on June 26, 2017 Xenetic Biosciences, Inc. (NASDAQ: XBIO) ("Xenetic" or the "Company"), a clinical-stage biopharmaceutical company focused on the discovery, research and development of next-generation biologic drugs and novel orphan oncology therapeutics, reported that patient enrollment has commenced in its Phase 2 clinical study of XBIO-101 (sodium cridanimod) in conjunction with progestin therapy for the treatment of endometrial cancer, in a population of patients who have either failed progestin monotherapy or who have been identified as having progesterone receptor negative ("PrR-") tumors (Press release, Xenetic Biosciences, JUN 26, 2017, View Source [SID1234519692]).

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XBIO-101, Xenetic’s lead product candidate in development, is a small-molecule immunomodulator and interferon inducer which, in preliminary studies, has been shown to increase progesterone receptor ("PrR") expression in endometrial tumor tissue.

"We are very pleased to commence patient enrollment in this Phase 2 study with our flagship product candidate and believe this trial is designed to provide greater understanding of XBIO-101 for the treatment of progestin resistant endometrial cancer," stated M. Scott Maguire, Xenetic’s CEO. "Based on these preliminary findings, we believe that XBIO-101 has the potential to increase the expression of PrR on endometrial tumors thereby making them more responsive to treatment with traditional progestin therapy, and ultimately provide a much-needed solution for late stage endometrial cancer patients."

The primary objective of the open-label, multi-center, single-arm, two-period Phase 2 study is to assess the antitumor activity of XBIO-101 in conjunction with progestin therapy as measured by Overall Disease Control Rate ("ODCR") in women with recurrent or persistent endometrial carcinoma not amenable to surgical treatment or radiotherapy who have either failed progestin monotherapy or who have been identified as PrR-. Secondary objectives include assessments of efficacy and safety/tolerability parameters.

The study is expected to enroll a total of 72 women with recurrent or persistent endometrial cancer not amenable to surgical treatment or radiotherapy but suitable to be treated with progestins. All subjects determined to be PrR- at screening, as well as those subjects who experience disease progression after at least 4 weeks of progestin monotherapy, will receive XBIO-101 in combination with continued progestin treatment. Subjects will receive treatment until disease progression as defined according to RECIST 1.1 criteria.

For more information about the Phase 2 clinical study of XBIO-101 in conjunction with progestin therapy for the treatment of endometrial cancer, please visit clinicaltrials.gov and reference Identifier NCT03077698.

About Endometrial Cancer

Endometrial cancer is the most common malignancy of the female genital tract and represents a major health concern, as overall five-year survival rates have not improved over the past three decades. Annually in the United States, an estimated 60,050 patients are diagnosed with endometrial cancer and 10,470 deaths occur from this disease, representing 1.8% of all cancer deaths in the US. The incidence of endometrial cancer is on the rise with a lifetime risk of approximately 3% while the disease-specific mortality of endometrial carcinoma has been rising in the last 25 years. Endometrial cancer patients whose tumors no longer express progesterone receptors are not candidates for progestin-based therapy. Patients who fail monotherapy with progestins have no additional treatment options. XBIO-101 may improve sensitivity to progestin therapy in subjects with advanced or recurrent PrR tumors.

About XBIO-101

XBIO-101 is a small-molecule immunomodulator and interferon inducer which, in preliminary studies, has been shown to increase progesterone receptor ("PrR") expression in endometrial tissue. Restoration of PrR expression may re-sensitize endometrial tumor tissue to progestin therapy in previously unresponsive tumors.

Xenetic has commenced patient enrollment in the Phase 2 clinical study of XBIO-101 in conjunction with progestin therapy for the treatment of progestin resistant endometrial cancer, and has filed a protocol under its existing Investigational New Drug application ("IND") to expand the development of XBIO-101 into a biomarker study for the treatment of triple negative breast cancer ("TNBC").

On June 26, 2017 Onconova Therapeutics, Inc. (NASDAQ:ONTX), a Phase 3-stage biopharmaceutical company focused on discovering and developing novel small molecule drug candidates to treat cancer, with a primary focus on Myelodysplastic Syndromes (MDS), reported demonstrating responses of oral rigosertib with azacitidine in Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS), as well as oral rigosertib as a single agent (Press release, Onconova, JUN 26, 2017, View Source [SID1234519691]). The findings were presented by Onconova, Mount Sinai, and SymBio at the 22nd Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) taking place on June 22-24 in Madrid, Spain.

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"Advancing oral rigosertib in the clinic as a stand-alone agent, and providing further evidence for activity of rigosertib in combination with azacitidine in patients with MDS and AML represents an extension of our pipeline," said Dr. Ramesh Kumar, CEO of Onconova. "We are positioned for multiple key milestones in 2017 and beyond, beginning with the interim analysis of our pivotal Phase 3 INSPIRE trial later this year."

Full copies of the posters and oral presentations can be accessed by visiting "Scientific Presentations" in the Investors section of Onconova’s website.

Oral Presentation: Oral Rigosertib Combined with Azacitidine in Patients with AML and MDS; Effects in Treatment Naive and Relapsed/Refractory Patients

A novel combination therapy of oral rigosertib plus injectable azacitidine was tested in this trial (09-08) at three sites in the U.S. and Europe, representing a first-in-man study of this approach. Eight AML patients were evaluable for response, with an overall response rate (ORR) of 37.5%, and responses in both secondary and refractory AML. Two additional patients had stable disease (25%). Responses were durable, with the longest response in AML approaching one year.

Among 33 evaluable MDS patients, ORR was 76%. Complete remission (CR) in eight (24%), concurrent marrow CR (mCR) and hematologic improvement (HI) in 10 (30%), mCR alone in six (18%), and HI alone in 1 (3%). ORR was 85% in hypomethylating agent (HMA) naïve patients and 62% in HMA resistant patients.

Earlier, Phase 1 and Phase 2 data in first and second-line higher risk (HR)-MDS patients were presented at the 2016 American Society of Hematology (ASH) (Free ASH Whitepaper) Meeting and updated at the 2017 ASH (Free ASH Whitepaper) and MDS Foundation meetings. Based on these results, the authors determined that continued study in AML is warranted.

A Phase 3 study of the combination of oral rigosertib and azacitidine in patients with treatment naïve HR-MDS is currently being designed based on an end-of-phase 2 meeting with the Food and Drug Administration.

E-Poster: Rigosertib Combined with Azacitidine Epigenetically Modulates Chromatin and Hematopoietic Stem Cell Populations in MDS

Onconova’s collaborators from the Mount Sinai School of Medicine investigated the in vitro effects of rigosertib combined with azacitidine or vorinostat on two cell lines and on bone marrow samples from patients treated in the Phase 1-2 study, obtained prior to and after one cycle of the combination regimen. Azacitidine is an HMA and vorinostat is an inhibitor of Histone Deacetylase. Rigosertib’s mechanism of action is reported to be mediated by binding to a Ras Binding Domain present in Ras and its effector proteins, including PI3 Kinase and Raf. Chromatin remodeling by changes in methylation and acetylation were noted in cell-lines treated with all three agents, as well as after treatment with the two combinations. The nature of the changes induced with the two combinations was distinct.

The authors propose that rigosertib potentially functions as a chromatin modifying agent in combination with azacitidine and may overcome HMA resistance through chromatin remodeling. Rigosertib alone, and in combination, also leads to epigenetic reprogramming of hematopoietic stem cell populations (HSPCs) that may manifest in hematological improvements in the clinical setting. A U.S. patent describing the synergistic activity of rigosertib in combination with azacitidine has been issued.

SymBio, Onconova’s Partner in Japan and Korea, Presents Phase 1 data Demonstrating Oral Rigosertib as a Single Agent

E-Poster: A Multicenter, Open-label, Phase 1 Clinical Study; Safety, Efficacy, and Pharmacokinetics of Oral Rigosertib in Japanese Patients with Recurrent/Relapsed or Refractory MDS

A multicenter, open-label, Phase 1 clinical study of oral rigosertib (primary endpoint was dose-limiting toxicity) indicated that the recommended dose for a Phase 2 clinical study is 560 mg BID in a 2-out-of-3-week administration scheme in Japanese patients with recurrent/relapsed or refractory MDS. This regimen of oral rigosertib was well tolerated.

The primary endpoint of the study was dose-limiting toxicity. The secondary endpoints were 1) safety as assessed by adverse events and laboratory results, 2) efficacy as defined by the International Working Group 2006 Criteria, and 3) pharmacokinetics. Both hematological remission rate and hematological improvement rate were 11.1% of the nine patients with a median age of 70. In this study, the recommended dose was 560 mg BID. This study and a companion Phase 1 study with IV rigosertib were designed to obtain pharmacokinetics, safety, tolerability and efficacy data in MDS patients in Japan. Currently, SymBio is enrolling patients in a pivotal Phase 3 INSPIRE global study to assess the safety and efficacy of IV rigosertib.

Publication: Safety, Efficacy and Pharmacokinetics of Intravenous Rigosertib in Japanese Patients with Recurrent/Relapsed or Refractory MDS; A Multicenter, Open-label, Phase 1 Study

A multicenter, open-label, Phase 1 study of intravenous rigosertib was conducted to evaluate its safety, efficacy, and pharmacokinetics and to determine the recommended dose (RD) for Japanese patients.

The Phase 1 study showed that intravenous rigosertib (1,800 mg daily) for consecutive 72 hours was well-tolerated, indicating that this is the RD for Japanese patients with MDS, similar to a Phase 3 study in the U.S. Based on these clinical outcomes, Japanese patients with MDS are participating in a global randomized Phase 3 study to compare rigosertib with physicians’ choice of treatment.

On June 26, 2017 TG Therapeutics, Inc. (NASDAQ:TGTX), reported clinical data from two triple combination therapy trials using TGR-1202 (umbralisib), the Company’s oral, next generation PI3K delta inhibitor and TG-1101 (ublituximab), the Company’s novel glycoengineered anti-CD20 monoclonal antibody, as the backbone of the combinations (Press release, TG Therapeutics, JUN 26, 2017, View Source [SID1234519689]). The data presentations include a recap of the data from the combination of TGR-1202, TG-1101, and ibrutinib, as well as from the triple combination of TGR-1202, TG-1101, and bendamustine. Data from these trials were presented this past weekend at the 22nd European Hematology Association (EHA) (Free EHA Whitepaper) Annual Congress in Madrid, Spain. These data sets were presented earlier this month at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting and/or at the 14th International Conference on Malignant Lymphoma (ICML).

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Highlights from the presentations include the following:

Oral Presentation: Chemo-free triplet combination of TGR-1202, ublituximab, and ibrutinib is well tolerated and highly active in patients with advanced CLL and NHL

This oral presentation includes data from patients with Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) and Non-Hodgkin’s Lymphoma (NHL) treated with the triple combination of TGR-1202, TG-1101, and ibrutinib. All patients were relapsed or refractory to prior therapy, except 3 CLL patients who were treatment naïve. Three cohorts each for CLL/SLL and NHL were evaluated with TGR-1202 dose escalation starting with doses of 400 mg (cohort 1), followed by 600 mg (cohort 2) and 800 mg (cohort 3), in combination with TG-1101 at 900 mg and ibrutinib daily at 420 mg (CLL) and 560 mg (NHL).

Safety & Tolerability
Thirty-eight (38) patients were evaluable for safety (20 CLL/SLL patients, and 18 NHL patients). The triple combination appeared to be well tolerated in all patients, with neutropenia (32% all grades, 18% Grade 3/4) and pneumonia (18% all grades, 11% Grade 3/4), being the only Grade 3/4 AEs in > 10% of patients. Of the 38 patients treated to date, only two AEs (sepsis and pneumonia) led to treatment discontinuation. Median time on study was 11.1 months (range 0.4 – 30+ months) with 81% of patients on study > 6 months.

Clinical Activity
Clinical activity was observed at all dose levels with 36 of 38 patients evaluable for efficacy (19 CLL/SLL patients, and 17 NHL patients), with 2 patients having discontinued prior to first efficacy assessment (1 pneumonia, and 1 investigator discretion).

CLL/SLL Efficacy highlights include:

100% (19 of 19) Overall Response Rate (ORR), including a 32% Complete Response (CR) rate observed in patients with CLL/SLL (4 of 6 CR’s pending bone marrow confirmation)

50% of the CLL patients had a 17p and/or 11q deletion

3 CLL patients had prior BTK and/or PI3Kδ inhibitor therapy, including one patient refractory to both idelalisib and ibrutinib who attained a complete response (ongoing for 1.5+ years)
NHL Efficacy highlights include:

Response Rates observed in patients with NHL:
100% (2 of 2) ORR, including one CR in patients with Marginal Zone Lymphoma (MZL)
100% (4 of 4) ORR, including 50% CR rate in patients with Mantle Cell Lymphoma (MCL)
80% (4 of 5) ORR, including 20% CR rate in patients with Follicular Lymphoma (FL)
17% (1 of 6) ORR in patients with Diffuse Large B-cell Lymphoma (DLBCL)

FL patients were heavily pretreated including 2 with prior Autologous Stem Cell Transplant (ASCT), 1 refractory to prior ibrutinib, and 1 with 5 prior lines of rituximab based therapy

DLBCL patients had a median of 4 prior therapies, and 4 of 6 were of non-GCB subtype
Poster Presentation: Combination of TGR-1202, Ublituximab, and Bendamustine is safe and highly active in patients with advanced DLBCL and Follicular Lymphoma

This poster presentation includes data from patients with relapsed or refractory Diffuse Large B-Cell Lymphoma (DLBCL) or Follicular Lymphoma (FL) treated with the triple combination of TGR-1202 (umbralisib), TG-1101 (ublituximab), and bendamustine. Thirty-three patients were evaluable for safety of which 24 were evaluable for efficacy (9 patients were note evaluable; 7 were too early to evaluate and 2 patients were off study prior to an efficacy assessment: 1 non-related adverse event (AE) and 1 investigator decision). The triple combination appears well tolerated with no discontinuations for a treatment related AE. No events of pneumonitis and no Grade 3/4 transaminitis were reported. Twenty-one patients (64%) were refractory to prior treatment. Mean time on study was approximately 6 months.

Efficacy highlights from this poster include:

100% (4 of 4) ORR, including a 50% CR rate, observed in patients with relapsed DLBCL

50% (6 of 12) ORR, including a 42% CR rate, observed in patients with refractory DLBCL with durable CR and PR responses observed (PR on-going for > 16+ months)

88% (7 of 8) ORR, including a 50% CR rate, observed in patients with relapsed or refractory FL
PRESENTATION DETAILS:

The above referenced presentations are available on the Publications page, located within the Pipeline section, of the Company’s website at www.tgtherapeutics.com/publications.cfm.

On June 26, 2017 Atossa Genetics Inc. (NASDAQ: ATOS), a clinical-stage pharmaceutical company developing novel therapeutics and delivery methods to treat breast cancer and other breast conditions, reported that it has received a positive interim safety assessment of the first cohort receiving proprietary oral Endoxifen in its Phase 1 dose escalation study (Press release, Atossa Genetics, JUN 26, 2017, http://ir.atossagenetics.com/news/detail/816/atossa-genetics-receives-positive-safety-committee-assessment-of-first-cohort-receiving-oral-formulation-of-endoxifen-in-phase-1-dose-escalation-study [SID1234519688]). Endoxifen is an active metabolite of the FDA approved drug tamoxifen, which is indicated for breast cancer and breast cancer prevention in high-risk patients. The Independent Safety Committee reviewed the blinded data generated from the first cohort receiving the oral formulation (8 subjects) and concluded that the study may advance to the next oral dosing level.

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The study includes two arms: one receiving a topical formulation of Endoxifen and another receiving an oral formulation, each with three cohorts. The topical arm has been fully enrolled and dosed and the first of the three oral cohorts has now been dosed.

"Our Phase 1 study of our proprietary Endoxifen is progressing quickly and as planned," stated Dr. Steve Quay, CEO and President. "This interim safety determination allows us to proceed to the next dosing level and, based on the progress to date, we expect to complete enrollment in the next six weeks."

The Phase 1 study is a double-blinded, placebo-controlled, repeat dose study of 48 healthy female subjects and its objectives are to assess the pharmacokinetics of proprietary formulations of both oral and topical Endoxifen dosage forms over 28 days, as well as to assess safety and tolerability. The study is being conducted on behalf of Atossa by CPR Pharma Services Pty Ltd., Thebarton, SA, Australia.

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.