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A Phase I intermittent dose-escalation trial of ZD1839 (IressaTM) in Japanese patients with solid malignant tumors
Chemotherapy and toxicity. ZD0473 is a new-generation platinum agent targeted to deliver an extended spectrum of antitumour activity and overcome classical platinum resistance. Preclinical studies have shown that ZD0473 has activity against cisplatin- and carboplatin-resistant cell lines and human tumour xenografts. The use of ZD0473 with the antitumour agent paclitaxel may therefore provide an effective combination in the clinical setting. Methods: The aim of this Phase I, multicentre, open-label, doseescalation study is to determine the dose that will be used in further studies with ZD0473 and paclitaxel in combination in patients with solid turnouts. On day 1 of each cycle a 3-hour intravenous paclitaxel infusion is given and after 30 minutes, a 1-hour intravenous infusion of ZD0473 is administered. Each cycle is repeated at 3-week intervals. Clinical assessments are made at days 1, 8 and 15 of each cycle, at treatment withdrawal, and 30 days following the last dose. Seven close levels have been planned: paclitaxe1135 mg/m 2 with ZD0473 60 mg/m 2 (level 1), 90 mg/m 2 (level 2) or 120 mg/m 2 (level 3); ZD0473 120 mg/m 2 with paclitaxel 150 mg/m 2 (level 4), 175 mg/m 2 (level 5), 200 mg/m 2 (level 6) or 225 mg/m 2 (level 7), with three patients initially recruited at each dose level. Toxicities are assessed using the National Cancer Institute Common Toxicity Criteria grading system. If patients experience dose-limiting toxicity (DLT; febrile neutropenia or grade 4 neutropenia lasting at least 7 days; or grade 4 thrombocytopenia [<25 x 109/L]; or any grade 3-4 non-haematological toxicity except alopecia, nausea and vomiting, grade 3-4 transient increase in transaminases; or treatment delayed >2 weeks due to unresolved toxicity) in the first cycle, three additional patients are recruited. Dose escalation continues until MTD (the dose at which DLT occurs in 2/6 patients) has been determined. The dose recommended for further studies will be one dose level lower than the MTD. Results: To date, four patients (patients 3 and 4 were recruited at 2 institutions at the same time) have received dose level 1 and no DLT has been reported. Study completion is anticipated in Q3, 2000. Conclusion: This study will provide valuable data on the appropriate doses and the pharmacokinetics of ZD0473 and paclitaxel used in combination, as well as the safety and efficacy of this combination as an alternative therapy in NSCLC and ovarian cancer.
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Phase I intermittent dose-escalation trial of ZD1839 (Iressa') in Japanese patients with solid malignant tumors
T. Tamura 1, K. Nakagawa 2, M. Fukuoka 2, S. Kudoh 3, N. Yoshimura 3, S. Negoro4, K. Takeda4, H. Kelly5. ~National Cancer Center, Tokyo;
2Kinki University School of Medicine; 3Osaka City University School of Medicine; 40sake City General Hospital, Japan, 5AstraZeneca, Alderley Park, UK ZD 1839 (Iressa") is an orally active, selective EGFR-TKI (epidermal growth factor receptor tyrosine kinase inhibitor) which blocks signal transduction pathways implicated in cancer growth and survival. The objective of this ongoing trial is to investigate the tolerability, pharmacokinetics and efficacy of intermittent daily oral dosing of ZD1839 in Japanese patients (pts) with solid tumors known to commonly express or overexpress EGFR. To date, 19 pts (median age 59 yrs; PS 0-1) with NSCLC (14), CRC (4) and H & N (1) tumors have been recruited. All pts had adequate hematologic, renal and cardiac function at baseline. Pts received ZD1839 50 mg (n = 5), 100 mg (n = 4), 225 mg (n = 6) or400 mg (n = 4). Those pts treated with 50 to 225 mg ZD1839 received an initial single oral dose and were observed for 10 to 14 days. Thereafter, they entered a 14-day treatment period at the same dose of ZD1839, given once daily (4 pts per dose level, with 2 additional pts recruited if NCI grade 3 toxicity occurred). Pts at the 400 mg ZD1839 dose level entered the 14-day treatment period directly (this will also apply to future planned dose escalations), In the absence of progression, or dose-limiting toxicity (DLT), ZD1839 was re-initiated at the same dose for a further 14-day treatment period every 28 days. ZD1839 was generally well tolerated. No DLT was observed at doses up to 400 mg daily. One patient at 225 mg had grade 3 elevation of GOT and GPT, necessitating recruitment of 2 additional pts at this
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dose level. At the 50 mg dose 1 pt discontinued due to atrial fibrillation unrelated to ZD1839 treatment. Pts are currently being recruited at 525 mg dose level. Following multiple dosing for 14 days, ZD1839 exhibited doserelated increases in mean Cmax and AUCo_24h (73.8 to 860.8 ng/mL and 1236 to 12981 ng.h/mL, respectively). The half-life was approximately 45 hours. These results are similar to pharmacokinetic data from Western pts. To date, 1 pt (225 mg) with NSCLC has had a confirmed partial response. In conclusion, interim results indicate that once-daily oral ZD1839 is well tolerated and shows evidence of clinical activity in Japanese pts. Updated results will be presented at the Conference.
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Pilot trial of ZD1839 (IressaT"), an oral inhibitor of epidermal growth factor receptor (EGFR) tyroaine kinase, in combination with carboplatin (C) and paclitaxel (P) in previously untreated advanced non-small cell lung cancer (NSCLC)
S.A. Laurie I , V.A. Miller 1, D. Johnson 2, K.K. Ng 1, R.T. Heelan 1, B.A. Pizzo 1, W.J. Perez I , M.G. Kris I , J. Ochs 3, S. Averbuch 3.
1Memorial Sloan-Kettering Cancer Center, New York, NY," 2 Vanderbilt University, Nashville, TN; SAstraZeneca, Wilmington, DE, USA Background: ZD1839 (Iressa TM) is an orally active, selective EGFRTKI (epidermal growth factor receptor tyrosine kinase inhibitor) which blocks signal transduction pathways implicated in cancer cell proliferation, survival and other host-dependent processes promoting cancer cell growth. In Phase I trials of intermittent and daily dosing schedules of ZD1839, toxicity consisted primarily of grade 1-2 rash and diarrhea, without myelosuppression. Objective responses as well as long-lasting stabilizations were seen in heavily pretreated patients (pts) with NSCLC. In lung xenograft models, additive or superadditive antitumor activity has been found with both platinum and taxanes. This potential additive antitumor activity, and the mild, non-overlapping toxicity profile, encourage the study of ZD1839 in combination with a standard cytotoxic chemotherapy regimen. Objectives: To assess the safety of ZD1839, given intermittently or continuously, concurrent with standard doses of C + P, and to assess whether the pharmacokinetic profiles of C, P or ZD1839 are altered by the concurrent administration. Eligibility criteria: Stage IIIB (pleural effusion) or IV NSCLC; no prior chemotherapy; PS < 1. Treatment plan: Part 1 - pts randomized to intermittent ZD 1839 combined with C + P in one of two schedules: (a) ZD1839 days 1-14, C + P days 8 and 36; or (b) C + P days 1 and 29, ZD1839 days 22-36. Doses: C, AUC = 6; P, 200 mg/m 2 over 3 hours; escalating ZD1839, 250/500 mg orally once daily. Six pts will be enrolled at each ZD1839 dose level, with expansion to 12 pts if dose-limiting toxicity (DLT) is seen in 2 or 3 pts. Dose escalation of ZD1839 will occur if there is no DLT in the first 3 pts or if DLT occurs in 2/6 or 3/12 pts; dose escalation in individual pts is not permitted. Part 2 - In up to 12 pts, the highest safe dose in part 1 will be given daily, concurrently with C + I? All pts are evaluated for response at day 56. Results: Seven pts have been enrolled at 250 mg ZD1839 in part 1 as one pt came off study due to a severe hypersensitivity reaction to paclitaxel. To date, no grade 3 or 4 adverse effects have been observed. Three pts are evaluable for response (4 ton early); 2 pts have attained partial response and 1 had progressive disease. Conclusions: Combining ZD1839 with C + P appears feasible, with no increased toxicity observed to date. Enrollment continues; updated clinical and pharmacokinetic results will be available for presentation in September 2000.
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Phase I intermittent dose-escalation trial of ZD1839 (Iressa') in Japanese patients with solid malignant tumors
T. Tamura 1, K. Nakagawa 2, M. Fukuoka 2, S. Kudoh 3, N. Yoshimura 3, S. Negoro4, K. Takeda4, H. Kelly5. ~National Cancer Center, Tokyo;
2Kinki University School of Medicine; 3Osaka City University School of Medicine; 40sake City General Hospital, Japan, 5AstraZeneca, Alderley Park, UK ZD 1839 (Iressa") is an orally active, selective EGFR-TKI (epidermal growth factor receptor tyrosine kinase inhibitor) which blocks signal transduction pathways implicated in cancer growth and survival. The objective of this ongoing trial is to investigate the tolerability, pharmacokinetics and efficacy of intermittent daily oral dosing of ZD1839 in Japanese patients (pts) with solid tumors known to commonly express or overexpress EGFR. To date, 19 pts (median age 59 yrs; PS 0-1) with NSCLC (14), CRC (4) and H & N (1) tumors have been recruited. All pts had adequate hematologic, renal and cardiac function at baseline. Pts received ZD1839 50 mg (n = 5), 100 mg (n = 4), 225 mg (n = 6) or400 mg (n = 4). Those pts treated with 50 to 225 mg ZD1839 received an initial single oral dose and were observed for 10 to 14 days. Thereafter, they entered a 14-day treatment period at the same dose of ZD1839, given once daily (4 pts per dose level, with 2 additional pts recruited if NCI grade 3 toxicity occurred). Pts at the 400 mg ZD1839 dose level entered the 14-day treatment period directly (this will also apply to future planned dose escalations), In the absence of progression, or dose-limiting toxicity (DLT), ZD1839 was re-initiated at the same dose for a further 14-day treatment period every 28 days. ZD1839 was generally well tolerated. No DLT was observed at doses up to 400 mg daily. One patient at 225 mg had grade 3 elevation of GOT and GPT, necessitating recruitment of 2 additional pts at this
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dose level. At the 50 mg dose 1 pt discontinued due to atrial fibrillation unrelated to ZD1839 treatment. Pts are currently being recruited at 525 mg dose level. Following multiple dosing for 14 days, ZD1839 exhibited doserelated increases in mean Cmax and AUCo_24h (73.8 to 860.8 ng/mL and 1236 to 12981 ng.h/mL, respectively). The half-life was approximately 45 hours. These results are similar to pharmacokinetic data from Western pts. To date, 1 pt (225 mg) with NSCLC has had a confirmed partial response. In conclusion, interim results indicate that once-daily oral ZD1839 is well tolerated and shows evidence of clinical activity in Japanese pts. Updated results will be presented at the Conference.
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Pilot trial of ZD1839 (IressaT"), an oral inhibitor of epidermal growth factor receptor (EGFR) tyroaine kinase, in combination with carboplatin (C) and paclitaxel (P) in previously untreated advanced non-small cell lung cancer (NSCLC)
S.A. Laurie I , V.A. Miller 1, D. Johnson 2, K.K. Ng 1, R.T. Heelan 1, B.A. Pizzo 1, W.J. Perez I , M.G. Kris I , J. Ochs 3, S. Averbuch 3.
1Memorial Sloan-Kettering Cancer Center, New York, NY," 2 Vanderbilt University, Nashville, TN; SAstraZeneca, Wilmington, DE, USA Background: ZD1839 (Iressa TM) is an orally active, selective EGFRTKI (epidermal growth factor receptor tyrosine kinase inhibitor) which blocks signal transduction pathways implicated in cancer cell proliferation, survival and other host-dependent processes promoting cancer cell growth. In Phase I trials of intermittent and daily dosing schedules of ZD1839, toxicity consisted primarily of grade 1-2 rash and diarrhea, without myelosuppression. Objective responses as well as long-lasting stabilizations were seen in heavily pretreated patients (pts) with NSCLC. In lung xenograft models, additive or superadditive antitumor activity has been found with both platinum and taxanes. This potential additive antitumor activity, and the mild, non-overlapping toxicity profile, encourage the study of ZD1839 in combination with a standard cytotoxic chemotherapy regimen. Objectives: To assess the safety of ZD1839, given intermittently or continuously, concurrent with standard doses of C + P, and to assess whether the pharmacokinetic profiles of C, P or ZD1839 are altered by the concurrent administration. Eligibility criteria: Stage IIIB (pleural effusion) or IV NSCLC; no prior chemotherapy; PS < 1. Treatment plan: Part 1 - pts randomized to intermittent ZD 1839 combined with C + P in one of two schedules: (a) ZD1839 days 1-14, C + P days 8 and 36; or (b) C + P days 1 and 29, ZD1839 days 22-36. Doses: C, AUC = 6; P, 200 mg/m 2 over 3 hours; escalating ZD1839, 250/500 mg orally once daily. Six pts will be enrolled at each ZD1839 dose level, with expansion to 12 pts if dose-limiting toxicity (DLT) is seen in 2 or 3 pts. Dose escalation of ZD1839 will occur if there is no DLT in the first 3 pts or if DLT occurs in 2/6 or 3/12 pts; dose escalation in individual pts is not permitted. Part 2 - In up to 12 pts, the highest safe dose in part 1 will be given daily, concurrently with C + I? All pts are evaluated for response at day 56. Results: Seven pts have been enrolled at 250 mg ZD1839 in part 1 as one pt came off study due to a severe hypersensitivity reaction to paclitaxel. To date, no grade 3 or 4 adverse effects have been observed. Three pts are evaluable for response (4 ton early); 2 pts have attained partial response and 1 had progressive disease. Conclusions: Combining ZD1839 with C + P appears feasible, with no increased toxicity observed to date. Enrollment continues; updated clinical and pharmacokinetic results will be available for presentation in September 2000.