On February 4, 2016 Amgen (NASDAQ:AMGN) reported that the results of a prespecified interim analysis showed that the primary endpoint of improved overall survival was met in the Phase 3 TOWER study (Press release, Amgen, FEB 4, 2016, View Source [SID:1234508978]). The randomized, open-label TOWER study evaluated the efficacy of BLINCYTO (blinatumomab) versus standard of care (SOC) in adult patients with Philadelphia chromosome-negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL). The independent data monitoring committee recommended, and Amgen has accepted, that the study end early for efficacy.

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The BLINCYTO adverse events observed in the TOWER study were consistent with the known safety profile of BLINCYTO. Secondary endpoints are currently being evaluated. These interim data will be submitted to a future medical conference and for publication.

"The FDA’s breakthrough therapy designation and accelerated approval of BLINCYTO underscore the dire prognosis for these patients. This is the first study to demonstrate an overall survival benefit for these patients with an immunotherapy, and this is a tremendously rare achievement in relapsed and refractory ALL," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "We will work with regulatory authorities towards a full approval for BLINCYTO in this population."

About TOWER Study

The TOWER study was a Phase 3, randomized, open-label study investigating the efficacy of the BiTE antibody BLINCYTO versus SOC chemotherapy in adult subjects with Philadelphia chromosome-negative relapsed or refractory B-cell precursor ALL. Patients were randomized in a 2:1 ratio to receive BLINCYTO or treatment with investigator choice of one of four protocol defined SOC chemotherapy regimens. The primary endpoint was OS. Click here to read about the trial on ClinicalTrials.gov.

About ALL

ALL is an aggressive cancer of the blood and bone marrow, the spongy tissue inside bones where blood cells are made. The disease progresses rapidly and affects immature blood cells. Patients with ALL have abnormal white blood cells (lymphocytes) that crowd out healthy white blood cells, red blood cells and platelets, leading to infection, anemia (fatigue), easy bleeding and other serious side effects.

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 now approved in the U.S. for the treatment of Philadelphia chromosome-negative relapsed or refractory B-cell precursor ALL. This indication is approved under accelerated approval. Continued approval for this indication may be contingent upon verification of clinical benefit in subsequent trials.

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

Important Safety Information Regarding BLINCYTO (blinatumomab) U.S. Indication

This safety information is specific to the current U.S. approved indication.

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): Life-threatening or fatal CRS 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 50% of patients receiving BLINCYTO in clinical trials experienced neurological toxicities. Severe, life-threatening, or fatal neurological toxicities occurred in approximately 15% of patients, including encephalopathy, convulsions, speech disorders, disturbances in consciousness, confusion and disorientation, and coordination and balance disorders. The median time to onset of any neurological toxicity was 7 days. 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): Life-threatening or fatal TLS 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. The majority of these events were observed in the setting of CRS. The median time to onset was 15 days. Grade 3 or greater elevations in liver enzymes occurred in 6% 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.

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 anti-leukemic 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).

Adverse Reactions

The most commonly reported adverse reactions (≥ 20%) in clinical trials were pyrexia (62%), headache (36%), peripheral edema (25%), febrile neutropenia (25%), nausea (25%), hypokalemia (23%), rash (21%), tremor (20%), diarrhea (20%) and constipation (20%).

Serious adverse reactions were reported in 65% of patients. The most common serious adverse reactions (≥ 2%) included febrile neutropenia, pyrexia, pneumonia, sepsis, neutropenia, device-related infection, tremor, encephalopathy, infection, overdose, confusion, Staphylococcal bacteremia, and headache.

U.S. 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 U.S. Prescribing Information and medication guide for BLINCYTO at www.BLINCYTO.com.

On February 4, 2016 Merck (NYSE: MRK), known as MSD outside the United States and Canada, reported that the U.S. Food and Drug Administration (FDA) has approved a supplemental new drug application (sNDA) for single-dose EMEND (fosaprepitant dimeglumine) for injection, Merck’s substance P/neurokinin-1 (NK1) receptor antagonist, in combination with other antiemetic medicines, for the prevention of delayed nausea and vomiting in adults receiving initial and repeat courses of moderately emetogenic chemotherapy (MEC) (Press release, Merck & Co, FEB 4, 2016, View Source [SID:1234508976]). EMEND has not been studied for the treatment of established nausea and vomiting.

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The FDA approval is supported by data from a Phase 3 study that showed single-dose EMEND for injection, combined with other anti-vomiting medicines, provided greater protection from delayed nausea and vomiting following administration of moderately emetogenic chemotherapy versus an active control regimen. With this approval, EMEND for injection is the first intravenous single-dose NK1 receptor antagonist approved in the U.S. for both highly emetogenic chemotherapy (HEC) as well as MEC.

EMEND for injection is contraindicated in patients who are hypersensitive to any component of the product and in patients taking pimozide.

"Despite significant advances in supportive care, nausea and vomiting has remained a challenge for many cancer patients undergoing moderately emetogenic chemotherapy – and has historically required multi-day antiemetic therapy," said Stuart Green, vice president, clinical research, Merck Research Laboratories. "Today’s approval of an expanded indication for EMEND for injection means that physicians now have a new single-dose intravenous option, combined with other anti-vomiting medicines, for the prevention of delayed nausea and vomiting in these patients."

Data Supporting the FDA Approval

The FDA approval of this new indication was based in part on findings from a randomized, parallel, double-blind, active comparator-controlled study that evaluated EMEND (fosaprepitant dimeglumine) for injection (150 mg) as a single intravenous infusion in combination with ondansetron and dexamethasone (referred to as the EMEND regimen) (n=502) compared with ondansetron and dexamethasone alone (control regimen) (n=498) in patients receiving MEC. The primary endpoint was complete response (defined as no vomiting and no use of rescue therapy) in the delayed phase (25 to 120 hours following initiation of chemotherapy) of chemotherapy-induced nausea and vomiting. A 78.9 percent complete response rate was observed with the EMEND regimen compared to 68.5 percent with the control regimen (p<0.001). The results of this trial were presented at the 2015 annual meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper), and have now been published in the journal Annals of Oncology.

The most common adverse reactions reported in the EMEND regimen versus control regimen were fatigue (15% vs 13%), diarrhea (13% vs 11%), neutropenia (8% vs 7%), asthenia (4% vs 3%), anemia (3% vs 2%), peripheral neuropathy (3% vs 2%), leukopenia (2% vs 1%), dyspepsia (2% vs 1%), urinary tract infection (2% vs 1%), and pain in extremity (2% vs 1%).

About EMEND (fosaprepitant dimeglumine) for Injection

EMEND for injection is an intravenous prodrug of the oral formulation of EMEND (aprepitant). When EMEND for injection is administered, fosaprepitant is rapidly converted in the body to aprepitant. EMEND (aprepitant) is a selective high-affinity antagonist of human substance P/neurokinin-1 (NK1) receptors. Aprepitant has little or no affinity for serotonin (5-HT3), dopamine, and corticosteroid receptors, the targets of existing therapies for chemotherapy-induced nausea and vomiting (CINV).

EMEND for injection, in combination with other antiemetic agents, is indicated in adults for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC) including high-dose cisplatin and for the prevention of delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC).

EMEND has not been studied for the treatment of established nausea and vomiting.

Selected Important Safety Information for EMEND (fosaprepitant dimeglumine) for Injection

EMEND is contraindicated in patients who are hypersensitive to any component of the product. Hypersensitivity reactions including anaphylactic reactions, flushing, erythema, and dyspnea have been reported. If symptoms occur, discontinue the infusion and administer appropriate medical therapy. Do not reinitiate the infusion in patients who experience these symptoms during first-time use.

EMEND is contraindicated in patients taking pimozide. Inhibition of CYP3A4 by aprepitant, the active drug, could result in elevated plasma concentrations of this drug, which is a CYP3A4 substrate, potentially causing serious or life-threatening reactions, such as QT prolongation.

Fosaprepitant, a prodrug of aprepitant, is a weak inhibitor of CYP3A4, and aprepitant is a substrate, inhibitor, and inducer of CYP3A4. Use of EMEND with other drugs that are CYP3A4 substrates, may result in increased plasma concentrations of the concomitant drug. Use of EMEND with strong or moderate CYP3A4 inhibitors (eg, ketoconazole, diltiazem) may increase plasma concentrations of aprepitant and result in an increased risk of adverse reactions related to EMEND. Use of EMEND with strong CYP3A4 inducers (eg, rifampin) may result in a reduction in aprepitant plasma concentrations and decreased efficacy of EMEND.

Reduce the dose of the co-administered corticosteroid on Days 1 and 2 for patients receiving HEC and on Day 1 for patients receiving MEC as follows: oral dexamethasone by approximately 50%; oral methylprednisolone by approximately 50%; and intravenous methylprednisolone by approximately 25%.

Monitor patients taking vinblastine, vincristine, or ifosfamide or other chemotherapeutic agents that are metabolized by CYP3A4 for chemotherapeutic-related adverse reactions. No dosage adjustments are needed when etoposide, vinorelbine, paclitaxel, or docetaxel are administered.

Coadministration of EMEND with warfarin (a CYP2C9 substrate) may result in a clinically significant decrease in international normalized ratio (INR) of prothrombin time. In patients on chronic warfarin therapy, monitor the INR in the 2-week period, particularly at 7 to 10 days, following initiation of EMEND with each chemotherapy cycle.

The efficacy of hormonal contraceptives (including birth control pills, skin patches, implants, and certain IUDs) may be reduced during coadministration with and for 28 days after the last dose of EMEND. Advise patients to use effective alternative or backup methods of contraception during treatment with EMEND (fosaprepitant dimeglumine) and for 1 month following administration of EMEND.

In the MEC study, the most common adverse reactions reported in at least 2% of patients treated with the EMEND regimen and at a greater incidence than the control regimen were: fatigue (15% EMEND regimen vs 13% control regimen), diarrhea (13% vs 11%), neutropenia (8% vs 7%), asthenia (4% vs 3%), anemia (3% vs 2%), peripheral neuropathy (3% vs 2%), leukopenia (2% vs 1%), dyspepsia (2% vs 1%), urinary tract infection (2% vs 1%), and pain in extremity (2% vs 1%). In the HEC study, the safety profile was generally similar to that seen in the MEC study with fosaprepitant and prior HEC studies with aprepitant.

In the MEC study, infusion-site reactions were reported in 2.2% of patients treated with the EMEND regimen compared to 0.6% of patients treated with the control regimen, including infusion-site pain (1.2% EMEND regimen vs 0.4% control regimen), injection-site irritation (0.2% vs 0.0%), vessel puncture-site pain (0.2% vs 0.0%), and infusion-site thrombophlebitis (0.6% vs 0.0%). In the HEC study, which compared fosaprepitant to aprepitant, infusion-site reactions occurred at a higher incidence in the fosaprepitant group (3.0%) than in the aprepitant group (0.5%). The following additional infusion-site reactions occurred in the HEC study and were not reported in the MEC study: infusion-site erythema (0.5% for fosaprepitant vs 0.1% for aprepitant), infusion-site pruritus (0.3% vs 0.0%), and infusion-site induration (0.2% vs 0.1%).

On February 4, 2016 Seattle Genetics, Inc., (Nasdaq: SGEN) reported that it will receive a one-time $20 million milestone payment under its ADCETRIS (brentuximab vedotin) collaboration with Takeda Pharmaceutical Company Limited (Takeda) (Press release, Seattle Genetics, FEB 4, 2016, View Source [SID:1234508973]).

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The milestone was triggered by Takeda surpassing annual ADCETRIS net sales of $200 million in its territory during 2015. The milestone will be recognized as royalty revenue in the first quarter of 2016. In addition, the company announced that the European Commission recently approved a Type II variation that includes data on the retreatment of adult patients with relapsed or refractory (R/R) Hodgkin lymphoma or R/R systemic anaplastic large cell lymphoma (sALCL) who previously responded to ADCETRIS and who later relapse. The label update follows a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) in October 2015.

"This sales milestone and recent label update in Europe to include data on retreatment underscore the strong commercial and regulatory progress that Takeda has made in its territory," said Clay B. Siegall, Ph.D., President and Chief Executive Officer at Seattle Genetics. "We and Takeda are focused on the goal of establishing ADCETRIS as the foundation of care for CD30-expressing lymphomas through global commercialization activities and a broad clinical development program that includes three phase 3 trials."

Seattle Genetics and Takeda are jointly developing ADCETRIS. Under the terms of the collaboration agreement, Seattle Genetics has U.S. and Canadian commercialization rights and Takeda has rights to commercialize ADCETRIS in the rest of the world. Seattle Genetics is entitled to royalties based on a percentage of Takeda’s net sales in its territory at rates that range from the mid-teens to the mid-twenties based on sales volume subject to offsets for royalties paid by Takeda to third parties. In addition, Seattle Genetics is entitled to receive progress- and sales-dependent milestone payments based on net sales of ADCETRIS within Takeda’s licensed territory. Seattle Genetics and Takeda are funding joint development costs for ADCETRIS on a 50:50 basis, except in Japan where Takeda is solely responsible for development costs.

About ADCETRIS (Brentuximab Vedotin)
ADCETRIS is an ADC comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Seattle Genetics’ proprietary technology. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells. CD30 is a member of the tumor necrosis factor receptor (TNFR) superfamily. In HL, CD30 may be involved in tumor cell proliferation by interacting with immune cells in the tumor microenvironment.

ADCETRIS for intravenous injection has received approval from the FDA for three indications: (1) regular approval for the treatment of patients with classical HL after failure of autologous hematopoietic stem cell transplantation (auto-HSCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates, (2) regular approval for the treatment of classical HL patients at high risk of relapse or progression as post-auto-HSCT consolidation, and (3) accelerated approval for the treatment of patients with systemic anaplastic large cell lymphoma (sALCL) after failure of at least one prior multi-agent chemotherapy regimen. The sALCL indication is approved under accelerated approval based on overall response rate. Continued approval for the sALCL indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Health Canada granted ADCETRIS approval with conditions for relapsed or refractory HL and sALCL.

ADCETRIS was granted conditional marketing authorization by the European Commission in October 2012 for two indications: (1) for the treatment of adult patients with relapsed or refractory CD30-positive HL following autologous stem cell transplant (ASCT), or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option, and (2) the treatment of adult patients with relapsed or refractory sALCL. In January 2016, the European Commission approved a Type II variation to include data on the retreatment of adult patients with Hodgkin lymphoma or sALCL who previously responded to ADCETRIS and who later relapse. ADCETRIS has received marketing authorization by regulatory authorities in 60 countries. See important safety information below.

ADCETRIS (brentuximab vedotin) U.S. Important Safety Information

BOXED WARNING
Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS (brentuximab vedotin).

Contraindication
ADCETRIS is contraindicated with concomitant bleomycin due to pulmonary toxicity (e.g., interstitial infiltration and/or inflammation).

Warnings and Precautions

Peripheral neuropathy: ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness and institute dose modifications accordingly.

Anaphylaxis and infusion reactions: Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If an infusion-related reaction occurs, interrupt the infusion and institute appropriate medical management. If anaphylaxis occurs, immediately and permanently discontinue the infusion and administer appropriate medical therapy.

Hematologic toxicities: Prolonged (≥1 week) severe neutropenia and Grade 3 or 4 thrombocytopenia or anemia can occur with ADCETRIS. Febrile neutropenia has been reported with ADCETRIS. Monitor complete blood counts prior to each dose of ADCETRIS and consider more frequent monitoring for patients with Grade 3 or 4 neutropenia. Monitor patients for fever. If Grade 3 or 4 neutropenia develops, consider dose delays, reductions, discontinuation, or G-CSF prophylaxis with subsequent doses.

Serious infections and opportunistic infections: Infections such as pneumonia, bacteremia, and sepsis or septic shock (including fatal outcomes) have been reported in patients treated with ADCETRIS. Closely monitor patients during treatment for the emergence of possible bacterial, fungal or viral infections.

Tumor lysis syndrome: Closely monitor patients with rapidly proliferating tumor and high tumor burden.

Increased toxicity in the presence of severe renal impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with severe renal impairment compared to patients with normal renal function. Avoid the use of ADCETRIS in patients with severe renal impairment.

Increased toxicity in the presence of moderate or severe hepatic impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with moderate or severe hepatic impairment compared to patients with normal hepatic function. Avoid the use of ADCETRIS in patients with moderate or severe hepatic impairment.

Hepatotoxicity: Serious cases of hepatotoxicity, including fatal outcomes, have occurred with ADCETRIS. Cases were consistent with hepatocellular injury, including elevations of transaminases and/or bilirubin, and occurred after the first dose of ADCETRIS or rechallenge. Preexisting liver disease, elevated baseline liver enzymes, and concomitant medications may also increase the risk. Monitor liver enzymes and bilirubin. Patients experiencing new, worsening, or recurrent hepatotoxicity may require a delay, change in dose, or discontinuation of ADCETRIS.

Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death has been reported in ADCETRIS-treated patients. First onset of symptoms occurred at various times from initiation of ADCETRIS therapy, with some cases occurring within 3 months of initial exposure. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities. Hold ADCETRIS if PML is suspected and discontinue ADCETRIS if PML is confirmed.

Pulmonary Toxicity: Events of noninfectious pulmonary toxicity including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome, some with fatal outcomes, have been reported. Monitor patients for signs and symptoms of pulmonary toxicity, including cough and dyspnea. In the event of new or worsening pulmonary symptoms, hold ADCETRIS dosing during evaluation and until symptomatic improvement.

Serious dermatologic reactions: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), including fatal outcomes, have been reported with ADCETRIS. If SJS or TEN occurs, discontinue ADCETRIS and administer appropriate medical therapy.

Embryo-fetal toxicity: Fetal harm can occur. Advise pregnant women of the potential hazard to the fetus.

Most Common Adverse Reactions:
ADCETRIS was studied as monotherapy in 160 patients with relapsed classical HL and sALCL in two uncontrolled single-arm trials. Across both trials, the most common adverse reactions (≥20%), regardless of causality, were neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, pyrexia, rash, thrombocytopenia, cough and vomiting.

ADCETRIS was studied in 329 patients with classical HL at high risk of relapse or progression post-auto-HSCT in a placebo-controlled randomized trial. The most common adverse reactions (≥20%) in the ADCETRIS-treatment arm (167 patients), regardless of causality, were neutropenia, peripheral sensory neuropathy, thrombocytopenia, anemia, upper respiratory tract infection, fatigue, peripheral motor neuropathy, nausea, cough, and diarrhea.

Drug Interactions:
Concomitant use of strong CYP3A4 inhibitors or inducers, or P-gp inhibitors, has the potential to affect the exposure to monomethyl auristatin E (MMAE).

Use in Specific Populations:
MMAE exposure and adverse reactions are increased in patients with moderate or severe hepatic impairment or severe renal impairment. Avoid use.

For additional Important Safety Information, including Boxed WARNING, please see the full Prescribing Information for ADCETRIS at View Source

On February 4, 2016 ImmunoGen, Inc. (Nasdaq: IMGN), a biotechnology company that develops novel anticancer therapeutics using its ADC technology, and Merck, known as MSD outside the United States and Canada, reported that they have entered into a clinical research collaboration for the assessment of ImmunoGen’s mirvetuximab soravtansine in combination with Merck’s anti-PD-1 therapy, Keytruda (pembrolizumab), for the treatment of patients with FRα-positive ovarian cancer (Press release, ImmunoGen, FEB 4, 2016, View Source [SID:1234508972]).

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Mirvetuximab soravtansine is an experimental ADC for FRα-positive cancers that has shown notable activity for FRα-positive ovarian cancer in early clinical testing. Mirvetuximab soravtansine contains a monoclonal antibody that enables it to bind to FRα-positive tumor cells with ImmunoGen’s DM4, a maytansinoid cancer-killing agent, attached to kill these cells. In preclinical research conducted by ImmunoGen and academics, ADCs with maytansinoids have been found to enhance the maturation and activation of the dendritic cells of the immune system that stimulate antitumor responses.1,2 Keytruda is a humanized monoclonal antibody that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. Keytruda blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T-lymphocytes, which may affect both tumor cells and healthy cells.

"We look forward to evaluating our mirvetuximab soravtansine ADC in combination with Merck’s anti-PD-1 therapy, Keytruda," said Daniel Junius, ImmunoGen President and Chief Executive Officer. "In early clinical testing, mirvetuximab soravtansine has demonstrated notable activity as a single agent for FRα-positive ovarian cancer, and we are aggressively advancing it for this use. At the same time, we believe mirvetuximab soravtansine should be evaluated in different combination regimens to potentially provide the greatest benefit to the most patients. Keytruda has a different mechanism of action than the other agents being assessed."

"Fully realizing the potential for Keytruda to help patients with cancer requires strategic collaborations, such as this agreement with ImmunoGen, that explore how complementary approaches might result in improved outcomes for patients," said Dr. Eric Rubin, vice president and therapeutic area head, oncology early-stage development, Merck Research Laboratories. "We look forward to evaluating the data from this combined approach in patients with FRα-positive ovarian cancer."

ImmunoGen is conducting a Phase 1b/2 clinical trial, FORWARD II, that evaluates mirvetuximab soravtansine for FRα-positive ovarian cancer used in doublet combination with other anticancer agents. The assessment of mirvetuximab soravtansine with Keytruda will be added to this trial, with Merck supplying the Keytruda. ImmunoGen expects this cohort to open for patient enrollment in the second half of 2016.

The agreement is between ImmunoGen and Merck, through a subsidiary. The agreement includes a provision for potential expansion of the collaboration to include a subsequent Phase 3 clinical trial. Additional details were not disclosed.

About Mirvetuximab Soravtansine

ImmunoGen developed mirvetuximab soravtansine as a potential treatment for ovarian cancer and other FRα-positive solid tumors. In early clinical testing, mirvetuximab soravtansine demonstrated notable activity when used as a single agent to treat platinum-resistant FRα-positive ovarian cancer.3 ImmunoGen is assessing the ADC used as a single agent for pretreated FRα-positive ovarian cancer in its Phase 2 trial, FORWARD I, which is intended to support an Accelerated Approval pathway. Mirvetuximab soravtansine is also now being assessed in separate combinations with pegylated liposomal doxorubicin (Doxil), bevacizumab (Avastin), and carboplatin in the Phase 1b/2 trial, FORWARD II.

About Ovarian Cancer

Each year there are approximately 240,000 new cases of ovarian cancer diagnosed and 140,000 deaths from the disease on a global basis.4 Among all gynecologic cancers, ovarian cancer accounts for the most deaths on an annual basis.

On February 4, 2016 Ignyta, Inc. (Nasdaq: RXDX), a precision oncology biotechnology company, reported that Cancer Research UK has initiated a new, investigator-sponsored Phase 1/1b clinical trial of a combination of paclitaxel with taladegib – the company’s novel, orally available, hedgehog/smoothened inhibitor – in patients with platinum-resistant, recurrent ovarian cancer or recurrent, advanced solid tumors (Press release, Ignyta, FEB 4, 2016, View Source [SID:1234508971]).

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This clinical trial is an open label dose-escalation and expansion study designed to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D), tolerability, pharmacokinetics and preliminary clinical activity of the combination of taladegib and weekly paclitaxel in this patient population. The lead investigator will be Dr. Rosalind Glasspool of the Beatson West of Scotland Cancer Centre, Glasgow, Scotland.

"We are excited that Cancer Research UK has expanded the clinical investigation of taladegib through the initiation of this combination study"

"We are excited that Cancer Research UK has expanded the clinical investigation of taladegib through the initiation of this combination study," said Jonathan Lim, M.D., Chairman and CEO of Ignyta. "We look forward to supporting Cancer Research UK in this trial, and to evaluating the data, including potentially identifying the impact of this therapeutic intervention on the hedgehog pathway at both the mRNA and protein levels and correlating these changes with the patients’ disease and potential clinical response."

About Taladegib

Taladegib, which Ignyta exclusively licensed from Eli Lilly and Company in November 2015, is a potent, orally bioavailable small molecule hedgehog/smoothened antagonist that has achieved clinical proof-of-concept and a recommended Phase 2 dose based on results from prior clinical studies. Ignyta believes taladegib represents a potential first-in-class hedgehog/smoothened inhibitor for second-line treatment of locally advanced or metastatic basal cell carcinoma, as well as a potential best-in-class hedgehog/smoothened inhibitor for first-line treatment of these patients. In addition, Ignyta believes taladegib alone or in combination has the potential to treat selected patients with solid tumors outside of basal cell carcinoma that are driven by hedgehog pathway alterations. Ignyta also granted back to Lilly exclusive rights for Lilly to develop and commercialize taladegib-containing products in combination with certain Lilly compounds.