EAST HANOVER, N.J., Dec. 8 /PRNewswire/ -- In a large Phase III clinical trial, Tasigna(R) (nilotinib) 200 mg capsules demonstrated greater efficacy over Gleevec(R) (imatinib mesylate) tablets* in the treatment of adult patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase(1).
In the first head-to-head comparison of these two oral therapies as initial treatment for this life-threatening blood cancer, Tasigna results showed statistically significant improvement over Gleevec in every measure of efficacy, including major molecular response (MMR), complete cytogenetic response (CCyR) and prevention of progression to accelerated or blastic phase(1). The new data were presented as a late breaker abstract at the 51st annual meeting of the American Society of Hematology (ASH), held in December, in New Orleans, USA.
"The outstanding rates of response observed with Tasigna, combined with the very low rate of disease progression, strongly indicate that patients who begin their treatment with Tasigna may have long-term improvement of progression-free survival," said Giuseppe Saglio, University of Turin, San Luigi Hospital, Orbassano-Torino, Italy, a member of the study management committee. "The efficacy results and tolerability of Tasigna should support its use in newly diagnosed Ph+ CML patients."
MMR was defined in the study as reduction in the level of the abnormal Bcr-Abl protein to less than or equal to 0.1% of the pre-treatment level based on an internationally agreed standard(1). This can be interpreted to mean that for every 1,000 cells containing Bcr-Abl that were present in the blood at the start of therapy, only one cell was present at the 12-month follow-up. CCyR indicates that no CML cells containing the diagnostic Ph chromosome can be seen in a sample of bone marrow taken from the patient.
Tasigna is a potent and selective inhibitor of the Bcr-Abl protein that causes production of cancer cells in Ph+ CML(2,3). Upon initial reports of resistance in the Gleevec registration trials, Novartis scientists created a new molecule, Tasigna, just a year after the launch of Gleevec. The first clinical trials began just 21 months after discovery. The drug received its first regulatory approval in the second-line indication in 2007.
Study details
ENESTnd is being conducted at 220 global sites with 846 patients enrolled. Patients were randomized to receive Tasigna 400 mg twice daily (n = 281), Tasigna 300 mg twice daily (n = 282) or Gleevec 400 mg once daily (n = 283). The primary endpoint was MMR at 12 months; a secondary endpoint was CCyR by 12 months(1). Planned follow-up is for five years(2). Patients on the Gleevec treatment arm who had suboptimal response or treatment failure will be able to escalate dose and/or switch to Tasigna via a protocol extension.
All patients had a minimum of 12 months of treatment or discontinued early; the median follow-up was 14 months. Overall, 84%, 82% and 79% of patients remained in the study on Tasigna 300 mg twice daily, Tasigna 400 mg twice daily and Gleevec 400 mg once daily, respectively.
Rates of CCyR by 12 months were significantly higher for Tasigna at 300 mg twice daily compared with Gleevec 400 mg once daily (80% vs. 65%, p < 0.0001) and for Tasigna 400 mg twice daily compared with Gleevec 400 mg once daily (78% vs. 65%, p = 0.0005). Overall, progression to advanced disease was lower for Tasigna 300 mg twice daily (2 patients) and Tasigna 400 mg twice daily (1 patient) compared with Gleevec 400 mg once daily (11 patients).
About Ph+ CML
About Tasigna(3)
Tasigna important safety information
Tasigna prolongs the QT interval. Sudden deaths have been reported in patients receiving nilotinib. Tasigna should not be used in patients with hypokalemia, hypomagnesemia, or long QT syndrome. Hypokalemia or hypomagnesemia must be corrected prior to Tasigna administration and should be periodically monitored. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided. Patients should avoid food 2 hours before and 1 hour after taking dose. A dose reduction is recommended in patients with hepatic impairment. ECGs should be obtained to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, as well as following any dose adjustments.
Do not use in patients with hypokalemia, hypomagnesemia, or long QT syndrome.
Myelosuppression
QT prolongation
Significant prolongation of the QT interval may occur when Tasigna is inappropriately taken with food, and/or strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT. Therefore, co-administration with food must be avoided and concomitant use with strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT should be avoided. The presence of hypokalemia and hypomagnesemia may further enhance this effect.
There were sudden deaths reported in the safety population and in the expanded access program. Ventricular repolarization abnormalities may have contributed to their occurrence.
Caution is recommended in patients with a history of pancreatitis. Check serum lipase levels monthly or as clinically indicated.
Serum bilirubin and hepatic transaminases
The use of Tasigna may result in elevations in bilirubin, AST/ALT, and alkaline phosphatase. Hepatic function tests should be checked monthly or as clinically indicated.
Tasigna can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia. Correct electrolyte abnormalities prior to initiating Tasigna and monitor periodically during therapy.
Nilotinib exposure is increased in patients with impaired hepatic function. A lower starting dose is recommended for patients with mild to severe hepatic impairment and QT interval should be monitored closely.
The concomitant use of QT prolonging drugs and strong inhibitors or inducers of CYP3A4 should be avoided as they may affect serum concentration of Tasigna.
Concomitant strong CYP3A4 inducers
The concomitant use of strong CYP3A4 inducers should be avoided (including, but not limited to, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital). Patients should also refrain from taking St John's Wort. If patients must be co-administered a strong CYP3A4 inducer, the dose of Tasigna may need to be increased, depending on patient tolerability. If the strong inducer is discontinued, the Tasigna dose should be reduced to the indicated Tasigna dose. Tasigna is a competitive inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6, and UGT1A1. In vitro studies also suggest that nilotinib may induce CYP2B6, CYP2C8, and CYP2C9, and decrease the concentrations of drugs which are eliminated by these enzymes. Single-dose administration of Tasigna to healthy subjects did not change the pharmacokinetics and pharmacodynamics of warfarin (a CYP2C9 substrate). The ability of Tasigna to induce metabolism has not been determined in vivo. Caution should be exercised when co-administering Tasigna with substrates for these enzymes that have a narrow therapeutic index. Tasigna inhibits human P-glycoprotein. If Tasigna is administered with drugs that are substrates of Pgp, increased concentrations of the substrate are likely and caution should be exercised.
Food increases blood levels of Tasigna. Patients should avoid food 2 hours before and at least 1 hour after the dose is taken.
Since the capsules contain lactose, Tasigna is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency with a severe degree of intolerance to lactose-containing products, or of glucose-galactose malabsorption.
There are no adequate and well controlled studies of Tasigna in pregnant women. However, Tasigna may cause fetal harm when administered to a pregnant woman. Women of child-bearing potential should avoid becoming pregnant while taking Tasigna and should be advised of the potential hazard to the fetus if they do.
In chronic phase patients, the most commonly reported adverse reactions (>10%) were rash (33%), pruritus (29%), nausea (31%), fatigue (28%), headache (31%), constipation (21%), diarrhea (22%), and vomiting (21%). The most common (>10%) Grade 3/4 adverse reactions were thrombocytopenia (28%), neutropenia (28%), elevated lipase (15%), and hyperglycemia (11%). In accelerated phase patients, the most commonly reported adverse reactions (>10%) were rash (28%), pruritus (20%), and constipation (18%). The most common (>10%) Grade 3/4 adverse reactions were thrombocytopenia (37%), neutropenia (37%), anemia (23%), and elevated lipase (17%). Other serious adverse reactions included pneumonia, febrile neutropenia, leukopenia, intracranial hemorrhage, and pyrexia (Grade 3/4: 2%).
Tasigna may need to be temporarily withheld and/or dose reduced for QT prolongation, hematological toxicities that are not related to underlying leukemia, clinically significant moderate or severe nonhematologic toxicities, laboratory abnormalities, or concomitant use of strong CYP3A4 inhibitors. With concomitant use of strong CYP3A4 inducers, the dose of Tasigna may need to be increased, depending on patient tolerability.
Hepatic impairment
If possible, consider alternative therapies. If Tasigna must be administered to patients with hepatic impairment, a lower starting dose is recommended in patients with hepatic impairment and QT interval should be monitored. The following dose reduction should be considered:
Other patients in whom Tasigna should be used with caution
About Gleevec(9)
Gleevec important safety information
Cytopenias have been reported. Complete blood counts should be performed weekly for the first month, biweekly for the second month, and periodically thereafter as clinically indicated (for example, every 2-3 months).
In Ph+ CML trials,** severe (NCI Grades 3/4) lab abnormalities--including neutropenia (3.6%-48%), anemia (1%-42%), thrombocytopenia (<1%-33%), and hepatotoxicity (approx 5%)--and severe adverse reactions (NCI Grades 3/4), including hemorrhage (1.8%-19%), fluid retention (eg, pleural effusion, pulmonary edema, and ascites) (2.5%-11%) and superficial edema (1.5%-6%), and musculoskeletal pain (2%-9%) were reported among patients receiving Gleevec. Severe fluid retention appears to be dose-related, was more common in the advanced phase studies (where the dosage was 600 mg/day), and is more common in the elderly.
Hepatotoxicity, occasionally severe, may occur. Assess liver function before initiation of treatment and monthly thereafter or as clinically indicated. Monitor liver function when combined with chemotherapy known to be associated with liver dysfunction. A 25% decrease in the recommended dose should be used for patients with severe hepatic impairment.
In the newly diagnosed CML trial, 2% of patients had (NCI Grades 3/4) hemorrhage.
Bullous dermatologic reactions (eg, erythema multiforme and Stevens-Johnson syndrome) have also been reported. In some cases, the reaction recurred upon rechallenge. Several postmarketing reports describe patients able to tolerate the reintroduction of Gleevec at a lower dose with or without concomitant corticosteroids or antihistamines following resolution or improvement of the bullous reaction.
Consider potential toxicities--specifically liver, kidney, and cardiac toxicity, and immunosuppression from long-term use.
Gleevec is metabolized by the CYP3A4 isoenzyme and is an inhibitor of CYP3A4, CYP2D6, and CYP2C9. Dosage of Gleevec should increase by at least 50%, and clinical response should be carefully monitored, in patients receiving Gleevec with a potent CYP3A4 inducer such as rifampin or phenytoin. Examples of commonly used drugs that may significantly interact with Gleevec include ketoconazole, acetaminophen, warfarin, erythromycin, and phenytoin. (Please see full Prescribing Information for other potential drug interactions.)
Common side effects of Gleevec tablets
The majority of adult patients with Ph+ CML who received Gleevec in clinical studies experienced adverse reactions at some time, but most were mild to moderate in severity. The most frequently reported adverse reactions (all Grades) were superficial edema (60%-74%), nausea (50%-73%), diarrhea (43%-57%), musculoskeletal pain (38%-49%), rash and related terms (36%-47%), muscle cramps (28%-62%), and vomiting (23%-58%).**^
Gleevec tablets should be taken with food and a large glass of water to minimize GI irritation. Gleevec tablets should not be taken with grapefruit juice and other foods known to inhibit CYP3A4.
**Numbers indicate the range of percentages in 4 studies among adult patients with newly diagnosed Ph+ CML and patients in BC, AP, and CP after failure of interferon-alpha therapy.
The foregoing release contains forward-looking statements that can be identified by terminology such as "to file," "may," "should," "potential," "promise," "plans," "will," or similar expressions, or by express or implied discussions regarding potential new indications or labeling for Tasigna or regarding potential future revenues from Tasigna or Gleevec. You should not place undue reliance on these statements. Such forward-looking statements reflect the current views of management regarding future events, and involve known and unknown risks, uncertainties and other factors that may cause actual results with Tasigna or Gleevec to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that Tasigna will be submitted or approved for any additional indications or labeling in any market. Nor can there be any guarantee that Tasigna or Gleevec will achieve any particular levels of revenue in the future. In particular, management's expectations regarding Tasigna and Gleevec could be affected by, among other things, unexpected clinical trial results, including unexpected new clinical data and unexpected additional analysis of existing clinical data; unexpected regulatory actions or delays or government regulation generally; the company's ability to obtain or maintain patent or other proprietary intellectual property protection; competition in general; government, industry and general public pricing pressures; the impact that the foregoing factors could have on the values attributed to the Novartis Group's assets and liabilities as recorded in the Group's consolidated balance sheet, and other risks and factors referred to in Novartis AG's current Form 20-F on file with the US Securities and Exchange Commission. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those anticipated, believed, estimated or expected. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.
Located in East Hanover, New Jersey, Novartis Pharmaceuticals Corporation is an affiliate of Novartis AG, which provides healthcare solutions that address the evolving needs of patients and societies. Focused solely on healthcare, the Novartis Group offers a diversified portfolio to best meet these needs: innovative medicines, preventive vaccines, diagnostic tools, cost-saving generic pharmaceuticals and consumer health products. The Novartis Group is the only company with leading positions in each of these areas. In 2008, the Group's continuing operations achieved net sales of USD 41.5 billion and net income of USD 8.2 billion. Approximately USD 7.2 billion was invested in R&D activities throughout the Group. Headquartered in Basel, Switzerland, Novartis Group companies employ approximately 99,000 full-time-equivalent associates and operate in more than 140 countries around the world. For more information, please visit http://www.us.novartis.com.
(1) Saglio G, Kim DW, Issaragrisil S, Philipp le Coutre, et al. Nilotinib Demonstrates Superior Efficacy Compared with Imatinib in Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase: Results from the International Randomized Phase III ENESTnd Trial. Abstract #LBA-1. American Society of Hematology 2009 Annual Meeting.
(3) Tasigna (nilotinib) Prescribing Information. East Hanover, New Jersey, USA: Novartis Pharma. http://www.pharma.us.novartis.com/product/pi/pdf/tasigna.pdf.
(5) NCCN Practice Guidelines in Oncology - v.1.2010. Chronic Myelogenous Leukemia.
(7) American Cancer Society. Detailed Guide: CML. What are the key statistics about CML? (Sept 2008 revision) Available at: http://www.cancer.org/docroot/CRI/content/CRI_2_4_1x_What_Are_the_Key_Statistics_About_Chronic_Myeloid_Leukemia_CML.asp?rnav=cri. Accessed April 2009.
(9) Gleevec(R) (imatinib mesylate) tablets prescribing information. East Hanover, NJ: Novartis Pharmaceuticals Corporation; November 2008.
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