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 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]

S-1 in combination with docetaxel and oxaliplatin (DOS) every 2 weeks (DOS2w) or every 3 weeks (DOS3w) in patients with advanced gastro-esophageal adenocarcinoma (aGEA): Final results of 2 parallel phase I studies.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 153-153
Author(s):  
Camilla Qvortrup ◽  
Jon Kroll Bjerregaard ◽  
Per Pfeiffer
Keyword(s):  
Clinical Trial ◽  
Febrile Neutropenia ◽  
Phase I ◽  
Dose Level ◽  
Dose Finding ◽  
Fixed Dose ◽  
Hematological Toxicity ◽  
Finding Study ◽  
Grade 3 ◽  
Dose Levels

153 Background: S-1 in combination with cisplatin is one of several accepted doublets, but triplet combinations with docetaxel (D) increase efficacy and substitution with oxaliplatin (O) and oral fluoropyrimidines (S-1) ease the administration. Based on our recent phase I study, we wanted to establish a recommended dose (RD) for an every 3 week regimen (DOS3w) but inspired by promising data from the GATE study, we also sought for an every second week regimen (DOS2w). Therefore we designed this dose-finding study which present the first experience with the combination of D+O+S-1 (DOS) in Caucasian patients (Clinical trial ID: 2011-003471-11). Methods: All pts had chemo-naïve aGEA. We used a standard 3+3 phase I design. DOS2w (dose levels 1A-4A) was given with escalating doses of D (30 to 50 mg/m2 day 1) and S-1 (2x30 to 2x35 mg/m2/day - days 1-7) with a fixed dose of O (70 mg/m2day 1) every 2 weeks for a maximum of 9 cycles. DOS3w (dose levels 1B-3B) was given with escalating doses of D (40 to 60 mg/m2 day 1) and fixed doses of O (100 mg/m2 day 1) and S-1 (2x25 mg/m2/day - days 1-14 every 3 weeks) for a maximum of 6 cycles. After the planned number of DOS, S-1 maintenance therapy (2x30 mg/m2days 1-14 every 3 weeks) was administered until PD or toxicity. Toxicity was evaluated according to NCIC-CTC 4.0. Dose-limiting toxicity (DLT) was evaluated after the first course of DOS and defined as non-hematological toxicity grade ≥ 3 or febrile neutropenia. RD was defined as the highest level at which less than 2/6 of pts experienced a DLT. Once RD was established, this level was expanded to at least 6 pts. Results: From Oct. 2013 to Mar. 2015, 18 and 16 patients received DOS2w and DOS3w, respectively. Median age was 63 years (49-78). DLTs in both cohorts were febrile neutropenia. Response rates were 56% and 57% and OS were 13.8 and 11.6 months, respectively. Conclusions: We recommend DOS2w at dose level 3A (D 40 mg/m2 day 1; O 70 mg/m2 day 1 and S-1 2x35 mg/m2/day orally days 1-7 every 2 weeks) and DOS3w at dose level 2B (D 50 mg/m2 day 1; O 100 mg/m2 day 1 and S-1 2x25 mg/m2/day orally days 1-14 every 3 weeks). Both regimens are well-tolerated in an out-patient setting. Clinical trial information: 2011-003471-11.

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.

scholarly journals Phase I Trial of Rituximab, Cladribine and Temsirolimus (RCT) for Initial Therapy of Mantle Cell Lymphoma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3661-3661 ◽  
Author(s):  
David J. Inwards ◽  
Paul Fishkin ◽  
Betsy R. LaPlant ◽  
Matthew T. Drake ◽  
Paul Kurtin ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
Mantle Cell Lymphoma ◽  
Dose Level ◽  
Cell Lymphoma ◽  
Maximum Tolerated Dose ◽  
Hematologic Toxicity ◽  
Mantle Cell ◽  
Grade 3 ◽  
Dose Levels

Abstract Abstract 3661 Objective: We conducted this trial to determine the maximum tolerated dose (MTD) and schedule of temsirolimus added to an established regimen comprised of rituximab and cladribine for the initial treatment of mantle cell lymphoma and to generate preliminary information on the toxicity and efficacy of this combination. Methods: A standard phase I cohort of 3 study design was utilized. MTD was defined as the dose level below the lowest dose that induces dose-limiting toxicity (DLT) in at least one-third of patients (at least 2 of a maximum of 6 new patients). DLT was defined as grade 4 ANC (<500) for ≥5 days, grade 4 ANC (<500) associated with fever (>100.5 F) and/or active infection, PLT <25,000, grade 4 infection, or ≥grade 3 non-hematologic toxicity during the first cycle of therapy as per NCI Common Terminology Criteria for Adverse Events v3.0. The fixed doses of rituximab and cladribine were 375 mg/m2 IV day 1 and 5 mg/m2/d IV days 1–5 of a 28 day cycle, respectively, as previously published. There were 5 planned temsirolimus IV dose levels: 15 mg day 1; 25 mg day 1; 25 mg days 1 and 15; 25 mg days 1,8 and 15; and 25 mg days 1,8,15, and 22. The fifth dose level is as previously published in combination with rituximab. Results: A total of 17 patients were treated: 3 each at dose levels 1–4 and 5 at dose level 5 (25 mg temsirolimus days 1,8,15, and 22). The median age was 75 years (52–86). There were 11 males and 6 females. At presentation 88% had stage IV disease, and 94% had extranodal disease. MIPI scores were low in 6% (1 patient), intermediate in 59% (10 patients), and high in 35% (6 patients). There was a single DLT recorded at dose level 3 based on the initial DLT criteria, though this cytokine release syndrome was clearly rituximab related, and occurred prior to the first dose of temsirolimus. Five patients were treated at the highest planned temsirolimus dose level (25 mg days 1,8,15, and 22) with no DLT observed. No further dose escalation was planned, and this level was determined to be tolerated, though higher levels may be tolerable. All patients were evaluable for adverse events. Hematologic toxicity was frequent, with grade 3 anemia in 12% of patients, grade 3 thrombocytopenia in 35%, grade 4 thrombocytopenia in 30%, grade 4 lymphopenia in 47%, grade 3 neutropenia in 24%, and grade 4 neutropenia in 18% of patients. There were 3 thrombotic episodes, 2 of which were attributed to therapy, and 3 episodes of pneumonitis. The overall response rate was 94% with 53% CR and 41% PR. The median progression free survival was 18.7 months. Conclusions: Temsirolimus 25 mg IV weekly may be safely added to rituximab and cladribine at 375 mg/m2 IV day 1 and 5 mg/m2/d IV days 1–5 of a 28 day cycle, respectively. This regimen had promising preliminary activity in an elderly cohort of patients with mantle cell lymphoma. Disclosures: Off Label Use: Temsirolimus for mantle cell lymphoma.

Phase I study of sirolimus plus gemcitabine in patients with advanced solid tumors: A Spanish Group for Research on Sarcomas (GEIS) study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3096-3096
Author(s):  
Juan Martin Liberal ◽  
Marta Gil ◽  
Laura Jimenez ◽  
Maria Ochoa de Olza ◽  
Carmen Munoz ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Phase I Study ◽  
Mtor Pathway ◽  
Advanced Solid Tumors ◽  
Level 3 ◽  
Skin Biopsies ◽  
Grade 3 ◽  
Dose Levels

3096 Background: In preclinical studies, combination of sirolimus with gemcitabine enhances apoptosis in vitro and increases anti-tumor efficacy in vivo. Methods: Patients with advanced solid tumors, age 18-70 years, no prior mTOR inhibitor or gemcitabine, ECOG PS 0-1, and adequate hematological, renal and hepatic function, were enrolled in this phase I study to assess safety, tolerability, pharmacokinetics (PK), and to identify the dose limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended dose (RD) of the combination of sirolimus and gemcitabine. A 3+3 dose escalation design with cohorts of 3-6 patients was used. Sirolimus was given po continuously. Gemcitabine was given iv 10mg/m2/minute on days 1 and 8 every 3 weeks. Dose levels 1, 2 and 3 corresponded to sirolimus 2, 2 and 5mg/24h plus gemcitabine 800, 1000 and 1000mg/m2 respectively. After observing DLTs at higher dose level and poorer mTOR signaling inhibition at lower doses, a new cohort of sirolimus 5mg/24h plus gemcitabine 800 mg/m2 was added. Skin biopsies pre and post treatment were performed to assess the inhibition of mTOR pathway. Results: 19 patients were enrolled: median age 51 years (36-70); gender 12M, 7F. Median number of cycles was 4. Patients were treated at 4 dose levels, the MTD was reached at level 3 and the RD was: sirolimus 5mg/24h and gemcitabine 800mg/m2. 3 DLTs were observed, 1 at dose level 2 and 2 at dose level 3: transaminitis grade 3, thrombocytopenia grade 3 and thrombocytopenia grade 4. Other toxicities grade 1-2 included anemia, neutropenia, asthenia, mucositis and high cholesterol levels. 2 patients achieved partial response (1 uterine cervix cancer and 1 colon cancer). Immunohistochemistry of pS6 in skin biopsies showed significative inhibition of mTOR pathway at RD. PK parameters estimated were in agreement with those previously reported in the literature. No influence of sirolimus administration on gemcitabine clearance was found. Conclusions: Combination of sirolimus and gemcitabine is feasible and safe, allowing administration of active doses of both agents and achieving mTOR signaling inhibition. A phase II study to assess the activity of this combination in sarcomas is ongoing.

A phase I dose escalation study of sunitinib in combination with gemcitabine + cisplatin for advanced non-small cell lung cancer (NSCLC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 18057-18057 ◽  
Author(s):  
M. Reck ◽  
N. Frickhofen ◽  
U. Gatzemeier ◽  
H. Fuhr ◽  
S. Lanzalone ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Kinase Inhibitor ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Dose Escalation Study ◽  
Finding Study ◽  
Grade 3 ◽  
Multitargeted Tyrosine Kinase Inhibitor

18057 Background: Sunitinib malate (SU) is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET, and FLT3, approved internationally for the treatment of advanced RCC and imatinib-resistant or -intolerant GIST. SU has also shown single- agent activity in NSCLC. In this study we assess the safety, tolerability, and pharmacokinetics (PK) of SU in combination with gemcitabine (G) and cisplatin (C). Methods: This is a phase I, dose-finding study in pts with untreated, stage IIIB/IV NSCLC not amenable to curative treatment. Planned dose levels include: oral SU (37.5 or 50 mg/day for 2 wks followed by 1 wk off treatment [2/1 schedule]) plus G (1000 or 1250 mg/m2 iv on days 1 and 8 of a 21-day cycle) and C (80 mg/m2 iv on day 1 of each cycle). SU doses are escalated in serial pt cohorts to determine the maximum tolerated dose (MTD) for both schedules. SU continuous dosing (CD) schedule will also be tested. PK and antitumor efficacy are also assessed. Results: As of Oct 2006, 13 pts were treated on the 2/1 schedule: 6 pts with SU 37.5 mg + G 1000 mg/m2 + C 80 mg/m2, and 7 pts with SU 50 mg + G 1000 mg/m2 + C 80 mg/m2. No dose-limiting toxicities (DLTs) were observed with SU 37.5 mg, while 2 pts experienced neutropenia and infection as DLTs with SU 50 mg. Grade 3/4 hematological AEs included neutropenia (n=3 at dose level 1 and n=5 at dose level 2), thrombocytopenia (n=1 and 5) and anemia (n=2 and 0). 3 pts achieved a partial tumor response at the SU 50 mg/day dose level. There were no apparent drug-drug interactions between SU in combination with G and C based on their systemic exposures in this study. Conclusions: The combination of SU (37.5 mg) on schedule 2/1 with G (1000 mg/m2) and C (80 mg/m2) in advanced NSCLC appears safe and tolerable in this pt population. Testing with G escalated to 1250 mg/m2 or with SU administered on a CD schedule is ongoing. No significant financial relationships to disclose.

Phase I trial of temsirolimus (TEM), irinotecan (IRN), and temozolomide (TMZ) in children with refractory solid tumors:  A Children's Oncology Group study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 9540-9540
Author(s):  
Rochelle Bagatell ◽  
Robin Elizabeth Norris ◽  
Ashish M Ingle ◽  
Charlotte H Ahern ◽  
Jennifer Saggio ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Phase I Trial ◽  
Mtor Inhibitor ◽  
Systemic Steroid ◽  
Level 3 ◽  
Grade 3 ◽  
Elevated Transaminases ◽  
Dose Levels

9540 Background: Inhibitors of mTOR have demonstrated activity in preclinical pediatric solid tumor models. A phase I trial to define the dose limiting toxicities (DLTs) associated with the mTOR inhibitor TEM in combination with IRN and TMZ was conducted in patients (pts) with refractory solid tumors. Methods: Escalating doses of TEM were administered intravenously on days (d) 1 and 8 of a 21-d cycle for a maximum of 1 year (y). IRN (50 mg/m2/dose) was administered orally on d1-5. TMZ (100 mg/m2/dose) was administered orally on d1-5. When the maximum planned dose of TEM was reached (35 mg/m2/dose), IRN was escalated stepwise from 50 to 90 mg/m2/dose. Pts were enrolled on 6 dose levels using the rolling-six design. Results: 46 eligible pts (30 male, median age 11y, range 1 – 21) were enrolled; 37 were fully evaluable for toxicity [neuroblastoma (9), osteosarcoma (4), Ewing sarcoma (3), rhabdomyosarcoma (3), CNS (10) or other (8) tumors]. 173 cycles, median 2 (range 1 – 17) have been delivered. Dose-limiting hyperlipidemia was observed during cycle 1 in 2 pts at dose level 3 (TEM 25 mg/m2, IRN 50 mg/m2, TMZ 100 mg/m2); both pts were on chronic corticosteroids. The protocol was amended to preclude chronic systemic steroid use and modify hyperlipidemia management. Dose-limiting hyperlipidemia was not observed in subsequent pts. Cycle 1 DLT (elevated GGT) was observed in 1 pt treated with TEM 35 mg/m2, IRN 65 mg/m2, TMZ 100 mg/m2. DLT has not been observed in 4 of the first 6 pts treated at the highest planned dose level (TEM 35 mg/m2, IRN 90 mg/m2, TMZ 100 mg/m2). Additional ≥Grade 3 regimen-related toxicities occurring in >1 evaluable pt include neutropenia (12), lymphopenia (10), leukopenia (6), thrombocytopenia (4), anemia (2), nausea or vomiting (5), hypokalemia (4), hypophosphatemia (2), diarrhea (2), elevated transaminases (2), and infection (2). 1 pt had a Grade 3 allergic reaction to TEM. 1 pt had a confirmed partial response and 4 have remained on protocol therapy for ≥1 year. Conclusions: The combination of TEM (35 mg/m2/dose) d 1 and 8, IRN (90 mg/m2/dose) d 1-5, and TMZ (100 mg/m2/dose) d 1-5 of a 21-d cycle appears to be well tolerated in children with refractory solid tumors.

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]

Phase I-II Trial of Oral Cyclophosphamide, Prednisone and Lenalidomide (Revlimid®) (CPR) for the Treatment of Patients with Relapsed and Refractory Multiple Myeloma.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1723-1723
Author(s):  
Donna E. Reece ◽  
Esther Masih-Khan ◽  
Arooj Khan ◽  
Peter Anglin ◽  
Christine Chen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Level ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Oral Cyclophosphamide ◽  
Varicella Zoster ◽  
Refractory Multiple Myeloma ◽  
Grade 3 ◽  
Dose Levels

Abstract Oral cyclophosphamide and prednisone is a convenient regimen in relapsed and refractory multiple myeloma (MM), with a partial response (PR) rate of 40% and median progression-free survival of 19 months in our retrospective analysis of patients in first or second relapse after autologous stem cell transplantation (ASCT) (Trieu Y, et al, Mayo Clin Proc2005; 80: 1582). We sought to enhance the efficacy of this regimen by adding oral lenalidomide (Revlimid®), a potent anti-myeloma agent, in a phase I-II trial. The CPR regimen consisted of cyclophosphamide on days 1, 8 and 15, lenalidomide on days 1–21, and prednisone 100 mg every other day in a 28-day cycle. ASA 81 mg/day was given to all patients (pts) as prophylaxis for DVT. Three dose levels were evaluated using a 3 by 3 dose escalation design. Between 11/2007–07/2008, 15 pts with relapsed/refractory MM were entered onto study. Median age was 60 (45–78) years and 60% were male. Immunoglobulin subtype was IgGκ:λ in 10:1; IgA κ:λ in 2:1 and κ light chain in 1. Median number of prior regimens was 2 (1–3) and 14 had undergone previous ASCT, including double transplants in 2 pts. Prior therapy also included thalidomide in 3 (20%) and bortezomib in 6 (40%). FISH cytogenetics were available in 9, but none had 13q deletion, t(4;14) or p53 deletion. At the time of protocol entry, median β2-microglobulin level was 222 (92–325) nm/L, albumin 38 (35–46) g/L, creatinine 78 (50–100) μmol/L, platelet count 230 (93–318) x 109/L and ANC 2.5 (1.9–9.0) x 109/L. Protocol treatment is summarized in Table 1. Dose level N Cyclophosphamide dose (mg/m2) Lenalidomide dose (mg) Prednisone dose (mg) Median # cycles given 1 3 150 15 100 9 2 3 150 25 100 6 3 6 300 25 100 4 3 (expanded) 3 300 25 100 1 Dose limiting toxicity was not observed during cycle 1 at any of the dose levels and the maximum tolerated dose of this regimen has not yet been reached at the highest dose level planned; all pts remain on active therapy. Grade 3/4 thrombocytopenia was seen in 1 pt (cohort 2) and neutropenia in 4 pts (1 in cohort 1, 1 in cohort 2 and 2 in cohort 3) and were managed with dose reduction and/or growth factor support. No episodes of febrile neutropenia occurred in any pt. Only 1 pt experienced varicella zoster; routine antiviral prophylaxis was not used. Other grade 3/4 non-hematologic toxicities were uncommon and included abdominal pain/bacteremia in 1 pt in cohort 1, hypokalemia in 1 pt in cohort 2, and DVT in 1 pt in cohort 3. Mild grade 1/2 constipation (47%), muscle cramps (33%) and fatigue (33%) were also noted. To date, best response includes the following: dose level 1 (1 near complete remission [nCR], 2 PR); dose level 2 (3 PR); dose level 3 (4 PR, 2 minimal response [MR]); expanded cohort 3 (1 MR, 2 too early). We conclude: 1) the combination of full doses of the agents in CPR can be given in a 28-day cycle with minimal toxicity; 2) the overall response rate (nCR + PR + MR) in 13 evaluable pts to date is 87%; 3) no pts have progressed in this preliminary analysis; 4) longer follow-up is required to assess the long-term efficacy of this regimen.

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.

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