On June 23, 2017 Takeda Pharmaceutical Company Limited (TSE: 4502) reported that data from two Phase 1/2 clinical trials evaluating NINLARO (ixazomib) in patients with newly diagnosed multiple myeloma will be presented during oral sessions at the 2017 European Hematology Association (EHA) (Free EHA Whitepaper) annual meeting on Saturday, June 24, 11:45 a.m. – 12 p.m. CEST and Sunday, June 25, 8:15 a.m. – 8:30 a.m. CEST (Press release, Takeda, JUN 23, 2017, View Source [SID1234519679]). Both studies evaluated NINLARO plus lenalidomide and dexamethasone in newly diagnosed patients with multiple myeloma who did not undergo stem cell transplant (SCT), followed by maintenance with single-agent ixazomib. NINLARO is currently not approved for the treatment of newly diagnosed multiple myeloma or in the maintenance setting.

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"Despite recent progress, multiple myeloma remains a rare, devastating and incurable hematologic cancer. Data being presented at EHA (Free EHA Whitepaper) demonstrate Takeda’s ongoing commitment to exploring new ways to provide effective and sustainable treatment for patients with multiple myeloma, both at the time of diagnosis and for long-term use," said Jesus Gomez Navarro, M.D., Vice President, Head of Oncology Clinical Research and Development, Takeda. "These Phase 1/2 data demonstrate the potential use of ixazomib in combination with lenalidomide-dexamethasone in newly diagnosed multiple myeloma and as a single-agent maintenance therapy, which resulted in patients achieving deepening responses with continual use of the treatment. Ixazomib’s efficacy and safety profile – coupled with its administration as a completely oral regimen – potentially can reduce some logistical burdens, and help patients be able to sustain a multiple myeloma therapy."

Deep and Durable Responses with Weekly Ixazomib, Lenalidomide and Dexamethasone in Patients with Newly Diagnosed Multiple Myeloma: Long-Term Follow-up of Patients who did not Undergo SCT (Abstract S408, oral presentation at 11:45 a.m. CEST on June 24, 2017 at IFEMA Madrid, Hall A)
In this Phase 1/2 study, patients with newly diagnosed multiple myeloma received weekly oral ixazomib (1.68 – 3.95 mg/m2 in Phase 1 and 4.0 mg in Phase 2) plus lenalidomide and dexamethasone for up to twelve, 28-day induction cycles. Of the 65 enrolled patients, 42 continued on study treatment without withdrawing early for SCT. After initial therapy, 25 patients went on to receive weekly, single-agent ixazomib at the last tolerated dose given during induction until disease progression or unacceptable toxicity.

Key findings, which will be presented by Dr. Shaji Kumar of the Mayo Clinic, Rochester, Minnesota, include:

Patients who did not undergo SCT and were treated with ixazomib plus lenalidomide and dexamethasone at induction achieved high response rates, demonstrate the activity of this regimen
At a median follow-up of 55.2 months, the confirmed overall response rate (ORR) was 80%, complete plus very good partial response (CR+VGPR) rate was 63% and CR rate was 32%
Of the patients who achieved sCR/CR and were evaluated for minimal residual disease (MRD), 6 of 7 (86%) were MRD-negative.
Median progression-free survival (PFS) was 29.4 months
Median overall survival (OS) was not reached at a median follow-up of 55.2 months; four-year landmark OS estimate was 82%
A total of 86% of patients had grade > 3 adverse events (AEs) and 52% of patients had serious AEs. The most common grade > 3 AEs were neutropenia, thrombocytopenia, diarrhea, back pain, vomiting, rashes, eruptions and exanthems, peripheral neuropathy and nausea. Of the two patients who died on study, one was considered to be treatment-related and was due to respiratory syncytial viral pneumonia
After completing 12 cycles of induction therapy with lenalidomide and dexamethasone, 25 patients went on to receive maintenance single-agent ixazomib
Increased depth of response occurred in a number of patients who received maintenance therapy with single-agent ixazomib; 32% of patients improved their response during maintenance
The occurrence of the most common grade > 3 AEs and adverse drug reactions (ADRs), which included neutropenia, thrombocytopenia, back pain and rashes, eruptions and exanthems, was confined almost exclusively to the induction period
Less toxicity was reported during the maintenance versus induction periods
"Based on an increasing body of evidence that long-term therapy may improve clinical outcomes, this Phase 1/2 trial focused on continuous treatment of patients with newly diagnosed multiple myeloma," said lead investigator Shaji Kumar, M.D., Mayo Clinic, Rochester, Minn. "The trial evaluated patients who received weekly ixazomib plus lenalidomide and dexamethasone as an induction regimen followed by maintenance with single-agent ixazomib. Data showed that patients had deep responses on single-agent therapy and median progression-free survival of more than two years. We remain committed to gathering additional data of ixazomib in this investigational, maintenance setting."

Twice Weekly Ixazomib Plus Lenalidomide-Dexamethasone in Patients with Newly Diagnosed Multiple Myeloma: Long-Term Follow-up Data for Patients who did not Undergo Stem Cell Transplant (SCT) (Abstract S780, oral presentation at 8:15 a.m. CEST on June 25, 2017 at IFEMA Madrid, Hall D)
This Phase 1/2 study evaluated twice-weekly oral ixazomib (3.0 or 3.7 mg) plus lenalidomide and dexamethasone for up to sixteen, 21-day cycles followed by maintenance therapy with single-agent twice weekly ixazomib (at last tolerated dose). Of the 64 patients enrolled, 41 continued on study treatment without early withdrawal for SCT.

Key findings, which will be presented by Deborah Berg, Senior Scientific Director, Oncology Clinical Research, Takeda, on behalf of Dr. Paul Richardson, Dana-Farber Cancer Institute, Boston, Mass., include:

In patients who did not undergo SCT, initial treatment with twice-weekly ixazomib plus lenalidomide and dexamethasone was associated with deep responses
At median follow-up of 47 months, the ORR was 92%, the CR + VGPR rate was 69% and the CR rate was 31%
Of the patients who achieved sCR/CR and were evaluated for minimal residual disease (MRD), 8 of 9 (89%) were MRD-negative
Median PFS for patients was 24.9 months and median OS was not estimable; three-year landmark OS estimate was 86%
A total of 85% of patients had grade > 3 AEs and 54% of patients had serious AEs. The most common grade >3 AEs included rash, eruptions and exanthems, hyperglycemia, peripheral neuropathy, peripheral edema, thrombocytopenia and neutropenia. There was one on-study treatment-related death due to cardio respiratory arrest.
After completing induction therapy, 18 patients went on to receive maintenance with twice-weekly single-agent ixazomib
Patients on maintenance therapy received a median of 31.5 treatment cycles
22% patients improved their responses during maintenance
44% of patients who received maintenance therapy had an onset of a grade > 3 AE and ADRs in cycle 17 or beyond. The most common grade > 3 AEs and ADRs were hyperglycemia, rashes, eruptions and exanthems, diarrhea, vomiting, peripheral neuropathy, nausea and neutropenia
"The addition of ixazomib – a first in class oral proteasome inhibitor – to doublet therapy has been shown to substantially improve efficacy in newly diagnosed multiple myeloma patients," said lead investigator Paul Richardson, M.D., Dana-Farber Cancer Institute. "In this Phase 1/2 trial in newly diagnosed multiple myeloma, ixazomib plus lenalidomide and dexamethasone resulted not only in high quality of responses using a twice a week schedule but also in an encouraging deepening of responses over time in patients who did not receive a stem cell transplant. In addition, impressive durable clinical benefit was seen as patients went on to receive maintenance therapy with single-agent ixazomib after successful induction/remission therapy using this all oral approach."

About Multiple Myeloma
Multiple myeloma is a cancer of the plasma cells, which are found in the bone marrow. In multiple myeloma, a group of monoclonal plasma cells, or myeloma cells, becomes cancerous and multiplies. These malignant plasma cells have the potential to affect many bones in the body, possibly resulting in compression fractures, lytic bone lesions and related pain. Multiple myeloma can cause a number of serious health problems affecting the bones, immune system, kidneys and red blood cell count, with some of the more common symptoms including bone pain and fatigue, a symptom of anemia. Multiple myeloma is a rare form of cancer, with approximately 114,000 new cases globally per year.

About NINLAROTM (ixazomib) capsules
NINLAROTM (ixazomib) is an oral proteasome inhibitor which is also being studied across the continuum of multiple myeloma treatment settings as well as systemic light-chain (AL) amyloidosis. It was the first oral proteasome inhibitor to enter Phase 3 clinical trials and to receive approval. NINLARO was approved by the U.S. Food and Drug Administration (FDA) in November 2015 following a priority review and by the European Commission in November 2016. In the U.S. and Europe, NINLARO is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy.

Ixazomib was granted orphan drug designation in multiple myeloma in both the U.S. and Europe in 2011 and for AL amyloidosis in both the U.S. and Europe in 2012. Ixazomib received Breakthrough Therapy status by the U.S. FDA for relapsed or refractory systemic light-chain (AL) amyloidosis in 2014.

The comprehensive ixazomib clinical development program, TOURMALINE, further reinforces Takeda’s ongoing commitment to developing innovative therapies for people living with multiple myeloma worldwide and the healthcare professionals who treat them. TOURMALINE includes a total of five ongoing pivotal trials – four, which together are investigating every major multiple myeloma patient population, and one in light-chain amyloidosis:

TOURMALINE-MM1, investigating ixazomib vs. placebo, in combination with lenalidomide and dexamethasone in relapsed and/or refractory multiple myeloma
TOURMALINE-MM2, investigating ixazomib vs. placebo, in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma
TOURMALINE-MM3, investigating ixazomib vs. placebo as maintenance therapy in patients with newly diagnosed multiple myeloma following induction therapy and autologous stem cell transplant (ASCT)
TOURMALINE-MM4, investigating ixazomib vs. placebo as maintenance therapy in patients with newly diagnosed multiple myeloma who have not undergone ASCT; this study is currently enrolling
TOURMALINE-AL1, investigating ixazomib plus dexamethasone vs. physician choice of selected regimens in patients with relapsed or refractory AL amyloidosis; this study is currently enrolling
TOURMALINE-MM5, investigating ixazomib plus dexamethasone vs. pomalidomide plus dexamethasone in patients with relapsed and/or refractory multiple myeloma who have become resistant to lenalidomide
TOURMALINE-MM6, investigating ixazomib vs. placebo, in combination with lenalidomide and dexamethasone in patients with multiple myeloma transitioning from a bortezomib-based triplet induction regimen
In addition to the TOURMALINE program, ixazomib is being evaluated in multiple therapeutic combinations for various patient populations in investigator initiated studies globally.

NINLAROTM (ixazomib): Global Important Safety Information
SPECIAL WARNINGS AND PRECAUTIONS

Thrombocytopenia has been reported with NINLARO (28% vs. 14% in the NINLARO and placebo regimens, respectively) with platelet nadirs typically occurring between Days 14-21 of each 28-day cycle and recovery to baseline by the start of the next cycle. It did not result in an increase in hemorrhagic events or platelet transfusions. Monitor platelet counts at least monthly during treatment with NINLARO and consider more frequent monitoring during the first three cycles. Manage with dose modifications and platelet transfusions as per standard medical guidelines.

Gastrointestinal toxicities have been reported in the NINLARO and placebo regimens respectively, such as diarrhea (42% vs. 36%), constipation (34% vs. 25%), nausea (26% vs. 21%), and vomiting (22% vs. 11%), occasionally requiring use of antiemetic and anti-diarrheal medications, and supportive care.

Peripheral neuropathy was reported with NINLARO (28% vs. 21% in the NINLARO and placebo regimens, respectively). The most commonly reported reaction was peripheral sensory neuropathy (19% and 14% in the NINLARO and placebo regimens, respectively). Peripheral motor neuropathy was not commonly reported in either regimen (< 1%). Monitor patients for symptoms of peripheral neuropathy and adjust dosing as needed.

Peripheral edema was reported with NINLARO (25% vs. 18% in the NINLARO and placebo regimens, respectively). Evaluate patients for underlying causes and provide supportive care, as necessary. Adjust the dose of dexamethasone per its prescribing information or the dose of NINLARO for severe symptoms.

Cutaneous reactions occurred in 19% of patients in the NINLARO regimen compared to 11% of patients in the placebo regimen. The most common type of rash reported in both regimens was maculo-papular and macular rash. Manage rash with supportive care, dose modification or discontinuation.

Hepatotoxicity drug-induced liver injury, hepatocellular injury, hepatic steatosis, and hepatitis cholestatic have been uncommonly reported with NINLARO. Monitor hepatic enzymes regularly and adjust dose for Grade 3 or 4 symptoms.

Pregnancy NINLARO can cause fetal harm. Advise male and females patients of reproductive potential to use contraceptive measures during treatment and for an additional 90 days after the final dose of NINLARO. Women of childbearing potential should avoid becoming pregnant while taking NINLARO due to potential hazard to the fetus. Women using hormonal contraceptives should use an additional barrier method of contraception.

Lactation It is not known whether NINLARO or its metabolites are excreted in human milk. There could be potential adverse events in nursing infants and therefore breastfeeding should be discontinued.

SPECIAL PATIENT POPULATIONS

Hepatic Impairment: Reduce the NINLARO starting dose to 3 mg in patients with moderate or severe hepatic impairment.

Renal Impairment: Reduce the NINLARO starting dose to 3 mg in patients with severe renal impairment or end-stage renal disease (ESRD) requiring dialysis. NINLARO is not dialyzable and, therefore, can be administered without regard to the timing of dialysis.

DRUG INTERACTIONS

Co-administration of strong CYP3A inducers with NINLARO is not recommended.

ADVERSE REACTIONS

The most frequently reported adverse reactions (≥ 20%) in the NINLARO regimen, and greater than in the placebo regimen, were diarrhea (42% vs. 36%), constipation (34% vs. 25%), thrombocytopenia (28% vs. 14%), peripheral neuropathy (28% vs. 21%), nausea (26% vs. 21%), peripheral edema (25% vs. 18%), vomiting (22% vs. 11%), and back pain (21% vs. 16%). Serious adverse reactions reported in ≥ 2% of patients included thrombocytopenia (2%) and diarrhea (2%). For each adverse reaction, one or more of the three drugs was discontinued in ≤ 1% of patients in the NINLARO regimen.

For European Union Summary of Product Characteristics: View Source

For US Prescribing Information: View Source

For Canada Product Monograph: View Source

About Takeda

On June 23, 2017 Novartis reported results from additional analyses of the ENESTfreedom and ENESTop clinical trials, which found that approximately half of adult patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in the chronic phase (CP) who discontinued Tasigna [] (nilotinib) remain in Treatment-free Remission (TFR) nearly two years after stopping treatment (Press release, Novartis, JUN 23, 2017, View Source [SID1234519673]). The 96-week results from these two open-label Phase II trials, presented at the 22nd Congress of the European Hematology Association (EHA) (Free EHA Whitepaper), add to the growing body of evidence examining the ability to remain in TFR in patients who achieved a sustained deep molecular response (DMR) with Tasigna and met additional eligibility criteria prior to discontinuing treatment. TFR is the ability to maintain molecular response (MR) after stopping tyrosine kinase inhibitor (TKI) therapy in patients with Ph+ CML-CP [3].

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"These trials show that about half of Ph+ CML patients that met strict eligibility criteria and discontinued Tasigna continue to maintain TFR at 96 weeks, and demonstrate that more than 90% of patients who were in TFR at 48 weeks remain in TFR at 96 weeks," said Timothy P. Hughes, M.D., ENESTop study investigator, Cancer Theme Leader at the South Australian Health and Medical Research Institute and Clinical Professor at the University of Adelaide, Australia. "Achieving deep molecular response is an important eligibility criteria prior to attempting TFR."

ENESTfreedom and ENESTop evaluate the potential to maintain MR after stopping therapy in eligible adult patients with Ph+ CML-CP who achieved a sustained DMR with Tasigna [ ]in the first-line setting and in patients who achieved a sustained DMR with Tasigna after switching from Glivec [] (imatinib)*, respectively.

"The findings from the 96-week analyses, as well as the recent regulatory decisions to add TFR data to the Tasigna product label in the European Union (EU), Chile and Ecuador, mark significant progress in the treatment of CML," said Vas Narasimhan, M.D., Global Head Drug Development and Chief Medical Officer, Novartis. "We are proud that our innovation with Tasigna has contributed directly to this progress and that physicians now have the opportunity to consider TFR in both first- and second-line Tasigna patients."

Results from ENESTfreedom, which evaluated the potential for discontinuing Tasigna in eligible Ph+ CML-CP patients who achieved a sustained DMR following at least three years of first-line treatment with Tasigna, found that 48.9% of 190 CML patients (confidence interval [CI] 95%: 41.6%-56.3%) were able to discontinue therapy and remain in major molecular response (MMR; BCR-ABL1 International Scale [IS] <= 0.1%) at 96 weeks. Of the 88 patients who restarted treatment with Tasigna due to loss of MMR by the cut-off date, 98.9% were able to regain MMR (n=87). One patient discontinued the study at 7.1 weeks without regaining MMR after reinitiating treatment with Tasigna [1]. No new major safety findings were observed in ENESTfreedom in patients treated with Tasigna beyond those in the known safety profile of Tasigna [1]. Among patients who remained in TFR for more than 48 weeks (n=100), the frequency of adverse events (AEs) was lower during the second 48 weeks of TFR compared to the first 48 weeks. AEs in the predefined musculoskeletal pain grouping also decreased from 34.0% to 9.0% during the first and second 48 weeks of the TFR phase, respectively [1], versus 17.0% during the treatment consolidation phase.

ENESTop, which evaluated the potential for discontinuing Tasigna in 126 eligible Ph+ CML-CP patients who were able to achieve a sustained DMR following at least three years of Tasigna therapy, but not with prior Glivec therapy, found that more than half (53.2%) of patients were able to remain in TFR at 96 weeks (95% CI: 44.1%-62.1%) [2]. In the study, 56 patients with confirmed loss of MR4.0 (BCR-ABL1 IS <= 0.01%) or loss of MMR restarted Tasigna by the cut-off date. Of these patients, 92.9% (n=52) regained both MR4.0 and MR4.5. By weeks 12.0 and 13.1 of treatment re-initiation with Tasigna, 50% of retreated patients achieved MR4.0 and MR4.5, respectively [2]. No new major safety findings were observed in ENESTop in patients treated with Tasigna beyond those in the known safety profile of Tasigna [2]. Among patients who remained in the TFR phase of the trial for more than 48 weeks (n=73), rates of all-grade AEs were 82.2% and 63.0% for the first 48 weeks and second 48 weeks of the TFR phase, respectively, versus 79.5% during the treatment consolidation phase. Rates of musculoskeletal pain-related AEs decreased from 47.9% to 15.1% during the first and second 48 weeks of the TFR phase, respectively, versus 13.7% during the treatment consolidation phase [2].

Discontinuation of treatment in ENESTfreedom and ENESTop was conducted under the conditions of the trials in patients who met the rigorous predefined criteria of the trials. 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 after discontinuation of Tasigna allows timely determination of loss of MR4.0 and MMR and prompt re-initiation of treatment [1,2].

On May 24, the European Commission (EC) approved an update of the Tasigna Summary of Product Characteristics (SmPC) to include data from the ENESTfreedom and ENESTop TFR clinical trials. With this EC approval, Tasigna is the first and only TKI to include information in its EU label on stopping therapy in eligible patients with Ph+ CML-CP in both the first-line setting and after switching from Glivec. The decision to add TFR data to the Tasigna SmPC is applicable to all 28 EU member states plus Iceland and Norway.

Information regarding TFR was also recently added to the Tasigna label in Chile and Ecuador.

In all other countries, discontinuation of Tasigna in patients who achieve a sustained DMR is being investigated and should only be attempted in the context of a clinical study. There is no guarantee Tasigna TFR data will be approved for inclusion in the label by other health authorities.

Novartis commitment to CML
Over the past several decades, Novartis research in Ph+ CML has helped transform the disease from a fatal leukemia to a chronic condition in most patients and, today, the company continues its long-standing commitment to the global CML community. Evaluating more than 1,000 patients, the Tasigna TFR studies, which include ENESTfreedom and ENESTop as well as two other ongoing company-sponsored TFR studies and multiple investigator-initiated studies, are part of a large international Ph+ CML-CP clinical trial program to assess TKI discontinuation. 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, such as ABL001, which is currently being tested in patients who are relapsed, refractory or intolerant to existing TKIs in a Phase I trial as a single agent and in combination with several TKIs.

About ENESTfreedom
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-CP receiving Tasigna for at least three years, after the patients had achieved a response of MR4.5 with Tasigna and a sustained DMR for one year as a first-line treatment. The study is ongoing with planned follow-up to evaluate the ability of patients to sustain remission for longer durations following discontinuation of Tasigna.

About ENESTop
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-CP receiving Tasigna for at least three years, after patients had achieved and sustained DMR for one year with Tasigna following Glivec. The study is ongoing with planned follow-up to evaluate the ability of patients to sustain remission for longer durations following discontinuation of Tasigna.

About Tasigna (nilotinib)
Tasigna (nilotinib) is approved in more than 122 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 (imatinib), and in more than 110 countries for the treatment of adult patients with newly diagnosed Ph+ CML in chronic phase.

IMPORTANT SAFETY INFORMATION for TASIGNA (nilotinib) Capsules
Use with caution in patients with uncontrolled or significant cardiac disease and in patients who have or may develop prolongation of QTc. Low levels of potassium or magnesium must be corrected prior to Tasigna administration. Monitor closely for an effect on the QTc interval. Baseline ECG is recommended prior to initiating therapy and as clinically indicated. Cases of sudden death have been reported in clinical studies in patients with significant risk factors. Avoid use of concomitant drugs known to prolong the QT interval and strong CYP3A4 inhibitors. Avoid food 2 hours before and 1 hour after taking dose. Reactivation of hepatitis B can occur in patients who are chronic carriers of this virus after receiving TKI treatment.

Use with caution in patients with liver impairment, with a history of pancreatitis and with total gastrectomy. Patients with rare hereditary problems of galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption should not use Tasigna. Tasigna may cause fetal harm in pregnant women. If pregnancy is planned during the treatment-free remission phase, the patient must be informed of a potential need to re-initiate treatment with Tasigna during pregnancy. Women taking Tasigna should not breastfeed.

Cases of cardiovascular events included ischemic heart disease-related events, peripheral arterial occlusive disease, and ischemic cerebrovascular events have been reported. Serious cases of hemorrhage from various sites including gastrointestinal were reported in patients receiving Tasigna. Grade 3 or 4 fluid retention including pleural effusion, pericardial effusion, ascites and pulmonary edema have been reported. Cases of tumor lysis syndrome have been reported in Tasigna-treated patients who were resistant or intolerant to prior CML therapy.

Eligible patients who are confirmed to express the typical BCR-ABL transcripts, e13a2/b2a2 or e14a2/b3a2, can be considered for treatment discontinuation. Frequent monitoring of BCR-ABL transcript levels in patients eligible for treatment discontinuation must be performed with a quantitative diagnostic test validated to measure molecular response levels with a sensitivity of at least MR4.5 (BCR-ABL/ABL <=0.0032% IS). BCR-ABL transcript levels must be assessed prior to and during treatment discontinuation. Loss of major molecular response (MMR=BCR-ABL/ABL <=0.1%IS) or confirmed loss of MR4 (two consecutive measures separated by at least 4 weeks showing loss of MR4 (MR4=BCR-ABL/ABL <= 0.01%IS)) will trigger treatment re-initiation within 4 weeks of when loss of remission is known to have occurred. It is crucial to perform frequent monitoring of BCR-ABL transcript levels and complete blood count with differential in order to detect possible loss of remission. For patients who fail to achieve MMR after three months of treatment re initiation, BCR-ABL kinase domain mutation testing should be performed.

The most frequent Grade 3 or 4 adverse events are hematological (neutropenia, thrombocytopenia, anemia) which are generally reversible and usually managed by withholding Tasigna temporarily or dose reduction. Chemistry panels, including electrolytes, lipid profile, liver enzymes, and glucose should be checked prior to therapy and periodically. Tasigna can cause increases in serum lipase. The most frequent non-hematologic adverse events were rash, pruritus, nausea, fatigue, headache, alopecia, myalgia, constipation and diarrhea.

Musculoskeletal pain, myalgia, pain in extremity, arthralgia, bone pain and spinal pain may occur upon discontinuing treatment with Tasigna within the framework of attempting treatment-free remission.

Please see full Prescribing Information including Boxed WARNING at www.tasigna.com.

About Glivec (imatinib)
Glivec (imatinib) is approved in more than 110 countries, for the treatment of adult patients in all phases of Ph+ CML, for the treatment of patients with KIT (CD117)-positive gastrointestinal 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.

Not all indications are available in every country.

Glivec Important Safety Information

Glivec is contraindicated in patients who are hypersensitive to imatinib or any of the excipients.

Glivec 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.

Glivec has been associated with severe edema (swelling) and serious fluid retention. Cytopenias (anemia, neutropenia, thrombocytopenia) are common, generally reversible and usually managed by withholding Glivec or dose reduction. Monitor blood counts regularly. Severe congestive heart failure and left ventricle dysfunction, severe liver problems including cases of fatal liver failure and severe liver injury requiring liver transplants have been reported. Caution in patients with cardiac dysfunction and hepatic dysfunction. Monitor carefully. Reactivation of hepatitis B can occur in patients who are chronic carriers of this virus after receiving TKI treatment.

Bleeding may occur. Severe gastrointestinal (GI) bleeding has been reported in patients with KIT+ GIST. Skin reactions, hypothyroidism in patients taking levothyroxine replacement, GI perforation, in some cases fatal, tumor lysis syndrome which can be life threatening have also been reported with Glivec. Correct dehydration and high uric acid levels prior to treatment. Long-term use may result in potential liver, kidney, and/or heart toxicities; immune system suppression may also result from long-term use. In patients with hypereosinophilic syndrome and heart involvement, cases of heart disease have been associated with the initiation of Glivec therapy. Growth retardation has been reported in children taking Glivec. The long-term effects of extended treatment with Glivec on growth in children are unknown.

The most common side effects include fluid retention, muscle cramps or pain and bone pain, abdominal pain, loss of appetite, vomiting, diarrhea, decreased hemoglobin, abnormal bleeding, nausea, fatigue and rash. Glivec should be taken with food and a large glass of water.

Please see full Prescribing Information available at www.glivec.com.

On June 23, 2017 Novartis reported updated results from the ELIANA clinical trial demonstrating CTL019 (tisagenlecleucel) remission rates are maintained at six months in relapsed/refractory (r/r) pediatric and young adult patients with B-cell acute lymphoblastic leukemia (ALL) (Press release, Novartis, JUN 23, 2017, View Source [SID1234519672]). These data from this pivotal trial of CTL019 show that 83% (52 of 63; 95% confidence interval [CI]: 71%-91%) of patients achieved complete remission (CR) or CR with incomplete blood count recovery within three months of infusion. No minimal residual disease (MRD) was detected among responding patients[1]. MRD, which measures the elimination of residual disease in the blood and bone marrow at the molecular level following treatment, is important because it may be an indicator of potential relapse[2]. Results from this study of CTL019 – an investigational chimeric antigen receptor T cell (CAR-T) therapy – will be presented at the European Hematology Association (EHA) (Free EHA Whitepaper) Annual Meeting (Abstract #S476; Saturday, June 24, 4:00 PM CEST).

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The ELIANA study also showed that the relapse-free probability was 75% (95% CI, 57%-87%; median duration of response not reached) at six months and 64% (95% CI, 42%-79%) at 12 months among responders. In addition, the probability of survival was 89% (95% CI, 77%-94%) at six months and 79% (95% CI, 63%-89%) at 12 months. The median time from infusion to data cutoff was 8.8 months[1].

"The updated CTL019 ELIANA data illustrating early observed response rates that have held steady over six months’ time are exciting findings. Durability is an important measure for children and young adults with relapsed or refractory B-cell ALL, and we are truly encouraged by the results of this study," said lead investigator Stephan Grupp, MD, PhD, the Yetta Deitch Novotny Professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania (Penn), and Director of the Cancer Immunotherapy Frontier Program at the Children’s Hospital of Philadelphia (CHOP).

Forty-seven percent of patients in ELIANA experienced grade 3 or 4 cytokine release syndrome (CRS), a known complication of the investigational therapy that may occur when the engineered cells become activated in the patient’s body. CRS was managed globally using prior site education on implementation of the CRS treatment algorithm. There were no deaths due to refractory CRS and no incidents of cerebral edema were reported. Fifteen percent of patients experienced grade 3 neurologic events, with no grade 4 events seen[1].

The ELIANA trial enrolled 88 patients. Of the 88, 16 patients discontinued before infusion and the majority (nine patients) did so due to rapid progression of their disease or deterioration in their clinical status. This reflects the acute and progressive nature of this disease. Of the 16 patients who weren’t infused, seven were a result of insufficiently formulated CAR-T cell product. Additionally, five infused patients had not reached three-month follow-up and four patients were pending infusion at the time of data cutoff.

"These positive, updated ELIANA data help us better understand the ability for CTL019 to maintain durable responses in r/r ALL," said Vas Narasimhan, MD, Global Head of Drug Development and Chief Medical Officer, Novartis. "The results, including relapse-free survival findings at six and 12 months, reaffirm our confidence in CTL019 to potentially become an effective treatment for pediatric and young adult patients with r/r ALL in need of more options."

ELIANA (NCT02435849) is the first pediatric global CAR-T cell therapy registration trial, with study enrollment having occurred across 25 centers in the US, Canada, EU, Australia and Japan. The single-arm, open-label, multicenter Phase II study included patients aged three to 23 years who were primary refractory, refractory to chemotherapy after their first relapse, relapsed after second line therapy or ineligible for an allogeneic stem cell transplant (SCT). Patients in the trial received a median of three prior lines of therapy and 59% of patients had a prior SCT.

CTL019 was first developed by Penn and uses the 4-1BB costimulatory domain to enhance cellular responses. In 2012, Novartis and Penn entered into a global collaboration to further research, develop and then commercialize CAR-T cell therapies, including CTL019, for the investigational treatment of cancers.

Additional CTL019 data at EHA (Free EHA Whitepaper)
A pooled data analysis from two multicenter trials of CTL019 in pediatric and young adult patients with r/r B-cell ALL, including ELIANA and ENSIGN (NCT02228096), will also be highlighted in a presentation at the meeting. This research is aimed to identify any new safety issues with CTL019 as a result of its use in multicenter trials, which included 25 sites across 11 countries. Study authors concluded that there were no new safety issues and that CRS and neurologic events were effectively managed. Prolonged follow-up will be required to determine the long-term safety of B-cell aplasia (Abstract #P517; Saturday, June 24, 5:30 PM CEST).

An oral presentation will feature pooled analyses from two multicenter trials of CTL019 in pediatric and young adult patients with r/r B-cell ALL, including ELIANA and ENSIGN, observing response analysis and impact of intrinsic/extrinsic and manufacturing factors on CTL019 expansion and persistence (Abstract #S477; Saturday, June 24, 4:15 PM CEST).

Novartis will also present an encore of results from its global, pivotal multi-center Phase II JULIET study (NCT02445248; Abstract #LB2604, June 25, 12:00 PM CEST), evaluating CTL019 in adults with r/r diffuse large-b-cell lymphoma (DLBCL).

CTL019 was granted Priority Review from the FDA earlier this year in the treatment of r/r pediatric and young adult patients with B-cell ALL, and Novartis plans to file with the European Medicines Agency (EMA) later in 2017. The investigational therapy received PRIME (PRIority MEdicines) designation from the EMA in 2016. The FDA also granted Breakthrough Therapy designation to CTL019 for the treatment of adult patients with r/r DLBCL, whose disease has progressed on or after two or more prior therapies.

About CTL019 Manufacturing
Novartis leukapheresis process using cryopreservation allowed for manufacturing and treatment of patients from around the world. Cryopreserved leukapheresis gives physicians the flexibility to schedule apheresis at a time that is in the best interest of their patients. Novartis commercial manufacturing for CTL019 continues to build on its experience in its Morris Plains, New Jersey facility, which has already manufactured CTL019 for hundreds of patients in global clinical trials. Novartis believes that experience is important in cell therapy manufacturing, and the experience gained at the Morris Plains, New Jersey facility will be a foundation for commercial manufacturing of CAR-T therapies. Novartis has made and continues to make investments in manufacturing.

About CAR-T and CTL019
CAR-T is different from typical small molecule or biologic therapies because it is manufactured for each individual patient using their own cells. During the treatment process, T cells are drawn from a patient’s blood and reprogrammed in the laboratory to create T cells that are genetically coded to hunt the patient’s cancer cells and other B-cells expressing a particular antigen. In March 2017, Novartis announced that the FDA granted Priority Review for the company’s Biologics License Application for CTL019 in the treatment of r/r pediatric and young adult patients with B-cell ALL.

Because CTL019 is an investigational therapy, the safety and efficacy profile has not yet been established. Access to investigational therapies is available only through carefully controlled and monitored clinical trials. These trials are designed to better understand the potential benefits and risks of the therapy. Because of the uncertainty of clinical trials, there is no guarantee that CTL019 will ever be commercially available anywhere in the world.

About ALL
Acute lymphoblastic leukemia makes up approximately 25% of cancer diagnoses among children under 15 years old and is the most common childhood cancer in the US[3]. Patients with r/r ALL have limited treatment options, and the chance of survival for children with the disease who relapse or fail to attain remission is between 16% to 30.1%[4]

On June 23, 2017 Novartis reported the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending approval of Kisqali (ribociclib) in combination with an aromatase inhibitor for treatment of postmenopausal women with hormone receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) locally advanced or metastatic breast cancer as initial endocrine-based therapy (Press release, Novartis, JUN 23, 2017, View Source [SID1234519671]). The CHMP recommendation of combining Kisqali with any aromatase inhibitor means that, if approved, oncologists could prescribe Kisqali with letrozole, anastrozole or exemestane, giving them the discretion to select the therapy they believe is most appropriate for each individual patient.

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"This positive CHMP opinion brings us one step closer to improving the lives of women diagnosed with advanced or metastatic breast cancer throughout Europe," said Bruno Strigini, CEO, Novartis Oncology. "There is currently no cure for advanced breast cancer, and approximately 30 percent of those affected by early-stage breast cancer will go on to develop advanced disease. We look forward to working with European health authorities to make Kisqali available to those who may benefit from it as quickly as possible."

The positive CHMP opinion is based on superior efficacy and demonstrated safety of Kisqali plus letrozole versus letrozole alone in the pivotal Phase III MONALEESA-2 trial. The trial, which globally enrolled 668 postmenopausal women with HR+/HER2- advanced or metastatic breast cancer who received no prior systemic therapy for their advanced breast cancer, showed that Kisqali plus the aromatase inhibitor letrozole reduced the risk of progression or death by 44% over letrozole alone at interim analysis[1]. Most adverse events in the MONALEESA-2 trial were mild to moderate in severity, identified early through routine monitoring, and generally managed through dose interruption and/or reduction[1].

A subsequent, pre-planned analysis of overall survival with an additional 11 months of follow-up demonstrated a median PFS of 25.3 months for Kisqali plus letrozole and 16.0 months for letrozole alone (HR=0.568 (95% CI: 0.457-0.704; p<0.0001))[2]. More than half of women with measurable disease taking Kisqali plus letrozole saw their tumor size shrink by at least 30% (overall response rate (ORR) in patients with measurable disease = 55% vs 39%, p=0.00025)[2],[4]. Follow-up to measure overall survival is ongoing as data remain immature[4].

The European Commission will review the CHMP recommendation and usually delivers its final decision within two months. The decision will be applicable to all 28 European Union member states plus Iceland, Norway and Liechtenstein. Additional regulatory filings are underway with other health authorities worldwide.

In March 2017, Kisqali was approved by the US Food and Drug Administration (FDA) in combination with an aromatase inhibitor as initial endocrine-based therapy for treatment of postmenopausal women with HR+/HER2- advanced or metastatic breast cancer. Kisqali can be taken with or without food as a once-daily oral dose of 600 mg (three 200 mg film-coated tablets) for three weeks, followed by one week off treatment. Kisqali is taken in combination with four weeks of any aromatase inhibitor.

Globally, an estimated 250,000 women will be diagnosed with advanced breast cancer each year[3]. Up to one-third of patients with early-stage breast cancer will subsequently develop metastatic disease, for which there is currently no cure[5],[6].

About Kisqali (ribociclib)
Kisqali (ribociclib) is a selective cyclin-dependent kinase inhibitor, a class of drugs that help slow the progression of cancer by inhibiting two proteins called cyclin-dependent kinase 4 and 6 (CDK4/6). These proteins, when over-activated, can enable cancer cells to grow and divide too quickly. Targeting CDK4/6 with enhanced precision may play a role in ensuring that cancer cells do not continue to replicate uncontrollably.

Kisqali was developed by the Novartis Institutes for BioMedical Research (NIBR) under a research collaboration with Astex Pharmaceuticals. In the European Union, Kisqali is an investigational agent and has not been approved.

About the Kisqali Clinical Trial Program
Novartis is continuing to assess Kisqali through the robust MONALEESA clinical trial program, which includes two additional Phase III trials, MONALEESA-3 and MONALEESA-7 that are evaluating Kisqali in combination with multiple endocrine therapy partners across a broad range of patients, including premenopausal women. MONALEESA-3 is evaluating Kisqali in combination with fulvestrant compared to fulvestrant alone in postmenopausal women with HR+/HER2- advanced breast cancer who have received no or a maximum of one prior endocrine therapy. MONALEESA-7 is investigating Kisqali in combination with endocrine therapy and goserelin compared to endocrine therapy and goserelin alone in premenopausal women with HR+/HER2- advanced breast cancer who have not previously received endocrine therapy. These trials are fully enrolled.

Novartis is initiating two multi-center, randomized, double-blind Phase III clinical trials, EarLEE-1 and EarLEE-2, to evaluate the safety and efficacy of Kisqali with endocrine therapy as adjuvant therapy in pre- and postmenopausal women who have not previously received treatment with CDK4/6 or aromatase inhibitors. EarLEE-1 will assess Kisqali with adjuvant endocrine therapy compared to adjuvant endocrine therapy alone in women with HR+/HER2- high-risk early breast cancer. EarLEE-2 will investigate Kisqali with adjuvant endocrine therapy compared to adjuvant endocrine therapy alone in women with HR+/HER2- intermediate-risk early breast cancer.

The CompLEEment study is evaluating the safety and efficacy of Kisqali plus letrozole in men and pre- or postmenopausal women with HR+/HER2- advanced breast cancer with no prior hormonal therapy for advanced disease. The open-label, multicenter, Phase IIIb CompLEEment-1 trial is currently enrolling participants.

About Novartis in Advanced Breast Cancer
For more than 25 years, Novartis has been at the forefront of driving scientific advancements for breast cancer patients and improving clinical practice in collaboration with the global community. With one of the most diverse breast cancer pipelines and the largest number of breast cancer compounds in development, Novartis leads the industry in discovery of new therapies and combinations, especially in HR+ advanced breast cancer, the most common form of the disease.

Kisqali (ribociclib) Important Safety Information FROM THE US PRESCRIBING INFORMATION
KISQALI (ribociclib) is a prescription medicine used in combination with an aromatase inhibitor as the first hormonal-based therapy to treat women who have gone through menopause with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer. It is not known if KISQALI is safe and effective in children. KISQALI can cause a heart problem known as QT prolongation. This condition can cause an abnormal heartbeat and may lead to death. Patients should tell their health care provider right away if they have a change in their heartbeat (a fast or irregular heartbeat), or if they feel dizzy or faint. KISQALI can cause serious liver problems. Patients should tell their health care provider right away if they get any of the following signs and symptoms of liver problems: yellowing of the skin or the whites of the eyes (jaundice), dark or brown (tea-colored) urine, feeling very tired, loss of appetite, pain on the upper right side of the stomach area (abdomen), and bleeding or bruising more easily than normal. Low white blood cell counts are very common when taking KISQALI and may result in infections that may be severe. Patients should tell their health care provider right away if they have signs and symptoms of low white blood cell counts or infections such as fever and chills. Before taking KISQALI, patients should tell their health care provider if they are pregnant, or plan to become pregnant as KISQALI can harm an unborn baby. Females who are able to become pregnant and who take KISQALI should use effective birth control during treatment and for at least 3 weeks after the last dose of KISQALI. Do not breastfeed during treatment with KISQALI and for at least 3 weeks after the last dose of KISQALI. Patients should tell their health care provider about all of the medicines they take, including prescription and over-the-counter medicines, vitamins, and herbal supplements since they may interact with KISQALI. Patients should avoid pomegranate or pomegranate juice, and grapefruit or grapefruit juice while taking KISQALI. The most common side effects (incidence >=20%) of KISQALI when used with letrozole include white blood cell count decreases, nausea, tiredness, diarrhea, hair thinning or hair loss, vomiting, constipation, headache, and back pain. The most common grade 3/4 side effects in the KISQALI + letrozole arm (incidence >2%) were low neutrophils, low leukocytes, abnormal liver function tests, low lymphocytes, and vomiting. Abnormalities were observed in hematology and clinical chemistry laboratory tests.

Please see full Prescribing Information for KISQALI, available at www.kisqali.com (link is external).

On June 23, 2017 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported new data from multiple studies of Venclexta/Venclyxto (venetoclax), presented at the 22nd European Hematology Association (EHA) (Free EHA Whitepaper) Annual Congress, 22-25 June, in Madrid (Press release, Hoffmann-La Roche, JUN 23, 2017, View Source [SID1234519670]). Data presented in relapsed or refractory chronic lymphocytic leukaemia (CLL) confirmed the efficacy of Venclexta/Venclyxto with high and durable response rates and a well-tolerated safety profile in this high-risk population, including people with 17p chromosomal deletion who had previously received treatment. Additionally, phase Ib data demonstrated the anti-cancer activity of Venclexta/Venclyxto in acute myeloid leukaemia (AML) and relapsed or refractory multiple myeloma (MM), further supporting the potential of this treatment in a broader range of blood cancers. Venclexta/Venclyxto is being developed by AbbVie and Roche. It is jointly commercialised by AbbVie and Genentech, a member of the Roche Group, in the United States and commercialised by AbbVie outside of the United States.

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"Confirmation that Venclexta/Venclyxto achieves a high response rate in relapsed or refractory chronic lymphocytic leukaemia in people with 17p deletion is very promising, as these patients have a particularly poor prognosis," said Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development. "We are also pleased to see early data highlighting the potential central role of BCL-2 in other difficult-to-treat blood cancers and look forward to validating these results in further studies."

The safety and efficacy of Venclexta/Venclyxto is being evaluated in a number of clinical studies in patients with CLL, some of which have led to European Medicines Agency (EMA) conditional marketing authorisation (M13-982 and M14-032) of Venclyxto and Food and Drug Administration (FDA) accelerated approval (M13-982) for Venclexta monotherapy in CLL. Data being presented at EHA (Free EHA Whitepaper) include:

Oral presentation of phase II monotherapy data in high-risk patients with relapsed/refractory CLL with 17p deletion showed an acceptable safety profile and a high response rate of 79%. Minimal residual disease (MRD)-negativity, an exploratory endpoint that is a measure of absence of residual blood cancer in patients’ blood or bone marrow, correlated with a progression-free survival (PFS) rate of 100% at 24 months. [Study M13-982 – Abstract S771, oral presentation Sunday, 25 June, 8:30 CET]. In addition, Venclexta/Venclyxto monotherapy demonstrated improved quality of life (QoL), with sustained and clinically meaningful improvement of several key aspects of functioning and health-related QoL. [Study M13-982 – Abstract S771, oral presentation Sunday 25 June, 8:30 CET and Study M14-032 – Abstract P728, poster presentation Saturday, 24 June, 17:30 CET].

Phase Ib data with Venclexta/Venclyxto in combination with MabThera/Rituxan (rituximab) in patients with relapsed/refractory CLL/small lymphocytic leukaemia (SLL) showed an acceptable safety profile and deep and durable responses, with 51% patients achieving a complete response (CR/CRi), 59% achieving marrow MRD-negativity and an overall response rate (ORR) of 86%. Data in patients achieving MRD-negativity suggested a prolonged treatment-free remission period even after Venclexta/Venclyxto treatment was stopped. [M13-365 study – Abstract P247, poster presentation Friday, 23 June, 17:15 CET].

The safety and efficacy of Venclexta/Venclyxto is also being evaluated in other blood cancers, including AML, an aggressive form of leukaemia that starts in myeloid cells, and MM, a cancer formed from malignant plasma cells.
In AML, Venclexta/Venclyxto has shown an acceptable safety profile in combination with decitabine or azacitidine and a high ORR of 68% in elderly patients with previously untreated AML. [Study M14-358 – Abstract S472, oral presentation Saturday, 24 June, 16:15 CET]. A further open-label phase I/II study in previously untreated elderly patients with AML showed durable efficacy with an acceptable safety profile for Venclexta/Venclyxto in combination with low-dose cytarabine. [Study M14-387 – Abstract E911 to be presented as an Eposter].

In MM, data from a phase Ib study of Venclexta/Venclyxto in combination with bortezomib and dexamethasone demonstrated an acceptable safety profile and anti-myeloma activity. When treated with Venclexta/Venclyxto, an overall response rate of 67% was achieved in patients with relapsed or refractory MM. [Study M12-901- Abstract S460, oral presentation Saturday, 24 June, 17:00 CET].

About Venclexta/Venclyxto
Venclexta/Venclyxto is a small molecule designed to selectively bind and inhibit the BCL-2 protein, which plays an important role in a process called apoptosis (programmed cell death). Overexpression of the BCL-2 protein in CLL has been associated with resistance to certain therapies. It is believed that blocking BCL-2 may restore the signalling system that tells cells, including cancer cells, to self-destruct.

Venclexta/Venclyxto is being co-developed by AbbVie and Roche. Together, the companies are committed to research with Venclexta/Venclyxto , which is currently being evaluated in phase III clinical trials for the treatment of relapsed, refractory and previously untreated CLL, along with studies in several other cancers. Venclexta/Venclyxto is commercialised jointly by AbbVie and Genentech, a member of the Roche Group, in the United States and commercialised by AbbVie outside of the United States.

About Roche in haematology
For more than 20 years, Roche has been developing medicines that redefine treatment in haematology. Today, we are investing more than ever in our effort to bring innovative treatment options to people with diseases of the blood. In addition to approved medicines MabThera/Rituxan (rituximab), Gazyva/Gazyvaro (obinutuzumab), and Venclexta/Venclyxto (venetoclax) in collaboration with AbbVie, Roche’s pipeline of investigational haematology medicines includes Tecentriq (atezolizumab), an anti-CD79b antibody drug conjugate (polatuzumab vedotin/RG7596) and a small molecule antagonist of MDM2 (idasanutlin/RG7388). Roche’s dedication to developing novel molecules in haematology expands beyond malignancy, with the development of the investigational haemophilia A treatment emicizumab.