Introduction
Aldara®
Alimta®
Alimta® for NSCLC
Arimidex®
Avastin®
Bexxar®
Erbitux®
Eloxatin™
Faslodex®
Gemzar®
Gleevec™ for CML
Gleevec™ for Pediatric CML
GLIADEL® Wafer
Iressa®
Mesnex®
Sterile Talc Powder™
Taxotere® for Breast Cancer
Taxotere® for NSCLC
Taxotere® for Prostate Cancer
Velcade®
Vidaza™
Introduction
Included here are brief descriptions of therapies that have been newly approved
for the treatment of cancer by the U.S. Food and Drug Administration (FDA 1).
The FDA is the division of the U.S. Department of Health and Human Services
charged with ensuring the safety and effectiveness of new drugs and other
products. (See "Understanding
the Approval Process for New Cancer Treatments 2.") The FDA's mission is
to promote and protect the public health by helping safe and effective products
to reach the market in a timely way, and monitoring products for continued
safety after they are in use.
Sometimes the therapies listed here will be brand new. Other times, therapies
already approved for one use will have received FDA approval for specific,
newly documented uses ("indications") in the treatment of cancer.
The summaries are provided by Richard Pazdur, M.D., director of the FDA's
Division of Oncology Drug Products, and Patricia Keegan, M.D., director of the
FDA's Division of Clinical Trials Design and Analysis. Each summary includes a
link to the complete product label, which provides clinical information on the
indication, contraindications, dosing and safety of the product.
For further information related to oncology drug approvals, regulatory
information and other oncology resources, please refer to the FDA's
Oncology Tools 3 Web site.
Aldara®
On July 15, 2004, the FDA announced the approval of a new indication for Aldara® (imiquimod) topical cream. This product is currently approved for the treatment of actinic keratosis and external genital warts. The FDA has now approved its use for the treatment of superficial basal cell carcinoma (sBCC), a type of skin cancer.
This type of skin cancer is diagnosed by a healthcare provider after biopsy and is different from other types of skin cancer including other types of basal cell carcinoma.
Superficial basal cell carcinoma is usually treated by surgical removal. Aldara should be used for treatment of sBCC only when surgery is medically less appropriate, because the chances of effectively treating sBCC are generally greater with surgery. Patients treated with Aldara for sBCC should have regular follow-up visits after treatment to make sure the skin cancer is completely treated.
The safety and effectiveness of Aldara were established in two double-blind controlled studies with approximately 364 patients. In these studies, 75 percent of patients (139/185) who had their sBCC treated with Aldara had no evidence clinically or on repeat biopsy of their sBCC at 12 weeks after finishing treatment. In a separate long-term study involving 182 patients, 79 percent of patients had no evidence of their sBCC at two years after finishing treatment.
Skin cancer can occur anywhere on the body, but it is most common on skin that has been exposed to sunlight. The most common type of skin cancer is basal cell carcinoma, affecting at least 800,000 Americans each year. The superficial type of basal cell carcinoma usually occurs on the arms, legs or on parts of the body such as the chest or back. Now FDA is approving Aldara for treatment of sBCC on the body, neck, arms or legs, but not for treatment of sBCC on the face.
Most patients using Aldara Cream for the treatment of sBCC experienced skin reactions at the treatment site, which include redness, swelling, a sore or blister, peeling, itching, and burning.
Aldara Cream is manufactured by 3M Pharmaceuticals of St. Paul , Minn.
Full prescribing information 4 is available, including clinical trial information, safety, dosing, drug-drug interactions and contraindications.
Alimta®
On February 4, 2004, the FDA approved pemetrexed for injection (Alimta®, made by 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 multicenter, 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 (in which the bone marrow produces fewer blood cells), fatigue, nausea, vomiting, and dyspnea (difficulty breathing). 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 one to three weeks after treatment discontinuation. A vitamin B12 injection, 1000 micrograms intramuscularly, was administered one to three weeks before the first chemotherapy dose and repeated approximately every nine 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 is available 5, including clinical trial information, safety, dosing, drug-drug interactions and contraindications.
Alimta® for NSCLC
On August 19, 2004, the FDA granted accelerated approval to pemetrexed for injection (Alimta®, made by Eli Lilly and Company) as a single agent for the treatment of patients with locally advanced or metastatic nonsmall cell lung cancer after prior chemotherapy.
Safety and efficacy were demonstrated in one multi-center, randomized trial in 571 patients comparing single-agent Alimta versus docetaxel. Alimta, 500 mg/m2 intravenously, was administered over 10 minutes on day 1 of each 21-day cycle. Patients receiving Alimta also received dexamethasone for skin rash prophylaxis and vitamin B12 and folic acid supplementation.
The primary efficacy endpoint was survival. Alimta failed to demonstrate superior survival compared to docetaxel. Non-inferiority for overall survival could not be demonstrated because there was only one small historical study (total 104 patients) from which to estimate docetaxel's survival effect. A meta-analysis of multiple historical studies is usually required for this survival effect estimation. In addition, comparison of the survival effect in the current randomized trial was confounded by a 32% crossover rate of Alimta patients to docetaxel after tumor progression. The median survival time was 8.3 months for Alimta-treated patients and 7.9 months for docetaxel-treated patients. Secondary efficacy endpoints included response rate (Alimta 9.1%, docetaxel 8.8%), progression-free survival (Alimta and docetaxel, medians 2.9 months) and time-to-progressive disease (Alimta, median 3.4 months; docetaxel, median 3.5 months).
Alimta has a more favorable safety profile than docetaxel. Alimta caused less neutropenia, febrile neutropenia, neutropenic infections and need for granulocyte/macrophage colony stimulating factors. Alimta causes less severe alopecia. Elevation of hepatic transaminases was more frequent with Alimta than docetaxel. Accelerated approval was based on the improved safety profile and effects on surrogate endpoints.
As a condition of accelerated approval, Eli Lilly and Company is required to conduct additional studies to demonstrate a clinical benefit, such as increased survival or improved disease-related symptoms.
Full prescribing information is available 6, including clinical trial information, safety, dosing, drug-drug interactions and contraindications.
Arimidex®
On September 5, 2002, the FDA granted accelerated approval to anastrozole (Arimidex®, a trademark of AstraZeneca) for the adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer. The FDA received the application on March 5, 2002, and approved it on September 5, 2002.
Investigators enrolled 9,366 postmenopausal women with operable breast cancer (84 percent hormone receptor positive) in an international, multicenter, double-blind, randomized trial (ATAC). Patients were randomly allocated to receive adjuvant treatment with either 1 milligram of Arimidex daily, 20 milligrams of tamoxifen daily, or both drugs for five years or until recurrence of the disease.
At a median efficacy follow up of 33 months, preliminary results showed that recurrence-free survival was improved in the Arimidex arm compared to the tamoxifen arm. Similar results were observed in the hormone receptor-positive population.
Women receiving Arimidex had an increase in musculoskeletal events and fractures (including fractures of spine, hip and wrist), compared with those receiving tamoxifen. More patients receiving Arimidex were reported to have an elevated serum cholesterol compared to patients receiving tamoxifen.
Women receiving Arimidex had a decrease in hot flashes, vaginal bleeding, vaginal discharge, endometrial cancer, venous thromboembolic events (including deep venous thrombosis) and ischemic cerebrovascular events compared with those receiving tamoxifen.
In the ATAC bone substudy, women receiving Arimidex had a mean decrease in both lumbar spine and total hip bone mineral density (BMD) compared to baseline.
Women receiving tamoxifen had a mean increase in both lumbar spine and total hip BMD compared to baseline. Clinical and pharmacokinetic results suggest that tamoxifen should not be administered with Arimidex. Estrogen-containing therapies should not be used with Arimidex.
The approved dose of Arimidex is one 1 milligram tablet taken daily. For adjuvant (additional) treatment of early breast cancer in postmenopausal women, the optimal duration of therapy is unknown. The FDA has required mature survival and safety data at study completion be submitted to fulfill requirements of accelerated approval.
Full prescribing information 7 is available, including clinical trial information, safety, dosing, drug-drug interactions and contraindications.
Avastin®
On February 26, 2004, the FDA approved bevacizumab (Avastin®, a trademark of Genentech, Inc.) as a first-line treatment for patients with metastatic colorectal cancer - cancer that has spread to other parts of the body. Avastin, a monoclonal antibody, is the first product to be approved that works by preventing the formation of new blood vessels, a process known as angiogenesis.
Avastin was shown to extend patients' lives by about five months when given intravenously as a combination treatment along with standard chemotherapy drugs for colon cancer (the "Saltz regimen" also known as IFL). IFL treatment includes ironotecan, 5-fluorouracil (5FU) and leucovorin.
Avastin is a genetically engineered version of a mouse antibody that contains both human and mouse components. (Antibodies are substances produced by the body's immune system to fight foreign substances.) Special technology also allows it to be produced in large quantities in the laboratory.
This new monoclonal antibody is believed to work by targeting and inhibiting the function of a natural protein called "vascular endothelial growth factor" (VEGF) that stimulates new blood vessel formation. When VEGF is targeted and bound to Avastin, it cannot stimulate the growth of blood vessels, thus denying tumors blood, oxygen and other nutrients needed for growth.
Angiogenesis inhibitors such as Avastin have been studied, first in the laboratory and then in patients, for three decades with the hope they might prevent the growth of cancer. This is the first such product that has been proven to delay tumor growth and more importantly, significantly extend the lives of patients.
"The approval of Avastin is the result of many years of research and development exploring a promising new approach to fighting cancer, and it is one of a number of recent new treatments for colorectal cancer that taken together, have significantly improved the armamentarium for fighting this disease," said Mark B. McClellan, M.D., Ph.D., FDA Commissioner. "These medical achievements reflect the innovation of drug developers and the hard work of FDA's cancer review teams, and they are proof of the promise offered by biomedical innovation. The dedication of everyone involved in these efforts is making a real difference in the lives of cancer patients."
Colorectal cancer - cancer of the colon or rectum - is the third most common cancer affecting men and women in the U.S. and, according to the Centers for Disease Control and Prevention (CDC), is the second leading cause of cancer-related death. Colorectal cancer is also one of the most commonly diagnosed cancers in the U.S.; approximately 147,500 new cases were diagnosed in 2003.
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, 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 percent compared to 35 percent 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.
On August 12, 2004, the FDA and Genentech, Inc. issued an important drug warning 8 to healthcare providers that there is evidence of an increased risk of serious arterial thromboembolic events, including cerebrovascular accident, myocardial infarctions, transient ischemic attacks, and angina related to Avastin. The risk of fatal arterial thrombotic events is also increased. In randomized, active-controlled studies conducted in patients with metastatic colorectal cancer, the risks of a serious arterial thrombotic event was approximately two-fold higher in patients receiving infusional 5-FU based chemotherapy plus Avastin, with an estimated overall rate of up to 5 percent. A revised Avastin package insert containing more detailed information on arterial thromboembolic events is in development.
Until then, you may see the current prescribing information 9, which includes clinical trial information, safety, dosing, drug-drug interactions and contraindications.
Bexxar®
On June 27, 2003, the FDA approved Tositumomab and Iodine I 131 Tositumomab (Bexxar®, a trademark of Corixa Corp) for the treatment of CD20 positive, follicular non-Hodgkin’s lymphoma, with or without transformation, which is untreatable with Rituximab and has relapsed following chemotherapy.
Bexxar is a multi-step treatment involving a mouse monoclonal antibody (Tositumomab) linked to a radioactive molecule (Iodine I 131). Tositumomab targets a protein (CD20) that is found on the surface of normal and malignant lymphocytes.
Bexxar 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 milligrams (mg) of Tositumomab over 60 minutes and followed by infused over 20 minutes. The Iodine I 131 Tositumomab dose administered in the dosimetric step contains 35 mg of Tositumomab and 5 mCi Iodine-131.
The Iodine I 131 Tositumomab dose administered in the therapeutic step contains 35 mg of Tositumomab and that dose of Iodine I 131 calculated to deliver 75 cGy total body irradiation. For patients with mild (NCI CTC grade 1) thrombocytopenia (a blood condition that may result in bruising and excessive bleeding) the therapeutic dose of Iodine I 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. Bexxar will only be distributed to physicians who have successfully completed the training program.
The efficacy of Bexxar 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 Bexxar was based on evidence of durable responses without evidence of an effect on survival.
The overall response rate was 63 percent, with a median duration of response of 25 months. The complete response rate was 29 percent; 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, multi-center studies. In these studies, the overall response rates ranged from 47 percent to 64 percent 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 (decreases in neutrophils, platelets, and red blood cells) and the consequences 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 10 is available, including clinical trial information, safety, dosing, drug-drug interactions, and contraindications.
Erbitux®
On February 12, 2004, the FDA approved cetuximab (Erbitux®, made by Imclone Systems, Inc.), a monoclonal antibody directed against the epidermal growth factor receptor. Erbitux is approved for use, in combination with irinotecan, for the treatment of EGFR-expressing, metastatic colorectal carcinoma in patients who are refractory to irinotecan-based chemotherapy.
Erbitux is also approved for use as a single agent for the treatment of EGFR-expressing, recurrent metastatic colorectal carcinoma in patients who are intolerant to irinotecan-based chemotherapy.
Erbitux is a recombinant, human/mouse chimeric IgG1 monoclonal antibody that binds specifically to the extracellular domain of the human epidermal growth factor receptor (EGFR). Erbitux binds specifically to the epidermal growth factor receptor (EGFR, HER1, c-ErbB-1) on both normal and tumor cells, and competitively inhibits the binding of epidermal growth factor (EGF) and other ligands, such as transforming growth factor–alpha.
Binding of ERBITUX to the EGFR blocks phosphorylation and activation of receptor-associated kinases, resulting in inhibition of cell growth, induction of apoptosis, and decreased matrix metalloproteinase and vascular endothelial growth factor production. The EGFR is constitutively expressed in many normal epithelial tissues, including the skin and hair follicle. Over-expression of EGFR is also detected in many human cancers including those of the colon and rectum.
The recommended dose of Erbitux, in combination with irinotecan or as monotherapy, is 400 mg/m2 as an initial loading dose (first infusion only) administered as a 120-minute IV infusion. The recommended weekly maintenance dose is 250 mg/m2 infused over 60 minutes.
Premedication with an H1 antagonist is recommended. Appropriate medical resources for the treatment of severe infusion reactions should be available during Erbitux infusions. The rate of Erbitux infusion should be reduced for mild or moderate infusion reactions; Erbitux should be discontinued for severe infusion reactions. Dose reductions are also recommended for moderate or severe skin toxicity.
The data establishing the efficacy and safety of Erbitux were derived mainly from the results of a multicenter, randomized, controlled clinical trial conducted in 329 patients; patients were randomized to receive either Erbitux plus irinotecan (218 patients) or Erbitux monotherapy (111 patients).
Supporting data were derived from an open-label, single-arm trial (138 patients) of Erbitux plus irinotecan and an open-label single-arm trial (57 patients) of Erbitux as a single agent. All studies enrolled patients with EGFR-expressing (75-82 percent of those screened were positive), recurrent, metastatic colorectal cancer. All patients had received prior irinotecan; two-thirds of the patients in the randomized study and half of those in the supportive study had progressed during or within 30 days of receiving an adequate course of irinotecan.
In the randomized trial, 38 percent had also received prior oxaliplatin. Determination of clinical benefit was based on evidence of durable responses without evidence of an effect on survival. In the randomized trial, the overall response rate was 23 percent with a median duration of response of 5.7 months in the Erbitux plus irinotecan arm. The overall response rate was 12 percent with a median duration of response of 4.1 months in the Erbitux monotherapy arm.
The median time to progression was significantly longer for patients receiving combination therapy (4.1 vs. 1.5 months). Comparable results were observed in the single arm studies of Erbitux plus irinotecan (15 percent ORR, 6.5 months median response duration) and Erbitux monotherapy (9 percent ORR, 1.4 months median response duration).
The most serious adverse reactions observed in clinical trials of Erbitux, alone or in combination with irinotecan, were infusion reactions (3 percent), dermatologic toxicity (1 percent), interstitial lung disease (0.5 percent), fever (5 percent), sepsis (3 percent); renal dysfunction (2 percent), pulmonary embolism (1 percent), dehydration (5 percent in patients receiving Erbitux plus irinotecan; 2 percent in patients receiving Erbitux monotherapy), and diarrhea (6 percent in patients receiving Erbitux plus irinotecan, 0 percent in patients receiving Erbitux monotherapy).
Thirty-seven (10 percent) patients receiving Erbitux plus irinotecan and 14 (5 percent) patients receiving Erbitux monotherapy discontinued treatment primarily because of adverse events.
The most common adverse events seen in 354 patients receiving Erbitux plus irinotecan were acneform rash (88 percent), asthenia/malaise (73 percent), diarrhea (72 percent), nausea (55 percent), abdominal pain (45 percent), and vomiting (41 percent).
The most common adverse events seen in 279 patients receiving Erbitux monotherapy were acneform rash (90 percent), asthenia/malaise (49 percent), fever (33 percent), nausea (29 percent), constipation (28 percent), and diarrhea (28 percent).
Full prescribing information is available 11, including clinical trial information, safety, dosing, drug-drug interactions and contraindications.
Eloxatin™
On January 9, 2004, the FDA approved oxaliplatin for injection (Eloxatin™, a trademark of Sanofi-Synthelabo Inc.), for use in combination with infusional 5-fluorouracil (5-FU) and leucovorin (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 six months of completion of first-line therapy with the combination of bolus 5-FU/LV and irinotecan.
Safety and efficacy were demonstrated in one multicenter, 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 seven arms at different times during its conduct, four of which were closed either due to 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 percent 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 percent Grade ¾) in clinical studies and was usually managed with standard epinephrine, corticosteroid, antihistamine therapy, and may require discontinuation of therapy.
Full prescribing information 12 is available, including clinical trial information, safety, dosing, drug-drug interactions and contraindications.
Faslodex®
On April 25, 2002, the FDA approved fulvestrant (Faslodex®, a trademark of AstraZeneca Pharmaceuticals LP) 250 milligrams monthly intramuscular injections for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy.
Intramuscular fulvestrant was compared with oral anastrozole (Arimidex®, also a trademark of AstraZeneca) in two randomized 13, controlled clinical trials (a North American double-blinded study and a European open-label study) in postmenopausal women with locally advanced or metastatic breast cancer. All patients had progressed after previous therapy with an antiestrogen or progestin for breast cancer in the adjuvant or advanced disease setting. The majority of patients in these trials had estrogen receptor-positive (ER+) and/or progestin receptor-positive (PgR+) tumors. Patients who had ER-/PgR- or unknown disease must have shown prior response to endocrine therapy. A total of 851 patients were enrolled, with 428 randomized to receive fulvestrant 250 milligrams monthly by intramuscular injection and 423 patients randomized to receive anastrozole 1 milligram daily. Response rates of 17 percent and 20 percent were reported in the fulvestrant treatment arms in the North American and European trials, respectively; these rates were similar to the 17 percent and 15 percent response rates reported in the anastrozole treatment arms. There were no significant differences in time to progression or survival between the two arms in either trial.
The safety profile of fulvestrant was similar to that of anastrozole. Most commonly reported adverse events were of mild to moderate severity and included nausea, vomiting, constipation, diarrhea and abdominal pain, headache, back pain, vasodilatation (hot flashes) and pharyngitis. Mild injection site reactions were reported in 7 percent and 27 percent of patients (1 percent and 5 percent of treatments) given single 5 milliliter and 2 x 2.5 milliliter fulvestrant injections, respectively.
Full prescribing information 14 is available, including clinical trial information, safety, dosing, drug-drug interactions and contraindications.
Gemzar®
On May 19, 2004, the FDA approved gemcitabine HCl for injection (Gemzar®, made by Eli Lilly and Company) in combination with paclitaxel for the first-line 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 multicenter, 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 percent versus 22.1 percent, 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 15 is available, including clinical trial information, safety, dosing, drug-drug interactions and contraindications.
Gleevec™ for CML
On December 20, 2002, the FDA granted accelerated approval to imatinib mesylate 16 (Gleevec™, a trademark of Novartis) for use as a first-line (initial) treatment for newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML). (Leukemic cells of more than 95 percent of patients with CML have a distinctive cytogenetic abnormality, the Philadelphia or “Ph” chromosome.) Gleevec had been initially approved by the FDA on May 10, 2001, for the treatment of advanced CML and as a second-line therapy for chronic phase CML that failed to respond to interferon.
Investigators enrolled 1,106 patients with newly diagnosed Ph+ CML in an international multicenter randomized open-label trial conducted by the IRIS (International Randomized IFN vs. STI571) Study Group. Patients were randomly allocated to receive treatment with either Gleevec 400 mg (milligrams) daily by mouth or interferon and cytarabine by subcutaneous injections.
Interferon-alpha was initiated at 3 million units three times a week and escalated to a target dose of 5 million units/m2/day. Cytarabine was to be added at a dose of 20 mg/m2/day for 10 days every month. The dose intensity of the interferon arm was 57 percent relative to the target dose, and the dose intensity of Gleevec was 97 percent.
The protocol-specified analysis was to have occurred at 5 years. However an interim analysis revealed a significantly higher cytogenetic response rate in the Gleevec arm and the study was analyzed after a median follow-up of 14 months.
At the time of analysis the risk of progression was significantly decreased with a hazard ratio of 0.183 (95 percent C.I. of 0.117, 0.285) for treatment with Gleevec compared with interferon, and the log-rank test p-value was much less than 0.001.
Prior to crossover, complete hematologic response rates were 95 percent and 55 percent, and the confirmed major cytogenetic response rates were 76 percent and 12 percent on the Gleevec and interferon arms, respectively. These differences were highly statistically significant. Presently, there was no statistically significant difference in survival between treatment arms.
The most common adverse events (>20 percent of patients) reported by patients receiving Gleevec included nausea, muscle cramps, fatigue, diarrhea, headache, arthralgia, periorbital edema, myalgia, and rash. Patients receiving interferon most commonly reported fatigue, nausea, headache, diarrhea, myalgia and arthralgia. The only grade 3 adverse events reported in > 1 percent of patients taking Gleevec were neutropenia, thrombocytopenia and arthralgia. Edema was seen in 54 percent of Gleevec patients, but was seldom greater than grade 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.
The FDA has required mature survival, other efficacy and safety data at study completion be submitted to fulfill requirements of accelerated approval under subpart H (21 Code of Federal Regulations 314.500).
Full prescribing information 17 is available, including clinical trial information, safety, dosing, drug-drug interactions, and contraindications.
Gleevec™ for Pediatric CML
On May 20, 2003, the FDA granted accelerated approval 18 of imatinib mesylate tablets (Gleevec™, a trademark of 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 become resistant to the drug interferon alpha. (Leukemic cells of more than 95 percent of patients with CML have a distinctive cytogenetic – chromosomal – abnormality, the Philadelphia or “Ph” chromosome.)
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 (drug activity in the body) information, and a safe pediatric dose. Approval is enabled by the separate approval of the scored 100 milligram (mg) tablet on April 18, 2003, for dosing in children. Novartis plans to make the tablets commercially available in July 2003.
Two phase 1 studies evaluated a total of 17 children who had experienced a recurrence of CML after they’d undergone stem cell transplant or become 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, nine had a complete cytogenetic response (56 percent). 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 (an abnormal decrease in the number of neutrophils, a type of white blood cell ) or thrombocytopenia (a decrease in the number of platelets in the blood) in the following circumstances: disease progression (at any time); failure to achieve a satisfactory hematologic response after at least three 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 three 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 19 is available, including clinical trial information, safety, dosing, drug-drug interactions and contraindications.
GLIADEL® Wafer
On February 25, 2003, the FDA approved polifeprosan 20 with carmustine implant (GLIADEL® Wafer, a trademark of Guilford Pharmaceuticals, Inc.) as an adjunct to surgery and radiation for the treatment of patients with newly diagnosed, high-grade malignant glioma. The implantable wafer delivers the chemotherapy drug carmustine directly into the tumor site after the tumor has been removed by surgery.
In 1996, the FDA approved GLIADEL Wafer as an adjunct to surgery for the treatment of patients with recurrent glioblastoma multiforme (GBM) brain tumors.
The effectiveness of GLIADEL Wafer for the treatment of patients with newly diagnosed, high-grade malignant glioma was assessed in an international, multicenter, double-blinded, randomized, placebo-controlled Phase III trial. Two hundred and forty patients were randomized to the GLIADEL treatment arm or the placebo treatment arm. The trial design stipulated that patients would undergo initial surgery with wafer implantation followed by standard radiation therapy.
After maximal resection of the tumor, up to eight wafers containing either GLIADEL or placebo were placed against the resection cavity (the site where the tumor had been removed). Within three weeks of surgery, the majority of patients started radiation therapy.
The primary efficacy endpoint for this study was overall survival. Median survival increased from 11.6 months with placebo to 13.9 months with GLIADEL Wafer (p-value <0.05, log-rank test). The hazard ratio for GLIADEL Wafer treatment was 0.73 (95 percent CI: 0.56-0.95).
The toxicities seen in the study may reflect either the surgical procedure or implantation of the GLIADEL wafers or both. The primary toxicities were seizures, brain hemorrhages, brain cyst, and wound infection/brain abscesses.
Full prescribing information 20 is available, including clinical trial information, safety, dosing, drug-drug interactions and contraindications.
Iressa®
On May 5, 2003, the FDA approved gefitinib (Iressa®, a trademark of AstraZeneca) for treatment of advanced non-small cell lung cancer (NSCLC), the most common form of lung cancer in the United States. Gefitinib is intended for patients whose cancer has progressed despite treatment with other chemotherapy drugs.
Specifically, the FDA approved gefitinib 250 milligram (mg) tablets as monotherapy treatment for patients with locally advanced or metastatic non-small cell lung cancer after failure of both platinum-based and docetaxel chemotherapies. Gefitinib is not recommended for use in combination with chemotherapy.
Gefitinib was evaluated in a multicenter United States clinical trial in patients with advanced non-small cell lung cancer. Patients were entered in the trial after their disease had progressed or they’d experienced intolerable toxicity associated with at least two prior chemotherapy regimens, including both a platinum-based drug and the drug docetaxel.
One hundred forty-two evaluable patients (that is, those with disease that cannot be measured directly by the size of the tumor but can be evaluated by other methods) received gefitinib at a dose of either 250 milligrams a day (mg/day) or 500 mg/day. Approximately 75 percent had adenocarcinoma histology (alone or mixed with squamous cell histology).
Partial tumor responses occurred in 15 of 142 evaluable patients for a response rate of 10.6 percent (95CI: 6-16.8 percent) overall. Responses occurred in 9 of 66 patients receiving 250 mg/day (13.6 percent) and in 6 of 76 patients receiving 500 mg/day (7.8 percent). Median duration of response was 7.0 months (range 4.6 -18.6+ months).
Two large controlled randomized trials in the first-line treatment of NSCLC showed no benefit from adding gefitinib to doublet, platinum-based chemotherapy.
In the patients who received Iressa monotherapy for treatment of NSCLC, the most common adverse drug reactions reported were diarrhea (sometimes associated with dehydration), rash, acne, dry skin, nausea, vomiting, and pruritis (a severe itching reaction). These events generally occurred within the first month of therapy and usually were mild to moderate.
Cases of interstitial lung disease (ILD) have been observed in patients receiving gefitinib at an overall incidence of about 1 percent, and approximately one-third of the cases have been fatal. (The reported incidence of ILD was about 2 percent in the Japanese post-marketing experience, about 0.3 percent in approximately 23,000 patients treated with gefitinib in a U.S. expanded access program, and about 1 percent in the studies of first-line use in NSCLC [but with similar rates in both treatment and placebo groups]).
In the event of acute onset or worsening of pulmonary symptoms (dyspnea, cough, fever), gefitinib therapy should be interrupted and a prompt investigation of these symptoms should occur. If interstitial lung disease is confirmed, gefitinib should be discontinued and the patient treated appropriately.
The approved dose for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of both platinum-based and docetaxel chemotherapies is one 250 mg tablet once a day with or without food. Higher doses do not give a better response and cause increased toxicity.
This indication is approved on the basis of objective response rate under accelerated approval provisions. Randomized controlled clinical trials will be performed to evaluate whether gefitinib treatment is associated with clinical benefit, such as improved survival or symptom improvement. Gefitinib received fast-track designation and priority review.
Full prescribing information 21 is available, including clinical trial information, safety, dosing, drug-drug interactions and contraindications.
Mesnex®
On March 21, 2002, the FDA approved mesna tablets (Mesnex®, a trademark of Baxter Healthcare S.A.) as a prophylactic agent to reduce the incidence of ifosfamide-induced hemorrhagic cystitis. Ifosfamide is chemotherapy that is given as a treatment for some types of cancer. After ifosfamide and the first dose of mesna are administered intravenously, subsequent doses of mesna may be given intravenously or orally.
Clinical studies comparing the recommended IV-IV-IV and the IV-oral-oral mesna regimens demonstrated < 5 percent incidence of grade 3 – 4 hematuria in both arms when used in conjunction with ifosfamide 1.2-2.0 gm/m2 for 3-5 days.
In a meta-analysis of four controlled studies, the safety profile of the IV-oral-oral regimen (N=119) was similar to the all IV regimen (N=119). Nausea and vomiting were the most common adverse events. Because mesna is used in combination with ifosfamide, it is difficult to distinguish the adverse reactions which may be due to mesna from those caused by the concomitantly administered cytotoxic agent. The most frequently reported adverse reactions from single dose Phase I studies of IV mesna alone were headache, injection site reactions, flushing, dizziness, nausea, vomiting, somnolence, diarrhea, anorexia, fever, pharyngitis, hyperaesthesia, influenza-like symptoms and coughing.
Mesna does not prevent hemorrhagic cystitis in all patients and does not decrease the incidence of other chemotherapy-related adverse events.
Dosage and administration: The recommended IV and oral mesna regimens differ in the ratio of mesna:ifosfamide and times of administration after ifosfamide. The recommended dosing schedules are as follows:
IV-IV-IV: Mesna is given as an IV bolus injection in a dosage equal to 20 percent of the ifosfamide dosage at the time of ifosfamide administration and 4 and 8 hours after each dose of ifosfamide. The total daily dose of mesna is 60 percent of the ifosfamide dose.
IV-oral-oral: Mesna is given as an IV bolus injection in a dosage equal to 20 percent of the ifosfamide dosage at the time of ifosfamide administration. Mesna tablets are given orally in a dosage equal to 40 percent of the ifosfamide dose at 2 and 6 hours after each dose of ifosfamide. The total daily dose of mesna is 100 percent of the ifosfamide dose.
Patients who vomit within two hours of taking oral mesna should repeat the dose or receive IV mesna. The efficacy and safety of this ratio of IV-oral-oral mesna has not been established as being effective for daily doses of ifosfamide higher than 2.0 gm/m2 for 3-5 days.
Full prescribing information 22 is available, including clinical trial information, safety, dosing, drug-drug interactions and contraindications.
Sterile Talc Powder™
On December 15, 2003, the FDA approved Sterile Talc Powder™ (a trademark of Bryan Corporation), administered intrapleurally (within the pleural cavity) via chest tube, as a sclerosing agent to decrease the recurrence of malignant pleural effusions in symptomatic patients.
Malignant pleural effusion results from an accumulation of fluid in the pleural space, the area between the layer lining the chest cavity (parietal pleura) and the membrane covering the lungs (visceral pleura). It is a common complication of malignant disease, particularly in patients with advanced cancer.
The data demonstrating safety and efficacy are from the published medical literature. There were five randomized studies that were designed to evaluate the risk of recurrence of malignant pleural effusions in patients with a variety of solid tumors. For each study, talc slurry was compared with a concurrent control, using a prospectively defined objective measure of "success." For the 89 evaluable patients studied in the five randomized controlled trials, there was an 89 percent success rate (range 79-100 percent). Thirteen additional single-arm trials and retrospective series from the literature are also supportive of efficacy with variously defined “success” rates ranging from 75-100 percent.
Adverse events (AEs) most frequently reported in the literature in association with intrapleurally administered talc slurry are fever and pain. Acute pneumonitis and Acute Respiratory Distress Syndrome (ARDS) have been reported in association with intrapleural talc administration.
Sterile Talc Powder should be administered after adequate drainage of the effusion. The success of pleurodesis appears to be related to the completeness of drainage of the pleural fluid, as well as the full re-expansion of the lung. The recommended dose is 5 grams, dissolved in 50-100 milliliters of sodium chloride solution. Although the optimal dose for effective pleurodesis is unknown, 5 grams was the dose most frequently reported in the published literature.
The only other licensed formulation of talc (Sclerosol Intrapleural Aerosol™, also made by Bryan Corporation) is packaged with a chlorofluorocarbon (CFC) propellant for direct insufflation into the open pleural surface intraoperatively or during thoracoscopy.
Full prescribing information 23 is available, including clinical trial information, safety,dosing, drug-drug interactions and contraindications.
Taxotere® for Breast Cancer
On August 18, 2004, the FDA approved docetaxel for injection (Taxotere®, a
trademark of Aventis Pharmaceuticals, Inc.) for use in combination with
doxorubicin and cyclophosphamide for the
adjuvant
treatment
of women with operable node-positive breast cancer.
Investigators enrolled 1491 women with node positive operable breast cancer in
an international, multicenter, randomized trial (TAX316). Patients were
stratified according to the number of positive axillary lymph nodes (1-3, 4+)
and were randomly allocated to receive adjuvant treatment with either docetaxel
75 mg/m2 administered 1-hour after doxorubicin 50 mg/m2 and cyclophosphamide
500 mg/m2 (TAC arm), or doxorubicin 50 mg/m2 followed by fluorouracil 500 mg/m2
and cyclophosphamide 500 mg/m2 (FAC arm). Both regimens were given every 3
weeks for 6 cycles. After the last cycle of chemotherapy, patients with
positive estrogen and/or progesterone receptors received tamoxifen 20 mg daily
for up to 5 years.
The primary endpoint, disease free survival (DFS), included local and distant
recurrences,
contralateral
breast cancer and deaths from
any cause. At a median follow up of 55 months, results from a second interim
analysis showed that the TAC regimen has significantly longer DFS than FAC,
with an overall reduction in risk of relapse of 25.7% (hazard ratio= 0.74;
2-sided 95% CI= 0.60, 0.92, stratified log rank p = 0.0047). At the time of
this interim analysis, based on 219 deaths, overall survival was longer for TAC
than FAC (hazard ratio=0.69, 2-sided 95% CI=0.53, 0.90). There will be further
analysis at the time survival data mature.
Women receiving TAC had an increase in anemia, grade > 3 neutropenia,
stomatitis, amenorrhea, fever in absence of infection, hypersensitivity
reactions, peripheral edema, neurosensory and skin events compared to those
receiving FAC. The toxicity, while significant, did not cause a large number of
patients to withdraw from treatment. As with other
anthracycline/cyclophosphamide-containing regimens, long-term serious toxicity
for the TAC regimen included leukemia (0.4%) and congestive heart failure
(1.6%).
The approved dose of docetaxel for the adjuvant treatment of operable
node-positive breast cancer is 75 mg/m2 administered 1-hour after doxorubicin
50 mg/m2 and cyclophosphamide 500 mg/m2 every 3 weeks for 6 cycles.
Full prescribing information 24
is available, including
clinical trial information, safety, dosing, drug-drug interactions and
contraindications.
Taxotere® for NSCLC
On November 27, 2002, the FDA approved docetaxel (Taxotere®, a trademark of Aventis Pharmaceuticals, Inc.) for use in combination with cisplatin for the treatment of patients with unresectable (not removable by surgery), locally advanced or metastatic non-small cell lung cancer (NSCLC) who have not previously received chemotherapy for this condition.
Docetaxel was assessed in a single, open-label randomized multicenter international trial. A total of 1,218 patients with unresectable stage IIIB or IV NSCLC and no prior chemotherapy were randomized to receive one of three treatments: docetaxel 75 mg/m2 as a one hour infusion immediately followed by cisplatin 75 mg/m2 over 30-60 minutes every three weeks; vinorelbine 25 mg/m2 administered over 6-10 minutes on days 1, 8, 15, 22 followed by cisplatin 100 mg/m2 administered on day 1 of cycles repeated every four weeks; or a combination of docetaxel and carboplatin.
The primary endpoint was overall survival. There was no statistically significant difference in overall survival between patients receiving docetaxel + cisplatin compared to patients receiving vinorelbine + cisplatin (median survival 10.9 months versus 10.0 months, p = 0.12). The efficacy of Taxotere in this combination was established by a non-inferiority analysis.
Efficacy of docetaxel when used in combination with carboplatin was not established. There was no statistically significant difference in survival between patients receiving docetacel + carboplatin versus patients receiving vinorelbine + cisplatin (median survival 9.1 months versus 10.0 months, p = 0.66). The docetaxel + carboplatin arm did not demonstrate non-inferiority when compared to vinorelbine + cisplatin.
The most common adverse events (> 50 percent of patients) were neutropenia, anemia, nausea, vomiting, fluid retention, asthenia, pain and alopecia. Other common adverse events (20-50 percent of patients) were diarrhea, weight loss, stomatitis, infection, hemoptysis, constipation, and neurosensory events.
Febrile neutropenia and grade 3 / 4 infection occurred in 5 percent and 8 percent of patients in the cisplatin-containing regimens, respectively. Less common adverse events (< 20 percent of patients) were thrombocytopenia, hypersensitivity reactions, neuro-hearing cerebellar or motor adverse events, myalgia, arthralgia, dehydration, and nail disorders. The toxic death rate (deaths within 30 days of drug administration) was 2.2 percent in the docetaxel + cisplatin arm and 2 percent in the cisplatin + vinorelbine arm.
For chemotherapy-naïve patients, the recommended dose of docetaxel is 75 mg/m2 administered intravenously over one hour immediately followed by cisplatin 75 mg/m2 over 30-60 minutes every three weeks.
Full prescribing information 25 is available, including clinical trial information, safety, dosing, drug-drug interactions and contraindications.
Taxotere® for Prostate Cancer
On May 19, 2004, the FDA approved docetaxel for injection (Taxotere®, made by 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, multicenter 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:
- mitoxantrone + prednisone (MTX + P),
- weekly Taxotere (TXT qw) + prednisone, or
- 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 26 is available, including clinical trial information, safety, dosing, drug-drug interactions and contraindications. There is also an FDA press release 27.
Velcade®
On May 13, 2003, the FDA approved bortezomib (Velcade®, a trademark of 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 United States. In the primary efficacy study, 202 patients were entered after having received at least two prior therapies and progressing on the most recent therapy. Bortezomib was administered intravenously at 1.3 milligrams (mg) /m2/dose twice weekly for 2 weeks, followed by a 10-day rest period (21 day treatment cycle) for a maximum of 8 treatment cycles. In the study population, the median number of prior therapies was six, and 64 percent of patients had received stem cell transplant or other high dose therapy. Results (Blade criteria) in the 188 eligible and evaluable patients included complete responses in 5 patients, for a complete response rate of 2.7 percent (95 CI: 1 percent, 6 percent); partial responses occurred in 47 patients for a PR rate of 25 percent (95 CI: 19 percent, 32 percent). Clinical remissions by SWOG criteria were observed in 17.6 percent of patients (95CI: 12 percent, 24 percent). Median duration of response was 365 days.
Adverse events (AEs) occurring in greater than 50 percent of patients included fatigue or malaise, nausea, and diarrhea. AEs occurring in greater than 30 percent of patients were anorexia, constipation, thrombocytopenia, peripheral neuropathy, pyrexia, vomiting, and anemia. Severe AEs with incidences greater than 10 percent 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 January 21, 2003.
Full prescribing information 28 is available, including clinical trial information, safety, dosing, drug-drug interactions and contraindications.
Vidaza™
On May 19, 2004, the FDA approved azacitidine for injectable suspension (Vidaza™, made by 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 multicenter, 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 multicenter 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 treatment. Greater than 50 percent of observation only patients crossed over to Vidaza 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 percent of the azacitidine patients. The response rates were similar in patients randomized to Vidaza treatment (15.7 percent), in patients who crossed over from the observation arm to Vidaza treatment (12.8 percent), and in patients in the two single arm trials (12.7 percent and 19.1 percent). None of the patients in the observation only arm had clinical response. The difference in response rates between Vidaza 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 percent of Vidaza-treated patients had either reduction of the need for transfusions and/or ≤50 percent 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 29 is available, including clinical trial information, safety, dosing, drug-drug interactions and contraindications. There is also an FDA press release 30.
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