On September 24, 2019 UroGen Pharma Ltd. (Nasdaq: URGN), a clinical-stage biopharmaceutical company developing treatments to address unmet needs in the field of urology, reported that updates on its advancing pipeline for urologic cancers and UGN-101 launch readiness at its Investor Day in New York on September 24, 2019 (Press release, UroGen Pharma, SEP 24, 2019, View Source [SID1234539752]).

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"At UroGen, we are 100 percent committed to overcoming obstacles that have stunted much needed innovation in uro-oncology," said Liz Barrett, President and Chief Executive Officer of UroGen. "While we prepare for a potential launch of UGN-101, we believe this is just the beginning of what is possible with our pipeline. The data from an interim analysis for UGN-102 unveiled at our Investor Day further highlight the potential of our RTGel platform to transform treatments in this space for an even larger patient population with bladder cancer. We look forward to pushing innovation beyond our foundational platform and moving UGN-201, our TLR 7/8 agonist for high-grade bladder cancer, into clinical studies in 2020."

UroGen detailed data updates for its lead investigational product candidates UGN-101 and UGN-102:

UGN-101 (mitomycin gel) for instillation for patients with low-grade upper tract urothelial cancer (LG UTUC):
Complete response (CR) rate of 59 percent observed in 71 patients with LG UTUC from Phase 3 OLYMPUS trial. Data remain consistent with previously presented data.
Durability of response determined to be 89 percent at six months and 84 percent at twelve months.
In the OLYMPUS trial, the most common treatment emergent adverse events (TEAE) included ureteral stenosis, urinary tract infection, hematuria, flank pain, dysuria, renal impairment, hydronephrosis and frequency. Most TEAEs were characterized as mild to moderate and transient.
At the time of database lock, the most common Grade 3 TEAE’s included ureteral stenosis (8.5%), hematuria, flank pain, and urinary tract infection (3% each). There was one Grade 4 TEAE of subdural hematoma (1.4%).
Rolling NDA submission is on track for Q4 2019 with potential approval and launch in 1H 2020.
If approved, UGN-101 will be the first drug for the primary chemoablative treatment of LG UTUC.
UGN-102 (mitomycin gel) for intravesical instillation for patients with intermediate risk low-grade non-muscle invasive bladder cancer (LG NMIBC):
In an interim analysis, 63% (20/32) of patients from the Phase 2b OPTIMA II trial achieved a CR.
In an interim analysis, the most common treatment emergent adverse events (TEAEs) observed were dysuria, pollakiuria, fatigue, hematuria and urinary tract infection. The majority were characterized as mild or moderate and transient.
Patients will continue to be followed with 12-month durability to be reported at a later date.
Trial enrolled patients with intermediate risk LG NMIBC, defined as those with one or two of the following criteria: multifocal disease, large tumors and rapid rates of recurrence.
Trial completed enrollment of 62 patients ahead of schedule.
The Company intends to initiate a pivotal Phase 3 trial in 2020 following discussion with the FDA.
UroGen discussed its ongoing activities to build awareness of unmet needs in UTUC, educate the market and commercialize UGN-101 following anticipated regulatory approval:

Increased scientific awareness of UGN-101 clinical data developments in urologic community.
Engagement with payers and proactive market access strategy to ensure patient access and reimbursement.
UGN-101 treatment expected to fit well into existing physician reimbursement models.
Planned convenience kit for UGN-101 will facilitate preparation and administration for practitioners.
Experienced commercial team with track record of success in uro-oncology.
Nimble salesforce with seven Regional Business Managers (RBMs) hired, and 50 sales reps to be hired by end of 2019.
The Company also provided an update on UGN-201, it’s investigational TLR 7/8 agonist for the treatment of high-grade NMIBC. UGN-201 is believed to stimulate innate and adaptive antitumor immunity. It likely works in conjunction with other potent immunoregulatory molecules. Nonclinical data shows an efficacy signal when UGN-201 is administered locally with anti-CTLA4 antibody in a murine model of high-grade bladder cancer. The Company plans to optimize combinations and advance into human studies.

About UGN-101

UGN-101 (mitomycin gel) for instillation is an investigational drug formulation of mitomycin in Phase 3 development for the treatment of low-grade upper tract urothelial cancer (LG UTUC). Utilizing the RTGel technology platform, UroGen’s proprietary sustained release, hydrogel-based formulation, UGN-101 is designed to enable longer exposure of urinary tract tissue to mitomycin, thereby enabling the treatment of tumors by non-surgical means. UGN-101 is delivered to patients using standard ureteral catheters. The Company initiated its rolling submission of the UGN-101 New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) in December 2018. The FDA previously granted Orphan Drug, Fast Track, and Breakthrough Therapy Designations to UGN-101 for the treatment of UTUC. If approved, UGN-101 would be the first drug approved for the non-surgical treatment of LG UTUC.

About UGN-102

UGN-102 (mitomycin gel) for instillation is an investigational drug formulation of mitomycin in Phase 2b development for the treatment of low-grade non-muscle invasive bladder cancer (LG NMIBC). Utilizing the RTGel Technology Platform, UroGen’s proprietary sustained release, hydrogel-based formulation, UGN-102 is designed to enable longer exposure of bladder tissue to mitomycin, thereby enabling the treatment of tumors by non-surgical means. UGN-102 is delivered to patients using standard intravesical catheters. The Company completed enrollment in the Phase 2b OPTIMA II trial of UGN-102 for the treatment of LG NMIBC in September 2019 and intends to advance the program to a pivotal study to further investigate UGN-102 in the treatment of this condition.

On September 24, 2019 Pfizer Inc. (NYSE: PFE) reported the presentation of four IBRANCE (palbociclib) real-world analyses (Press release, Pfizer, SEP 24, 2019, View Source [SID1234539737]). The studies support the effectiveness of IBRANCE combination therapy in everyday clinical practice and provide additional insights on its use in certain patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). The posters will be presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2019 in Barcelona, Spain on Sunday, September 29.

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Among the data, Pfizer will share the first real-world comparative analysis of a CDK 4/6 inhibitor in combination with an aromatase inhibitor compared to an aromatase inhibitor alone.

"We have an opportunity to make positive changes in cancer care by incorporating learnings from real-world data in addition to data gathered from clinical trials," said Chris Boshoff, M.D., Ph.D., Chief Development Officer, Oncology, Pfizer Global Product Development. "We are pleased to share this view of the impact IBRANCE has had on patients treated outside of traditional clinical studies, as it continues to add to the body of evidence for IBRANCE and provides insights into the patient experience."

About the Real-World Comparative Analysis

In this retrospective analysis (Abstract #329P: Comparative effectiveness of palbociclib plus letrozole vs. letrozole for metastatic breast cancer in U.S. real-world clinical practices), treatment with IBRANCE plus letrozole demonstrated a statistically significant improvement in real-world progression-free survival (rwPFS) compared to letrozole alone: 24.5 months (95% CI = 20.7 – 32.7) versus 17.1 months (95% CI = 13.7 – 19.8) (HR = 0.68, 95% CI = 0.56 – 0.84, p = 0.0003).

"To help deliver the best care to our patients, it is critical that physicians have compelling evidence of a medicine’s benefit on patients who resemble those who they treat every day," said Rachel Layman, M.D., Associate Professor, Department of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center. "The real-world evidence presented at ESMO (Free ESMO Whitepaper) provides a more robust understanding of the effectiveness of IBRANCE in patients who may not be reflected in the randomized trials."

The analysis compared 906 matched patients with HR+, HER2- MBC who started IBRANCE plus letrozole as initial endocrine-based therapy in the metastatic setting (n=453) or letrozole alone (n=453) from February 2015 to August 2018. rwPFS was measured by the treating physician’s clinical assessment of source evidence, such as radiographic scans or pathology from the Flatiron Health longitudinal database. The most recent update for this database includes de-identified electronic health records from more than 280 cancer clinics representing more than 2.2 million cancer patients in the U.S.

The additional real-world posters at ESMO (Free ESMO Whitepaper) examining the use of IBRANCE in patients with HR+, HER2- MBC are:

Abstract #327P: Palbociclib plus an aromatase inhibitor as first-line therapy for metastatic breast cancer in U.S. clinical practices: Real-world progression-free survival analysis
This single-arm analysis of real-world disease progression and overall survival rates in patients treated with IBRANCE plus an aromatase inhibitor (AI), also from the Flatiron database, examined the use of IBRANCE combination therapy as initial treatment for patients with HR+, HER2- MBC.
Abstract #338P: Real-world effectiveness of first-line palbociclib + letrozole for metastatic breast cancer 4 years post approval in the U.S.
An analysis of clinical effectiveness of IBRANCE plus letrozole in patients who began treatment on or after February 2015, using the Cardinal Health Oncology Provider Extended Network.
Abstract #365P: Measures of functional status in adults aged >70 years with advanced breast cancer receiving palbociclib combination therapy in POLARIS
A subgroup analysis from the ongoing prospective, observational POLARIS study provides insights into the use of IBRANCE in geriatric patients (age 70 or older) treated in everyday clinical practice – a population for which limited data are available.
To further educate the global oncology community about the importance of real-world data at ESMO (Free ESMO Whitepaper), Pfizer is sponsoring a satellite symposium, Real World Data in Oncology: Its Growing Role in Research and Patient Care. The symposium will take place on Friday, September 27, from 6:00 – 8:00 pm CEST at Fira Gran Via in the Alicante Auditorium (Hall 3).

About IBRANCE (palbociclib) 125 mg capsules

IBRANCE is an oral inhibitor of CDKs 4 and 6,1 which are key regulators of the cell cycle that trigger cellular progression.2,3 In the U.S., IBRANCE is indicated for the treatment of adult patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-)advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine based therapy in postmenopausal women or in men; or with fulvestrant in patients with disease progression following endocrine therapy.

The most common adverse reactions (incidence ≥10%) associated with IBRANCE are neutropenia, infections, leukopenia, fatigue, nausea, stomatitis, anemia, alopecia, diarrhea, thrombocytopenia, rash, vomiting, decreased appetite, asthenia, and pyrexia. Today in the U.S., IBRANCE is the most prescribed FDA-approved oral combination treatment for HR+, HER2- metastatic breast cancer.

IBRANCE currently is approved in more than 90 countries and has been prescribed to more than 230,000 patients globally.

The full U.S. Prescribing Information for IBRANCE can be found here.

IMPORTANT IBRANCE (palbociclib) SAFETY INFORMATION FROM THE U.S. PRESCRIBING INFORMATION

Neutropenia was the most frequently reported adverse reaction in PALOMA-2 (80%) and PALOMA-3 (83%). In PALOMA-2, Grade 3 (56%) or 4 (10%) decreased neutrophil counts were reported in patients receiving IBRANCE plus letrozole. In PALOMA-3, Grade 3 (55%) or Grade 4 (11%) decreased neutrophil counts were reported in patients receiving IBRANCE plus fulvestrant. Febrile neutropenia has been reported in 1.8% of patients exposed to IBRANCE across PALOMA-2 and PALOMA-3. One death due to neutropenic sepsis was observed in PALOMA-3. Inform patients to promptly report any fever.

Monitor complete blood count prior to starting IBRANCE, at the beginning of each cycle, on Day 15 of first 2 cycles and as clinically indicated. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia.

Severe, life-threatening, or fatal interstitial lung disease (ILD) and/or pneumonitis can occur in patients treated with CDK4/6 inhibitors, including IBRANCE when taken in combination with endocrine therapy. Across clinical trials (PALOMA-1, PALOMA-2, PALOMA-3), 1.0% of IBRANCE-treated patients had ILD/pneumonitis of any grade, 0.1% had Grade 3 or 4, and no fatal cases were reported. Additional cases of ILD/pneumonitis have been observed in the post-marketing setting, with fatalities reported.

Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis (e.g. hypoxia, cough, dyspnea). In patients who have new or worsening respiratory symptoms and are suspected to have developed pneumonitis, interrupt IBRANCE immediately and evaluate the patient. Permanently discontinue IBRANCE in patients with severe ILD or pneumonitis.

Based on the mechanism of action, IBRANCE can cause fetal harm. Advise females of reproductive potential to use effective contraception during IBRANCE treatment and for at least 3 weeks after the last dose. IBRANCE may impair fertility in males and has the potential to cause genotoxicity. Advise male patients to consider sperm preservation before taking IBRANCE. Advise male patients with female partners of reproductive potential to use effective contraception during IBRANCE treatment and for 3 months after the last dose. Advise females to inform their healthcare provider of a known or suspected pregnancy. Advise women not to breastfeed during IBRANCE treatment and for 3 weeks after the last dose because of the potential for serious adverse reactions in nursing infants.

The most common adverse reactions (≥10%) of any grade reported in PALOMA-2 for IBRANCE plus letrozole vs placebo plus letrozole were neutropenia (80% vs 6%), infections (60% vs 42%), leukopenia (39% vs 2%), fatigue (37% vs 28%), nausea (35% vs 26%), alopecia (33% vs 16%), stomatitis (30% vs 14%), diarrhea (26% vs 19%), anemia (24% vs 9%), rash (18% vs 12%), asthenia (17% vs 12%), thrombocytopenia (16% vs 1%), vomiting (16% vs 17%), decreased appetite (15% vs 9%), dry skin (12% vs 6%), pyrexia (12% vs 9%), and dysgeusia (10% vs 5%).

The most frequently reported Grade ≥3 adverse reactions (≥5%) in PALOMA-2 for IBRANCE plus letrozole vs placebo plus letrozole were neutropenia (66% vs 2%), leukopenia (25% vs 0%), infections (7% vs 3%), and anemia (5% vs 2%).

Lab abnormalities of any grade occurring in PALOMA-2 for IBRANCE plus letrozole vs placebo plus letrozole were decreased WBC (97% vs 25%), decreased neutrophils (95% vs 20%), anemia (78% vs 42%), decreased platelets (63% vs 14%), increased aspartate aminotransferase (52% vs 34%), and increased alanine aminotransferase (43% vs 30%).

The most common adverse reactions (≥10%) of any grade reported in PALOMA-3 for IBRANCE plus fulvestrant vs placebo plus fulvestrant were neutropenia (83% vs 4%), leukopenia (53% vs 5%), infections (47% vs 31%), fatigue (41% vs 29%), nausea (34% vs 28%), anemia (30% vs 13%), stomatitis (28% vs 13%), diarrhea (24% vs 19%), thrombocytopenia (23% vs 0%), vomiting (19% vs 15%), alopecia (18% vs 6%), rash (17% vs 6%), decreased appetite (16% vs 8%), and pyrexia (13% vs 5%).

The most frequently reported Grade ≥3 adverse reactions (≥5%) in PALOMA-3 for IBRANCE plus fulvestrant vs placebo plus fulvestrant were neutropenia (66% vs 1%) and leukopenia (31% vs 2%).

Lab abnormalities of any grade occurring in PALOMA-3 for IBRANCE plus fulvestrant vs placebo plus fulvestrant were decreased WBC (99% vs 26%), decreased neutrophils (96% vs 14%), anemia (78% vs 40%), decreased platelets (62% vs 10%), increased aspartate aminotransferase (43% vs 48%), and increased alanine aminotransferase (36% vs 34%).

Avoid concurrent use of strong CYP3A inhibitors. If patients must be administered a strong CYP3A inhibitor, reduce the IBRANCE dose to 75 mg. If the strong inhibitor is discontinued, increase the IBRANCE dose (after 3-5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor. Grapefruit or grapefruit juice may increase plasma concentrations of IBRANCE and should be avoided. Avoid concomitant use of strong CYP3A inducers. The dose of sensitive CYP3A substrates with a narrow therapeutic index may need to be reduced as IBRANCE may increase their exposure.

For patients with severe hepatic impairment (Child-Pugh class C), the recommended dose of IBRANCE is 75 mg. The pharmacokinetics of IBRANCE have not been studied in patients requiring hemodialysis.

On September 24, 2019 Medpace Holdings, Inc. (Nasdaq: MEDP) ("Medpace") reported that it will report its third quarter 2019 financial results after the market close on Monday, October 28, 2019 (Press release, Medpace, SEP 24, 2019, View Source [SID1234539753]). The Company will host a conference call the following morning, Tuesday, October 29, 2019, at 9:00 a.m. ET to discuss these results.

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To participate in the conference call, dial 800-219-7113 (domestic) or 574-990-1030 (international) using the passcode 7668623.

To access the conference call via webcast, visit the "Investors" section of Medpace’s website at investor.medpace.com. The webcast replay of the call will be available at the same site approximately one hour after the end of the call.

A supplemental slide presentation will also be available at the "Investors" section of Medpace’s website prior to the start of the call.

A recording of the call will be available from 12:00 p.m. ET on Tuesday, October 29, 2019 until 12:00 p.m. ET on Tuesday, November 12, 2019. To hear this recording, dial 855-859-2056 (domestic) or 404-537-3406 (international) using the passcode 7668623.

On September 24, 2019 Pfizer Inc. (NYSE: PFE) and Flatiron Health reported an expanded strategic collaboration to further integrate and increase the use of real-world data in Pfizer’s development of innovative targeted cancer medicines (Press release, Pfizer, SEP 24, 2019, View Source [SID1234539738]). Under the terms of the agreement, Pfizer will draw on de-identified, real-world datasets and analytical expertise from Flatiron Health to inform development strategies and activities for a number of clinical development projects across major tumor types, as well as jointly explore other innovative ways to drive clinical development innovation with real-world data.

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The collaboration, which was first established in 2014, builds on recent pioneering work by Pfizer and Flatiron Health to incorporate real-world evidence as part of a regulatory submission to expand the area of use for one of Pfizer’s breast cancer medicines.

"Real-world data and evidence, and the technologies that capture and analyze them, are increasingly valuable ways for us to improve medicines development. They can augment the data we collect in traditional trials and enable greater efficiency and effectiveness in our clinical trial design and operations," said Rod MacKenzie, Ph.D., Chief Development Officer and Executive Vice President, Pfizer. "We are pleased to expand our relationship with Flatiron Health as we continue to work with leading technology companies and transform clinical trials to better deliver breakthroughs to patients."

The expanded collaboration will be governed by a Joint Steering Committee to set strategic objectives for the collaboration as well as oversee identification and execution of projects in support of these objectives. Collaborative projects will include datasets from tumor types such as non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). Pfizer and Flatiron Health will explore appropriate venues to share learnings from these research projects, as well as broader implications for the application of real-world data, with the scientific and healthcare communities to further explore the role of real-world evidence in regulatory decision making.

"This collaboration is geared toward uncovering valuable insights to inform clinical development within Pfizer’s oncology portfolio, as well as identifying future areas of collaboration that will evolve the role of real-world evidence in bringing innovative cancer treatments to patients," said Zach Weinberg, president and co-founder, Flatiron Health. "We believe that the use of real-world evidence holds the potential to significantly accelerate cancer research, and we are proud to expand our relationship with Pfizer Oncology, a leader in this space."

On September 24, 2019 Amgen (NASDAQ:AMGN) reported that the results of a prespecified interim analysis of an open-label, randomized, controlled global multicenter Phase 3 trial (20120215) showed that the primary endpoint of event-free survival was met (Press release, Amgen, SEP 24, 2019, View Source [SID1234539754]). The study evaluated the efficacy, safety and tolerability of BLINCYTO (blinatumomab) compared to conventional consolidation chemotherapy in pediatric patients with high-risk, B-cell acute lymphoblastic leukemia (ALL) at first relapse. Enrollment was terminated early due to encouraging efficacy in the BLINCYTO arm and was based on a recommendation from the Independent Data Monitoring Committee (DMC). Follow up will continue as prescribed per protocol.

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In addition, a randomized, Phase 3 trial (AALL1331) conducted by the Children’s Oncology Group (COG) using BLINCYTO in pediatric B-cell ALL patients at first relapse has closed to accrual for the high-risk and intermediate risk-arm based on the recommendation of the COG DMC. The DMC closure decision was based on a strong trend towards improved disease-free survival and improved overall survival, markedly lower toxicity, and better minimal residual disease (MRD) clearance for BLINCYTO compared to chemotherapy. The COG DMC recommended that the AALL1331 low-risk group continue to enroll and randomize patients until enrollment goals are reached. AALL1331 is sponsored by the Cancer Therapy Evaulation Program of the National Cancer Institute (NCI), part of the National Institutes of Health, and is conducted by the NCI-funded COG. Amgen provided BLINCYTO for AALL1331 under a Collaborative Research and Development Agreement between the NCI and Amgen.

"Considered together, the results of these studies are remarkable. Children and adolescents who relapse with acute lymphoblastic leukemia face a poor prognosis and there remains a need for additional treatment options, particularly for those that are identified as high-risk. These data have the potential to be practice-changing and may provide a treatment approach to prevent further relapse that is superior to chemotherapy," said David M. Reese, M.D., executive vice president of Research and Development at Amgen. "We look forward to discussing these data with regulatory authorities."

The BLINCYTO adverse events observed in the Phase 3 20120215 and the COG AALL1331 studies were consistent with the known safety profile of BLINCYTO. These interim data will be submitted to a future medical conference and for publication.

About the 20120215 Study

Study 20120215 is a Phase 3 open-label, multicenter, randomized, controlled trial to evaluate event-free survival after treatment with BLINCYTO compared with standard of care consolidation chemotherapy in pediatric patients with high-risk first relapsed B-cell ALL. Key secondary endpoints included incidence of overall survival and MRD response, AEs, 100-day mortality after alloHSCT, incidence of anti-blinatumomab antibody formation, cumulative incidence of relapse. This is a global study that is being conducted as part of the PIP (Pediatric Investigation Plan) agreed to between Amgen and the EMA. The study is being conducted in Australia and various countries in EU and Latin America. Click here to read about the trial on ClinicalTrials.gov.

About the COG AALL1331 Study

The COG AALL1331 study is a risk-stratified, randomized, Phase 3 trial of blinatumomab in first relapse of pediatric B-ALL to evaluate disease-free survival (DFS) of high-risk (HR) and intermediate-risk (IR) relapsed B-ALL patients who are randomized following induction block 1 chemotherapy to receive either two intensive chemotherapy blocks or two 5-week blocks of blinatumomab. It also compares the DFS of low risk (LR) relapse B-ALL patients who are randomized following block 1 chemotherapy to receive either chemotherapy alone or chemotherapy plus blinatumomab. Key secondary endpoints include overall survival of HR, IR, and LR relapsed B-ALL patients. This is a global study that is being conducted in Australia, Canada, New Zealand and United States. Click here to read about the trial on ClinicalTrials.gov.

About BLINCYTO (blinatumomab)

BLINCYTO is a bispecific CD19-directed CD3 T cell engager (BiTE) antibody construct that binds specifically to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells.

BiTE antibody constructs are a type of immunotherapy being investigated for fighting cancer by helping the body’s immune system to detect and target malignant cells. The modified antibodies are designed to engage two different targets simultaneously, thereby juxtaposing T cells (a type of white blood cell capable of killing other cells perceived as threats) to cancer cells. BiTE antibody constructs help place the T cells within reach of the targeted cell, with the intent of allowing T cells to inject toxins and trigger the cancer cell to die (apoptosis). BiTE antibody constructs are currently being investigated for their potential to treat a wide variety of cancers.

BLINCYTO was granted breakthrough therapy and priority review designations by the U.S. Food and Drug Administration and is approved in the U.S. for the treatment of:

relapsed or refractory B-cell precursor ALL in adults and children.
B-cell precursor ALL in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1% in adults and children.
This indication is approved under accelerated approval based on MRD response rate and hematological relapse-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
In the EU, BLINCYTO is indicated as monotherapy for the treatment of:

adults with Philadelphia chromosome negative CD19 positive relapsed or refractory B-precursor acute lymphoblastic leukaemia (ALL).
adults with Philadelphia chromosome negative CD19 positive B-precursor ALL in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1%.
paediatric patients aged 1 year or older with Philadelphia chromosome negative CD19 positive B-precursor ALL which is refractory or in relapse after receiving at least two prior therapies or in relapse after receiving prior allogeneic hematopoietic stem cell transplantation
About BiTE Technology

Bispecific T cell engager (BiTE) technology is a targeted immuno-oncology platform designed to engage patients’ own T cells to any tumor-specific antigen, activating the cytotoxic potential of T cells to eliminate detectable cancer. BiTE antibody constructs are currently being investigated for their potential to treat a wide variety of cancers. For more information, visit www.biteantibodies.com.

IMPORTANT SAFETY INFORMATION

WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGICAL TOXICITIES

Cytokine Release Syndrome (CRS), which may be life-threatening or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO and treat with corticosteroids as recommended.
Neurological toxicities, which may be severe, life-threatening or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO as recommended.
Contraindications

BLINCYTO is contraindicated in patients with a known hypersensitivity to blinatumomab or to any component of the product formulation.

Warnings and Precautions

Cytokine Release Syndrome (CRS): CRS, which may be life-threatening or fatal, occurred in 15% of patients with R/R ALL and in 7% of patients with MRD-positive ALL. The median time to onset of CRS is 2 days after the start of infusion and the median time to resolution of CRS was 5 days among cases that resolved. Closely monitor and advise patients to contact their healthcare professional for signs and symptoms of serious adverse events such as fever, headache, nausea, asthenia, hypotension, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased total bilirubin (TBILI), and disseminated intravascular coagulation (DIC). The manifestations of CRS after treatment with BLINCYTO overlap with those of infusion reactions, capillary leak syndrome, and hemophagocytic histiocytosis/macrophage activation syndrome. If severe CRS occurs, interrupt BLINCYTO until CRS resolves. Discontinue BLINCYTO permanently if life-threatening CRS occurs. Administer corticosteroids for severe or life-threatening CRS.
Neurological Toxicities: Approximately 65% of patients receiving BLINCYTO in clinical trials experienced neurological toxicities. The median time to the first event was within the first 2 weeks of BLINCYTO treatment and the majority of events resolved. The most common (≥ 10%) manifestations of neurological toxicity were headache and tremor. Severe, life‐threatening, or fatal neurological toxicities occurred in approximately 13% of patients, including encephalopathy, convulsions, speech disorders, disturbances in consciousness, confusion and disorientation, and coordination and balance disorders. Manifestations of neurological toxicity included cranial nerve disorders. Monitor patients for signs or symptoms and interrupt or discontinue BLINCYTO as outlined in the PI.
Infections: Approximately 25% of patients receiving BLINCYTO in clinical trials experienced serious infections such as sepsis, pneumonia, bacteremia, opportunistic infections, and catheter-site infections, some of which were life-threatening or fatal. Administer prophylactic antibiotics and employ surveillance testing as appropriate during treatment. Monitor patients for signs or symptoms of infection and treat appropriately, including interruption or discontinuation of BLINCYTO as needed.
Tumor Lysis Syndrome (TLS), which may be life-threatening or fatal, has been observed. Preventive measures, including pretreatment nontoxic cytoreduction and on-treatment hydration, should be used during BLINCYTO treatment. Monitor patients for signs and symptoms of TLS and interrupt or discontinue BLINCYTO as needed to manage these events.
Neutropenia and Febrile Neutropenia, including life-threatening cases, have been observed. Monitor appropriate laboratory parameters (including, but not limited to, white blood cell count and absolute neutrophil count) during BLINCYTO infusion and interrupt BLINCYTO if prolonged neutropenia occurs.
Effects on Ability to Drive and Use Machines: Due to the possibility of neurological events, including seizures, patients receiving BLINCYTO are at risk for loss of consciousness, and should be advised against driving and engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery while BLINCYTO is being administered.
Elevated Liver Enzymes: Transient elevations in liver enzymes have been associated with BLINCYTO treatment with a median time to onset of 3 days. In patients receiving BLINCYTO, although the majority of these events were observed in the setting of CRS, some cases of elevated liver enzymes were observed outside the setting of CRS, with a median time to onset of 19 days. Grade 3 or greater elevations in liver enzymes occurred in approximately 7% of patients outside the setting of CRS and resulted in treatment discontinuation in less than 1% of patients. Monitor ALT, AST, gamma-glutamyl transferase, and TBILI prior to the start of and during BLINCYTO treatment. BLINCYTO treatment should be interrupted if transaminases rise to > 5 times the upper limit of normal (ULN) or if TBILI rises to > 3 times ULN.
Pancreatitis: Fatal pancreatitis has been reported in patients receiving BLINCYTO in combination with dexamethasone in clinical trials and the post-marketing setting. Evaluate patients who develop signs and symptoms of pancreatitis and interrupt or discontinue BLINCYTO and dexamethasone as needed.
Leukoencephalopathy: Although the clinical significance is unknown, cranial magnetic resonance imaging (MRI) changes showing leukoencephalopathy have been observed in patients receiving BLINCYTO, especially in patients previously treated with cranial irradiation and antileukemic chemotherapy.
Preparation and administration errors have occurred with BLINCYTO treatment. Follow instructions for preparation (including admixing) and administration in the PI strictly to minimize medication errors (including underdose and overdose).
Immunization: Vaccination with live virus vaccines is not recommended for at least 2 weeks prior to the start of BLINCYTO treatment, during treatment, and until immune recovery following last cycle of BLINCYTO.
Risk of Serious Adverse Reactions in Pediatric Patients due to Benzyl Alcohol Preservative: Serious and fatal adverse reactions including "gasping syndrome," which is characterized by central nervous system depression, metabolic acidosis, and gasping respirations, can occur in neonates and infants treated with benzyl alcohol-preserved drugs including BLINCYTO (with preservative). When prescribing BLINCYTO (with preservative) for pediatric patients, consider the combined daily metabolic load of benzyl alcohol from all sources including BLINCYTO (with preservative) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known. Due to the addition of bacteriostatic saline, 7-day bags of BLINCYTO solution for infusion with preservative contain benzyl alcohol and are not recommended for use in any patients weighing < 22 kg.
Adverse Reactions

The most common adverse reactions (≥ 20%) in clinical trial experience of patients with MRD-positive B-cell precursor ALL (BLAST Study) treated with BLINCYTO were pyrexia (91%), infusion-related reactions (77%), headache (39%), infections (pathogen unspecified [39%]), tremor (31%), and chills (28%). Serious adverse reactions were reported in 61% of patients. The most common serious adverse reactions (≥ 2%) included pyrexia, tremor, encephalopathy, aphasia, lymphopenia, neutropenia, overdose, device related infection, seizure, and staphylococcal infection.
The most common adverse reactions (≥ 20%) in clinical trial experience of patients with Philadelphia chromosome-negative relapsed or refractory B-cell precursor ALL (TOWER Study) treated with BLINCYTO were infections (bacterial and pathogen unspecified), pyrexia, headache, infusion-related reactions, anemia, febrile neutropenia, thrombocytopenia, and neutropenia. Serious adverse reactions were reported in 62% of patients. The most common serious adverse reactions (≥ 2%) included febrile neutropenia, pyrexia, sepsis, pneumonia, overdose, septic shock, CRS, bacterial sepsis, device related infection, and bacteremia.
Adverse reactions that were observed more frequently (≥ 10%) in the pediatric population compared to the adults with relapsed or refractory B-cell precursor ALL were pyrexia (80% vs. 61%), hypertension (26% vs. 8%), anemia (41% vs. 24%), infusion-related reaction (49% vs. 34%), thrombocytopenia (34% vs. 21%), leukopenia (24% vs. 11%), and weight increased (17% vs. 6%).
In pediatric patients less than 2 years old (infants), the incidence of neurologic toxicities was not significantly different than for the other age groups, but its manifestations were different; the only event terms reported were agitation, headache, insomnia, somnolence, and irritability. Infants also had an increased incidence of hypokalemia (50%) compared to other pediatric age cohorts (15-20%) or adults (17%).
Dosage and Administration Guidelines

BLINCYTO is administered as a continuous intravenous infusion at a constant flow rate using an infusion pump which should be programmable, lockable, non-elastomeric, and have an alarm.
It is very important that the instructions for preparation (including admixing) and administration provided in the full Prescribing Information are strictly followed to minimize medication errors (including underdose and overdose).
Please see full Prescribing Information and medication guide for BLINCYTO at www.BLINCYTO.com.

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