EAST HANOVER, N.J., June 4, 2016 /PRNewswire/ -- Novartis today announced at the 52nd American Society of Clinical Oncology (ASCO) Annual Meeting, the first results from the Tasigna (nilotinib) Treatment-free Remission (TFR) clinical trial program. These studies evaluated the potential to maintain molecular response (MR) after stopping therapy in adult patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in the chronic phase who achieved a sustained deep level of molecular response with Tasigna – a concept called TFR3. Findings from two open label trials, ENESTfreedom and ENESTop, showed that more than 50% of Ph+ CML patients who met the rigorous predefined response criteria of the trials were able to maintain TFR after stopping Tasigna both in the first-line setting and after switching from Gleevec (imatinib mesylate)*1,2. Discussions with regulatory authorities are underway with potential submissions in 2016.
Results from the ENESTfreedom study found that more than half (51.6%) of 190 CML patients (confidence interval [CI] 95%: 44.2%-58.9%) who achieved a sustained deep molecular response following at least three years of first-line treatment with Tasigna were able to discontinue therapy and remain in TFR for 48 weeks1. ENESTfreedom did not meet its primary objective, the percentage of patients in major molecular response (MMR; BCR-ABL1 International Scale [IS] ≤ 0.1%) at 48 weeks in the TFR phase, per the original statistical assumption that the lower limit of the 95% CI will be equal to or greater than 50%1. The median treatment duration in this trial was 3.6 years which is a short length of tyrosine kinase inhibitor (TKI) exposure prior to attempting TFR. Of the 86 patients who restarted treatment with Tasigna due to loss of MMR, 98.8% were able to regain MMR (n=85) and 88.4% were able to regain MR4.5 (BCR-ABL1 IS ≤ 0.0032%; n=76)1. By weeks 7.9 and 15.0 of treatment reinitiation with Tasigna, 50% of retreated patients already achieved MMR and MR4.5, respectively1. One patient discontinued the study at 7.1 weeks without regaining MMR after reinitiating treatment with Tasigna1.
"ENESTfreedom is the first trial to show that, after a short treatment duration with nilotinib of 3.6 years, more than 50 percent of patients who stopped therapy were able to remain treatment-free at 48 weeks," said Dr. Andreas Hochhaus, Head of the Department of Hematology and Medical Oncology, Jena University Hospital, Germany, and primary investigator for the ENESTfreedom study. "Findings from the nilotinib TFR trials add to the existing body of research exploring the discontinuation of tyrosine kinase inhibitor treatment in CML and may help to establish safe and appropriate criteria for eligible patients to stop treatment1,2,3."
ENESTop, the second Novartis TFR trial at ASCO, evaluated 126 patients who were able to achieve a sustained deep molecular response with Tasigna, but not with prior Gleevec therapy2. In this trial, nearly 6 out of 10 (57.9%) patients (95% CI: 48.8%-66.7%) who achieved a sustained deep molecular response following at least three years of Tasigna therapy maintained a molecular response 48 weeks after stopping treatment2. The study met its primary endpoint of the proportion of patients without confirmed loss of MR4.0 (BCR-ABL1 IS ≤ 0.01%) or loss of MMR within 48 weeks of Tasigna discontinuation in the TFR phase2. In the study, 51 patients with confirmed loss of MR4.0 or loss of MMR restarted Tasigna2. Of these patients, 98.0% (n=50) regained at least MMR, with 94.1% (n=48) and 92.2% (n=47) regaining MR4.0 and MR4.5, respectively2. By weeks 12.0 and 13.1 of treatment reinitiation with Tasigna, 50% of retreated patients already achieved MR4.0 and MR4.5, respectively2. One patient entered the treatment reinitiation phase but did not regain MMR by 20 weeks and discontinued the study. The BCR-ABL1 for this patient was 62.2% at the start of Tasigna retreatment and 9.8% at study exit2.
"Novartis has been at the forefront of advancements in the treatment and understanding of CML for 20 years," said Alessandro Riva, MD, Global Head, Novartis Oncology Development and Medical Affairs. "The exploration of TFR in patients treated with Tasigna, which includes Novartis support of eight TFR studies, is the next step in our commitment to advancing care for patients living with this disease."
Results from ENESTfreedom were presented today in an oral session (Abstract #7001, 3:12 PM CDT) at ASCO in Chicago. Data from ENESTop will be presented in a poster session on June 6 (Abstract #7054, 8:00-11:00 AM CDT). Both studies are ongoing, with planned follow-up to evaluate the ability of patients to sustain remission for longer durations following discontinuation of Tasigna. These are the first presentations of data from the Novartis Tasigna TFR clinical trial program.
An important part of the Tasigna TFR studies is regular and frequent molecular monitoring with a well-validated assay able to measure BCR-ABL transcript levels down to MR4.5. Frequent patient monitoring during TFR allows timely determination of loss of MR4.0 and MMR and need for treatment initiation1.2.
No new major safety findings were observed in these studies in patients treated with Tasigna beyond those in the known safety profile of Tasigna1,2. In ENESTfreedom, 24.7% of patients experienced musculoskeletal pain during the first year of the TFR phase versus 16.3% while still taking Tasigna in the one-year consolidation phase1. In ENESTop, the rates of all grade musculoskeletal pain were 42.1% in the first year of the TFR phase versus 14.3% while still taking Tasigna in the consolidation phase2. No patients progressed to advance phase/blast crisis in the two studies1,2.
Stopping CML treatment is currently not a clinical recommendation and should only be attempted in the context of a clinical study. Discontinuation of treatment in ENESTfreedom and ENESTop was conducted under the conditions of the trials and in patients who met the rigorous predefined criteria of the trials1,2.
Novartis commitment to CML
Novartis is supporting eight studies as part of its TFR clinical trial program, which includes ENESTfreedom and ENESTop, as well as two other ongoing company-sponsored TFR studies and four investigator-initiated studies that are now underway in more than 100 global sites across 40 countries. Over the past several decades, Novartis research in Ph+ CML has helped transform the disease from a fatal leukemia to a chronic condition and, today, the company continues its long-standing commitment to the global CML community. Novartis follows the science and builds upon existing evidence to explore what could be the next major contribution in the treatment of Ph+ CML through these TFR trials as well as investigational compounds.
ENESTfreedom (Evaluating Nilotinib Efficacy and Safety in Clinical Trials – Following REsponsE in De nOvo CML-CP Patients) is an open label Phase II study involving 215 Ph+ CML patients in the chronic phase, conducted at 132 sites across 19 countries. ENESTfreedom evaluated stopping treatment in 190 adults with Ph+ CML after the patients had achieved a response of MR4.5 with Tasigna and a sustained deep molecular response for one year as a first-line treatment.
ENESTop (Evaluating Nilotinib Efficacy and Safety Trial) is an open label Phase II study involving 163 Ph+ CML patients, conducted at 63 sites across 18 countries. The trial evaluated stopping treatment in 126 adults with Ph+ CML in the chronic phase after patients had achieved and sustained deep molecular response for one year with Tasigna following Gleevec.
TASIGNA® (nilotinib) is approved for the treatment of adult patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase. The effectiveness of TASIGNA for this indication is based on major molecular response and cytogenetic response rates at 12 months.
TASIGNA is also approved in more than 122 countries for the treatment of chronic phase and accelerated phase Ph+ CML in adult patients resistant or intolerant to at least one prior therapy, including Gleevec, and in more than 120 countries for the treatment of adult patients with newly diagnosed Ph+ CML in chronic phase. The effectiveness of TASIGNA for this indication is based on hematologic and cytogenetic response rates.
IMPORTANT SAFETY INFORMATION for TASIGNA® (nilotinib) Capsules
WARNING: QT PROLONGATION AND SUDDEN DEATHS
- Myelosuppression: Treatment with TASIGNA can cause Grade 3/4 thrombocytopenia, neutropenia, and anemia. Complete blood counts should be performed every 2 weeks for the first 2 months and then monthly thereafter
- Cardiac and Vascular Events: Cases of cardiovascular events included ischemic heart disease-related events, peripheral arterial occlusive disease, and ischemic cerebrovascular events have been reported
- Pancreatitis and Elevated Serum Lipase: TASIGNA can cause increases in serum lipase. Caution is recommended in patients with a history of pancreatitis
- Hepatotoxicity: The use of TASIGNA may result in elevations in bilirubin, AST/ALT, and alkaline phosphatase
- Electrolyte Abnormalities: TASIGNA can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia
- Drug Interactions: The concomitant use of strong CYP3A4 inhibitors or anti -arrhythmic drugs and other drugs that may prolong the QT interval should be avoided. Grapefruit products should also be avoided
- The concomitant use of strong CYP3A4 inducers should be avoided. The concomitant use of proton pump inhibitors with TASIGNA is not recommended
- When the concurrent use of a H2 blocker is necessary, administer approximately 10 hours before and approximately 2 hours after the TASIGNA dose. If necessary, an antacid may be administered approximately 2 hours before or approximately 2 hours after the TASIGNA dose
- Food Effects: TASIGNA must be taken on an empty stomach. No food should be consumed for at least 2 hours before the dose and for at least 1 hour after the dose is taken
- Hepatic Impairment: TASIGNA exposure is increased in patients with impaired hepatic function
- Tumor Lysis Syndrome: Cases of tumor lysis syndrome have been reported in TASIGNA-treated patients who were resistant or intolerant to prior CML therapy. Due to potential for tumor lysis syndrome, maintain adequate hydration and correct uric acid levels prior to initiating therapy with TASIGNA
- Total Gastrectomy: The exposure of TASIGNA is reduced in patients with total gastrectomy
- Lactose: 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
- Monitoring Laboratory Tests: Chemistry panels, including electrolytes, calcium, magnesium, lipid profile, and glucose should be checked prior to therapy and periodically
- Embryo-Fetal Toxicity: Women of childbearing potential should avoid becoming pregnant while taking TASIGNA and should be advised of the potential hazard to the fetus if they do
- Reactivation of hepatitis B can occur in patients who are chronic carriers of this virus after receiving TKI treatment
- ADVERSE REACTIONS: The most commonly reported non-hematologic adverse reactions (≥20% in patients) were nausea, rash, headache, fatigue, pruritus, vomiting, diarrhea, cough, constipation, arthralgia, nasopharyngitis, pyrexia, and night sweats. Hematologic adverse drug reactions include myelosuppression: thrombocytopenia, neutropenia and anemia
- DOSE ADJUSTMENTS OR MODIFICATIONS: TASIGNA may need to be temporarily withheld and/or dose reduced for QT prolongation, hematologic toxicities that are not related to underlying leukemia, clinically significant moderate or severe non hematologic toxicities, laboratory abnormalities or concomitant use of strong CYP3A4 inhibitors
Please see full Prescribing Information including Boxed WARNING.
Gleevec® (imatinib mesylate) tablets are indicated for newly diagnosed adult patients with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in the chronic phase (CP). Gleevec is also indicated for the treatment of patients with Ph+ CML in blast crisis (BC), accelerated phase (AP), or in CP after failure of interferon-alpha therapy.
GLEEVEC Important Safety Information
GLEEVEC can cause fetal harm when administered to a pregnant woman. Women should not become pregnant, and should be advised of the potential risk to the unborn child.
GLEEVEC is often associated with edema (swelling) and serious fluid retention. Studies have shown that edema (swelling) tended to occur more often among patients who are 65 and older or those taking higher doses of GLEEVEC.
Cytopenias (reduction or lack of certain cell elements in blood circulation), such as anemia, have occurred. If the cytopenia is severe, your doctor may reduce your dose or temporarily stop your treatment with GLEEVEC.
Severe congestive heart failure and left ventricle dysfunction have been reported, particularly in patients with other health issues and risk factors. Patients with heart disease or risk factors or history of renal failure will be monitored and treated for the condition. Reactivation of hepatitis B can occur in patients who are chronic carriers of this virus after receiving TKI treatment.
Severe liver problems (hepatotoxicity) may occur. Cases of fatal liver failure and severe liver injury requiring liver transplants have been reported with both short-term and long-term use of GLEEVEC.
Bleeding may occur. Severe gastrointestinal (GI) bleeding has been reported in patients with KIT+ GIST. GI tumor sites may be the cause of this bleeding; therefore, GI symptoms should be monitored at the start of treatment.
In patients with hypereosinophilic syndrome (a condition with increased eosinophils, which are a type of white blood cell) and heart involvement, cases of heart disease (cardiogenic shock/left ventricular dysfunction) have been associated with the initiation of GLEEVEC therapy.
Skin reactions, such as fluid-filled blisters, have been reported with the use of GLEEVEC.
Clinical cases of hypothyroidism (reduction in thyroid hormones) have been reported in patients taking levothyroxine replacement with GLEEVEC.
Long-term use may result in potential liver, kidney, and/or heart toxicities; immune system suppression may also result from long-term use.
GI perforation (small holes or tears in the walls of the stomach or intestine), in some cases fatal, has been reported.
Growth retardation has been reported in children taking GLEEVEC. The long-term effects of extended treatment with GLEEVEC on growth in children are unknown.
Cases of tumor lysis syndrome (TLS), which refers to a metabolic and electrolyte disturbance caused by the breakdown of tumor cells, have been reported and can be life-threatening in some cases. Correction of clinically significant dehydration and treatment of high uric acid levels are recommended prior to initiation of GLEEVEC.
Reports of motor vehicle accidents have been received in patients receiving GLEEVEC. Caution patients about driving a car or operating machinery.
Almost all patients treated with GLEEVEC experience side effects at some time. Some common side effects you may experience are fluid retention, muscle cramps or pain and bone pain, abdominal pain, loss of appetite, vomiting, diarrhea, decreased hemoglobin, abnormal bleeding, nausea, fatigue and rash.
GLEEVEC is sometimes associated with stomach or intestinal irritation. GLEEVEC should be taken with food and a large glass of water to minimize this problem. There have been rare reports, including deaths, of stomach or intestinal perforation (a small hole or tear).
If you are experiencing any of the mentioned side effects, please be sure to speak with your doctor immediately.
Do not take any other medications without talking to your doctor or pharmacist first, including Tylenol® (acetaminophen); herbal products (St. John's wort, Hypericum perforatum); Coumadin® (warfarin sodium); rifampin; erythromycin; metoprolol; ketoconazole; and Dilantin® (phenytoin). Taking these with GLEEVEC may affect how they work, or affect how GLEEVEC works.
You should also tell your doctor if you are taking or plan to take iron supplements. Patients should also avoid grapefruit juice and other foods that may affect how GLEEVEC works.
Please see full Prescribing Information.
The foregoing release contains forward-looking statements that can be identified by words such as "potential," "underway," "exploring," "may," "exploration," "next step," "commitment," "continues," "explore," "could," "investigational," or similar terms, or by express or implied discussions regarding potential new indications or labeling for Tasigna or Gleevec, regarding potential marketing approvals for Novartis investigational compounds, or regarding potential future revenues from Tasigna, Gleevec or such investigational compounds. You should not place undue reliance on these statements. Such forward-looking statements are based on the current beliefs and expectations of management regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that Tasigna or Gleevec will be submitted or approved for any additional indications or labeling in any market, or at any particular time. Neither can there be any guarantee that any Novartis investigational compounds will be submitted or approved for sale in any market, or at any particular time. Nor can there be any guarantee that Tasigna, Gleevec or any Novartis investigational compounds will be commercially successful in the future. In particular, management's expectations regarding Tasigna, Gleevec and such investigational compounds could be affected by, among other things, the uncertainties inherent in research and development, including unexpected clinical trial results and additional analysis of existing clinical data; unexpected regulatory actions or delays or government regulation generally; the company's ability to obtain or maintain proprietary intellectual property protection; general economic and industry conditions; global trends toward health care cost containment, including ongoing pricing pressures; unexpected manufacturing issues, and other risks and factors referred to in Novartis AG's current Form 20-F on file with the US Securities and Exchange Commission. 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.
Novartis Pharmaceuticals Corporation researches, develops, manufactures and markets innovative medicines aimed at improving patients' lives. We offer a broad range of medicines for cancer, cardiovascular disease, endocrine disease, inflammatory disease, infectious disease, neurological disease, organ transplantation, psychiatric disease, respiratory disease and skin conditions. The company's mission is to improve people's lives by pioneering novel healthcare solutions.
Located in East Hanover, New Jersey, Novartis Pharmaceuticals Corporation is an affiliate of Novartis AG, which provides innovative healthcare solutions that address the evolving needs of patients and societies. Headquartered in Basel, Switzerland, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, eye care and cost-saving generic pharmaceuticals. Novartis is the only global company with leading positions in these areas. In 2015, the Group achieved net sales of USD 49.4 billion, while R&D throughout the Group amounted to approximately USD 8.9 billion (USD 8.7 billion excluding impairment and amortization charges). Novartis Group companies employ approximately 118,000 full-time-equivalent associates. Novartis products are available in more than 180 countries around the world. For more information, please visit http://www.novartis.com.
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*Known as Glivec® (imatinib) outside the US, Canada and Israel.
- Hochhaus, A. et al. Treatment-free remission (TFR) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) treated with frontline nilotinib: Results from the ENESTfreedom study. Oral Presentation. Abstract #7001. 2016 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, IL, USA.
- Hughes, H.P. et al. Treatment-free remission (TFR) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) treated with second-line nilotinib (NIL): First results from the ENESTop study. Poster Presentation. Abstract #7054. 2016 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, IL, USA.
- Hughes, H.P. and Ross, R.M. Moving treatment-free remission into mainstream clinical practice in CML. Blood. 2016. Advance online publication. doi# 10.1182/blood-2016-01-694265.
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