On June 26, 2017 Takeda Pharmaceutical Company Limited (TSE:4502) and Seattle Genetics, Inc. (NASDAQ: SGEN) reported that the Phase 3 ECHELON-1 clinical trial met its primary endpoint of a statistically significant improvement in modified progression-free survival (PFS) versus the control arm (Press release, Seattle Genetics, JUN 26, 2017, View Source [SID1234519686]). ECHELON-1 is a randomized, multicenter trial evaluating ADCETRIS (brentuximab vedotin) as part of a frontline combination chemotherapy regimen in 1,334 patients with previously untreated advanced classical Hodgkin lymphoma. ADCETRIS is an antibody-drug conjugate (ADC) directed to CD30, a defining marker of classical Hodgkin lymphoma. ADCETRIS is currently not approved as a frontline therapy for Hodgkin lymphoma.

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Patients in ECHELON-1 were randomized to receive either a combination of ADCETRIS+AVD (Adriamycin, vinblastine, dacarbazine) or ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine), a recognized standard of care for frontline Hodgkin lymphoma. The results of the ECHELON-1 trial demonstrated that combination treatment with ADCETRIS resulted in a statistically significant improvement in modified PFS versus the control arm as assessed by an Independent Review Facility (hazard ratio=0.770; p-value=0.035). The two-year modified PFS rate for patients in the ADCETRIS arm was 82.1 percent compared to 77.2 percent in the control arm. Interim analysis of overall survival (OS), the key secondary endpoint, also trended in favor of the ADCETRIS+AVD arm. An abstract will be submitted for data presentation at the American Society of Hematology (ASH) (Free ASH Whitepaper) annual meeting, December 9-12, 2017, in Atlanta, Ga.

The safety profile of ADCETRIS+AVD in the ECHELON-1 trial was consistent with that known for the single-agent components of the regimen. There was an increased incidence of febrile neutropenia and peripheral neuropathy in the ADCETRIS+AVD arm. Febrile neutropenia was reduced through the use of prophylactic growth factors in a subset of patients, and peripheral neuropathy was managed through dose modifications. The control arm had an increased rate and severity of pulmonary toxicity.

"We are excited about the positive result which shows a statistically significant improvement in the primary endpoint of modified PFS," said Dirk Huebner, M.D., Executive Medical Director, Oncology Therapeutic Area Unit, Takeda Pharmaceutical Company. "The results of this trial signify an important step forward in the development of ADCETRIS and have the potential to change the treatment approach of frontline advanced Hodgkin lymphoma."

"The outcome of the Phase 3 ECHELON-1 trial represents a significant milestone for the Hodgkin lymphoma community," said Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics. "Seattle Genetics’ goal is to establish ADCETRIS as the foundation of care for CD30-expressing lymphomas, including Hodgkin lymphoma. Notably, this is the first clinical trial in frontline advanced Hodgkin lymphoma to show superior efficacy of a regimen that eliminates bleomycin."

Takeda and Seattle Genetics plan to submit these results to regulatory authorities for approval in their respective territories.

ECHELON-1 Phase 3 Clinical Trial Design

The randomized, open-label, Phase 3 trial is investigating ADCETRIS+AVD versus ABVD as frontline therapy in patients with advanced classical Hodgkin lymphoma. The primary endpoint is modified progression-free survival per Independent Review Facility assessment using the Revised Response Criteria for Malignant Lymphoma. Modified PFS is defined as the time to progression, death or receipt of additional anticancer therapy for patients who are not in complete response after completion of frontline therapy per Independent Review Facility. This endpoint was chosen as it provides a clearer picture of the efficacy of frontline chemotherapy and eliminates the confounding impact of salvage and consolidation chemotherapies and radiotherapy. Secondary endpoints include overall survival, complete remission and safety. The multi-center trial was conducted in North America, Europe, South America, Australia, Asia and Africa. The study enrolled 1,334 patients who had a histologically-confirmed diagnosis of Stage III or IV classical Hodgkin lymphoma and had not been previously treated with systemic chemotherapy or radiotherapy. The ECHELON-1 trial is being conducted under a Special Protocol Assessment (SPA) agreement from the U.S. Food and Drug Administration (FDA) and the trial also received European Medicines Agency (EMA) scientific advice.

Please see Important Safety Information at the end of this press release.

Seattle Genetics Conference Call Details

Seattle Genetics’ management will host a conference call and webcast to discuss this announcement. The event will be held today at 5:30 a.m. Pacific Time (PT) / 8:30 a.m. Eastern Time (ET). The live event will be available from Seattle Genetics’ website at View Source, under the Investors section, or by calling 877-723-9521 (domestic) or 719-325-2138 (international). The access code is 9916080. A replay of the discussion will be available beginning at approximately 8:30 a.m. PT / 11:30 a.m. ET today from Seattle Genetics’ website or by calling 888-203-1112 (domestic) or 719-457-0820 (international), using access code 9916080. The telephone replay will be available until 5:00 p.m. PT / 8:00 p.m. ET Wednesday, June 28, 2017.

About Classical Hodgkin Lymphoma

Lymphoma is a general term for a group of cancers that originate in the lymphatic system. There are two major categories of lymphoma: Hodgkin lymphoma and non-Hodgkin lymphoma. Classical Hodgkin lymphoma is distinguished from other types of lymphoma by the presence of one characteristic type of cell, known as the Reed-Sternberg cell. The Reed-Sternberg cell expresses CD30.

About ADCETRIS

ADCETRIS is being evaluated broadly in more than 70 clinical trials in CD30-expressing lymphomas, including three Phase 3 studies: the completed ECHELON-1 trial in frontline classical Hodgkin lymphoma, the completed ALCANZA trial in cutaneous T-cell lymphoma, and the ongoing ECHELON-2 trial in frontline mature T-cell lymphomas.

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.

ADCETRIS for intravenous injection has received approval from the FDA for three indications: (1) regular approval for the treatment of patients with classical Hodgkin lymphoma 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 Hodgkin lymphoma 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 Hodgkin lymphoma 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 Hodgkin lymphoma 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 June 2016, the European Commission extended the current conditional approval of ADCETRIS and approved ADCETRIS for the treatment of adult patients with CD30-positive Hodgkin lymphoma at increased risk of relapse or progression following ASCT.

ADCETRIS has received marketing authorization by regulatory authorities in 67 countries for relapsed or refractory Hodgkin lymphoma and sALCL. See important safety information below.

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 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.

ADCETRIS (brentuximab vedotin) Global Important Safety Information

CONTRAINDICATIONS

ADCETRIS is contraindicated for patients with hypersensitivity to brentuximab vedotin and its excipients. In addition, combined use of ADCETRIS with bleomycin is contraindicated as it causes pulmonary toxicity.

SPECIAL WARNINGS & PRECAUTIONS

Progressive multifocal leukoencephalopathy (PML): John Cunningham virus (JCV) reactivation resulting in PML and death can occur in patients treated with ADCETRIS. PML has been reported in patients who received ADCETRIS after receiving multiple prior chemotherapy regimens.

Patients should be closely monitored for new or worsening neurological, cognitive, or behavioral signs or symptoms, which may be suggestive of PML. Suggested evaluation of PML includes neurology consultation, gadolinium-enhanced magnetic resonance imaging of the brain, and cerebrospinal fluid analysis for JCV DNA by polymerase chain reaction or a brain biopsy with evidence of JCV. ADCETRIS dosing should be held for any suspected case of PML and should be permanently discontinued if a diagnosis of PML is confirmed.

Pancreatitis: Acute pancreatitis has been observed in patients treated with ADCETRIS. Fatal outcomes have been reported. Patients should be closely monitored for new or worsening abdominal pain, which may be suggestive of acute pancreatitis. Patient evaluation may include physical examination, laboratory evaluation for serum amylase and serum lipase, and abdominal imaging, such as ultrasound and other appropriate diagnostic measures. ADCETRIS should be held for any suspected case of acute pancreatitis. ADCETRIS should be discontinued if a diagnosis of acute pancreatitis is confirmed.

Pulmonary Toxicity: Cases of pulmonary toxicity, some with fatal outcomes, have been reported in patients receiving ADCETRIS. Although a causal association with ADCETRIS has not been established, the risk of pulmonary toxicity cannot be ruled out. New or worsening pulmonary symptoms should be promptly evaluated and treated appropriately.

Serious infections and opportunistic infections: Serious infections such as pneumonia, staphylococcal bacteremia, sepsis/septic shock (including fatal outcomes), and herpes zoster, and opportunistic infections such as Pneumocystis jiroveci pneumonia and oral candidiasis have been reported in patients treated with ADCETRIS. Patients should be carefully monitored during treatment for emergence of possible serious and opportunistic infections.

Infusion-related reactions (IRR): Immediate and delayed IRR, as well as anaphylaxis, have occurred with ADCETRIS. Patients should be carefully monitored during and after an infusion. If anaphylaxis occurs, administration of ADCETRIS should be immediately and permanently discontinued and appropriate medical therapy should be administered. If an IRR occurs, the infusion should be interrupted and appropriate medical management instituted. The infusion may be restarted at a slower rate after symptom resolution. Patients who have experienced a prior IRR should be premedicated for subsequent infusions. IRRs are more frequent and more severe in patients with antibodies to ADCETRIS.

Tumor lysis syndrome (TLS): TLS has been reported with ADCETRIS. Patients with rapidly proliferating tumor and high tumor burden are at risk of TLS. These patients should be monitored closely and managed according to best medical practice.

Peripheral neuropathy (PN): ADCETRIS treatment may cause PN, both sensory and motor. ADCETRIS-induced PN is typically cumulative and reversible in most cases. Patients should be monitored for symptoms of PN, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness. Patients experiencing new or worsening PN may require a delay and a dose reduction or discontinuation of ADCETRIS.

Hematological toxicities: Grade 3 or Grade 4 anemia, thrombocytopenia, and prolonged (equal to or greater than one week) Grade 3 or Grade 4 neutropenia can occur with ADCETRIS. Complete blood counts should be monitored prior to administration of each dose.

Febrile neutropenia: Febrile neutropenia has been reported. Patients should be monitored closely for fever and managed according to best medical practice if febrile neutropenia develops.

Stevens-Johnson syndrome (SJS): SJS and toxic epidermal necrolysis (TEN) have been reported with ADCETRIS. Fatal outcomes have been reported. If SJS or TEN occurs, treatment with ADCETRIS should be discontinued and appropriate medical therapy should be administered.

Gastrointestinal (GI) Complications: GI complications, some with fatal outcomes, including intestinal obstruction, ileus, enterocolitis, neutropenic colitis, erosion, ulcer, perforation and haemorragh, have been reported. New or worsening GI symptoms should be promptly evaluated and treated appropriately.

Hepatotoxicity: Elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) have been reported. Serious cases of hepatotoxicity, including fatal outcomes, have also occurred. Liver function should be tested prior to treatment initiation and routinely monitored in patients receiving ADCETRIS. Patients experiencing hepatotoxicity may require a delay, dose modification, or discontinuation of ADCETRIS.

Hyperglycemia: Hyperglycemia has been reported during trials in patients with an elevated body mass index (BMI) with or without a history of diabetes mellitus. However, any patient who experiences an event of hyperglycemia should have their serum glucose closely monitored. Anti-diabetic treatment should be administered as appropriate.

Renal and Hepatic Impairment: There is limited experience in patients with renal and hepatic impairment. Available data indicate that MMAE clearance might be affected by severe renal impairment, hepatic impairment, and by low serum albumin concentrations. The recommended starting dose in patients with hepatic impairment or severe renal impairment is 1.2 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks. Patients with renal or hepatic impairment should be closely monitored for adverse events.

Sodium content in excipients: This medicinal product contains a maximum of 2.1 mmol (or 47 mg) of sodium per dose. To be taken into consideration for patients on a controlled sodium diet.

INTERACTIONS

Patients who are receiving a strong CYP3A4 and P-gp inhibitor, concomitantly with ADCETRIS may have an increased risk of neutropenia and should be closely monitored. Co-administration of ADCETRIS with a CYP3A4 inducer did not alter the plasma exposure of ADCETRIS but it appeared to reduce plasma concentrations of MMAE metabolites that could be assayed. ADCETRIS is not expected to alter the exposure to drugs that are metabolized by CYP3A4 enzymes.

PREGNANCY: Women of childbearing potential should be using two methods of effective contraception during treatment with ADCETRIS and until 6 months after treatment. There are no data from the use of ADCETRIS in pregnant women, although studies in animals have shown reproductive toxicity. ADCETRIS should not be used during pregnancy unless the benefit to the mother outweighs the potential risks to the fetus. If a pregnant woman needs to be treated, she should be clearly advised on the potential risk to the fetus.

LACTATION (breast-feeding): There are no data as to whether ADCETRIS or its metabolites are excreted in human milk, therefore a risk to the newborn/infant cannot be excluded. With the potential risk, a decision should be made whether to discontinue breast-feeding or discontinue/abstain from therapy with ADCETRIS.

FERTILITY: In nonclinical studies, ADCETRIS treatment has resulted in testicular toxicity, and may alter male fertility. Men being treated with this medicine are advised not to father a child during treatment and for up to 6 months following the last dose.

ADVERSE REACTIONS

Serious adverse drug reactions were: pneumonia, acute respiratory distress syndrome, headache, neutropenia, thrombocytopenia, constipation, diarrhea, vomiting, nausea, pyrexia, peripheral motor neuropathy, peripheral sensory neuropathy, hyperglycemia, demyelinating polyneuropathy, tumor lysis syndrome, and Stevens-Johnson syndrome.

In the clinical studies of ADCETRIS, adverse reactions defined as very common (≥1/10) were: infection, upper respiratory tract infection, neutropenia, PN (sensory and motor), cough, dyspneoa, diarrhea, nausea, vomiting, constipation, abdominal pain, alopecia, pruritus, myalgia, arthralgia, fatigue, chills, pyrexia, infusion-related reactions and weight decreased. Adverse reactions defined as common (≥1/100 to <1/10) were: Sepsis/septic shock, herpes zoster, pneumonia, herpes simplex, anemia, thrombocytopenia, hyperglycemia, dizziness, demyelinating polyneuropathy, ALT/AST increased, rash, and back pain.

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.

Contraindication

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

Warnings and Precautions

Peripheral neuropathy (PN): ADCETRIS treatment causes a PN that is predominantly sensory. Cases of motor PN have also been reported. ADCETRIS-induced PN 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. Patients who experienced a prior infusion-related reaction should be premedicated for subsequent infusions. Premedication may include acetaminophen, an antihistamine, and a corticosteroid.
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.
Gastrointestinal (GI) complications: Fatal and serious GI complications, including perforation, hemorrhage, erosion, ulcer, intestinal obstruction, enterocolitis, neutropenic colitis, and ileus have been reported in ADCETRIS-treated patients. Lymphoma with preexisting GI involvement may increase the risk of perforation. In the event of new or worsening GI symptoms, perform a prompt diagnostic evaluation and treat appropriately.
Embryo-fetal toxicity: Based on the mechanism of action and findings in animals, ADCETRIS can cause fetal harm when administered to a pregnant woman. Females of reproductive potential should avoid pregnancy during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS.
Adverse Reactions

In two uncontrolled single-arm trials of ADCETRIS as monotherapy in 160 patients with relapsed classical HL and sALCL, 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.

In a placebo-controlled trial of ADCETRIS in 329 patients with classical HL at high risk of relapse or progression post-auto-HSCT, 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.

Advise females of reproductive potential to avoid pregnancy during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS.

Advise males with female sexual partners of reproductive potential to use effective contraception during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS.

Advise patients to report pregnancy immediately and avoid breastfeeding while receiving ADCETRIS.

For additional Important Safety Information, including Boxed WARNING, please see the full Prescribing Information for ADCETRIS at www.seattlegenetics.com or www.ADCETRIS.com.

On June 26, 2017 ImmunoGen, Inc. (Nasdaq:IMGN), a leader in the expanding field of antibody-drug conjugates (ADCs) for the treatment of cancer, reported data from the ongoing Phase 1 study evaluating single agent IMGN779 in patients with relapsed or refractory adult acute myeloid leukemia (AML) whose tumors express CD33 (Press release, ImmunoGen, JUN 26, 2017, View Source [SID1234519685]). The first-in-human data demonstrate the safety and tolerability of IMGN779 across seven dose levels, with no dose limiting toxicities (DLTs), as well as evidence of dose-dependent biological and anti-leukemia activity. These results were presented in a poster presentation on Saturday, June 24, 2017, at the 22nd Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) in Madrid, Spain.

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IMGN779 combines a high-affinity, humanized anti-CD33 antibody with one of ImmunoGen’s novel indolino-benzodiazepine payloads, called IGNs, which alkylate DNA without crosslinking, resulting in potent anti-leukemia activity with relative sparing of normal hematopoietic progenitor cells.

Safety, pharmacokinetic (PK), and pharmacodynamic (PD) data, as well as initial anti-leukemia activity for IMGN779 through dose level seven were presented at EHA (Free EHA Whitepaper). Key findings included:

No DLTs have been observed through dose level seven, with reported adverse events consistent with the underlying disease.
No increase in the nature, frequency, or severity of any treatment-emergent adverse event has been reported with escalating doses and no evidence of cumulative toxicity has been observed with repeated dosing.
Favorable PK/PD reveal prolonged exposure and CD33 saturation at dose levels six and seven.
Initial anti-leukemia activity was observed at dose levels six and seven in patients who failed intensive frontline therapy.
The Phase 1 trial is designed to establish the maximum tolerated dose and determine the recommended Phase 2 dose for IMGN779 administered as monotherapy. The trial is also intended to evaluate safety and tolerability and characterize PK, PD, and preliminary anti-leukemia activity in relapsed or refractory AML. Dose escalation continues.

"We have designed our DNA-alkylating IGNs to be ultra-potent while providing the tolerability necessary for ongoing retreatment," said Richard Gregory, Ph.D., executive vice president and chief scientific officer of ImmunoGen. "We believe that by combining IGNs with our ADC technology, we may be able to treat a number of additional cancers that don’t respond to existing ADC therapies. These data suggest favorable tolerability and encouraging activity in patients with AML, and we look forward to determining the recommended dose for IMGN779 and moving quickly into later-stage development."

Preclinical data for IMGN779 were also presented at EHA (Free EHA Whitepaper) showing the agent is highly active in multiple AML xenograft models and is well-tolerated in preclinical repeat dosing regimens. Findings from the preclinical evaluation provided the foundation for the clinical evaluation of IMGN779 in AML.

Poster Details

Title: Initial results from a first-in-human study of IMGN779, a CD33-targeting antibody-drug conjugate (ADC) with novel DNA alkylating activity, in patients with relapsed or refractory AML
Abstract: P526

Title: Designing the next generation CD33-targeting ADC: IMGN779, selected for potency, novel mechanism and preclinical tolerability, with high activity in disseminated AML models and multi-dose regimens
Abstract: P562

Additional information – including the full abstracts – can be found at www.ehaweb.org.

About ImmunoGen, Inc.

ImmunoGen is a clinical-stage biotechnology company that develops targeted cancer therapeutics using its proprietary ADC technology. ImmunoGen’s lead product candidate, mirvetuximab soravtansine, is in a Phase 3 trial for FRα-positive platinum-resistant ovarian cancer, and is in Phase 1b/2 testing in combination regimens for earlier-stage disease. ImmunoGen’s ADC technology is used in Roche’s marketed product, Kadcyla, in three other clinical-stage ImmunoGen product candidates, and in programs in development by partners Amgen, Bayer, Biotest, CytomX, Debiopharm, Lilly, Novartis, Sanofi and Takeda. More information about the Company can be found at www.immunogen.com.

About Acute Myeloid Leukemia (AML)

AML is a cancer of the bone marrow cells that produce white blood cells. It causes the marrow to increasingly generate abnormal, immature white blood cells (blasts) that do not mature into effective infection-fighting cells. The blasts quickly fill the bone marrow, impacting the production of normal platelets and red blood cells. The resulting deficiencies in normal blood cells leave the patient vulnerable to infections, bleeding problems and anemia.

It is estimated that, in the U.S. alone, 20,000 patients will be diagnosed with AML this year and 10,000 patients will die from the disease.1 CD33 is expressed in virtually all cases of AML.

About IMGN779

IMGN779 is the first antibody drug conjugate (ADC) to utilize one of ImmunoGen’s new family of indolino-benzodiazepine cancer-killing agents known as IGNs. IMGN779 is comprised of a CD33-targeting antibody with a potent DNA-alkylating agent, the IGN DGN462, attached. The antibody serves to target the ADC to the CD33-positive AML cells which DGN462 can then kill. IMGN779 is wholly owned by ImmunoGen.

About IGNs

Indolino-benzodiazepine cancer-killing agents, or IGNs, are a new class of cancer-killing agent developed by ImmunoGen for use in ADCs. These ultra-potent, DNA-alkylating IGNs are expected to extend the types of cancers able to be effectively treated with ADC therapies beyond those addressable with ImmunoGen’s well-established tubulin-acting agents. Such cancers can include ones insensitive to tubulin-acting agents and/or with reduced antigen expression.

1American Cancer Society (2016), Leukemia – Acute Myeloid (Myelogenous) Detailed Guide.

This press release includes forward-looking statements. For these statements, ImmunoGen claims the protection of the safe harbor for forward-looking statements provided by the Private Securities Litigation Reform Act of 1995. It should be noted that there are risks and uncertainties related to the development of novel anticancer products, including IMGN779, including risks related to preclinical and clinical studies, their timings and results. A review of these risks can be found in ImmunoGen’s Annual Report on Form 10-K for the six-month transition period ended December 31, 2016 and other reports filed with the Securities and Exchange Commission.

On June 26, 2017 Epizyme, Inc. (NASDAQ:EPZM), a clinical-stage biopharmaceutical company creating novel epigenetic therapies, reported that it has expanded its clinical collaboration with Genentech, a member of the Roche Group (Press release, Epizyme, JUN 26, 2017, View Source [SID1234519684]). Under the new agreement, tazemetostat administered in combination with atezolizumab (TECENTRIQ) will be evaluated in a Phase 1b/2 clinical study for the treatment of patients with relapsed/refractory metastatic non-small cell lung cancer (NSCLC). The study will be part of MORPHEUS, Genentech’s open-label, multi-center, randomized umbrella study evaluating the efficacy and safety of multiple immunotherapy-based treatment combinations for metastatic NSCLC.

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"The MORPHEUS clinical platform is aimed at rapidly evaluating new cancer immunotherapy combination treatment regimens in patients with metastatic NSCLC," said Scott Clarke, global head, Roche oncology partnering. "The goal of this collaboration is to assess the role this combination therapy may play in immune-cell priming, activation and T-cell infiltration, potentially enhancing an anti-cancer response."

"A key part of Epizyme’s long-term vision is expanding the benefit that tazemetostat can bring to a broad range of patients, which includes evaluating tazemetostat in combination with a variety of anti-cancer agents, such as checkpoint inhibitors," said Robert Bazemore, president and chief executive officer of Epizyme. "NSCLC is a devastating form of lung cancer affecting nearly 200,000 people in the U.S. and major European countries. This study marks our second immuno-oncology combination with Genentech, and we look forward to working together to understand the benefit combination treatment with tazemetostat and atezolizumab may have for patients with this difficult cancer."

Genentech will sponsor the planned Phase 1b/2 clinical trial, which is expected to be initiated by the end of 2017. It is anticipated that the study will enroll up to 40 patients who have experienced disease progression during or following treatment with a platinum-containing chemotherapy regimen and a PD‑L1/PD-1 checkpoint inhibitor. Financial terms are not disclosed and Epizyme will retain global development and commercialization rights to tazemetostat.

Epizyme’s original collaboration with Genentech was announced in June 2016 to evaluate tazemetostat and atezolizumab as a combination regimen in a Phase 1b clinical trial for the treatment of patients with relapsed or refractory diffuse large B-cell lymphoma. That combination study is ongoing and continuing to enroll patients.

About the Tazemetostat Clinical Trial Program
Tazemetostat, a first-in-class EZH2 inhibitor, is currently being studied in ongoing Phase 2 programs in both follicular lymphoma and diffuse large B-cell lymphoma (DLBCL) forms of non-Hodgkin lymphoma; certain molecularly defined solid tumors, including epithelioid sarcoma and other INI1-negative tumors; and mesothelioma, as well as in combination studies in DLBCL. Tazemetostat has been granted Fast Track designation by the U.S. Food and Drug Administration for follicular lymphoma regardless of EZH2 mutation and for DLBCL with EZH2-activating mutations, as well as Orphan Drug designation for soft tissue sarcoma and malignant rhabdoid tumors.

On June 26, 2017 Sumitomo Dainippon Pharma Co., Ltd. (Head Office: Osaka, Japan; President: Masayo Tada) reported that the Company decided to unblind the BRIGHTER study, a phase 3 global study in patients with gastric and gastro-esophageal junction (GEJ) cancer of napabucasin (generic name, product code: BBI608), an investigational cancer stemness inhibitor, based on a recommendation by the study’s independent Data and Safety Monitoring Board (DSMB), following a pre-specified interim analysis (Press release, Dainippon Sumitomo Pharma, JUN 26, 2017, View Source [SID1234519683]).

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The study will be continued as an open label study to follow all endpoints as defined in the protocol.

The DSMB determined that the study was unlikely to reach its primary endpoint of superior overall survival for the napabucasin arm versus the control arm at the conclusion of the study. No safety concerns were identified by the DSMB.

Sumitomo Dainippon Pharma remains committed to other ongoing phase 3 studies (CanStem303C for colorectal cancer, CanStem111P for pancreatic cancer) with an aim to obtain marketing authorization of napabucasin as early as possible.

"Advanced gastric/GEJ cancer is a tumor type with high unmet need, and our hope was to develop a new therapeutic option for these patients. We are disappointed with the results of this interim analysis," said Patricia S. Andrews, Chief Executive Officer, Boston Biomedical, Inc. "We remain committed to our ongoing studies with napabucasin as well as our other first-in-class investigational compounds."

Sumitomo Dainippon Pharma is currently examining the effects that this matter will have on its consolidated business performance and will promptly make an announcement if it finds that there is a need to make further disclosures.

【About napabucasin】
Napabucasin is an investigational first-in-class anti-cancer agent created by Boston Biomedical, Inc., wholly-owned subsidiary of Sumitomo Dainippon Pharma. Napabucasin is an orally administered small molecule agent with a novel mechanism of action designed to inhibit cancer stemness pathways by targeting STAT3. Besides the gastric and GEJ cancer, napabucasin is currently being investigated in phase 3 studies for advanced colorectal and pancreatic cancer.


【About the BRIGHTER study】
The BRIGHTER study is a randomized, double blind global clinical phase 3 study to evaluate the efficacy and safety of administration of napabucasin plus weekly paclitaxel in comparison with weekly paclitaxel alone in the U.S., Japan and etc. A total of 714 patients with advanced gastric and GEJ cancer were previously treated with one prior line of platinum/fluoropyrimidine-containing regimen, randomized in a 1:1 ratio to receive napabucasin plus weekly paclitaxel or weekly paclitaxel alone. The primary endpoint is overall survival (OS) in the general study population; secondary endpoints include progression free survival (PFS), OS and PFS in a predefined biomarker-positive sub-population, objective response rate, disease control rate, and safety. The interim analysis of the BRIGHTER study was performed when the cumulative number of events reached 380.

On June 26, 2017 Bayer reported that the Ministry of Health, Labour and Welfare (MHLW) in Japan has granted marketing authorization for Stivarga (regorafenib) tablets for the second-line treatment of patients with unresectable hepatocellular carcinoma (HCC) who have progressed after treatment with cancer chemotherapy (Press release, Bayer, JUN 26, 2017, View Source [SID1234519682]). Stivarga, an oral inhibitor of multiple kinases involved in normal cellular functioning and in pathological processes such as oncogenesis, tumor angiogenesis, metastasis and tumor immunity, is the first and only treatment to demonstrate significant improvement in overall survival in second-line HCC patients who previously had no other options.

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"The number of patients suffering from liver cancer continues to increase in Japan and for years Nexavar was the first and only approved systemic treament option with proven overall survival benefit to help address this unmet need", said Robert LaCaze, Executive Vice President and Head of the Oncology Strategic Business Unit at Bayer. "The approval of Stivarga in Japan for second-line HCC is a significant step forward for patients and their treating doctors. For the first time, patients have a proven treatment plan involving Stivarga directly after Nexavar which could establish a new standard of care."

Since 1990, the annual mortality rate of liver cancer in Japan has increased by over 50%. Globally it is the second leading cause of cancer-related deaths.

The approval of Stivarga in HCC in Japan marks the third time that this therapy has been granted MHLW approval based on priority review, which is an expedited program given to medicines on the basis of their clinical usefulness and severity of the disease. The product is already approved in more than 90 countries worldwide for metastatic colorectal cancer (CRC), including Japan, and in more than 80 countries globally for the treatment of metastatic gastrointestinal stromal tumors (GIST), including Japan. Additional regulatory filings for Stivarga in HCC are under review in countries around the world and Stivarga in HCC has been approved by the FDA in the U.S.

The HCC approval is based on data from the international, multicenter, placebo-controlled Phase III RESORCE trial, which investigated patients with unresectable HCC whose disease had progressed during treatment with sorafenib. In the trial, regorafenib plus best supportive care (BSC) was shown to provide a statistically significant and clinically meaningful improvement in overall survival (OS) versus placebo plus BSC (HR 0.63; 95% CI 0.5-0.79; p<0.0001), which translates to a 37% reduction in the risk of death over the trial period.

The most common treatment-emergent adverse events (regorafenib vs. placebo group) were palmar-plantar erythrodysesthesia syndrome (53% vs. 8%), diarrhea (41% vs. 15%), fatigue (40% vs. 32%) and hypertension (31% vs. 6%).

About Hepatocellular Carcinoma
Hepatocellular carcinoma, or HCC, is the most common form of liver cancer and represents approximately 70-85 percent of liver cancer worldwide. Liver cancer is the sixth most common cancer in the world and the second leading cause of cancer-related deaths globally. More than 780,000 cases of liver cancer are diagnosed worldwide each year (52,000 in the European Union, 501,000 in the Western Pacific region and 30,000 in the United States) and the incidence rate is increasing. In 2012, approximately 746,000 people died of liver cancer including approximately 48,000 in the European Union, 477,000 in the Western Pacific region and 24,000 in the United States.

About Regorafenib (Stivarga)
Regorafenib is an oral multi-kinase inhibitor that potently blocks multiple protein kinases involved in tumor angiogenesis (VEGFR1, -2, -3, TIE2), oncogenesis (KIT, RET, RAF-1, BRAF), metastasis (VEGFR3, PDGFR, FGFR) and tumor immunity (CSF1R).

Regorafenib is approved under the brand name Stivarga in more than 90 countries worldwide, including the U.S., countries of the EU, China and Japan for the treatment of metastatic colorectal cancer (mCRC). The product is also approved in over 80 countries, including the U.S., countries of the EU, China and Japan, for the treatment of metastatic gastrointestinal stromal tumors (GIST). It was recently approved in the U.S. for second-line treatment of HCC and is now approved in Japan in this indication as well. Additional regulatory filings for Stivarga in HCC are under review in countries around the world, including the EU and China.

In the EU, Stivarga is indicated for the treatment of adult patients with mCRC who have been previously treated with, or are not considered candidates for, available therapies including fluoropyrimidine-based chemotherapy, an anti-VEGF therapy and an anti-EGFR therapy, as well as for the treatment of adult patients with unresectable or metastatic GIST who progressed on or are intolerant to prior treatment with imatinib and sunitinib.

Regorafenib is a compound developed by Bayer. In 2011, Bayer entered into an agreement with Onyx, now an Amgen subsidiary, under which Onyx receives a royalty on all global net sales of regorafenib in oncology.