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Richard Pazdur - One of the best experts on this subject based on the ideXlab platform.
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metastasis free survival a new end point in prostate cancer trials
The New England Journal of Medicine, 2018Co-Authors: Julia A. Beaver, Paul G. Kluetz, Richard PazdurAbstract:Transitioning to Clinical Metastases The FDA’s Approval of apalutamide for use in nonmetastatic castration-resistant prostate cancer (nmCRPC) was based on an improvement in metastasis-free survival. It was the first Drug Approval for nmCRPC and the first use of this primary end point to support Drug Approval.
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fda Drug Approval elotuzumab in combination with lenalidomide and dexamethasone for the treatment of relapsed or refractory multiple myeloma
Clinical Cancer Research, 2017Co-Authors: Nicole J Gormley, Edvardas Kaminskas, Ann T Farrell, Albert B Deisseroth, Lei Nie, Natasha L Kormanik, Kirsten B Goldberg, Richard PazdurAbstract:On November 30, 2015, the FDA approved elotuzumab (Empliciti; Bristol-Myers Squibb) in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who received one to three prior therapies. FDA Approval was based primarily on the results of a phase III, randomized, open-label, multicenter trial, CA204004, which evaluated elotuzumab in combination with lenalidomide and dexamethasone (E-Ld) compared with lenalidomide and dexamethasone (Ld) alone in patients with relapsed or refractory multiple myeloma. Coprimary endpoints were progression-free survival (PFS) and overall response rate (ORR). The key secondary endpoint was overall survival, but these data were not mature at the time of clinical database cutoff. The trial demonstrated a statistically significant improvement in PFS, with an estimated HR of 0.70 for E-Ld over Ld [95% confidence interval (CI), 0.57-0.85; P = 0.0004). Estimated median PFS was 19.4 months in the E-Ld arm and 14.9 months in the Ld arm. ORR was 75.8% in the E-Ld arm compared with 65.5% in the Ld arm. Serious adverse reactions were reported in 65% of patients in the E-Ld arm compared with 57% in the Ld arm. The FDA approved elotuzumab with the following warnings and precautions: infusion reactions, infections, second primary malignancies, hepatotoxicity, and interference with the determination of complete response. Clin Cancer Res; 23(22); 6759-63. ©2017 AACR.
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pathological complete response and accelerated Drug Approval in early breast cancer
The New England Journal of Medicine, 2012Co-Authors: Tatiana M Prowell, Richard PazdurAbstract:Neoadjuvant trials introduce new Drugs preoperatively in patients with localized breast cancer, using the rate of pathological complete response as the primary end point. The FDA has issued guidance for using this end point in applying for accelerated Drug Approval.
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fda Drug Approval summary bevacizumab avastin as treatment of recurrent glioblastoma multiforme
Oncologist, 2009Co-Authors: Martin H Cohen, Yuan Li Shen, Patricia Keegan, Richard PazdurAbstract:On May 5, 2009, the U.S. Food and Drug Administration granted accelerated Approval to bevacizumab injection (Avastin;Genentech,Inc.,SouthSanFrancisco,CA)asa single agent for patients with glioblastoma multiforme (GBM) with progressive disease following prior therapy. The Approval was based on durable objective responses (independent radiologic review with stable or decreasing corticosteroiduse).Twotrialsevaluatingbevacizumab,10 mg/kg by i.v. infusion every 2 weeks, were submitted. One trial also randomized patients to bevacizumab plus irinotecan treatment. All patients had received prior surgery, radiotherapy, and temozolomide. Patients with active brainhemorrhagewereexcluded.Onetrialenrolled78independently confirmed GBM patients. Partial responses were observed in 25.9% (95% confidence interval [CI], 17.0%–36.1%)ofthepatients.Themedianresponsedurationwas4.2months(95%CI,3.0–5.7months).Thesecond trialenrolled56GBMpatients.Partialresponseswereobserved in 19.6% (95% CI, 10.9%–31.3%) of the patients. The median response duration was 3.9 months (95% CI, 2.4–17.4 months). Safety data were provided for the first study. The most frequently reported bevacizumab adverse events of any grade were infection, fatigue, headache, hypertension, epistaxis, and diarrhea. Grade 3–5 bevacizumab-related adverse events included bleeding/hemorrhage, central nervous system (CNS) hemorrhage, hypertension, venous and arterial thromboembolic events, wound-healing complications, proteinuria, gastrointestinal perforation, and reversible posterior leukoencephalopathy. The attribution of certain adverse events (e.g., CNS hemorrhage, wound-healing complications, and thromboembolic events) to either bevacizumab, underlying disease, or both could not be determined because of the single-arm, noncomparative study design.The Oncologist 2009;14:000–000
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fda Drug Approval summary bevacizumab avastin as treatment of recurrent glioblastoma multiforme
Oncologist, 2009Co-Authors: Martin H Cohen, Yuan Li Shen, Patricia Keegan, Richard PazdurAbstract:On May 5, 2009, the U.S. Food and Drug Administration granted accelerated Approval to bevacizumab injection (Avastin; Genentech, Inc., South San Francisco, CA) as a single agent for patients with glioblastoma multiforme (GBM) with progressive disease following prior therapy. The Approval was based on durable objective responses (independent radiologic review with stable or decreasing corticosteroid use). Two trials evaluating bevacizumab, 10 mg/kg by i.v. infusion every 2 weeks, were submitted. One trial also randomized patients to bevacizumab plus irinotecan treatment. All patients had received prior surgery, radiotherapy, and temozolomide. Patients with active brain hemorrhage were excluded. One trial enrolled 78 independently confirmed GBM patients. Partial responses were observed in 25.9% (95% confidence interval [CI], 17.0%-36.1%) of the patients. The median response duration was 4.2 months (95% CI, 3.0-5.7 months). The second trial enrolled 56 GBM patients. Partial responses were observed in 19.6% (95% CI, 10.9%-31.3%) of the patients. The median response duration was 3.9 months (95% CI, 2.4-17.4 months). Safety data were provided for the first study. The most frequently reported bevacizumab adverse events of any grade were infection, fatigue, headache, hypertension, epistaxis, and diarrhea. Grade 3-5 bevacizumab-related adverse events included bleeding/hemorrhage, central nervous system (CNS) hemorrhage, hypertension, venous and arterial thromboembolic events, wound-healing complications, proteinuria, gastrointestinal perforation, and reversible posterior leukoencephalopathy. The attribution of certain adverse events (e.g., CNS hemorrhage, wound-healing complications, and thromboembolic events) to either bevacizumab, underlying disease, or both could not be determined because of the single-arm, noncomparative study design.
Martin H Cohen - One of the best experts on this subject based on the ideXlab platform.
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fda Drug Approval summary bevacizumab avastin as treatment of recurrent glioblastoma multiforme
Oncologist, 2009Co-Authors: Martin H Cohen, Yuan Li Shen, Patricia Keegan, Richard PazdurAbstract:On May 5, 2009, the U.S. Food and Drug Administration granted accelerated Approval to bevacizumab injection (Avastin;Genentech,Inc.,SouthSanFrancisco,CA)asa single agent for patients with glioblastoma multiforme (GBM) with progressive disease following prior therapy. The Approval was based on durable objective responses (independent radiologic review with stable or decreasing corticosteroiduse).Twotrialsevaluatingbevacizumab,10 mg/kg by i.v. infusion every 2 weeks, were submitted. One trial also randomized patients to bevacizumab plus irinotecan treatment. All patients had received prior surgery, radiotherapy, and temozolomide. Patients with active brainhemorrhagewereexcluded.Onetrialenrolled78independently confirmed GBM patients. Partial responses were observed in 25.9% (95% confidence interval [CI], 17.0%–36.1%)ofthepatients.Themedianresponsedurationwas4.2months(95%CI,3.0–5.7months).Thesecond trialenrolled56GBMpatients.Partialresponseswereobserved in 19.6% (95% CI, 10.9%–31.3%) of the patients. The median response duration was 3.9 months (95% CI, 2.4–17.4 months). Safety data were provided for the first study. The most frequently reported bevacizumab adverse events of any grade were infection, fatigue, headache, hypertension, epistaxis, and diarrhea. Grade 3–5 bevacizumab-related adverse events included bleeding/hemorrhage, central nervous system (CNS) hemorrhage, hypertension, venous and arterial thromboembolic events, wound-healing complications, proteinuria, gastrointestinal perforation, and reversible posterior leukoencephalopathy. The attribution of certain adverse events (e.g., CNS hemorrhage, wound-healing complications, and thromboembolic events) to either bevacizumab, underlying disease, or both could not be determined because of the single-arm, noncomparative study design.The Oncologist 2009;14:000–000
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fda Drug Approval summary bevacizumab avastin as treatment of recurrent glioblastoma multiforme
Oncologist, 2009Co-Authors: Martin H Cohen, Yuan Li Shen, Patricia Keegan, Richard PazdurAbstract:On May 5, 2009, the U.S. Food and Drug Administration granted accelerated Approval to bevacizumab injection (Avastin; Genentech, Inc., South San Francisco, CA) as a single agent for patients with glioblastoma multiforme (GBM) with progressive disease following prior therapy. The Approval was based on durable objective responses (independent radiologic review with stable or decreasing corticosteroid use). Two trials evaluating bevacizumab, 10 mg/kg by i.v. infusion every 2 weeks, were submitted. One trial also randomized patients to bevacizumab plus irinotecan treatment. All patients had received prior surgery, radiotherapy, and temozolomide. Patients with active brain hemorrhage were excluded. One trial enrolled 78 independently confirmed GBM patients. Partial responses were observed in 25.9% (95% confidence interval [CI], 17.0%-36.1%) of the patients. The median response duration was 4.2 months (95% CI, 3.0-5.7 months). The second trial enrolled 56 GBM patients. Partial responses were observed in 19.6% (95% CI, 10.9%-31.3%) of the patients. The median response duration was 3.9 months (95% CI, 2.4-17.4 months). Safety data were provided for the first study. The most frequently reported bevacizumab adverse events of any grade were infection, fatigue, headache, hypertension, epistaxis, and diarrhea. Grade 3-5 bevacizumab-related adverse events included bleeding/hemorrhage, central nervous system (CNS) hemorrhage, hypertension, venous and arterial thromboembolic events, wound-healing complications, proteinuria, gastrointestinal perforation, and reversible posterior leukoencephalopathy. The attribution of certain adverse events (e.g., CNS hemorrhage, wound-healing complications, and thromboembolic events) to either bevacizumab, underlying disease, or both could not be determined because of the single-arm, noncomparative study design.
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fda Drug Approval summary lapatinib in combination with capecitabine for previously treated metastatic breast cancer that overexpresses her 2
Oncologist, 2008Co-Authors: Qin Ryan, Martin H Cohen, Rajeshwari Sridhara, Robert Justice, Amna Ibrahim, John R. Johnson, Richard PazdurAbstract:On March 13, 2007, the U.S. Food and Drug Administration approved lapatinib (Tykerb tablets; GlaxoSmithKline, Philadelphia), an oral, small molecule, dual tyrosine kinase inhibitor of ErbB-2 and ErbB-1, for use in combination with capecitabine for the treatment of patients with human epidermal growth factor receptor (HER)-2-overexpressing metastatic breast cancer who had received prior therapy including an anthracycline, a taxane, and trastuzumab. One multicenter, open-label, randomized trial was submitted. Eligible patients had stage IIIb or IV breast cancer, ErbB-2 overexpression (immunohistochemistry 3+ or 2+ with fluorescence in situ hybridization confirmation), measurable disease, a 0 or 1 Eastern Cooperative Oncology Group performance status score, a cardiac ejection fraction within the institutional normal range, and adequate laboratory function. Patients received either lapatinib (1,250 mg once daily on days 1-21) plus capecitabine (1,000 mg/m(2) every 12 hours on days 1-14) every 21 days or capecitabine alone (1,250 mg/m(2) every 12 hours on days 1-14) every 21 days. The primary endpoint was time to progression (TTP) determined by a blinded independent review panel. After TTP results of a prespecified interim analysis were made available, study enrollment was discontinued (399 patients enrolled). The median TTP was 27.1 versus 18.6 weeks (hazard ratio, 0.57; p = .00013) favoring the lapatinib plus capecitabine arm. Response rates were 23.7% (lapatinib plus capecitabine) versus 13.9% (capecitabine alone). Survival data were not mature. Although the toxicities observed in the lapatinib and capecitabine combination arm were generally similar to those in the capecitabine alone arm, a higher incidence of diarrhea and rash was noted with the combination. Grade 3 or 4 adverse reactions that occurred with a frequency of >5% in patients on the combination arm were diarrhea (13%) and palmar-plantar erythrodysesthesia (12%). There was a 2% incidence of reversible decreased left ventricular function in the combination arm.
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fda Drug Approval summary nelarabine arranon for the treatment of t cell lymphoblastic leukemia lymphoma
Oncologist, 2008Co-Authors: Martin H Cohen, Robert Justice, John R. Johnson, Richard PazdurAbstract:Purpose. To describe the clinical trials leading to U.S. Food and Drug Administration (FDA) Approval of nelarabine (Arranon), a new purine analogue, for the treatment of patients with T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) whose disease has not responded to or has relapsed following treatment with at least two chemotherapy regimens. Experimental Design. Two phase II trials, one conductedinpediatricpatientsandtheotherinadultpatients, were reviewed. Patients were in their first or subsequent relapse and/or were refractory to first-line therapy. The dose and schedule of i.v. nelarabine in the pediatric and adult studies were 650 mg/m 2 per day daily for 5 days and 1,500 mg/m 2 i.v. on days 1, 3, and 5, respectively. Treat
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fda Drug Approval summary pegaspargase oncaspar for the first line treatment of children with acute lymphoblastic leukemia all
Oncologist, 2007Co-Authors: Patricia Anne Dinndorf, Martin H Cohen, Patricia Keegan, Joseph E Gootenberg, Richard PazdurAbstract:On July 24, 2006, the U.S. Food and Drug Administration granted Approval to pegaspargase (Oncaspar; Enzon Pharmaceuticals, Inc., Bridgewater, NJ; hereafter, O) for the first-line treatment of patients with acute lymphoblastic leukemia (ALL) as a component of a multiagent chemotherapy regimen. O was previously approved in February 1994 for the treatment of patients with ALL who were hypersensitive to native forms of L-asparaginase. The trial supporting this new indication was an open label, randomized, multicenter clinical trial that enrolled 118 children (age, 1-9 years) with previously untreated, standard risk ALL. Patients received either native Escherichia coli asparaginase (Elspar; Merck, Whitehouse Station, NJ; hereafter, E) or O along with multiagent chemotherapy during remission induction and delayed intensification (DI) phases of treatment. O, at a dose of 2,500 IU/m(2), was administered i.m. on day 3 of the 4-week induction phase and on day 3 of each of two 8-week DI phases. E, at a dose of 6,000 IU/m(2), was administered i.m. three times weekly for nine doses during induction and for six doses during each DI phase. This study allowed direct comparison of O and E for asparagine depletion, asparaginase activity, and development of asparaginase antibodies. An unplanned comparison of event-free survival (EFS) was conducted to rule out a deleterious O efficacy effect. Following induction and DI treatment there was complete ( 0.03 IU/ml in O-treated subjects was greater than the number of days in E-treated subjects during both the induction and DI phases of treatment. There was no correlation, however, between asparaginase activity and serum asparagine levels, making the former determination less clinically relevant. Using the protocol-prespecified threshold for a positive result of >2.5 times the control, 7 of 56 (12%) O subjects tested at any time during the study demonstrated antiasparaginase antibodies and 16 of 57 (28%) E subjects tested at any time during the study had antiasparaginase antibodies. In both study arms EFS was in the range of 80% at 3 years. The most serious, sometimes fatal, O toxicities were anaphylaxis, other serious allergic reactions, thrombosis (including sagittal sinus thrombosis), pancreatitis, glucose intolerance, and coagulopathy. The most common adverse events were allergic reactions (including anaphylaxis), hyperglycemia, pancreatitis, central nervous system thrombosis, coagulopathy, hyperbilirubinemia, and elevated transaminases. Disclosure of potential conflicts of interest is found at the end of this article.
Grant Williams - One of the best experts on this subject based on the ideXlab platform.
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united states food and Drug administration Drug Approval summary gefitinib zd1839 iressa tablets
Clinical Cancer Research, 2004Co-Authors: Martin H Cohen, Grant Williams, Rajeshwari Sridhara, Gang Chen, David W Mcguinn, David L Morse, Sophia Abraham, Atiqur Rahman, Chenyi Liang, Richard T LostrittoAbstract:On May 5, 2003, gefitinib (Iressa; ZD1839) 250-mg tablets (AstraZeneca Inc.) received accelerated Approval by the United States Food and Drug Administration as monotherapy for patients with locally advanced or metastatic non-small cell lung cancer after failure of both platinum-based and docetaxel chemotherapies. Information provided in this summary includes chemistry manufacturing and controls, clinical pharmacology, and clinical trial efficacy and safety results. Gefitinib is an anilinoquinazoline compound with the chemical name 4-quinazolinamine,N-(3-chloro-4-flurophenyl)-7-methoxy-6-[3-(4-morpholinyl)propoxy]. It has the molecular formula C(22)H(24)ClFN(4)O(3). Gefitinib is often referred to as a "specific" or "selective" inhibitor of epidermal growth factor receptor. Studies demonstrate, however, that gefitinib inhibits the activity of other intracellular transmembrane tyrosine-specific protein kinases at concentrations similar to those at which it inhibits the epidermal growth factor signal. Maximum plasma concentrations resulting from clinically relevant doses are 0.5-1 microM or more, well within the IC(50) values of several tyrosine kinases. No clinical studies have been performed that demonstrate a correlation between epidermal growth factor receptor expression and response to gefitinib. Gefitinib is 60% available after oral administration and is widely distributed throughout the body. Gefitinib is extensively metabolized in the liver by cytochrome P450 3A4 enzyme. Over a 10-day period, approximately 86% of an orally administered radioactive dose is recovered in the feces, with <4% of the dose in the urine. After daily oral administration, steady-state plasma levels are reached in 10 days and are 2-fold higher than those achieved after single doses. Gefitinib effectiveness was demonstrated in a randomized, double-blind, Phase II, multicenter trial comparing two oral doses of gefitinib (250 versus 500 mg/day). A total of 216 patients were enrolled. The 142 patients who were refractory to or intolerant of a platinum and docetaxel comprised the evaluable population for the efficacy analysis. A partial tumor response occurred in 14% (9 of 66) of patients receiving 250 mg/day gefitinib and in 8% (6 of 76) of patients receiving 500 mg/day gefitinib. The overall objective response rate (RR) for both doses combined was 10.6% (15 of 142 patients; 95% confidence interval, 6.0-16.8%). Responses were more frequent in females and in nonsmokers. The median duration of response was 7.0 months (range, 4.6-18.6+ months). Other submitted data included the results of two large trials conducted in chemotherapy-naive, stage III and IV non-small cell lung cancer patients. Patients were randomized to receive gefitinib (250 or 500 mg daily) or placebo, in combination with either gemcitabine plus cisplatin (n = 1093) or carboplatin plus paclitaxel (n = 1037). Results from this study showed no benefit (RR, time to progression, or survival) from adding gefitinib to chemotherapy. Consequently, gefinitib is only recommended for use as monotherapy. Common adverse events associated with gefitinib treatment included diarrhea, rash, acne, dry skin, nausea, and vomiting. Interstitial lung disease has been observed in patients receiving gefitinib. Worldwide, the incidence of interstitial lung disease was about 1% (2% in the Japanese post-marketing experience and about 0.3% in a United States expanded access program). Approximately one-third of the cases have been fatal. Gefitinib was approved under accelerated Approval regulations on the basis of a surrogate end point, RR. No controlled gefitinib trials, to date, demonstrate a clinical benefit, such as improvement in disease-related symptoms or increased survival. Accelerated Approval regulations require the sponsor to conduct additional studies to verify that gefitinib therapy produces such benefit.
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united states food and Drug administration Drug Approval summary gefitinib zd1839 iressa tablets
Clinical Cancer Research, 2004Co-Authors: Martin H Cohen, Grant Williams, Rajeshwari Sridhara, Gang Chen, David W Mcguinn, David L Morse, Sophia Abraham, Atiqur Rahman, Chenyi Liang, Richard T LostrittoAbstract:On May 5, 2003, gefitinib (Iressa; ZD1839) 250-mg tablets (AstraZeneca Inc.) received accelerated Approval by the United States Food and Drug Administration as monotherapy for patients with locally advanced or metastatic non-small cell lung cancer after failure of both platinum-based and docetaxel chemotherapies. Information provided in this summary includes chemistry manufacturing and controls, clinical pharmacology, and clinical trial efficacy and safety results. Gefitinib is an anilinoquinazoline compound with the chemical name 4-quinazolinamine, N -(3-chloro-4-flurophenyl)-7-methoxy-6-[3-(4-morpholinyl)propoxy]. It has the molecular formula C 22 H 24 ClFN 4 O 3 . Gefitinib is often referred to as a “specific” or “selective” inhibitor of epidermal growth factor receptor. Studies demonstrate, however, that gefitinib inhibits the activity of other intracellular transmembrane tyrosine-specific protein kinases at concentrations similar to those at which it inhibits the epidermal growth factor signal. Maximum plasma concentrations resulting from clinically relevant doses are 0.5–1 μm or more, well within the IC 50 values of several tyrosine kinases. No clinical studies have been performed that demonstrate a correlation between epidermal growth factor receptor expression and response to gefitinib. Gefitinib is 60% available after oral administration and is widely distributed throughout the body. Gefitinib is extensively metabolized in the liver by cytochrome P450 3A4 enzyme. Over a 10-day period, approximately 86% of an orally administered radioactive dose is recovered in the feces, with versus 500 mg/day). A total of 216 patients were enrolled. The 142 patients who were refractory to or intolerant of a platinum and docetaxel comprised the evaluable population for the efficacy analysis. A partial tumor response occurred in 14% (9 of 66) of patients receiving 250 mg/day gefitinib and in 8% (6 of 76) of patients receiving 500 mg/day gefitinib. The overall objective response rate (RR) for both doses combined was 10.6% (15 of 142 patients; 95% confidence interval, 6.0–16.8%). Responses were more frequent in females and in nonsmokers. The median duration of response was 7.0 months (range, 4.6–18.6+ months). Other submitted data included the results of two large trials conducted in chemotherapy-naive, stage III and IV non-small cell lung cancer patients. Patients were randomized to receive gefitinib (250 or 500 mg daily) or placebo, in combination with either gemcitabine plus cisplatin ( n = 1093) or carboplatin plus paclitaxel (n = 1037). Results from this study showed no benefit (RR, time to progression, or survival) from adding gefitinib to chemotherapy. Consequently, gefinitib is only recommended for use as monotherapy. Common adverse events associated with gefitinib treatment included diarrhea, rash, acne, dry skin, nausea, and vomiting. Interstitial lung disease has been observed in patients receiving gefitinib. Worldwide, the incidence of interstitial lung disease was about 1% (2% in the Japanese post-marketing experience and about 0.3% in a United States expanded access program). Approximately one-third of the cases have been fatal. Gefitinib was approved under accelerated Approval regulations on the basis of a surrogate end point, RR. No controlled gefitinib trials, to date, demonstrate a clinical benefit, such as improvement in disease-related symptoms or increased survival. Accelerated Approval regulations require the sponsor to conduct additional studies to verify that gefitinib therapy produces such benefit.
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fda Drug Approval summary gefitinib zd1839 iressa tablets
Oncologist, 2003Co-Authors: Martin H Cohen, Grant Williams, Rajeshwari Sridhara, Gang Chen, Richard PazdurAbstract:On May 5, 2003, gefitinib (Iressa), ZD1839) 250-mg tablets received accelerated Approval by the U.S. Food and Drug Administration as monotherapy treatment for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of both platinum-based and docetaxel chemotherapies. Information provided in this summary includes efficacy and safety results of relevant clinical trials. Effectiveness was demonstrated in a randomized, double-blind, phase II, multicenter trial comparing two oral doses of gefitinib (250 mg/day versus 500 mg/day). Two hundred sixteen patients were enrolled. The 142 patients who were refractory to or intolerant of a platinum and docetaxel comprised the evaluable population for the efficacy analysis. A partial tumor response occurred in 14% (9 of 66) of patients receiving gefitinib 250 mg/day and in 8% (6 of 76) of patients receiving gefitinib 500 mg/day. The overall objective response rate for both doses combined was 10.6% (15 of 142 patients) (95% confidence interval 6.0%-16.8%). Responses were more frequent in females and in nonsmokers. The median duration of response was 7.0 months (range 4.6-18.6+ months). Other submitted data included the results of two large trials conducted in chemotherapy-naive, stage III and IV NSCLC patients. Patients were randomized to receive gefitinib (250 mg or 500 mg daily) or placebo, in combination with either gemcitabine plus cisplatin (n = 1,093) or carboplatin plus paclitaxel (n = 1,037). Results from those studies showed no benefit (response rate, time to progression, or survival) from adding gefitinib to chemotherapy. Consequently, gefinitib is only recommended for use as monotherapy. Common adverse events associated with gefitinib treatment included diarrhea, rash, acne, dry skin, nausea, and vomiting. Most toxicities were Common Toxicity Criteria grade 1 or 2. Interstitial lung disease (ILD) has been observed in patients receiving gefitinib. Worldwide, the incidence of ILD is about 1% (2% in the Japanese postmarketing experience and about 0.3% in a U.S. expanded access program). Approximately one-third of the cases were fatal. Physicians should promptly evaluate new or worsening pulmonary symptoms. If ILD is confirmed, appropriate management includes discontinuation of gefitinib. Gefitinib was approved under accelerated Approval regulations on the basis of a surrogate end point response rate. No controlled gefitinib trials, to date, demonstrate a clinical benefit, such as improvement in disease-related symptoms or greater survival. Accelerated Approval regulations require the sponsor to conduct further studies to verify that gefitinib therapy produces such a benefit.
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u s food and Drug administration Drug Approval summaries imatinib mesylate mesna tablets and zoledronic acid
Oncologist, 2002Co-Authors: Martin H Cohen, Grant Williams, Ramzi Dagher, Amna Ibrahim, Donna Griebel, Alison Martin, Nancy S Scher, Gerald H Sokol, Richard PazdurAbstract:The purpose of this report is to summarize information on Drugs recently approved by the U.S. Food and Drug Administration. Three Drugs have recently been approved: Gleevec ™ (imatinib mesylate) at a starting dose of 400 or 600 mg daily for the treatment of malignant unresectable and/or metastatic gastrointestinal stromal tumors; Mesnex ® (mesna) tablets as a prophylactic agent to reduce the incidence of ifosfamideinduced hemorrhagic cystitis, and Zometa ® (zoledronic acid) for the treatment of patients with multiple myeloma and for patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy. The recommended dose and schedule is 4 mg infused over 15 minutes every 3-4 weeks. These three Drugs represent three different types of Drug Approval: Gleevec is an accelerated Approval and supplemental new Drug application (NDA); Mesnex tablets represent an oral formulation of a Drug approved 14 years ago as an intravenous formulation, and Zometa represents a standard NDA for a noncytotoxic, supportive-care Drug. Information provided includes rationale for Drug development, study design, efficacy and safety results, and pertinent literature references. The Oncologist 2002;7:393-400
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Drug Approval summaries: arsenic trioxide, tamoxifen citrate, anastrazole, paclitaxel, bexarotene.
The oncologist, 2001Co-Authors: Martin H Cohen, Grant Williams, Steven Hirschfeld, Susan Flamm Honig, Amna Ibrahim, John R. Johnson, James J. O'leary, Robert M. White, Richard PazdurAbstract:This report summarizes information on Drugs recently approved by the Food and Drug Administration, Office of Drug Evaluation I, Division of Oncology Drug Products. Five applications supporting new claims will be discussed: Trisenox (arsenic trioxide) for induction of remission and consolidation in patients with acute promyelocytic leukemia who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy, and whose disease is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression; Nolvadex (tamoxifen citrate) in women with ductal carcinoma in situ, following breast surgery and radiation, to reduce the risk of invasive breast cancer; Arimidex (anastrazole) for first-line treatment of postmenopausal women with hormone receptor positive or hormone receptor unknown locally advanced or metastatic breast cancer; Taxol (paclitaxel), 175 mg/m(2) by 3 h infusion in combination with cisplatin for first-line treatment of advanced ovarian cancer; and Targretin gel (bexarotene) for the topical treatment of cutaneous lesions in patients with stage IA and IB cutaneous T-cell lymphoma who have not tolerated other therapies or who have refractory or persistent disease. Information provided includes rationale for Drug development, study design, efficacy and safety results, and pertinent literature references.
Rajeshwari Sridhara - One of the best experts on this subject based on the ideXlab platform.
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fda Drug Approval summary lapatinib in combination with capecitabine for previously treated metastatic breast cancer that overexpresses her 2
Oncologist, 2008Co-Authors: Qin Ryan, Martin H Cohen, Rajeshwari Sridhara, Robert Justice, Amna Ibrahim, John R. Johnson, Richard PazdurAbstract:On March 13, 2007, the U.S. Food and Drug Administration approved lapatinib (Tykerb tablets; GlaxoSmithKline, Philadelphia), an oral, small molecule, dual tyrosine kinase inhibitor of ErbB-2 and ErbB-1, for use in combination with capecitabine for the treatment of patients with human epidermal growth factor receptor (HER)-2-overexpressing metastatic breast cancer who had received prior therapy including an anthracycline, a taxane, and trastuzumab. One multicenter, open-label, randomized trial was submitted. Eligible patients had stage IIIb or IV breast cancer, ErbB-2 overexpression (immunohistochemistry 3+ or 2+ with fluorescence in situ hybridization confirmation), measurable disease, a 0 or 1 Eastern Cooperative Oncology Group performance status score, a cardiac ejection fraction within the institutional normal range, and adequate laboratory function. Patients received either lapatinib (1,250 mg once daily on days 1-21) plus capecitabine (1,000 mg/m(2) every 12 hours on days 1-14) every 21 days or capecitabine alone (1,250 mg/m(2) every 12 hours on days 1-14) every 21 days. The primary endpoint was time to progression (TTP) determined by a blinded independent review panel. After TTP results of a prespecified interim analysis were made available, study enrollment was discontinued (399 patients enrolled). The median TTP was 27.1 versus 18.6 weeks (hazard ratio, 0.57; p = .00013) favoring the lapatinib plus capecitabine arm. Response rates were 23.7% (lapatinib plus capecitabine) versus 13.9% (capecitabine alone). Survival data were not mature. Although the toxicities observed in the lapatinib and capecitabine combination arm were generally similar to those in the capecitabine alone arm, a higher incidence of diarrhea and rash was noted with the combination. Grade 3 or 4 adverse reactions that occurred with a frequency of >5% in patients on the combination arm were diarrhea (13%) and palmar-plantar erythrodysesthesia (12%). There was a 2% incidence of reversible decreased left ventricular function in the combination arm.
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fda Drug Approval summary azacitidine 5 azacytidine vidaza for injectable suspension
Oncologist, 2005Co-Authors: Edvardas Kaminskas, Rajeshwari Sridhara, Ann T Farrell, Yongcheng Wang, Richard PazdurAbstract:On May 19, 2004, azacitidine (5-azacytidine; Vidaza(trade mark); Pharmion Corporation, Boulder, CO, http://www.pharmion.com) for injectable suspension received regular Approval by the U.S. Food and Drug Administration (FDA) for the treatment of all subtypes of myelodysplastic syndrome (MDS). This report summarizes the basis for this Approval. Effectiveness was demonstrated in one randomized, controlled trial comparing azacitidine administered s.c. with best supportive care (observation group) and in two single-arm studies, one in which azacitidine was administered s.c. and in the other in which it was administered i.v. The dose of azacitidine, 75 mg/m2/day for 7 days every 28 days, was the same in all three studies. In the randomized trial, study participants were well matched with respect to age, sex, race, performance status, MDS subtype, and use of transfusion during the 3 months before study entry. Patients in the observation arm were permitted by protocol to cross over to azacitidine treatment if their disease progressed according to prespecified criteria. During the course of the study, more than half of the patients in the observation arm did cross over to the azacitidine treatment arm. The primary efficacy end point was the overall response rate. Response consisted of complete or partial normalization of blood cell counts and of bone marrow morphology. The response rate in the azacitidine arm was about 16%; there were no responses in the observation arm. The response rates in the two single-arm studies were similar (13% and 19%). The responses were sustained, with median durations of 11 months and 17 months respectively. Responding patients who were transfusion dependent at study entry lost the need for transfusions. In addition, about 19% of patients had less than partial responses (termed improvement), and two-thirds of them became transfusion independent. Common adverse events associated with azacitidine treatment were gastrointestinal (nausea, vomiting, diarrhea, constipation, and anorexia), hematologic (neutropenia, thrombocytopenia), fevers, rigors, ecchymoses, petechiae, injection site events, arthralgia, headache, and dizziness. Liver function abnormalities occurred in 16% of patients with intercurrent hepatobiliary disorders and in two patients with previously diagnosed liver cirrhosis. Renal failure occurred in patients during sepsis and hypotension. There were no deaths attributed to azacitidine. Azacitidine, the first Drug approved by the U.S. FDA for MDS, has a favorable safety profile and provides a clinical benefit of eliminating transfusion dependence and complete or partial normalization of blood counts and bone marrow blast percentages in responding patients.
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united states food and Drug administration Drug Approval summary gefitinib zd1839 iressa tablets
Clinical Cancer Research, 2004Co-Authors: Martin H Cohen, Grant Williams, Rajeshwari Sridhara, Gang Chen, David W Mcguinn, David L Morse, Sophia Abraham, Atiqur Rahman, Chenyi Liang, Richard T LostrittoAbstract:On May 5, 2003, gefitinib (Iressa; ZD1839) 250-mg tablets (AstraZeneca Inc.) received accelerated Approval by the United States Food and Drug Administration as monotherapy for patients with locally advanced or metastatic non-small cell lung cancer after failure of both platinum-based and docetaxel chemotherapies. Information provided in this summary includes chemistry manufacturing and controls, clinical pharmacology, and clinical trial efficacy and safety results. Gefitinib is an anilinoquinazoline compound with the chemical name 4-quinazolinamine,N-(3-chloro-4-flurophenyl)-7-methoxy-6-[3-(4-morpholinyl)propoxy]. It has the molecular formula C(22)H(24)ClFN(4)O(3). Gefitinib is often referred to as a "specific" or "selective" inhibitor of epidermal growth factor receptor. Studies demonstrate, however, that gefitinib inhibits the activity of other intracellular transmembrane tyrosine-specific protein kinases at concentrations similar to those at which it inhibits the epidermal growth factor signal. Maximum plasma concentrations resulting from clinically relevant doses are 0.5-1 microM or more, well within the IC(50) values of several tyrosine kinases. No clinical studies have been performed that demonstrate a correlation between epidermal growth factor receptor expression and response to gefitinib. Gefitinib is 60% available after oral administration and is widely distributed throughout the body. Gefitinib is extensively metabolized in the liver by cytochrome P450 3A4 enzyme. Over a 10-day period, approximately 86% of an orally administered radioactive dose is recovered in the feces, with <4% of the dose in the urine. After daily oral administration, steady-state plasma levels are reached in 10 days and are 2-fold higher than those achieved after single doses. Gefitinib effectiveness was demonstrated in a randomized, double-blind, Phase II, multicenter trial comparing two oral doses of gefitinib (250 versus 500 mg/day). A total of 216 patients were enrolled. The 142 patients who were refractory to or intolerant of a platinum and docetaxel comprised the evaluable population for the efficacy analysis. A partial tumor response occurred in 14% (9 of 66) of patients receiving 250 mg/day gefitinib and in 8% (6 of 76) of patients receiving 500 mg/day gefitinib. The overall objective response rate (RR) for both doses combined was 10.6% (15 of 142 patients; 95% confidence interval, 6.0-16.8%). Responses were more frequent in females and in nonsmokers. The median duration of response was 7.0 months (range, 4.6-18.6+ months). Other submitted data included the results of two large trials conducted in chemotherapy-naive, stage III and IV non-small cell lung cancer patients. Patients were randomized to receive gefitinib (250 or 500 mg daily) or placebo, in combination with either gemcitabine plus cisplatin (n = 1093) or carboplatin plus paclitaxel (n = 1037). Results from this study showed no benefit (RR, time to progression, or survival) from adding gefitinib to chemotherapy. Consequently, gefinitib is only recommended for use as monotherapy. Common adverse events associated with gefitinib treatment included diarrhea, rash, acne, dry skin, nausea, and vomiting. Interstitial lung disease has been observed in patients receiving gefitinib. Worldwide, the incidence of interstitial lung disease was about 1% (2% in the Japanese post-marketing experience and about 0.3% in a United States expanded access program). Approximately one-third of the cases have been fatal. Gefitinib was approved under accelerated Approval regulations on the basis of a surrogate end point, RR. No controlled gefitinib trials, to date, demonstrate a clinical benefit, such as improvement in disease-related symptoms or increased survival. Accelerated Approval regulations require the sponsor to conduct additional studies to verify that gefitinib therapy produces such benefit.
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united states food and Drug administration Drug Approval summary gefitinib zd1839 iressa tablets
Clinical Cancer Research, 2004Co-Authors: Martin H Cohen, Grant Williams, Rajeshwari Sridhara, Gang Chen, David W Mcguinn, David L Morse, Sophia Abraham, Atiqur Rahman, Chenyi Liang, Richard T LostrittoAbstract:On May 5, 2003, gefitinib (Iressa; ZD1839) 250-mg tablets (AstraZeneca Inc.) received accelerated Approval by the United States Food and Drug Administration as monotherapy for patients with locally advanced or metastatic non-small cell lung cancer after failure of both platinum-based and docetaxel chemotherapies. Information provided in this summary includes chemistry manufacturing and controls, clinical pharmacology, and clinical trial efficacy and safety results. Gefitinib is an anilinoquinazoline compound with the chemical name 4-quinazolinamine, N -(3-chloro-4-flurophenyl)-7-methoxy-6-[3-(4-morpholinyl)propoxy]. It has the molecular formula C 22 H 24 ClFN 4 O 3 . Gefitinib is often referred to as a “specific” or “selective” inhibitor of epidermal growth factor receptor. Studies demonstrate, however, that gefitinib inhibits the activity of other intracellular transmembrane tyrosine-specific protein kinases at concentrations similar to those at which it inhibits the epidermal growth factor signal. Maximum plasma concentrations resulting from clinically relevant doses are 0.5–1 μm or more, well within the IC 50 values of several tyrosine kinases. No clinical studies have been performed that demonstrate a correlation between epidermal growth factor receptor expression and response to gefitinib. Gefitinib is 60% available after oral administration and is widely distributed throughout the body. Gefitinib is extensively metabolized in the liver by cytochrome P450 3A4 enzyme. Over a 10-day period, approximately 86% of an orally administered radioactive dose is recovered in the feces, with versus 500 mg/day). A total of 216 patients were enrolled. The 142 patients who were refractory to or intolerant of a platinum and docetaxel comprised the evaluable population for the efficacy analysis. A partial tumor response occurred in 14% (9 of 66) of patients receiving 250 mg/day gefitinib and in 8% (6 of 76) of patients receiving 500 mg/day gefitinib. The overall objective response rate (RR) for both doses combined was 10.6% (15 of 142 patients; 95% confidence interval, 6.0–16.8%). Responses were more frequent in females and in nonsmokers. The median duration of response was 7.0 months (range, 4.6–18.6+ months). Other submitted data included the results of two large trials conducted in chemotherapy-naive, stage III and IV non-small cell lung cancer patients. Patients were randomized to receive gefitinib (250 or 500 mg daily) or placebo, in combination with either gemcitabine plus cisplatin ( n = 1093) or carboplatin plus paclitaxel (n = 1037). Results from this study showed no benefit (RR, time to progression, or survival) from adding gefitinib to chemotherapy. Consequently, gefinitib is only recommended for use as monotherapy. Common adverse events associated with gefitinib treatment included diarrhea, rash, acne, dry skin, nausea, and vomiting. Interstitial lung disease has been observed in patients receiving gefitinib. Worldwide, the incidence of interstitial lung disease was about 1% (2% in the Japanese post-marketing experience and about 0.3% in a United States expanded access program). Approximately one-third of the cases have been fatal. Gefitinib was approved under accelerated Approval regulations on the basis of a surrogate end point, RR. No controlled gefitinib trials, to date, demonstrate a clinical benefit, such as improvement in disease-related symptoms or increased survival. Accelerated Approval regulations require the sponsor to conduct additional studies to verify that gefitinib therapy produces such benefit.
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fda Drug Approval summary gefitinib zd1839 iressa tablets
Oncologist, 2003Co-Authors: Martin H Cohen, Grant Williams, Rajeshwari Sridhara, Gang Chen, Richard PazdurAbstract:On May 5, 2003, gefitinib (Iressa), ZD1839) 250-mg tablets received accelerated Approval by the U.S. Food and Drug Administration as monotherapy treatment for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of both platinum-based and docetaxel chemotherapies. Information provided in this summary includes efficacy and safety results of relevant clinical trials. Effectiveness was demonstrated in a randomized, double-blind, phase II, multicenter trial comparing two oral doses of gefitinib (250 mg/day versus 500 mg/day). Two hundred sixteen patients were enrolled. The 142 patients who were refractory to or intolerant of a platinum and docetaxel comprised the evaluable population for the efficacy analysis. A partial tumor response occurred in 14% (9 of 66) of patients receiving gefitinib 250 mg/day and in 8% (6 of 76) of patients receiving gefitinib 500 mg/day. The overall objective response rate for both doses combined was 10.6% (15 of 142 patients) (95% confidence interval 6.0%-16.8%). Responses were more frequent in females and in nonsmokers. The median duration of response was 7.0 months (range 4.6-18.6+ months). Other submitted data included the results of two large trials conducted in chemotherapy-naive, stage III and IV NSCLC patients. Patients were randomized to receive gefitinib (250 mg or 500 mg daily) or placebo, in combination with either gemcitabine plus cisplatin (n = 1,093) or carboplatin plus paclitaxel (n = 1,037). Results from those studies showed no benefit (response rate, time to progression, or survival) from adding gefitinib to chemotherapy. Consequently, gefinitib is only recommended for use as monotherapy. Common adverse events associated with gefitinib treatment included diarrhea, rash, acne, dry skin, nausea, and vomiting. Most toxicities were Common Toxicity Criteria grade 1 or 2. Interstitial lung disease (ILD) has been observed in patients receiving gefitinib. Worldwide, the incidence of ILD is about 1% (2% in the Japanese postmarketing experience and about 0.3% in a U.S. expanded access program). Approximately one-third of the cases were fatal. Physicians should promptly evaluate new or worsening pulmonary symptoms. If ILD is confirmed, appropriate management includes discontinuation of gefitinib. Gefitinib was approved under accelerated Approval regulations on the basis of a surrogate end point response rate. No controlled gefitinib trials, to date, demonstrate a clinical benefit, such as improvement in disease-related symptoms or greater survival. Accelerated Approval regulations require the sponsor to conduct further studies to verify that gefitinib therapy produces such a benefit.
Richard T Lostritto - One of the best experts on this subject based on the ideXlab platform.
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united states food and Drug administration Drug Approval summary gefitinib zd1839 iressa tablets
Clinical Cancer Research, 2004Co-Authors: Martin H Cohen, Grant Williams, Rajeshwari Sridhara, Gang Chen, David W Mcguinn, David L Morse, Sophia Abraham, Atiqur Rahman, Chenyi Liang, Richard T LostrittoAbstract:On May 5, 2003, gefitinib (Iressa; ZD1839) 250-mg tablets (AstraZeneca Inc.) received accelerated Approval by the United States Food and Drug Administration as monotherapy for patients with locally advanced or metastatic non-small cell lung cancer after failure of both platinum-based and docetaxel chemotherapies. Information provided in this summary includes chemistry manufacturing and controls, clinical pharmacology, and clinical trial efficacy and safety results. Gefitinib is an anilinoquinazoline compound with the chemical name 4-quinazolinamine,N-(3-chloro-4-flurophenyl)-7-methoxy-6-[3-(4-morpholinyl)propoxy]. It has the molecular formula C(22)H(24)ClFN(4)O(3). Gefitinib is often referred to as a "specific" or "selective" inhibitor of epidermal growth factor receptor. Studies demonstrate, however, that gefitinib inhibits the activity of other intracellular transmembrane tyrosine-specific protein kinases at concentrations similar to those at which it inhibits the epidermal growth factor signal. Maximum plasma concentrations resulting from clinically relevant doses are 0.5-1 microM or more, well within the IC(50) values of several tyrosine kinases. No clinical studies have been performed that demonstrate a correlation between epidermal growth factor receptor expression and response to gefitinib. Gefitinib is 60% available after oral administration and is widely distributed throughout the body. Gefitinib is extensively metabolized in the liver by cytochrome P450 3A4 enzyme. Over a 10-day period, approximately 86% of an orally administered radioactive dose is recovered in the feces, with <4% of the dose in the urine. After daily oral administration, steady-state plasma levels are reached in 10 days and are 2-fold higher than those achieved after single doses. Gefitinib effectiveness was demonstrated in a randomized, double-blind, Phase II, multicenter trial comparing two oral doses of gefitinib (250 versus 500 mg/day). A total of 216 patients were enrolled. The 142 patients who were refractory to or intolerant of a platinum and docetaxel comprised the evaluable population for the efficacy analysis. A partial tumor response occurred in 14% (9 of 66) of patients receiving 250 mg/day gefitinib and in 8% (6 of 76) of patients receiving 500 mg/day gefitinib. The overall objective response rate (RR) for both doses combined was 10.6% (15 of 142 patients; 95% confidence interval, 6.0-16.8%). Responses were more frequent in females and in nonsmokers. The median duration of response was 7.0 months (range, 4.6-18.6+ months). Other submitted data included the results of two large trials conducted in chemotherapy-naive, stage III and IV non-small cell lung cancer patients. Patients were randomized to receive gefitinib (250 or 500 mg daily) or placebo, in combination with either gemcitabine plus cisplatin (n = 1093) or carboplatin plus paclitaxel (n = 1037). Results from this study showed no benefit (RR, time to progression, or survival) from adding gefitinib to chemotherapy. Consequently, gefinitib is only recommended for use as monotherapy. Common adverse events associated with gefitinib treatment included diarrhea, rash, acne, dry skin, nausea, and vomiting. Interstitial lung disease has been observed in patients receiving gefitinib. Worldwide, the incidence of interstitial lung disease was about 1% (2% in the Japanese post-marketing experience and about 0.3% in a United States expanded access program). Approximately one-third of the cases have been fatal. Gefitinib was approved under accelerated Approval regulations on the basis of a surrogate end point, RR. No controlled gefitinib trials, to date, demonstrate a clinical benefit, such as improvement in disease-related symptoms or increased survival. Accelerated Approval regulations require the sponsor to conduct additional studies to verify that gefitinib therapy produces such benefit.
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united states food and Drug administration Drug Approval summary gefitinib zd1839 iressa tablets
Clinical Cancer Research, 2004Co-Authors: Martin H Cohen, Grant Williams, Rajeshwari Sridhara, Gang Chen, David W Mcguinn, David L Morse, Sophia Abraham, Atiqur Rahman, Chenyi Liang, Richard T LostrittoAbstract:On May 5, 2003, gefitinib (Iressa; ZD1839) 250-mg tablets (AstraZeneca Inc.) received accelerated Approval by the United States Food and Drug Administration as monotherapy for patients with locally advanced or metastatic non-small cell lung cancer after failure of both platinum-based and docetaxel chemotherapies. Information provided in this summary includes chemistry manufacturing and controls, clinical pharmacology, and clinical trial efficacy and safety results. Gefitinib is an anilinoquinazoline compound with the chemical name 4-quinazolinamine, N -(3-chloro-4-flurophenyl)-7-methoxy-6-[3-(4-morpholinyl)propoxy]. It has the molecular formula C 22 H 24 ClFN 4 O 3 . Gefitinib is often referred to as a “specific” or “selective” inhibitor of epidermal growth factor receptor. Studies demonstrate, however, that gefitinib inhibits the activity of other intracellular transmembrane tyrosine-specific protein kinases at concentrations similar to those at which it inhibits the epidermal growth factor signal. Maximum plasma concentrations resulting from clinically relevant doses are 0.5–1 μm or more, well within the IC 50 values of several tyrosine kinases. No clinical studies have been performed that demonstrate a correlation between epidermal growth factor receptor expression and response to gefitinib. Gefitinib is 60% available after oral administration and is widely distributed throughout the body. Gefitinib is extensively metabolized in the liver by cytochrome P450 3A4 enzyme. Over a 10-day period, approximately 86% of an orally administered radioactive dose is recovered in the feces, with versus 500 mg/day). A total of 216 patients were enrolled. The 142 patients who were refractory to or intolerant of a platinum and docetaxel comprised the evaluable population for the efficacy analysis. A partial tumor response occurred in 14% (9 of 66) of patients receiving 250 mg/day gefitinib and in 8% (6 of 76) of patients receiving 500 mg/day gefitinib. The overall objective response rate (RR) for both doses combined was 10.6% (15 of 142 patients; 95% confidence interval, 6.0–16.8%). Responses were more frequent in females and in nonsmokers. The median duration of response was 7.0 months (range, 4.6–18.6+ months). Other submitted data included the results of two large trials conducted in chemotherapy-naive, stage III and IV non-small cell lung cancer patients. Patients were randomized to receive gefitinib (250 or 500 mg daily) or placebo, in combination with either gemcitabine plus cisplatin ( n = 1093) or carboplatin plus paclitaxel (n = 1037). Results from this study showed no benefit (RR, time to progression, or survival) from adding gefitinib to chemotherapy. Consequently, gefinitib is only recommended for use as monotherapy. Common adverse events associated with gefitinib treatment included diarrhea, rash, acne, dry skin, nausea, and vomiting. Interstitial lung disease has been observed in patients receiving gefitinib. Worldwide, the incidence of interstitial lung disease was about 1% (2% in the Japanese post-marketing experience and about 0.3% in a United States expanded access program). Approximately one-third of the cases have been fatal. Gefitinib was approved under accelerated Approval regulations on the basis of a surrogate end point, RR. No controlled gefitinib trials, to date, demonstrate a clinical benefit, such as improvement in disease-related symptoms or increased survival. Accelerated Approval regulations require the sponsor to conduct additional studies to verify that gefitinib therapy produces such benefit.
