000/25/60; and level 2, 1000/25/80. In each cycle, gemcitabine and cisplatin were administered intravenously on days 1 and 15, and S-1 was administered orally twice daily on days 1 to 7 and days 15 to 21, every 4 wk.RESULTS: Twelve patients were enrolled, and level 0 was chosen as the starting dose. None of the first three patients had DLTs at level 0, and the dose was escalated to level 1. One of six patients had DLTs (grade 4 febrile neutropenia, leucopenia, and neutropenia; grade 3 thrombocytopenia) at level 1. We then proceeded to level 2. None of three patients had DLTs during the first cycle. Although the MTD was not determined, level 2 was designated at the RD for a subsequent phase II study.CONCLUSION: The RD was defined as gemcitabine 1000 mg/m² (days 1, 15), cisplatin 25 mg/m² (days 1, 15), and S-1 80 mg/m² per day (days 1-7, 15-21), every 4 weeks. A phase II study is planned to evaluate the effectiveness of combination chemotherapy with gemcitabine, cisplatin, and S-1 in advanced biliary tract cancer.     

A phase I study of combination of intravenous gemcitabine, oxaliplatin, and 5-FU with daily oral thalidomide (GOFT) in metastatic/locally advanced pancreatic carcinoma patients

BACKGROUND/AIMS: The phase I study was to determine the maximum tolerance dose and dose-limiting toxicity of gemcitabine/oxaliplatin/5-FU/thalidomide (GOFT) in patients with advanced pancreatic cancer. METHODOLOGY: Chemotherapy-naive patients with histologically proven locally advanced or metastatic pancreatic cancer were enrolled. Gemcitabine was given in a 1-hour infusion followed by oxaliplatin in a 2-hour infusion on day 1, and 5-FU in a 24-hour infusion on day 2, and oral thalidomide 100mg was given daily after intravenous chemotherapy. This regimen was given every 2 weeks. Dose levels of regimen were: level I: gemcitabine 1000mg/m2 + oxaliplatin 60mg/ m2 + 5-FU 1000mg/m2 + thalidomide 100mg/day, level II: gemcitabine 1000mg/m2 + oxaliplatin 70mg/m2 + 5-FU 1000mg/m2 + thalidomide 100mg/day, level III: gemcitabine 1250mg/m2 + oxaliplatin 60mg/m2 + 5-FU 1000mg/m2 + thalidomide 100mg/day. The NCI-CTC grade 3/4 toxicity was used for dose-limiting toxicity. Maximum tolerance dose was determined after the first two cycles in each patient. RESULTS: There were 6 patients in level I, 6 patients in level II, and 1 patient in level III. One of the 6 patients had DLT in level I (grade 3 infection and vomiting), 2 of 6 patients had DLT in level II (grade 3 leukopenia) and 1 patient in level III had DLT (grade 3 leukopenia and stomatitis). Other toxicities at level I/II were grade 1/2 leukopenia (7 episodes), grade 1/2 anemia (5), grade 1/2 nausea (5), grade 1 diarrhea (2), grade 1 alopecia (2), grade 1 skin (2), grade 1 allergy (1). CONCLUSIONS: The GOFT regimen was well tolerated and showed good treatment effect on the pancreatic cancer. We recommended the dose of level II GOFT regimen for further phase II trial.     

Phase I study of biweekly gemcitabine followed by oxaliplatin and simplified 48-h infusion of fluorouracil/leucovorin for advanced pancreatic cancer

OBJECTIVES: To evaluate the feasibility and maximal tolerated dose (MTD) of oxaliplatin of a triplet regimen consisting of gemcitabine, oxaliplatin and infusional fluorouracil (5-FU)/leucovorin (LV) (GOFL) for advanced pancreatic cancer. PATIENTS AND METHODS: Patients with histologically proven metastatic or unresectable, locally advanced pancreatic adenocarcinoma were eligible to take part in the study. The treatment consisted of fixed-rate infusion (10 mg/m2/minute) of 800 mg/m2 gemcitabine followed by 2-h infusion of oxaliplatin and then 48-h infusion of 5-FU/LV day 1 and day 15 every 4 weeks. The oxaliplatin would be evaluated at three dose levels, 65, 75 and 85 mg/m2. RESULTS: A total of 15 patients were enrolled at three dose levels. Dose-limiting toxicity of neutropenic fever and grade 4 thrombocytopenia occurred in one of each six patients at oxaliplatin dose level of 65 mg/m2 and 85 mg/m2, respectively. The MTD of oxaliplatin for this combination was 85 mg/m2. After a median four cycles of treatment, grade 3/4 neutropenia occurred in 46.7% of patients and thrombocytopenia in 13.3%. Non-hematological toxicities were generally of grade 1/2. Objective tumor response was observed in five patients (33.3%, 95% confidence interval, 6.3-60.4%). CONCLUSION: Biweekly GOFL is a feasible regimen for advanced pancreatic cancer. For further phase II studies, the recommended dose of oxaliplatin is 85 mg/m2.     

A phase I trial of CPT-11 in combination with 5-fluorouracil plus leucovorin chemotherapy for patients with metastatic colorectal cancer

BACKGROUND/AIMS: To establish a safe and practical chemotherapeutic regimen using CPT-11 in combination with 5-FU plus leucovorin (5-FU/LV) for patients with metastatic colorectal cancer in an outpatient setting, a phase I clinical trial was conducted. METHDOLOGY: Eligible patients received the RPMI regimen of I-LV (200 mg/m2, for 2 hours) plus 5-FU (333 mg/m2, bolus) weekly for 4 weeks followed by a 2-week rest. CPT-11 was administered over the 5-FU/LV therapy at the 1st and 3rd week of every treatment cycle before the bolus 5-FU. Dose escalation of CPT-11 from 25 to 100 mg/m2 was done for every cohort consisting of at least 3 patients to define a dose-limiting toxicity (DLT), maximal tolerated dose (MTD), and recommended dose (RD) for a phase II trial. RESULTS: Twenty-one patients with metastatic colorectal cancer were enrolled. Hematologic toxicity was very infrequently observed. One patient enrolled at level 1 (25 mg/m2 CPT-11), but not the other patients, had muscle weakness at grade 3 and needed to be hospitalized. Hair loss at grade 1 was observed in 3 of 21 patients. Gastrointestinal toxicity, including nausea, was commonly observed throughout the dose levels. Diarrhea was frequently observed at doses higher than level 4 (60 mg/m2 CPT-11), and 2 of the 3 patients at dose level 6 (100 mg/m2 CPT-11) experienced diarrhea at grade 3 and needed to be hospitalized. As for the overall tumor responses, 3 partial responses (PR), 10 stable diseases, and 6 progressive diseases were observed, with 2 of the PRs occurring at dose level 5 (80 mg/m2 CPT-11). CONCLUSIONS: These results suggest that our treatment regimen using CPT-11 in combination with 5-FU/LV is a safe regimen in an outpatient setting and effective for patients with metastatic colorectal cancer. The DLT is diarrhea at the MTD of 100 mg/m2 of CPT-11, and 80 mg/m2 CPT-11 is recommended for the next phase II trial.     

A phase II trial of docetaxel and CPT-11 in patients with metastatic adenocarcinoma of the esophagus,gastroesophageal junction,and gastric cardia

PURPOSE: The incidence of adenocarcinoma of the lower third of the esophagus, esophagogastric junction, and gastric cardia has been rising in the face of limited treatment options for patients with metastatic disease. With the emergence of data to suggest that single agent docetaxel and irinotecan carry antineoplastic effects in this setting, we determined the response rate of these agents when given in combination. PATIENTS AND METHODS: Forty-six patients with metastatic adenocarcinoma of the lower third of the esophagus, esophagogastric junction, and gastric cardia were evaluated. Patients received docetaxel 50 mg/m2/d and irinotecan 130 mg/m2/d intravenously at 21-d intervals with a tumor assessment after 2 cycles. Because of unacceptable toxicity among the first 13 patients, dosing was reduced to docetaxel 40 mg/m2/d and irinotecan 100 mg/m2/d intravenously at 21-d intervals. RESULTS: The response rate for the entire cohort was 26% (95% confidence interval: 14%, 41%) with 12 confirmed partial responses. Five of these 12 responses were observed in patients treated at the higher chemotherapy dose. However, because 8 of 13 patients suffered grade 4 neutropenia and fevers, a dose reduction was incorporated into the protocol, and the remainder of the cohort was treated at the lower dose. All except 4 of the 15 observed grade 4 toxicities occurred at the higher dose, and these toxicities included nausea and vomiting, dyspnea, hypotension, dysrhythmias, and diarrhea in addition to neutropenia and fevers. There were no grade 5 toxicities. The median survival for the entire cohort was 7.3 mo. CONCLUSION: The combination of docetaxel and irinotecan provides modest antineoplastic activity among patients with adenocarcinoma of the esophagus, esophagogastric junction, and gastric cardia. Doses of docetaxel 40 mg/m2/d and irinotecan 100 mg/m2/d at 21-d intervals provide an acceptable safety profile, but higher doses appear to result in unacceptable toxicity.     

A phase I trial of CPT-11 and S-1 combination chemotherapy in patients with metastatic colorectal cancer

BACKGROUND/AIMS: To establish a safe and practical chemotherapeutic regimen using CPT-11 in combination with an oral 5FU derivative S-1 for patients with metastatic colorectal cancer, a phase I clinical trial was conducted in an outpatient setting. METHODOLOGY: Nine patients with metastatic colorectal cancer were enrolled. S-1 was administered at approved doses of 80 mg/body/day to eligible patients with a body surface area (BSA) of less than 1.25m2, 100 mg/body/day to those with a BSA of 1.25-1.5m2, and 120 mg/body/day to those with a BSA of more than 1.5m2, for 2 weeks followed by 1 week rest, comprising one treatment cycle of 3 weeks. CPT-11 was administered on day 8 of the S-1 cycle. The dose of CPT-11 was escalated from 60-120 mg/m2 by every 20 mg/m2 for every cohort consisting of at least 3 patients in order to define dose-limiting toxicity (DLT), maximal tolerated dose (MTD), and recommended dose (RD) in preparation for a phase II trial. RESULTS: In regard to the hematologic toxicity, a decrease of WBC to less than grade 2 was observed in 2 patients until the dose was escalated to 100 mg/m2 of CPT-11, which delayed the treatment for 1 week in 1 patient. Regarding non-hematologic toxicity, fatigue and gastrointestinal toxicity, including anorexia and nausea/vomiting, at grades 1 and 2 were commonly observed throughout the dose levels. Diarrhea at grade 3 was observed at the 4th cycle of 100 mg/m2 CPT-11 in 2 of 3 patients, both of whom required hospitalization. All patients were able to complete more than 3 treatment cycles, and 1 patient at 80 mg/m2 of CPT-11 was able to receive 31 treatment cycles. Observed tumor responses included 1 partial response (PR), 2 moderate responses, 4 stable diseases, and 2 progressive diseases. Serum CEA level decreased in 7 of the 9 patients enrolled. CONCLUSIONS: These results suggest that this treatment regimen using CPT-11 in combination with oral S-1 therapy is a safe regimen in an outpatient setting and effective for patients with metastatic colorectal cancer. The DLT is diarrhea at a MTD of 100 mg/m2 of CPT-11, and 80 mg/m2 CPT-11 is recommended for the next phase II trial.     

Combined bendamustine, prednisolone and thalidomide for refractory or relapsed multiple myeloma after autologous stem-cell transplantation or conventional chemotherapy: results of a Phase I clinical trial

Thalidomide is an effective agent for advanced refractory or relapsed multiple myeloma (MM), although dose-limiting toxicity (DLT) may limit its use. This Phase I study found that a combination of low-dose thalidomide with bendamustine and prednisolone (BPT) maintained or increased efficacy, whilst avoiding DLT in 28 patients with MM that was refractory or that had relapsed after conventional chemotherapy or high-dose therapy with stem-cell support. BPT comprised fixed doses of bendamustine (60 mg/m(2)) and prednisolone (100 mg), and escalating doses of thalidomide (50, 100, 200 mg). Treatment cycles were repeated every 28 d until the occurrence of maximum response, DLT, or disease progression. Twenty-four patients responded after at least two cycles (four complete remission, six very good partial remission, 14 partial remission). Median progression-free and overall survival for all patients was 11 and 19 months respectively. Only mild/moderate non-haematological side effects were observed and no patient developed dose-limiting haematotoxicity. Transient grade 3-4 neutropenia was reported in 12 patients, and grade 3-4 thrombocytopenia occurred in two patients. We conclude that BPT therapy was well tolerated in patients with relapsed or refractory MM, with a response rate higher than 80%. The maximum tolerated dose of thalidomide was not reached in this study.     

Targeting of the Hedgehog/GLI and mTOR pathways in advanced pancreatic cancer,a phase 1 trial of Vismodegib and Sirolimus combination

Background/ObjectivesPreclinical data indicated a functional and molecular interaction between Hedgehog (HH)/GLI and PI3K-AKT-mTOR pathways promoting pancreatic ductal adenocarcinoma (PDAC). A phase I study was conducted of Vismodegib and Sirolimus combination to evaluate maximum tolerated dose (MTD) and preliminary anti-tumor efficacy.MethodsCohort I included advanced solid tumors patients following a traditional 3 + 3 design. Vismodegib was orally administered at 150 mg daily with Sirolimus starting at 3 mg daily, increasing to 6 mg daily at dose level 2. Cohort II included only metastatic PDAC patients. Anti-tumor efficacy was evaluated every two cycles and target assessment at pre-treatment and after a single cycle.ResultsNine patient were enrolled in cohort I and 22 patients in cohort II. Twenty-eight patients were evaluated for dose-limiting toxicities (DLTs). One DLT was observed in each cohort, consisting of grade 2 mucositis and grade 3 thrombocytopenia. The MTD for Vismodegib and Sirolimus were 150 mg daily and 6 mg daily, respectively. The most common grade 3–4 toxicities were fatigue, thrombocytopenia, dehydration, and infections. A total of 6 patients had stable disease. No partial or complete responses were observed. Paired biopsy analysis before and after the first cycle in cohort II consistently demonstrated reduced GLI1 expression. Conversely, GLI and mTOR downstream targets were not significantly affected.ConclusionsThe combination of Vismodegib and Sirolimus was well tolerated. Clinical benefit was limited to stable disease in a subgroup of patients. Targeting efficacy demonstrated consistent partial decreases in HH/GLI signaling with limited impact on mTOR signaling. These findings conflict with pre-clinical models and warrant further investigations.     

Phase I clinical and pharmacokinetic study of combination chemotherapy with topotecan and ifosfamide in patients with progressive or relapsed solid tumors

PURPOSE: Topotecan and ifosfamide are effective in the treatment of various solid tumors. Up to the time of this study, the two drugs have been combined just once (Smith et al. 1998). Due to its hematotoxicity, topotecan has been used predominantly within monochemotherapy protocols. However, the combination of topotecan and alkylating agents is supra-additive in many preclinical models. This phase-I trial was primarily performed to evaluate the maximum tolerable dose (MTD) and dose-limiting toxicity (DLT) of a combination chemotherapy with topotecan and ifosfamide using a 5-day schedule. A secondary goal was to estimate the response rate in a group of heavily pretreated patients with advanced solid tumors. METHODS: The pharmacokinetics of topotecan were preliminarily determined in some of the patients. A total of 12 patients (three female/nine male), median age 49 years (range 19-69), 11 with prior chemotherapy, received a total of 24 courses of chemotherapy at three dose-levels of topotecan. Ifosfamide was administered by intravenous infusion over 3 h immediately followed by a 30-min infusion of topotecan. Mesna (3 x 300 mg x m(2) x day) was given routinely during chemotherapy as a uroprotector. G-CSF (filgrastim) was permitted only in cases of febrile neutropenia (FN). RESULTS: The major toxicity was non-hematologic; severe liver and renal toxicity were observed in three out of 11 patients. Two treatment-related deaths occurred. No clinical remissions occurred in 11 evaluable patients. The pharmacokinetics of topotecan were relatively similar in our patients and supported findings in recent literature. The MTD of this combination was defined at dose-level 2 (1.0 mg/m(2) of topotecan and 750 mg/m(2) of ifosfamide). CONCLUSIONS: Further trials should not exceed this dose. The pharmacological causes for the pronounced toxicity have to be clarified.     

Phase 1 trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with advanced hematologic malignancies

Proteasome inhibitors, a novel class of chemotherapeutic agents, enhance the antitumor efficacy of anthracyclines in vitro and in vivo. We therefore sought to determine the maximum tolerated dose (MTD) and dose-limiting toxicities of bortezomib and pegylated liposomal doxorubicin (PegLD). Bortezomib was given on days 1, 4, 8, and 11 from 0.90 to 1.50 mg/m2 and PegLD on day 4 at 30 mg/m2 to 42 patients with advanced hematologic malignancies. Grade 3 or 4 toxicities in at least 10% of patients included thrombocytopenia, lymphopenia, neutropenia, fatigue, pneumonia, peripheral neuropathy, febrile neutropenia, and diarrhea. The MTD based on cycle 1 was 1.50 and 30 mg/m2 of bortezomib and PegLD, respectively. However, due to frequent dose reductions and delays at this level, 1.30 and 30 mg/m2 are recommended for further study. Pharmacokinetic and pharmacodynamic studies did not find significant drug interactions between these agents. Antitumor activity was seen against multiple myeloma, with 8 of 22 evaluable patients having a complete response (CR) or near-CR, including several with anthracycline-refractory disease, and another 8 having partial responses (PRs). One patient with relapsed/refractory T-cell non-Hodgkin lymphoma (NHL) achieved a CR, whereas 2 patients each with acute myeloid leukemia and B-cell NHL had PRs. Bortezomib/PegLD was safely administered in this study with promising antitumor activity, supporting further testing of this regimen.     

Clofarabine, a novel nucleoside analog, is active in pediatric patients with advanced leukemia

Despite progress in leukemia therapy, most children who experience relapse have a dismal prognosis. New, effective approaches are needed. We conducted a phase 1 study of a novel nucleoside analog, clofarabine, in pediatric patients with refractory and relapsed leukemia. Clofarabine was infused intravenously over 1 hour each day for 5 days. Six dose levels, between 11.25 and 70 mg/m(2) per day for 5 days, were studied in 25 patients. A modified 3 + 3 phase 1 design was followed with 30% dose escalation until the dose-limiting toxicity (DLT) was defined. The maximum tolerated dose (MTD) was 52 mg/m(2) per day for 5 days. At the end of infusion at MTD, clofarabine triphosphate levels in leukemia blasts varied between 6 microM and 19 microM, which resulted in complete and sustained inhibition of DNA synthesis. The DLT was reversible hepatotoxicity and skin rash at 70 mg/m(2) per day for 5 days. Twenty-five patients were treated. Five patients achieved complete remission (CR), and 3 achieved partial remission (PR), for an overall response rate of 32%. Clofarabine is well tolerated and shows significant antileukemic activity in heavily pretreated children. Multicenter phase 2 trials in pediatric acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) are ongoing.     

Chemoradiotherapy in patients with pancreatic carcinoma: phase-I study with a fixed radiation dose and escalating doses of weekly gemcitabine.

AIM: The aim of this phase-I study is to determine the maximum tolerated dose (MTD) of weekly gemcitabine in concurrent combination with a total radiation dose of 54 Gy in patients with pancreatic cancer. METHODS: In all patients, a total dose of 54 Gy was delivered in 30 fractions of 1.8 Gy/day. Gross tumor volume and regional lymph nodes were included in the irradiated volume with a 1- to 1.5-cm margin. The doses of weekly gemcitabine were escalated from 100 mg/m2 by increments of 50 mg/m2. Dose-limiting toxicity (DLT) was defined as hematologic toxicity, prolonged grade-3 non-hematologic toxicity, and incompletion of the planned treatment. RESULTS: Twenty-six patients entered the trial. From level 1 (100 mg/m2) to level 4 (250 mg/m2), no patient experienced DLT except for 1 patient at level 1. At level 5 (300 mg/m2), 3 of the 5 patients met the DLT criteria. One patient developed severe pulmonary abscess, and the other 2 patients had hematologic DLT. The overall partial response rate was 29%, and the median survival time was 13.7 months. The first relapse occurred at the in-field primary site in 6 patients and at distant organs in 13 patients. CONCLUSION: The MTD of weekly gemcitabine was 250 mg/m2 in the present chemoradiotherapy setting. The efficacy of this chemoradiotherapy regimen is currently being evaluated in the phase-II setting.     

An open-label phase I/II study of tamibarotene in patients with advanced hepatocellular carcinoma

Aim

Tamibarotene is a synthetic retinoid expected to inhibit tumor-cell proliferation and to induce apoptosis by selective interaction with retinoic acid receptor α/β. We conducted an open-label phase I/II study to determine the maximum tolerated dose (MTD) and recommended dose (RD), and to evaluate the pharmacokinetics, efficacy, and safety profiles for advanced hepatocellular carcinoma (HCC).

Methods

Patients with histologically confirmed, measurable, unresectable HCC of Child-Pugh classification A or B and with no effective systemic or local therapies were eligible. In phase I, patients were assigned based on the 3 + 3 dose escalation criteria to receive tamibarotene at 8, 12, and 16 mg/day. The RD determined in phase I was employed for phase II. The planned sample size in phase II was 25, including the RD-treated patients in phase I.

Results

Thirty-six patients were enrolled. No patients experienced dose-limiting toxicity (DLT) at 8 mg/day. However, two out of six patients experienced the DLTs at 12 mg/day: one experienced thrombosis in a limb vein and pulmonary artery, and the other experienced an increase of γ-GTP. The MTD and RD were determined as 12 and 8 mg/day, respectively. In phase II, one patient achieved partial response, and seven achieved stable disease. The disease control rate was 32 % (95 % CI: 15.0–53.5). The following drug-related serious adverse events were reported: thrombosis in a limb vein, pulmonary artery, and portal vein; interstitial lung disease; and vomiting.

Conclusions

Tamibarotene demonstrated the inhibition of tumor cell growth in advanced HCC with acceptable tolerance.     

A multicenter phase II study of the efficacy and safety of docetaxel plus cisplatin in Asian chemonaïve patients with metastatic or locally advanced non-small cell lung cancer

AIMS: To evaluate the efficacy and safety of docetaxel-cisplatin in patients with metastatic or locally advanced non-small cell lung cancer (NSCLC). METHODS: Chemotherapy-na?ve patients with histologically confirmed TNM stage III or IV NSCLC were recruited from 12 Asian trial centers. Patients received docetaxel (75 mg/m2) and cisplatin (75 mg/m2) every 3 weeks for 6 cycles. RESULTS: 130 of 146 patients were evaluable for efficacy (60% stage IV). Three complete and 58 partial responses were observed (overall response rate: 46.9%; 95% CI: 38.3-55.5%). Median time to progression was 6.9 months and median survival was 14.0 months; 1-year survival was 59.5%. Grade 3/4 neutropenia, thrombocytopenia and anemia occurred in 69.2%, 6.2% and 18.5% of patients, respectively. Grade 3/4 vomiting was observed in 13.7% and grade 3/4 neurosensory effects were observed in 2.7% of patients. There was one case of treatment-related death due to sepsis. CONCLUSION: Docetaxel-cisplatin is an effective and well-tolerated treatment in Asian patients with NSCLC.     

Pilot study of postoperative adjuvant chemoradiation for advanced gastric cancer： Adjuvant 5-FU/cisplatin and chemoradiation with capecitabine

AIM:To evaluate the efficacy and toxicity of postopera-tive chemoradiation using FP chemotherapy and oralcapecitabine during radiation for advanced gastric cancerfollowing curative resection.METHODS:Thirty-one patients who had underwent apotentially curative resection for Stage Ⅲ and Ⅳ(MO)gastric cancer were enrolled.Therapy consists of onecycle of FP(continuous infusion of 5-FU 1000 mg/m~2on d 1 to 5 and cisplatin 60 mg/m~2 on d 1)followed by4500 cGy(180 cGy/d)with capecitabine(1650 mg/m~2daily throughout radiotherapy).Four wk after completionof the radiotherapy,patients received three additionalcycles of FP every three wk.The median follow-up dura-tion was 22.2 mo.RESULTS:The 3-year disease free and overall survivalin this study were 82.7% and 83.4%,respectively.Fourpatients(12.9%)showed relapse during follow-up.Eightpatients did not complete all planned adjuvant therapy.Grade 3/4 toxicities included neutropenia in 50.2%,ane-mia in 12.9%,thrombocytopenia in 3.2% and nausea/vomiting in 3.2%.Neither grade 3/4 hand foot syndromenor treatment related febrile neutropenia or death wereobserved.CONCLUSION:These preliminary results suggest thatthis postoperative adjuvant chemoradiation regimen ofFP before and after capecitabine and concurrent radio-therapy appears well tolerated and offers a comparable toxicity profile to the chemoradiation regimen utilized inINT-0116.This treatment modality allowed successfulloco-regional control rate and 3-year overall survival.     

A phase II study of docetaxel-irinotecan combination in advanced pancreatic cancer

BACKGROUND/AIMS: Chemotherapy provides dismal results in advanced pancreatic cancer patients, even when new compounds, such as gemcitabine, are used. Phase I studies of single-drug therapy with docetaxel or irinotecan suggested a response rate of about 15% in these patients. We report here a phase II study of docetaxel-irinotecan combination in advanced pancreatic cancer patients. METHODOLOGY: Docetaxel 60 mg/m2 was given in combination with irinotecan 250 mg/m2 every 3 weeks. Prednisolone premedication and anti-HT3 drugs were systematically administered. Hematopoietic growth factors were given in case of febrile neutropenia or grade 4 neutropenia at the previous cycle. Endpoints were response rate, progression-free survival, and tolerance. RESULTS: Twenty-seven patients were enrolled, of whom 25 had metastatic disease. We observed 3 partial responses and 11 stabilizations. The median progression-free survival was 4.3 months. Myelosuppression was the main toxicity with 18% of patients experiencing a grade 3-4 event. One patient died of neglected febrile neutropenia. Gastrointestinal toxicity was well controlled. Other toxicities were mild. CONCLUSIONS: This combination has acceptable tolerance and, despite an 11% response rate, some partial responses and prolonged stabilizations were observed. The treatment induced clinical benefit in 33% of the patients. Further trials should focus on docetaxel or irinotecan, possibly used in combination with more conventional strategies (gemcitabine).