On July 10, 2017 Bristol-Myers Squibb Company (NYSE:BMY) reported that the U.S. Food and Drug Administration (FDA) accepted its supplemental New Drug Application (sNDA) to include an indication for Sprycel (dasatinib) to treat children with Philadelphia chromosome-positive chronic phase (CP) chronic myeloid leukemia (CML), as well as a powder for oral suspension (PFOS) formulation of Sprycel (Press release, Bristol-Myers Squibb, JUL 10, 2017, View Source [SID1234519774]). The application is under priority review with an action date of November 9, 2017.

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"Today’s news reinforces our commitment to addressing the unique and often unmet needs of pediatric oncology patients, including children with newly diagnosed and imatinib intolerant or resistant CML," said Murdo Gordon, executive vice president and chief commercial officer, Bristol-Myers Squibb. "Sprycel also has the potential to be the first drug in its class approved for pediatric use with an oral solution."

The sNDA includes data from CA180-226 (NCT00777036), an ongoing Phase 2, open-label, non-randomized trial studying Sprycel in pediatric patients with CP-CML that are resistant to or intolerant of imatinib and in pediatric patients newly diagnosed with CP-CML. The efficacy endpoints included cumulative major cytogenetic response rate among imatinib-resistant or intolerant patients and cumulative complete cytogenetic response rate in newly diagnosed patients. Additional efficacy measures were time to and duration of response, progression-free survival, overall survival and major molecular response. Safety was also assessed.

Data from this study were shared in oral presentations at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting 2017 in Chicago on June 5 and the 22nd Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) on June 24.

About Sprycel

Sprycel first received FDA approval in 2006 for the treatment of adults with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP) who are resistant or intolerant to prior therapy including imatinib. At that time, Sprycel was also approved for adults with Ph+ acute lymphoblastic leukemia (ALL) who are resistant or intolerant to prior therapy. Sprycel is approved and marketed worldwide for these indications in more than 60 countries.

Sprycel is also an FDA-approved treatment for adults with newly diagnosed CP Ph+ CML (since October 2010). Sprycel received accelerated FDA approval for this indication. This indication is approved in more than 50 countries.

U.S. FDA-APPROVED INDICATIONS FOR SPRYCEL

SPRYCEL (dasatinib) is indicated for the treatment of adults with:

Newly diagnosed adults with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase.
Chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib.
Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy.
IMPORTANT SAFETY INFORMATION

Myelosuppression

Treatment with SPRYCEL is associated with severe (NCI CTC Grade 3/4) thrombocytopenia, neutropenia, and anemia, which occur earlier and more frequently in patients with advanced phase CML or Ph+ ALL than in patients with chronic phase CML. Myelosuppression was reported in patients with normal baseline laboratory values as well as in patients with pre-existing laboratory abnormalities.

In patients with chronic phase CML, perform complete blood counts (CBCs) every 2 weeks for 12 weeks, then every 3 months thereafter, or as clinically indicated
In patients with advanced phase CML or Ph+ ALL, perform CBCs weekly for the first 2 months and then monthly thereafter, or as clinically indicated
Myelosuppression is generally reversible and usually managed by withholding SPRYCEL temporarily and/or dose reduction
In clinical studies, myelosuppression may have also been managed by discontinuation of study therapy
Hematopoietic growth factor has been used in patients with resistant myelosuppression
Bleeding-Related Events

SPRYCEL caused thrombocytopenia in human subjects. In addition, dasatinib caused platelet dysfunction in vitro. In all CML or Ph+ ALL clinical studies, ≥grade 3 central nervous system (CNS) hemorrhages, including fatalities, occurred in <1% of patients receiving SPRYCEL. Grade 3 or greater gastrointestinal hemorrhage, including fatalities, occurred in 4% of patients and generally required treatment interruptions and transfusions. Other cases of ≥grade 3 hemorrhage occurred in 2% of patients.

Most bleeding events in clinical studies were associated with severe thrombocytopenia
Concomitant medications that inhibit platelet function or anticoagulants may increase the risk of hemorrhage
Fluid Retention

SPRYCEL may cause fluid retention. After 5 years of follow-up in the randomized newly diagnosed chronic phase CML study (n=258), grade 3/4 fluid retention was reported in 5% of patients, including 3% of patients with grade 3/4 pleural effusion. In patients with newly diagnosed or imatinib resistant or intolerant chronic phase CML, grade 3/4 fluid retention occurred in 6% of patients treated with SPRYCEL at the recommended dose (n=548). In patients with advanced phase CML or Ph+ ALL treated with SPRYCEL at the recommended dose (n=304), grade 3/4 fluid retention was reported in 8% of patients, including grade 3/4 pleural effusion reported in 7% of patients.

Patients who develop symptoms of pleural effusion or other fluid retention, such as new or worsened dyspnea on exertion or at rest, pleuritic chest pain, or dry cough should be evaluated promptly with a chest x-ray or additional diagnostic imaging as appropriate
Fluid retention events were typically managed by supportive care measures that may include diuretics or short courses of steroids
Severe pleural effusion may require thoracentesis and oxygen therapy
Consider dose reduction or treatment interruption
Cardiovascular Events

After 5 years of follow-up in the randomized newly diagnosed chronic phase CML trial (n=258), the following cardiac adverse events occurred:

Cardiac ischemic events (3.9% dasatinib vs 1.6% imatinib), cardiac related fluid retention (8.5% dasatinib vs 3.9% imatinib), and conduction system abnormalities, most commonly arrhythmia and palpitations (7.0% dasatinib vs 5.0% imatinib). Two cases (0.8%) of peripheral arterial occlusive disease occurred with imatinib and 2 (0.8%) transient ischemic attacks occurred with dasatinib
Monitor patients for signs or symptoms consistent with cardiac dysfunction and treat appropriately.

Pulmonary Arterial Hypertension (PAH)

SPRYCEL may increase the risk of developing PAH, which may occur any time after initiation, including after more than 1 year of treatment. Manifestations include dyspnea, fatigue, hypoxia, and fluid retention. PAH may be reversible on discontinuation of SPRYCEL.

Evaluate patients for signs and symptoms of underlying cardiopulmonary disease prior to initiating SPRYCEL and during treatment. If PAH is confirmed, SPRYCEL should be permanently discontinued
QT Prolongation

In vitro data suggest that dasatinib has the potential to prolong cardiac ventricular repolarization (QT interval).

In clinical trials of patients treated with SPRYCEL at all doses (n=2440), 16 patients (<1%) had QTc prolongation reported as an adverse reaction. Twenty-two patients (1%) experienced a QTcF >500 ms
In 865 patients with leukemia treated with SPRYCEL in five Phase 2 single-arm studies, the maximum mean changes in QTcF (90% upper bound CI) from baseline ranged from 7.0 to 13.4 ms
SPRYCEL may increase the risk of prolongation of QTc in patients including those with hypokalemia or hypomagnesemia, patients with congenital long QT syndrome, patients taking antiarrhythmic medicines or other medicinal products that lead to QT prolongation, and cumulative high-dose anthracycline therapy
Correct hypokalemia or hypomagnesemia prior to and during SPRYCEL administration
Severe Dermatologic Reactions

Cases of severe mucocutaneous dermatologic reactions, including Stevens-Johnson syndrome and erythema multiforme, have been reported in patients treated with SPRYCEL.

Discontinue permanently in patients who experience a severe mucocutaneous reaction during treatment if no other etiology can be identified
Tumor Lysis Syndrome (TLS)

TLS has been reported in patients with resistance to prior imatinib therapy, primarily in advanced phase disease.

Due to potential for TLS, maintain adequate hydration, correct uric acid levels prior to initiating therapy with SPRYCEL, and monitor electrolyte levels
Patients with advanced stage disease and/or high tumor burden may be at increased risk and should be monitored more frequently
Embryo-Fetal Toxicity

Based on limited human data, SPRYCEL can cause fetal harm when administered to a pregnant woman. Hydrops fetalis, fetal leukopenia and fetal thrombocytopenia have been reported with maternal exposure to SPRYCEL. Transplacental transfer of dasatinib has been measured in fetal plasma and amniotic fluid at concentrations comparable to those in maternal plasma.

Advise females of reproductive potential to avoid pregnancy, which may include the use of effective contraception, during treatment with SPRYCEL and for 30 days after the final dose
Lactation

No data are available regarding the presence of dasatinib in human milk, the effects of the drug on the breastfed infant or the effects of the drug on milk production. However, dasatinib is present in the milk of lactating rats.

Because of the potential for serious adverse reactions in nursing infants from SPRYCEL, breastfeeding is not recommended during treatment with SPRYCEL and for 2 weeks after the final dose
Drug Interactions

SPRYCEL is a CYP3A4 substrate and a weak time-dependent inhibitor of CYP3A4.

Drugs that may increase SPRYCEL plasma concentrations are:
CYP3A4 inhibitors: Concomitant use of SPRYCEL and drugs that inhibit CYP3A4 should be avoided. If administration of a potent CYP3A4 inhibitor cannot be avoided, close monitoring for toxicity and a SPRYCEL dose reduction should be considered
Strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole). If SPRYCEL must be administered with a strong CYP3A4 inhibitor, a dose decrease or temporary discontinuation should be considered
Grapefruit juice may also increase plasma concentrations of SPRYCEL and should be avoided
Drugs that may decrease SPRYCEL plasma concentrations are:
CYP3A4 inducers: If SPRYCEL must be administered with a CYP3A4 inducer, a dose increase in SPRYCEL should be considered
Strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital) should be avoided. Alternative agents with less enzyme induction potential should be considered. If the dose of SPRYCEL is increased, the patient should be monitored carefully for toxicity
St John’s Wort may decrease SPRYCEL plasma concentrations unpredictably and should be avoided
Antacids may decrease SPRYCEL drug levels. Simultaneous administration of SPRYCEL and antacids should be avoided. If antacid therapy is needed, the antacid dose should be administered at least 2 hours prior to or 2 hours after the dose of SPRYCEL
H 2 antagonists/proton pump inhibitors (eg, famotidine and omeprazole): Long-term suppression of gastric acid secretion by use of H2 antagonists or proton pump inhibitors is likely to reduce SPRYCEL exposure. Therefore, concomitant use of H2 antagonists or proton pump inhibitors with SPRYCEL is not recommended
Drugs that may have their plasma concentration altered by SPRYCEL are:
CYP3A4 substrates (eg, simvastatin) with a narrow therapeutic index should be administered with caution in patients receiving SPRYCEL
Adverse Reactions

The safety data reflects exposure to SPRYCEL at all doses tested in clinical studies including 324 patients with newly diagnosed chronic phase CML and 2388 patients with imatinib resistant or intolerant chronic or advanced phase CML or Ph+ ALL.

The median duration of therapy in all 2712 SPRYCEL-treated patients was 19.2 months (range 0–93.2 months). Median duration of therapy in:

1618 patients with chronic phase CML was 29 months (range 0–92.9 months)
Median duration for 324 patients in the newly diagnosed chronic phase CML trial was approximately 60 months
1094 patients with advanced phase CML or Ph+ ALL was 6.2 months (range 0–93.2 months)
In the newly diagnosed chronic phase CML trial, after a minimum of 60 months of follow-up, the cumulative discontinuation rate for 258 patients was 39%.

In the overall population of 2712 SPRYCEL-treated patients, 88% of patients experienced adverse reactions at some time and 19% experienced adverse reactions leading to treatment discontinuation.

Among the 1618 SPRYCEL-treated patients with chronic phase CML, drug-related adverse events leading to discontinuation were reported in 329 (20.3%) patients.

In the newly diagnosed chronic phase CML trial, drug was discontinued for adverse reactions in 16% of SPRYCEL-treated patients with a minimum of 60 months of follow-up
Among the 1094 SPRYCEL-treated patients with advanced phase CML or Ph+ ALL, drug-related adverse events leading to discontinuation were reported in 191 (17.5%) patients.

Patients ≥65 years are more likely to experience the commonly reported adverse reactions of fatigue, pleural effusion, diarrhea, dyspnea, cough, lower gastrointestinal hemorrhage, and appetite disturbance, and more likely to experience the less frequently reported adverse reactions of abdominal distention, dizziness, pericardial effusion, congestive heart failure, hypertension, pulmonary edema and weight decrease, and should be monitored closely.

In newly diagnosed chronic phase CML patients:
Drug-related serious adverse events (SAEs) were reported for 16.7% of SPRYCEL-treated patients. Serious adverse reactions reported in ≥5% of patients included pleural effusion (5%)
The most common adverse reactions (≥15%) included myelosuppression, fluid retention, and diarrhea
Grade 3/4 laboratory abnormalities included neutropenia (29%), thrombocytopenia (22%), anemia (13%), hypophosphatemia (7%), hypocalcemia (4%), elevated bilirubin (1%), and elevated creatinine (1%)
In patients resistant or intolerant to prior imatinib therapy:
Drug-related SAEs were reported for 26.1% of SPRYCEL-treated patients treated at the recommended dose of 100 mg once daily in the randomized dose-optimization trial of patients with chronic phase CML resistant or intolerant to prior imatinib therapy. Serious adverse reactions reported in ≥5% of patients included pleural effusion (10%)
The most common adverse reactions (≥15%) included myelosuppression, fluid retention events, diarrhea, headache, fatigue, dyspnea, skin rash, nausea, hemorrhage and musculoskeletal pain
Grade 3/4 hematologic laboratory abnormalities in chronic phase CML patients resistant or intolerant to prior imatinib therapy who received SPRYCEL 100 mg once daily with a minimum follow up of 60 months included neutropenia (36%), thrombocytopenia (24%), and anemia (13%). Other grade 3/4 laboratory abnormalities included: hypophosphatemia (10%), and hypokalemia (2%)
Among chronic phase CML patients with resistance or intolerance to prior imatinib therapy, cumulative grade 3/4 cytopenias were similar at 2 and 5 years including: neutropenia (36% vs 36%), thrombocytopenia (23% vs 24%), and anemia (13% vs 13%)
Grade 3/4 elevations of transaminases or bilirubin and Grade 3/4 hypocalcemia, hypokalemia, and hypophosphatemia were reported in patients with all phases of CML
Elevations in transaminases or bilirubin were usually managed with dose reduction or interruption
Patients developing Grade 3/4 hypocalcemia during the course of SPRYCEL therapy often had recovery with oral calcium supplementation
Please see the US full Prescribing Information here .

On Exelixis, Inc. (NASDAQ:EXEL) and Bristol-Myers Squibb Company (NYSE:BMY) reported the initiation of the phase 3 CheckMate 9ER trial to evaluate Opdivo (nivolumab) in combination with CABOMETYX (cabozantinib) tablets, a small molecule inhibitor of receptor tyrosine kinases, or Opdivo and Yervoy (ipilimumab) in combination with CABOMETYX versus sunitinib in patients with previously untreated, advanced or metastatic renal cell carcinoma (RCC). The primary endpoint for the trial is progression-free survival (PFS).

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"There is strong scientific evidence showing that CABOMETYX results in a more immune permissive tumor environment, and we are eager to determine if combining these active agents with complementary and potentially cooperative mechanisms of action has the potential to further improve patient outcomes," said Gisela Schwab, M.D., President, Product Development and Medical Affairs and Chief Medical Officer, Exelixis. "We are excited to initiate this first clinical trial from our broad development program with Bristol-Myers Squibb looking at the potential of Opdivo in combination with CABOMETYX, with or without Yervoy, in a variety of tumor types."

"While existing therapies have improved outcomes for some patients with advanced or metastatic kidney cancer, high rates of relapse and disease progression demonstrate a need for additional therapeutic options, especially among poor and intermediate risk patients," said Fouad Namouni, M.D., Head of Development, Oncology, Bristol-Myers Squibb. "Combination therapy with agents that target different and complementary pathways—in this case, the combination of immune checkpoint inhibitors and tyrosine kinase inhibitors—may be a potential new approach for these patients."

CheckMate 9ER is an open-label, randomized, multi-national phase 3 trial that aims to enroll approximately 1,014 patients with previously untreated advanced or metastatic RCC. Patients will be randomized 1:1:1 to one of three arms: CABOMETYX and Opdivo; CABOMETYX, Opdivo and Yervoy; or sunitinib. The primary efficacy analysis will compare the doublet combination versus sunitinib and the triplet combination versus sunitinib in intermediate/poor risk patients with RCC.

More information about this trial is available at ClinicalTrials.gov.

About Advanced Renal Cell Carcinoma

The American Cancer Society’s 2017 statistics cite kidney cancer as among the top ten most commonly diagnosed forms of cancer among both men and women in the U.S.1 Clear cell RCC is the most common type of kidney cancer in adults.2 If detected in its early stages, the five-year survival rate for RCC is high; for patients with advanced or late-stage metastatic RCC, however, the five-year survival rate is only 12 percent, with no identified cure for the disease.3 Approximately 30,000 patients in the U.S. and 68,000 globally require treatment.4

The majority of clear cell RCC tumors have lower than normal levels of a protein called von Hippel-Lindau, which leads to higher levels of MET, AXL and VEGF.5,6 These proteins promote tumor angiogenesis (blood vessel growth), growth, invasiveness and metastasis.7-10 MET and AXL may provide escape pathways that drive resistance to VEGF receptor inhibitors.6,7

About CABOMETYX

CABOMETYX is the tablet formulation of cabozantinib. Its targets include MET, AXL and VEGFR-1, -2 and -3. In preclinical models, cabozantinib has been shown to inhibit the activity of these receptors, which are involved in normal cellular function and pathologic processes such as tumor angiogenesis, invasiveness, metastasis and drug resistance.

CABOMETYX is available in 20 mg, 40 mg or 60 mg doses. The recommended dose is 60 mg orally, once daily.

On April 25, 2016, the FDA approved CABOMETYX tablets for the treatment of patients with advanced renal cell carcinoma who have received prior anti-angiogenic therapy. On September 9, 2016, the European Commission approved CABOMETYX tablets for the treatment of advanced renal cell carcinoma in adults who have received prior vascular endothelial growth factor (VEGF)-targeted therapy in the European Union, Norway and Iceland.

On July 10, 2017 BioLineRx Ltd. (NASDAQ/TASE: BLRX), a clinical-stage biopharmaceutical company focused on oncology and immunology, reported that Genentech, a member of the Roche Group, has commenced a Phase 1b/2 study for BL-8040 in combination with atezolizumab (TECENTRIQ), Genentech’s anti-PDL1 cancer immunotherapy agent, evaluating the combination in metastatic pancreatic ductal adenocarcinoma (Press release, BioLineRx, JUL 10, 2017, View Source [SID1234519772]).

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Up to 40 patients are planned to be enrolled in this Phase 1b/2, multicenter, randomized, controlled, open-label study to evaluate the clinical response, safety and tolerability, as well as multiple pharmacodynamic parameters, of BL-8040 in combination with atezolizumab. Initially, patients will receive BL-8040 injections as priming monotherapy for five consecutive days, after which, from day 8, they will receive both BL-8040 and atezolizumab, and continue with multiple treatment cycles for up to two years or until disease progression, clinical deterioration or unacceptable toxicity.

The clinical study collaboration between BioLineRx and Genentech, a member of the Roche Group, is part of MORPHEUS, Roche’s Novel Cancer Immunotherapy Development Platform. MORPHEUS is a phase 1b/2 adaptive platform to assess the efficacy and safety of combination cancer immunotherapies.

Philip Serlin, Chief Executive Officer of BioLineRx, stated, "We are very pleased with the launch of the first clinical study under our cancer immunotherapy collaboration with Genentech. Pancreatic cancer is a very difficult cancer to treat, and both conventional chemotherapy and immunotherapy have failed to demonstrate a significant benefit for these patients. BL-8040 has been shown to have robust mobilization of immune cells, improve the infiltration of T cells into solid tumors, and affect the immunosuppressive tumor micro-environment. We are therefore hopeful that combining atezolizumab with BL-8040 can lead to a significant advancement in the treatment of pancreatic cancer, and of other solid tumors that are difficult to treat. We look forward to the initiation of additional combination studies under this collaboration, all planned for the second half of this year."

BioLineRx is carrying out a larger cancer immunotherapy collaboration with Genentech to conduct several Phase 1b/2 studies investigating BL-8040 in combination with atezolizumab in multiple cancer indications, announced in September 2016.

BL-8040, BioLineRx’s lead oncology platform, is a CXCR4 antagonist that has been shown in clinical trials to be a robust mobilizer of immune cells and to be effective in inducing direct tumor cell death. Additional findings suggest that BL-8040 may be effective in inducing the migration of anti-tumor T cells into the tumor micro-environment, as well as improving the infiltration of T cells into solid tumors. Atezolizumab is a humanized monoclonal antibody designed to bind to PD-L1 in tumor cells and tumor infiltrating immune cells and blocks interactions with the PD-1 and B7.1 receptors. Through this interaction, atezolizumab may enable the activation of T cells, whose migration into the tumor may be enhanced by BL-8040.

About BL-8040

BL-8040 is a short peptide for the treatment of acute myeloid leukemia, solid tumors, and stem cell mobilization. It functions as a high-affinity antagonist for CXCR4, a chemokine receptor that is directly involved in tumor progression, angiogenesis, metastasis and cell survival. CXCR4 is over-expressed in more than 70% of human cancers and its expression often correlates with disease severity. In a number of clinical and pre-clinical studies, BL-8040 has shown robust mobilization of cancer cells from the bone marrow, thereby sensitizing these cells to chemo- and bio-based anti-cancer therapy, as well as a direct anti-cancer effect by inducing cell death (apoptosis). In addition, BL-8040 has also demonstrated robust stem-cell mobilization, including the mobilization of colony-forming cells, T, B and NK cells. BL-8040 was licensed by BioLineRx from Biokine Therapeutics and was previously developed under the name BKT-140.