On October 30, 2017 Cellectar Biosciences, Inc. (Nasdaq: CLRB) (the “company”), an oncology-focused, clinical stage biotechnology company, reported data demonstrating that the company’s phospholipid ether delivery vehicle conjugated to a non-reactive iodine (I-127), or CLR 127, decreased tumor volumes and markedly delayed tumor regrowth in preclinical in vitro and in vivo animal studies of both pediatric and adult cancers. Investigators observed that CLR 127 was taken up and retained in the tumor cells at 6-10 fold higher level than normal tissue and sensitized the tumor cells to external radiation (Filing, 8-K, Cellectar Biosciences, OCT 30, 2017, View Source [SID1234521312]).

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University of Wisconsin investigator, Dr. Mario Otto presented these data during a poster presentation held at the AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) held by the American Association for Cancer Research (AACR) (Free AACR Whitepaper), National Cancer Institute and European Organisation for Research and Treatment of Cancer. The poster, titled “The Phospholipid Ether Analog CLR 127 Delays Radiation-Induced dsDNA Damage Repair in Pediatric and Adult Solid Tumors,” was presented on Saturday, October 28th at 12:30 PM ET at the Pennsylvania Convention Center in Philadelphia.

Dr. Otto and his fellow investigators treated adult and pediatric cancer cells and in vivo xenograft-bearing mice with CLR 127 followed by external radiation. The group reported that the effect of the radiation was meaningfully increased versus external radiation alone and persisted at higher levels for up to 24 hours post-administration of the external radiation. Additionally, treatment with CLR 127 appears to inhibit DNA repair function that typically occurs in the tumor cells following radiation treatment.

“The data presented by Dr. Otto and his team provide external confirmation of Cellectar’s PDC tumor targeting capabilities and retention in the tumor cells that may improve clinical outcomes,” said Jim Caruso, president and CEO of Cellectar Biosciences. “This study reports important additional data regarding the potential benefits of combining our PDC platform with external beam radiation for the treatment of both adults and pediatric cancers.”

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 designed its phospholipid ether (PLE) carrier platform to be coupled with a variety of payloads to facilitate the discovery and development of improved targeted novel therapeutic compounds. 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 more than 80 different xenograft models of cancer.

On October 30, 2017 Transgene (Paris:TNG), a biotech company that designs and develops viral-based immunotherapies, reported that it will be presenting a poster on additional immunology data generated from the randomized, placebo-controlled Phase 2b trial (TIME) that evaluated the combination regimen of TG4010 and chemotherapy in patients with advanced lung cancer at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Meeting 2017, in National Harbor, Maryland, November 8-12 (Press release, Transgene, OCT 30, 2017, View Source [SID1234521307]).

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Poster title: Immune mechanisms of the response to TG4010, a viral-based vaccine, in patients with advanced non-small cell lung carcinoma

• Poster ID: P137

• Date, time, location: Saturday, November 11, 2017, 12:30 – 2:00 pm and 6:30 – 8:00 pm

The abstract will be published on November 7, 2017, on the SITC (Free SITC Whitepaper) website.

All publications on TG4010 can be accessed via www.transgene.fr, Pipeline>Publications.

About TG4010
TG4010 is an immunotherapy that has been designed to express the coding sequences of the MUC1 tumor-associated antigen and the cytokine, Interleukin-2 (IL2) in a modified Vaccinia virus (MVA).
The combination of TG4010 immunotherapy and chemotherapy has demonstrated significant efficacy in terms of progression-free survival and overall survival in patients with advanced stage NSCLC (Quoix et al. Lancet Oncol. 2015). TG4010 is currently being investigated in combination with nivolumab (ICI) for the 2nd-line treatment of advanced NSCLC (NCT02823990). A trial in 1st-line treatment of NSCLC is expected to begin at the end of 2017, evaluating the combination regimen of TG4010 + nivolumab + chemotherapy in patients whose tumors express low or undetectable levels of PD-L1.

On October 30, 2017 Syros Pharmaceuticals (NASDAQ:SYRS), a biopharmaceutical company pioneering the development of medicines to control the expression of disease-driving genes, reported that new preclinical pharmacodynamic (PD) and pharmacokinetic (PK) data providing a rationale for the twice weekly dosing regimen currently being used in the ongoing Phase 1 clinical trial of SY-1365, its first-in-class selective cyclin-dependent kinase 7 (CDK7) inhibitor, in advanced solid tumors were presented at the 2017 AACR (Free AACR Whitepaper)-NCI-EORTC Molecular Targets and Cancer Therapeutics Conference in Philadelphia (Press release, Syros Pharmaceuticals, OCT 30, 2017, View Source [SID1234521306]).

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“We are encouraged by the preclinical PK and PD data for SY-1365,” said David A. Roth, M.D., Chief Medical Officer of Syros. “The prolonged PD effect, coupled with the sustained tumor regressions seen in multiple preclinical models of difficult-to-treat cancers using intermittent dosing, support investigation of a twice-a-week dosing regimen for patients. Additionally, based on the correlation between CDK7 target occupancy and the anti-tumor activity of SY-1365, we developed a PD marker for use in our ongoing Phase 1 trial that we believe will help us efficiently identify the optimal dose and regimen for SY-1365.”

Syros scientists evaluated the relationship between SY-1365’s PK, PD and anti-tumor activity in multiple in vivo models, including preclinical models of triple negative breast cancer (TNBC) and acute myeloid leukemia (AML), across a range of doses and regimens from daily to weekly dosing. SY-1365 is a covalent inhibitor that binds irreversibly to CDK7. The data showed:

A prolonged PD effect, as measured by CDK7 target occupancy, with a half-life of about three days, supporting intermittent dosing.
A dose-dependent relationship between CDK7 target occupancy and anti-tumor activity in a preclinical model of AML.
Sustained tumor regressions in multiple in vivo models using a twice weekly dosing regimen consistent with the initial regimen in the ongoing Phase 1 clinical trial.
CDK7 target occupancy in blood cells in preclinical models similar to that seen in tumor cells, supporting the use of an assay measuring target occupancy in patients’ blood samples as a PD marker in the ongoing Phase 1 trial to help guide optimization of the dose and regimen to establish a recommended Phase 2 dose.
The Phase 1 trial of SY-1365 is a multi-center, open-label trial that is expected to enroll approximately 70 patients with advanced solid tumors. The primary objective of the trial is to assess the safety and tolerability of escalating doses of SY-1365, with the goal of establishing a maximum tolerated dose and a recommended Phase 2 dose and regimen. The dose-escalation phase is open to solid tumor patients for whom standard curative or palliative measures do not exist or are no longer effective. Following the dose-escalation phase, expansion cohorts are planned to further evaluate the safety and anti-tumor activity of SY-1365 in patients with triple negative breast, small cell lung and ovarian cancers, to confirm a recommended Phase 2 dose and regimen, and to enroll patients with tumors of any histology in a cohort focused on analyzing biopsied tumor tissue. Additional details about the trial can be found using the identifier NCT03134638 at www.clinicaltrials.gov.

Syros also announced that a publication co-authored by two of its scientific founders Nathanael S. Gray, Ph.D., and Richard A. Young, Ph.D., in the peer-reviewed scientific journal Cancer Discovery (Rusan M., et al., “Suppression of adaptive responses to targeted cancer therapy by transcriptional repression”) highlighted CDK7 inhibition in combination with targeted therapies as a promising new approach for combatting drug resistance. In multiple in vitro and in vivo models of treatment-resistant cancers, a research tool compound, known as THZ1, which inhibits CDK7, enhanced tumor cell killing and impeded the emergence of drug-resistant cell populations when combined with targeted therapies, including MEK, BRAF, EGFR and ALK inhibitors, compared to either THZ1 or the targeted therapy alone. These findings suggest that CDK7 inhibition prevents the formation of active enhancers that drive the increased expression of genes promoting the emergence of drug resistance in response to targeted therapy and blocks transcriptional programs required for the growth and survival of cancer.

Syros has an exclusive, worldwide license from the Dana-Farber Cancer Institute under certain patents relating to CDK7 inhibitors, including THZ1. Using its internal drug discovery capabilities, Syros generated SY-1365 to have better drug-like properties than THZ1, making it suitable for clinical development.

On October 30, 2017 Spectrum Pharmaceuticals, Inc. (NasdaqGS: SPPI), a biotechnology company with fully integrated commercial and drug development operations with a primary focus in Hematology and Oncology, reported the initiation of a Phase 2 trial evaluating poziotinib in non-small cell lung cancer patients with an exon 20 insertion mutation in EGFR or HER2 (Press release, Spectrum Pharmaceuticals, OCT 30, 2017, View Source [SID1234521305]). The first patient has been enrolled and the Company expects to enroll patients at several leading cancer institutions in the United States.

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“Following the promising preliminary data from the University of Texas MD Anderson Cancer Center’s study, we are excited to launch this multicenter trial,” said Rajesh C. Shrotriya, MD, Chairman and Chief Executive Officer of Spectrum Pharmaceuticals. “Earlier this month, results presented at the 18th IASLC World Conference on Lung Cancer showed that poziotinib has the potential to address unmet needs of lung cancer patients with EGFR Exon 20 insertion mutations. The efficacy of first-generation tyrosine-kinase inhibitors has been found to be unsatisfactory in such patients, resulting in single digit response rates and a progression-free survival of around two months. We are grateful for the guidance the Food and Drug Administration has provided in designing this trial.”

The goal of this Phase 2 trial is to evaluate both the efficacy and safety of poziotinib in patients with non-small cell lung cancer (NSCLC) that is locally advanced or metastatic and have an exon 20 insertion mutation in either EGFR or HER2. This trial will enroll up to 87 patients with EGFR exon 20 insertion mutations and up to 87 patients with HER2 exon 20 insertion mutations in several leading cancer institutions. The study will evaluate objective response rate (ORR) as the primary endpoint, and disease control rate (DCR), duration of response (DOR), and safety as secondary endpoints. In addition, progression-free survival (PFS) and quality of life (QoL) will be evaluated.

Poziotinib is a novel, oral pan-HER inhibitor that irreversibly blocks signaling through the Epidermal Growth Factor Receptor (EGFR, HER) family of tyrosine-kinase receptors, including HER1 (erbB1; EGFR), HER2 (erbB2), and HER4 (erbB4), and importantly, also HER receptor mutations; this, in turn, leads to the inhibition of the proliferation of tumor cells that overexpress these receptors. Mutations or overexpression/amplification of EGFR family receptors have been associated with a number of different cancers, including non-small cell lung cancer (NSCLC), breast cancer, and gastric cancer.

On October 30, 2017 Sierra Oncology, Inc. (NASDAQ: SRRA), a clinical stage drug development company focused on advancing next generation DNA Damage Response (DDR) therapeutics for the treatment of patients with cancer, reported preclinical data supporting the ongoing clinical development strategy for its Chk1 inhibitor, SRA737 (Press release, Sierra Oncology, OCT 30, 2017, View Source [SID1234521304]). The results were presented in a poster on October 29th at the AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) held in Philadelphia, Pennsylvania.

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“The data generated from these experiments are consistent with recent findings from our research and demonstrate that a potent and selective Chk1 inhibitor such as SRA737 can effectively synergize with sub-therapeutic doses of gemcitabine to induce replication catastrophe and tumor cell death,” said Dr. Alan R. Eastman, Professor at the Geisel School of Medicine at Dartmouth and the founding Director of the Molecular Therapeutics Research Program of the Norris Cotton Cancer Center at Dartmouth-Hitchcock. “I look forward to results from the clinical study Sierra is conducting which translates this novel strategy for the treatment of patients with advanced cancers.”

“Chk1 is essential for managing replication stress (RS), which is intrinsically elevated in certain oncogene-transformed tumors, and can also be further enhanced by chemotherapeutic drugs like gemcitabine. While gemcitabine likely causes RS by depleting deoxynucleotide (dNTP) and damaging DNA, Chk1 protects against RS through a variety of molecular mechanisms. Consequently, tumor cells become highly reliant on Chk1 to manage replication stress and its downstream consequences in order to survive and continue to proliferate,” added Dr. Christian Hassig, Senior Vice President of Research at Sierra Oncology. “Through our research, we have demonstrated that SRA737 has the potential to synergize with several clinically important chemotherapeutic inducers of RS to kill tumor cells in vitro at low concentrations. We also demonstrated that the combination of SRA737 and gemcitabine may prove efficacious in gemcitabine-resistant clinical settings and that SRA737 can be potentiated by sub-therapeutic doses of gemcitabine in animal models of cancer.”

“Replication stress has been recognized as a potent driver of genomic instability, a fundamental hallmark of cancer, and is rapidly emerging as an area of dynamic scientific research,” stated Dr. Nick Glover, President and CEO of Sierra Oncology. “Tumors harboring high levels of intrinsic or exogenous forms of replication stress are potential candidates for therapeutic intervention using SRA737. We are actively leveraging these concepts in our ongoing monotherapy and low-dose gemcitabine combination clinical trials.”

About the Poster
Title: The Chk1 inhibitor, SRA737, demonstrates chemical synthetic lethality with replication stress-inducing agents, including novel low-dose gemcitabine, in preclinical models of cancer.
Poster #181; Abstract #B181:
The Poster is available on the company’s website at www.sierraoncology.com.

Data reported in the Poster demonstrated that:

The combination of SRA737 with a range of RS-inducing agents was highly synergistic in a panel of 15 cell lines of diverse tissue lineages, with the strongest synergy observed with gemcitabine.
Profound synergy between SRA737 and gemcitabine was observed in several bladder cancer cell lines as well as in human patient-derived bladder cancer 3D cultures, further supporting the clinical development of this RS-inducing combination.

Significant anti-tumor activity and increased survival (vs. control) were observed when SRA737 and gemcitabine were dosed in combination in a highly aggressive gemcitabine resistant bladder carcinoma PDX model. These findings suggest that the combination of SRA737 and gemcitabine may be efficacious in gemcitabine-resistant clinical settings.
Strikingly, anti-tumor activity was observed when SRA737 was combined with a sub-therapeutic dose of gemcitabine in xenograft models of colorectal adenocarcinoma and osteosarcoma. This combination was shown to increase RS markers by three to five-fold over the change noted with gemcitabine alone. These findings support i) the development of SRA737 in combination with low, sub-therapeutic doses of gemcitabine and, ii) the broader application of this unique combination in tumor indications where gemcitabine is not standard of care.