1stOncology™: Cancer Intelligence Service – Page 15830 – 1stOncology is recognized as a Top 10 Global Pharma Analytic Provider

Chi-Med Presents Pre-clinical Data for Selective Syk Inhibitor HMPL-523 at the 2016 American Society of Hematology Annual Meeting

On December 6, 2016 Hutchison China MediTech Limited ("Chi-Med") (AIM/Nasdaq: HCM) reported that data from a recent pre-clinical study, investigating the in vitro and in vivo anti-tumor activities of novel Spleen Tyrosine Kinase ("Syk") inhibitor, HMPL-523, was presented at the Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) ("ASH"), being held in San Diego, CA, USA from December 3 to December 6, 2016 (Press release, Hutchison China MediTech, DEC 6, 2016, http://www.chi-med.com/hmpl-523-data-at-ash-2016/ [SID1234516989]).

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!

Syk, a non-receptor type of tyrosine kinase, plays a pivotal role in the regulation of the B-cell receptor (BCR) signaling pathway, which regulates proliferation, differentiation and survival of B lymphocytes. The abnormal activation of BCR signaling is closely related to transformation and development of B-cell lymphoma.

Presentation Title: HMPL-523, a Novel Syk Inhibitor, Showed Anti-Tumor Activities in Vitro and in Vivo
Authors: Na Yang, Wei Deng, Qiaoling Sun, Junqing Liang, Linfang Wang, Shiming Fan, Renxiang Tang, Ying Yu, Junen Sun, Feng Zhou, Guangxiu Dai, Weiguo Qing, Weiguo Su and Yongxin Ren
Abstract No: 3970
Session: 605. Molecular Pharmacology, Drug Resistance—Lymphoid and Other Diseases
Date & Time: Monday, December 5, 2016, 6:00PM – 8:00PM (PST)

The presentation is available at www.chi-med.com/wp-content/uploads/2016/12/pre161206_523ash.pdf.

Potent anti-tumor activity and combination synergy with other therapies

In vitro in B-cell lymphoma cell lines with Syk/BCR dysregulation, HMPL-523 was found to block phosphorylation of B-cell linker protein as well as inhibit cell viability by inhibiting cell survival and increasing apoptotic rate. HMPL-523 also showed synergistic anti-tumor activity on human diffused large B-cell lymphoma cells, in combination with other drugs such as Phosphoinositide-3-Kinase δ inhibitors, B-cell lymphoma 2 family inhibitors, or chemotherapies. Potent anti-tumor activity was also demonstrated in nude mice bearing B-cell lymphoma xenograft tumors with Syk/BCR dysregulation.

Clinical development in oncology and immunology

In hematological malignancies, HMPL-523 is currently being studied in a Phase I dose escalation study, which was initiated in Australia in January 2016 and is expected to complete in the first half of 2017. This study is in patients with relapsed and/or refractory B-cell non-Hodgkin’s lymphoma or chronic lymphocytic leukemia for whom there is no standard therapy.

HMPL-523 is also being studied in immunological indications. Clinical data for HMPL-523 in a Phase I dose-escalating study in healthy volunteers in Australia was recently presented at the 2016 Annual Meeting of the American College of Rheumatology/Association of Rheumatology Health Professionals, which was held in November 2016. The detailed poster presentation can be viewed at www.chi-med.com/wp-content/uploads/2016/11/pre1611141.png. The Company plans to initiate a Phase II study in the U.S. in 2017.

About the ASH (Free ASH Whitepaper) Annual Meeting

The ASH (Free ASH Whitepaper) annual meeting, a scientific conference focused on malignant and non-malignant hematology, brings together more than 20,000 hematology professionals from around the world. The meeting provides an educational experience, with thousands of scientific abstracts highlighting the latest research in the field available for review, as well as the opportunity to network with a global community of professionals from every subspecialty.

About B-cell signaling

The BCR signaling pathway regulates proliferation, differentiation and survival of B lymphocytes, a major cellular component of the immune system. The abnormal activation of BCR signaling is closely related to transformation and development of hematological cancers (i.e. B-cell malignancies) including lymphoma and leukemia, as well as autoimmune diseases, such as rheumatoid arthritis. Targeted B-cell receptor signaling therapies, including monoclonal antibodies and small molecules, have been proven to be clinically effective for the treatment of B-cell malignancies, leading to scientific and commercial success.

Syk is a key protein involved in the B-cell signaling pathway.

Cellectar Biosciences Presents Poster at the 58th Annual Meeting of the American Society of Hematology

On December 6, 2016 Cellectar Biosciences, Inc. (Nasdaq: CLRB) (the "company"), an oncology-focused, clinical stage biotechnology company, reported that it presented a poster at the 58th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) in San Diego, which provides highlights of the company’s ongoing Phase I dose escalation clinical study of CLR 131 to assess safety and tolerability of the compound in patients with relapsed or refractory multiple myeloma (Filing, 8-K, Cellectar Biosciences, DEC 6, 2016, View Source [SID1234516979]). The poster provided detailed data related to the first two study cohorts.

The poster followed patients from initial infusion of CLR 131, the company’s lead PDC radiotherapeutic, through November 1, 2016. Results demonstrated all eight evaluable patients (of the total of ten enrolled) achieving a minimum of stable disease. The poster also reported a mean of approximately three months of progression-free survival (PFS) in Cohort 1 and four months in Cohort 2. To date, one patient in Cohort 2 continues to experience PFS. Significantly, four of eight patients experienced a greater than 50 percent reduction in serum free light chains (FLC), which are a key efficacy indicator for multiple myeloma. Per the International Myeloma Working Group (IMWG) criteria, in the absence of M protein, an FLC reduction of 50 percent or greater, is defined as a partial response. Overall, Cohort 2 patients experienced a more significant FLC reduction and a more sustained FLC response versus Cohort 1, with the difference in reduction being maintained across the entire study, and increasing at the subsequent evaluation time points. Cohort 2 patients achieved a 20 percent greater reduction in FLC on day 22 than was experienced by patients in Cohort 1, a 38 percent greater reduction at Day 43 and 43 percent greater FLC reduction at the final evaluation time point, Day 64.

Importantly, seven of eight evaluable patients achieved a reduction in either serum or urine M protein, which also are key efficacy indicators for multiple myeloma. Similar to the FLC marker, the Cohort 2 reduction of M protein was more sustained with the patients experiencing continued reduction in M protein beyond day 64. It is also important to note that based upon M protein reduction 38 percent of patients experienced a minimal response at these low, one-time doses.

The primary endpoint for this study is to determine the safety and tolerability of CLR 131 in a heavily pre-treated patient population. Evaluable study patients received an average of four prior lines of treatment. The adverse event profile in both cohorts was similar and showed no dose dependency. While the leading adverse events were leukopenia and thrombocytopenia (30 percent each) with a median grade of 2 (mild to moderate) for both, there have been no dose-limiting toxicity events to date. Importantly, no patients experienced non-hematologic adverse events as seen with many other compounds used to treat this patient population. Specifically, there were no reports of peripheral neuropathy, fatigue, cardiovascular events, or venous thromboembolisms. The efficacy and safety profile of CLR 131 shown to date allows future development of the compound, either at the Cohort 2 dose of 18.75 mCi/m2 or at one of the future higher doses being tested. The study is currently completing Cohort 3 at a single 25 mCi/m2 dose.

"ASH is a prestigious conference and this presentation represents a peer reviewed opportunity to report encouraging efficacy and safety data from our Phase I study of CLR 131 in relapsed/refractory multiple myeloma," said Jim Caruso, president and CEO of Cellectar Biosciences. "We look forward to reporting data from Cohort 3 at a single 25 mCi/m2 dose and the initiation of our NCI-sponsored Phase II trial in multiple myeloma and other hematologic malignancies."

The Phase I multi-center, open label, dose escalation study described in the poster outlines that CLR 131 was administered as a single dose, 30-minute intravenous infusion on Day 1 with a 40 mg oral dexamethasone dose weekly for 12 weeks. Each cohort consisted of five patients, of which four were evaluable (three men, one woman in Cohort 1 and two men, two women in Cohort 2). Patients in both cohorts received an average of 4 prior treatments. Half of all patients received a stem cell transplant. All patients received proteasome inhibitors and immunomodulatory drugs prior to enrollment as well as triple combination therapy at least once.

About CLR 131
CLR 131 is an investigational compound under development for a range of hematologic malignancies. It is currently being evaluated in a Phase I clinical trial in patients with relapsed or refractory multiple myeloma. The company plans to initiate a Phase II clinical study to assess efficacy in a range of B-cell malignancies in the first quarter of 2017. Based upon pre-clinical and interim Phase I study data, treatment with CLR 131 provides a novel approach to treating hematological diseases and may provide patients with therapeutic benefits, including overall response rate (ORR), an improvement in progression-free survival (PFS) and overall quality of life. CLR 131 utilizes the company’s patented PDC tumor targeting delivery platform to deliver a cytotoxic radioisotope, iodine-131 directly to tumor cells. The FDA has granted Cellectar an orphan drug designation for CLR 131 in the treatment of multiple myeloma.

About Phospholipid Drug Conjugates (PDCs)
Cellectar’s product candidates are built upon its patented cancer cell-targeting delivery and retention platform of optimized phospholipid ether-drug conjugates (PDCs). The company deliberately designed its phospholipid ether (PLE) carrier platform to be coupled with a variety of payloads to facilitate both therapeutic and diagnostic applications. The basis for selective tumor targeting of our PDC compounds lies in the differences between the plasma membranes of cancer cells compared to those of normal cells. Cancer cell membranes are highly enriched in lipid rafts, which are glycolipoprotein microdomains of the plasma membrane of cells that contain high concentrations of cholesterol and sphingolipids, and serve to organize cell surface and intracellular signaling molecules. PDCs have been tested in over 70 different xenograft models of cancer.

About Relapsed or Refractory Multiple Myeloma
Multiple myeloma is the second most common blood or hematologic cancer with approximately 30,000 new cases in the United States every year. It affects a specific type of blood cells known as plasma cells. Plasma cells are white blood cells that produce antibodies to help fight infections. While treatable for a time, multiple myeloma is incurable and almost all patients will relapse or the cancer will become resistant/refractory to current therapies.

Bio-Path Holdings Presents Clinical Data Evaluating BP1001 as a Treatment for Chronic Myelogenous Leukemia at the 58th Annual American Society of Hematology Annual Meeting

On December 5, 2016 Bio-Path Holdings, Inc., (NASDAQ: BPTH), a biotechnology company leveraging its proprietary DNAbilize liposomal delivery and antisense technology to develop a portfolio of targeted nucleic acid cancer drugs, reported that a review of BP1001 data as a treatment for chronic myelogenous leukemia (CML) was presented in a poster at the 58th Annual American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting taking place from December 3-6, 2016 in San Diego, CA (Filing, 8-K, Bio-Path Holdings, DEC 6, 2016, View Source [SID1234516978]).

Ana Tari Ashizawa, Ph.D., Bio-Path’s director of research, presented the poster titled "BP1001, a Novel Therapeutic for Chronic Myelogenous Leukemia." The results demonstrated that BP1001 decreased the proliferation of Gleevec (imatinib)-resistant CML cells in a dose-dependent manner. In addition, BP1001 pretreatment enhanced the inhibitory effects of Sprycel (dasatinib) in CML cells, leading to cell death. Five CML blast phase patients were enrolled in the first cohort (5 mg/m2 BP1001) of the Phase 1 BP1001 clinical study. Two CML patients, who had T315I mutation, showed significant reductions in circulating blasts during treatment. One patient’s blasts were reduced from 89% to 12%, while another patient’s blasts were reduced from 24% to 7%.

"These patient data, supported by previous in vivo and in vitro results, suggest that BP1001 has the potential to treat the 33% of CML patients who are resistant to Gleevec, the current standard of care. Sprycel is a second-generation tyrosine kinase inhibitor that is often used for Gleevec resistant patients. We are pleased that our preclinical results showed that BP1001 can enhance Sprycel activity in CML cells. These positive data give us confidence that BP1001 could play a valuable role in treating this patient population and encourage us to move forward with the initiation of our safety segment of the Phase 2 trial in patients with CML," said Peter Nielsen, chief executive officer of Bio-Path Holdings.

About BP1001

BP1001 (Liposomal Grb2 antisense) is Bio-Path’s lead product candidate, a neutral-charge, liposome-incorporated antisense drug designed to inhibit protein synthesis of Grb2 (growth factor receptor bound protein 2). Grb2 plays an essential role in cancer cell activation via the RAS pathway. Grb2 is an adapter protein that bridges signals between activated and mutated tyrosine kinases, such as Flt3, c-Kit, and Bcr-Abl, and the Ras pathway, leading to activation of the ERK and AKT proteins. Inhibition of Grb2 by BP1001 represents a significant advance in treating cancers with activated tyrosine kinases using a target not druggable with antibodies or kinase inhibitors. Inhibition of Grb2 has been demonstrated to halt cell proliferation and enhance cell killing by chemotherapeutic agents without added toxicity.

Juno Therapeutics Highlights Progress with Best-in-Class Strategy in B-Cell Malignancies at ASH

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]).

"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.

Geron Reports Imetelstat Presentations at American Society of Hematology Annual Meeting

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.

"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.