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Novartis data shows Treatment-free Remission rates are consistently above 50% regardless of reason for switch to Tasigna® from Glivec®

On December 5, 2016 Novartis reported at the 58th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition new data from the Tasigna (nilotinib) ENESTop Treatment-free Remission (TFR) study, which demonstrate that TFR rates are consistent among Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) patients who switched from Glivec (imatinib)* due to intolerance, resistance or physician preference (Press release, Novartis, DEC 5, 2016, View Source [SID1234516939]). ENESTop evaluated stopping Tasigna treatment in eligible Ph+ CML adults with chronic phase disease after they achieved and sustained deep molecular response (MR) for at least one year with Tasigna but had not achieved and sustained this response previously with Glivec[1],[2]. Results of this post-hoc analysis were presented today in an oral session (ASH Abstract #792).

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"Findings from this post-hoc analysis of ENESTop suggest that the reason for switching from Glivec to Tasigna did not impact a patient’s chance of maintaining TFR," said Timothy P. Hughes, MD, ENESTop study investigator, Cancer Theme Leader at the South Australian Health and Medical Research Institute and Clinical Professor at the University of Adelaide, Australia. "CML is considered a chronic disease due to the success of tyrosine kinase inhibitors (TKIs), but there remains a need for continued advancements and these findings are an exciting and important contribution to clinical research in CML treatment."

This new post-hoc analysis of ENESTop evaluated rates of TFR at 48 weeks after stopping treatment with Tasigna among subgroups of patients who switched from Glivec due to intolerance, resistance or physician preference. The analysis, which included 125 patients, found that more than 50% of patients in each of the subgroups maintained TFR at 48 weeks and that the proportion of patients who maintained TFR at 48 weeks was similar across the three subgroups: 30 of 51 (58.8%; 95% confidence interval [CI], 44.2%-72.4%) in the intolerance subgroup, 16 of 30 (53.3%; 95% CI, 34.3%-71.7%) in the resistance subgroup, and 27 of 44 (61.4%; 95% CI, 45.5%-75.6%) in the physician preference subgroup[1]. One patient who stopped treatment in the ENESTop trial was found to have had atypical transcripts and was excluded from this analysis[3].

ENESTop is part of a larger Tasigna TFR clinical trial program to evaluate the potential to maintain molecular response after stopping therapy in adult patients with Ph+ CML in the chronic phase who achieved a sustained deep level of molecular response with Tasigna. In the primary analysis of ENESTop, 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 treatment[3]. No new major safety findings were observed in ENESTop in patients treated with Tasigna beyond those in the known safety profile of Tasigna. 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 phase. No patients progressed to advanced phase/blast crisis. These results were previously presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting and the Annual Congress of European Hematology Association (EHA) (Free EHA Whitepaper) in June 2016. Results from additional studies in the Tasigna TFR clinical trial program were also presented at ASH (Free ASH Whitepaper) in poster sessions, including ENESTpath (Abstract #3094) and ENESTfreedom (Abstract #3066).

"Our mission at Novartis is to help transform cancer therapy through bold science and innovation, and there is no better example of this than our support of eight TFR studies in patients with CML," said Bruno Strigini, CEO of Novartis Oncology. "Our further exploration of results from the ENESTop trial, beyond the primary analysis, reinforces our ongoing commitment to CML patients and contributes to the growing body of science that goes into treating this cancer."

Regular and frequent molecular monitoring with a well-validated assay able to measure BCR-ABL transcript levels down to MR4.5 is an important part of Tasigna TFR studies. Frequent patient monitoring during TFR allows timely determination of loss of MR4.0 or major molecular response (MMR) and the need for treatment initiation[3].

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 ENESTop was conducted under the conditions of the trial and in patients who met the rigorous predefined criteria of the trial[3].

Novartis commitment to CML
Novartis is supporting eight studies as part of its TFR clinical trial program, which includes ENESTop, as well as three 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.

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 in the chronic phase after patients had achieved and sustained deep molecular response 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 120 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. 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.

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.

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.

Disclaimer

Juno Therapeutics Presents Data From TRANSCEND Study Showing 60% Complete Response in Patients with Relapsed or Refractory Aggressive CD19+ Non-Hodgkin Lymphoma

On December 5, 2016 Juno Therapeutics, Inc. (NASDAQ:JUNO), a biopharmaceutical company developing innovative cellular immunotherapies for the treatment of cancer, reported encouraging preliminary clinical data for JCAR017 in patients with relapsed or refractory (r/r) aggressive non-Hodgkin lymphoma (NHL) in a presentation at the 58th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, Juno, DEC 5, 2016, View Source [SID1234516938]). JCAR017 uses a defined CD4:CD8 cell composition and 4-1BB as the costimulatory domain, which differentiates it from other CD19-directed CAR T product candidates in clinical development.

"Our potential best-in-class CAR T candidate, JCAR017, has demonstrated an impressive early response rate in these sick NHL patients," said Mark J. Gilbert, M.D., Juno’s Chief Medical Officer. "In particular, the side effect profile and persistence of CAR T cells that we observed, even in patients who relapsed, will allow us to explore higher doses and the possibility for combination therapies to potentially increase durable response rates."
In the multi-center Phase I trial (ASH Abstract #4192), led by principal investigator Jeremy Abramson, M.D., of Massachusetts General Hospital Cancer Center, patients with r/r diffuse large B cell lymphoma (DLBCL), follicular lymphoma grade 3B or mantle cell lymphoma (MCL) were treated with fludarabine/cyclophosphamide (flu/cy) lymphodepletion and JCAR017.
Key data include:
In 22 safety-evaluable patients (19 r/r DLBCL, 1 follicular lymphoma grade 3B, and 2 MCL patients) treated at dose level 1, single-dose schedule, no severe cytokine release syndrome (sCRS) was observed. Grade 3-4 neurotoxicity was observed in 3/22 (14%) patients, all of whom received the steroid dexamethasone for neurotoxicity. A single patient received tocilizumab for early onset grade 2 CRS. The most frequently reported treatment-emergent adverse events were neutropenia (100%), decreased appetite (36%) and fatigue (32%).
In 20 efficacy-evaluable patients with r/r DLBCL (N=19) and follicular lymphoma grade 3B (N=1) treated at dose level 1 (5×107 cells), single-dose schedule, the overall response was 16/20 (80%) and complete response (CR) was 12/20 (60%) patients.
For DLBCL patients treated more than three months prior to the data cut-off date, 8/19 (42%) patients continue to experience an ongoing response.
In dose level 2 (1×108 cells), 2/2 (100%) patients evaluable for efficacy have a complete response, and no patients evaluable for safety to date (N=3) have had sCRS or grade 3-4 neurotoxicity.
In addition, multiple patients had persistent cells at relapse, suggesting the potential for combination therapy to improve long-term outcomes. One of these patients subsequently achieved a second complete response after endogenous re-expansion of persistent T cells without second infusion.
The Phase I TRANSCEND trial continues, enrolling more patients at dose levels 1 and 2. Juno intends to initiate a pivotal trial in the U.S. in patients with r/r DLBCL in 2017. JCAR017 is also being studied in a Phase II study in children with r/r acute lymphoblastic leukemia.

Stemline Therapeutics’ SL-401 Phase 2 BPDCN Data Delivered Via Oral Presentation at ASH; High Response Rates Maintained Across All Lines

On December 5, 2016 Stemline Therapeutics, Inc. (Nasdaq:STML) reported the oral presentation of positive clinical data from its ongoing SL-401 Phase 2 potentially pivotal clinical trial in blastic plasmacytoid dendritic cell neoplasm (BPDCN) (Press release, Stemline Therapeutics, DEC 5, 2016, View Source [SID1234516936]). The trial results were delivered via an oral presentation by Naveen Pemmaraju, M.D., from the University of Texas MD Anderson Cancer Center, on Sunday morning at the 2016 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, being held at the San Diego Convention Center in San Diego, CA.

The full presentation is now available on the Stemline website, under the "Scientific Presentations" tab (see link: View Source).

The Phase 2 BPDCN data presented at ASH (Free ASH Whitepaper) cover 32 evaluable adult BPDCN patients treated with SL-401. Results demonstrated that SL-401 produced a 100% (16/16) overall response rate (ORR), including an 81% (13/16) complete response (CR) rate in first-line BPDCN patients treated at the recommended dose of 12 ug/kg/day and a 95% (18/19) ORR in first-line patients treated at the recommended dose or lower. In relapsed/refractory patients, the ORR was 69% (9/13) with a CR rate of 31% (4/13). See Tables 1 and 2 for a summary of efficacy and safety.

Response duration data continue to appear promising, with 69% (11/16) first-line BPDCN patients treated at 12 ug/kg/day remaining relapse-free (range: 1+ to 20+ months, ongoing). This includes four patients receiving SL-401 therapy (range: 1+ to 15+ months, ongoing), six patients in durable remission from SL-401 who were then successfully bridged to stem cell transplant (SCT) and remain in remission (range: 5+ to 20+ months progression-free after first SL-401 dose), and one additional patient undergoing SCT preparation. In the relapsed/refractory setting, 46% (6/13) patients are relapse-free (range: 1+ to 7+ months). This includes five patients receiving SL-401 therapy (range: 1+ to 4+ months, ongoing) and one patient in durable remission from SL-401 who was then successfully bridged to SCT and remains in remission for approximately 8+ months, ongoing. The median progression-free and overall survival for first-line has not been reached and for relapsed/refractory it is currently 8.5 months.

Naveen Pemmaraju, M.D., Assistant Professor, Department of Leukemia at the University of Texas MD Anderson Cancer Center (Houston, TX), an investigator on the study, commented, "The encouraging results generated to date with SL-401 continue to indicate the agent could very well emerge as the standard of care for both first-line and relapsed/refractory BPDCN, a devastating disease for which there had previously been no effective therapy. In addition to strong clinical activity, manifested by high levels of durable responses, the safety profile with SL-401 continues to be predictable and manageable over increasing patient experience." Dr. Pemmaraju continued, "Together with Stemline, we are working to bring this promising new agent to patients as expeditiously as possible in BPDCN and other malignancies."

Andrew A. Lane, M.D., Ph.D., Assistant Professor, Medical Oncology at the Dana-Farber Cancer Institute (Boston, MA), and a co-investigator on the study, commented, "The clinical outcomes seen with SL-401 in first-line and relapsed/refractory BPDCN continue to be exciting, particularly given that these are two greatly under-served patient populations. SL-401 has also begun to show early promising signs in other clinical settings." Dr. Lane continued, "We are very pleased to be ongoing contributors to this study, and look forward to helping to advance this active agent in BPDCN and other hematologic malignancies as well."

Table 1. SL-401 Summary of Clinical Efficacy

Line of Therapy First-line First-line R/R All lines
Dose Group All Doses 12 ug/kg 12 ug/kg All Doses
n (evaluable/total) 19 16 13 32
ORR 18/19 (95%) 16/16 (100%) 9/13 (69%) 27/32 (84%)
CR*, n (rate) 14 (74%) 13 (81%) 4 (31%) 18 (56%)
Bridged to SCT, n 6 6 1 7 (22%)
(allo+auto) (3+3) (3+3) (1+0) (4+3)
*CR includes CRi (CR with incomplete hematopoietic recovery) and CRc (CR in non-skin organs and gross reduction in cutaneous lesions with residual microscopic disease).

Table 2. Most Common Adverse Events (≥ 15% treatment-related adverse effects, TRAEs)

All Grades (% of patients) Grade ≥ 3 (% of patients)
TRAEs All AEs TRAEs All AEs
Transaminase elevation 52 60 40 42
Hypoalbuminemia 39 42 0 0
Chills 31 35 0 0
Pyrexia 27 42 0 0
Nausea 23 46 0 0
Fatigue 23 42 0 8
Thrombocytopenia 19 19 19 19
Hypotension 19 19 0 0
Weight increased 19 27 0 0
Capillary leak syndrome (CLS) 19 19 8 8
Anemia 19 31 11 15
Decreased appetite 19 23 0 0
Edema peripheral 23 46 0 0

AbbVie and Northwestern University’s Lurie Cancer Center to collaborate on multi-year cancer research agreement

On December 5, 2016 AbbVie (NYSE: ABBV), a global biopharmaceutical company, and Northwestern University reported they signed a five-year collaboration agreement with the goal of advancing research and discovery in oncology (Press release, AbbVie, DEC 5, 2016, View Source [SID1234516933]). Together, AbbVie and the Robert H. Lurie Comprehensive Cancer Center of Northwestern University will work in several areas of oncology research, which in addition to others could include, lung, colorectal, breast, prostate and hematological cancer.

"One of the best steps AbbVie can take to deliver new therapies in oncology is to combine our research and discovery expertise with the talents and insight of our colleagues in academic medicine," said Gary Gordon, M.D., Ph.D., vice president, oncology clinical development, AbbVie. "The opportunity to work with leading researchers and clinicians from the Lurie Cancer Center enhances AbbVie’s ability to help oncology patients even more in the future."

The collaboration provides Lurie Cancer Center scientists with the opportunity to access new therapies developed by AbbVie for preclinical research funded under the agreement. Lurie Cancer Center scientists will also work closely with AbbVie’s research teams to support scientific knowledge exchange. In addition, the agreement provides AbbVie with the option to obtain an exclusive license of certain Lurie Cancer Center discoveries made as a result of the five-year collaboration.

"The ability to investigate new therapeutic agents with AbbVie provides us with a great opportunity to expand our translational oncology efforts," said Leonidas C. Platanias, M.D., Ph.D., director of the Lurie Cancer Center. "Our partnership with AbbVie will facilitate and accelerate the development of innovative new therapies against a wide variety of different cancers."

A joint steering committee comprised of representatives from both organizations will determine the research projects that the collaboration will undertake. Researchers from AbbVie and the Lurie Cancer Center will also hold a symposium at least once each year to discuss their joint research and potential ideas for new research projects.

Pfizer and Avillion Announce Positive Top-Line Results for Phase 3 BFORE Study of BOSULIF for First-Line Treatment of Philadelphia Chromosome Positive Chronic Myeloid Leukemia

On December 5, 2016 Pfizer Inc. and its partner Avillion LLP reported results from the Phase 3 BFORE (Bosutinib trial in First line chrOnic myelogenous leukemia tREatment) trial demonstrating superiority of BOSULIF (bosutinib) over imatinib as a first-line treatment for patients with chronic phase Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) (Press release, Pfizer, DEC 5, 2016, View Source [SID1234516930]). The study met its primary endpoint of major molecular response (MMR) at 12 months. No new or unexpected safety issues were identified. BOSULIF is currently indicated in the U.S. and EU for the treatment of adult patients with Ph+ CML with resistance or intolerance to prior therapy.

"Since its approval, the efficacy and distinct tolerability profile of BOSULIF has provided an important treatment option for patients with Ph+ CML who are resistant or intolerant to prior therapy. The positive outcome of the BFORE study represents a key step in potentially broadening treatment options for patients in the first-line setting," said Mace Rothenberg, MD, chief development officer, Oncology, Pfizer Global Product Development. "This is an important milestone for Pfizer’s emerging hematology portfolio as we work to develop new treatments for patients with acute and chronic hematologic malignancies."

"This successful partnership between Pfizer and Avillion is good news for CML patients because additional first-line treatment options allow physicians to tailor therapy based on individual patient considerations," said Allison Jeynes-Ellis, MD, Chief Executive Officer of Avillion. "The outcome of this partnership reinforces our belief in the potential of our innovative business model for the co-development and partnership of late-stage clinical candidates."

Based on the results of the study, Pfizer will work with the U.S. Food and Drug Administration (FDA) and other regulatory authorities to potentially make BOSULIF available for Ph+ CML patients in the first-line setting. Detailed efficacy and safety data from this study will be submitted for a future congress or peer-reviewed journal.

Pfizer and Avillion entered into an exclusive collaborative development agreement in 2014 to conduct the BFORE trial. Under the terms of the agreement, Avillion provided funding and conducted the trial to generate the clinical data that will be used to support potential regulatory filings for marketing authorization of BOSULIF as first-line treatment of patients with chronic phase Ph+ CML. If approved for this indication, Avillion will be eligible to receive milestone payments from Pfizer. Pfizer retains all rights to commercialize BOSULIF globally.

Pfizer is advancing a broad range of therapies that leverage select pathways and mechanisms of action to address acute and chronic leukemias, myeloproliferative disorders and lymphoma.

About the BFORE Study

BFORE (Bosutinib trial in First line chrOnic myelogenous leukemia tREatment) is a multi-center, open-label Phase 3 study designed to assess the effectiveness and safety of BOSULIF (bosutinib) as a first-line treatment for patients with chronic phase Ph+ CML. The study enrolled 536 patients at multiple sites in North America, Asia and Europe. Patients were randomized 1:1 to receive BOSULIF 400mg or imatinib, a standard of care, for the duration of the study. The primary outcome was to show superiority of bosutinib over imatinib at 12 months by comparing MMR, or the proportion of patients in each arm whose levels of the Bcr-Abl1 kinase have dropped below 0.1%.

ABOUT BOSULIF (bosutinib)

BOSULIF (bosutinib) is an oral, once-daily, tyrosine kinase inhibitor (TKI), which inhibits the Bcr-Abl kinase that promotes CML; it is also an inhibitor of Src-family kinases. BOSULIF was approved in September 2012 in the U.S. for the treatment of adult patients with Ph+ CML with resistance or intolerance to prior therapy and offers an important treatment option for these patients. In Europe, BOSULIF was granted conditional marketing authorization in March 2013 for the treatment of adult patients with Ph+ CML previously treated with one or more TKIs and for whom imatinib, nilotinib and dasatinib are not considered appropriate treatment options. The current approved dose of BOSULIF is 500 mg orally once daily with food. For more information on BOSULIF resources available for healthcare professionals and patients, please visit www.BOSULIF.com (link is external).

IMPORTANT BOSULIF (bosutinib) SAFETY INFORMATION

Contraindication: Hypersensitivity to BOSULIF. Anaphylactic shock occurred in less than 0.2% of treated patients.

Gastrointestinal Toxicity: Diarrhea, nausea, vomiting, and abdominal pain can occur. In the clinical trial, median time to onset for diarrhea was 2 days, median duration was 1 day, and median number of episodes per patient was 3 (range 1-221). Monitor and manage patients using standards of care, including antidiarrheals, antiemetics, and/or fluid replacement. Withhold, dose reduce, or discontinue BOSULIF as necessary.

Myelosuppression: Thrombocytopenia, anemia, and neutropenia can occur. Perform complete blood counts weekly for the first month and then monthly or as clinically indicated. Withhold, dose reduce, or discontinue BOSULIF as necessary.

Hepatic Toxicity: Twenty percent of patients experienced an increase in either ALT or AST. Liver enzyme elevation usually occurs early in treatment. Perform hepatic enzyme tests monthly for the first 3 months and as clinically indicated. In patients with transaminase elevations, monitor liver enzymes more frequently. Drug-induced liver injury has occurred. Withhold, dose reduce, or discontinue BOSULIF as necessary. In patients with mild, moderate, or severe hepatic impairment, the recommended starting dose is 200 mg daily.

Renal Toxicity: An on-treatment decline in estimated glomerular filtration rate has occurred in patients treated with BOSULIF. Monitor renal function at baseline and during therapy, with particular attention to patients with preexisting renal impairment or risk factors. Consider dose adjustment in patients with baseline and treatment emergent renal impairment. The recommended starting doses for patients with severe renal impairment (CrCL <30 mL/min) or moderate renal impairment (CrCL 30-50 mL/min) are 300 mg and 400 mg daily, respectively.

Fluid Retention: Fluid retention can occur and may cause pericardial effusion, pleural effusion, pulmonary edema, and/or peripheral edema. Monitor and manage patients using standards of care. Interrupt, dose reduce, or discontinue BOSULIF as necessary.

Embryofetal Toxicity: BOSULIF may cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised of potential hazard to the fetus and to avoid becoming pregnant while receiving BOSULIF.

Adverse Reactions: The most common adverse reactions observed in greater than 20% of patients in the Phase 1/2 safety population (N=546) were diarrhea, nausea, thrombocytopenia, vomiting, abdominal pain, rash, anemia, pyrexia, and fatigue. The most common Grade 3/4 adverse reactions and laboratory abnormalities observed in greater than 10% of patients were thrombocytopenia, anemia, and neutropenia.

CYP3A Inhibitors and Inducers: Avoid concurrent use with strong or moderate CYP3A inhibitors or inducers.

Proton Pump Inhibitors: Consider using short-acting antacids or H2 blockers instead of PPIs to avoid a reduction in BOSULIF exposure. Separate antacid or H2 blocker dosing and BOSULIF dosing by more than 2 hours.

Nursing Mothers: Given the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or BOSULIF, taking into account the importance of the drug to the mother.

Please see full Prescribing Information at www.bosulif.com (link is external).