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Cytovia Inc, Immune Pharmaceuticals’ Oncology Subsidiary, Enters into a Definitive Agreement with Pint Pharma for the Licensing and Commercialization of Ceplene® in Latin America

On July 11, 2017 Cytovia Inc. ("Cytovia") the oncology subsidiary of Immune Pharmaceuticals Inc. (NASDAQ: IMNP) ("Immune") reported that it has entered into a licensing agreement with Pint Pharma International S.A. ("Pint") a pharmaceutical company focused on Latin America and other markets, for the marketing and distribution of Ceplene throughout Latin America (the "territory") (Press release, Immune Pharmaceuticals, JUL 11, 2017, View Source [SID1234519793]). Pint Gmbh will separately enter into an investment agreement, which will lead to an investment of $4 million into Cytovia. Dr. Massimo Radaelli, Executive Chairman of Pint, will also join the board of Cytovia upon completion of the investment and effective spin off of Cytovia from Immune.

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"Following the acquisition from Mylan of Ceplene rights in Europe and Asia, Cytovia is pleased to confirm the partnership with Pint for Latin America markets. This will provide Cytovia an opportunity to generate revenues from Latin American sales of Ceplene. This potential is incremental to revenues expected from European sales where Ceplene is approved in thirty countries." said Daniel Teper, of Cytovia.

"We intend to immediately initiate regulatory registration of Ceplene in the LATAM markets based on the European approval. Furthermore, Pint has extensive experience with Early Access Programs for orphan drugs and is planning to offer a similar program to AML patients who are candidates for treatment with Ceplene" added David Munoz, CEO of Pint.

Ceplene is the only drug currently approved in 30 European countries and Israel for the maintenance of first remission in Acute Myeloid Leukemia (AML). Ceplene has a reimbursed cost of therapy of approximately $25,000/year in Europe based on a full course of treatment. The addressable market for remission maintenance in AML is estimated at 7000 patients in Europe. Additionally the addressable market in Latin America is estimated at 4000 patients. There are currently no alternative drugs approved in the remission setting.

About Ceplene
Ceplene (histamine dihydrochloride) is administered in conjunction with low dose interleukin-2 (IL-2), for maintenance of first remission in patients with Acute Myeloid Leukemia (AML). It has been shown in clinical studies to prevent leukemic relapses in AML patients in first remission and prolong leukemia-free survival, while maintaining good quality of life during treatment. Ceplene acts by enhancing the immunostimulatory effect of IL-2 and countering reactive oxygen species-induced dysfunction and apoptosis of T and NK cells, thereby inducing immune-mediated killing of leukemic cells, providing a strong rationale for this combination therapy. A recent Phase IV study presented at the meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) in 2016 confirmed the safety and efficacy of Ceplene in the international study that supported European approval.

About Acute Myeloid Leukemia (AML)
AML patients receive intensive induction treatment with chemotherapeutic drugs at diagnosis and typically become free of detectable leukemia, achieving "complete remission." However, within 1-2 years, the majority (75-80%) of adult patients will experience a relapse of leukemia, with a survival prognosis of 33% in younger patients and 15-20% in patients over 60 years of age. According to the American Cancer Society, there will be approximately 21,380 new cases of AML and 10,590 deaths from AML in the US in 2017. The prognosis following first remission is poor and there are no other effective remission therapies currently available. AML represents an orphan condition with high unmet need.

FDA Advisory Committee Votes in Favor of Pfizer’s MYLOTARG (gemtuzumab ozogamicin) for Acute Myeloid Leukemia

On July 11, 2017 Pfizer Inc. (NYSE:PFE) reported that the U.S. Food and Drug Administration’s (FDA) Oncologic Drug Advisory Committee (ODAC) voted that the results of ALFA-0701 demonstrated a favorable risk:benefit profile for MYLOTARG (gemtuzumab ozogamicin) 3 mg/m2 on days 1, 4 and 7 added to chemotherapy for patients with newly-diagnosed CD33-positive acute myeloid leukemia (AML) (Press release, Pfizer, JUL 11, 2017, View Source [SID1234519788]). The role of the Advisory Committee is to provide recommendations to the FDA. The FDA decision on whether or not to approve the MYLOTARG application is anticipated by September 2017.

"We are extremely pleased with the Committee’s recommendation and believe this is an important step toward our goal of making MYLOTARG available to patients with newly-diagnosed AML," said Mace Rothenberg, MD, Chief Development Officer, Oncology, Pfizer Global Product Development. "We look forward to working closely with the FDA as we continue the regulatory process. We are grateful to both the investigators who led MYLOTARG clinical trials and the patients who participated."

The ODAC discussions were based on the Biologics License Application (BLA) currently under review by the FDA. The BLA includes Pfizer-sponsored studies from the original New Drug Application (NDA) for MYLOTARG, an investigator-led Phase 3 randomized, open-label study (ALFA-0701) and an individual patient data meta-analysis from over 3,000 patients in five randomized Phase 3 studies (including ALFA-0701). These studies span 10 years of research and include more than 4,300 patients.

"Clinical studies investigating MYLOTARG have provided a significant body of evidence supporting the risk:benefit profile of MYLOTARG in AML," said Jorge Cortes, MD, University of Texas, MD Anderson Cancer Center. "Based on the totality of the efficacy and safety data, MYLOTARG, if approved, has the potential to be an important treatment option for adult patients with AML."

Due to the critical unmet need for patients with newly-diagnosed AML, there has been great interest among AML investigators to evaluate MYLOTARG in this population using different doses and different schedules of MYLOTARG. These investigator-led clinical trials have provided more information on the efficacy and safety of MYLOTARG.

ODAC is an independent panel of experts that evaluates data concerning the efficacy and safety of marketed and investigational cancer treatments and makes recommendations to the FDA. Its vote is not binding, but is considered by the FDA in its decision-making process.

About AML

Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults and accounts for approximately 80% of all cases of acute leukemia.1 About 21,380 people are expected to be diagnosed with AML in the United States in 2017.2 Despite recent developments in understanding the scientific basis of AML and its treatment, there has been little progress in increasing the long-term survival rate in AML patients.3 Only one in four patients with AML survive longer than five years.2

About MYLOTARG (gemtuzumab ozogamicin)

MYLOTARG is an investigational antibody-drug conjugate (ADC) comprised of the cytotoxic agent calicheamicin, attached to a monoclonal antibody (mAB) targeting CD33, an antigen expressed on the surface of myeloblasts in more than 90 percent of AML patients.4,5,6 When MYLOTARG binds to the CD33 antigen on the cell surface it is absorbed into the cell and calicheamicin is released causing cell death.4,5

MYLOTARG was originally approved under the FDA’s accelerated approval program in 2000 for use as a single agent in patients with CD33-positive AML who had experienced their first relapse and were 60 years or older. In 2010, Pfizer voluntarily withdrew MYLOTARG after a confirmatory Phase 3 trial (SWOG S0106) did not show a clinical benefit, and the rate of fatalities as a result of treatment-related toxicity was significantly higher in the MYLOTARG arm.

While ODAC discussed MYLOTARG for newly-diagnosed CD33-positive AML, Pfizer is currently seeking approval in the U.S. for MYLOTARG in two indications:

In combination with standard chemotherapy for the treatment of previously untreated de novo CD33-positive AML.
As monotherapy for the treatment of CD33-positive AML patients in first relapse who are 60 years of age or older and who are not considered candidates for other cytotoxic chemotherapy.
MYLOTARG is commercially available in Japan where it is approved for the treatment of patients with relapsed or refractory CD33-positive AML who are not considered candidates for other cytotoxic chemotherapy.

MYLOTARG originates from a collaboration between Pfizer and Celltech, now UCB. Pfizer has sole responsibility for all manufacturing and clinical development activities for this molecule.

FDA Grants Full Approval for BLINCYTO® (blinatumomab) to Treat Relapsed or Refractory B-cell Precursor Acute Lymphoblastic Leukemia in Adults and Children

On July 11, 2017 Amgen (NASDAQ:AMGN) reported that the U.S. Food and Drug Administration (FDA) has approved the supplemental Biologics License Application (sBLA) for BLINCYTO (blinatumomab) to include overall survival (OS) data from the Phase 3 TOWER study (Press release, Amgen, JUL 11, 2017, View Source [SID1234519787]). The approval converts BLINCYTO’s accelerated approval to a full approval. The sBLA approval also included data from the Phase 2 ALCANTARA study supporting the treatment of patients with Philadelphia chromosome-positive (Ph+) relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL). The approval expands the indication of BLINCYTO for the treatment of relapsed or refractory B-cell precursor ALL in adults and children.

"For researchers and physicians, overall survival is the primary goal of treatment and the gold standard of outcomes, demonstrating a clear value to patients," said Anthony Stein, M.D., study investigator and co-director of the Gehr Family Center for Leukemia Research, City of Hope, Duarte, Calif. "Data from the TOWER study support the use of this single agent bispecific T cell engager immunotherapy, the first to demonstrate superior overall survival in patients with Philadelphia chromosome-negative relapsed or refractory B-cell precursor ALL, offering a much needed alternative with significantly improved outcomes over standard of care chemotherapy."

BLINCYTO, the first single-agent immunotherapy to treat patients with Philadelphia chromosome-negative (Ph-) relapsed or refractory B-cell precursor ALL, was previously granted breakthrough therapy designation and accelerated approval. It is also the first-and-only FDA-approved CD19-directed CD3 bispecific T cell engager (BiTE) immunotherapy, and the first bispecific antibody construct from Amgen’s BiTE platform.

"Relapsed or refractory ALL is often a lethal disease, with a median overall survival of just four months on standard of care chemotherapy," said Bijal D. Shah, M.D., medical oncologist, Moffitt Cancer Center, Tampa, Fla. "As a physician, my goal is to identify treatments that improve response rates in patients with aggressive hematologic malignancies. BLINCYTO is an option that has been shown to help these high-risk patients fight their disease."

The approval is based on results from the TOWER study, which found that BLINCYTO demonstrated a superior improvement in median OS over standard of care (SOC) chemotherapy, nearly doubling median OS. The study showed that median OS was 7.7 months (95 percent CI: 5.6, 9.6) for BLINCYTO versus four months (95 percent CI: 2.9, 5.3) for SOC (hazard ratio for death=0.71; p=0.012). The approval is also based on data from the Phase 2 ALCANTARA study, which evaluated the efficacy of BLINCYTO in adult patients with Ph+ relapsed or refractory B-cell precursor ALL.

"We are pleased that the FDA has granted full approval for BLINCYTO, marking a significant milestone for certain patients with relapsed or refractory ALL," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "This approval supports the use of BLINCYTO in a broader spectrum of patients, including those with few options to date, such as Philadelphia chromosome-positive patients, and reinforces the potential of the BiTE platform as a novel approach to immuno-oncology."

The FDA-approved prescribing information for BLINCYTO includes a boxed warning for cytokine release syndrome and neurologic toxicities. BLINCYTO is also under a risk evaluation and mitigation strategy (REMS) program in the U.S.

Safety results among patients who received BLINCYTO were comparable to those seen in the Phase 2 studies in adult patients with Ph- relapsed or refractory B-cell precursor ALL. For the most common adverse events (greater than or equal to 10 percent incidence rate) in the BLINCYTO arm, six events (pyrexia, infusion-related reaction, cough, cytokine release syndrome, tremor, decreased immunoglobulins) occurred at an incidence rate that was at least five percent higher for BLINCYTO compared to SOC chemotherapy.

On May 3, 2017, the FDA also approved the sBLA for the administration of BLINCYTO to be infused over seven days with preservative, adding to the previously approved administration options for infusion over 24 and 48 hours preservative-free, and allowing physicians to customize a treatment plan to fit the needs of their patients. The BLINCYTO intravenous bag for a seven-day infusion contains Bacteriostatic 0.9 percent Sodium Chloride, USP (containing 0.9 percent benzyl alcohol), which permits continuous intravenous infusion of BLINCYTO at 28 mcg/day or 15 mcg/m2/day for a total of seven days. The seven-day infusion is not recommended for patients weighing less than 22 kg due to the risk of serious and sometimes fatal adverse events associated with benzyl alcohol in pediatric patients. Please see the full prescribing information for BLINCYTO for more information.

ALL is a rare and rapidly progressing cancer of the blood and bone marrow.1,2 Currently, there is no broadly accepted standard treatment regimen for adult patients with relapsed or refractory ALL beyond chemotherapy.3 Adults with relapsed or refractory ALL typically have a very poor prognosis, with a median OS of three to five months.4 In adult ALL, approximately 75 percent is B-cell precursor ALL, of which 75-80 percent is Ph- and roughly half will be refractory to treatment or experience relapse.5

About the TOWER Study
The TOWER study was a Phase 3, randomized, active-controlled, open-label study investigating the efficacy of BLINCYTO versus SOC chemotherapy in 405 adult patients with Ph- relapsed or refractory B-cell precursor ALL. The study enrolled a difficult-to-treat patient population which included patients from several stages of relapse. In the BLINCYTO arm, this included 35 percent of patients that had relapsed post-allogenic hematopoietic stem cell transplant (alloHSCT), and excluded those with late first relapse (≥12 months after initial remission). Patients were randomized in a 2:1 ratio to receive BLINCYTO (n=271) or treatment with investigator choice of SOC chemotherapy (n=134). The determination of efficacy was based on OS. Per the recommendation of an independent data monitoring committee, Amgen ended the study early for evidence of superior efficacy in the BLINCYTO arm versus SOC chemotherapy. These results were published in The New England Journal of Medicine.

About the ALCANTARA Study
The ALCANTARA study was a Phase 2, single-arm, multicenter, open-label study investigating the efficacy of BLINCYTO in 45 adult patients with Ph+ B-cell precursor ALL, who had relapsed after or were refractory to at least one second-generation or later tyrosine kinase inhibitor (TKI), or were intolerant to second-generation or later TKIs and intolerant or refractory to imatinib. BLINCYTO was administered in 28-day cycles by continuous intravenous infusion. Efficacy was based on the complete remission rate, duration of complete remission and proportion of patients with an MRD-negative complete remission or complete remission with partial hematologic recovery within two cycles. Results of the study, one of the largest conducted in this patient population, were published in the Journal of Clinical Oncology.

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.

BLINCYTO was granted breakthrough therapy and priority review designations by the FDA, and is now approved in the U.S. for the treatment of relapsed or refractory B-cell precursor ALL in adults and children.

In November 2015, BLINCYTO was granted conditional marketing authorization in the EU for the treatment of adults with Ph- relapsed or refractory B-cell precursor ALL. Additional regulatory applications for BLINCYTO are underway and have been submitted to health authorities worldwide.

About BiTE Technology
Bispecific T cell engager (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. For more information, visit www.biteantibodies.com.

BLINCYTO U.S. Product Safety Information

Indication and Important Safety Information, including Boxed WARNINGS, for BLINCYTO (blinatumomab) for injection, for intravenous use

INDICATION

BLINCYTO is indicated for the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) in adults and children.

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 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 patients receiving BLINCYTO. Infusion reactions have occurred and may be clinically indistinguishable from manifestations of CRS. Closely monitor patients for signs and symptoms of serious events such as pyrexia, headache, nausea, asthenia, hypotension, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased total bilirubin (TBILI), disseminated intravascular coagulation (DIC), capillary leak syndrome (CLS), and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS). Interrupt or discontinue BLINCYTO as outlined in the Prescribing Information (PI).
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. Monitor patients for signs or symptoms and interrupt or discontinue BLINCYTO as outlined in the PI.
Infections: Approximately 25% of patients receiving BLINCYTO experienced serious 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): 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 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 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 (GGT), 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 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 in Philadelphia chromosome-negative relapsed or refractory B-cell precursor ALL (TOWER Study) (≥ 20%) in the BLINCYTO arm 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 adult population 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, including Boxed WARNINGS and Medication Guide, for BLINCYTO.

Cascadian Therapeutics Announces Positive Regulatory Update for Tucatinib in Europe

On July 11, 2017 Cascadian Therapeutics, Inc. (NASDAQ:CASC), a clinical-stage biopharmaceutical company, reported the outcome of discussions with the European Medicines Agency (EMA) regarding the development of tucatinib, an investigational medicine for the treatment of HER2-positive metastatic breast cancer (Press release, Cascadian Therapeutics, JUL 11, 2017, View Source [SID1234519781]). Following these discussions, the Company has received confirmation that positive results from its ongoing pivotal trial of tucatinib, known as HER2CLIMB, could serve as a single registrational trial for submission of a Marketing Authorization Application (MAA) to the EMA and potential marketing approval. The Company had received similar confirmation from the U.S. Food and Drug Administration (FDA) in 2016.

"Our interactions with regulators in the U.S. and Europe continue to support the design of our pivotal trial as a registrational pathway for tucatinib in both regions," said Marc Lesnick, Ph.D., Senior Vice President Regulatory Affairs and Quality at Cascadian Therapeutics. "We look forward to continued productive discussions in our future interactions with the EMA, the FDA and other health authorities."

Scott Myers, President and Chief Executive Officer, Cascadian Therapeutics, added, "This is an important milestone for the company. We had anticipated providing an update on our European regulatory strategy later this year; and we are pleased with this early feedback from the EMA that the current design of the global HER2CLIMB trial, if positive, could support approval and a potentially shorter path to the European market for tucatinib. Site and patient enrollment is currently ahead of schedule in North America, and we are now poised to begin enrolling patients in HER2CLIMB in other countries."

About Tucatinib

Tucatinib is an investigational, orally bioavailable, potent tyrosine kinase inhibitor that is highly selective for HER2 without significant inhibition of EGFR. Inhibition of EGFR has been associated with significant toxicities, including skin rash and diarrhea. Tucatinib has shown activity as a single agent and in combination with both chemotherapy and other HER2 directed agents such as trastuzumab.1,2 Studies of tucatinib in these combinations have shown activity both systemically and in brain metastases. HER2 is a growth factor receptor that is overexpressed in multiple cancers, including breast, ovarian and gastric cancers. HER2 mediates cell growth, differentiation and survival. Tumors that overexpress HER2 (HER2-positive) are more aggressive and historically have been associated with poor overall survival, compared with HER2-negative cancers.

About HER2CLIMB Pivotal Trial

HER2CLIMB is a randomized (2:1), double-blind, placebo-controlled pivotal clinical trial comparing tucatinib vs. placebo, each in combination with capecitabine and trastuzumab and without loperamide or budesonide prophylaxis, in patients with locally advanced or metastatic HER2-positive breast cancer who have had prior treatment with a taxane, trastuzumab, pertuzumab and ado-trastuzumab emtansine, also known as T-DM1. The primary endpoint is progression-free survival (PFS) based upon independent radiologic review. Key objectives related to assessing activity in brain metastases include a key secondary endpoint of PFS in a subset of patients with brain metastases. All patients will be followed for overall survival. HER2CLIMB is currently enrolling patients in the United States, Canada, Western Europe and Australia. Additional information is available at www.HER2CLIMB.com.

About HER2-Positive Metastatic Breast Cancer

Patients with HER2-positive breast cancer have tumors with high levels of a protein called human epidermal growth factor receptor 2 (HER2), which promotes the aggressive spread of cancer cells. The American Cancer Society estimates that 20-25 percent of the approximately 246,660 annual new cases of breast cancer diagnoses in the U.S. are HER2-positive. Historically, HER2 disease has been associated with shorter survival times as well as a higher risk of recurrence and CNS disease (brain metastases). Approximately 30 to 50 percent of HER2-positive breast cancer patients develop brain metastases over time.3,4 Over the past two decades, the approvals of four targeted treatments (trastuzumab, pertuzumab, lapatinib, and T-DM1) have led to improved time to progression and survival rates of patients with HER2-positive breast cancer. Despite these advances, there is still a significant need for new therapies that can impact metastatic disease, including brain metastases, and be tolerated for longer periods of time.

ArQule Announces First Patient Dosed in Phase 1 Trial of BTK Inhibitor, ARQ 531, for B-cell Malignancies

On July 11, 2017 ArQule, Inc. (Nasdaq: ARQL) reported that the first patient has been dosed in a phase 1a/b trial with its BTK inhibitor, ARQ 531, in patients with B-cell malignancies refractory to other approved therapies (Press release, ArQule, JUL 11, 2017, View Source [SID1234519780]). The trial can enroll up to 120 patients . ARQ 531 is an investigational, orally bioavailable, potent and reversible inhibitor of both wild type and C481S-mutant Bruton’s tyrosine kinase (BTK).

The phase 1 trial is designed to enroll patients with B-cell malignancies including B-cell lymphomas, chronic lymphocytic leukemia, and Waldenstrom’s macroglobulinemia. The phase 1a portion of the trial will be a dose escalation study open to all refractory patients, with the aim of establishing a recommended dose. Upon completion of the phase 1a trial, the company plans to begin the phase 1b portion of trial that will consist of a number of expansion cohorts including patients with the C481S mutation who are refractory to other approved therapies. The goal of the phase 1b portion would be to establish proof of concept and early signs of activity.

"There is a clear clinical need to address the refractory population in B-cell malignancies, particularly those with the BTK C481S mutation," said Dr. Brian Schwartz, M.D., Head of Research and Development and Chief Medical Officer at ArQule. "Our clinical strategy is to rapidly identify a recommended dose and then begin to enroll a number of expansion cohorts including one dedicated to patients with the C481S mutation."

B-cell malignancies, like chronic lymphocytic leukemia, Waldenstrom’s macroglobulinemia, diffuse large B-cell lymphoma and mantle cell lymphoma are driven by BTK. The only approved BTK inhibitor, ibrutinib, is irreversible and makes a covalent bond with the C481 residue of the targeted protein. Although ibrutinib has demonstrated excellent responses in patients with elevated B-cell receptor signaling, clinical resistance has been observed, and the BTK C481S mutation is emerging as a predominant mechanism of resistance. As a reversible inhibitor, ARQ 531 does not require interaction with the C481 residue, a binding site essential for irreversible ibrutinib binding to BTK, thus positioning ARQ 531 as a targeted therapy for patients harboring C481S-mutant BTK who have developed resistance to irreversible BTK inhibitors.

About BTK and ARQ 531

ARQ 531 is an investigational, orally bioavailable, potent and reversible Bruton’s tyrosine kinase (BTK) inhibitor. Biochemical and cellular studies have shown that ARQ 531 inhibits both the wild type and C481S-mutant forms of BTK. The C481S mutation is a known emerging resistance mechanism for first generation irreversible BTK inhibitors. In preclinical studies ARQ 531 has demonstrated high oral bioavailability as well as good ADME, pharmacokinetic and metabolic properties. A phase 1 trial commenced in the third quarter of 2017. BTK is a therapeutic target that has been clinically proven to inhibit B-cell receptor signaling in blood cancers.