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.

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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.

On December 7, 2015 ImmunoCellular Therapeutics, Ltd. ("ImmunoCellular") (NYSE MKT: IMUC) reported the establishment of an agreement with a major cancer research group, Alliance Foundation Trials, LLC (AFT), for the phase 3 registrational trial of its cancer immunotherapy ICT-107 in patients with newly diagnosed glioblastoma (Press release, ImmunoCellular Therapeutics, DEC 7, 2015, View Source [SID:1234508455]). AFT in conjunction with the Alliance for Clinical Trials in Oncology comprises nearly 10,000 cancer specialists at hospitals, medical centers, and community clinics across the United States. AFT will support the phase 3 trial by providing access to its large network of clinical sites and patients, with the goal of accelerating patient enrollment in the trial. Multiple phase 3 clinical trial sites have been opened for patient enrollment in the US, with additional sites anticipated to open in Canada and Europe in the coming weeks and months.

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Andrew Gengos, ImmunoCellular Chief Executive Officer, commented: "Working in collaboration with AFT has the potential to significantly accelerate enrollment in the ICT-107 phase 3 trial, and to engage the participation of important clinical sites throughout in the US. AFT is one of the most highly respected cancer organizations in America, and we are appreciative of their endorsement and support for our registrational trial."

ImmunoCellular has reached agreement with the FDA on a Special Protocol Assessment (SPA) with respect to the primary and secondary endpoints as well as the statistical plan for the phase 3 trial. ImmunoCellular has also been awarded a $19.9 million grant from the governing Board of the California Institute for Regenerative Medicine (CIRM), California’s stem cell agency, to implement the phase 3 registration trial.

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.

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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 7, 2015 MEI Pharma, Inc. (Nasdaq: MEIP), an oncology company focused on the clinical development of novel therapies for cancer, reported positive results from a Phase II study of its investigational drug candidate Pracinostat in combination with azacitidine (marketed as Vidaza) in elderly patients with newly diagnosed acute myeloid leukemia (AML) (Press release, MEI Pharma, DEC 7, 2015, View Source [SID:1234508456]). The results were presented earlier today at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Orlando. A copy of the presentation is now available at www.meipharma.com.

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According to the oral presentation by principal investigator Dr. Guillermo Garcia-Manero, MD Anderson Cancer Center, 28 of the 50 patients in the study (56%) achieved the primary endpoint of complete response (CR) plus complete response with incomplete blood count recovery (CRi) plus morphologic leukemia-free state (MLFS), including 21 patients (42%) who achieved a CR. Notably, 19 of the 21 patients who achieved a CR are still alive with a 100% one-year survival rate among all CR patients, indicating a correlation between CR and survival with this low intensity therapy.

Median overall survival for all 50 patients in the study has not been reached, with 28 patients still living and a median observation time of 14.3 months. These data compare favorably to a recent international Phase III study of azacitidine (AZA-001)1, which showed a median overall survival of 10.4 months with azacitidine alone and a CR rate of 19.5% in a similar patient population. Median survival among patients with high-risk cytogenetics in this study (n=21) was 13.3 months, more than double the median survival of the high-risk population in the AZA-001 study (6.4 months).

"These are impressive results by virtually any measure for a group of patients in dire need of effective new treatment options," said Dr. Garcia-Manero. "Not only did we observe a high rate of responses, but many occurred rapidly and continued to improve with ongoing therapy. Most importantly, we are seeing an encouraging trend in overall survival, particularly among patients who achieved a complete response. These data clearly support further development of Pracinostat in combination with azacitidine for the treatment of elderly patients with AML."

The open-label study enrolled a total of 50 patients at 15 centers across the U.S. Median age in the study was 76 years. Patients received 60 mg of Pracinostat orally three times a week for three weeks followed by one week of rest and 75 mg m2 of azacitidine via subcutaneous injection or intravenous infusion for the first seven days of each 28-day cycle. The combination of Pracinostat and azacitidine was generally well tolerated in the study, with no unexpected toxicities. The most common grade 3/4 treatment-emergent adverse events reported in >10% of all patients included febrile neutropenia, thrombocytopenia, anemia and fatigue.

"We are very excited about our growing body of AML data, which continues to exceed expectations and guide us forward with the development of this program," said Daniel P. Gold, Ph.D., President and Chief Executive Officer of MEI Pharma. "Over the past several months we have learned that our randomized study of Pracinostat and azacitidine in myelodysplastic syndrome (MDS) was hindered by a high rate of discontinuations due to adverse events, but appeared to show a benefit for patients who were able to tolerate treatment for at least four cycles compared to azacitidine alone. The results from our AML study demonstrate that many patients are achieving responses within the first two cycles, with fewer discontinuations overall due to adverse events compared to our MDS study, suggesting a prudent development path forward for the combination.

"Based on these findings," continued Dr. Gold, "we will now begin to prepare for a Phase III registration study of Pracinostat and azacitidine in elderly patients with newly diagnosed AML, which we plan to initiate in the second half of 2016. We look forward to sharing more information regarding the design of this study in the months ahead."

About Pracinostat

Pracinostat is a potent oral inhibitor of a group of enzymes called histone deacetylases, or HDACs. HDACs belong to a larger set of proteins collectively known as epigenetic regulators that can alter gene expression by chemically modifying DNA or its associated chromosomal proteins. Abnormal activity of these regulators is believed to play an important role in cancer and other diseases. Pracinostat has been tested in multiple Phase I and Phase II clinical studies in advanced hematologic diseases and solid tumor indications. The results of these studies suggest that Pracinostat has potential best-in-class pharmacokinetic properties when compared to other oral HDAC inhibitors, with side effects often associated with drugs of this class, including fatigue and myelofibrosis. Pracinostat has not been approved for commercial distribution in the U.S.

MEI Pharma owns exclusive worldwide rights to Pracinostat.

About AML

Acute myeloid leukemia (also known as acute myelogenous leukemia) is the most common acute leukemia affecting adults, and its incidence is expected to continue to increase as the population ages. The American Cancer Society estimates about 20,830 new cases of AML per year in the U.S., with an average age of about 67 years. Treatment options for AML remain virtually unchanged over the past 30 years. Front line treatment consists primarily of chemotherapy, while the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology recommend azacitidine or decitabine (marketed as Dacogen) as low intensity treatment options for AML patients over the age of 60 who are unsuitable for induction chemotherapy.

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.

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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.