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What's New New approvals from the Office of Oncology Drug Products, 2006 to the present New Approvals: Drugs & Biologicals On March 15, 2005 the U. S. Food and Drug Administration approved temozolomide (Temodar® capsules, Schering Corporation) for the treatment of adult patients with newly diagnosed glioblastoma multiforme (GBM) concomitantly with radiotherapy and then as maintenance treatment. Temozolomide (TMZ) previously received accelerated approval in 1999 for the treatment of adult patients with refractory anaplastic astrocytoma. This treatment indication is also converted to full approval based on the results of the GBM study described below. Safety and efficacy were demonstrated in a Phase 3 study conducted by the European Organization for Research and Treatment of Cancer (EORTC) in newly diagnosed GBM patients. Five hundred and seventy-three patients were randomized to receive either TMZ + Radiotherapy (RT) (n= 287) or RT alone (n=286). Patients in the TMZ + RT arm received concomitant TMZ (75 mg/m2) once daily, starting the first RT day until the last RT day, for 42 days (maximum 49 days). Six cycles of TMZ alone (150 or 200 mg/m2) followed on days 1-5 of every 28-day cycle, starting 4 weeks after the RT end. Patients in the control arm received RT only. In both arms RT was delivered as 60 Gy/30 fractions to the tumor bed or resection site with a 2-3 cm margin. Pneumocystis carinii pneumonia (PCP) prophylaxis was required during the TMZ + radiotherapy treatment, regardless of lymphocyte count, and was to continue until recovery of lymphocytopenia (CTC grade <1). At disease progression, patients in either study arm could receive TMZ treatment. The TMZ + RT and the RT only treatment arms were well matched with regard to baseline demographic characteristics. Approximately 60% were male and approximately 70% were >50 years of age. A total of 88% in both treatment groups had a WHO performance status of 0 or 1 and 84% had undergone debulking surgery within 6 weeks of study entry. At the time of disease progression, TMZ was administered to 161 patients of the 282 (57 %) in the RT alone arm, and 62 patients of the 277 (22%) in the TMZ + RT arm. Significant improved overall survival in patients receiving concomitant and maintenance TMZ + RT was observed. The hazard ratio was 0.63 (95 % CI for HR=0.52-0.75) with a log-rank p <0.0001 in favor of the combined modality arm. Median survival was 14.6 months (TMZ + RT) versus 12.1 months (RT alone). Adverse events during TMZ + RT treatment included thrombocytopenia, nausea, vomiting, anorexia and constipation. The most common adverse events across the total TMZ exposure were alopecia, nausea, vomiting, anorexia, headache, and constipation. Forty-nine percent (49%) of patients treated with TMZ reported one or more severe or life-threatening events, most commonly fatigue (13%), convulsions (6%), headache (5%) and thrombocytopenia (5%). Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available at www.fda.gov/cder/foi/label/2005/021029s008lbl.pdf On January 7, 2005 the U. S. Food and Drug Administration approved paclitaxel protein-bound particles for injectable suspension (albumin-bound) (Abraxane(tm), American BioScience, Inc) for treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated. The clinical database included two single arm studies enrolling a total of 106 patients and one multi-center randomized trial. The multi-center trial was conducted in 460 patients with metastatic breast cancer who were randomized to receive either Abraxane 260 mg/m2 administered as a 30-minute infusion or paclitaxel 175 mg/m2 given over 3 hours. Fifty-nine percent of patients had received one or more prior chemotherapy regimens, and 77% had received an anthracycline-containing regimen. The objective response rate verified by central review was 21.5% (95% CI: 16.2% to 26.7%) for Abraxane compared to 11.1% (95% CI: 6.9% to 15.1%) for paclitaxel (p=0.003). Clinically important adverse events (all grade) in the randomized trial comparing Abraxane to paclitaxel included neutropenia (80% with Abraxane and 82% with paclitaxel), anemia (33% vs. 25%), infections (24% vs. 20%), hypersensitivity reactions (4% vs. 12%), sensory neuropathy (71% vs. 56%), edema (10% vs. 8%), nausea (30% vs. 21%), vomiting (18% vs. 9%), diarrhea (26% vs. 15%), and mucositis (7% in both arms). Severe adverse events (grade 3 or 4) included neutropenia (9% with Abraxane and 22% with paclitaxel), myalgia/arthralgia (8% vs. 4%) and vomiting (4% vs. 1%). Ten percent (24 patients) treated with Abraxane developed grade 3 peripheral neuropathy; 14 of these patients showed some improvement of neuropathy at a median of 22 days. Two percent of patients receiving paclitaxel developed grade 3 peripheral neuropathy. The recommended dose of Abraxane is 260 mg/m2 administered intravenously over 30 minutes every 3 weeks. No premedication to prevent hypersensitivity reactions is required prior to Abraxane administration. Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available at www.fda.gov/cder/foi/label/2005/021660lbl.pdf. On December 28, 2004 the U. S. Food and Drug Administration granted accelerated approval for clofarabine (ClolarTM For Intravenous Infusion, Genzyme Corporation), a purine nucleoside antimetabolite, for treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens. The approval of this indication is based on the induction of complete responses. Clinical studies demonstrating increased survival or other clinical benefit have not been conducted. Approval was granted under accelerated approval regulations that require the applicant to conduct and complete additional clinical studies to confirm clinical benefit. Efficacy and safety were demonstrated in a single multi-center trial that enrolled 49 patients. Most patients had received 2 to 4 prior regimens and 15/49 (31%) had undergone at least one transplant. The median age was 12 years. Clofarabine was given at a dose of 52 mg/m2, intravenously, over 2 hours daily x 5 repeated every 2 to 6 weeks following recovery or return to baseline organ function. The study endpoints were the rate of complete response (CR) and the rate of complete response without platelet recovery (CRp). The former was defined as no evidence of circulating blasts or extramedullary disease, an M1 bone marrow, and recovery of peripheral platelet and absolute neutrophil counts; the latter was defined as meeting all criteria for CR except for platelet count recovery. Response rates were determined by an Independent Response Review Panel (IRRP). Six patients (12%) achieved a CR and 4 patients (8%) achieved a CRp, and 5 patients (10%) achieved a PR. Of the 15 responding patients, 6 had post-clofarabine bone marrow transplantation. Hence, response durations could not be determined. In the patients who were not transplanted, the response durations for CR were 43, 50, 82, 93+, and 160+ days; for CRp the response duration was 32 days. The principal clofarabine toxicities were nausea, vomiting, hematologic toxicity, febrile neutropenia, hepatobiliary toxicity, infections and renal toxicity. Clofarabine can produce systemic inflammatory response syndrome/capillary leak syndrome (SIRS), manifested by the rapid development of tachypnea, tachycardia, hypotension, shock, and multi-organ failure. Cardiac toxicity was characterized as left ventricular systolic dysfunction; tachycardia may also occur. Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available at www.fda.gov/cder/foi/label/2004/021673lbl.pdf. On November 18, 2004 the U. S. Food and Drug Administration approved erlotinib (TarcevaTM tablets, OSI Pharmaceuticals Inc.) for treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen. Safety and efficacy were demonstrated in a 731 patient double-blind, multi-national, randomized trial comparing erlotinib 150 mg p.o. daily to placebo. Survival was significantly prolonged on the erlotinib arm with a median overall survival of 6.7 months and 4.7 months in the erlotinib and placebo groups, respectively. The adjusted Hazard Ratio (HR) for death in the erlotinib group relative to the placebo group was 0.73, p = <0.001. Progression-free survival was significantly prolonged on the erlotinib arm with a median PFS of 9.9 weeks vs. 7.9 weeks in erlotinib and placebo groups, respectively. The adjusted HR for progression was 0.59, p < 0.001. The objective response rate by RECIST in the erlotinib group was 8.9% (95% CI: 6.4 to 12.0%). The median response duration was 34.3 weeks, ranging from 9.7 to 57.6+ weeks. Two responses (0.9%, 95% CI: 0.1 to 3.4) were reported in the placebo group. An exploratory analysis of Epidermal Growth Factor Receptor (EGFR) protein expression status on treatment survival effect was performed; however, EGFR status was known for only 33% of patients. The EGFR expression was determined using the DAKO EGFR pharmDx(tm) kit. About half of the patients with known EGFR status were positive and half were negative. In the EGFR positive subgroup, erlotinib prolonged survival compared to placebo (median 10.7 vs. 3.8 months, HR=0.65, p=0.033). No apparent erlotinib survival effect was observed in the EGFR negative subgroup (erlotinib median: 5.2 months vs. placebo median: 7.5 months; HR=1.01, p=0.958). However, the confidence intervals for the EGFR positive and negative subgroups are wide and overlap. Thus, an erlotinib survival effect in the EGFR negative subgroup can not be excluded. Post approval clinical trials will prospectively examine the relationship of EGFR status and survival effects. An additional subgroup survival analysis examining the effect of smoking status showed that the erlotinib survival benefit was greater in patients who had never smoked (HR 0.42; 95% CI: 0.3, 0.6) than in smokers (HR 0.87; 95% CI: 0.7, 1.1). The most common adverse reactions in patients receiving erlotinib were diarrhea and rash. Grade 3/4 rash and diarrhea occurred in 9% and 6%, respectively. Rash and diarrhea each resulted in study discontinuation in 1% of erlotinib-treated patients. Only 6% and 1% of patients required dose reductions for rash and diarrhea, respectively. The median time to onset of rash was 8 days; the median time to onset of diarrhea was 12 days. Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available at www.fda.gov/cder/foi/label/2004/021743lbl.pdf. On November 4, 2004, the U.S. Food and Drug Administration approved oxaliplatin for injection (EloxatinTM, Sanofi-Synthelabo Inc.) in combination with infusional 5-fluorouracil/leucovorin (5-FU/LV) for adjuvant treatment of stage III colon cancer patients who have undergone complete resection of the primary tumor. Approval is based on an improvement in disease-free survival (DFS), with no demonstrated benefit in overall survival after a median follow-up of 4 years. Safety and efficacy were demonstrated in a multi-center, randomized, open-label, international clinical trial. There were 2246 patients with stage II or III colon cancer, who had undergone complete resection of the primary tumor, that were equally randomized to one of two arms: oxaliplatin plus infusional 5FU/LV (FOLFOX 4 regimen) and infusional 5FU/LV (De Gramont regimen). Treatment was administered every two weeks for 12 cycles (6 months). At a median follow-up of 4 years, there was a statistically significant improvement in the primary endpoint of DFS for the oxaliplatin combination compared to infusional 5FU/LV, both in the overall study population (4 year DFS: 76% vs. 69%; hazard ratio = 0.76, 95%CI: 0.65, 0.90; p=0.0008) and in the subgroup with stage III disease (4 year DFS: 70% vs. 61%; hazard ratio = 0.75, 95% CI: 0.62, 0.90; p=0.002; N=1347). Survival data were not mature at the time of the analysis with a median follow-up of 47 months. No statistical difference in overall survival was shown between the treatment arms in the overall study population (hazard ratio 0.89, 95% CI: 0.72, 1.09; p=0.236) or in stage III patients. No statistical difference was observed either in DFS or survival in stage II patients. The incidence of grade 3 or grade 4 events was 70% and 31% on the oxaliplatin combination arm and infusional 5FU/LV arm, respectively. Granulocytopenia, paresthesia, diarrhea, vomiting and nausea were the most common grade 3 or 4 adverse events. Paresthesia was seen in 92% of patients on the oxaliplatin combination; 21% had residual paresthesia at 18 month follow-up. Three percent and 0.5% had grade 2 and 3 paresthesias, respectively, at 18 month follow-up. Grade 3 or 4 hypersensitivity was noted in 3% and may require discontinuation of therapy. Hepatotoxicity, evidenced by increase in transaminases (57% vs. 34 %) and alkaline phosphatases (42% vs. 20 %), was observed more commonly in the oxaliplatin combination arm. The incidence of increased bilirubin was similar on both arms. Hepatic vascular disorders should be considered and investigated if abnormal liver function tests or portal hypertension are present and can not be explained by liver metastases or other known etiologies. Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available at www.fda.gov/cder/foi/label/2004/021492s004lbl.pdf. On October 29, 2004, the U.S. Food and Drug Administration granted accelerated approval for letrozole tablets (Femara(r), Novartis Pharmaceuticals Corporation) for the extended adjuvant treatment of early breast cancer in postmenopausal women who had received 5 years of adjuvant tamoxifen therapy. Approval was granted under accelerated approval regulations that require the sponsor to provide long-term outcome analyses. Safety and efficacy were evaluated in a double-blind, multicenter, international clinical study in post-menopausal women with hormone receptor positive early stage breast cancer who had received 5 years of adjuvant therapy with tamoxifen. A total of 5187 women were randomized 1:1, within 3 months of completion of adjuvant tamoxifen, to receive 5 years of letrozole or placebo. Patients were stratified by hormone receptor status, lymph node status and prior adjuvant chemotherapy. Assessment of both safety and efficacy is limited because of short follow-up. The median duration of follow-up was 28 months; 30% of patients completed 3 or more years of follow-up and less than 1% were followed for 5 years or greater. Approval was based on an analysis of disease free survival (DFS), defined as the time from randomization to the earliest event of time-to-loco-regional or distant recurrence of the primary disease, development of contralateral breast cancer, or death. At the time of analysis, the frequency of DFS events was 4.7% in patients receiving letrozole compared to 7.5% in patients receiving placebo (HR=0.62, 95% CI: 0.49, 0.78; p=0.00003). The risk of distant metastases was also significantly lower for letrozole than placebo (HR 0.61, 95% CI: 0.44, 0.84; p=0.003). Data on survival were not mature enough for analysis. The long term risks of letrozole have not been fully evaluated. With short follow-up, the incidences of clinical fractures were comparable between patients who received letrozole (5.9%) and those receiving placebo (5.5%). The incidence of self-reported osteoporosis was higher in patients who received letrozole (6.9%) than in patients who received placebo (5.5%). Preliminary results (20 month median follow-up) from a bone sub-study demonstrated that the mean decrease in hip bone mineral density (BMD) compared to baseline at 2 years was 3% versus 0.4% for letrozole versus placebo, respectively (p=0.048). The mean decrease in BMD from baseline for the lumbar spine at 2 years was 4.6% decrease and 2.2% for letrozole and placebo, respectively (p=0.069). The incidence of cardiovascular ischemic events from the core randomized study was comparable between patients receiving letrozole (6.8%) and placebo (6.5%). In the extended adjuvant setting, the optimal treatment duration with letrozole is unknown. In the randomized trial the median treatment duration was 24 months, with only 25% of patients treated for at least 3 years and less than 1% of patients treated for 5 years (the planned treatment duration). Treatment should be discontinued at tumor relapse. Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available at www.fda.gov/cder/foi/label/2004/020726s011lbl.pdf. On May 19, 2004 the U.S. Food and Drug Administration approved azacitidine for injectable suspension (Vidaza(tm), Pharmion Corporation) for use in patients with all subtypes of myelodysplastic syndromes. Approval was based on response rates supported by reduction or elimination of transfusion dependence. Safety and efficacy were demonstrated in one multi-center, randomized trial in 191 patients with all five French, American and British subtypes of myelodysplastic syndromes comparing azacitidine treatment to observation only, and in two multi-center single-arm azacitidine trials in 120 patients. Azacitidine was administered at a dose of 75 mg/m2/day for 7 days every 28 days subcutaneously in the randomized trial and in one of the single-arm trials. Patients in the "observation only" arm of the randomized trial were permitted to cross over to Vidaza(tm) treatment. Greater than 50% of observation only patients crossed over to Vidaza(tm) treatment at the time of disease progression. Patients with an adjudicated diagnosis of AML at baseline were excluded from the efficacy analysis of response rate. Clinical response (complete and partial) was observed in approximately 16% of the azacitidine patients. The response rates were similar in patients randomized to Vidaza(tm) treatment (15.7%), in patients who crossed over from the observation arm to Vidaza(tm) treatment (12.8%), and in patients in the two single arm trials (12.7% and 19.1%). None of the patients in the observation only arm had clinical response. The difference in response rates between Vidaza(tm) treated patients and "observation only" patients was statistically significant (p<0.0001). Median response duration was greater than 330 days in the randomized trial. The response duration could not be accurately estimated, because most patients remained in response status at the time of study completion. In addition to complete and partial responses, approximately 24% of Vidaza-treated patients had either reduction of the need for transfusions and/or ≤50% normalization of blood cell counts and/or bone marrow blast percentages. The major toxicity of azacitidine was myelosuppression, as manifested by thrombocytopenia (and bleeding), neutropenia (and infections), and anemia. Myelosuppression decreased with the onset of a response. Other common adverse events were gastrointestinal (nausea, vomiting, diarrhea, constipation, anorexia), constitutional (fatigue, weakness, fever, rigors), musculoskeletal (arthralgia, pain in limb), pulmonary (cough, dyspnea), and skin and soft tissue (ecchymoses, rash, erythema). Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available at http://www.fda.gov/cder/foi/label/2004/050794lbl.pdf On May 19, 2004, the U.S. Food and Drug Administration approved gemcitabine HCl for injection (Gemzar®, Eli Lilly and Company) in combination with paclitaxel for the firstline treatment of patients with metastatic breast cancer after failure of prior anthracycline containing adjuvant chemotherapy, unless anthracyclines were clinically contraindicated. Safety and efficacy were demonstrated in one multi-center, multinational, randomized trial in 529 patients comparing the combination of Gemzar and paclitaxel with paclitaxel alone. Gemzar 1250 mg/m2 (intravenous infusion over 30 minutes) was administered on Days 1 and 8 of a 21day cycle with paclitaxel 175 mg/m2 (intravenous infusion over 3 hours) administered prior to Gemzar on Day 1 of each cycle. Singleagent paclitaxel 175 mg/m2 (intravenous infusion over 3 hours) was administered on Day 1 of each 21day cycle as the control arm. The primary endpoint of the study was overall survival. Time to documented progressive disease was a co-primary endpoint. Gemzar in combination with paclitaxel resulted in statistically significant improvement in time to documented disease progression (median TtDPD 5.2 months versus 2.9 months, p<0.0001), and overall response rate (RR 40.6% versus 22.1%, p<0.0001) compared to monotherapy with paclitaxel. The combination of Gemzar plus paclitaxel also showed a strong trend toward improved survival in an interim survival analysis. The principal Grade 3 and 4 adverse effects of the Gemzar plus paclitaxel regimen were hematologic (neutropenia, anemia and thrombocytopenia). Grade 3 and 4 liver enzyme elevation was also more common with Gemzar plus paclitaxel treatment. Grade 3 and 4 non-laboratory toxicities associated with Gemzar plus paclitaxel therapy included fatigue, neuropathy and myalgias. Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available at http://www.fda.gov/cder/foi/label/2004/020509s029lbl.pdf On May 19, 2004, the U.S. Food and Drug Administration approved docetaxel for injection (Taxotere(r), Aventis Pharmaceuticals, Inc) for use in combination with prednisone for the treatment of metastatic, androgen-independent (hormone refractory) prostate cancer. Safety and efficacy were demonstrated in TAX327, a randomized, multi-center global clinical trial designed to evaluate chemotherapy with Taxotere and prednisone in the treatment of men with metastatic, hormone-refractory prostate cancer. One thousand and six patients were randomized to one of three treatment arms: (1) mitoxantrone + prednisone (MTX + P), (2) weekly Taxotere (TXT qw) + prednisone, or (3) Taxotere once every three weeks (TXT q3w) + prednisone. The primary efficacy endpoint was survival. The treatment arm of TXT q3w + prednisone demonstrated a statistically significant survival advantage over MTX+P control (median survival 18.9 vs. 16.5 months, respectively, p = 0.0094). The TXT qw + prednisone arm did not demonstrate an advantage in overall survival over the control arm. Adverse events included anemia, neutropenia, infection, nausea, vomiting, anorexia, and fatigue. Adverse events occurring more frequently with TXT q3w compared to MTX+P included allergic reactions, fluid retention, sensory neuropathy, alopecia, nail changes, diarrhea, and stomatitis. The approved dose for this indication is 75 mg/m2 docetaxel given intravenously as a 1-hour infusion every 21 days on day 1 plus 5 mg oral prednisone twice daily for 10 cycles. Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available at http://www.fda.gov/cder/foi/label/2004/020449s028lbl.pdf On February 26, 2004, the U.S. Food and Drug Administration approved bevacizumab (Avastin, Genentech) as a first-line treatment for patients with metastatic colorectal cancer. The safety and efficacy of Avastin was primarily shown in a randomized, double-blind clinical trial of more than 800 patients with metastatic colorectal cancer designed to find out whether Avastin extended the lives of patients. Roughly half the patients received IFL(irinotecan with bolus 5-FU and leucovorin), the standard chemotherapy combination, and the other half received Avastin once every two weeks in addition to IFL. Overall, patients given Avastin in combination with IFL survived about five months longer and the average time before tumors started regrowing or new tumors appeared was four months longer than patients receiving IFL alone. The overall response rate to the treatment was 45% compared to 35% for the control arm of the trial. Serious, but uncommon, side-effects of Avastin include formation of holes in the colon (gastrointestinal perforation) generally requiring surgery and sometimes leading to intra-abdominal infections, impaired wound healing, and bleeding from the lungs or internally. Other, more common, side-effects are high blood pressure, tiredness, blood clots, diarrhea, decreased white blood cells (lowering immunity to diseases) headache, appetite loss and mouth sores.Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available at http://www.fda.gov/cder/foi/label/2004/125085lbl.pdf On February 12, 2004, the U.S. Food and Drug Administration approved cetuximab (Erbitux ImClone Systems Incoroporated) in combination with irinotecan for metastatic colorectal cancer that is refractory to irinotecan-based chemotherapy. The efficacy and safety of Erbitux alone or in combination with irinotecan were studied in a randomized, controlled trial with 329 patients and also in combination with irinotecan in 138 patients in which all patients received both drugs. Erbitux was further evaluated as a single agent in a third clinical trial with 57 patients. Safety data from an additional 111 patients treated only with Erbitux was also evaluated. All of the trials included patients with epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer, whose disease had progressed after receiving irinotecan. Erbitux can cause serious side-effects, usually during the administration of the first treatment, which may include difficulty breathing and low blood pressure. Infrequent interstitial lung disease (ILD) has been reported; however, it is difficult to determine if Erbitux caused ILD. ILD occurs when the lung becomes stiff due to scarring of the tissue between the air sacs of the lungs. Other more common side-effects of Erbitux treatment include acne-like rash, dry skin, tiredness or weakness, fever, constipation, and abdominal pain. Erbitux will be distributed and marketed by Bristol-Myers Squibb Company, Princeton, N.J. FDA also today approved a test kit, manufactured by DakoCytomation California, Inc., that is used to analyze a colon tissue sample. The kit detects a protein in the body (HER-1) that stimulates cancerous tissue cell growth. Presence of this protein indicates that a patient is eligible for colon cancer treatment with cetuximab. Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available at http://www.fda.gov/cder/foi/label/2004/125084lbl.pdf On February 4, 2004, the U.S. Food and Drug Administration approved pemetrexed for injection (Alimta*, Eli Lilly and Company) in combination with cisplatin for the treatment of patients with malignant pleural mesothelioma whose disease is either unresectable or who are not otherwise candidates for curative surgery. Safety and efficacy were demonstrated in one multi-center, randomized trial in 456 patients comparing the combination of Alimta and cisplatin with cisplatin alone. Supplementation with vitamin B12 and folic acid was instituted during the trial to decrease adverse effects. Subsequently, all patients, including previously enrolled patients, were given vitamin supplementation. In an analysis of all patients who were randomized and treated, the combination of Alimta and cisplatin was associated with a statistically significant improvement in survival compared to cisplatin alone. The median survivals were 12.1 versus 9.3 months, respectively (p=0.020). This superiority in the combination arm was also demonstrated in the fully vitamin supplemented subgroup. The median survivals were 13.3 and 10.0 months in the combination and cisplatin alone groups, respectively (p=0.051). The principal adverse effects of the Alimta plus cisplatin regimen were myelosuppression, fatigue, nausea, vomiting, and dyspnea. Most grade 3-4 adverse effects were significantly reduced by vitamin supplementation without any efficacy decrement. Alimta, 500 mg/m2, was diluted in 100 mL normal saline and administered as a 10-minute intravenous infusion. Approximately 30 minutes after Alimta administration, cisplatin, 75 mg/m2 over 2 hours, was administered. Both drugs were given every 21 days. Folic acid, 350 to 1000 micrograms orally, was given daily, beginning 1 to 3 weeks prior to the first chemotherapy dose and continued daily for 1 to 3 weeks after treatment discontinuation. A vitamin B12 injection, 1000 micrograms intramuscularly, was administered 1 to 3 weeks before the first chemotherapy dose and repeated approximately every 9 weeks until treatment discontinuation. Dexamethasone 4 mg (or an equivalent corticosteroid) twice daily was administered orally for skin rash prophylaxis to all patients one day prior to, on the day of, and one day after each Alimta dose. Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available at www.fda.gov/cder/foi/label/2004/021462lbl.pdf On January 9, 2004 the U.S. Food and Drug Administration approved oxaliplatin for injection (EloxatinTM, Sanofi-Synthelabo Inc.), for use in combination with Infusional 5-FU/LV for the initial treatment of advanced colorectal cancer. Eloxatin previously received accelerated approval on August 9, 2002 for use in combination with Infusional 5-FU/LV for the treatment of patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed during or within 6 months of completion of first-line therapy with the combination of Bolus 5-FU/LV and irinotecan. Safety and efficacy were demonstrated in one multi-center, randomized controlled clinical trial sponsored by the National Cancer Institute as an inter-group study led by the North Central Cancer Treatment Group. The study had 7 arms at different times during its conduct, four of which were closed due to either changes in the standard of care, toxicity or simplification. During the study, the control arm was changed to irinotecan plus Bolus 5-FU/LV. The Eloxatin + Infusional FU/LV regimen was compared to an approved control regimen of irinotecan plus Bolus 5-FU/LV in 531 concurrently randomized patients previously untreated for locally advanced or metastatic colorectal cancer. Patients may have received adjuvant therapy for resected Stage II or III disease without recurrence within 12 months. After completion of enrollment, the dose of irinotecan plus 5-FU/LV was decreased due to toxicity. The Eloxatin + Infusional FU/LV regimen showed superior survival to the irinotecan plus Bolus FU/LV regimen with median survivals of 19.4 and 14.6 months (p=0.0001), respectively. Time to tumor progression and tumor response rate were also superior on the Eloxatin + Infusional FU/LV regimen. Fatigue, neuropathy, nausea, vomiting, diarrhea, stomatitis, neutropenia and thrombocytopenia were the more common adverse events. Febrile neutropenia or requirement for platelet transfusion were not increased as compared to the irinotecan + Bolus 5-FU/LV. Eloxatin has been associated with pulmonary fibrosis (<1% of study patients), which may be fatal. There have been reports while on study and from post-marketing surveillance of prolonged prothrombin time and INR occasionally associated with hemorrhage in patients who received Eloxatin plus 5-FU/LV while on anticoagulants. Patients requiring oral anticoagulants may require closer monitoring. Hypersensitivity has been observed (<2% Grade 3/4) in clinical studies and was usually managed with standard epinephrine, corticosteroid, antihistamine therapy, and may require discontinuation of therapy. Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available at www.fda.gov/cder/foi/label/2004/021492s002lbl.pdf On December 8, 2003 the Food and Drug Administration
(FDA) converted the approval of imatinib mesylate tablets (Gleevec(r), Novartis Pharmaceuticals Corporation) for the treatment
of adult patients with Philadelphia chromosome positive (Ph+) chronic myeloid
leukemia (CML) in blast crisis (BC), accelerated phase (AP), or in chronic
phase after failure of interferon-alpha therapy (IFN) from accelerated to
regular approval. Gleevec was originally approved, under the accelerated
approval program, for use in these settings in May, 2001. Follow-up was short at the time of accelerated
approval. Novartis
Pharmaceuticals, was required to conduct longer
follow-up of the clinical trials to determine duration of response and obtain
longer term safety data. Five hundred thirty-two patients in chronic phase
CML after failure of IFN therapy were treated at a starting dose of 400 mg
daily; dose escalation to 600 mg was allowed.
The patients were distributed in three main categories according to
their response to prior IFN: failure to achieve (within 6 months), or loss of
a complete hematologic response (29%), failure to achieve
(within 1 year) or loss of a major cytogenetic
response (35%), or intolerance to IFN (36%).
Patients had received a median of 14 months of prior IFN therapy at
doses > 25 × 106 IU/week and were all in late chronic phase, with a median
time from diagnosis of 32 months. Gleevec effectiveness was evaluated on the basis of the
rate of hematologic response and by bone marrow
exams to assess the rate of major cytogenetic response
(up to 35% Ph+ metaphases) or complete cytogenetic
response (0% Ph+ metaphases). Median
duration of Gleevec treatment was 29 months with
81% of patients treated for 24 months (maximum = 31.5 months). A complete hematologic
response (CHR) was achieved in 95% of patients. The confirmed (second evaluation after ? 4 weeks) major cytogenetic
response rates (MCyR) was 60%. The confirmed complete cytogenetic
response (CCyR) rate was 39%. Favorable treatment
responses were sustained. An estimated
87.8% of patients who achieved MCyR maintain their
response 2 years after achieving their initial response. After 2 years of treatment, an estimated
85.4% of patients were free of progression to AP or BC, and estimated overall
survival was 90.8% [95% CI 88.3, 93.2]. The approved dose of Gleevec
is 400 mg/day for adult patients with CML in chronic phase, either newly
diagnosed or after treatment with interferon; and 600 mg/day for CML patients
in accelerated phase or blast crisis.
The long-term effects of treatment with Gleevec
are unknown. Please see package insert
for updated data for CML blast crisis and accelerated phase studies. Gleevec was also approved under accelerated approval for
treatment of newly diagnosed CML on Full prescribing information, including clinical
trial information, safety, dosing, drug-drug interactions and
contraindications is available at www.fda.gov/cder/foi/label/2003/021588s002lbl.pdf
On June 27, 2003 the Food and Drug
Administration (FDA) approved Tositumomab and
Iodine I 131 Tositumomab (BexxarÒ,
Corixa Corp), a monoclonal antibody-based, radioimmunotherapeutic regimen for the treatment of CD20
positive, follicular non-Hodgkin’s lymphoma, with or without transformation,
which is refractory to Rituximab and has relapsed
following chemotherapy. The Bexxar therapeutic
regimen is a multi-step treatment involving a mouse monoclonal antibody (Tositumomab) linked to a radioactive molecule
(Iodine-131). Tositumomab is a mouse monoclonal
antibody that targets a protein (CD20) that is found on the surface of normal
and malignant lymphocytes. The Bexxar therapeutic
regimen is administered in two discrete steps: the dosimetric
and therapeutic steps. The therapeutic step is administered 7-14 days after
the dosimetric step. Each step consists of a
sequential infusion of 450 mg of Tositumomab over
60 minutes and followed by an infusion over 20 minutes. The Iodine-131 Tositumomab dose administered in the dosimetric
step contains 35 mg of Tositumomab and 5 mCi Iodine-131. The Iodine-131 Tositumomab
dose administered in the therapeutic step contains 35 mg of Tositumomab and that dose of Iodine-131 calculated to
deliver 75 cGy total body irradiation. For patients
with mild (NCI CTC grade 1) thrombocytopenia, the therapeutic dose of
Iodine-131 Tositumomab is reduced; the dose in
patients with thrombocytopenia is that dose of Iodine I 131 calculated to
deliver 65 cGy total body irradiation. The
determination of the dose of radiation is calculated based upon the first
step (the dosimetric dose). This is a complicated
procedure, involving multiple calculations and specific measurements. The
company (Corixa) has developed a training program
to ensure that physicians and their staff are appropriately trained in prescribing
and administering of the product. The BEXXAR therapeutic regimen will only be
distributed to physicians who have successfully completed the training
program. The efficacy of the BEXXAR therapeutic regimen was evaluated in a
multi-center, single-arm study in patients with low grade or transformed
low-grade or follicular large-cell lymphoma whose disease had not responded
to or had progressed after Rituximab therapy.
Determination of clinical benefit of the BEXXAR therapeutic regimen was based
on evidence of durable responses without evidence of an effect on survival.
The overall response rate was 63%, with a median duration of response of 25
months. The complete response rate was 29%; the median duration of complete
response has not been reached. These findings were supported by demonstration
of durable complete and partial objective responses in patients with low
grade or transformed low-grade or follicular large-cell lymphoma in four
additional, single arm, multicenter
studies. In these studies, the overall response rates ranged from 47% to 64%
with median durations of responses ranging from 12 to 18 months. The most
serious adverse reactions observed in the clinical trials were severe and
prolonged cytopenias (neutrophils,
platelets, & red blood cells) and the sequelae
of cytopenias which included infections (sepsis),
and hemorrhage in thrombocytopenic patients, allergic reactions (bronchospasm and angioedema),
secondary leukemia and myelodysplasia. The most
common adverse reactions occurring in the clinical trials included neutropenia, thromobocytopenia,
and anemia that are both prolonged and severe. Less common but severe adverse
reactions included pneumonia, pleural effusion and dehydration. Additional
adverse events included infusion reactions, delayed onset hypothyroidism and
the development of human anti-mouse antibodies (HAMA). Full prescribing
information, including clinical trial information, safety, dosing, drug-drug
interactions and contraindications, and the approval letter will be available
at www.fda.gov/cber. For assistance in locating
information, contact Joyce McKeough at
301-827-2000, in CBER’s Office of Communications,
Training, and Manufacturer’s Assistance. On May 20, 2003 the FDA
granted accelerated approval of imatinib
mesylate tablets (GleevecTM,
Novartis Pharmaceuticals) for treatment of
pediatric patients with chronic phase Philadelphia chromosome positive (Ph+)
chronic myelogenous leukemia (CML) whose disease
has recurred after stem cell transplant or is resistant to interferon alpha.
Approval is based on extrapolation of results from adults with CML and
additional information from studies in children. Supportive pediatric
information included complete cytogenetic
responses, pharmacokinetic information, and a safe pediatric dose. Approval
is enabled by the separate approval of the scored 100-mg tablet on April 18,
2003 for dosing in children. Novartis plans to make
the tablets commercially available in July. Two phase 1 studies evaluated a total of 17
children with CML recurrent after stem cell transplant or resistant to alpha
interferon therapy. Patients were treated at doses of 260 mg/m2/day to 570
mg/m2/day. Dose limiting toxicity was not seen. In 16 patients with chronic
phase CML for whom cytogenetic data are available
for these two studies, 9 had a complete cytogenetic
response (56%). Cytogenetic response rate appeared
similar at all dose levels. The recommended dose is 260 mg/m2/day. A dose
increase to 340 mg/m2/day may be considered in the absence of severe adverse
drug reaction and severe non-leukemia related neutropenia
or thrombocytopenia in the following circumstances: disease progression (at
any time); failure to achieve a satisfactory hematologic
response after at least 3 months of treatment; failure to achieve a cytogenetic response after 6-12 months of treatment; or
loss of a previously achieved hematologic or cytogenetic response. There is no experience with imatinib treatment in children under
3 years of age. Accelerated approval was granted based on evidence from surrogate
endpoints. There are no controlled trials in children demonstrating a
clinical benefit, such as improvement in disease-related symptoms or
increased survival. As a condition of approval Novartis
has agreed to provide data from an ongoing NCI-sponsored Phase 2 study in
children with chronic phase Ph+ CML. Full prescribing information, including
clinical trial information, safety, dosing, drug-drug interactions and
contraindications is available at www.fda.gov/cder/foi/label/2003/021588s001lbl.pdf On May 13, 2003 the U.S. Food and Drug
Administration approved bortezomib (Velcade, Millennium Pharmaceuticals, Inc.) for the
treatment of multiple myeloma patients who have
received at least two prior therapies and have demonstrated disease
progression on the last therapy. Bortezomib was evaluated in 256 patients with multiple myeloma in two open-label multicenter
studies conducted in the Adverse events (AEs)
occurring in greater than 50% of patients included fatigue or malaise,
nausea, and diarrhea. AEs occurring in greater than
30% of patients were anorexia, constipation, thrombocytopenia, peripheral
neuropathy, pyrexia, vomiting, and anemia. Severe AEs
with incidences greater than 10% were thrombocytopenia, peripheral
neuropathy, neutropenia and asthenia. Bortezomib approval is based on objective response rate and response
duration under accelerated approval provisions. Randomized controlled
clinical trials will be performed to evaluate whether bortezomib
treatment is associated with clinical benefit. Bortezomib
received fast-track designation and priority review. The filing date of this
application was Full prescribing information, including
clinical trial information, safety, dosing, drug-drug interactions and
contraindications is available at
www.fda.gov/cder/foi/label/2003/021602lbl.pdf On On On On On August 9, 2002 the Food and Drug
Administration (FDA) approved oxaliplatin (EloxatinTM, Sanofi-Synthelabo, Inc)
in combination with infusional 5-fluorouracil
(5-FU) and leucovorin (LV) for the treatment of
patients with metastatic carcinoma of the colon or
rectum whose disease has recurred or progressed during or within 6 months of
completion of first-line therapy with the combination of bolus 5-FU/LV and irinotecan. The approval of oxaliplatin
is based on the response rate and time-to-tumor progression observed in an
ongoing trial. There are no mature controlled trials that demonstrate a
clinical benefit, such as improvement of disease-related symptoms or
increased survival. A multicenter, randomized,
three-arm study was conducted in the On On On On New on this Site More languages available! In addition to
French, we have added Arabic, Dutch, German and Japanese. More pages in
Arabic will follow. Other languages coming soon are Chinese and Spanish. The
index of advisory committee meeting minutes has been updated to include links
to related documents such as agendas, slides, and briefing documents. FDA/Center for Drug Evaluation and
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