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.

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]

Oxaliplatin, Fludarabine, Cytarabine, and Rituximab Combination Therapy Induces High Response Rates in Agressive Chronic Lymphocytic Leukemia (CLL) and Richter's Syndrome (RS).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3443-3443 ◽  
Author(s):  
Apostolia-Maria Tsimberidou ◽  
William Wierda ◽  
William Plunkett ◽  
Susan O'Brien ◽  
Thomas J. Kipps ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Research Funding ◽  
Response Rates ◽  
Off Label ◽  
Level 3 ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

Abstract Abstract 3443 Poster Board III-331 Introduction The first Phase I-II clinical trial of oxaliplatin, fluradabine, cytarabine (Ara-C), and rituximab (OFAR1) demonstrated significant activity in refractory CLL and RS (Tsimberidou et al, J Clin Oncol, 2008;26:196). To enhance the response rate and decrease myelosuppression, the dose of oxaliplatin was increased to 30mg daily, the dose of Ara-C was decreased to 0.5g/m2 daily and the optimal number of days of fluradabine and Ara-C administration was explored (OFAR2). Methods In a Phase I-II study of OFAR2, patients were treated with oxaliplatin 30mg/m2, D1-4; fludarabine 30mg/m2, Ara-C 0.5g/m2; rituximab 375mg/m2, D3; and pelfigrastim 6mg, D6. Fludarabine and Ara-C were given on D2-3 (dose level 1) D2-4 (dose level 2) or D2-5 (dose level 3); courses were repeated every 4 weeks. Patients received prophylaxis for tumor lysis, DNA viruses, and PCP. A “3+3” design was used and the planned number of patients in the Phase II was 90 (CLL, 60; RS, 30). Results Ninety-one patients (CLL, 67; RS, 24) have been treated to date: Phase I, 12 patients (by dose level: 1, n=3; 2, n=6; and 3, n=3). DLTs were noted in 2 of 3 patients on dose level 3 (G4 diarrhea, 1; G4 neutropenic sepsis, 1); thus, dose level 2 was the MTD. Seventy-nine patients (relapsed CLL, 58; RS, 19) have been treated in the Phase II portion of the study. Patient characteristics were as follows: age > 60 years, 65%; 17p deletion, 38%; 11q deletion, 13%; 13q deletion, 16%; trisomy 12, 21%; no findings, 12%; unmutated IgVH, 80%; ZAP70-positive, 75%; and CD38 ≥30%, 58%. Response in patients treated in the Phase II recommended dose is shown in Table (evaluable, 67). The overall response rates in patients with 17p and 11q deletions were 48% and 55%, respectively. The median survival duration was 21 months (CLL, 21 months; RS, 9.5 months). At 18 months, the survival rates in patients with 17p and 11q deletions were 66% and 76%, respectively. Twelve patients underwent stem cell transplantation after OFAR2 (as post-remission therapy, n=10; as salvage, n=2). Overall, 196 cycles were administered. Grade 3-4 neutropenia, thrombocytopenia, and anemia were noted in 63%, 72%, and 39% of patients and in 57%, 70%, and 25% of cycles and Grade 3-4 infections in 19% of patients. Conclusion Preliminary results demonstrated that OFAR2 induced response in 40% of patients with RS and 63% of patients with relapsed/refractory CLL. OFAR2 had antileukemic activity in patients with 17p deletion. Clinical outcomes appeared to be superior to those of OFAR1 in refractory CLL, whereas results of OFAR1 appeared to be superior to those of OFAR2 in RS. Accrual is ongoing. Disclosures Tsimberidou: ASCO: ASCO Career Development Award; Sanofi: Research Funding. Off Label Use: Oxaliplatin is used off-label. Wierda:Genentech: Honoraria; Bayer, Sanofi-Aventis, Abbott, GSK: Research Funding; GSK, Trubion, Ligand, Genentech, Medimmune, Abbot: Consultancy; Celgene: Speakers Bureau. Plunkett:Sanofi-Aventis: Research Funding. O'Brien:Genentech: Research Funding; Sanofi: Consultancy. Kipps:NCI: Grant P01CA-81534.

A phase I study of S-1 administration and a 24-h infusion of cisplatin plus paclitaxel in patients with advanced gastric cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 4074-4074
Author(s):  
H. Iwase ◽  
M. Shimada ◽  
T. Tsuzuki ◽  
M. Okeya ◽  
K. Kobayashi ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Antitumor Activity ◽  
Advanced Gastric Cancer ◽  
Dose Level ◽  
Combination Chemotherapy ◽  
Single Agent ◽  
Fixed Dose ◽  
Hematological Toxicity ◽  
Level 3 ◽  
Grade 3

4074 Background: S-1 may have a major role in the treatment of gastric cancer as single agent or as a component of combination chemotherapy in Japan. We previously reported a multicentric phase II study of S-1 combined with a 24-h infusion of cisplatin in patients with advanced gastric cancer. This combination was active, safe and had the possibility of being combined with other anticancer drug. Combination chemotherapy with S-1 and cisplatin plus paclitaxel for advanced gastric cancer might yield a stronger antitumor effect. The objective of this study was to determine the dose-limiting toxicity (DLT), the maximum tolerated dose (MTD), the recommended dose (RD), and the preliminary antitumor activity of S-1 and cisplatin plus paclitaxel for advanced gastric cancer. Methods: Paclitaxel was administered on day 1. A fixed dose of S-1 (70 mg/m2/day) was orally administered for 14 consecutive days from day 1, and a 24-h infusion of a fixed dose of cisplatin (60 mg/m2) was administered on day 14 of every 28-day cycle. Four dose escalation levels of paclitaxcel were studied (120, 140, 160, and 180 mg/m2). The DLT was defined as any of the following: grade 3 neutropenia lasting more than 5 days, grade 4 hematological toxicity, grade 3 non-hematological toxicity, or treatment delay of greater than 2 weeks as a result of toxicity. Results: Twenty patients were enrolled. Hematological and non- hematological toxicity of over grade 2 was not observed at dose level 1 and 2. Three patients started at dose level 3. One developed grade 3 neutropenia for 5 days following by grade 2 neutropenia lasted more than 10 days. Five more patients were added at this level. The treatment was delayed over 2 weeks in 1 out of 8 patients. Three patients started at dose level 4. One developed grade 3 neutropenia and needed longer than 14 days to recover. Three patients added this level. In total, at dose level 4 the treatment was delayed over 2 weeks in 3 out of 6 patients as a result of neutropenia. We considered level 4 is the MTD and the RD of paclitaxcel was 160 mg/m2 (dose level 3). The overall response rate was 75%. Conclusions: Triple combination chemotherapy consisting of S-1, cisplatin, and paclitaxel showed a tolerable dose of adverse reactions and favorable antitumor activity for gastric cancer. No significant financial relationships to disclose.

Phase I study of biweekly intravenous paclitaxel plus intraperitoneal cisplatin and paclitaxel for gastric cancer with peritoneal metastasis.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 139-139
Author(s):  
H. Ishigami ◽  
J. Kitayama ◽  
S. Kaisaki ◽  
H. Yamaguchi ◽  
H. Yamashita ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Phase I ◽  
Cancer Patients ◽  
Dose Level ◽  
Peritoneal Metastasis ◽  
Phase I Study ◽  
Level 1 ◽  
Grade 3 ◽  
Gastric Cancer Patients ◽  
Experienced Grade

139 Background: Intraperitoneal (IP) chemotherapy is promising for the treatment of gastric cancer with peritoneal metastasis. We previously verified the safety and efficacy of IP paclitaxel (PTX) combined with S-1 and intravenous (IV) PTX in phase I and phase II studies (Oncology. 2009; Ann Oncol. 2010). Secondly, we developed a new IP-containing chemotherapy regimen, IV PTX plus IP cisplatin (CDDP) and PTX, for patients who have failed S-1-based chemotherapy. We performed a phase I study to determine the maximum-tolerated dose (MTD) and recommended dose (RD) in gastric cancer patients. Methods: A total of 9 gastric cancer patients were enrolled who had shown progression of peritoneal metastasis after S-1-based chemotherapy. PTX was administered intravenously at a dose of 100 mg/m2 and intraperitoneally over 1 hour with an initial dose of 20 mg/m2 (level 1), stepped up to 30 or 40 mg/m2 depending on observed toxicity. CDDP was subsequently administered intraperitoneally at a dose of 30 mg/m2 over 24 hours after PTX infusion. PTX and CDDP were administered on days 1 and 15 in 4-week cycles. Results: At dose level 1, dose-limiting toxicities (DLTs) were observed in 2 of 3 patients. One patient experienced grade 4 leukopenia, and the other grade 3 vomiting. Because of higher toxicities than anticipated, the initial dose-escalation schedule was abandoned, and the doses of IV PTX and IP CDDP were reduced to 80 mg/m2 and 25 mg/m2, respectively, while keeping the dose of IP PTX at 20 mg/m2 (level 0). At dose level 0, one of the first 3 patients experienced grade 3 nausea, and an additional 3 patients experienced no DLTs. Consequently, the MTD and RD were determined to be dose level 1 and dose level 0, respectively. No patients experienced complications related to the peritoneal access device or IP infusion. Conclusions: Combination chemotherapy of IV PTX plus IP CDDP and PTX was shown to be a safe regimen that should be further explored in clinical trials. No significant financial relationships to disclose.

Phase I/II trial of bortezimib and pemetrexed in patients with advanced non-small cell lung cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 18145-18145 ◽  
Author(s):  
R. B. Natale ◽  
M. McKinley ◽  
J. Hilger ◽  
T. Myers
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Dose Finding ◽  
Mantle Cell ◽  
Finding Study ◽  
Heavily Pretreated ◽  
Level 3 ◽  
Previously Treated Patients ◽  
Grade 3 ◽  
Dose Levels

18145 Background: Bortezomib (Vc) is a novel proteosome inhibitor with activity in several malignancies including multiple myeloma, mantle cell lymphoma, and NSCLC. In NSCLC, Vc has additive activity combined with carboplatin and gemcitabine in first line and with docetaxel in second line treatment. Pemetrexed (P) is active in NSCLC and preclinical data suggests a pro-apoptotic synergy between Vc and P. Therefore, we initiated a phase I/II dose finding study of Vc + P in previously-treated patients (pts) with advanced or metastatic NSCLC. Methods: Fifteen pts have been accrued to 3 of 4 planned dose levels of Vc + P. Starting doses (and # pts treated) were Vc 1.4 mg/m2 day 1 & 8 + P 400 mg/m2 day 1 every 3 weeks (3 pts). The 2nd and 3rd dose levels were Vc 1.6 mg/m2 day 1 & 8 + P 500 mg/m2 day 1 (8 pts, 5 new + 3 from dose level 1) and Vc 1.8 mg/m2 day 1 & 8 + P 500 mg/m2 day 1 (7 pts). Results: 15 pts are evaluable for response and toxicity and include 8 males, 7 females, median age 67 (range, 55–82), PS 0/1 (3/12 pts), median of 2 prior therapies (range 1–3). Confirmed PRs occurred in 2 pts (13%) and stable disease in 5 (33%). Dose limiting toxicities consisted of grade 4 fatigue (1 pt) and neutropenia/fever (1 pt) at dose level 2, and grade 3 abdominal pain and fatigue (1 pt) and grade 3 diarrhea and vomiting (1 pt) at dose level 3. Conclusions: The above combination is safe at the doses tested thus far and active in pts with heavily pretreated, advanced NSCLC. We are currently exploring Vc 2.0 mg.m2 Day 1 & 8 + P 500 mg/m2 day 1 every 3 weeks to determine the MTD and plan a multi-site Phase II study to determine response rate and survival in a larger pt population. No significant financial relationships to disclose.

Phase I trial of combination becatecarin and oxaliplatin in patients with advanced solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2561-2561
Author(s):  
S. Manda ◽  
C. Mauser ◽  
J. Bokar ◽  
M. Cooney ◽  
J. Brell ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Phase Ii ◽  
Phase I Trial ◽  
Performance Status ◽  
Advanced Solid Tumors ◽  
Phase Ii Studies ◽  
Grade 3 ◽  
Level 2

2561 Background: Becatecarin (rebeccamycin analogue-RA) is an anti-tumor antibiotic with inhibitory activity against both topoisomerase II and I as well as DNA intercalating properties. We performed a phase I trial to a) determine the maximum tolerated dose (MTD) of RA in combination with oxaliplatin; b) determine the dose limiting toxicities (DLT) (c) obtain data on pharmacokinetics and (d) observe for any antitumor activity. Methods: Eligibility criteria included patients with advanced solid tumors refractory to standard therapy; performance status 0–2; adequate hematologic, renal and liver function. Patients were treated with RA as a 1 hour infusion daily x 5 and oxaliplatin on day 5 only, after RA infusion. Treatment was repeated q 21 days. The following dose levels were evaluated: Dose level 1: RA 80 mg/m2/d and oxaliplatin 90 mg/m2; Dose level 2: RA 80 mg/m2/d and oxaliplatin 130 mg/m2; Dose level 3: RA 110 mg/m2/d and oxaliplatin 130 mg/m2. Results: A total of 15 evaluable patients were enrolled. Median age was 56 (8 male, 7 female). A variety of tumor types were enrolled. A total of 56 cycles were administered. DLT occurred at a dose of RA at 110 mg/m2/d x 5 days and oxaliplatin at 130 mg/m2 and consisted of grade 3 hypophosphatemia and grade 4 atrial fibrillation. At this dose level 2 of 3 enrolled patients also developed grade 3 neutropenia. The MTD and recommended phase II dose was RA at 80 mg/m2/daily x 5 along with oxaliplatin 130 mg/m2 day 5 q 21 days. Three confirmed partial responses were observed in patients with hepatocellular, gallbladder and esophageal cancers. Six patients experienced stable disease. Conclusions: At the MTD combination RA and oxaliplatin is well tolerated and given the response rate and stable diseases observed, phase II studies are recommended. Supported by Grants U01 CA62502, MO1-RR-00080, K23 CA109348–01 from the National Institutes of Health. No significant financial relationships to disclose.

Phase I dose-finding study of sorafenib in combination with capecitabine and cisplatin as a first-line treatment in patients with advanced gastric cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4559-4559
Author(s):  
C. Kim ◽  
J. Lee ◽  
Y. Choi ◽  
B. Kang ◽  
M. Ryu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Phase I ◽  
Dose Level ◽  
Dose Finding ◽  
Finding Study ◽  
Level 3 ◽  
Dose Finding Study ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

4559 Background: We conducted a phase I dose-finding study of sorafenib (S) in combination with capecitabine (X) and cisplatin (P) in patients with previously untreated metastatic or inoperable advanced gastric cancer. Methods: Four dose levels of S, X, and P combination were tested. The doses of S (p.o. daily), X (p.o. on days 1–14), and P (i.v. on day 1) were escalated at the following schedule; level 1: S 400 mg/d, X 1,600 mg/m2/d, P 80 mg/m2; level 2: S 800 mg/d, X 1,600 mg/m2/d, P 80 mg/m2; level 3: S 800 mg/d, X 2,000 mg/m2/d, P 80 mg/m2; level 1A: S 800 mg/d, X 1,600 mg/m2/d, P 60 mg/m2. The cycle was repeated every 3 weeks. Dose limiting toxicities (DLTs) were evaluated only in the first cycles and a standard 3+3 dose escalation design was implemented. Results: A total 21 pts were enrolled in the study. No DLTs were observed at dose level 1 (n=3). One DLT (grade 3 diarrhea) was noted at dose level 2 (n=6), and 2 DLTs (two grade 4 neutropenias longer than 5 days in duration) were observed at dose level 3 (n=6), which made the level 3 dose the maximum tolerated dose (MTD). However, at cycle 2 and thereafter at dose level 2, the relative dose intensity (RDI) of S and X could not be maintained (mostly below 80%) due to the frequent dose reductions and cycle delays. So, we explored a new dose level (1A) between dose level 1 and 2. Since no DLTs were found in 6 patients at level 1A with RDI mostly above 80% throughout the treatment period, level 1A was determined as recommended dose (RD). Most frequent grade 3 and 4 hematologic toxicities were neutropenia (25.0% of cycles), and most frequent grade 2 and 3 non-hematologic toxicities were hand-foot syndrome (9.4%), asthenia (7.0%), and anorexia (5.5%). The objective responses were confirmed in 10 out of 16 patients with measurable lesions (62.5%; 95% CI, 38.8–86.2%). With a median follow-up of 8.1 months, estimated median progression-free survival was 10.0 months (95% CI, 1.6–18.4 months) and median overall survival has not been reached. Conclusions: Diarrhea and neutropenia were DLTs in this S, X, and P combination. The dose schedule of sorafenib 400 mg po bid daily with capecitabine 800 mg/m2 po bid on days 1–14, and cisplatin 60 mg/m2 iv on day 1 in every 3 weeks is recommended for further development in AGC. [Table: see text]

Phase I Study of Bendamustine in Refractory Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4156-4156
Author(s):  
Mary Beth Rios ◽  
Elias Jabbour ◽  
Farhad Ravandi ◽  
Tapan Kadia ◽  
Zeev Estrov ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Alkylating Agents ◽  
Dose Schedule ◽  
Median Number ◽  
Ring Structure ◽  
Leukemic Cells ◽  
Phase Ii Studies ◽  
Grade 3

Abstract Abstract 4156 Background Alkylating agents are active in leukemia. Examples are cyclophosphamide, chlorambucil, melphalan, busulfan, and others. Bendamustine, a rationally designed drug that incorporates alkylating agent properties plus an adenosine-like ring structure, may be active in leukemia. Fractionated doses of alkylators may improve efficacy (e.g. fractioned cyclophosphamide in ALL). Methods We initiated a phase I-II study of bendamustine in patients with refractory leukemia, chronic myelomonocytic leukemia, or myelodysplastic syndromes. Starting dose was 50mg/m2 IV BID over 1-2 hours for 4 days every 4 weeks (3 pts.) with escalation to 75mg (3 pts.), and 100mg (6 pts). Three additional patients were treated at 50mg/m2 once that dose was declared safe as allowed by study design. Diagnoses were AML 12, ALL 2, MDS 1. Median age was 48 (range 22 to 88). All patients were refractory or had relapsed after multiple courses of chemotherapy. The median number of prior therapies was 3 (range 1 to 9). Five patients had chromosome 5, 7, or 8 abnormalities, 6 patients had miscellaneous abnormalities, 4 patients were diploid. Results Toxicity – Grade 1-2 expected toxicities of nausea, vomiting, diarrhea, and transient transaminase elevations were seen at all dose levels. At the 75 mg/m2 dose level grade 3 transaminase elevation was seen in 1 pt. which occurred with rash and diarrhea, was thought to be related to GVHD and all subsided with dose increase of tacrolimus. One patient who began therapy with a creatinine of 1.8 had creatinine increase to 3.3 mg/DL. At the 100mg/m2 dose level 2/3 patients developed creatinine increase to 3.2 and 2.6 mg/DL. The creatinine increase occurred on day 7 and subsided by day 11 in both pts. An additional 3 pts. were treated at this dose level with no increase in creatinine to >2 mg/DL. Results Response – Antileukemic activity was encouraging: 8/15 patients with peripheral blasts had >90% reduction of the leukemic cells; 2 patients had >50% reduction of marrow blasts % (90 to 10, 86 to 40). Bendamustine has shown activity in this heavily pretreated refractory leukemia group. While the creatinine elevations were not severe (grade 3-4 NCI CTC) they were consistent to consider a bendamustine dose schedule of 50-75 mg/m2 IV BID x 4 days as a reasonable phase II schedule to explore in better prognosis patients, particularly in adult ALL in phase II studies. Disclosures: Ravandi: Cephalon: Consultancy, Honoraria. Kantarjian:Cephalon: Research Funding.

Early Results of a Phase Ib/II Dose-Escalation Trial of Romidepsin in Association with CHOP in Patients with Peripheral T-Cell Lymphomas (PTCL)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2673-2673
Author(s):  
Jehan Dupuis ◽  
Rene-Olivier Casasnovas ◽  
Franck Morschhauser ◽  
Herve Ghesquieres ◽  
Catherine Thieblemont ◽  
...  
Keyword(s):  
T Cell ◽  
Dose Level ◽  
Phase Ii ◽  
Qt Interval ◽  
Research Funding ◽  
Hematological Toxicity ◽  
Phase Ii Studies ◽  
Starting Dose ◽  
Grade 3 ◽  
Previous Phase

Abstract Abstract 2673 Background: Romidepsin is a potent histone deacetylase inhibitor approved by the FDA for patients with cutaneous T-cell lymphoma and PTCL who have received at least 1 prior systemic therapy. In recurrent/refractory PTCL, it has been evaluated as a single agent in 2 previous phase II studies with overall response rates of 30–38% (Piekarz et al., Blood 2011;117:5827; Coiffier et al., Blood 2010;116(21S):114). The observed toxicity was mainly hematological and digestive. Prolongation of the QT interval has been reported. The aim of the present study was to evaluate the safety, tolerability and efficacy of escalating doses of romidepsin in association with CHOP in patients with previously untreated PTCL. Methods: Patients with biopsy-proven PTCL are planned to receive 8 cycles of CHOP (cyclophosphamide 750 mg/m2 day 1, doxorubicin 50 mg/m2 day 1, vincristine 1,4 mg/m2 day 1, prednisone 40 mg/m2 days 1–5) in association with escalating doses of romidepsin. Based on pharmacokinetic data and results of previous phase II studies, the starting dose of 10 mg/m2 on days 1 & 8 has been chosen as the starting dose. At least 3 patients are to be treated at each dose level, and 3 more at the same dose level if 1 of the first three exhibited dose-limiting toxicity (DLT) during the first 2 cycles. Results: Six patients (3 male, 3 female, aged 47 to 67) have been included so far and are analyzable for toxicity on the first two cycles. Diagnoses were: PTCL, not otherwise specified (n=3), angioimmunoblastic TCL (n=1), primary cutaneous CD4+ small-medium TCL (n=1), enteropathy-associated TCL (n=1). ECOG performance status was good (0–1) in all patients; 5/6 had stage IV disease; IPI score was 1 (n=1), 2 (n=3), 3 (n=1), 4 (n=1). Among the first 3 patients treated at the starting dose of 10 mg/m2, one exhibited a DLT (grade 3 malaise after cycle 2), thus 3 more patients were treated at this dose level. Among those 3, we observed 2 other DLTs: one grade 3 general status deterioration and grade 3 haematological toxicity lasting more than 7 days in the same patient, and one grade 4 hematological toxicity lasting more than 3 days. A total of 269 adverse events (AEs) were observed during 34 analyzable cycles. The most frequent AEs were: neutropenia n=22 (grade 3–4 =12), thrombocytopenia n=28 (grade 3–4 n=5), digestive complaints n=18 (no grade >2), and asymptomatic increase of liver enzymes n=7 (1 grade 3). The mean increase in the corrected QT interval between pre- and post-romidepsin EKGs was 19 ms (range −43 to +79). No clinically relevant cardiac event was reported. One patient progressed after 5 cycles, 2 have finished the 8 planned cycles and are both in CR, and 3 are still under treatment without evidence of progression. Conclusion: Romidepsin can be combined with CHOP without unexpected toxicity. The dose of 10 mg/m2 on days 1& 8 is associated with excessive hematological toxicity. The study is ongoing with a lower dose of 8 mg/m2 on day 1 & 8 of each cycle. Updated results will be presented at the meeting. Disclosures: Coiffier: CELGENE: Consultancy, Research Funding, Speakers Bureau; ALLOS THERAPEUTICS: Consultancy, Research Funding, Speakers Bureau; ESAI: Consultancy, Research Funding, Speakers Bureau.

Phase I study of NK105, a paclitaxel-incorporating micellar nanoparticle, in patients with advanced cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2018-2018 ◽  
Author(s):  
K. Kato ◽  
T. Hamaguchi ◽  
H. Yasui ◽  
T. Okusaka ◽  
H. Ueno ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Phase I ◽  
Phase Ii ◽  
Phase I Study ◽  
Polymeric Micelle ◽  
Preclinical Study ◽  
Hematological Toxicity ◽  
Phase Ii Studies ◽  
Grade 3

2018 Background: NK105 is a new polymeric micelle carrier system for paclitaxel (PTX). A preclinical study revealed that the plasma AUC and tumor AUC of NK105 were 90-fold higher and 25-fold higher, respectively, than those of free-PTX, i.e., the conventional PTX formulation. NK105 had higher in vivo antitumor activity and lower neurotoxicity than free-PTX. This phase I study was designed to examine the MTD, DLTs, recommended dose (RD) for phase II, and the pharmacokinetics of NK105. Methods: NK105 was administered as a 1-hour intravenous infusion every 3 weeks, without antiallergic premedication. The starting dose was 10 mg PTX equivalent/m2, and the dose was escalated according to the accelerated titration method. Results: To date, 17 patients (pts) have received the following doses: 10 mg/m2 (n=1); 20 mg/m2 (n=1); 40 mg/m2 (n=1); 80 mg/m2 (n=1); 110 mg/m2 (n=3); 150 mg/m2 (n=5); and 180 mg/m2 (n=5). The tumor types treated included pancreatic (n=9), bile duct (n=5), gastric (n=2), and colonic (n=1) cancers. Neutropenia was the most common hematological toxicity. Grade 3 fever developed in 1 pt given 180 mg/m2. No other grade 3 or 4 non-hematological toxicity, including neuropathy, was observed. DLTs occurred in pts given 180 mg/m2 (grade 4 neutropenia lasting for more than 5 days). This dose was designated as the MTD. Allergic reactions developed in only one pt at 180 mg/m2, who was sensitive to other drugs such as antibiotics anti-inflammatory. A partial response was observed in one pt with pancreatic cancer and pts with colonic and gastric cancer had stable disease. The Cmax and AUC of NK105 were dose dependent. The plasma AUC of NK105 at 180 mg/m2 was approximately 30-fold higher than that of the conventional formulation of PTX. Conclusions: Accrual is ongoing at the 150 mg/m2 dose level to determine the RD. DLT was Grade 4 neutropenia. NK105 produces prolonged high levels of PTX in plasma. A 1-hour infusion of NK105 every 3 weeks was feasible, well tolerated, and effective in patients with pancreatic cancer. Even after the long term usage, only grade 1 or 2 neuropathy was observed. NK105 will be evaluated in Phase II studies of patients with advanced pancreatic and gastric cancers. No significant financial relationships to disclose.

Sign in / Sign up

Export Citation Format

Share Document