On December 6, 2016 Juno Therapeutics, Inc. (NASDAQ: JUNO), a biopharmaceutical company developing innovative cellular immunotherapies for the treatment of cancer, reported an update of key data from studies of its investigational chimeric antigen receptor (CAR) T cell product candidates, presented at the 58th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in San Diego, December 3-6, 2016 (Press release, Juno, DEC 6, 2016, View Source;p=RssLanding&cat=news&id=2228009 [SID1234516977]).

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"We are encouraged by the safety and efficacy results we are seeing with JCAR017 and JCAR014 in several B-cell malignancy settings, including in non-Hodgkin lymphoma, chronic lymphocytic leukemia, and pediatric acute lymphoblastic leukemia, and the possibilities suggested by early data in treating patients with CD19-negative disease," said Hans Bishop, Juno’s President and CEO. "We are also learning more about factors that contribute to efficacy and managing the toxicities associated with CAR T therapy and will apply what we learn to our broader development pipeline."

Pediatric Acute Lymphoblastic Leukemia (ALL): JCAR017
Final results from the Phase I Pediatric Leukemia Adoptive Therapy-02 (PLAT-02) study with JCAR017 in children and young adults with relapsed or refractory (r/r) CD19-positive ALL were presented in an oral session by Rebecca Gardner, M.D., of Seattle Children’s Research Institute (Abstract #219), on Saturday, December 4. JCAR017 uses a defined CD4:CD8 cell composition and 4-1BB as the costimulatory domain, which differentiates it from other CD19-directed CAR T product candidates in clinical development.

The presentation updated data previously presented at ASCO (Free ASCO Whitepaper) in June 2016. It included 43 pediatric and young adult patients treated with JCAR017 who were evaluable for response.

Key results:
40/43 (93%) patients experienced a minimal residual disease (MRD)-negative complete remission (CR).
In patients who received preconditioning with fludarabine/cyclophosphamide (flu/cy) lymphodepletion, the overall response (OR) rate was 14/14 (100%) patients. The estimated 12-month event-free survival is 50.8% (95%CI 36.9, 69.9) and overall survival (OS) is 69.5% (95%CI 55.8, 86.5).
Severe cytokine release syndrome (sCRS) was observed in 10/43 (23%) patients.
A second study presented by Dr. Gardner examined toxicity management in the PLAT-02 trial (Abstract #586). In the study, two cohorts were given either anti-IL6 (tocilizumab) alone or the combination of tocilizumab and the steroid dexamethasone, with the goal of preventing sCRS. Results showed:
Both cohorts experienced similar overall rates of Grade 1-2 CRS following treatment: 21/23 (91%) in cohort 1 and 19/20 (95%) on in the early intervention cohort. In the tocilizumab arm, 7 of 23 (30%) patients experienced sCRS, versus 3/20 (15%) in the tocilizumab / dexamethasone arm.
Early intervention with immunomodulation appeared to decrease the rates of sCRS, while preserving the previously observed high rates of MRD-negative CR.
Long-term persistence of CD19 CAR-T cells is protective against relapse.
Pediatric ALL: JCAR018
Nirali N. Shah, M.D., of the National Cancer Institute, presented data from a Phase I study of JCAR018, a CAR T cell product candidate targeting CD22, in 16 pediatric patients with r/r CD19-negative ALL (Abstract #650) on Monday, December 5. The study is the first to evaluate CAR T cell therapy in patients expressing CD22. All of the patients had been previously treated with anti-CD19 CAR T cell therapy and had previously undergone at least one allogeneic stem cell transplant.
Key results:
The primary adverse event was grade 1-2 cytokine release syndrome, with no severe or irreversible neurotoxicity. There was one death due to sepsis in a patient after resolution of CRS.
3/9 (33%) patients are in ongoing remission ranging 3-12+ months.
Results showed 7/8 (88%) patients achieved an MRD-negative CR with flu/cy lymphodepletion followed by JCAR018 at dose level 2 (1 x 106 transduced CAR T cells/kg).
The study continues to enroll patients. Juno is currently testing pre-clinical constructs to better understand the optimal way to target these two antigens in the same product.
Diffuse Large B-Cell Lymphoma (DLBCL): JCAR017
In a poster presentation on Monday, December 5, Jeremy Abramson, M.D., of Massachusetts General Hospital Cancer Center, presented results from the Phase I TRANSCEND study in patients with r/r DLBCL, follicular lymphoma grade 3B or mantle cell lymphoma (MCL) who were treated with flu/cy lymphodepletion and JCAR017.
Topline results included a 12/20 (60%) complete response in patients with r/r DLBCL (N=19) and follicular lymphoma grade 3B (N=1) treated with a single dose of JCAR017 at dose level 1 (5×107 cells). No sCRS was observed; grade 3-4 neurotoxicity was observed in 3/22 (14%) patients, all of whom received the steroid dexamethasone for neurotoxicity. In addition, the side effect profile plus cell persistence suggests the potential for combination therapy.
The Phase I TRANSCEND trial continues, enrolling more patients at dose levels 1 and 2. Juno intends to initiate a pivotal trial in the U.S. in patients with r/r DLBCL in 2017.
Chronic Lymphocytic Leukemia (CLL): JCAR014
In an oral presentation on Saturday, December 4, Cameron Turtle, M.B.B.S., Ph.D., of the Fred Hutchinson Cancer Research Center, reported on results from a Phase I study of heavily pre-treated patients with CLL who failed treatment with ibrutinib, the standard-of-care treatment for CLL. Fifteen of 17 (88%) efficacy-evaluable patients who had bone marrow disease at the start of the trial and treated with flu/cy and the two lowest doses of JCAR014 had a complete marrow response by flow cytometry. Fourteen of the complete bone marrow response patients had a response assessment by the more sensitive method of IgH deep sequencing, with 7/14 (50%) having no detectable disease. All seven of these patients are alive and progression free with follow-up ranging from 3 to 26 months.
Two of 24 (8%) patients developed grade 3-5 sCRS and 6/24 (25%) patients developed grade 3-5 severe neurotoxicity. There was one treatment-related mortality (4%) in the trial in a patient who received flu/cy lymphodepletion, with both grade 5 CRS and cerebral edema.
Plans to study JCAR014 in combination with ibrutinib in CLL are underway, with a cohort expected to begin enrollment in early 2017. Juno is evaluating the use of this data with JCAR014 as a monotherapy and in combination with ibrutinib in support of a potential Juno-sponsored trial with JCAR017 in CLL.

On December 6, 2016 Geron Corporation (Nasdaq:GERN) reported four presentations of exploratory preclinical and clinical data related to the imetelstat program at the 58th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition held in San Diego, California from December 3-6, 2016 (Press release, Geron, DEC 6, 2016, View Source;p=RssLanding&cat=news&id=2228012 [SID1234516976]). The presentations are available on Geron’s website at www.geron.com/presentations.

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"The imetelstat data presented at ASH (Free ASH Whitepaper) this year indicate the potential application of imetelstat in multiple myeloid malignancies," said John A. Scarlett, M.D., Geron’s President and Chief Executive Officer. "These presentations reflect the ongoing work by academic scientists, clinical investigators and our colleagues at Janssen to advance the imetelstat program, and support the clinical trials being conducted by Janssen in patients with myelofibrosis and myelodysplastic syndromes, who are in need of new treatment options."

Oral Presentation

Title: The preclinical efficacy of a novel telomerase inhibitor, imetelstat, in AML – a randomized trial in patient-derived xenografts (Abstract #578)

Academic scientists presented data of imetelstat’s activity in human acute myeloid leukemia (AML) xenograft models. The preclinical data demonstrated that imetelstat prolonged overall survival of AML xenografts derived from nine out of 15 individual patient samples compared to saline-treated controls, with robust responses associated with favorable cytogenetic risk groups and mutations in molecular pathways controlling DNA damage. The effects on normal human hematopoiesis were modest and predominantly seen in the B-lymphocyte lineage with relative preservation of myeloid and stem cell populations. These data build on previously published preclinical work conducted in patient-derived models of AML and suggest potential application of imetelstat in the treatment of AML.

Poster Presentations

Title: Characterization of Disease, Treatment Patterns, and Outcomes of Patients with Myelofibrosis: Analysis of 2 United States Commercial Claims Databases (Abstract #4769)

Janssen presented an analysis of treatment patterns and outcomes of patients with myelofibrosis (MF) diagnosed between 2006 and 2015 from two United States medical health insurance claims databases. The analysis suggests that many MF patients (43%) received no treatment or supportive care, and only a fraction received ruxolitinib in spite of a favorable median overall survival associated with frontline treatment (30 months compared with 22 months for patients receiving other treatments). Among patients who failed or discontinued frontline ruxolitinib, the median overall survival was seven months, which underscores the need for new treatment options for this disease.

Title: Dynamics of Telomere Length Reflect the Clonal Suppression Seen with the Telomerase Inhibitor Imetelstat in Patients with Essential Thrombocythemia (Abstract #1938)

Academic scientists and clinical investigators from the prior Geron-sponsored proof-of-concept study in patients with essential thrombocythemia (ET) presented new clinical data on telomere length dynamics following treatment with imetelstat. The data showed that in 10 out of 13 ET patients, telomere length in granulocytes was higher after nine months of treatment with imetelstat, and the change correlated with the reduction of JAK2V617F mutational burden. These observations suggest that imetelstat may suppress neoplastic clones and favor recovery of normal hematopoiesis in these patients providing further evidence of the potential disease-modifying activity of imetelstat in hematologic myeloid malignancies.

Title: Telomerase Inhibition with Imetelstat Eradicates β-catenin Activated Blast Crisis Chronic Myeloid Leukemia Stem Cells (Abstract #3065)

Academic scientists presented a preliminary investigation into the potential impact of imetelstat on leukemia stem cells in non-clinical models of chronic myeloid leukemia (CML) in blast crisis. The preclinical data suggest that imetelstat plus dasatinib, a standard treatment for CML, may inhibit self-renewal of blast crisis cells in vitro compared with normal bone marrow progenitors. In mouse xenograft models of blast crisis CML, imetelstat treatment reduced the number of leukemia progenitor cells detected in bone marrow and decreased expression of β-catenin, which is believed to be required for the self-renewal of leukemic stem cells in CML. This is the first report of data to suggest that imetelstat might inhibit proliferation of malignant progenitors in CML.

About Imetelstat

Imetelstat (GRN163L; JNJ-63935937) is a potent and specific inhibitor of telomerase that is administered by intravenous infusion. This first-in-class compound, discovered by Geron, is a specially designed and modified short oligonucleotide, which targets and binds directly with high affinity to the active site of telomerase. Preliminary clinical data suggest imetelstat has disease-modifying activity by inhibiting malignant progenitor cell clones associated with hematologic malignancies in a relatively select manner. Most commonly reported adverse events in imetelstat clinical studies include fatigue, gastrointestinal symptoms and cytopenias. Patients in these studies also experienced elevated liver enzymes, which resolved to normal or baseline in the majority of patients followed after imetelstat treatment was withdrawn. Imetelstat has not been approved for marketing by any regulatory authority.

On December 6, 2016 TG Therapeutics, Inc. (NASDAQ:TGTX), reported that the target enrollment of 120 patients in the GENUINE Phase 3 study has been met and enrollment will be closed shortly (Press release, TG Therapeutics, DEC 6, 2016, View Source [SID1234516974]). The GENUINE Phase 3 study is a randomized study of TG-1101, the Company’s novel, glycoengineered anti-CD20 monoclonal antibody in combination with ibrutinib, the oral Bruton’s tyrosine kinase (BTK), versus ibrutinib alone in approximately 120 patients with high-risk relapsed or refractory Chronic Lymphocytic Leukemia (CLL). In October, the study was modified to convert the primary endpoint solely to Overall Response Rate (ORR). If the study results are positive, and subject to a positive outcome of pre-BLA meeting with the FDA, the Company plans to utilize the results to file for accelerated approval. The Company expects to release top-line data from the GENUINE Phase 3 study in the first half of 2017.

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Michael S. Weiss, the Company’s Executive Chairman and Interim CEO commenting on the announcement stated, "Today’s news puts us on a clear path toward our first pivotal data for TG-1101. As demonstrated in our Phase 2 study evaluating TG-1101 plus ibrutinib, we believe the addition of an anti-CD20 monoclonal antibody can enhance the clinical response of single agent ibrutinib by more rapidly reducing tumor burden, increasing the rate of response, deepening responses and, ideally, leading to better long-term outcomes. Overall response rate has been utilized as an acceptable surrogate endpoint for improved progression free survival and overall survival for a number of recent approvals in high-risk CLL and we believe the results, if positive, may support an accelerated approvable for the combination. We want to thank our clinical collaborators and their patients for their participation in this study."

On December 6, 2016 TG Therapeutics, Inc. (NASDAQ:TGTX), reported the presentation yesterday of data from three combination studies involving the Company’s lead compounds, TGR-1202, the Company’s once-daily PI3K delta inhibitor, and TG-1101 (ublituximab), the Company’s novel glycoengineered anti-CD20 monoclonal antibody at the 58th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, in San Diego, California (Press release, TG Therapeutics, DEC 6, 2016, View Source [SID1234516973]).

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Michael S. Weiss, the Company’s Executive Chairman and Interim CEO stated, "We are very pleased to continue to see a highly differentiated safety profile for TGR-1202 across multiple double and triple combination studies with a high level of activity. Each of the four clinical studies presented at the ASH (Free ASH Whitepaper) meeting, enhanced our overall understanding of the breadth of activity of TGR-1202. In addition to DLBCL, FL and CLL, where we have already shown data previously, it was nice to see the flexibility of TGR-1202 and its ability to be combined with brentuximab vedotin in relapsed or refractory Hodgkin’s and with ruxolitinib in Myelofibrosis." Mr. Weiss continued, "We are also encouraged by the triple combination data of TG-1101, TGR-1202, and bendamustine in relapsed or refractory, difficult to treat, DLBCL and FL patients which showed no discontinuations for a treatment related adverse event, as well as an 80% overall response rate across both DLBCL and FL patients and a high level of CR’s. We, and our investigators, believe this triplet combination is a promising regimen and plan to study it in this patient population in a registration-directed trial."

Highlights from yesterday’s presentations include the following:

Poster Presentation: Combination of Ublituximab, TGR-1202, and Bendamustine Demonstrates Significant Activity in Patients with Advanced DLBCL and Follicular Lymphoma (Abstract Number 4197)

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 TG-1101 (ublituximab), TGR-1202 and bendamustine. Nineteen patients were evaluable for safety of which 15 were evaluable for efficacy (3 patients were too early to evaluate and 1 patient had a non-related adverse event (AE) prior to efficacy assessment). The triple combination appears well tolerated with no discontinuations for a treatment related AE. Neutropenia and anemia were the only Grade 3/4 AE’s occurring in more than 1 patient. Importantly, no Grade 3/4 transaminitis was reported, no events of pneumonia or pneumonitis, and only 1 transient event of Grade 3 diarrhea, with a duration of 1 day, was observed. Eleven patients (58%) were refractory to prior treatment. Median time on study at the data cut off was approximately 6 months with the majority of patients continuing on study and follow-up ongoing.

Efficacy highlights from this poster include:

71% (5 of 7) Overall Response Rate (ORR), including a 43% Complete Response (CR) rate observed in patients with relapsed or refractory DLBCL
88% (7 of 8) ORR, including a 37% CR rate observed in patients with relapsed or refractory FL 4/6 CR’s that were achieved between the DLBCL and FL groups occurred at the first 8 week efficacy assessment
First response assessment occurred at Month 3 following initiation of therapy, with durable responses observed notably amongst DLBCL patients.
Poster Presentation: A Phase I Trial of TGR-1202, a Next Generation Once-Daily PI3Kδ Inhibitor, in Combination with Brentuximab Vedotin, in Patients with Relapsed/Refractory Hodgkins Lymphoma (Abstract Number 4146)

This poster presentation includes data from patients with relapsed and refractory Hodgkin’s Lymphoma (HL) treated with TGR-1202 at either 400mg or 600mg dosed orally once daily in combination with brentuximab vedotin in continuous 21 day cycles. 14 patients were evaluable for safety, of which 11 were evaluable for efficacy (3 discontinued prior to disease evaluation (2 AE’s and 1 withdrew consent)). 43% (6 of 14) of patients had prior exposure to brentuximab vedotin and all were refractory to prior brentuximab vedotin therapy. The combination demonstrated tolerability with nausea, diarrhea, and neutropenia being the most prevalent adverse events. Notably all but one case of diarrhea was Grade 1 or 2 in severity.

Efficacy highlights from this poster include:

60% (3 of 5) ORR, including a 40% CR rate observed across brentuximab vedotin refractory patients
64% (7 of 11) ORR, including a 45% CR rate observed across all patients treated

Oral Presentation: Preliminary Results from a Phase I Dose Escalation Trial of Ruxolitinib and the PI3Kδ Inhibitor TGR-1202 in Myelofibrosis (Abstract Number 1125)
This oral presentation includes data from patients with myelofibrosis treated with the combination of ruxolitinib, the JAK1/2 inhibitor and TGR-1202. The combination was well tolerated and efficacious in the twelve patients treated. The most prevalent adverse events deemed at least possibly related to TGR-1202 included anemia, thrombocytopenia, neutropenia, AST/ALT elevation and amylase/lipase elevation and diarrhea, all of which were notably Grade 1/2 with the exception of Grade 3 amylase/lipase elevation seen in 2 patients (16.7%), and Grade 3 diarrhea seen in 1 patient (8.3%). Presentation highlights included:

The patient population enrolled was advanced, with the majority having 2 or more prior mutations at baseline;
Per protocol, all enrolled patients were on a stable dose of ruxolitinib monotherapy with best response to ruxolitinib monotherapy achieved prior to enrollment;
Following the addition of TGR-1202, 11/12 patients experienced improvement in hemoglobin, many with a concomitant reduction in platelet counts indicating clinical benefit beyond ruxolitinib monotherapy; and
83% of study participants experienced clinical benefit (hematologic improvement, reduced spleen size and/or improvement in symptoms) including one patient who achieved a CR and continues on study, now out 72 weeks

PRESENTATION DETAILS:
Copies of the above referenced presentations are available on the Company’s website at www.tgtherapeutics.com, located on the Publications page.

TG THERAPEUTICS INVESTOR & ANALYST EVENT:
TG Therapeutics held an investor and analyst reception yesterday, at the Marriott Gaslamp, in San Diego, California. The audio file and slide presentation are available for review on the Events page, located within the Investors & Media section of the Company’s website at www.tgtherapeutics.com.

On December 6, 2016 Oncolytics Biotech Inc. ("Oncolytics" or the "Company") (TSX:ONC) (OTCQX:ONCYF) reported that Dr. Kevin Kelly and colleagues made a poster presentation at the 58th American Society of Hematology (ASH) (Free ASH Whitepaper) ("ASH") Annual Meeting (Filing, 6-K, Oncolytics Biotech, DEC 6, 2016, View Source [SID1234516972]). The poster presentation, titled "Oncolytic Reovirus Immune Priming: A Phase Ib Study of REOLYSIN with Bortezomib and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma," provides initial findings from the Company’s REO 019 Phase Ib trial. The ASH (Free ASH Whitepaper) Annual Meeting runs from December 3rd to 6th in San Diego, CA.

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The study is a two-stage open-label Phase Ib trial of adult patients with relapsed or refractory multiple myeloma following at least one line of therapy. This study was designed to evaluate tolerability, to confirm that the addition of REOLYSIN to bortezomib increases endoplasmic reticulum stress and death of myeloma cells (as shown in preclinical models) and to document pharmacodynamic effects as part of the characterization of the mechanism(s) of action of REOLYSIN in multiple myeloma. Kevin Kelly, M.D., Ph.D. of the Keck School of Medicine of the University of Southern California (USC), is the principal investigator.

"The combination of REOLYSIN, bortezomib and dexamethasone was well-tolerated in these heavily pre-treated patients, even in those who had been previously exposed to bortezomib," said Dr. Kevin Kelly. "Preliminary evidence of activity of this combination was documented. It was also shown that the combination therapy induced the apoptosis of myeloma cells and stimulated the immune system, highlighted by improved cytotoxic T cell infiltration and activation of checkpoint inhibitors (IDO, PD-L1) in the tumor."

The dose escalation study tested three doses ranging from 3 to 9×1010 TCID50 on days 1, 2, 8, 9, 15 and 16, with 40 mg dexamethasone and 1.5 mg/m2 bortezomib on days 1, 8, and 15. Cycles were repeated every 28 days. A maximum tolerated dose was not defined because there were no dose-limiting toxicities in the first two cohorts. Cohort 3 is still enrolling patients. The combination was well tolerated and most treatment emergent toxicities were transient and easily managed with supportive care. The most common treatment related toxicities were grade 1 diarrhea, grade 1 fatigue, grade 1 flu-like symptoms and grade 1 headache.

Three patients completed 1 cycle of treatment only, 2 completed 3 cycles, 1 completed 4 cycles and 1 completed 7 cycles. Two patients remain on protocol (1 has completed 3 cycles (Cohort 3) and the other 7 cycles (Cohort 2)). Six patients were evaluable for response, 4 patients had stable disease lasting at least 1 cycle, whereas 3 patients had progressive disease at the end of cycle 1.

"It is intriguing that this combination therapy with REOLYSIN induced an immune response with mainly grade 1 level toxicity, which is consistent with what we have observed in studies with other REOLYSIN combinations in solid tumors," said Dr. Matt Coffey, Interim President and CEO of Oncolytics Biotech. "These data build on what we have observed in previous studies in both multiple myeloma and solid tumours, and further investigation is needed to evaluate if the immune modulatory and anti-tumor activity of REOLYSIN can provide a therapeutic opportunity to patients with hematological malignancies when combined with other targeted treatments including immunotherapies."

A copy of the poster will be available on the Oncolytics website at: View Source

About Multiple Myeloma
Multiple Myeloma is a cancer of the plasma cells and the second most common hematological malignancy. The American Cancer Society estimates there will be 30,330 new cases diagnosed in the United States and 12,650 deaths from the disease in 2016.