On April 16, 2018 BeiGene, Ltd. (NASDAQ:BGNE), a commercial-stage biopharmaceutical company focused on developing and commercializing innovative molecularly targeted and immuno-oncology drugs for the treatment of cancer, reported that preliminary clinical data from an ongoing Phase 1 trial of its investigational PARP inhibitor pamiparib in Chinese patients with locally advanced or metastatic high-grade non-mucinous ovarian cancer (HGOC), including fallopian cancer, or triple-negative breast cancer (TNBC), who had disease progression following at least one line of chemotherapy were presented at the 2018 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, being held in Chicago (Press release, BeiGene, APR 16, 2018, View Source;p=RssLanding&cat=news&id=2342698 [SID1234525331]). Data presented from the dose-escalation phase of the ongoing Phase 1 trial confirmed the recommended Phase 2 dose (RP2D) of 60mg twice daily (BID) in Chinese patients and demonstrated that pamiparib showed antitumor activity and was generally well tolerated in these patients.

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"In these heavily pre-treated patients with ovarian and breast cancers, the preliminary results support the recommended pamiparib dosing regimen and demonstrated antitumor activity, including partial responses in platinum-resistant or refractory patients with ovarian cancer. We saw no dose-limiting toxicities and found pamiparib to be generally well tolerated among these patients," said Binghe Xu, M.D., Director of the Department of Medical Oncology, at the Cancer Hospital, Chinese Academy of Medical Sciences in Beijing, China, and the lead author of the poster presentation.

"In China, there are no currently approved PARP inhibitors, yet there are an aggregate of approximately 75,000 new cases of ovarian cancer1 and triple-negative breast cancer diagnosed each year1,2, and it is estimated that between 25 and 30 percent of ovarian cancer3 and between 15 and 204 percent of triple-negative breast cancer patients harbor a germline mutation in BRCA1/2 and therefore may benefit from a PARP inhibitor. We look forward to advancing pamiparib’s development in China as well as initiating a global Phase 3 trial," commented Amy Peterson, M.D., Chief Medical Officer for Immuno-Oncology of BeiGene.

Summary of Results from the Ongoing Phase 1 Trial
This open-label, multi-center Phase 1 dose-escalation trial of pamiparib (NCT03333915) was designed to confirm RP2D and to evaluate its safety, tolerability and antitumor activity in Chinese patients with locally advanced or metastatic HGOC, including fallopian and primary peritoneal cancer, or patients with TNBC. Patients were dosed at 20mg, 40mg, or 60mg BID. As of September 25, 2017, 15 female patients were enrolled, nine with HGOC and six with TNBC. Nine patients received four or more prior lines of therapies. All nine patients with HGOC were platinum-resistant (n=8) or refractory (n=1). Seven patients had a confirmed BRCA1/2 mutation (BRCAm), including five patients with HGOC and two patients with TNBC and the remaining patients had BRCA 1/2 wildtype (BRCA-WT). The median duration of treatment was 2.5 months (range: 8-260 days).

Pamiparib was shown to be generally well tolerated. No dose-limiting toxicities were reported across the dose range, with RP2D confirmed as 60mg BID. Asthenia (n=12) and nausea (n=12) were the most commonly reported treatment-emergent adverse events (AE). Severity of all adverse events was grade 3 or less. Overall, three patients experienced a serious AE (grade 2 abdominal infection, n=1; grade 3 pleural effusion, n=1; grade 3 ileus, n=1), none of which were considered related to treatment. Two of the serious AEs led to treatment withdrawal (abdominal infection, n=1; pleural effusion, n=1).

As of September 25, 2017, 13 of the 15 patients were evaluable for antitumor activity; five patients remained on treatment. Two of the nine HGOC patients achieved a confirmed partial response including one platinum-refractory patient with BRCA wildtype status and one platinum-resistant patient with BRCA1/2 mutation, six HGOC patients had stable disease (BRCAm, n=4 and BRCA-WT, n=2) and one patient discontinued before the first radiographic assessment. Of the six treated TNBC patients, five (BRCAm, n=1, BRCA-WT, n=4) experienced disease progression and one patient (BRCAm) discontinued before the first radiographic assessment. Four of these evaluable TNBC patients were BRCA-WT and all experienced disease progression during the previous platinum-based chemotherapy.

About Pamiparib
Pamiparib (BGB-290) is an investigational inhibitor of PARP1 and PARP2 which has demonstrated pharmacological properties such as brain penetration and PARP–DNA complex trapping in preclinical models. Pamiparib is being evaluated in a pivotal clinical trial in China. It is currently in global clinical development as a monotherapy, and in combination with other agents, including BeiGene’s investigational anti-PD1 antibody, tislelizumab (BGB-A317), for a variety of solid tumor malignancies.

On April 16, 2018 BeiGene, Ltd. (NASDAQ:BGNE), a commercial-stage biopharmaceutical company focused on developing and commercializing innovative molecularly targeted and immuno-oncology drugs for the treatment of cancer, reported that the first patient was dosed in a global Phase 2 clinical trial of tislelizumab, an investigational anti-PD-1 antibody, in patients with relapsed or refractory mature T- and natural killer (NK)-cell lymphomas (Press release, BeiGene, APR 16, 2018, View Source;p=RssLanding&cat=news&id=2342635 [SID1234525330]). Tislelizumab is also being studied in global Phase 3 trials in solid tumors, including non-small cell lung cancer, hepatocellular carcinoma, and esophageal squamous cell carcinoma, and two pivotal Phase 2 trials in China in relapsed/refractory classical Hodgkin lymphoma and urothelial cancer.

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"We are pleased to be enrolling patients in our first global Phase 2 study in hematology of tislelizumab, for which we maintain global development and commercial rights," commented John V. Oyler, Founder, Chief Executive Officer, and Chairman of BeiGene.

"We believe that patients with relapsed or refractory mature T-cell and NK-cell lymphomas represent a significant unmet need. There are no currently approved treatments for the majority of mature T-cell lymphomas, in particular extranodal NK/T-cell lymphomas. We believe that these virally-associated diseases represent logical targets for checkpoint inhibition and we are excited to evaluate tislelizumab as a potential treatment option for these patients," commented Jane Huang, M.D., Chief Medical Officer, Hematology, at BeiGene.

The Phase 2, open-label, multi-center trial is designed to assess the efficacy and safety of tislelizumab in patients with relapsed or refractory mature T- and NK-cell neoplasms. Patients will receive 200 mg of tislelizumab every three weeks in each of the trial’s two histological cohorts:

Cohort 1 – patients with relapsed or refractory extranodal NK/T cell lymphoma (nasal or non-nasal type); and
Cohort 2 – patients with other mature T-cell neoplasms, limited to histologies including peripheral T-cell lymphoma not otherwise specified (NOS), angioimmunoblastic T-cell lymphoma, and anaplastic large cell lymphoma.
Approximately 90 patients who had previously received appropriate first-line systemic therapy and experienced disease progression are planned to be enrolled in Greater China (including Hong Kong and Taiwan), Italy, Germany, France and the United States. The primary efficacy endpoint is objective response rate as determined by independent central review. Secondary endpoints include duration of response, progression-free survival, overall survival, rate of complete response or complete metabolic response, and time to response.
"Tislelizumab has shown promising anti-tumor activity and has been generally well-tolerated in clinical trials to-date in patients with a variety of cancers. We are excited to test the efficacy and safety of this agent in NK/-T cell lymphomas, where new treatment options are badly needed," said Huiqiang Huang, M.D., Chief Physician at the Sun Yat-sen University Cancer Center, Guangdong Province, China, and a member of the steering committee of the trial.
For more information about the trial, patients and physicians should email BeiGene at [email protected].
About Mature T- and NK-cell Neoplasms

T-lymphocytes (T-cells) are a type of white blood cell that can develop into lymphoma, or blood cancer. T-cell lymphomas account for approximately 10-15 percent of all non-Hodgkin’s lymphomas.i Natural killer (NK) cell neoplasms are more rare but are generally grouped with other T-cell lymphomas.ii The World Health Organization classifies several different types of leukemia under the term Mature (peripheral) T-cell Neoplasms (abnormal mass of tissue or blood), including: T-cell prolymphocytic leukemia, T-cell granular lymphocytic leukemia, aggressive NK-cell leukemia, adult T-cell lymphoma/leukemia (HTLV-1 positive), extranodal NK/T-cell lymphoma/ nasal type, enteropathy-type T-cell lymphoma, hepatosplenic gamma-delta T-cell lymphoma, subcutaneous panniculities-like T-cell lymphoma, mycosis fungoides/Sezary syndrome, anaplastic large-cell lymphoma, T-/null cell, primary cutaneous type; peripheral T-cell lymphoma; angioimmunoblastic T-cell lymphoma, anaplastic large-cell lymphoma, T-/null cell, primary systemic type.

About Tislelizumab
Tislelizumab (BGB-A317) is an investigational humanized monoclonal antibody that belongs to a class of immuno-oncology agents known as immune checkpoint inhibitors. It is designed to bind to PD-1, a cell surface receptor that plays an important role in downregulating the immune system by preventing the activation of T-cells. Tislelizumab has demonstrated high affinity and specificity for PD-1. It is potentially differentiated from the currently approved PD-1 antibodies in an engineered Fc region, which is believed to minimize potentially negative interactions with other immune cells, based on preclinical data. Tislelizumab is being developed as a monotherapy and in combination with other therapies for the treatment of a broad array of both solid tumor and hematologic cancers. BeiGene and Celgene Corporation have a global strategic collaboration for the development of tislelizumab in solid tumor cancers outside of Asia (except Japan).

On April 16, 2018 Aptose Biosciences Inc. (NASDAQ:APTO) (TSX:APS) reported the presentation of preclinical data demonstrating the robust cell killing ability of CG’806, a pan-FLT3/pan-BTK inhibitor, in multiple types of AML and B-cell malignancies (Press release, Aptose Biosciences, APR 16, 2018, View Source;p=RssLanding&cat=news&id=2342648 [SID1234525329]). Data further demonstrated that CG’806 targets multiple pathways and overcomes drug resistance seen with other inhibitors. The data were presented in a poster on Sunday, April 15, 2018 at the 2018 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Conference being held April 14-18, in Chicago, IL.

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The poster, entitled CG’806, a first-in-class pan-FLT3/pan-BTK inhibitor, targets multiple pathways to kill diverse subtypes of acute myeloid leukemia and B-cell malignancy in vitro, explores the potency and molecular mechanisms of the pan-FLT3/pan-BTK inhibitor CG’806 in hematologic malignancies relative to other FLT3 or BTK inhibitors commercialized or in development. The Aptose research team led by Dr. Hannah Zhang, Senior Director of Research, demonstrated that in FLT3-ITD AML cells, CG’806 induced apoptosis through inhibition of FLT3 signaling, and CG806 was approximately 10-fold more potent than quizartinib. Although FLT3-ITD is found in approximately 30% of AML patient, most AML patients express wild type (WT) FLT3. CG’806 was superior to quizartinib, gilteritinib and crenolanib FLT3 inhibitors in FLT3-WT AML cell lines. In B cell malignancies, BTK signaling plays a pivotal pathogenic role. CG’806 decreased BTK phosphorylation in all malignant B cell lines tested and inhibited cell proliferation and colony formation 50-6,000 times more potently than ibrutinib, an effect explained by the ability of CG’806 to target multiple rescue pathways rather than merely the exclusive inhibition of BTK signaling.

CG’806 demonstrated the ability to target all wild type (WT) and mutant forms of FLT3 and BTK and to inhibit multiple signaling pathways, producing killing of diverse subtypes of hematologic malignancies driven by different genomic aberrations.

"This study directly compares CG’806 to other FLT3 or BTK inhibitors in development and confirms the potent and extended activity we have seen with the molecule," said William G. Rice, Ph.D., Chairman and Chief Executive Officer of Aptose. "As a pan-FLT3/pan-BTK multi-kinase inhibitor that can eliminate tumors in the absence of toxicity in animal models, CG’806 has demonstrated the ability to kill a broad range of AML and B-cell malignancies through inhibition of multiple oncogenic pathways. We are eager to pursue its clinical development."
Separately, Aptose and Oregon Health & Science University (OHSU) Knight Cancer Center researchers also announced new data on CG’806 presented at AACR (Free AACR Whitepaper) (see press release here). Both poster presentations will be published in the AACR (Free AACR Whitepaper) Conference Proceedings. The posters can also be accessed here or at the Publications & Presentations section of the Aptose website, www.aptose.com.

About CG’806
CG‘806 is an oral, first-in-class pan-FLT3/pan-BTK multi-kinase inhibitor. This small molecule demonstrates potent inhibition of wild type and mutant forms of FLT3 (including internal tandem duplication, or ITD, and mutations of the receptor tyrosine kinase domain and gatekeeper region), eliminates acute myeloid leukemia (AML) tumors in the absence of toxicity in murine xenograft models, and represents a potential best-in-class therapeutic for patients with AML. Likewise, CG’806 demonstrates potent, non-covalent inhibition of the wild type and Cys481Ser mutant forms of the BTK enzyme, as well as other oncogenic kinase pathways operative in B cell malignancies, suggesting CG’806 may be developed for various B cell malignancy patients (including CLL, MCL, DLBCL and others) that are resistant/refractory/intolerant to covalent BTK inhibitors. CG’806 is currently in preclinical development in partnership with CrystalGenomics.

On April 16, 2018 Oregon Health & Science University (OHSU) Knight Cancer Institute and Aptose Biosciences Inc. (NASDAQ:APTO) (TSX:APS) reported the presentation of preclinical data demonstrating that CG’806, a highly potent pan-FLT3/pan-BTK inhibitor, kills malignant cells in samples from patients with various hematologic malignancies and demonstrates superiority to other kinase inhibitors (Press release, Aptose Biosciences, APR 16, 2018, View Source c=116148&p=RssLanding&cat=news&id=2342649 [SID1234525328]). The data were presented in a poster on Sunday, April 15, at the 2018 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Conference being held April 14-18, in Chicago, IL.

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The poster, entitled CG’806, a first-in-class pan-FLT3/pan-BTK inhibitor, demonstrates superiority to other FLT3 and BTK inhibitors against primary patient samples, demonstrated the broad activity of CG’806 against primary bone marrow specimens from patients with various hematologic malignancies. CG’806 is a small molecule that potently inhibits wild type (WT) FLT3, as well as FLT3 housing the ITD mutation or with point mutations in the tyrosine kinase domain (TKD, including D835G, D835Y, D835H) or in the gatekeeper region (F691L); it also inhibits BTK WT and BTK-C481S. As part of the Beat AML Initiative, researchers at OHSU tested CG’806 against freshly isolated primary samples from patients with acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL) and other hematologic malignancies to determine its potency and range of action. Against AML patient samples, CG’806 was evaluated relative to other FLT3 inhibitors. In parallel, CG’806 and ibrutinib, a covalent BTK inhibitor approved for CLL and certain other B-cell malignancies, were compared directly for sensitivities on primary CLL samples and various B-cell and other hematologic malignancies. CG’806 was shown to have greater potency against a broader subset of AML samples relative to other FLT3 inhibitors, including midostaurin, gilteritinib, quizartinib, sorafenib, crenolanib, and dovitinib. This was especially true in FLT3-ITD and FLT3-TKD positive cases, although enhanced activity was also observed in FLT3 WT samples. CG’806 was also shown to have greater potency and range of activity on primary CLL samples than ibrutinib.

"The clinical benefit of current FLT3 inhibitors in AML is transient, as resistance develops after several months of treatment," said Stephen E. Kurtz, Ph.D., lead author and Research Assistant Professor at the OHSU Knight Cancer Institute. "Similarly, ibrutinib, a covalent BTK inhibitor approved for CLL and certain other B-cell malignancies, is limited by acquired resistance, as well as refractory disease and tolerance challenges. As a pan-FLT3/pan-BTK inhibitor – especially in the absence of observed toxicity in murine AML models – CG’806 offers important potential to address these limitations."

"CG’806 appears superior to other FLT3 and BTK inhibitors, and the wealth of data supporting its development in AML and B-cell malignancies continues to grow," said William G. Rice, Ph.D., Chairman and Chief Executive Officer of Aptose. "These studies are critical for understanding how to develop and position CG’806 as we prepare for clinical development in these challenging hematologic malignancies."
Separately, Aptose researchers also announced new data on CG’806 presented at AACR (Free AACR Whitepaper) (see press release here). Both poster presentations will be published in the AACR (Free AACR Whitepaper) Conference Proceedings. The posters can also be accessed here or at the Publications & Presentations section of the Aptose website, www.aptose.com.
For more information on Beat AML refer to View Source

About CG’806

CG‘806 is an oral, first-in-class pan-FLT3/pan-BTK multi-kinase inhibitor. This small molecule demonstrates potent inhibition of wild type and mutant forms of FLT3 (including internal tandem duplication, or ITD, and mutations of the receptor tyrosine kinase domain and gatekeeper region), eliminates acute myeloid leukemia (AML) tumors in the absence of toxicity in murine xenograft models, and represents a potential best-in-class therapeutic for patients with AML. Likewise, CG’806 demonstrates potent, non-covalent inhibition of the wild type and Cys481Ser mutant forms of the BTK enzyme, as well as other oncogenic kinase pathways operative in B cell malignancies, suggesting CG’806 may be developed for various B cell malignancy patients (including CLL, MCL, DLBCL and others) that are resistant/refractory/intolerant to covalent BTK inhibitors. CG’806 is currently in preclinical development in partnership with CrystalGenomics

On April 16, 2018 Adaptimmune Therapeutics plc (Nasdaq:ADAP), a leader in T-cell therapy to treat cancer, reported that it presented two posters summarizing preclinical research with its MAGE-A4 and MAGE-A10 SPEAR T-cells at the annual AACR (Free AACR Whitepaper) meeting at McCormick Place in Chicago, Illinois (Press release, Adaptimmune, APR 16, 2018, View Source;p=RssLanding&cat=news&id=2342743 [SID1234525326]).

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The MAGE-A4 poster presented the discovery process and extensive preclinical validation work performed by Adaptimmune to characterize the specificity, affinity, and potency of MAGE-A4 SPEAR T-cells. The T-cell receptor (TCR) engineered to target MAGE-A4 was found to be specific for MAGE-A4 with an appropriate affinity and avidity, and there were no safety concerns identified preclinically. Further, the examination of more than 500 non-small lung cancer (NSCLC) tumor samples stained by MD Anderson Cancer Center scientists through its strategic collaboration with Adaptimmune revealed that the MAGE-A4 antigen is expressed in approximately 51% of squamous cell carcinomas of the lung, 8% of adenocarcinomas, and in 24% of all NSCLC cases. In addition, numerous other tumors express MAGE-A4 at variable levels. Details about the selection and affinity enhancement of MAGE-A10 SPEAR T‑cells were also presented. The refined methods used to test this SPEAR T-cell candidate are expected to further mitigate risk of unexpected off-target toxicities.

"Our proprietary preclinical development and validation program for our SPEAR T-cells, developed over more than 10 years, enables us to generate TCRs that have the right level of specificity, affinity, and overall avidity for cancer cells expressing specific targets, while minimizing the risk of off-target toxicity," said Rafael Amado, Adaptimmune’s Chief Medical Officer. "MAGE-A4 and MAGE-A10 are in clinical trials in a variety of solid tumors, and we expect to deliver data on the benefit:risk profile of these products throughout the second half of 2018."

Session, date, time, and location (for both posters):

• Date: Monday, Apr 16, 2018
• Time: 1:00 PM – 5:00 PM (CDT)
• Location: McCormick Place South, Exhibit Hall A, Poster Section 24
Poster 1 – MAGE-A4
• Title: Affinity-enhanced T-cell receptor (TCR) for adoptive T-cell therapy targeting MAGE-A4
• Poster Board Number: 21
• Permanent Abstract Number: 2562
• Objectives:
Determine the frequency of MAGE-A4 expression in non-small cell lung cancer (NSCLC) to identify patients most likely to benefit from SPEAR T-cell therapy
Perform preclinical testing for specificity, potency, and safety of MAGE-A4 SPEAR T-cells

• Methods:
MAGE-A4 expression in NSCLC: 534 resected NSCLC cases (stage I to IV) with clinicopathological information including overall survival and recurrence were analyzed for MAGE-A4 expression by immunohistochemistry (IHC)
Preclinical testing for specificity, potency, and safety of MAGE-A4 SPEAR T-cells:
− Potency/efficacy testing of MAGE-A4 SPEAR T-cells by antigen driven proliferation, cytokine release, and cytotoxicity assays
− In vitro testing against panels of primary normal cells from multiple organ systems in 2-D, 3-D, and induced pluripotent stem cell culture formats to identify cross-reactivities in more physiologically relevant cultures
− Molecular mapping of the TCR peptide-major histocompatibility complex (MHC) binding preferences to identify potential cross-reactive peptides, verification of identified peptides by loading candidates on antigen-presenting cells, and expression of source proteins in antigen-presenting cells to confirm lack of candidate peptide processing and presentation

• Conclusions:
MAGE-A4 expression was observed in ~24% of all NSCLC cases, with higher frequency observed in squamous cell carcinoma (SCC) (51%) versus adenocarcinoma (8%)
Extensive in vitro preclinical safety assessment and identified no major safety concerns for MAGE-A4 SPEAR T-cell reactivity
This MAGE-A4 SPEAR T-cell is being evaluated in a clinical trial in patients with in bladder, melanoma, head & neck, ovarian, NSCLC, esophageal, and gastric cancers
Poster 2 – MAGE-A10
• Title: Selection of affinity-enhanced T-cell receptors for adoptive T-cell therapy targeting MAGE‑A10
• Poster Board Number: 23
• Permanent Abstract Number: 2564
• Objectives: Generate and systematically test affinity-enhanced TCRs that recognize an HLA-A*02 restricted epitope from MAGE-A10 cancer/testis antigens
• Develop an extensive in vitro testing strategy to characterize and reduce the risk of TCR cross-reactivity, including a novel approach for generating peptide specificity profiles for candidate TCRs – the peptide X-scan
• Methods:
Twenty-one parental TCRs recognizing the HLA-A*0201-restricted MAGE-A10 peptide GLYDGMEHL254-262 (MAGE-A10254-262) epitope were characterized using surface plasmon resonance (SPR)
Ten parental TCRs were cloned into a lentiviral vector and transduced into primary human T-cells, and screened for recognition of natively processed antigen using MAGE-A10–positive and –negative cell lines and primary cells as targets
Three parental TCRs selected for affinity enhancement, and the complementarity-determining regions (CDRs) of their α- and β‑chains were mutated, and resulting TCRs tested for affinity and specificity

• Conclusions:
Adaptimmune developed an affinity-enhanced TCR with high specificity and potency against cells expressing HLA-A*0201 and the cancer antigen MAGE-A10
− After generating TCR mutants with diverse germline and CDR loop sequences, the optimal candidate for preclinical testing was identified by applying a novel comprehensive specificity screen (X-scan)
− Together with other key developments in preclinical safety and potency assessments, this strategy is expected to mitigate the risk of unexpected off-target crossreactivity and resulting clinical toxicities
The MAGE-A10 SPEAR T-cell that was selected is being evaluated in clinical trials in NSCLC, and a triple tumor study in bladder, melanoma, and head & neck cancers