ASH News Daily - Sunday, December 11, 2011 - (Page A-4)

Page A–4 ® Sickle Cell «« From Page A-1 as a screening test to be applied to all patients with SCD” and thus the benefit of screening asymptomatic adult patients and children is uncertain and the treatment for pulmonary hypertension is yet to be defined. The randomized, placebo-controlled Treatment of Pulmonary Hypertension and SCD With Sildenafil Trial was stopped early due to increased pain in the treatment arm. However, Dr. Hassell stated that, “despite finding that the use of sildenafil may be associated with increased pain, other experience suggests that sickle cell ZELBORAF™ (vemurafenib) tablet, oral Initial U.S. Approval: 2011 This is a brief summary of information about TRADENAME. Before prescribing, please refer to the full Prescribing Information. 1 INDICATIONS AND USAGE ZELBORAF™ is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAFV600E FDA-approved test. mutation as detected by an Limitation of Use: ZELBORAF is not recommended for use in patients with wild-type BRAF melanoma. 5 WARNINGS AND PRECAUTIONS 5.1 Cutaneous Squamous Cell Carcinoma (cuSCC) Cases of cuSCC, including both SCCs of the skin and keratoacanthomas, have been reported in patients treated with ZELBORAF [see Adverse Reactions (6.1)]. The incidence of cuSCC in ZELBORAF-treated patients in Trial 1 was 24%. CuSCC usually occurred early in the course of treatment with a median time to the first appearance of 7 to 8 weeks. Of the patients who experienced cuSCC, approximately 33% experienced > 1 occurrence with median time between occurrences of 6 weeks. Potential risk factors associated with cuSCC in ZELBORAF clinical studies included age (≥ 65 years), prior skin cancer, and chronic sun exposure. In the clinical trials, cases of cuSCC were managed with excision, and patients were able to continue treatment without dose adjustment. It is recommended that all patients receive a dermatologic evaluation prior to initiation of therapy and every two months while on therapy. Any suspicious skin lesions should be excised, sent for dermatopathologic evaluation and treated as per standard of care. Monitoring should be considered for 6 months following discontinuation of ZELBORAF. 5.2 Hypersensitivity Reactions Serious hypersensitivity reactions, including anaphylaxis, have been reported in association with ZELBORAF and upon re-initiation of treatment. Severe hypersensitivity reactions included generalized rash and erythema or hypotension. In patients who experience a severe hypersensitivity reaction, ZELBORAF treatment should be permanently discontinued. 5.3 Dermatologic Reactions Severe dermatologic reactions have been reported in patients receiving ZELBORAF, including one case of Stevens-Johnson syndrome and one case of toxic epidermal necrolysis in Trial 1. In patients who experience a severe dermatologic reaction, ZELBORAF treatment should be permanently discontinued. 5.4 QT Prolongation Pharmacology (12.3)]. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes. Treatment with ZELBORAF is not recommended in patients with uncorrectable electrolyte abnormalities, long QT syndrome, or who are taking medicinal products known to prolong the QT interval. mutation-positive metastatic melanoma [see Clinical ECG and electrolytes, including potassium, magnesium, and calcium, should be monitored before treatment with ZELBORAF and after dose modification. Monitoring of ECGs should occur 15 days after treatment initiation and then monthly during the first 3 months of treatment, followed by every 3 months thereafter or more often as clinically indicated. Initiation of treatment with ZELBORAF is not recommended in patients with QTc > 500 ms. If during treatment the QTc exceeds 500 ms (CTC-AE ≥ Grade 3), ZELBORAF treatment should be temporarily interrupted, electrolyte abnormalities should be corrected, and cardiac risk factors for QT prolongation (e.g., congestive heart failure, bradyarrhythmias) should be controlled. Re-initiation of treatment should occur at a lower dose once the QTc decreases below 500 ms [see Dosage and Administration (2.2)]. Permanent discontinuation of ZELBORAF treatment is recommended if after correction of associated risk factors, the QTc increase meets values of both > 500 ms and > 60 ms change from pre-treatment values. 5.5 Liver Laboratory Abnormalities Liver laboratory abnormalities have occurred with ZELBORAF (Table 3) [see Adverse Reactions (6.1)]. Liver enzymes (transaminases and alkaline phosphatase) and bilirubin should be monitored before initiation of treatment and monthly during treatment, or as clinically indicated. Laboratory abnormalities should be managed with dose reduction, treatment interruption, or treatment discontinuation [see Dosage and Administration (2.2)]. 5.6 Photosensitivity Mild to severe photosensitivity was reported in patients treated with ZELBORAF in clinical trials [see Adverse Reactions (6.1)]. All patients should be advised to avoid sun exposure while taking ZELBORAF. While taking the drug, patients should be advised to wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors to help protect against sunburn. For intolerable grade 2 (tender erythema covering 10 - 30% body surface area) or greater photosensitivity, dose modifications are recommended [see Dosage and Administration (2.2)]. 5.7 Ophthalmologic Reactions In Trial 1, five cases of uveitis have been reported in patients treated with ZELBORAF. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Patients should be routinely monitored for signs and symptoms of uveitis. Additionally, there were five patients with blurry vision, five patients with iritis and six patients with photophobia. There was one case of retinal vein occlusion in Trial 2. 5.8 New Primary Malignant Melanoma There were eight skin lesions in seven patients reported as new primary malignant melanoma in Trial 1. Cases were managed with excision, and patients continued treatment without dose adjustment. Monitoring for skin lesions should occur as outlined above [see Warnings and Precautions (5.1)]. 5.9 Use in Pregnancy Pregnancy Category D ZELBORAF may cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)]. 5.10 BRAFV600E Testing an FDA-approved test is required for selection of patients for ZELBORAF therapy because these are the only patients studied and for whom benefit has been shown. For patients in ZELBORAF clinical studies, including Trial 1 and Trial 2, all enrolled patients tested positive when their tumor tissue was assessed with the cobas® Confirmation of BRAFV600E mutation-positive melanoma as detected by [see Clinical Studies (14)]. This test is designed to detect BRAFV600E mutations in DNA isolated from formalin-fixed, paraffin-embedded 4800 BRAF V600 Mutation Test Exposure-dependent QT prolongation was observed in an uncontrolled, open-label Phase 2 QT sub-study in previously treated patients with BRAFV600E Skin and subcutaneous tissue disorders Rash Photosensitivity reaction Alopecia Pruritis Hyperkeratosis Rash maculopapular Actinic keratosis Dry skin Rash papular Erythema Musculoskeletal and connective tissue disorders Arthralgia Myalgia Musculoskeletal pain Back pain General disorders and administration site conditions Fatigue Asthenia Gastrointestinal disorders Nausea Diarrhea Vomiting Constipation Nervous system disorders Headache Dysgeusia Neoplasms benign, malignant and unspecified (includes cysts and polyps) Skin papilloma Cutaneous SCC†# Seborrheic keratosis Investigations Gamma- glutamyltransferase increased Metabolism and nutrition disorders Decreased appetite 18 Respiratory, thoracic and mediastinal disorders Cough Injury, poisoning and procedural complications Sunburn - - 8 <1 - 21 - - 53 4 13 <1 Pain in extremity 18 <1 8 - 8 <1 Edema peripheral 17 <1 Pyrexia 38 2 19 <1 11 <1 35 2 28 <1 18 1 12 <1 23 <1 - 14 - - - - - - - - - - - - - - - 1 3 <1 - 6 2 4 <1 5 <1 33 2 - 5 9 <1 9 <1 43 2 13 <1 26 1 - 24 10 3 - - - - - - - - - - - - - - - - - 67 8 24 <1 - 9 11 - 11 <1 54 4 - 23 2 17 2 - 37 2 29 <1 26 2 - 16 27 11 - - - - - - - - - - - - - - - - - 37 8 33 3 - - 45 <1 - 23 1 24 1 - 9 2 8 - 19 - 5 <1 - 14 - - - 2 4 2 1 3 1 - - - - - - <1 - - <1 - - 2 - - - - - 52 7 - 49 3 - 36 - - 30 2 - 28 - - 21 6 - 17 - - 16 - - 13 - - 8 - - - - - - - - - - - ZELBORAF n= 336 ADRs All Grades (%) Grade 3 (%) Grade 4 (%) Dacarbazine n= 287 All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) patients with true pulmonary hypertension may have significant benefit from this treatment and may elect to risk some increase in pain.” This underscores the importance of asking patients what risk they would accept for potential benefit. Dr. Michael DeBaun, Monroe Carell Jr. Children’s Hospital at Vanderbilt, then discussed secondary prevention of overt stroke. He critically reviewed the literature regarding secondary prevention of overt strokes, concluding that treatment for overt stroke is yet to be defined. He noted that transfusions are the current treatment for overt stroke, although they are not a definitive treatment for secondary Safety:7" human melanoma tissue. The safety and efficacy of ZELBORAF have not been evaluated in patients whose melanoma tested negative by the cobas® FDA approved test kits,for detailed information. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 4800 BRAF V600 Mutation Test. Refer to the package inserts of Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice. The adverse drug reactions (ADRs) described in this section were identified from Trial 1 and Trial 2 [see Clinical Studies (14)]. In Trial 1, treatment naive patients with unresectable or metastatic melanoma (n=675) were allocated to ZELBORAF 960 mg orally twice daily or to dacarbazine 1000 mg/m2 (n=132) patients with metastatic melanoma and failure of at least one prior systemic therapy received treatment with ZELBORAF 960 mg orally twice daily. Adverse reactions reported in at least 10% of patients treated with ZELBORAF are presented in Table 2. The most common adverse reactions of any grade (≥ 30% in either study) reported in ZELBORAF-treated patients were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus and skin papilloma. The most common (≥ 5%) Grade 3 adverse reactions were cuSCC and rash. The incidence of Grade 4 adverse reactions was ≤ 4% in both studies. The incidence of adverse events resulting in permanent discontinuation of study medication in Trial 1 was 7% for the ZELBORAF arm and 4% for the dacarbazine arm. In Trial 2, the incidence of adverse events resulting in permanent discontinuation of study medication was 3% in ZELBORAF-treated patients. The median duration of study treatment was 4.2 months for ZELBORAF and 0.8 months for dacarbazine in Trial 1, and 5.7 months for ZELBORAF in Trial 2. Table 2 Adverse Reactions Reported in ≥ 10% of Patients Treated with ZELBORAF* Trial 1: Treatment Naive Patients Trial 2: Patients with Failure of at Least One Prior Systemic Therapy ZELBORAF n= 132 Grade 3 (%) Grade 4 (%) intravenously every 3 weeks. In Trial 2, “Despite finding that the use of sildenafil may be associated with increased pain, other experience suggests that sickle cell patients with true pulmonary hypertension may have significant benefit from this treatment and may elect to risk some increase in pain.” prevention based on the available literature. When determining optimal stroke treatment, Dr. DeBaun also conveyed that patient and family preference is critical but difficult to measure. Dr. DeBaun communicated his approach to secondary stroke prevention that includes in order of preference: 1) HLA-matched sibling Clinically relevant adverse events reported in < 10% of patients treated with ZELBORAF in the Phase 2 and Phase 3 studies include: Skin and subcutaneous tissue disorders: palmar-plantar erythrodysaesthesia syndrome, keratosis pilaris, erythema nodosum, Stevens-Johnson syndrome paralysis Musculoskeletal and connective tissue disorders: arthritis Nervous system disorders: dizziness, neuropathy peripheral, VIIth nerve Neoplasms benign, malignant and unspecified (includes cysts and polyps): basal cell carcinoma Infections and infestations: folliculitis Investigations: weight decreased Eye disorders: retinal vein occlusion, uveitis Vascular disorders: vasculitis Cardiac disorders: atrial fibrillation Table 3 shows the incidence of worsening liver laboratory abnormalities in Trial 1 summarized as the proportion of patients who experienced a shift from baseline to Grade 3 or 4. Table 3 Change From Baseline to Grade 3/4 Liver Laboratory Abnormalities* Change From Baseline to Grade 3/4 Parameter GGT AST ALT Alkaline phosphatase Bilirubin ZELBORAF (%) 11.5 0.9 2.8 2.9 1.9 Dacarbazine (%) 8.6 0.4 1.9 0.4 - * For ALT, alkaline phosphatase and bilirubin, there were no patients with a change to grade 4 in either treatment arm. 7 DRUG INTERACTIONS 7.1 Effects of Vemurafenib on Drug Metabolizing Enzymes Results from an in vivo drug-drug interaction study in patients with cancer demonstrated that vemurafenib is a moderate CYP1A2 inhibitor, a weak CYP2D6 inhibitor and a CYP3A4 inducer [see Clinical Pharmacology (12.3)]. Concomitant use of ZELBORAF with agents with narrow therapeutic windows that are metabolized by CYP1A2, CYP2D6 and CYP3A4 is not recommended as ZELBORAF may alter their concentrations. If coadministration cannot be avoided, exercise caution and consider a dose reduction of the concomitant CYP1A2 and CYP2D6 substrate drug. Coadministration of vemurafenib resulted in an 18% increase in AUC of S-warfarin (CYP2C9 substrate) [see Clinical Pharmacology (12.3)]. Exercise caution and consider additional INR monitoring when ZELBORAF is used concomitantly with warfarin. 7.2 Drugs that Inhibit or Induce CYP3A4 Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) and inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) should be used with caution when coadministered with ZELBORAF. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.9)]. ZELBORAF may cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well controlled studies in pregnant women. Women of childbearing potential and men should be advised to use appropriate contraceptive measures during ZELBORAF therapy and for at least 2 months after discontinuation of ZELBORAF. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. 8.3 Nursing Mothers It is not known whether vemurafenib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from ZELBORAF in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use Safety and efficacy in pediatric patients below the age of 18 have not been established. 8.5 Geriatric Use Ninety-four (28%) of 336 patients with unresectable or metastatic melanoma treated with ZELBORAF in Trial 1 were ≥ 65 years. Elderly patients (≥ 65 years) may be more likely to experience some adverse reactions, including cutaneous squamous cell carcinoma, nausea, decreased appetite, peripheral edema, keratoacanthoma and atrial fibrillation. The effects of ZELBORAF on overall survival, progressionfree survival and best overall response rate were similar in the elderly as compared to younger patients. 8.6 Gender The Grade 3 adverse events reported more frequently in females than males were rash, arthralgia, photosensitivity and increased creatinine. The Grade 3 adverse events reported more frequently in males than females were keratoacanthoma, increased alkaline phosphatase and increased total bilirubin. 8.7 Hepatic Impairment 21 <1 24 22 10 <1 5 3 - - - <1 - - <1 <1 1 - 1 - - - - - 30 - 24 24 14 - 15 6 - - - 4 No adjustment to the starting dose is needed for patients with pre-existing mild and moderate hepatic impairment. ZELBORAF should be used with caution in patients with pre-existing severe hepatic impairment [see Clinical Pharmacology (12.3)]. 8.8 Renal Impairment No adjustment to the starting dose is needed for patients with pre-existing mild and moderate renal impairment. ZELBORAF should be used with caution in patients with pre-existing severe renal impairment [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE There is no specific antidote for overdosage of ZELBORAF. Patients who develop adverse reactions should receive appropriate symptomatic treatment. In case of suspected overdose, ZELBORAF should be withheld and supportive care instituted. 8 10 - - - - 7 - - - - 12 - - 14 - - - * Adverse drug reactions, reported using MedDRA and graded using NCICTC-AE v 4.0 (NCI common toxicity criteria) for assessment of toxicity. † Includes both squamous cell carcinoma of the skin and keratoacanthoma. # All cases of cutaneous squamous cell carcinoma were to be reported as Grade 3 per instructions to study investigators and no dose modification or interruption was required. Manufactured by: Genentech, Inc. 1 DNA Way donor hematopoietic stem cell transplantation (if available), 2) regular transfusion therapy, and 3) less than optimal treatment may be selected based on patient and parent preference. Dr. DeBaun concluded his talk, stating, “We need consolidation of the SCD community to answer alternative therapy options for secondary prevention of strokes.” These alternative therapy options include experimental hematopoietic stem cell transplantation, revascularization procedures, and continued careful monitoring for those patients that continue on hydroxyurea. Dr. Alexis Thompson from Chil- dren’s Memorial Hospital in Chicago concluded by summarizing the data supporting primary prophylaxis in SCD emphasizing both the acceptability and feasibility of primary prophylaxis. Data presented included the role of consistent penicillin prophylaxis to reduce infectious complications in children with SCD and the role that transcranial doppler screening combined with chronic transfusions has had in the dramatic reduction of the incidence of first overt stroke. However, in the recent Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG), hydroxyurea did not show a benefit for primary prevention of reduced splenic or renal function. Dr. Thompson also affirmed Dr. Hassell’s discussions that research into SCD pulmonary complications has left us with the need for better tools to assess pulmonary status in young children in order to fully understand the natural history of SCD-related lung complications and to develop more effective interventions. “The lung is likely one of the most challenging organs to consider for primary prophylaxis” Dr. Thompson stated. It is truly amazing that the sub- stitution of valine for glutamic acid on the sixth position of the β-globin gene leads to significant multi-organ phenotypic disease variability and a century of research that leaves us with potentially more questions than answers – albeit much more informed questions. Certainly, the need to answer these questions is what keeps all of us striving for additional scientific discovery. Drs. Brandow and Panepinto indicated no relevant conflicts of interest. WiFi Supporters The ASH Annual Meeting is a free WiFi hot spot thanks to the support from: Bristol-Myers Squibb Incyte Millennium South San Francisco, CA 94080-4990 Initial U.S. Approval: August 2011 © 2011 Genentech, Inc BRF0000422000 Novartis Molecular Diagnostics Seattle Genetics ASH NEWS DAILY Sunday, December 11, 2011 Safety:10"

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ASH News Daily - Sunday, December 11, 2011

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