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A phase II clinical and pharmacokinetic study of weekly paclitaxel in elderly patients with non-small cell lung cancer
Chemotherapy~Non-small: Phase III
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phase II clinical and pharmacokinetic study of weekly paclitaxel in elderly patients with non-small cell lung cancer P. Fidias, J. Supko, R. Martins, A. Boral, A. Skarin, B. Johnson, R. Carey, M. Grossbard, M. Vasconcelles, G. Shapiro, T.J. Lynch.
Massachusetts General Hospital, Brigham and Women's Hospital, and Dana Farber Cancer Institute, Harvard Medical School, Boston, USA More than 50% of NSCLC occurs in patients older than 65 years of age, many of whom have poor tolerance to aggressive combination chemotherapy. Single agent paclitaxel (P) at a dose of 150 mg/m 2 given as a 3-hr weekly infusion shows a response rate of 39%, but also a 56% incidence of grade 2/3 neuropathy. We initiated a study of weekly P focusing on elderly patients (pts). Eligibility included: age > 70, performance status 0-3, stage Ills or IV, measurable or evaluable disease, adequate hematologic, renal, and hepatic function. From 9/18/98 until 12/30/99 we enrolled 28 pts: median age 75 (700 85), male: 68%, PS 001: 75%, stage IV: 82%, adenocarcinoma: 64%. Patients were treated with 1-hr P at a dose of 90 mg/m 2 for six consecutive weeks followed by a two-week break. Currently, 21 pts are evaluable for response and 20 for toxicity. Six pts achieved PR (28%, 95%Ch 11-50%). Grade 3/4 hematologic toxicity: WBC: 1/21 (5%), hemoglobin: 0/21 (0%), and platelets: 0/21 (0%). One patient, for whom hypersensitivity reaction to P could not be excluded, developed seizure during his third weekly dose in the setting of hypotension and dehydration. Neuropathy grade 2/3 was seen in 3/20 pts (15%), fatigue grade 2 in 7/20 pts (35%), and infection grade 1-3 in 6/20 pts (30%). A single patient died of pneumonia and myocardial infarction. Other grade 3 toxicities included the following: pancreatitis, constipation, dyspnea, and constitutional symptoms (1 patient each). No episodes of febrile neutropenia were observed. Paclitaxel plasma concentrationtime profiles were defined during treatment with the first and sixth weekly doses and analyzed by noncompartmental methods. The CL of pactitaxel (mean ± SD) during the first cycle of therapy (18.3 ± 2.6 I/hr/m 2, n = 6) was within the range of previously reported CL values for comparable doses (_<100 mg/m 2) of the drug given as a 1 hr iv infusion to younger adult cancer pts (16-25 I/hr/m2). The mean CL measured in the same pts after the sixth weekly dose (16.3 ± 4.1 I/hr/m 2) was not significantly different from the first dose (P = 0.261, paired two sample two tailed t-test). Weekly P appears to be a very effective and tolerable monotherapy for elderly pts with advanced NSCLC. Moreover, the pharmacokinetic behavior of paclitaxel given as a 1 hr iv infusion is comparable in eldedy and younger pts and is unchanged after repeated weekly administration.
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Gemcitabine + vinorelbine (GV) yields better survival than vinorelbine (V) alone in elderly non-small cell lung cancer (NSCLC) patients. Final analysis of a Southern Italy Cooperative Oncology Group (SlCOG) phase III trial
G. Frasci, V. Lorusso, N. Panza, P. Cornelia, G. De Cataldis, E. Micillo, N. lannelli, G. Filippelli, D. Muci, F.V. Piantedosi, M. Belli, G.P. Nicolella, V. Mascia, B. Massidda, G. Cornelia, M. De Lena.
For the Southern Italy Cooperative Oncology Group (SICOG) - c/o National Tumor institute of Naples, Italy
Purpose: To compare the impact on survival and QoL of the GV regimen with that of V alone.
Patients and Methods: NSCLC pts with locally advanced or metastatic disease aged between 71 and 85 years with ECOG PS <_ 2, were randomized to receive GV (G 1,200 rag/m2 + V 30 mg/m2 d 1 & 8 q 3 wk) or V (30 mg/m2 d 1 & 8 q3wk) alone. A final sample size of 120 pts for each arm had been chosen. An interim analysis had been planned after that 60 pts per arm had been enrolled. The study would have been eady stopped if the experimental regimen showed better survival outcome at a p level < 0.01. Results: Overall, 152 pts entered this trial. As planned, in May 1999, the survival data of the first 120 eligible pts (V = 60, GV = 60) randomized from June 1997 to February 1999 were analysed,
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when at least 12 weeks had elapsed from the accrual of the last patient. Stage: IIIB/IV = 49/71 pts, ECOG PS: 0-1/2 = 91/29 pts. At a 14 (range; 3-22)-month median potential follow-up, 93 pts have died (GV = 41, V = 52), and the observed MSTs were: GV = 29 wks and V = 18 wks. At multivariate Cox analysis the risk of death in GV compared with V arm was 0.48 [95% CI = 0.29-0.79], p < 0.01. The QoL score did not worsen during the treatment in 60% of pts of GV arm as compared to 40% of those receiving V alone. Overall, 22 pts responded to treatment, being the ORR 22% and 15% in the GV and V arm, respectively. Both hematologic and nonhematologic toxicities were not significantly different in the two arms. Conclusions: In elderly NSCLC patients GV treatment is associated to a significantly better survival in comparison with V alone. The magnitude of the difference, and the unexpectedly poor survival outcome observed in V arm justified the early closure of the study.
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Randomized phase II trial comparing trastuzumab plus weekly docetaxel versus trastuzumab plus weekly paclitaxel in previously untreated advanced non-small cell lung cancer (NSCLC)
L.M. Krug 1, V.A. Miller 1, J.P. Crapanzano 1, M.F. Zakowski 1, K.K. Ng 1, R.T. Heelan ~, J. Ross 2, C. Sheehan 2, E. Venkatraman 1, B.A. Pizzo 1, N.A. McClean 1, M.G. Kris 1. IMemorial Sloan-Kettering, New York,
NY," 2AIbany Medical Center, Albany, NY, USA The monoclonal antibody trastuzumab (Herceptin) targets the human epidermal growth factor receptor-2 (HER-2) and in combination with chemotherapy has improved response rates and survival in breast cancer patients. Because retrospective data suggests NSCLC overexpresses HER-2 in about 25% of cases, we chose to study trastuzumab in combination with weekly paclitaxel or docetaxel in this disease. The objectives include prospective pathologic assessment of HER2 status and comparison of toxicity and response rates between the two taxanes in combination with trastuzumab. Eligibility requires stage IIIB (pleural effusion) or IV NSCLC, measurable or evaluable disease, no prior chemotherapy, and normal cardiac function. Patients with or without HER-2 overexpression are enrolled. After stratification based on pretreatment HER-2 analysis by immunohistochemistry (IHC, DAKO), patients are randomized to treatment with trastuzumab + docetaxel or trastuzumab + paclitaxel. Trastuzumab is administered at 4 mg/kg on week one, then 2 mg/kg weekly. Docetaxel, 36 mg/m2, or paclitaxel, 90 mg/m2, are given weekly for 6 weeks in an eightweek cycle. Both groups are premedicated with dexamethasone 8 mg po BID for 3 doses starting the night before therapy in the first cycle, then 4 mg with subsequent cycles. Pathology Results: 28 samples from 26 patients have been analyzed for HER-2 by IHC. HER-2 overexpression was found in 6 patients (23%, 95% CI 9-41%)-2+ in 5 patients, 3+ in 1. Two of 12 primary tumors and 4i16 metastatic lesions stained 2 or In one patient, the primary tumor stained 0 while a bone metastasis stained 2+. Treatment Results: 18 patients have been treated: 5 (28%) have 2 or 3+ HER-2 expression, 72% Stage IV, median Karnofsky performance status 80%, 72% female. Fourteen patients are evaluable for toxicity and response. Toxicities: grade 3 non-neutropenic infection (docetaxel-1 patient), grade 2 fatigue (docetaxel°2, paclitaxel-2), grade 2 infusion reaction (docetaxel-1). One patient had docetaxel discontinued for nail and skin toxicity. One patient (paclitaxel) died after developing pulmonary emboli and progressive herpes pneumonia. The overall objective response rate is 29% (95% CI 10o54%) with 2 responses in each arm. Conclusions: 1) The rate of HER-2 overexpression by IHC in advanced NSCLC is similar to that reported in previous retrospective series. Correlation with fluorescence in-situ hybridization (FISH) is ongoing. 2) To date, toxicity has not increased over that expected with taxane therapy 3) Accrual continues with a goal of 44 patients in each arm. Supported, in part, by Genentech.
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phase II clinical and pharmacokinetic study of weekly paclitaxel in elderly patients with non-small cell lung cancer P. Fidias, J. Supko, R. Martins, A. Boral, A. Skarin, B. Johnson, R. Carey, M. Grossbard, M. Vasconcelles, G. Shapiro, T.J. Lynch.
Massachusetts General Hospital, Brigham and Women's Hospital, and Dana Farber Cancer Institute, Harvard Medical School, Boston, USA More than 50% of NSCLC occurs in patients older than 65 years of age, many of whom have poor tolerance to aggressive combination chemotherapy. Single agent paclitaxel (P) at a dose of 150 mg/m 2 given as a 3-hr weekly infusion shows a response rate of 39%, but also a 56% incidence of grade 2/3 neuropathy. We initiated a study of weekly P focusing on elderly patients (pts). Eligibility included: age > 70, performance status 0-3, stage Ills or IV, measurable or evaluable disease, adequate hematologic, renal, and hepatic function. From 9/18/98 until 12/30/99 we enrolled 28 pts: median age 75 (700 85), male: 68%, PS 001: 75%, stage IV: 82%, adenocarcinoma: 64%. Patients were treated with 1-hr P at a dose of 90 mg/m 2 for six consecutive weeks followed by a two-week break. Currently, 21 pts are evaluable for response and 20 for toxicity. Six pts achieved PR (28%, 95%Ch 11-50%). Grade 3/4 hematologic toxicity: WBC: 1/21 (5%), hemoglobin: 0/21 (0%), and platelets: 0/21 (0%). One patient, for whom hypersensitivity reaction to P could not be excluded, developed seizure during his third weekly dose in the setting of hypotension and dehydration. Neuropathy grade 2/3 was seen in 3/20 pts (15%), fatigue grade 2 in 7/20 pts (35%), and infection grade 1-3 in 6/20 pts (30%). A single patient died of pneumonia and myocardial infarction. Other grade 3 toxicities included the following: pancreatitis, constipation, dyspnea, and constitutional symptoms (1 patient each). No episodes of febrile neutropenia were observed. Paclitaxel plasma concentrationtime profiles were defined during treatment with the first and sixth weekly doses and analyzed by noncompartmental methods. The CL of pactitaxel (mean ± SD) during the first cycle of therapy (18.3 ± 2.6 I/hr/m 2, n = 6) was within the range of previously reported CL values for comparable doses (_<100 mg/m 2) of the drug given as a 1 hr iv infusion to younger adult cancer pts (16-25 I/hr/m2). The mean CL measured in the same pts after the sixth weekly dose (16.3 ± 4.1 I/hr/m 2) was not significantly different from the first dose (P = 0.261, paired two sample two tailed t-test). Weekly P appears to be a very effective and tolerable monotherapy for elderly pts with advanced NSCLC. Moreover, the pharmacokinetic behavior of paclitaxel given as a 1 hr iv infusion is comparable in eldedy and younger pts and is unchanged after repeated weekly administration.
F•]
Gemcitabine + vinorelbine (GV) yields better survival than vinorelbine (V) alone in elderly non-small cell lung cancer (NSCLC) patients. Final analysis of a Southern Italy Cooperative Oncology Group (SlCOG) phase III trial
G. Frasci, V. Lorusso, N. Panza, P. Cornelia, G. De Cataldis, E. Micillo, N. lannelli, G. Filippelli, D. Muci, F.V. Piantedosi, M. Belli, G.P. Nicolella, V. Mascia, B. Massidda, G. Cornelia, M. De Lena.
For the Southern Italy Cooperative Oncology Group (SICOG) - c/o National Tumor institute of Naples, Italy
Purpose: To compare the impact on survival and QoL of the GV regimen with that of V alone.
Patients and Methods: NSCLC pts with locally advanced or metastatic disease aged between 71 and 85 years with ECOG PS <_ 2, were randomized to receive GV (G 1,200 rag/m2 + V 30 mg/m2 d 1 & 8 q 3 wk) or V (30 mg/m2 d 1 & 8 q3wk) alone. A final sample size of 120 pts for each arm had been chosen. An interim analysis had been planned after that 60 pts per arm had been enrolled. The study would have been eady stopped if the experimental regimen showed better survival outcome at a p level < 0.01. Results: Overall, 152 pts entered this trial. As planned, in May 1999, the survival data of the first 120 eligible pts (V = 60, GV = 60) randomized from June 1997 to February 1999 were analysed,
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when at least 12 weeks had elapsed from the accrual of the last patient. Stage: IIIB/IV = 49/71 pts, ECOG PS: 0-1/2 = 91/29 pts. At a 14 (range; 3-22)-month median potential follow-up, 93 pts have died (GV = 41, V = 52), and the observed MSTs were: GV = 29 wks and V = 18 wks. At multivariate Cox analysis the risk of death in GV compared with V arm was 0.48 [95% CI = 0.29-0.79], p < 0.01. The QoL score did not worsen during the treatment in 60% of pts of GV arm as compared to 40% of those receiving V alone. Overall, 22 pts responded to treatment, being the ORR 22% and 15% in the GV and V arm, respectively. Both hematologic and nonhematologic toxicities were not significantly different in the two arms. Conclusions: In elderly NSCLC patients GV treatment is associated to a significantly better survival in comparison with V alone. The magnitude of the difference, and the unexpectedly poor survival outcome observed in V arm justified the early closure of the study.
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Randomized phase II trial comparing trastuzumab plus weekly docetaxel versus trastuzumab plus weekly paclitaxel in previously untreated advanced non-small cell lung cancer (NSCLC)
L.M. Krug 1, V.A. Miller 1, J.P. Crapanzano 1, M.F. Zakowski 1, K.K. Ng 1, R.T. Heelan ~, J. Ross 2, C. Sheehan 2, E. Venkatraman 1, B.A. Pizzo 1, N.A. McClean 1, M.G. Kris 1. IMemorial Sloan-Kettering, New York,
NY," 2AIbany Medical Center, Albany, NY, USA The monoclonal antibody trastuzumab (Herceptin) targets the human epidermal growth factor receptor-2 (HER-2) and in combination with chemotherapy has improved response rates and survival in breast cancer patients. Because retrospective data suggests NSCLC overexpresses HER-2 in about 25% of cases, we chose to study trastuzumab in combination with weekly paclitaxel or docetaxel in this disease. The objectives include prospective pathologic assessment of HER2 status and comparison of toxicity and response rates between the two taxanes in combination with trastuzumab. Eligibility requires stage IIIB (pleural effusion) or IV NSCLC, measurable or evaluable disease, no prior chemotherapy, and normal cardiac function. Patients with or without HER-2 overexpression are enrolled. After stratification based on pretreatment HER-2 analysis by immunohistochemistry (IHC, DAKO), patients are randomized to treatment with trastuzumab + docetaxel or trastuzumab + paclitaxel. Trastuzumab is administered at 4 mg/kg on week one, then 2 mg/kg weekly. Docetaxel, 36 mg/m2, or paclitaxel, 90 mg/m2, are given weekly for 6 weeks in an eightweek cycle. Both groups are premedicated with dexamethasone 8 mg po BID for 3 doses starting the night before therapy in the first cycle, then 4 mg with subsequent cycles. Pathology Results: 28 samples from 26 patients have been analyzed for HER-2 by IHC. HER-2 overexpression was found in 6 patients (23%, 95% CI 9-41%)-2+ in 5 patients, 3+ in 1. Two of 12 primary tumors and 4i16 metastatic lesions stained 2 or In one patient, the primary tumor stained 0 while a bone metastasis stained 2+. Treatment Results: 18 patients have been treated: 5 (28%) have 2 or 3+ HER-2 expression, 72% Stage IV, median Karnofsky performance status 80%, 72% female. Fourteen patients are evaluable for toxicity and response. Toxicities: grade 3 non-neutropenic infection (docetaxel-1 patient), grade 2 fatigue (docetaxel°2, paclitaxel-2), grade 2 infusion reaction (docetaxel-1). One patient had docetaxel discontinued for nail and skin toxicity. One patient (paclitaxel) died after developing pulmonary emboli and progressive herpes pneumonia. The overall objective response rate is 29% (95% CI 10o54%) with 2 responses in each arm. Conclusions: 1) The rate of HER-2 overexpression by IHC in advanced NSCLC is similar to that reported in previous retrospective series. Correlation with fluorescence in-situ hybridization (FISH) is ongoing. 2) To date, toxicity has not increased over that expected with taxane therapy 3) Accrual continues with a goal of 44 patients in each arm. Supported, in part, by Genentech.