Preliminary results of a phase I trial of sorafenib combined with cisplatin/etoposide (CE) or carboplatin/pemetrexed (CbP) in solid tumor patients (pts)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e13521-e13521
Author(s):  
N. S. Dhruva ◽  
T. E. Stinchcombe ◽  
C. M. Walko ◽  
M. A. Socinski ◽  
S. Bernard ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Phase I ◽  
Dose Level ◽  
Phase I Trial ◽  
Single Agent ◽  
Median Number ◽  
Maximum Tolerated Dose ◽  
Small Cell ◽  
Hematologic Toxicity ◽  
Level 1

e13521 Background: Sorafenib had demonstrated single agent activity in non-small cell and small cell lung cancer. Methods: A non-comparative, two arm phase I trial escalating sorafenib in combination with fixed doses of CE or CbP was performed. A 3-patient cohort design was utilized to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT). Dose level 0 for all pts was a sorafenib dose of 200 mg po BID continuously. Pts on arm A received C (60 mg/m2) on day 1 and E 120 mg/m2 on days 1,2,3 every 3 weeks with escalating doses of sorafenib. On arm B, pts received treatment with Cb (AUC=6) and P 500 mg/m2 every 3 weeks with escalating doses of sorafenib. However, excessive toxicity was observed on arm B, therefore the trial was amended such that Cb dose was lowered to AUC=5 (arm C). DLT were assessed in the 1st cycle and defined as grade (gr.) 4 anemia or thrombocytopenia, gr. 4 neutropenia lasting > 7 days, gr. ≥ 3 non-hematologic toxicity (except nausea, vomiting, and alopecia) and > 2 week dose delay. Response was assessed every 2 cycles according to RECIST, and best response was recorded. Results: Between 9/2007 and 9/2008, 20 pts were treated on the trial; median age 62 (range 47–73), male/female: 12/8, PS of 0/1: 6/14, and median number of prior therapies 2 (range 1–4). The most common tumor types were NSCLC (n=8), SCLC (n=4) and head/neck (n=2). At dose level 0 arm A (200 mg BID), 2 of 4 patients experienced DLT (gr.4 thrombocytopenia, gr.3 fatigue, febrile neutropenia and gr.4 neutropenia for > 7 days, gr.3 febrile neutropenia, diarrhea, hypokalemia, hyponatremia); 2 pts have been enrolled at dose level -1 (200 mg po QD) without DLT. Two of 3 patients enrolled on arm B at dose level 0 had gr.4 thrombocytopenia. On arm C at dose level 0 (200 mg po BID), 1/6 pts experienced DLT (gr.3 hyponatremia, dehydration, hypoglycemia). Enrollment continued at dose level 1 (400 mg po BID), but 2/5 pts experienced a DLT (both gr. 3 fatigue/anorexia). Responses observed were: PR (n=3) (all arm C), and SD (n=6). Conclusions: The MTD of sorafenib in combination with carboplatin (AUC=5) and pemetrexed 500 mg every 3 weeks is 200 mg po BID. The MTD of sorafenib in combination with cisplatin/etoposide has yet to be determined and is currently accruing at dose level -1. [Table: see text]

Phase I Trial Examining Addition of Gemcitabine to CHOP in Intermediate Grade NHL.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4765-4765
Author(s):  
John L. Reagan ◽  
James N. Butera ◽  
Alan G. Rosmarin ◽  
Ahmed Nadeem ◽  
Fred J. Schiffman ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Phase I ◽  
Phase I Trial ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Chop Chemotherapy ◽  
Intermediate Grade ◽  
Chemotherapeutic Regimen ◽  
Grade 3 ◽  
Dose Limiting Toxicity

Abstract Abstract 4765 BACKGROUND Gemcitabine induces a 20% response as single agent therapy in patients with relapsed or refractory NHL. We report phase I findings of gemcitabine in combination with standard CHOP chemotherapy with G-CSF support for intermediate grade NHL. The protocol was modified during enrollment to include rituximab in CD 20+ lymphomas. METHODS Patients received CHOP plus gemcitabine at 500 mg/m2 (Cohort 1) or 750 mg/m2 (Cohort 2) on days 1,4 of each 21 day cycle. Accrual was suspended once each cohort was filled. Dose escalation occurred after all patients in the cohort were determined to not have a dose limiting toxicity. RESULTS Between 4/02 and 5/04 10 patients were enrolled and completed the study treatment (6 in cohort 1, 4 in cohort 2). In Cohort 1, grade 3 toxicities included neutropenia, anemia, neuropathy, and constipation. Grade 4 toxicities were febrile neutropenia, and thrombocytopenia. In Cohort 2, grade 3 toxicities included neutropenia, thrombocytopenia, mucositis, anemia and intestinal obstruction. Grade 4 toxicities included febrile neutropenia, neutropenia, and thrombocytopenia. One patient developed MDS 36 months after chemotherapy. Three of four patients in Cohort 2 developed dose limiting toxicities (mucositis and thrombocytopenia) requiring dose reduction of gemcitabine after cycle 1. Overall, the survival rate at 2.5 years was 71%. CONCLUSIONS This Phase I trial concludes that gemcitabine 500mg/m2 on days 1 and 4 of each 21 day cycle is the maximum tolerated dose when combined with standard CHOP chemotherapy with G-CSF support for intermediate grade NHL. Response rates are encouraging for this novel chemotherapeutic regimen. Disclosures: Off Label Use: Gemcitabine was added to standard CHOP chemotherapy in this trial.. Sikov:Eli Lilly: Honoraria.

Final Results of a Phase I Study of the Fc Engineered CD19 Antibody XmAb®5574 (MOR00208) in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL).

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2894-2894 ◽  
Author(s):  
Jennifer A. Woyach ◽  
Farrukh Awan ◽  
Ian W. Flinn ◽  
Rolondo Enoch ◽  
Paul A. Foster ◽  
...  
Keyword(s):  
High Risk ◽  
Febrile Neutropenia ◽  
Adverse Events ◽  
Phase I ◽  
B Cell ◽  
Dose Level ◽  
Phase I Trial ◽  
Hematologic Toxicity ◽  
B Cell Malignancies ◽  
Dose Levels

Abstract Abstract 2894 Antibody (Ab) therapies such as the CD20 monoclonal abs rituximab and ofatumumab are commonly used in CLL alone and in combination with chemotherapy, however, CD20 density is low on CLL cells, suggesting this may not be the ideal target. CD19, which is ubiquitously expressed on CLL cells and those of other B cell malignancies is a reasonable candidate for ab targeting. XmAb5574 is a novel humanized IgG1 CD19 monoclonal ab with an engineered Fc region to enhance Fc gamma receptor binding affinity. In vitro, this ab demonstrates direct cytotoxicity and antibody dependent cellular phagocytosis similar to rituximab, however, shows enhanced natural killer antibody dependent cellular cytotoxicity compared to other therapeutic abs used in CLL (Awan, FT Blood 2009). We have performed a first in human trial of this ab as a single agent in relapsed or refractory (R/R) CLL, and present the results in this report. This study is a multi-institutional phase I trial of XmAb5574 in patients (pts) with R/R CLL. Eligible pts were those with CLL who had at least 1 prior therapy and required treatment by International Working Group on CLL (IWCLL) 2008 Guidelines (Hallek, M Blood 2008), had Eastern Cooperative Oncology Group Performance Status <3, had platelets ≥50,000/mm3, and had adequate organ function. Primary endpoints were to determine maximal tolerated dose (MTD), describe toxicity, and characterize pharmacokinetics (PK). A secondary endpoint was to explore efficacy. An accelerated titration design was used in which 1 pt was accrued to the first two dose levels provided there were no dose limiting toxicities (DLT) or ≥ grade 2 adverse events (AE), and then a standard 3×3 design was employed from dose level 3 forward. Dose levels included 0.3, 1, 3, 6, 9, and 12 mg/kg with an expansion to a total of 16 pts at the MTD. XmAb5574 was administered as an intravenous infusion on days 1, 4, 8, 15, and 22 of cycle (C) 1, and on days 1, 8, 15, and 22 of C2. Toxicity was assessed using the National Cancer Institute's Common Criteria for Adverse Events v4.0 for non-hematologic toxicity, and IWCLL 2008 guidelines for hematologic toxicity. Disease response assessment by physical exam was performed on C1D28, C2D28, and 4, 8, and 12 weeks after the end of C2. Radiographic assessment was performed C2D28. 27 pts were enrolled to this phase I trial. The median age of all pts was 66 years (range 40–84). The pts were generally high risk: 14 (52%) had high-risk disease by Rai stage, 8 (30%) had del(11q22.3) and 10 (37%) had del(17p13.1) by FISH, and 24 (89%) had IgVH unmutated disease. The median number of prior therapies was 4 (range 1–14). Toxicity with this agent was modest. Dose escalation continued without dose limiting toxicity (DLT) until the highest dose level, in which one patient experienced grade 4 neutropenia associated with febrile neutropenia which required dose discontinuation. 100% of patients experienced any AE, with the majority of AE being grade 1–2. The most common AEs were infusion reactions in 18 patients (67%), all of which were grade 1 or 2. Treatment-related Grade 3 or 4 AEs occurred in 5 pts (19%), and included neutropenia (n=3), thrombocytopenia (n=2), increased aspartate aminotransferase (AST) (n=1), febrile neutropenia (n=1), and tumor lysis syndrome (n=1). All were on the 12 mg/kg dose level except one pt receiving 1mg/kg who experienced neutropenia. Overall response rate by IWCLL 2008 criteria is 11%, all of which have been partial responses (PR). Using IWCLL 1996 response criteria which does not include CT scan assessment of disease resulted in a PR in 13 pts (42%). Only 2 pts had PD at the 8 week evaluation point. Responses occurred at the 6, 9, and 12 mg/kg dose levels. All objective responses were in pts categorized as CLL as opposed to SLL, and no patients with lymph nodes >5cm responded. PK was best modeled by a two-compartment model. Half-life was 14 days, with clearance 5mL/day/kg that was not dose-dependent. Across the dose range, area under the curve increased in a dose-proportional manner, while maximum concentration increased in a less than proportional manner. A steady-state was reached at or before infusion 9. XmAb5574 shows acceptable toxicity and signs of preliminary efficacy in patients with high-risk, heavily pretreated CLL. These results justify movement into phase II study in CLL as well as other B cell malignancies. Modest toxicity, in particular infectious toxicity, will potentially allow combinations with other active agents in CLL. Disclosures: Enoch: Xencor, Inc.: Employment. Foster:Xencor, Inc: Consultancy.

Final results from a phase I trial of ixabepilone in patients with advanced malignancies and lymphoma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2039-2039
Author(s):  
C. Aghajanian ◽  
O. O’Connor ◽  
M. Cohen ◽  
R. Peck ◽  
H. Burris
Keyword(s):  
Febrile Neutropenia ◽  
Phase I ◽  
Solid Tumors ◽  
Phase I Trial ◽  
Objective Response ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Hematologic Toxicity ◽  
Phase Ii Studies ◽  
Grade 3

2039 Background: Ixabepilone is the first analog in a new class of antineoplastic agents, the epothilones, which stabilizes microtubules and induces apoptosis. Ixabepilone has shown clinical activity in a broad range of tumors. Methods: This Phase I trial was designed to establish the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), efficacy, safety, pharmacokinetics and pharmacodynamics of ixabepilone when administered as a 1-hour infusion every 3 weeks to patients with advanced solid tumors or lymphoma. Eligible patients were aged ≥18 years with histologically/cytologically confirmed non-hematologic cancer, or a pathologic diagnosis of relapsed/primary refractory non-Hodgkin’s lymphoma (NHL) or relapsed/primary refractory mantle cell lymphoma, with ≤CTC Grade 1 neuropathy. Ixabepilone doses ranged from 7.5–65 mg/m2. Response was assessed every 6 weeks using RECIST. DLT was defined as Grade 4 neutropenia and/or febrile neutropenia, thrombocytopenia, ≥Grade 3 nausea/vomiting and non-hematologic toxicity, or treatment delay of >2 weeks due to delayed recovery. Results: Of 61 patients (median age 58, range 18–81), 75% had solid tumors; 25% had lymphoma. 98% and 67% of patients had received one or ≥ two prior chemotherapy regimens, respectively. The MTD of ixabepilone as a 1-hour infusion every 3 weeks was established as 50 mg/m2. The most common DLTs were neutropenia, myalgia, arthralgia and stomatitis/pharyngitis. A total of eight patients (13%) achieved a durable objective response. Complete responses were achieved in two patients with primary peritoneal cancer and NHL. A partial response was seen in six patients. The most common Grade 3/4 treatment-related adverse events (only observed at doses ≥40 mg/m2) were sensory neuropathy (13%), fatigue (13%), myalgia (10%), arthralgia (7%), nausea (5%), febrile neutropenia (5%) and neutropenia (5%). Recovery to baseline or ≤Grade 1 neuropathy occurred in some patients. Conclusions: The recommended dose of ixabepilone for the initiation of Phase II studies based on this study is 50 mg/m2 over 1 hour every 3 weeks. Ixabepilone demonstrates promising safety in patients with solid tumors or lymphoma who have failed standard therapy. Encouraging activity was reported in several tumor types. [Table: see text]

Phase I trial of bevacizumab plus sunitinib in patients (pts) with metastatic renal cell carcinoma (mRCC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5099-5099 ◽  
Author(s):  
D. R. Feldman ◽  
G. V. Kondagunta ◽  
E. A. Ronnen ◽  
P. Fischer ◽  
R. Chang ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase I Trial ◽  
Kinase Inhibitor ◽  
Maximum Tolerated Dose ◽  
Fixed Dose ◽  
Rapid Progression ◽  
Hematologic Toxicity ◽  
Phase Ii Trials ◽  
Dose Levels

5099 Background: Bevacizumab, an intravenous monoclonal antibody against VEGF, and sunitinib, an oral multi-targeted tyrosine kinase inhibitor of VEGF and PDGF receptors, both have activity in mRCC [NEJM 349:427–434; JAMA 295:2516–2524]. Combining bevacizumab and sunitinib may increase antitumor efficacy by maximizing inhibition of the VEGF pathway. The safety and maximum tolerated dose (MTD) of sunitinib in combination with bevacizumab was assessed in this Phase I trial. Methods: Cohorts of 3–6 pts with mRCC received escalating doses of sunitinib (dose levels: 25, 37.5, and 50 mg po) daily for 4 weeks (wks) followed by 2 wks off with fixed- dose bevacizumab (10 mg/kg iv) every 2 wks continuously. Pre-determined dose-limiting toxicities (DLTs) in the first 6-wk cycle included Grade (Gr) 4 neutropenia, ≥Gr 3 thrombocytopenia of ≥7 days, Gr 4 hypertension or proteinuria, and other Gr 3 non-hematologic toxicity of ≥7 days. Pts who came off study prior to completion of cycle 1 for any reason other than a DLT were replaced. Serum VEGF levels were measured before and during cycles 1 and 2. Results: 16 pts (11 male, 5 female, median age 57) were enrolled. Of 8 patients entered at the first dose level (sunitinib 25 mg, bevacizumab 10 mg/kg), 2 were replaced; 1 never received treatment and 1 did not complete cycle 1 due to rapid progression of disease (PD). No DLTs occurred in the remaining 6 evaluable pts in this cohort. At the 2nd dose level (n =6, sunitinib 37.5 mg, bevacizumab 10 mg/kg), 1 pt receiving low molecular weight heparin had a DLT of Gr 4 hemorrhage. 2 pts have enrolled in the 3rd dose level (sunitinib 50 mg, bevacizumab 10 mg/kg) but are not yet evaluable for toxicity or response. Gr 3/4 toxicities over all cycles included Gr 3 hypertension (n=4), Gr 3 proteinuria (n=2), Gr 3 abdominal pain (n=2), Gr 4 hemorrhage (n=1), and Gr 3 hand/foot syndrome (n=1). 13 pts were evaluated for best response–4 had partial responses, 7 had stable disease, and 2 had PD. Serum VEGF levels decreased during cycle 1 in all pts. Conclusions: The combination of sunitinib and bevacizumab in mRCC pts was tolerable at the first 2 dose levels. Once the MTD is identified, further testing of this combination in phase II trials may be indicated for mRCC as well as other malignancies. [Table: see text]

A phase I trial of pomalidomide for children with recurrent, progressive/refractory central nervous system (CNS) tumors: A Pediatric Brain Tumor Consortium (PBTC) study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 10543-10543
Author(s):  
Jason R. Fangusaro ◽  
Duane Anthony Mitchell ◽  
Mehmet Kocak ◽  
Arzu Onar-Thomas ◽  
Zsila Sousan Sadighi ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase I Trial ◽  
Pediatric Brain Tumor ◽  
Median Number ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Cns Tumors ◽  
Dependent Manner ◽  
Steroid Use

10543 Background: CNS malignancies are the most common solid tumors among children. Novel therapies are needed to help improve the survival outcomes in children with recurrent disease. Pomalidomide is an immunomodulatory agent thought to also function through a combination of anti-angiogenic, anti-inflammatory and cytotoixic activity making it a good candidate to explore in pediatric CNS tumors. Methods: A Phase I trial of pomalidomide was conducted among children ≥ 3 to < 21 years old with recurrent, progressive/refractory CNS tumors using the “rolling 6” dose escalation design. The primary objective was to determine the maximum tolerated dose (MTD) and/or recommended Phase II dose (RP2D) when given orally once daily for 21 consecutive days of a 28-day course. Once the MTD was established, 12 additional patients were enrolled on expansion cohorts based on age and steroid use. Results: 29 children were enrolled and 25 were evaluable for dose limiting toxicity (DLT) evaluation. The MTD was 2.6 mg/m2 (Dose level 2). DLTs observed at dose level 3 (3.4 mg/m2) included diarrhea (n = 1), thrombocytopenia (n = 1) and lung infection (n = 1), all grade 3. The most common toxicities were grade 1 lymphopenia (55%), leukopenia (62%) and thrombocytopenia (38%). There were no obvious differences in tolerability based on age or steroid use. Pharmacokinetics were similar to those observed in adults and increased in a dose-dependent manner. At the RP2D of 2.6 mg/m2, the Cmax was 97.4 ng/mL and the t½ was 4.1 hours. The median number of treatment cycles was 1.6 (0.2-12.3). Two patients, one with an oligodendroglioma and one with anaplastic pleomorphic xanthoastrocytoma, had long term stable disease for 9 and 18+ cycles. No objective responses were observed. Twelve month progression-free and overall-survivals were 5.2+/-3.6% and 12.8+/-8.5%, respectively. Immunologic correlate analyses are ongoing. Conclusions: The RP2D of pomalidomide is 2.6 mg/m2 in children with recurrent brain tumors. Further prospective evaluation of this agent alone or in combination will be necessary to better understand its efficacy in specific pediatric CNS tumor populations. Clinical trial information: NCT02415153.

Phase I trial of docetaxel, oxaliplatin and capecitabine (TEX) in patients with metastatic gastric cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 14051-14051 ◽  
Author(s):  
W. Grothe ◽  
R. D. Hofheinz ◽  
L. Mantovani Loeffler ◽  
J. Böhme ◽  
D. Arnold ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Phase I ◽  
Dose Level ◽  
Phase I Trial ◽  
Locally Advanced ◽  
Metastatic Gastric Cancer ◽  
Maximum Tolerated Dose ◽  
Primary Tumor Site ◽  
Level 1 ◽  
Ecog Ps

14051 Background: Combination regimens of 3 active drugs have shown promising activity in treatment of metastatic gastric cancer (GC). Docetaxel (D) combined with cisplatin and 5-FU (CF) yielded superior overall survival and response rates when compared to standard CF. However, toxicity profile showed the need for development of less toxic modifications. In this phase I trial, D was combined with oxaliplatin (Ox) and capecitabine (Cape) in order to define the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) in patients (pts) with metastatic GC. Methods: Pts had to have metastatic or locally advanced GC, adequate organ function, ECOG PS 0–2, no prior chemotherapy. Four dose levels were planned planned for the TEX regimen: D 35–40 mg/m2, Ox 70 mg/m2 d1 and d88, with Cape 800–1000 mg/m2 bid d1–14 q d22. Toxicity was assessed 3-weekly whereas CT scans were repeated 9-weekly. Results: 14 pts were enrolled: 9m/5f, age 64 (42–76) yrs, ECOG PS 1 [0–2]. All pts. had distant metastatis, 10 no gastrectomy. On dose level 1 (D 35 mg/m2, Ox 70 mg/m2, Cape 800 mg/m2) 3 pts were included initially. 1 pt. had grade 4 bleeding from primary tumor site after 2nd administration and therefore was excluded. For safety reasons, 6 more pts. were enrolled - without further DLT. On dose level 2 (D 40 mg/m2, Ox 70 mg/m2, Cape 800 mg/m2), diarrhea and mucositis grade 3 occurred as DLT in 2/2 patients. Level 1 was determined as MTD and 5 more pts were included to a total of 12 with toxicity displayed at the table. Out of 10 pts with measurable disease, 3 had a PR, 4 more had disease stabilization. Median PFS of all pts (5 censored) is 3.9+ (1–9.3+) mos. whereas median OS is not yet reached. Conclusion: TEX can safely be administered without higher graded toxicity in pts with GC. Preliminary efficacy results indicate promising activity that merits further testing in a phase II trial. [Table: see text] [Table: see text]

Phase I trial of the somatostatin analog octreotide acetate in the treatment of fluoropyrimidine-induced diarrhea.

1995 ◽  
Vol 13 (1) ◽  
pp. 222-226 ◽  
Author(s):  
S Wadler ◽  
H Haynes ◽  
P H Wiernik
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase I Trial ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Response To Therapy ◽  
Somatostatin Analog ◽  
Watery Diarrhea ◽  
Gastrointestinal Malignancies ◽  
Octreotide Acetate

PURPOSE Diarrhea is one of the dose-limiting toxicities for administration of fluorouracil (5FU) in patients with gastrointestinal malignancies and can result in severe morbidities or mortality. The somatostatin analog octreotide acetate has been used in the treatment of 5FU-induced diarrhea with promising results. A phase I trial was initiated to determine the maximum-tolerated dose of octreotide acetate that could be administered in this setting. PATIENTS AND METHODS Patients were required to have National Cancer Institute Common Toxicity Criteria > or = grade 2 diarrhea or watery diarrhea secondary to treatment with 5FU or a modulated 5FU regimen. At least three patients were treated at each dose level; after satisfactory completion of this dose level (zero of three or one of six patients with < or = grade 2 toxicity), additional patients were added at the next dose level. Doses of octreotide acetate studied were 50 to 2,500 micrograms subcutaneously three times daily for 5 days. RESULTS A total of 35 patients received 49 courses of therapy. The only significant toxicities occurred at 2,500 micrograms. At this dose level, one patient developed an allergic reaction with flushing, nausea, and dizziness after each of the first two injections. A second patient developed asymptomatic hypoglycemia with a serum glucose level of 26 mg/dL. The maximum-tolerated dose was 2,000 micrograms. The efficacy of the treatment correlated significantly (P = .01) with the dose of octreotide administered, and more patients completed the course of therapy at the higher doses. CONCLUSION Octreotide acetate can be safely administered for the treatment of fluoropyrimidine-induced diarrhea in patients with gastrointestinal malignancies. The dose-limiting toxicities were allergic (nausea, rash, and light-headedness) and endocrine (hypoglycemia). There was a significant correlation between complete response to therapy and octreotide dose.

Phase I and Pharmacokinetic Study of Docetaxel and Irinotecan in Patients With Advanced Solid Tumors

2000 ◽  
Vol 18 (20) ◽  
pp. 3545-3552 ◽  
Author(s):  
Corinne Couteau ◽  
Marie-Laure Risse ◽  
Michel Ducreux ◽  
Florence Lefresne-Soulas ◽  
Alessandro Riva ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Phase I ◽  
Solid Tumors ◽  
Pharmacokinetic Study ◽  
Topoisomerase I ◽  
Maximum Tolerated Dose ◽  
Hematologic Toxicity ◽  
Advanced Solid Tumors ◽  
Phase Ii Studies ◽  
Grade 3

PURPOSE: We conducted a phase I and pharmacokinetic study of docetaxel in combination with irinotecan to determine the dose-limiting toxicity (DLT), the maximum-tolerated dose (MTD), and the dose at which at least 50% of the patients experienced a DLT during the first cycle, and to evaluate the safety and pharmacokinetic profiles in patients with advanced solid tumors. PATIENTS AND METHODS: Patients with only one prior chemotherapy treatment (without taxanes or topoisomerase I inhibitors) for advanced disease were included in the study. Docetaxel was administered as a 1-hour IV infusion after premedication with corticosteroids followed immediately by irinotecan as a 90-minute IV infusion, every 3 weeks. No hematologic growth factors were allowed. RESULTS: Forty patients were entered through the following seven dose levels (docetaxel/irinotecan): 40/140 mg/m2, 50/175 mg/m2, 60/210 mg/m2, 60/250 mg/m2, 60/275 mg/m2, 60/300 mg/m2, and 70/250 mg/m2. Two hundred cycles were administered. Two MTDs were determined, 70/250 mg/m2 and 60/300 mg/m2; the DLTs were febrile neutropenia and diarrhea. Neutropenia was the main hematologic toxicity, with 85% of patients experiencing grade 4 neutropenia. Grade 3/4 nonhematologic toxicities in patients included late diarrhea (7.5%), asthenia (15.0%), febrile neutropenia (22.5%), infection (7.5%), and nausea (5.0%). Pharmacokinetics of both docetaxel and irinotecan were not modified with the administration schedule of this study. CONCLUSION: The recommended dose of docetaxel in combination with irinotecan is 60/275 mg/m2, respectively. At this dose level, the safety profile is manageable. The activity of this combination should be evaluated in phase II studies in different tumor types.

Phase I Trial of Intravenous Thymidine and Carboplatin in Patients With Advanced Cancer

1999 ◽  
Vol 17 (9) ◽  
pp. 2922-2922 ◽  
Author(s):  
H. Ian Robins ◽  
Kendra Tutsch ◽  
Doerthe M. Katschinski ◽  
Elaine Jacobson ◽  
Minesh Mehta ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase I Trial ◽  
Combined Therapy ◽  
High Grade Glioma ◽  
Maximum Tolerated Dose ◽  
Metastatic Colon Cancer ◽  
Minor Response ◽  
The North ◽  
A Minor

PURPOSE: To evaluate the biologic interactions and toxicities of carboplatin combined with a 24-hour infusion of thymidine 75 mg/m2 in a phase I trial. PATIENTS AND METHODS: Thirty-two patients with cancer refractory to conventional therapy were treated. The first set of patients (n = 7) received thymidine alone 4 weeks before subsequent planned courses of thymidine combined with carboplatin followed (4 weeks) by carboplatin alone. Carboplatin was administered over 20 minutes at hour 20 of the 24-hour thymidine infusion. The carboplatin dose was escalated in patient groups: 200 mg/m2 (n = 3); 300 mg/m2 (n = 7); 350 mg/m2 (n = 4); 400 mg/m2 (n = 3); 480 mg/m2 (n = 10); and 576 mg/m2 (n = 5). At the maximum-tolerated dose (480 mg/m2), five patients received combined therapy first and carboplatin alone second, and five patients received carboplatin first and combined therapy second. Maintenance therapy for stable or responding patients was combined therapy. RESULTS: Evaluation demonstrated a trend toward thymidine protection of carboplatin-induced treatment-limiting thrombocytopenia. Neutropenia with carboplatin alone or in combination was negligible. Thymidine alone had no myelosuppressive effects and produced reversible grade 1 or 2 nausea and vomiting (57%), headache (25%), and grade 1 neurotoxicity (22%). Thymidine did not enhance expected carboplatin toxicities. There was no therapy-related infection or bleeding. Analysis of platinum in plasma ultrafiltrate and urine showed no effect by thymidine. Similarly, thymidine pharmacokinetics was not affected by carboplatin. As predicted, nicotinamide adenine dinucleotide levels in peripheral lymphocytes were increased during exposure to carboplatin and/or thymidine but were decreased by carboplatin alone. In three patients with high-grade glioma, responses included one complete remission (21 months) and one partial remission (14 months) at the 480-mg/m2-dose level, and disease stabilization (7 months) at the 400-mg/m2-dose level. A minor response was observed in a patient with metastatic colon cancer (5 months) at the 480-mg/m2-dose level. CONCLUSION: The combination of carboplatin and thymidine as described is well tolerated. The data presented have resulted in a phase II study by the North American Brain Tumor Consortium.

A Phase I–II Trial of Bortezomib (Velcade) (Vc) and Oral Cyclophosphamide (CY) Plus Prednisone (P) for Relapsed/Refractory Multiple Myeloma (MM).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2556-2556 ◽  
Author(s):  
Donna E. Reece ◽  
Giovanni Piza ◽  
Suzanne Trudel ◽  
Christine Chen ◽  
Joseph R. Mikhael ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Hematologic Toxicity ◽  
Combination Regimen ◽  
Free Survival ◽  
Best Response ◽  
Level 3 ◽  
Ongoing Phase

Abstract We have previously reported that a simple, well-tolerated regimen of weekly oral CY (500mg) and alternate day prednisone (50–100mg) produced partial responses (PR) in 40% of 56 patients (pts) in relapse after ASCT; median progression-free survival was 18.6 months (Blood2004; 104[11]: 311b). To build upon these favorable results, we have designed an ongoing phase I–II trial adding Vc to this regimen. CY was given p.o. once weekly on days 1,8,15 and 22 of each 28 day cycle while prednisone was given every other morning. CY was given before Vc on appropriate days. A maximum of 8 cycles was administered. Sixteen pts have been entered so far. Patients characteristics: Median age was 59 (48–74) years; 9 were male. The Ig subtypes were: IgG kappa:lambda = 9:2, IgA kappa:lambda = 1:2; kappa light chain = 2. All had received VAD, i.v. CY (2.5 g/m2) + G-CSF mobilization followed by ASCT and 2 had undergone a second ASCT; other prior regimens included melphalan and prednisone in 5 pts, thalidomide in 10, lenalidomide in 1, α-interferon in 3, vaccine therapy in 1 and oral CY + P in 8. The median pretreament ß2-microglobulin level was 279 (147 – 875) nm/L, albumin 39 (30–42) g/L and creatinine 91 (60–112) umol/L. The dose escalation schedule to date is as follows: Dose Level N P dose CY dose (mg/m2) Vc dose (mg/m2) 1 6 100 150 0.7 d 1,8,15 2 3 100 300 0.7 d 1,8,15 3 3 100 300 1.0 d 1,8,15 4 4 100 300 1.0 d 1,4,8,11 Three further dose escalations to a maximum Vc dose of 1.5 mg/m2 days 1,8, and 15 are allowed if dose limiting toxicity does not occur. Toxicities during cycle 1: All pts have completed cycle 1. Three episodes of grade (gr) 3 sinopulmonary infection occurred during a community outbreak at dose level 1; levofloxacin prophylaxis during the first cycle was added and no further infections during the initial cycle were observed. One pt at dose level 3 experienced transient gr 4 hypophosphatemia which reversed without therapy. At dose level 4, cycle 1 was interrupted in one pt due to gr 4 leukopenia (gr 3 neutropenia and thrombocytopenia) related to disease, while a second pt developed grade 4 elevation in transaminases which recovered quickly when Vc was held on d 8. Pt accrual continues. Toxicities of subsequent cycles: To date, 47 additional cycles have been given. SAE’s consisted of pneumonia during cycle 2 in the same 3 patients with infection during cycle 1 and one of these with progressive disease had another bout during cycle 3. Gr 3 toxicities included anemia in 2 cycles, leucopenia in 2, neutropenia in 4, hypophosphatemia in 1 and hyperglycemia in 2; reversible gr 4 hypophosphatemia recurred in the pt mentioned above in 1 other cycle. No liver or other organ toxicity was observed. Maximum gr of peripheral neuropathy was 1. Responses: Responses were assessed after cycles 2, 4, 6 and 8. Best response included near CR (1), PR (4), MR (4), stable disease (5), progression (1) and too early (1). Two pts have completed all 8 cycles, while 4 have progressed; 10 remain on study. Preliminary Conclusions: 1) Vc can be added to a continuous program of oral CY + P with acceptable hematologic toxicity; 2) no neurotoxicity &gt; gr 1 has been observed; 3) the maximum tolerated dose (MTD) of this combination regimen has not yet been defined; 4) future plans include a randomized National Cancer Institute of Canada trial comparing the the MTD of this combination to Vc in relpased MM pts.

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