Bristol-Myers Squibb Company (NYSE: BMY) reported the first presentation of data from two cohorts of the Phase 2 CA180-226 clinical trial evaluating Sprycel (dasatinib) in imatinib-resistant or -intolerant (R/I to IM) and newly diagnosed (ND) pediatric patients with chronic phase chronic myeloid leukemia (Press release, Bristol-Myers Squibb, JUN 5, 2017, View Source [SID1234519377]).

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At minimum two-year follow-up, patients with CP-CML resistant to or intolerant of imatinib who received Sprycel demonstrated a cumulative major cytogenetic response (MCyR) rate of 55.2% (95% CI: 36, 74) 3 months into treatment, exceeding the defined threshold of clinical interest (>30%) for the primary endpoint of the cohort and increasing over time to greater than 90% (95% CI: 73, 98) at 24 months. Newly diagnosed patients with CP-CML, who received Sprycel orally or as powder for oral suspension (PFOS) once daily, achieved a cumulative complete cytogenetic response (CCyR) rate, the primary endpoint in the cohort, of 64% (95% CI: 53, 74) as early as 6 months into treatment, exceeding the defined threshold of clinical interest (>55%) and increasing over time to 94% (95% CI: 87, 98) at 24 months. The median durations of response were not estimable, or not yet reached, in each cohort at the time of follow-up (95% CI, R/I to IM: NE [54.9, NE]; ND: NE [49.9, NE]).

The secondary endpoint of estimated progression-free survival (PFS) at 48 months was greater than 75% for patients resistant to or intolerant of imatinib and greater than 90% for patients newly diagnosed with CP-CML. Sprycel was shown to have a comparable safety profile in pediatric patients with CP-CML to that reported in adults with CP-CML. In this study, there were no reported events of pleural/pericardial effusion, pulmonary edema/hypertension or pulmonary arterial hypertension related to Sprycel.

"Treatments for children and adolescents with newly diagnosed CML in chronic phase are limited, and even more so for those resistant to or intolerant of imatinib," said Lia Gore, MD, University of Colorado School of Medicine and Children’s Hospital of Colorado. "The time to and duration of responses along with the safety profile for patients studied suggest dasatinib could become an important option for pediatric patients with chronic phase CML."

These data will be presented today in the Pediatric Oncology II Oral Session from 8:24 to 8:36 a.m. CDT during the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting 2017 in Chicago.

"Chronic myeloid leukemia in pediatric patients is rare, making it difficult to study, and is often more aggressive in children and young adults," said Jonathan Leith, PhD, hematology development lead, Bristol-Myers Squibb. "As part of our commitment to advance new treatment options for pediatric cancer patients, this study was designed to evaluate the potential for Sprycel to address unmet needs for those with chronic phase CML, including a formulation developed specifically for children. The results demonstrate promising efficacy and safety in the first- and second-line settings."

Study CA180-226

CA180-226 is an ongoing Phase 2, open-label, nonrandomized study evaluating Sprycel in patients aged 18 years or younger with newly diagnosed chronic myeloid leukemia (CML) or Philadelphia chromosome-positive (Ph+) leukemias resistant to or intolerant of imatinib. Cohorts 1 and 3 examined 29 CP-CML pediatric patients resistant to or intolerant of imatinib and 84 pediatric patients with newly diagnosed CML in chronic phase (CP), respectively. Cohort 2 evaluated Sprycel in pediatric patients with accelerated/blast phase CML or Philadelphia chromosome-positive acute lymphoblastic leukemia.

Patients newly diagnosed with CP-CML received either Sprycel 60 mg/m2 tablets orally, once daily, or 72 mg/m2 Sprycel powder for oral suspension (PFOS) once daily, and patients with CP-CML resistant to or intolerant of imatinib received Sprycel tablets 60 mg/m2 orally, once daily.

One patient had a Sprycel-related AE leading to discontinuation, and one patient died from gastrointestinal bleeding unrelated to treatment. The most commonly reported AEs in newly diagnosed patients treated with Sprycel were nausea/vomiting (20%), rash (19%) and diarrhea (18%), and in imatinib-intolerant or -resistant patients were nausea/vomiting (31%), myalgia/arthralgia (17%), fatigue (14%) and rash (14%).

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. Additional country approvals for this indication total more than 50.

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 full Prescribing Information for SPRYCEL.

On June 5, 2017 Abbvie reported data on IMBRUVICA (ibrutinib) reduced cells that may play an important role in the survival and proliferation of chronic lymphocytic leukemia (CLL), without negatively impacting non-cancerous immune system cells, through one year of treatment, was presented today at the 53rd Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago (poster session: 8:00 a.m. – 11:30 a.m. CDT; abstract #7524) (Press release, AbbVie, JUN 5, 2017, View Source [SID1234519375]).1 The data regarding IMBRUVICA, a first-in-class Bruton’s tyrosine kinase (BTK) inhibitor, were announced by AbbVie (NYSE: ABBV), a global biopharmaceutical company. IMBRUVICA is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

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The data, which assessed the impact of treatment on the immune system and changes in circulating cells, found that IMBRUVICA reduced cancerous cells and other cells of the immunosuppressive tumor microenvironment including CLL cells (90 percent), myeloid-derived suppressor cells (MDSC, 61 percent) and some T cells (27-52 percent). At the same time, IMBRUVICA spared non-cancerous immune system cells, including naïve T cells, T memory stem cells (TSCM) and natural killer (NK) cells through one year of treatment. Classical monocytes (a type of white blood cell) were increased by 187 percent, while non-classical monocytes and intermediate monocytes remained relatively steady. The data were derived from the Phase 3 RESONATE-2 trial (PCYC-1115), which found IMBRUVICA reduced the risk of progression or death of treatment-naïve patients with CLL compared to the traditional chemotherapeutic chlorambucil.1

"These results show the IMBRUVICA mechanism of action at work and provide greater clarity on the potential role that BTK inhibition plays in tumor modulation," said Danelle James, M.D., M.S., Head of Clinical Science, Pharmacyclics LLC, an AbbVie company. "These data suggest that treatment with the chemotherapy agent chlorambucil has broad effects when administered to CLL patients – where almost all subsets of normal immune cells are impacted or decreased. In contrast, treatment with ibrutinib resulted in preservation of certain important immune cell subsets, providing evidence that IMBRUVICA may offer a more targeted treatment approach."

The study found treatment with chlorambucil indiscriminately affected most immune cell subsets in circulation, including progressively reducing circulating B, T, NK, NKT cells, MDSC and monocytes by 69-99 percent. All development stages of CD4+ and CD8+ T cells, except TSCM, decreased by 51-90 percent. Regulatory T cells (Treg) and PD1+ T cells also decreased similarly; however, long-term activated T cells (TLA) were not impacted.1

"We’ve made substantial progress in cancer treatment over the years with the discovery and introduction of novel therapies such as IMBRUVICA. We are able to more specifically target the tumor while sparing normal immune cells, and the study data show the potential for improved treatment options that eliminate or minimize the use of chemotherapy in CLL," added James.

CLL is a type of cancer that starts from cells that become certain white blood cells (called lymphocytes) in the bone marrow. The leukemia (cancer) cells start in the bone marrow but then spread into the blood. There are more than 20,000 newly diagnosed CLL patients every year.2 CLL is primarily a disease of the elderly, with a median age of 71 at diagnosis.3 To date, more than 25,000 CLL patients have been treated in the U.S. with IMBRUVICA since approval in 2014.

In the study over one year, immunophenotypic analyses were performed by flow cytometry on peripheral blood to assess lymphoid and myeloid cells of treatment-native CLL patients who received IMBRUVICA 420 mg once daily (n=50) or 0.5-0.8 mg/kg chlorambucil twice a month (n=30).1

About the RESONATE-2 Study

RESONATE-2 is a Pharmacyclics-sponsored, randomized, multi-center, open-label, Phase 3 study which enrolled 269 treatment-naïve patients with CLL/small lymphocytic leukemia (SLL) aged 65 years or older in the U.S., EU and other regions. Patients were randomized to receive either IMBRUVICA 420 mg orally, once daily until progression or unacceptable toxicity, or chlorambucil on days 1 and 15 of each 28-day cycle for up to 12 cycles. The starting dose for chlorambucil in Cycle 1 was 0.5 mg/kg and was increased based on tolerability in Cycle 2 by increments of 0.1 mg/kg to a maximum of 0.8 mg/kg. The study met its primary endpoint, demonstrating improved progression free survival (PFS), as assessed by an independent review committee (IRC).

The most common adverse events (AEs >20%) of all Grades in the RESONATE-2 trial for ibrutinib were diarrhea (42%), fatigue (30%), cough (22%) and nausea (22%); AEs for chlorambucil included nausea (39%), fatigue (38%), neutropenia (23%) and vomiting (20%). Hypertension occurred at a higher rate with ibrutinib (14%), including Grade 3 (4%) with no Grade 4 or 5 events. All six patients with Grade 3 hypertension were managed with hypertensive medication and did not require ibrutinib dose reduction or discontinuation. Atrial fibrillation occurred in eight patients (6%) in the ibrutinib arm and was primarily Grade 2 in six patients and Grade 3 in two patients. It was managed with discontinuation in two patients and without a dose modification in remaining patients.

Overall, AEs leading to treatment discontinuation were less frequent with ibrutinib than with chlorambucil (9% versus 23%). There were three deaths in the ibrutinib arm and 17 deaths in the chlorambucil arm over the median follow-up of 18.4 months. None of the patients who progressed on ibrutinib died during the subsequent follow-up period.

About IMBRUVICA
IMBRUVICA (ibrutinib) is a first-in-class, oral, once-daily therapy that inhibits a protein called Bruton’s tyrosine kinase (BTK). BTK is a key signaling molecule in the B-cell receptor signaling complex that plays an important role in the survival and spread of malignant B cells.3,4 IMBRUVICA blocks signals that tell malignant B cells to multiply and spread uncontrollably.4

IMBRUVICA is FDA-approved in five distinct patient populations: CLL, SLL, Waldenström’s macroglobulinemia (WM), along with previously-treated mantle cell lymphoma (MCL) and marginal zone lymphoma (MZL).4

IMBRUVICA was first approved for patients with MCL who have received at least one prior therapy in November 2013.
Soon after, IMBRUVICA was initially approved in CLL patients who have received at least one prior therapy in February 2014. By July 2014, the therapy received approval for CLL patients with 17p deletion, and by March 2016, the therapy was approved as a frontline CLL treatment.
IMBRUVICA was approved for patients with WM in January 2015.
In May 2016, IMBRUVICA was approved in combination with bendamustine and rituximab (BR) for CLL/SLL patients.
In January 2017, IMBRUVICA was approved for patients with MZL who require systemic therapy and have received at least one prior anti-CD20-based therapy.
Accelerated approval was granted for the MCL and MZL indications based on overall response rate. Continued approval for MCL and MZL may be contingent upon verification and description of clinical benefit in confirmatory trials.4

IMBRUVICA was one of the first medicines to receive U.S. FDA approval via the new Breakthrough Therapy Designation pathway. This designation is intended to expedite the development and review of a potential new drug for serious or life-threatening diseases. IMBRUVICA has been granted four Breakthrough Therapy Designations from the FDA, spanning CLL/SLL, WM, MCL, and chronic graft-versus-host-disease (cGVHD). In addition, IMBRUVICA is the first standard therapy specifically approved for patients with previously-treated MZL and WM.

IMBRUVICA is being studied alone and in combination with other treatments in several blood and solid tumor cancers and other serious illnesses. IMBRUVICA has one of the most robust clinical oncology development programs for a single molecule in the industry, with approximately 130 ongoing clinical trials. There are a total of 30 ongoing company-sponsored trials, 14 of which are in Phase 3, and approximately 100 investigator-sponsored trials and external collaborations that are active around the world. To date, 70,000 patients around the world have been treated with IMBRUVICA in clinical practice and clinical trials.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage – Fatal bleeding events have occurred in patients treated with IMBRUVICA. Grade 3 or higher bleeding events (intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA.

The mechanism for the bleeding events is not well understood. IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies and patients should be monitored for signs of bleeding. Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre- and postsurgery depending upon the type of surgery and the risk of bleeding.

Infections – Fatal and nonfatal infections have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 14% to 29% of patients. Cases of progressive multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii pneumonia (PJP) have occurred in patients treated with IMBRUVICA. Evaluate patients for fever and infections and treat appropriately.

Cytopenias – Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 13% to 29%), thrombocytopenia (range, 5% to 17%), and anemia (range, 0% to 13%) based on laboratory measurements occurred in patients treated with single agent IMBRUVICA. Monitor complete blood counts monthly.

Atrial Fibrillation – Atrial fibrillation and atrial flutter (range, 6% to 9%) have occurred in patients treated with IMBRUVICA, particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (eg, palpitations, lightheadedness) or new-onset dyspnea should have an ECG performed. Atrial fibrillation should be managed appropriately and if it persists, consider the risks and benefits of IMBRUVICA treatment and follow dose modification guidelines.

Hypertension – Hypertension (range, 6% to 17%) has occurred in patients treated with IMBRUVICA with a median time to onset of 4.6 months (range, 0.03 to 22 months). Monitor patients for new-onset hypertension or hypertension that is not adequately controlled after starting IMBRUVICA. Adjust existing antihypertensive medications and/or initiate antihypertensive treatment as appropriate.

Second Primary Malignancies – Other malignancies (range, 3% to 16%) including non-skin carcinomas (range, 1% to 4%) have occurred in patients treated with IMBRUVICA. The most frequent second primary malignancy was non-melanoma skin cancer (range, 2% to 13%).

Tumor Lysis Syndrome – Tumor lysis syndrome has been infrequently reported with IMBRUVICA therapy. Assess the baseline risk (eg, high tumor burden) and take appropriate precautions. Monitor patients closely and treat as appropriate.

Embryo-Fetal Toxicity – Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA and for 1 month after cessation of therapy. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Advise men to avoid fathering a child during the same time period.

ADVERSE REACTIONS

The most common adverse reactions (≥20%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were neutropenia** (61%), thrombocytopenia** (62%), diarrhea (43%), anemia** (41%), musculoskeletal pain (30%), rash (30%), nausea (29%), bruising (30%), fatigue (29%), hemorrhage (22%), and pyrexia (21%).

** Based on adverse reactions and/or laboratory measurements (noted as platelets, neutrophils, or hemoglobin decreased).

The most common Grade 3 or 4 non-hematologic adverse reactions (≥5%) in MCL patients were pneumonia (7%), abdominal pain (5%), atrial fibrillation (5%), diarrhea (5%), fatigue (5%), and skin infections (5%).

The most common Grade 3 or 4 non-hematologic adverse reactions (≥5%) in MZL patients were pneumonia (10%), fatigue (6%), diarrhea (5%), rash (5%), and hypertension (5%).

Approximately 6% (CLL/SLL), 14% (MCL), 11% (WM) and 10% (MZL) of patients had a dose reduction due to adverse reactions. Approximately 4%-10% (CLL/SLL), 9% (MCL), and 9% (WM [6%] and MZL [13%]) of patients discontinued due to adverse reactions. Most common adverse reactions leading to discontinuation were pneumonia, hemorrhage, atrial fibrillation, rash, and neutropenia (1% each) in CLL/SLL patients and subdural hematoma (1.8%) in MCL patients. The most common adverse reactions leading to discontinuation were interstitial lung disease, diarrhea, and rash (1.6% each) in WM and MZL patients.

DRUG INTERACTIONS

CYP3A Inhibitors – Avoid coadministration with strong and moderate CYP3A inhibitors. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA dose.

CYP3A Inducers – Avoid coadministration with strong CYP3A inducers.

SPECIFIC POPULATIONS

Hepatic Impairment – Avoid use in patients with moderate or severe baseline hepatic impairment. In patients with mild impairment, reduce IMBRUVICA dose.

Please see Full Prescribing Information: View Source

On June 5, 2017 Immunocore Limited, the world’s leading TCR company developing biological drugs to treat cancer, infectious diseases and autoimmune diseases reported compelling single agent clinical data from the intra-patient dose escalation Phase I clinical trial of its lead programme, IMCgp100, which was presented in a poster session at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago on June 3 2017 (Press release, Immunocore, JUN 5, 2017, View Source [SID1234519374]).

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Immunocore’s intra-patient dose escalation Phase I IMCgp100 study recruited 19 metastatic uveal melanoma patients and demonstrated a median progression free survival (PFS) by RECIST v1.1 of 5.6 months, which compares favourably with reported median PFS ranging from 2.6-2.8 months. The 24 weeks (6 months) PFS rate is 57%, which again compares favourably with 19-27% previously reported in other clinical studies.

Based on the promising data presented here with IMCgp100 in patients with metastatic uveal melanoma, Immunocore is initiating a pivotal trial in the first-line setting to advance IMCgp100 towards commercialization.

Dr Christina Coughlin, Chief Medical Officer at Immunocore, commented: "We are excited to share these data in advanced uveal melanoma at ASCO (Free ASCO Whitepaper). To our knowledge, no other drug treatments, including checkpoint inhibitors, have demonstrated such positive results in metastatic uveal melanoma before. We hope these data, combined with our orphan drug designation in the US, will help us to rapidly advance IMCgp100 through clinical development in order to make IMCgp100 available to patients as soon as possible."

Dr Takami Sato, MD, PhD, Department of Medical Oncology, Kimmel Cancer Center, Thomas Jefferson University, commented: "This new data presented here at ASCO (Free ASCO Whitepaper) are compelling and we believe there is an opportunity to have an effective new treatment option for patients with metastatic uveal melanoma where the unmet need is very high."

On June 5, 2017 Immune Design (Nasdaq:IMDZ), a clinical-stage immunotherapy company focused on oncology, reported updated clinical and biomarker data for its lead immuno-oncology product candidates, CMB305 and G100 (Press release, Immune Design, JUN 5, 2017, View Source [SID1234519373]). The data are being presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2017 Annual Meeting in Chicago.

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CMB305 Monotherapy in Soft Tissue Sarcoma Patients: Clinical Benefit, Safety and Patient Selection

Data in an oral presentation last Friday by Neeta Somaiah, M.D., Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, highlight the results of 25 soft tissue sarcoma (STS) patients with recurrent disease treated with CMB305:

Patient characteristics: 92% metastatic, 56% progressing upon trial entry, and 52% with ≥2 prior lines of chemotherapy
Survival: median overall survival (mOS) has still not yet been reached.
• The overall survival rate at 12 and 18 months was 83% and 76%, respectively.
• These new data compare favorably to mOS for approved second line and later sarcoma agents, which is only 12.4-13.5 months, as well as a published mOS of 11.7 months for synovial sarcoma patients specifically; the largest patient population enrolled in this trial.
Disease control: a disease control rate (CDR) of 64% (16/25) was observed, including durable tumor growth arrest in patients who had evidence of disease progression at study entry.
Safety: CMB305 was well tolerated, with only one related Grade 3 adverse event (AE).
Immune response: CMB305 generated a strong and broad anti-NY-ESO-1 immune response in >50% of the patients, with 32% patients experiencing an integrated response (T cells and antibodies).
Antigen spreading: induction of an immune response against other tumor antigens not targeted by CMB305 was detected in 33% of evaluable patients following CMB305 therapy.
In a related presentation today, Seth M. Pollack, M.D. of the Fred Hutchinson Cancer Research Institute, will present data examining the relationship between immune response against NY-ESO-1 and clinical benefit in a combined set of CMB305 and LV305 patients (n=64) with various tumor types. LV305 is the vector only, "prime" component of CMB305, and was the subject of a separate Phase 1 study:

NY-ESO-1 specific "public" T cell receptor (pTCR): three NY-ESO-1-specific T-cell receptor sequences isolated from a patient responding to therapy were found to be shared by approximately 50% of all study patients, as well as healthy blood donors, tested. These pTCR sequences indicate a low level of pre-existing anti-NY-ESO-1 immunity which appear to be expanded by CMB305.
Immune response: the induction of an integrated anti-NY-ESO-1 immune response (antibodies and T-cells) was observed in more than 30% of the patients who received therapy.
Biomarker (immune response) vs. Survival: the induction of an anti-NY-ESO-1 immune response by these agents is associated with improved patient survival, particularly in patients with pre-existing anti-NY-ESO-1 immunity.
Patient selection: these immune biomarkers, including novel bio-markers derived from pTCRs, may guide regulatory strategy via the selection of patients more likely to have survival benefit on CMB305 therapy.
G100 Monotherapy in Follicular NHL (FL) Patients: Clinical Benefit, Safety and Changes to the Tumor Microenvironment (TME)

In a poster presentation today, Christopher Flowers, M.D., Department of Hematology and Medical Oncology, Emory University School of Medicine, will present results of 9 patients with FL treated with escalating doses of G100 monotherapy (with local radiation (XRT)).

Patient characteristics: of the 9 FL patients enrolled, 45% were treatment-naïve and 56% were relapsed/refractory, and most had Stage III and IV disease (56% and 33%, respectively). Additionally, 55% of patients had received at least two prior therapies and 78% had progressive disease upon study entry.
Disease control:
• Objective responses were observed at all three dose levels tested.
• 44% of the patients achieved a partial response (PR) based on WHO criteria (at least a 50% tumor reduction).
• Some patients had tumor shrinkage over a prolonged period, e.g., continuing up to 8+ months, and a duration of response exceeding 4 months in some patients.
• DCR of 100% of patients (44% PR, 56% SD).
• 50% of evaluable patients experienced shrinkage of untreated distal (abscopal) lesion.
Safety: G100 was well tolerated, with no related Grade 3/4 AEs in all three dose levels tested.
Tumor microenvironment: G100 resulted in favorable tumor microenvironment changes
• Tumor biopsies showed increased inflammatory responses and T cell infiltrates in abscopal, non-treated tumors.
"These data demonstrate that both CMB305 and G100, our lead cancer immunotherapy product candidates, are capable of activating patients’ immune systems in ways that have a direct effect on patients’ tumor growth, whether it is tumor-growth arrest on CMB305 therapy and subsequent survival benefit, or ORR and systemic tumor shrinkage after local therapy with G100," said Sergey Yurasov, MD, PhD, Senior Vice President and Chief Medical Officer at Immune Design. "Also, importantly, we are evaluating immune biomarkers that may identify patients who are likely to benefit the most from CMB305 therapy. We plan to present these clinical data to regulatory agencies in planning for a pivotal trial that may lead to subsequent regulatory approval, and enable us to bring these novel, safe immunotherapies to cancer patients."

ASCO Presentation Details

ORAL PRESENTATION

Immune response, safety, and survival impact from CMB305 in NY-ESO-1+ recurrent soft tissue sarcomas (STS)

Abstract # 11006
Session Title: Sarcoma
Date: Friday, June 2, 2017
Time: 3 p.m. — 6 p.m. CT (oral session)
Location: S100bc
Presenter: Neeta Somaiah, M.D., Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center
POSTER PRESENTATIONS

The Association of CMB305 or LV305-induced and baseline anti-NY-ESO-1 immunity with survival in recurrent cancer patients

Abstract # 3090
Session Title: Developmental Therapeutics—Immunotherapy
Date: Monday, June 5, 2017
Time: 8 a.m. — 11:30 a.m. CT
Location: Hall A
Presenter: Seth M. Pollack, M.D., Fred Hutchinson Cancer Research Center
Intratumoral G100 to induce systemic immune responses and abscopal tumor regression in patients with follicular lymphoma

Abstract # 7537
Session Title: Hematologic Malignancies — Lymphoma and Chronic Lymphocytic Leukemia
Date: Monday, June 5, 2017
Time: 8 a.m. — 11:30 a.m. CT
Location: Hall A
Presenter: Christopher Flowers, M.D., Department of Hematology and Medical Oncology, Emory University School of Medicine
About CMB305

CMB305 is a prime-boost vaccine approach against NY-ESO-1-expressing tumors, designed to generate an integrated, anti-NY-ESO-1 immune response in vivo via a targeted, specific interaction with dendritic cells, a mechanism of action Immune Design believes differs from traditional cancer vaccines. CMB305 is being evaluated in STS patients in ongoing Phase 1 monotherapy and 2 combination studies with the anti-PD-L1 antibody, Tecentriq (atezolizumab), pursuant to a collaboration with Genentech. Immune Design has received Orphan Drug Designation for CMB305 from the U.S. Food and Drug Administration (FDA) for the treatment of soft tissue sarcoma, as well as from the FDA and European Medicines Agency for each of the components of CMB305 for the treatment of soft tissue sarcoma.

About G100

G100 contains a potent synthetic small molecule toll-like receptor-4 (TLR-4) agonist, Glucopyranosyl Lipid A (GLA), and is the lead product candidate in Immune Design’s Antigen Agnostic approach. It leverages the activation of both innate and adaptive immunity, including dendritic cells, in the tumor microenvironment to create an immune response against the tumor’s preexisting diverse set of antigens. G100 is being evaluated as both a monotherapy (with XRT) and in combination with Merck’s anti-PD-1 agent, Keytruda (pembrolizumab), pursuant to a clinical collaboration with Merck, in a randomized Phase 1/2 trial in patients with follicular non-Hodgkin’s lymphoma. The FDA has granted Orphan Drug Designation for G100 for the treatment of follicular non-Hodgkin’s lymphoma.

On June 5, 2017 Fortress Biotech, Inc. (NASDAQ: FBIO) ("Fortress"), a biopharmaceutical company dedicated to acquiring, developing and commercializing novel pharmaceutical and biotechnology products, reported that Mustang Bio, Inc. ("Mustang"), a subsidiary of Fortress, has entered into exclusive, worldwide licensing agreements with City of Hope ("COH") for the use of three novel CAR T therapies in the development of cancer treatments (Press release, Fortress Biotech, JUN 5, 2017, View Source [SID1234519371]). 

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The CAR T therapies covered under the agreements include: human epidermal growth factor receptor 2 (HER2) CAR T technology (HER2 Technology), which will initially be applied in the treatment of glioblastoma multiforme; CS1‐specific CAR T technology (CS1 Technology) to be directed against multiple myeloma; and prostate stem cell antigen (PSCA) CAR T technology (PSCA Technology) to be used in the treatment of prostate cancer. All three technologies were developed in the laboratory of Stephen J. Forman, M.D., director of COH’s T cell Immunotherapy Research Laboratory.  

Dr. Manuel Litchman, President and Chief Executive Officer of Mustang, said, "We believe the in‐licensing of this COH technology will enable us to expand our CAR T portfolio through the application of novel product candidates and new indications. We look forward to our continued partnership with Dr. Forman and his team at COH, as we work together to advance cutting‐edge treatment options for cancer patients."

This announcement builds upon established exclusive patent license agreements that Mustang has entered into with COH related to Mustang’s lead CAR T therapies, MB‐101 (IL13Rα2‐specific CAR) and MB‐102 (CD123 CAR), spacer technology to be used in the development of CAR T treatments, and intraventricular and intracerebroventricular methods of delivering T cells that express CARs.