Novartis marks World CML Day with update on global research program to evaluate whether Ph+ CML patients can live treatment-free

NovartisNovartis commemorates World CML Day by announcing the latest milestone in its unique clinical trial program evaluating the potential for patients with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) to maintain undetectable levels of disease after stopping drug therapy - a concept called treatment-free remission. More than 100 study sites are now enrolling patients to the trial program.

Since 2008, organizations around the world have recognized World CML Day[1]. The date, September 22 or 9/22, was symbolically chosen to represent the genetic material that is associated with CML - the missing section from chromosome 22 shifts to chromosome 9 and vice versa, in a phenomenon called "translocation[2]." Known as the Philadelphia chromosome, this genetic mutation is present in about 95% of CML patients[3].

"As a leader in CML, Novartis is proud to support World CML Day through our continued dedication to ongoing research in this disease," said Hervé Hoppenot, President, Novartis Oncology. "Given that nilotinib has been shown in large clinical trials to drive deeper levels of responses in more than twice as many patients as imatinib, we are now looking to the next phase and exploring if nilotinib can treat the disease to a point where drug therapy is no longer needed, representing the next step in what may be possible for patients living with Ph+ CML."

Over the past decades, Novartis research in Ph+ CML has helped transform the disease from a fatal diagnosis to a chronic condition for many patients. Today, the company continues its long-standing commitment to the global CML community. The Novartis treatment-free remission clinical trial program* includes eight studies that are now underway and actively enrolling Ph+ CML patients in more than 100 global sites across 40 countries[4]. In total, it is planned that more than 2,500 patients will be enrolled in these studies and an estimated nearly 1,000 patients will aim to stop treatment as part of these studies[4].

Globally, Novartis is sponsoring four treatment-free remission studies, including:

  • ENESTfreedom[5] - a Phase II study in Ph+ CML patients in chronic phase who achieved and maintained MR4.5 on nilotinib as first-line treatment. More information, including addresses and contact information for each study site, can be found on www.clinicaltrials.gov, identifier # NCT01784068.
  • ENESTop[6] - a Phase II study in Ph+ CML patients in chronic phase who have achieved and maintained MR4.5 on nilotinib after switching from imatinib. More information, including addresses and contact information for each study site, can be found on www.clinicaltrials.gov, identifier # NCT01698905.
  • ENESTpath[7] - a Phase III study in Ph+ CML patients in chronic phase who have switched to nilotinib from imatinib and have achieved and maintained MR4.0. More information, including addresses and contact information for each study site, can be found on www.clinicaltrials.gov, identifier # NCT01743989.
  • ENESTgoal[8] - a Phase II study in Ph+ CML patients in chronic phase who have achieved and maintained MR4.5 on nilotinib after switching from imatinib. More information, including addresses and contact information for each study site, can be found on www.clinicaltrials.gov, identifier # NCT01744665.

Novartis is also providing support for four investigator-initiated studies (STAT-2, NILst, CML V, NILO POST-STIM)[4]. These studies are led by independent investigators in sites in Japan, Germany and France.

Stopping treatment is not a clinical recommendation and should only be attempted in the context of a well conducted clinical study. A very important part of these treatment-free remission studies is the inclusion of regular molecular monitoring with International Scale Real-Time Quantitative Polymerase Chain Reaction (IS RT-Q-PCR) testing. Once treatment is stopped molecular monitoring is used to identify if a patient's level of disease remains in deep molecular response or if the reintroduction of treatment is needed[5]-[8].

ENESTfreedom study details[5]
ENESTfreedom is a Phase II, single-arm, open-label study to determine if adults with Ph+ CML can live without drug therapy after stopping treatment with nilotinib. Eligible patients must have maintained MR4.5 with nilotinib treatment in the first-line setting for at least two years before entering the study. Following a one-year consolidation phase, patients who continue to sustain MR4.5 will enter the treatment-free phase. Patients will be monitored closely with regular IS RT-Q-PCR testing.

The primary endpoint is the percentage of patients who are in major molecular response (MMR) at 48 weeks after starting the treatment-free phase and no restarting of nilotinib treatment.

ENESTop study details[6]
ENESTop is a Phase II, single-arm, open-label study designed to determine if adults with Ph+ CML can live without drug therapy after stopping treatment with nilotinib. Eligible patients have been on treatment with nilotinib for at least two years (with the combined time on imatinib and nilotinib for at least three years) and have maintained MR4.5 for at least one year before entering the treatment-free phase. Patients will be monitored closely with regular IS RT-Q-PCR testing.

The primary endpoint is the proportion of patients in treatment-free remission and no loss of MMR or MR4 within the first 12 months of nilotinib cessation.

ENESTpath study details[7]
ENESTpath is a prospective, randomized, open-label, two arm Phase III study designed to evaluate the rate of treatment-free remission in Ph+ CML patients at 12 months after two different durations of consolidation treatment with nilotinib. Eligible patients must have been treated with imatinib for a minimum of two years, being at least in complete cytogenetic response, but have not achieved MR4.0 at study start. Patients entering the study will have two years of nilotinib treatment. If sustained MR4.0 is achieved during the second year of nilotinib treatment, patients will be eligible to be randomized to either enter the treatment-free remission phase immediately, or continue for another year of consolidation with nilotinib treatment and, if still in sustained MR4.0, enter the treatment-free remission phase. Patients will be monitored closely with regular IS RT-Q-PCR testing.

The primary endpoint is the proportion of patients who remain in treatment-free remission (>= MR4.0) without molecular relapse at the end of 12 months in the treatment-free remission phase of the study. This study compares the nilotinib 12-month consolidation treatment arm (arm 1) with the nilotinib 24-month consolidation treatment arm (arm 2) to determine the optimal duration of the consolidation phase.

ENESTgoal study details[8]
ENESTgoal is a US-only Phase II randomized, open-label, two arm, multicenter study designed to determine if adults with Ph+ CML can live without drug therapy after stopping treatment with nilotinib. Eligible patients must have been on treatment with imatinib for at least one year and have achieved a BCR-ABL level of less than or equal to MMR and greater than MR4.5 as measured by IS RT-Q-PCR testing. Patients will switch to nilotinib once entering the study and will have three years of treatment. If MR4.5 is achieved during the third year of treatment, patients will be eligible to be randomized to either enter the treatment-free remission phase immediately, or continue receiving nilotinib for another year before being eligible to enter the treatment-free phase. Patients will be monitored closely with regu

lar IS RT-Q-PCR testing.

The primary endpoint is the percentage of patients remaining in the remission phase (no confirmed loss of MR4.0 and no restarting of treatment with nilotinib) at six months from the start of treatment-free phase, with no confirmed loss of MR4.0 and no restarting of treatment with nilotinib.

About Tasigna (nilotinib)
Tasigna® (nilotinib) is approved in more than 90 countries for the treatment of chronic phase and accelerated phase Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+ CML) in adult patients resistant or intolerant to at least one prior therapy, including Glivec+, and for the treatment of adult patients with newly diagnosed Ph+ CML in chronic phase. Take twice daily 12 hours apart. Do not take with food. No food to be consumed for 2 hours before or one hour after dosing. Avoid grapefruit juice and CYP3A4 inhibitors.

About Glivec (imatinib)
Glivec® (imatinib) is approved in more than 110 countries for the treatment of all phases of Ph+ CML, for the treatment of adult patients with KIT (CD117)-positive gastrointestinal stromal tumors (GIST), which cannot be surgically removed and/or have metastasized and for the treatment of adult patients following complete surgical removal of KIT+ GIST. Take with food and a large glass of water.

About Novartis
Novartis 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, cost-saving generic pharmaceuticals, preventive vaccines and diagnostic tools, over-the-counter and animal health products. Novartis is the only global company with leading positions in these areas. In 2012, the Group achieved net sales of USD 56.7 billion, while R&D throughout the Group amounted to approximately USD 9.3 billion (USD 9.1 billion excluding impairment and amortization charges). Novartis Group companies employ approximately 131,000 full-time-equivalent associates and operate in more than 140 countries around the world.

* In the Novartis treatment-free remission clinical trial program, molecular response (reduction of BCR-ABL transcripts in the blood of patients) is measured at four levels, based on an international standard:

  • MMR (<= 0.1% BCR-ABL)
  • MR4 (<= 0.01% BCR-ABL)
  • MR4.5 (<= 0.0032% BCR-ABL)
  • Undetectable BCR-ABL (no detectable BCR-ABL transcript level with sample sensitivity of at least 4.5 log)

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

1. What is World CML Day? CML Advocates Network. http://www.cmladvocates.net/worldcmlday/what-is-world-cml-day
2. National Comprehensive Cancer Network (NCCN): Clinical Practice Guidelines in Oncology: Chronic Myelogenous Leukemia, V.4.2013. Available at: http://www.nccn.org/professionals/physician_gls/pdf/cml.pdf.
3. Faderl, Stefan, et al. "The biology of chronic myeloid leukemia." New England Journal of Medicine.1999; 341.3: 164-172.
4. Novartis data on file.
5. Nilotinib Treatment-free Remission Study in CML (Chronic Myeloid Leukemia) Patients (ENESTFreedom). Trial identifier NCT01784068 . http://www.clinicaltrials.gov. Accessed August 2013.
6. A Phase II, Single Arm, Open Label Study of Treatment-free Remission After Achieving Sustained MR4.5 on Nilotinib (ENESTop). Trial identifier NCT01698905. http://www.clinicaltrials.gov. Accessed August 2013.
7. A Randomized Phase III Study to Assess the Effect of a Longer Duration of Consolidation Treatment With Nilotinib on TFR in CP CML (ENESTPath). Trial identifier NCT01743989. http://www.clinicaltrials.gov. Accessed August 2013.
8. Safety and Efficacy of CML Patients Who Switch to Nilotinib and Stop Treatment After Achieving Sustaining MR4.5. (ENESTgoal). Trial identifier NCT01744665. http://www.clinicaltrials.gov. Accessed August 2013.

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