Nilotinib Response Rates Continue To Improve In Patients With Chronic Myeloid Leukaemia Who Cannot Take Glivec(R) (Imatinib)

Main Category: Lymphoma / Leukemia
Article Date: 13 Dec 2007 - 16:00 PDT

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New clinical data presented at the 49th Annual Meeting of the American Society of Haematology (ASH) reveal that responses to second-generation tyrosine kinase inhibitor, nilotinib continue to improve over time in patients with resistance or intolerance to other treatments, including Glivec(R) (imatinib)*.

The new data show that nilotinib produced a positive response in 57% of patients in the chronic phase of Philadelphia chromosome-positive (Ph+) chronic myeloid leukaemia (CML), a five percent increase from figures reported last year.

High rates of response for previous non-responders

In patients that had not reached haematological response at the start of the trial (206 patients), 77% achieved complete haematological response on nilotinib treatment1. A major cytogenetic response (MCyR) was observed in 57% of patients (up from 52% reported at the ASH annual meeting in 2006) and complete cytogenetic response was seen in 40% of patients1. Overall survival of chronic phase patients with Ph+ CML was an estimated 95% at 12 months.

"Undoubtedly, nilotinib is an important advance for those Ph+ CML patients who develop resistance or intolerance to standard treatment with Glivec," said Professor Tessa Holyoake, University of Glasgow "These data show nilotinib is a much-needed and effective option for people with CML who are unable to take Glivec."

Patients in the accelerated phase of CML (more advanced disease) also responded well to treatment with nilotinib. Among 129 accelerated-phase patients, 26% achieved complete haematological and major cytogenetic response was observed in 31% of accelerated-phase patients2. Overall survival of accelerated-phase Ph+ CML patients was an estimated 81% at 12 months2.

Elizabeth Rees, CML Support UK welcomes the data "Nilotinib represents an important advance in medicine and a crucial second option to the small amount of people who are unable to take Glivec. The data shows that for most patients nilotinib provides an effective and potentially life-saving treatment option."

Potential of Nilotinib as a first-line therapy

Novartis are also investigating the potential of nilotinib as a first-line therapy in a head to head trial with Glivec. The Phase III first-line study for the treatment of newly diagnosed patients with chronic-phase Ph+ CML began in September 2007 and the company has also begun a study comparing the two targeted therapies in chronic-phase Ph+ CML patients who had sub-optimal responses to previous therapy.

New data from a small clinical trial (35 patients) comparing Tasigna and Glivec in the treatment of newly diagnosed patients with chronic-phase Ph+ CML were also presented at the ASH annual meeting. All evaluable patients (100%) achieved complete cytogenetic response within six months of treatment with Tasigna (96% within three months of treatment). At 12 months, major molecular response was achieved in 45% of patients receiving Tasigna. The most common side effects included thrombocytopenia, neutropenia and anaemia3.

References

1. Kantarjian, H. Nilotinib is Highly Active and Safe in Chronic Phase Chronic Myelogenous Leukemia (CML-CP) Patients with Imatinib-resistance or Intolerance. Oral Presentation. American Society of Hematology Annual Meeting, 2007. Abstract #25.

2. leCoutre, P. Nilotinib Is Safe and Effective in Accelerated Phase Chronic Myelogenous Leukemia (CML-AP) Patients with Imatinib Resistance or Intolerance. Oral Presentation. American Society of Hematology Annual Meeting, 2007. Abstract #25.

3. Jorge Cortes et al., Efficacy of Nilotinib (AMN107) in Patients with newly diagnosed, previously untreated Philadelphia Chromosome (Ph)-Positive Chronic Myelogenous Leukemia in early Chronic Phase (CML-CP). Oral Presentation. American Society of Hematology Annual Meeting, 2007. Abstract #29.

About Nilotinib

Taken twice daily, nilotinib works by inhibiting the proliferation of cells containing an abnormal chromosome. It does this by targeting the production of the Bcr-Abl protein, which is produced only by cells containing the abnormal Philadelphia chromosome. This protein is recognised as the key driver of the overproduction of cancer cells in patients with Ph+ CML.

Applying experience gained from the development of Glivec, a team of Novartis scientists created nilotinib in August 2002, just a year after the launch of Glivec. In preclinical studies, the medicine was able to overcome resistance resulting from Bcr-Abl kinase mutations in 32 of 33 cell lines commonly associated with Ph+ CML. Patients with a variety of these mutations also responded to treatment with nilotinib. Nilotinib was specifically designed to target the Bcr-Abl protein more preferentially than Glivec, without adding new mechanisms of action.

Nilotinib was approved in Switzerland in July 2007, followed by approvals by the U.S. Food and Drug Administration (FDA) and the European Commission. Nilotinib was also submitted for approval in Japan in June.

Phase II study details

The open-label Phase II study was designed to evaluate the safety and efficacy, as defined by haematologic (normalisation of white blood cell counts) and cytogenetic (reduction or elimination of the Ph+ chromosome) response rates of nilotinib administered to Glivec-resistant or intolerant patients with Ph+ CML in chronic phase and accelerated phase.

Of the 321 chronic-phase patients entering the trial, 115 were in complete haematological response at baseline. Of the remaining 206 patients, 77% achieved complete haematological response on nilotinib treatment. Major cytogenetic response (MCyR) was observed in 57% of patients (up from 52% reported at the ASH annual meeting in 2006) and complete cytogenetic response was seen in 41% of patients (up from 34% reported at the ASH annual meeting in 2006). The median times to complete haematological response and first major cytogenetic response were 1.0 months and 2.8 months, respectively. Responses were very durable with an estimated 89% of patients in MCyR for at least 12 months. Overall survival of chronic phase patients with Ph+ CML was an estimated 95% at 12 months. At the data cut-off, the median duration of treatment was 394 days (range 1��"714 days)1.

Among 129 accelerated-phase patients, 26% achieved complete haematological response with nilotinib treatment. Major cytogenetic response was observed in 31% of accelerated-phase patients. The median time to first major cytogenetic response was 2.0 months. The study investigators noted that cytogenetic response continues to increase with longer follow-up. Overall survival of accelerated-phase Ph+ CML patients was an estimated 81% at 12 months. At the data cut off, the median duration of treatment was 209.5 days (range 2-666 days)2.

The most common Grade 3/4 lab abnormalities included thrombocytopenia, neutropenia, anaemia and elevated serum lipase1,2. (See also "Nilotinib safety information - Adverse Reactions" below.)

Nilotinib safety information

Because taking nilotinib with food may increase the amount of drug in the blood, nilotinib should not be taken with food and patients should wait at least two hours after a meal before taking Tasigna. In addition, no food should be consumed for at least one hour after the dose is taken. Grapefruit juice and other foods that are known to inhibit CYP3A4 should be avoided.

In countries where it is approved, nilotinib is indicated for the treatment of chronic phase and accelerated phase Philadelphia chromosome-positive chronic myeloid leukaemia in adult patients resistant or intolerant to at least one prior therapy including Glivec. The effectiveness of nilotinib is based on confirmed hematologic and cytogenetic response rates. There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival.

The most frequent Grade 3 or 4 adverse events for nilotinib were primarily haematological in nature and included myelosuppression (thrombocytopenia, neutropenia and anaemia). Myelosuppression was generally reversible and usually managed by withholding nilotinib temporarily or by dose reduction. Elevations were seen in bilirubin, liver function tests, lipase enzymes and blood sugar, which were mostly transient and resolved over time. These cases were easily managed and rarely led to discontinuation. Pancreatitis was reported in less than 1% of cases. The most frequent non-haematologic drug-related adverse events were rash, pruritus, nausea, fatigue, headache, constipation, and diarrhoea. Most of these adverse events were mild to moderate in severity.

Nilotinib should be used with caution in patients with uncontrolled or significant cardiac disease (e.g. recent heart attack, congestive heart failure, unstable angina or clinically significant bradycardia), as well as in patients who have or may develop prolongation of QTc. These include patients with congenital long QT syndrome, patients taking anti-arrhythmic medicines or other drugs that may lead to QT prolongation. Low levels of potassium or magnesium must be corrected prior to nilotinib administration. Close monitoring for an effect on the QTc interval is advisable and a baseline ECG is recommended prior to initiating therapy with nilotinib and as clinically indicated.

The administration of nilotinib with agents that are strong CYP3A4 inhibitors should be avoided. Should treatment with these agents be required, it is recommended that therapy with nilotinib be interrupted if possible. If transient interruption of treatment with nilotinib is not possible, close monitoring of the patient for prolongation of the QT interval is indicated.

Concomitant use of nilotinib with medicinal products that are potent inducers of CYP3A4 is likely to reduce exposure to nilotinib to a clinically relevant extent. Therefore, in patients receiving nilotinib, co-administration of alternative therapeutic agents with less potential for CYP3A4 induction should be selected.

About Glivec

Glivec is approved in more than 90 countries including the US, EU and Japan for the treatment of all phases of Ph+ CML. Glivec is also approved in the EU, US and other countries for the treatment of patients with Kit (CD117)-positive gastrointestinal tumours (GIST), which cannot be surgically removed and/or have already spread to other parts of the body (metastasized). In Japan, Glivec is approved for the treatment of patients with Kit (CD117)-positive GIST. In the EU, Glivec is also approved for the treatment of adult patients with newly diagnosed Ph+ acute lymphoblastic leukaemia (Ph+ ALL) in combination with chemotherapy and as a single agent for patients with relapsed or refractory Ph+ ALL. Glivec is also approved for the treatment of adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans (DFSP) who are not eligible for surgery. Glivec is also approved for the treatment of patients with myelodysplastic/myeloproliferative diseases (MDS/MPD). Glivec is also approved for hypereosinophilic syndrome and/or chronic eosinophilic leukaemia (HES/CEL).

The effectiveness of Glivec is based on overall hematologic and cytogenetic response rates and progression-free survival in CML, on hematological and cytogenetic response rates in Ph+ ALL and on objective response rates in GIST and DFSP. There are no controlled trials demonstrating increased survival.

Not all indications are available in every country.

Glivec contraindications, warnings and adverse events The majority of patients treated with Glivec in clinical trials experienced adverse events at some time. Most events were of mild to moderate grade and treatment discontinuation was not necessary in the majority of cases.

The safety profile of Glivec was similar in all indications. The most common side effects included nausea, superficial edema, muscle cramps, skin rash, vomiting, diarrhea, abdominal pain, myalgia, arthralgia, haemorrhage, fatigue, headache, joint pain, cough, dizziness, dyspepsia and dyspnea, dermatitis, eczema, fluid retention, as well as neutropenia, thrombocytopenia and anaemia. Glivec was generally well-tolerated in all of the studies that were performed, either as monotherapy or in combination with chemotherapy, with the exception of a transient liver toxicity in the form of transaminase elevation and hyperbilirubinemia observed when Glivec was combined with high-dose chemotherapy.

Rare/serious adverse reactions include: sepsis, pneumonia, depression, convulsions, cardiac failure, thrombosis/embolism, ileus, pancreatitis, hepatic failure, exfoliative dermatitis, angio-oedema, Stevens-Johnson syndrome, renal failure, fluid retention, oedema (including brain, eye, pericardium, abdomen and lung), haemorrhage (including brain, eye, kidney and gastrointestinal tract), diverticulitis, gastrointestinal perforation, tumour haemorrhage/ necrosis, hip osteonecrosis/avascular necrosis.

Patients with cardiac disease or risk factors for cardiac failure should be monitored carefully and any patient with signs or symptoms consistent with cardiac failure should be evaluated and treated. Cardiac screening should be considered in patients with HES/CEL, and patients with MDS/MPD with high level of eosinophils (echocardiogram, serum troponin level).

Glivec is contraindicated in patients with known hypersensitivity to imatinib or any of its excipients. Women of childbearing potential should be advised to avoid becoming pregnant while taking Glivec.

About Novartis

Novartis AG (NYSE: NVS) is a world leader in offering medicines to protect health, cure disease and improve well-being. Our goal is to discover, develop and successfully market innovative products to treat patients, ease suffering and enhance the quality of life. We are strengthening our medicine-based portfolio, which is focused on strategic growth platforms in innovation-driven pharmaceuticals, high-quality and low-cost generics, human vaccines and leading self-medication OTC brands. Novartis is the only company with leadership positions in these areas. In 2006, the Group's businesses achieved net sales of USD 37.0 billion and net income of USD 7.2 billion. Approximately USD 5.4 billion was invested in R&D. Headquartered in Basel, Switzerland, Novartis Group companies employ approximately 100,000 associates and operate in over 140 countries around the world.

http://www.novartis.com

*Known as Gleevec( (imatinib mesylate) tablets in the US, Canada and Israel.