2090 Background: GEM and DOC have demonstrated single-agent antitumor activity against a variety of malignancies. Pharmacological studies of GEM have demonstrated that the intracellular concentration of its active triphosphate metabolite is maximized at a dose rate of approximately 10 mg/m2/minute. The major purposes of this study were to determine the maximally tolerated dose (MTD), dose-limiting toxicity (DLT), and toxicity profile for GEM and DOC when administered to patients with advanced solid tumors on a weekly schedule. Methods: Both GEM and DOC were administered on days 1 and 8 of each 21-day course, with GEM administered at a rate of 10 mg/m2/minute and DOC over 60 minutes (after GEM). The initial dose levels were 600 mg/m2 and 25 mg/m2 for GEM and DOC, respectively. Results: Eight patients (5 men, 3 women, median age 60 years old) with advanced solid tumors have been treated with 25+ courses at 2 dose levels. Three patients were treated at dose-level 1 without DLT. Five patients have now been treated at dose level 2 (GEM 800 mg/m2 and DOC 25 mg/m2), with 1 too early to evaluate. One patient developed DLT (grade IV neutropenia with fever) and 2 patients experienced grade III thrombocytopenia. No grade III-IV non-hematologic side effects have been observed. No major responses have been observed as of yet, but 3 patients had dissease stabilization for at least 4 courses of treatment. Conclusions: The MTD of GEM and DOC on the current weekly schedule has not been established as of yet. Patient accrual is on-going at dose-level 2. Six patients will be treated at this level before dose-escalation if no further DLT is observed. Updated results will be presented at the meeting. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly
Data from an in vitro human tumor-cloning assay suggested synergistic cytotoxicity when etoposide (VP16) and granulocyte-macrophage colony-stimulating factor (GM-CSF) were combined. To explore this potential, we undertook a prospectively randomized three-arm trial in a phase I setting with various schedules of VP16 and GM-CSF. Thirty-one patients were enrolled in the three-arm trial. Arm A consisted of oral VP16 daily for up to 21 days with cycles repeated every 35 days. Arm B included oral VP16 daily for up to 21 days plus concomitant GM-CSF at 5 micrograms/kg/day s.c. days 1-10. Arm C included oral VP16 daily for up to 21 days plus pretreatment with GM-CSF at the same dose for 5 days (days -6 to -2). VP16 was begun at 25 mg/m2/day on level 1 and increased to 50 mg/m2/day on level 2. Twenty-seven patients were evaluable for toxicity, nine on each arm (six patients on each arm on level 1, three patients on each arm on level 2). Neutropenia on arm B (concomitant VP16 and GM-CSF) was earlier and more profound than on arm A or C. The median absolute neutrophil count and day of nadir for arms A, B, and C were 3295, 988, and 1600/mm3 and days 23, 15, and 26, respectively. Thrombocytopenia was generally uncommon except on arm C level 2, where the median platelet count was 26,000/mm3. One partial response (arm B) in a patient with non-small cell lung cancer was seen. Dose intensity favored arm A. Neither concomitant therapy with VP16 and GM-CSF (arm B) nor pretreatment with GM-CSF (arm C) improved dose intensity over VP16 alone (arm A), and arms B and C were complicated by increased neutropenia and thrombocytopenia.
PURPOSE: To determine the principal toxicities, characterize the pharmacokinetics (PKs) and pharmacodynamics (PDs) of temozolomide (TMZ) on a daily-for-5-days schedule, and recommend a dose for subsequent disease-directed studies in both minimally pretreated (MP) and heavily pretreated (HP) patients. PATIENTS AND METHODS: Patients received TMZ as a single oral dose daily for 5 consecutive days every 28 days. TMZ doses were escalated from 100 to 150, and 150 to 200 mg/m 2 /d in separate cohorts of MP and HP patients. PK plasma was sampled on days 1 and 5. TMZ concentrations were analyzed and pertinent PK parameters were related to the principal toxicities of TMZ in PD analyses. RESULTS: Twenty-four patients were treated with 85 courses of TMZ. Thrombocytopenia and neutropenia were the principal dose-limiting toxicities (DLTs) of TMZ on this schedule. The cumulative rate of severe myelosuppressive effects was unacceptably high at TMZ doses exceeding 150 mg/m 2 /d in both MP and HP patients. TMZ was absorbed rapidly with maximum concentrations achieved in 0.90 hours, on average, and elimination was rapid, with a half-life and systemic clearance rate (Cl S/F ) averaging 1.8 hours and 115 mL/min/m 2 , respectively. When clearance was normalized to body-surface area (BSA), interpatient variability in Cl S/F was reduced from 20% to 13% on day 1 and from 16% to 10% on day 5. Patients who experienced DLT had significantly higher maximum drug concentration (median 16 v 9.5 μg/mL, P = .0084) and area under the concentration-time curve (median 36 v 23 μg-h/mL, P = .0019) values on day 5. CONCLUSION: Prior myelosuppressive therapy was not a determinant of toxicity. TMZ 150 mg/m 2 /d administered as a single oral dose daily for 5 days every 4 weeks is well tolerated by MP and HP patients, with higher doses resulting in unacceptably high rates of severe hematologic toxicity. TMZ doses should be individualized according to BSA rather than use of a prespecified oral dose for all individuals. TMZ is an optimal agent to develop in combination with other cytotoxic, biologic, and targeted therapeutics for patients with relevant malignancies.
3583 Background: Lapatinib is an orally active, reversible inhibitor of the tyrosine kinase activity of ErbB1 (EGFR) and ErbB2 (HER-2/neu). This multicenter, open-label, phase II study was designed to evaluate the safety and efficacy of single-agent lapatinib in patients with metastatic colorectal carcinoma, whose tumors progressed on first-line therapy with 5-fluorouracil in combination with irinotecan or oxaliplatin. Methods: Eighty-six (86) patients received 1250mg of oral lapatinib daily until disease progression or unacceptable toxicity. Safety and efficacy assessments were performed at 4-week and 8-week intervals respectively. Tumor response was determined by an independent review committee using RECIST guidelines. Results: The median age was 60 years (22–83) and median KPS was 90 (70–100). Patients were not selected based on ErbB expression; however, 54.2% and 44.1% of the patients had positive expression (+1, +2, +3) for ErbB1 and ErbB2, respectively. The most commonly encountered adverse events were: diarrhea (45% grade 1, 2, 5% grade 3), rash (33% grade 1, 2, 2% grade 3), fatigue (27% grade 1, 2, 2% grade 3), nausea (20% grade 1, 2, 1% grade 3), anorexia (16% grade 1, 2, 2% grade 3), and vomiting (14% grade 1, 2). In addition, 3 (3%) patients experienced a drug-related Grade 2 (≥20%) decrease in LVEF. All decreases in LVEF were asymptomatic and resolved within three weeks after discontinuation of lapatinib. One (1%) patient experienced a confirmed partial response; however, five patients experienced a minor response with cytoreduction of 20%, 22.4%, 22.8%, 26.8%, and 34% at week 8. Overall, five patients experienced clinical benefit with stable disease for ≥20 weeks. The median TTP and overall survival were 8 and 42.9 weeks respectively. Conclusions: Lapatinib was well tolerated, but demonstrated limited activity as second-line monotherapy in patients with recurrent metastatic colorectal cancer. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline
7143 Background: There is no defined role for MT beyond 4 cycles of combination chemotherapy for advanced NSCLC. Our previously reported randomized, Phase III trial (Belani et al, Proc Am Soc Clin Oncol, 23:619, 2004) evaluated weekly paclitaxel as MT for patients with CR, PR or SD after 4 cycles of chemotherapy. We now present results of the MT phase of that study. Methods: Patients were randomized to Arm 1 (carboplatin AUC=6 mg/ml.min every 4 weeks with paclitaxel 100 mg/m2 weekly for 3 out of 4 weeks) or Arm 2 (carboplatin AUC= 6 mg/ml.min and paclitaxel 225 mg/m2, both administered every 3 weeks). Following 4 cycles of therapy, patients with CR, PR or SD were eligible to receive MT with paclitaxel at 70 mg/m2 weekly for 3 of 4 weeks until progression. Results: Of the 444 patients enrolled, 183 were eligible for MT; 141 (77%) entered the MT phase. Sixty two percent of patients were male and median age was 63 years (35–83). For patients who participated in MT, the median number of paclitaxel doses was10 (1–51) for Arm 1 and 9 (1–80) for Arm 2. Median TTP was 33 weeks and 29 weeks respectively for Arms 1 and 2 for those patients receiving MT (n=141), compared to 12 weeks (Arm 1) and 11 weeks (Arm 2) for patients not eligible for MT (n=261) or who chose not to receive MT (n=42) combined (no MT). Median survival was 76 weeks (MT) versus 29 weeks (no MT). One- and 2-year survival rates were 69% and 33% (MT) versus 25% and 9% (no MT), respectively. Among those patients eligible for MT, median survival was significantly greater (p=0.016) for those who received MT (76 weeks) than for those who refused MT (50 weeks). The incidence of gr3/4neutropenia was 1.4% without any febrile neutropenia and gr3/4 neuropathy was 3.5%. Conclusions: Maintenance weekly paclitaxel for patients who achieve CR/PR/SD with initial therapy is associated with improved survival and minimal toxicity. MT therapy with weekly paclitaxel may be considered a potential therapeutic option for advanced NSCLC. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb
7149 Background: Elderly NSCLC patients are at increased risk for myelosuppression with standard chemotherapy. Weekly paclitaxel regimens are associated with a more favorable toxicity profile. We present the analysis of the elderly subgroup (≥70 years) treated with either the weekly or standard regimen of paclitaxel administered in combination with carboplatin from our randomized, Phase III trial (Belani et al, Proc Am Soc Clin Oncol, 23:619, 2004). Methods: Patients with stage IIIB/IV NSCLC (previously untreated) were randomized to one of two treatment arms: Weekly - carboplatin AUC=6 mg/ml.min every 4 weeks, in combination with paclitaxel 100 mg/m2 weekly for 3 out of 4 weeks or Standard - carboplatin AUC= 6 mg/ml.min and paclitaxel 225 mg/m2, both administered every 3 weeks. Results: Of the 444 patients enrolled to this trial, 136 (31%) patients were ≥70 years of age. Efficacy and toxicity results of the initial phase of therapy for patients ≥70 years receiving Weekly or Standard therapy are summarized below (intent-to-treat). Conclusion: For the elderly subgroup, the efficacy of the weekly regimen appears to be higher in terms of response rate, TTP and MST with reduction in neuropathy as compared to the standard regimen of paclitaxel and carboplatin administered every 3 weeks. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol- Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb
The major purposes of this study were to determine the maximally tolerated dose (MTD), dose-limiting toxicity (DLT), toxicity profile, and antitumor activity of gemcitabine (GEM) (Gemzar) and 5-fluorouracil (5-FU) combination therapy when administered to patients with advanced solid tumors. GEM was administered intravenously over 30 minutes on days 1, 8, and 15, and 5-FU was administered as a continuous intravenous infusion from day 1 through day 15 of each 28-day treatment course. Seventeen patients (13 men and 4 women, median age 57, all previously treated with chemotherapy) were treated with 68 courses at 3 dose levels: 800/200, 1,000/200, and 1,000/300 [GEM (mg/m2/week)/ 5-FU (mg/m2/day)]. Two further patients were not fully evaluable for toxicity; one died from a probable pulmonary embolism, and one refused further treatment after developing grade II mucositis and dermatitis after her day 1 to 7 treatment. At the third dose level, 2 of 4 patients developed grade III mucositis; one also developed grade IV neutropenia with fever and grade III thrombocytopenia. Patient accrual then resumed at the second dose level. At this level, 10 patients were treated, with two developing grade III mucositis. One of these patients also developed grade IV dermatitis. No other patient developed grade III or IV side effects. Prophylactic dexamethasone was initiated after 4 of the first 7 patients (including 1 of the not fully evaluable patients) developed dermatitis—grade IV in 1 patient and grade II in the remaining 3 patients. After the steroids were initiated, 4 of the last 11 patients treated developed dermatitis, but grade 1 in all cases. One patient with metastatic gastric cancer achieved a near-complete response of his gastric mass and adrenal metastasis. Minor responses were achieved in a patient with colon carcinoma and a patient with an ethmoid sinus adenoid cystic carcinoma. The MTD and recommended dose for phase II clinical trials of GEM and 5-FU on the above schedule is 1,000 mg/m2 and 200 mg/m2 respectively, with mucositis as the DLT.
