On December 7, 2015 Seattle Genetics, Inc. (Nasdaq: SGEN) reported data presentations evaluating ADCETRIS (brentuximab vedotin) in frontline non-Hodgkin lymphoma at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition taking place in Orlando, Florida, December 5-8, 2015 (Press release, Seattle Genetics, DEC 7, 2015, View Source;p=RssLanding&cat=news&id=2120760 [SID:1234508481]). The data include an oral presentation highlighting updated results from an ongoing phase 2 clinical trial evaluating ADCETRIS in combination with chemotherapy for newly diagnosed, high risk diffuse large B-cell lymphoma (DLBCL) patients. In addition, a poster presentation highlights a three-year durability analysis from a phase 1 clinical trial of ADCETRIS in combination with chemotherapy for the treatment of newly diagnosed peripheral T-cell lymphoma, also known as mature T-cell lymphoma (MTCL), patients. ADCETRIS is an antibody-drug conjugate (ADC) directed to CD30, a defining marker of classical Hodgkin lymphoma and is expressed on several types of non-Hodgkin lymphoma.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"There is a significant need to improve frontline treatment options in aggressive non-Hodgkin lymphomas. In particular, newly diagnosed patients with high-intermediate and high-risk DLBCL and MTCL have estimated three-year progression-free survival rates of approximately 55 percent and 30 percent, respectively," said Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics. "ADCETRIS has demonstrated high complete remission and progression-free survival rates when added to frontline chemotherapy regimens for DLBCL and MTCL. Our efforts to redefine frontline therapy for these diseases are part of our goal to establish ADCETRIS as the foundation of care for all CD30-expressing lymphomas."

ADCETRIS is currently not approved for the treatment of frontline DLBCL and MTCL. For more information about the clinical trials, including enrolling centers, visit www.clinicaltrials.gov.

Brentuximab Vedotin with RCHOP as Frontline Therapy in Patients with High-Intermediate/High-Risk Diffuse Large B-Cell Lymphoma (DLBCL): Results from an Ongoing Phase 2 Study (Abstract #814, oral presentation on Monday, December 7, 2015 at 5:15 p.m.)

Updated interim results were reported from an ongoing phase 2 clinical trial evaluating ADCETRIS in combination with the standard of care regimen consisting of rituximab (Rituxan), cyclophosphamide, doxorubicin, vincristine and prednisone (RCHOP) in frontline high-intermediate and high-risk DLBCL. Patients were randomized to receive standard dose RCHOP with either 1.2 milligrams per kilogram (mg/kg) or 1.8 mg/kg of ADCETRIS. The trial was designed to assess antitumor activity and the safety profile of ADCETRIS plus RCHOP in these patients. Exploratory endpoints included CD30 expression measured by immunohistochemistry (IHC) testing and the relationship between CD30 expression and response.

Data were reported from 51 frontline DLBCL patients with a median age of 67 years. Seventy-one percent of patients in the trial had stage IV disease, 37 percent were considered high-risk and 63 percent were considered high-intermediate risk. Key findings presented by Christopher Yasenchak, M.D., Willamette Valley Cancer Institute and Research Center/US Oncology Research, include:

Of 25 evaluable patients who had CD30-expressing disease (one percent expression or greater), 21 patients (84 percent) obtained an objective response, including 19 patients (76 percent) with a complete remission and two patients (eight percent) with a partial remission. The estimated progression-free survival rate for CD30-positive patients at both 12 and 15 months was 83 percent.
Subsets of patients known to have a poor prognosis appear to have favorable outcomes:

Eleven patients with CD30-positive activated B-cell like (ABC) DLBCL had a complete remission rate of 73 percent (eight of 11 patients). The estimated progression-free survival rate for these patients at both 12 and 15 months was 80 percent.
Six patients with Epstein-Barr virus (EBV)-positive lymphoma had a complete remission rate of 83 percent (five of six patients). The estimated progression-free survival rate for these patients at 12 months was 83 percent.

The most common treatment-emergent adverse events of any grade were fatigue and peripheral sensory neuropathy (63 percent each), diarrhea and nausea (57 percent each), and neutropenia and vomiting (37 percent each).The most common Grade 3 or 4 adverse events were febrile neutropenia (31 percent), neutropenia (33 percent) and anemia (24 percent). Based on an increased rate of Grade 3 peripheral neuropathy observed in the first 10 patients treated on the 1.8 mg/kg arm, remaining patients were treated with 1.2 mg/kg of ADCETRIS.

Based on these data, the phase 2 trial has been amended to add a randomized cohort exploring the activity and safety of ADCETRIS plus RCHP (without vincristine) versus RCHOP in frontline patients with CD30-expressing high-intermediate or high-risk DLBCL. Separately, a randomized phase 2 trial is also ongoing evaluating rituximab and bendamustine with or without ADCETRIS in relapsed or refractory DLBCL.

Frontline Treatment of CD30+ Peripheral T-cell Lymphomas with Brentuximab Vedotin in Combination with CHP: 3-Year Durability and Survival Follow-up (Abstract #1537, poster presentation on Saturday, December 5, 2015)

Data were reported from 26 frontline MTCL patients who received the combination regimen of ADCETRIS plus cyclophosphamide, doxorubicin and prednisone (CHP). Patients who achieved at least a partial remission with combination therapy were eligible to receive continued single-agent ADCETRIS treatment. The median age of patients was 56 years. Nineteen patients (73 percent) had a subtype of MTCL called systemic anaplastic large cell lymphoma (sALCL), including 16 patients (62 percent) with anaplastic lymphoma kinase (ALK) negative disease, which is typically associated with a poor prognosis. Seven patients had a diagnosis of other types of MTCL. The majority of patients had advanced stage disease and were considered high risk.

Updated key findings based on a median observation time of 38.7 months from first dose of therapy include:

The estimated three-year progression-free survival rate was 52 percent, with no patients receiving a consolidative stem cell transplant in first remission. There have been no progression events since the previous presentation at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress in September 2014. The estimated median progression-free survival has not yet been reached.
The estimated three-year overall survival rate was 80 percent.

The observed three-year progression-free survival and overall survival rates of 52 and 80 percent compare favorably to historical three-year progression-free survival and overall survival rates for frontline MTCL of approximately 30 and 40 percent, respectively.
The most common adverse events of any grade occurring in more than 30 percent of patients were nausea and peripheral sensory neuropathy (69 percent each), diarrhea (62 percent), fatigue (58 percent) and hair loss (54 percent). The most common Grade 3 or higher adverse events occurring in more than 10 percent of patients were febrile neutropenia (31 percent), neutropenia (23 percent), anemia (15 percent) and pulmonary embolism (12 percent).

Seventy-three percent of patients (19 of 26) experienced peripheral neuropathy, the majority of which was Grade 1 or 2. Ninety-five percent of these patients had complete resolution or some improvement of their symptoms at last follow-up with a median time to resolution of 1.3 months.

A global phase 3 study called ECHELON-2 is currently enrolling patients. The ECHELON-2 trial is a randomized, double-blind, placebo-controlled, multi-center trial designed to investigate A+CHP versus CHOP as frontline therapy in patients with CD30-positive MTCL. Approximately 450 patients (approximately 225 patients per treatment arm) will be randomized to receive A+CHP or CHOP every three weeks for six to eight cycles.

About ADCETRIS

ADCETRIS is being evaluated broadly in more than 70 ongoing clinical trials, including the phase 3 ALCANZA trial and two additional phase 3 studies, ECHELON-1 in frontline classical HL and ECHELON-2 in frontline mature T-cell lymphomas, as well as trials in many additional types of CD30-expressing malignancies, including B-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 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. ADCETRIS has received marketing authorization by regulatory authorities in more than 55 countries. 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.

About Seattle Genetics

Seattle Genetics is a biotechnology company focused on the development and commercialization of innovative antibody-based therapies for the treatment of cancer. Seattle Genetics is leading the field in developing antibody-drug conjugates (ADCs), a technology designed to harness the targeting ability of antibodies to deliver cell-killing agents directly to cancer cells. The company’s lead product, ADCETRIS (brentuximab vedotin) is a CD30-targeted ADC that, in collaboration with Takeda Pharmaceutical Company Limited, is commercially available in more than 55 countries, including the U.S., Canada, Japan and members of the European Union. Additionally, ADCETRIS is being evaluated broadly in more than 70 ongoing clinical trials in CD30-expressing malignancies. Seattle Genetics is also advancing a robust pipeline of clinical-stage programs, including vadastuximab talirine (SGN-CD33A; 33A), denintuzumab mafodotin (SGN-CD19A; 19A), SGN-LIV1A, SGN-CD70A, ASG-22ME, ASG-15ME and SEA-CD40. Seattle Genetics has collaborations for its ADC technology with a number of leading biotechnology and pharmaceutical companies, including AbbVie, Agensys (an affiliate of Astellas), Bayer, Genentech, GlaxoSmithKline and Pfizer. More information can be found at www.seattlegenetics.com.

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.

On December 07, 2015 Onconova Therapeutics, Inc. (NASDAQ:ONTX), a clinical-stage biopharmaceutical company focused on discovering and developing novel products to treat cancer, reported the presentation of data from an ongoing Phase 1/2 clinical trial of oral rigosertib and azacitidine in higher-risk myelodysplastic syndromes (HR-MDS) at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Orlando, Florida (Press release, Onconova, DEC 7, 2015, View Source [SID:1234508480]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"The high response rate observed in the 09-08 combination trial is impressive," said Lewis R. Silverman, M.D., investigator in the trial and Associate Professor of Medicine, Hematology and Medical Oncology, at the Icahn School of Medicine at Mount Sinai. "Furthermore, the tolerability profile of oral rigosertib and azacitidine suggests that this combination could be used in HR-MDS. These results provide strong support for the advancement of oral rigosertib into late-stage clinical trials."

The 09-08 study, which is fully enrolled, is an open label, multi-site clinical trial evaluating oral rigosertib in combination with the approved dose of injectable azacitidine for patients with MDS and AML. Results from the Phase 1 dose escalation portion of the study, presented at the 2014 ASH (Free ASH Whitepaper) Annual Meeting, identified the Recommended Phase Two Dose (RPTD) of oral rigosertib as 560 mg/280 mg twice daily. The Phase 2 portion of the trial was designed to assess whether treatment with the combination (oral rigosertib in combination with injectable azacitidine) reduces the number of bone marrow blasts and improves peripheral blood counts. Accrual in the 09-08 study was recently completed. Clinical trial sites included MD Anderson Cancer Center (Lead Investigator: Dr. Guillermo Garcia-Manero), Mount Sinai School of Medicine (Lead Investigator: Dr. Lewis Silverman) and Hôpital Saint-Louis (Lead Investigator: Dr. Pierre Fenaux).

Summary of Presented Data from the 09-08 Trial

Patient Demographics:

A total of 37 MDS patients have been treated to date at the RPTD. Thirty of these patients were evaluable for response at the time of this analysis.

The median age of MDS patients was 64. IPSS risk score (27% INT-1, 41% INT-2 and 32% High) and cytogenetic risk (22% Good, 38% Intermediate, 24% Poor and 16% unknown) were calculated for all MDS patients. Thirteen patients had received prior HMA therapy (ten azacitidine, three decitabine; one received both HMAs serially) and the remaining evaluable patients were HMA-naïve front-line patients.

This study is now closed for enrollment.

Safety/Tolerability:

The combination of oral rigosertib and azacitidine has been well tolerated to date.

The median duration of treatment at this time for MDS patients treated in the trial with the combination was four months (range 1 to 27 months to date).

Adverse events of Grade ≥3 experienced across all cycles with the combination included thrombocytopenia (27%), neutropenia (22%), hypokalaemia (5%), hematuria (5%) and diarrhoea (3%).

Notably, these side effects were similar to the side effects previously reported for azacitidine administered alone.

Efficacy:

Thirty MDS patients were evaluable for efficacy analysis per IWG 2006 criteria (Cheson et al., Blood 2006).
Twenty-three of 30 (77%) patients responded per IWG, including six patients who had complete remissions (CR).
Hematologic improvement (HI) per IWG, including tri-lineage response, was noted in 13 patients (50% of the 26 patients evaluable for HI response) and included improvements in erythroid (11 patients), platelet (12 patients) and neutrophil (7 patients) lineages.
Per IWG, 16 of 19 (84%) evaluable HMA-naïve patients responded to the combination therapy; 7 of 11 (64%) evaluable patients previously treated with HMAs responded.

Following these results, additional data from patients continuing to be treated in the study, and after consultation with key opinion leaders, Onconova intends to seek an end of Phase 2 meeting with U.S. and European regulators in order to discuss next steps for the combination program.

"The results for oral rigosertib in combination with azacitidine support moving this novel therapy towards pivotal trials for patients with MDS and myeloid malignancies," said Ramesh Kumar, Ph.D., President and CEO of Onconova. "We intend to provide clarity related to timing of further development for oral rigosertib at our upcoming investor event on December 16th."

Investor Event and Webcast

Onconova will host a live investor event on December 16th in New York, NY at 8:00 AM ET to review the clinical data presented at the ASH (Free ASH Whitepaper) Annual Meeting. The event will provide access to key opinion leaders involved with rigosertib clinical trials in MDS. A live webcast can be accessed by visiting "Events & Presentations" in the Investors and Media section of the Company’s website at www.onconova.com.

About Rigosertib

Rigosertib is a small molecule that inhibits cellular signaling by acting as a Ras mimetic. This is believed to be mediated by direct binding of rigosertib to the Ras-binding domain (RBD) found in many Ras effector proteins, including the Raf kinases and PI3K. The initial therapeutic focus for rigosertib is myelodysplastic syndromes (MDS), a group of bone marrow disorders characterized by ineffective formation of blood cells that often converts into acute myeloid leukemia (AML). Clinical trials for rigosertib are being conducted at MDS Centers of Excellence in the United States, Europe, and the Asia-Pacific region.

Intellectual Property

Rigosertib is protected by issued patents (composition of matter with earliest expiration in 2026) and has been awarded Orphan Designation for MDS in the United States, Europe and Japan. The combination of rigosertib and azacitidine is protected by an issued U.S. patent (US 8,664,272 with earliest expiration in 2028) covering the composition of the combination and methods for using the combination to treat MDS and AML.

On December 7, 2015 Immune Design (Nasdaq:IMDZ), a clinical-stage immunotherapy company focused on oncology, reported the presentation of data on G100 demonstrating both direct and abscopal (indirect) tumor regression, as well as tumor-specific, long-term immune protection (Press release, Immune Design, DEC 7, 2015, View Source [SID:1234508477]). G100 is Immune Design’s intratumoral TLR4 agonist-based product candidate and is currently in clinical trials. Results were highlighted during an oral presentation at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Orlando, Florida.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The research, authored by Ronald Levy and Idit Sagiv-Barfi of Stanford University and Hailing Lu, Jessica Hewitt, Frank Hsu and Jan ter Meulen of Immune Design, investigated the therapeutic impact and immune response of intratumoral administration of G100 in a preclinical model of lymphoma. Results demonstrated:

tumor regression in 60-100 percent across the animal models;

tumor growth inhibition reported in both injected tumors as well as uninjected tumors (abscopal effects);

responders remained tumor-free at least three months post G100 treatment and were resistant to secondary challenge with the same tumor type;

tumor-specific, systemic CD8 T cell responses were induced and shown to mediate anti-tumor protection;

combination with immune checkpoint modulation led to enhanced tumor protection and improved survival; and
G100 had an impact on the tumor microenvironment, changing it from a non-inflammatory state ("cold" tumor microenvironment) to an inflamed state ("hot" tumor microenvironment).

"These data demonstrate the ability of G100 to alter the tumor microenvironment and generate a systemic T-cell based anti-tumor response that is both specific and long-lasting," said Dr. Ronald Levy, Professor and Chief, Division of Oncology, Stanford University School of Medicine. "G100, either alone or in combination with immune checkpoint modulators, according to this model may hold potential as a treatment for lymphoma patients."

"These findings build on the strong set of preclinical and clinical data that support the ability of Immune Design’s G100 product candidate to have an impact on the immunotherapy landscape, including in combination with other immuno-oncology approaches," said Jan ter Meulen, MD, PhD, Chief Scientific Officer at Immune Design. "These data provide support for our planned clinical trial in patients with follicular non-Hodgkin’s lymphoma receiving local radiation, with or without the anti-PD-1 therapy, Keytruda, pursuant to our collaboration with Merck."

About G100

G100 is a product candidate generated from the company’s GLAASTM discovery platform, and includes a specific formulation of Glucopyranosyl Lipid A (GLA), a synthetic, toll-like receptor-4 (TLR-4) agonist. G100 is part of Immune Design’s intratumoral immune activation, or ‘Endogenous Antigen’ approach to treating cancer, which leverages the activation of dendritic and other immune cells in the tumor microenvironment to potentially create a robust immune response against the tumor’s preexisting diverse set of antigens. Preclinical and clinical data have demonstrated the ability of G100 to activate dendritic cells in tumors and to increase antigen-dependent systemic humoral and cellular Th1 immune responses.

G100 Study in Patients with Merkel Cell Carcinoma

A Phase 1 study of G100 in patients with Merkel cell carcinoma (MCC) recently completed enrollment, and Immune Design presented data at the 2015 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting. In the first eight patients of the MCC study, G100 had an acceptable safety profile and resulted in an objective response rate (ORR) of 50% per protocol.

G100 Study in Patients with Follicular Non-Hodgkin’s Lymphoma

A Phase 1 study evaluating intratumoral G100 in patients with follicular non-Hodgkin’s lymphoma is currently enrolling patients (NCT: 02501473). The study is being updated to examine intratumoral administration of G100 with intravenous administration of KEYTRUDA (pembrolizumab), Merck’s anti-PD-1 therapy, in patients with follicular non-Hodgkin’s lymphoma receiving local radiation. In addition to an evaluation of the safety of the combination, the study will assess the response in both injected and non-injected lesions.

On December 7, 2015 Bellicum Pharmaceuticals, Inc. (Nasdaq:BLCM), a clinical stage biopharmaceutical company focused on discovering and developing novel cellular immunotherapies for cancers and orphan inherited blood disorders, reported preclinical data from studies of its CIDeCAR CAR T-cell technology, including product candidate BPX-401, in an oral presentation at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting today (Press release, Bellicum Pharmaceuticals, DEC 7, 2015, View Source;p=RssLanding&cat=news&id=2120758 [SID:1234508476]). The preclinical in vivo data show that tumors can be eliminated quickly and safely with the Company’s CIDeCAR novel costimulatory domain and safety switch.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

In the oral presentation, "Expression of MyD88/CD40 Drives In Vivo Activation and Proliferation of Chimeric Antigen Receptor Modified T Cells That Can Be Effectively Regulated by Inducible Caspase-9," Bellicum scientists compared CIDeCARs targeting CD19 or other tumor antigens to CAR constructs based on 4-1BB and CD28. CIDeCAR combines Bellicum’s novel costimulatory domain MC (MyD88/CD40) and the CaspaCIDe safety switch. Bellicum’s small molecule rimiducid was used to activate the CaspaCIDe safety switch. The CaspaCIDe safety switch was also employed as a "dimmer switch," titrating the number of CIDeCAR cells in order to remain within a therapeutic window that maximizes both safety and efficacy, for improved clinical benefit.

Study Highlights

Activation:

The addition of the MC costimulatory domain led to a significant increase in in vivo activation and persistence of the CIDeCAR CAR T cells when compared to CARs constructed with conventional costimulatory domains CD28 and 4-1BB.
Studies also showed that CAR T cells with the MC costimulatory domain eliminated cancer cells faster in animal models than CARs using CD28 or 4-1BB.
Safety:

In CD19 and HER2 animal models, the majority of CAR T cells can be eliminated if needed, leading to rapid recovery from cytokine release-like syndrome, without tumor relapse.
Experiments also demonstrate that the CaspaCIDe safety switch can be titrated. Lower concentrations of small molecule activator rimiducid led to elimination of only a portion of circulating CAR T cells, including possibly the most active cells, without losing the antitumor effect of treatment.
GoCAR-T and GoTCR Poster Presentations

Two additional poster presentations1,2 at ASH (Free ASH Whitepaper) featured the Company’s GoCAR-T and GoTCR technologies. GoCAR-T technology uses rimiducid to control persistence of CAR-T cells in vivo for therapeutic effect. In animal experiments targeting CD19 and Prostate Stem Cell Antigen (PSCA), Bellicum scientists demonstrated that a single IV injection of GoCAR-T cells containing the proprietary iMC (inducible MyD88/CD40) activation switch could eliminate large, established solid tumors and lymphomas. Administration of rimiducid stimulated the survival and proliferation of GoCAR-T cells, which may allow more effective therapy of solid tumors in patients.

In an additional poster session, Bellicum scientists used the same iMC activation switch to complement HLA-A2/Preferentially Expressed Antigen in Melanoma (PRAME)-specific TCR-modified T cells to create "GoTCR"s that also could be activated by rimiducid, similar to the GoCAR-T platform. PRAME-targeted GoTCRs were active against PRAME-expressing tumors in vitro and in vivo. Activation with weekly administration of rimiducid led to more effective tumor control. In this application of the CID technology, toxicity is controlled by the cessation of rimiducid administration, acting like "lifting one’s foot off of a gas pedal," without the loss of tumor control.

"These preclinical data support the advancement of our product candidates BPX-401 and BPX-601 into clinical trials. We are also excited about the potential of our GoTCR platform to address the limitations of TCR therapy by enabling control over the cells’ proliferation and persistence," commented Tom Farrell, Bellicum’s President and CEO.

1 Foster A, Mahendravada A, Shinners N, et al. "Inducible MyD88/CD40 allows rimiducid-dependent activation to control proliferation and survival of chimeric antigen receptor-modified T cells." 2015 Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper), Orlando, FL

2 Hoang T, Foster A, Lu A, et al. "Inducible MyD88/CD40 enhances proliferation and survival of PRAME-specific TCR-engineered T cells and increases anti-tumor effects in myeloma 2015." Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper), Orlando, FL

On December 07, 2015 TG Therapeutics, Inc. (Nasdaq:TGTX), reported the presentation of updated clinical results from its ongoing Phase I single agent study of TGR-1202, the Company’s next generation PI3K delta inhibitor, as well as its Phase II combination study of TG-1101 (ublituximab), the Company’s novel, glycoengineered monoclonal antibody plus ibrutinib, the oral BTK inhibitor (Press release, TG Therapeutics, DEC 7, 2015, View Source [SID:1234508474]). Data from these studies are being presented today, Monday December 7, 2015 at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition being held at the Orange County Convention Center in Orlando, FL.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Michael S. Weiss, the Company’s Executive Chairman and Interim CEO commented on the data, "We are extremely pleased that the activity and safety profile of TGR-1202 continues to exhibit best in class attributes. As a once daily PI3K delta inhibitor, we believe the added convenience along with a low occurrence of hepatic toxicity, will make TGR-1202 a very appealing treatment option for physicians. More importantly, with over 80 patients having been exposed to TGR-1202 for over 6 months and another 42 on drug for more than a year, we believe the data supports that colitis associated with other PI3K deltas is not likely to be a major concern for TGR-1202. We are also excited about the final data from our 1101 plus ibrutinib study in patients with advanced Mantle Cell Lymphoma. More and more, physicians are recognizing the need to deepen ibrutinib responses to avoid relapse and the data demonstrating a doubling of CRs in patients with MCL compared to historical data of single agent ibrutinib seems very encouraging, although in a small number of patients. The deepening of responses in MCL, primarily a nodal disease, is further confirmation of the ability of TG-1101 to penetrate the nodes and improve responses. This is consistent with the deepening of responses seen with the combination in CLL, where we reported 25% CR and/or MRD negativity in rel/ref CLL, which compares favorably to the ibrutinib label. We believe this is further confirmation of the benefit we expect to see in our GENUINE Phase 3 trial."

Dr. Owen A. O’Connor, Professor of Medicine and the Director of the Center for Lymphoid Malignancies, at the Columbia University Medical Center and lead author for the TGR-1202 single agent poster presentation stated, "With many patients on daily TGR-1202 now for well over a year, and upwards of 2.5 years, we are very impressed with the continued tolerability and long term safety profile of TGR-1202, which we believe is truly differentiated from other PI3K delta inhibitors. Discontinuations due to adverse events have been particularly rare, translating into prolonged progression-free survival in relapsed and refractory CLL and indolent NHL patients of two years or more. We are excited at the potential to bring forward this important and needed treatment option for patients with advanced hematologic malignancies."

The following summarizes the posters presented today:

TGR-1202, a Novel Once Daily PI3K-Delta Inhibitor, Demonstrates Clinical Activity with a Favorable Safety Profile in Patients with CLL and B-Cell Lymphoma (Abstract Number 4154)

This poster presentation includes data from patients with relapsed and refractory Chronic Lymphocytic Leukemia (CLL) and B-Cell lymphoma (NHL and Hodgkin’s) treated with TGR-1202 as a single agent. Eighty-one patients were evaluable for safety, and 63 patients evaluable for efficacy, which includes patients treated with 800 mg of the initial formulation or higher, and any micronized dose level. Patients in this study were heavily pretreated with 57% of patients having seen ≥ 3 prior therapies, and 49% of patients being refractory to their prior therapy.

Highlights from this poster include:

94% (16 of 17) of CLL patients achieved a nodal PR, with the remaining patient still on study pending further evaluation

59% (10 of 17) of these CLL patients achieved a response per the iwCLL (Hallek 2008) criteria

Median progression free survival (PFS) in the CLL cohort was approximately 24 months

75% (12 of 16) of follicular lymphoma patients demonstrated tumor reductions, with a preliminary ORR of 38% (6 of 16), with 2 additional patients achieving 49% reductions in tumor burden, each continuing on study pending further efficacy assessments
Median PFS for the indolent NHL cohort was 27.3 months

TGR-1202 continues to demonstrate a favorable safety profile, differentiated from the other PI3K deltas inhibitors, with only 7% of patients discontinuing due to an adverse event

Limited grade 3/4 adverse events were reported with anemia and neutropenia (each 9%) being the only grade 3/4 adverse events reported in greater than 5% of patients

Long-term safety has been well characterized with 47% (38 of 81) of patients on study more than 6 months, 27% (22 of 81) of patients on study more than 12 months, and the longest exposed to drug for more than 2.5 years

No events of colitis have been reported, and grade 3/4 AST/ALT elevations have been seen in 2% of patients (4% all grades)
Safety and efficacy profile supports combination therapy with other novel targeted agents

Ublituximab (TG-1101), a Novel Glycoengineered Anti-CD20 Monoclonal Antibody, in Combination With Ibrutinib is Highly Active in Patients with Relapsed and/or Refractory Mantle Cell Lymphoma; Results of a Phase II Trial (Abstract Number 3980)

This poster presentation includes data from 15 patients with previously treated mantle cell lymphoma (MCL) treated with 900mg of TG-1101, in combination with ibrutinib at an oral daily dose of 560mg. There was no limit on prior type or number of therapies and patients previously treated with prior with a BTK inhibitor and/or a PI3K delta inhibitor were permitted. The combination appeared well tolerated in all patients treated, with neutropenia being the only reported grade 3/4 adverse event occurring in greater than 7% of patients and no infusion related reactions being reported for TG-1101.

Highlights from this poster include:

87% (13 of 15) investigator assessed ORR, including a 33% Complete Response rate which compares favorably to historical single agent ibrutinib data (66% investigator assessed ORR and 17% CR)
93% (14 of 15) of patients achieved some reduction in tumor burden on study, with the remaining patient having been refractory to prior anti-CD20 therapy and refractory to prior ibrutinib therapy progressing in Cycle 3
Greater depth of response was achieved over time, with a 62% median reduction in tumor burden at week 8 which increased to a 76% median reduction by week 20
No dose reductions were needed for TG-1101, however 20% (3 of 15) of patients had their ibrutinib dose reduced.

POSTER PRESENTATION DETAILS

A copy of the poster presentations are available on the Company’s website at www.tgtherapeutics.com, located on the Publications Page, within the Pipeline section.