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NW Bio Announces Completion of $12 Million Financing

On December 7, 2017 Northwest Biotherapeutics (OTCQB: NWBO) (NWBio), a biotechnology company developing DCVax personalized immune therapies for solid tumor cancers, reported that it has completed a $12 million financing to fund operations (Press release, Northwest Biotherapeutics, DEC 7, 2017, View Source [SID1234522446]). The majority of the financing is being provided by new investors.

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The financing is in the form of Series A Convertible Preferred Stock and Warrants. The Preferred Stock will be convertible into common stock, but only when common stock is available or after 6 months following issuance. The Warrants will be exercisable for common stock, but only when common stock is available. The shares are registered, but are subject to restrictions under which they may not be conveyed or traded until a shareholder vote takes place, pursuant to which the number of authorized shares is increased. The shares are also subject to a voting agreement, under which the investors have agreed to vote in support of such increase in authorized shares.

The investors are purchasing the Series A Preferred Stock at a price of $1.70 per share, and each such preferred share will be convertible into 10 common shares valued at $0.17 cents per share. The investors are also receiving Warrants for a number of common shares equal to the number of conversion shares, with an exercise price of $0.22 per share and an exercise period of two years.

As reported in the Company’s recent 10-Q filing, the Company has been in discussions with investors for this financing during the last couple of months. During this period, while the price of the Company’s common stock hovered mostly at $0.16- $0.17 per share, the terms were set at $0.17 per share of common stock and $0.22 exercise price for the warrants. As also previously reported, some of the investors provided advance funding prior to completion of the financing and its documentation.

Linda Powers, the Company’s CEO, commented, "We are pleased to see a growing number of new investors becoming interested in our DCVax technology and its encouraging potential, and providing the majority of the largest financing we have done this year. We are also grateful for our long-term, patient and loyal shareholder base, and their participation in this financing as well. It is gratifying to have both ongoing and expanded support as we move forward with our ongoing Phase 3 trial (in which we are continuing to ship doses, treat patients and collect data) and other programs we have been preparing."

Daiichi Sankyo Presents Updated Data for DS-8201 in Patients with HER2-Expressing Breast Cancer at San Antonio Breast Cancer Symposium

On December 7, 2017 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) reported that updated safety and efficacy data from two subgroups of patients with metastatic breast cancer from an ongoing phase 1 study of DS-8201, an investigational HER2-targeting antibody drug conjugate (ADC), were presented during a Spotlight Poster Discussion session at the 2017 San Antonio Breast Cancer Symposium (Press release, Daiichi Sankyo, DEC 7, 2017, View Source [SID1234522441]).

Updated preliminary results in a subgroup analysis of 57 efficacy evaluable patients with HER2-positive metastatic breast cancer pre-treated with ado-trastuzumab emtansine (T-DM1) showed that DS-8201 demonstrated a confirmed overall response rate of 61.4 percent (35 of 57 patients) and a disease control rate of 94.7 percent (54 of 57 patients). Among 50 of these patients who also were pre-treated with pertuzumab, DS-8201 demonstrated a confirmed overall response rate of 62 percent (31 of 50 patients) and a disease control rate of 94 percent (47 of 50 patients). In 39 efficacy evaluable HER2-positive patients with hormone-receptor positive disease, DS-8201 demonstrated an overall response rate of 56.4 percent (22 of 39 patients) and disease control rate of 92.3 percent (36 of 39 patients). The majority of patients with HER2-positive metastatic breast cancer were continuing to receive treatment at the time of data cut-off. Preliminary estimates of median progression free survival have reached 10.4 months.

Additionally, preliminary results in another subgroup showed that DS-8201 demonstrated a confirmed overall response rate of 31.6 percent (6 of 19 patients) and a disease control rate of 84.2 percent (16 of 19 patients) in 19 efficacy evaluable patients with heavily pretreated HER2 low-expressing breast cancer (defined as IHC2+/ISH- or IHC 1+). In 16 of these patients also classified with hormone-receptor positive disease, DS-8201 demonstrated an overall response rate of 31.3 percent (5 of 16 patients) and a disease control rate of 87.5 percent (14 of 16 patients). Most patients with HER2 low-expressing breast cancer were continuing to receive treatment at the time of data cut-off. Median progression free survival has not yet been reached.

"These updated data in HER2-positive metastatic breast cancer are exciting in that DS-8201 is showing potential in treating patients who have progressed on several other HER2-targeting agents," said Shanu Modi, MD, Breast Medical Oncologist, Memorial Sloan Kettering Cancer Center and study investigator. "Additionally, the results seen in patients with HER2 low-expressing breast cancer are compelling and could challenge how we define HER2-positive breast cancer with regards to ADC therapy. Clearly, further study of DS-8201 is warranted in both these types of HER2-expressing breast cancer."

"These data add to the growing evidence that underscore the potential of our smart chemotherapy DS-8201 to treat HER2-expressing breast cancer," said Antoine Yver, MD, MSc, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo. "While we already have advanced DS-8201 into a pivotal phase 2 trial for HER2-positive metastatic breast cancer, we are exploring next steps for the development of DS-8201 in HER2 low-expressing breast cancer."

Combined preliminary safety data for both HER2 low-expressing and HER2-positive breast cancer subgroups were reported. The most common adverse events (>30 percent any grade) included nausea (73.0 percent), decreased appetite (55.7 percent), alopecia (40.0 percent), vomiting (39.1 percent), anemia (34.8 percent), diarrhea (33.9 percent) and constipation (30.4 percent). Grade 3 adverse events occurring in >10 percent of patients included decreased neutrophil count (10.4 percent) and decreased white blood cell count (10.4 percent). Grade 4 adverse events included decreased neutrophil count (4.3 percent), decreased platelet count (2.6 percent) and anemia (0.9 percent). Two cases of potential Grade 5 pneumonitis have been reported and will be assessed by an interstitial lung disease (ILD) adjudication committee.

Unmet Need in HER2-Expressing Metastatic Breast Cancer
About one in five breast cancers overexpress HER2, a tyrosine kinase receptor growth-promoting protein found on the surface of some cancer cells, which is associated with aggressive disease.1 To be considered HER2-positive, tumor cancer cells are usually tested by one of two methods: immunohistochemistry (IHC) or fluorescent in situ hybridization (FISH).1 IHC test results are reported as: 0, IHC1+, IHC2+ or IHC3+.1 A finding of IHC3+ is considered HER2-positive.1 A finding of IHC2+ is borderline and typically is confirmed by a positive FISH test.1

Several unmet needs remain today in HER2-expressing metastatic breast cancer. Many tumors advance to the point where no currently approved HER2-targeting treatment continues to control the disease, and there is no current standard of care for HER2-positive tumors after treatment with trastuzumab, pertuzumab and T-DM1.2 Additionally, there are no anti-HER2 therapies indicated for HER2 low-expressing tumors (IHC2+/FISH- or IHC1+).

About the DS-8201 Phase 1 Study
The open-label, two-part phase 1 study is currently evaluating DS-8201 in patients with advanced/
unresectable or metastatic solid tumors that are refractory or intolerant to standard treatment, or for whom no standard treatment is available. The primary objective of the dose escalation phase of the study was to assess the safety and tolerability of DS-8201 and determine the maximum tolerated dose. In the dose expansion part of the phase 1 study, DS-8201 is given in one of two doses (5.4 mg/kg and 6.4 mg/kg) to patients with HER2-positive advanced or metastatic breast cancer and gastric cancer, HER2 low-expressing breast cancer and other HER2-expressing solid tumors. Patient enrollment in the two breast cancer cohorts and the HER2-expressing solid tumors cohort is ongoing in the U.S. and Japan. For more information about the study, please visit ClinicalTrials.gov.

About DS-8201
DS-8201 is the lead product in the ADC Franchise of the Daiichi Sankyo Cancer Enterprise. ADCs are targeted cancer medicines that deliver cytotoxic chemotherapy ("payload") to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells. Designed using Daiichi Sankyo’s proprietary ADC technology, DS-8201 is a smart chemotherapy comprised of a humanized HER2 antibody attached to a novel topoisomerase I inhibitor payload by a tetrapeptide-based linker. It is designed to target and deliver chemotherapy inside cancer cells and reduce systemic exposure to the cytotoxic payload (or chemotherapy) compared to the way chemotherapy is commonly delivered.

DS-8201 is currently in phase 2 clinical development for HER2-positive unresectable and/or metastatic breast cancer resistant or refractory to T-DM1 (DESTINY-Breast01), phase 2 development for HER2-positive advanced gastric cancer resistant or refractory to trastuzumab (DESTINY-Gastric01), and phase 1 development for other HER2-expressing advanced/unresectable or metastatic solid tumors.

DS-8201 has been granted Breakthrough Therapy designation for the treatment of patients with HER2-positive, locally advanced or metastatic breast cancer who have been treated with trastuzumab and pertuzumab and have disease progression after ado-trastuzumab emtansine (T-DM1), and Fast Track designation for the treatment of HER2-positive unresectable and/or metastatic breast cancer in patients who have progressed after prior treatment with HER2-targeted therapies including T-DM1 by the U.S. Food and Drug Administration (FDA). DS-8201 is an investigational agent that has not been approved for any indication in any country. Safety and efficacy have not been established.

About Daiichi Sankyo Cancer Enterprise
The vision of Daiichi Sankyo Cancer Enterprise is to leverage our world-class, innovative science and push beyond traditional thinking in order to create meaningful treatments for patients with cancer. We are dedicated to transforming science into value for patients, and this sense of obligation informs everything we do. Anchored by our Antibody Drug Conjugate (ADC) and Acute Myeloid Leukemia (AML) Franchises, our cancer pipeline includes more than 20 small molecules, monoclonal antibodies and ADCs stemming from our powerful research engines: our two laboratories for biologic/immuno-oncology and small molecules in Japan, and Plexxikon Inc., our small molecule structure-guided R&D center in Berkeley, CA. Compounds in development include: quizartinib, an oral FLT3 inhibitor, for newly-diagnosed and relapsed or refractory AML with FLT3-ITD mutations; DS-8201, an ADC for HER2-expressing breast and gastric cancer, and other HER2-expressing solid tumors; and pexidartinib, an oral CSF-1R inhibitor, for tenosynovial giant cell tumor (TGCT), which is also being explored in a range of solid tumors in combination with the anti-PD1 immunotherapy pembrolizumab. For more information, please visit: www.DSCancerEnterprise.com.

Long-Term Efficacy Data from the Phase III GeparSepto Study in High Risk Early Breast Cancer Patients Treated with ABRAXANE® Vs. Solvent-Based Paclitaxel to Be Reported

On December 7, 2017 The German Breast Group (GBG) and Celgene Corporation (NASDAQ:CELG) reported long-term invasive disease-free survival results from the GeparSepto clinical trial comparing the investigational use of ABRAXANE (paclitaxel albumin-bound particles for injectable suspension) to paclitaxel in early high-risk breast cancer patients at the 2017 San Antonio Breast Cancer Symposium (SABCS) (Press release, Celgene, DEC 7, 2017, View Source [SID1234522439]). The results from the 1,206 patient study found that ABRAXANE demonstrated a significantly higher disease-free survival rate, a secondary efficacy endpoint, in high risk early breast cancer patients when compared to conventional solvent-based paclitaxel.

In this large Phase III study, of which disease-free survival was a secondary endpoint, the investigational use of ABRAXANE (N=600) was compared to conventional solvent-based paclitaxel (N=606) followed by epirubicin/cyclophosphamide in both arms given all before surgery. The study found a significantly higher disease-free survival (DFS) rate in patients receiving ABRAXANE compared to those receiving paclitaxel as part of a neoadjuvant treatment regimen [HR=0.69, 95% CI (0.54-0.89); p=0.0044]). The rates of DFS were 87.1% vs. 80.7% at 3 years and 83.5% vs. 76.2% at 4 years, respectively. A treatment effect was observed in the predefined subset of patients with triple negative tumors and hormone receptor-positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) tumors. Patients with triple negative breast cancer (n=276) had DFS rates of 83.1% vs. 73.4% at 3 years, and 78.7% vs. 68.6% at 4 years. DFS was not significantly different in the TNBC subgroup [HR=0.66, 95% CI (0.42-1.04), p=0.0694]. HR+/HER2- patients had DFS rates of 86.3% vs. 78.6% at 3 years and 80.8% vs. 72.8% at 4 years [HR=0.71, 95% CI (0.49-1.02); p=0.0660]. Another secondary endpoint measure evaluated in the study was overall survival (OS). No difference in OS was observed, however the OS findings are not yet mature.

"These long-term findings show that weekly nab-paclitaxel followed by epirubicin/cyclophosphamide helped to significantly delay the progression of disease compared to solvent-based paclitaxel followed by epirubicin/cyclophosphamide in early high-risk breast cancer patients," stated Sibylle Loibl, Chair of GBG. "These findings are consistent with our previous findings and are very exciting, as they help us evaluate another potential treatment option for this high-risk patient group."

The primary endpoint of GeparSepto was pCR (pathological complete response) which has been reported previously and found a statistically significant and clinically meaningful 9% absolute improvement from 29% to 38% (p= < 0.001) when neoadjuvant (preoperative) chemotherapy was started with ABRAXANE instead of conventional solvent-based paclitaxel followed by epirubicin/cyclophosphamide given prior to surgery.

The most common adverse events ( > 30%) that were previously reported included anemia, alopecia, peripheral sensory neuropathy neutropenia, leukopenia, fatigue, lymphopenia, increased alanine aminotransferase, increased aspartate aminotransferase, headache, nausea, mucositis/stomatitis/ esophagitis, diarrhea, infection, arthralgia, epistaxis, skin rash maculopapular, and myalgia.

Follow-up data regarding long-term neurotoxicity and quality of life will be collected during the study follow-up period. These results will be forthcoming in future analyses.

"These latest results are very encouraging, illustrating that an ABRAXANE-containing investigational regimen may have activity in high-risk breast cancer patients in the neoadjuvant setting," said Nadim Ahmed, President, Hematology and Oncology for Celgene. "The long-term outcomes from this study offer researchers additional insight into how to potentially treat patients more effectively at an earlier stage of the disease."

ABRAXANE is not approved for neoadjuvant treatment of breast cancer, or for the treatment regimens studied in GeparSepto in any country. See label excerpts below for more information.

About GeparSepto

GeparSepto is a phase III clinical trial evaluating the safety and efficacy of the investigational use of a weekly treatment regimen of nab-paclitaxel compared to a solvent-based paclitaxel, both followed by epirubicin/cyclophosphamide given all before surgery to treat high-risk early breast cancer.

The trial evaluated 1,206 patients with high risk early breast cancer. Patients received either nab-paclitaxel 150 mg/m2 or paclitaxel 80 mg/m2 weekly for 12 weeks followed by epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2 every 3 weeks for 12 weeks. HER2 positive patients also received trastuzumab 8 (6) mg/kg and pertuzumab 840 (420) mg every 3 weeks during neoadjuvant treatment. The nab-paclitaxel dose was reduced to 125 mg/m2 after recruitment of 464 patients because of the evaluation of an interim safety analysis. The median age in each treatment arm was 49 (nab-paclitaxel) and 48 (paclitaxel) years. The primary endpoint of the trial was pathological complete response (pCR). Secondary endpoints evaluated in the study included invasive disease-free survival (DFS), distant disease-free survival (DDFS) and overall survival (OS).

Grade 3 and 4 neutropenia occurred in 23% and 38% of patients, respectively, in the nab-paclitaxel arm compared to 25% and 36% in the solvent-based paclitaxel arm. Peripheral sensory neuropathy was more common with nab-paclitaxel (8% for the 125 mg/m2 dose and 15% for the 150 mg/m2 dose) compared with solvent-based paclitaxel 80 mg/m2. Taxane discontinuation due to an adverse event occurred in 16% of patients on nab-paclitaxel and 6% on solvent-based paclitaxel.

Overall, 23% of patients were noted to have at least one serious adverse event based on the study drug received (26% in the nab-paclitaxel group and 21% in the solvent-based paclitaxel group [p=0.057]). There were three deaths (during epirubicin plus cyclophosphamide treatment) in the nab-paclitaxel group due to sepsis, diarrhea, and an accident unrelated to the trial, compared to one death in the solvent-based paclitaxel group (during paclitaxel treatment) due to cardiac failure.

GeparSepto is the largest randomized Phase III study ever completed with ABRAXANE and the first one completed in high risk early breast cancer. Celgene provided funding support for the GeparSepto trial.

ABOUT ABRAXANE

ABRAXANE for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.

Important Safety Information

WARNING – NEUTROPENIA

Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE
Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS
CONTRADINDICATIONS

Neutrophil Counts

ABRAXANE should not be used in patients who have baseline neutrophil counts of < 1500 cells/mm3
Hypersensitivity

Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug
WARNINGS AND PRECAUTIONS

Hematologic Effects

Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of ABRAXANE. In a clinical study, Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC)
Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Day 1
Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1,500 cells/mm3
In the case of severe neutropenia ( < 500 cells/mm3 for 7 days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patients with MBC
Resume treatment with every-3-week cycles of ABRAXANE after ANC recovers to a level > 1500 cells/mm3 and platelets recover to > 100,000 cells/mm3
Nervous System

Sensory neuropathy is dose- and schedule-dependent
The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification
If ≥ Grade 3 sensory neuropathy develops, withhold until resolution to Grade 1 or 2 followed by a dose reduction for all subsequent courses of ABRAXANE
Hypersensitivity

Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported
Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with this drug
Hepatic Impairment

Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution
Patients with hepatic impairment may be at an increased risk of toxicity, particularly from myelosuppression, and should be monitored for development of profound myelosuppression
For MBC, the starting dose should be reduced for patients with moderate or severe hepatic impairment
Albumin (Human)

ABRAXANE contains albumin (human), a derivative of human blood
Use in Pregnancy: Pregnancy Category D

ABRAXANE can cause fetal harm when administered to a pregnant woman
If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus
Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE
Use in Men

Men should be advised not to father a child while receiving ABRAXANE
ADVERSE REACTIONS

Randomized Metastatic Breast Cancer (MBC) Study

The most common adverse reactions (≥20%) with single-agent use of ABRAXANE vs paclitaxel injection in the MBC study are alopecia (90%, 94%), neutropenia (all cases 80%, 82%; severe 9%, 22%), sensory neuropathy (any symptoms 71%, 56%; severe 10%, 2%), abnormal ECG (all patients 60%, 52%; patients with normal baseline 35%, 30%), fatigue/asthenia (any 47%, 39%; severe 8%, 3%), myalgia/arthralgia (any 44%, 49%; severe 8%, 4%), AST elevation (any 39%, 32%), alkaline phosphatase elevation (any 36%, 31%), anemia (any 33%, 25%; severe 1%, < 1%), nausea (any 30%, 22%; severe 3%, < 1%), diarrhea (any 27%, 15%; severe < 1%, 1%) and infections (24%, 20%), respectively
Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients
Other adverse reactions of note with the use of ABRAXANE vs paclitaxel injection included vomiting (any 18%, 10%; severe 4%, 1%), fluid retention (any 10%, 8%; severe 0%, < 1%), mucositis (any 7%, 6%; severe < 1%, 0%), hepatic dysfunction (elevations in bilirubin 7%, 7%), hypersensitivity reactions (any 4%, 12%; severe 0%, 2%), thrombocytopenia (any 2%, 3%; severe < 1%, < 1%), neutropenic sepsis ( < 1%, < 1%), and injection site reactions ( < 1%, 1%), respectively. Dehydration and pyrexia were also reported
Renal dysfunction (any 11%, severe 1%) was reported in patients treated with ABRAXANE (n=229)
In all ABRAXANE-treated patients (n=366), ocular/visual disturbances were reported (any 13%; severe 1%)
Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients and included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension
Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported
Postmarketing Experience With ABRAXANE and Other Paclitaxel Formulations

Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or to human albumin has not been studied
There have been reports of congestive heart failure, left ventricular dysfunction, and atrioventricular block with ABRAXANE, primarily among individuals with underlying cardiac history or prior exposure to cardiotoxic drugs
There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration
DRUG INTERACTIONS

Caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit or induce either CYP2C8 or CYP3A4
USE IN SPECIFIC POPULATIONS

Nursing Mothers

It is not known whether paclitaxel is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother
Pediatric

The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated
Geriatric

A higher incidence of epistaxis, diarrhea, dehydration, fatigue, and peripheral edema was found in patients 65 years or older who received ABRAXANE for MBC in a pooled analysis of clinical studies
Renal Impairment

There are insufficient data to permit dosage recommendations in patients with severe renal impairment or end stage renal disease (estimated creatinine clearance < 30 mL/min)
DOSAGE AND ADMINISTRATION

Do not administer ABRAXANE to any patient with total bilirubin greater than 5 x ULN or AST greater than 10 x ULN
Reduce starting dose in MBC patients with moderate to severe hepatic impairment
Dose reductions or discontinuation may be needed based on severe hematologic or neurologic toxicity
Monitor patients closely
Please see full Prescribing Information, including Boxed WARNING.

About the German Breast Group

GBG is a large independent academic network of over 500 study centers in Germany with the world- wide largest experience in conducting neoadjuvant breast cancer trials. Since 1998, with joined forces from AGO-B, over 10.000 patients participated in the neoadjuvant "Gepardo" trial series. GBG has recruited at totality of over 35.000 patients to trials in breast cancer of all indications. Reports on these trials were previously published in the New England Journal of Medicine, The Lancet Oncology, the Journal of Clinical Oncology and the Journal of the National Cancer Institute (for more information go to www.germanbreastgroup.de). The GBG Research Institute received unrestricted grants and the provision of medication from Celgene and Roche for the conduct of the GeparSepto study. ABRAXANE is approved in the US and Europe for patients with metastatic breast cancer.

Prolonged Progression-Free Survival Reinforces Tucatinib’s Potential for Patients with Advanced HER2+ Metastatic Breast Cancer

On December 7, 2017 Cascadian Therapeutics, Inc. (NASDAQ:CASC), a clinical-stage biopharmaceutical company, reported that tucatinib in combination with standard of care agents demonstrated prolonged progression-free survival (PFS) in a subgroup of patients participating in two ongoing Phase 1b studies (Press release, Cascadian Therapeutics, DEC 7, 2017, View Source [SID1234522438]). Results from a subgroup analysis from these tucatinib combination studies showed 22 percent of patients with HER2-positive (HER2+) metastatic breast cancer with and without brain metastases achieved prolonged PFS defined as twice the median PFS seen in these studies or else defined as survival greater than 17 months. Patients received a median of two prior HER2-based regimens and the median duration of the last prior treatment in this subgroup was 9.03 months. Patients with prolonged PFS on tucatinib combination therapy included those with characteristics that historically predict poor outcome such as hormone receptor status, presence of visceral disease, burden of systemic or brain disease and age. Results from this analysis will be presented in a poster session at the 2017 San Antonio Breast Cancer Symposium (SABCS) on Friday, December 8, 2017 beginning at 5:00 p.m. CST.

"One of the challenges in the treatment of HER2+ breast cancer is the frequent development of brain metastases, which occur in up to 50 percent of patients with advanced disease," said Erika Hamilton, M.D., Director of Breast and Gynecology Cancer Research and Principal Investigator at Sarah Cannon Research Institute. "Tucatinib in combination has shown early signs of activity in HER2+ brain metastases. An active agent showing prolonged activity systemically as well as in the brain, with a tolerable safety profile, would represent a meaningful advancement in treating metastatic breast cancer."

Dr. Hamilton continued, "The more mature dataset from these Phase 1b combination studies show tucatinib may be combined with other standard targeted therapies to achieve disease control in patients who have received multiple prior lines of therapy."

Prolonged Progression-Free Survival in Advanced HER2+ Metastatic Breast Cancer with or without Brain Metastases: A Pooled Analysis of Tucatinib Phase 1b Studies

In this poster, data from two Phase 1b combination studies of tucatinib were pooled to analyze the subgroup of patients with prolonged PFS, which was identified as patients achieving at least twice the observed median PFS in the overall group. Baseline characteristics and radiology findings were compared between the subgroup of patients with or without prolonged PFS from two studies: tucatinib in combination with trastuzumab (Herceptin) and capecitabine (Xeloda) in heavily pre-treated patients with advanced HER2+ breast cancer with or without brain metastases (ONT-380-005/Triplet study; n=27), and tucatinib in combination with T-DM1 (ONT-380-004; n=50). Of the 77 patients in the pooled analysis, 47 percent (n=36) of patients are without brain metastases and 53 percent (n=41) are with brain metastases, including patients with untreated or progressive brain metastases after radiation therapy. Twenty-two percent (17/77) of patients demonstrated prolonged PFS; 20 percent (n=10/50) from Study 004 and 26 percent (n=7/27) from Study 005/Triplet. Data from pooled tucatinib studies suggest a similar proportion of patients with brain metastases in the subgroup of patients with prolonged PFS compared to the overall patient population.

In addition, the following investigator-initiated trial in progress poster was presented at SABCS.

Phase 1b/2 Open-Label Single Arm Study to Evaluate Safety and Efficacy of Tucatinib in Combination with Letrozole and Palbociclib in Subjects with Hormone Receptor Positive and HER2 Positive Metastatic Breast Cancer (TULiP Trial)

The University of Colorado Cancer Center presented a trials in progress poster summarizing the study design for the ongoing TULiP trial in patients with hormone receptor positive and HER2-positive (HR+/HER2+) metastatic breast cancer. In this study, tucatinib, a highly selective inhibitor of HER2 tyrosine kinase, is combined with an aromatase inhibitor letrozole and CDK4/6 inhibitor palbociclib. The TULiP study is expecting to enroll 40 patients. It is currently opened for enrollment at the University of Colorado Denver, and soon will be opened at five additional academic institutions (members of Academic Breast Cancer Research Consortium): North Western University, Chicago, IL; University of Texas Health and Science Center at San Antonio, TX; Stony Brook University, NY; University of Arizona, Tucson, AZ, and University of New Mexico, Albuquerque, NM. The Phase 1b part of the trial is expected to enroll 20 patients and will evaluate the tolerability of tucatinib given at maximum tolerated dose (300mg by mouth twice a day) with the standard doses of palbociclib and letrozole. The Phase 2 part of the trial is expected to enroll 20 additional patients to enable analysis of efficacy by overall response rate and progression-free survival. Because of documented activity of tucatinib in the CNS disease, the TULiP trial will include patients with brain metastases. For more information, visit ClinicalTrials.gov, Identifier: NCT03054363.

"Finding novel treatments for HR+/HER2+ breast cancers remains an area of unmet clinical need, because of intrinsic resistance of these tumors to both anti-hormonal treatments and HER2-targeted agents," said Elena Shagisultanova, MD, PhD, Assistant Professor at the University of Colorado Denver Cancer Center and Lead Principal Investigator of TULiP trial. "We are very excited about the TULiP trial. There is significant preclinical evidence on synergistic anti-tumor activity of CDK4/6 inhibitors and HER2-targeted agents. Tucatinib, palbociclib and letrozole have largely non-overlapping toxicity profiles and metabolic pathways. We believe that this triple combination of targeted agents will be well tolerated and highly patient centered, as an effective non-chemotherapy based regimen for treatment of patients with HR+/HER2+ metastatic breast cancer. We are grateful for the support we received from both Cascadian Therapeutics and Pfizer while working on this trial."

To access these poster presentations, please visit www.cascadianrx.com.

About Tucatinib

Tucatinib is an investigational, orally bioavailable, potent tyrosine kinase inhibitor that is highly selective for HER2 without inhibition of EGFR. Inhibition of EGFR has been associated with clinical toxicities, including skin rash and diarrhea. Tucatinib has shown activity as a single agent and in combination with both chemotherapy and other HER2 directed agents such as trastuzumab.1,2 Studies of tucatinib in these combinations have shown activity both systemically and in brain metastases. HER2 is a growth factor receptor that is overexpressed in multiple cancers, including breast, ovarian and gastric cancers. HER2 mediates cell growth, differentiation and survival. Tumors that overexpress HER2 (HER2+) are more aggressive and historically have been associated with poor overall survival, compared with HER2-negative cancers.

About HER2CLIMB Pivotal Trial

HER2CLIMB is a randomized (2:1), double-blind, placebo-controlled pivotal clinical trial comparing tucatinib vs. placebo, each in combination with capecitabine and trastuzumab and without loperamide or budesonide prophylaxis, in patients with locally advanced or metastatic HER2+ breast cancer who have had prior treatment with trastuzumab, pertuzumab and ado-trastuzumab emtansine, also known as T-DM1. The primary endpoint is progression-free survival (PFS) based upon independent radiologic review. Key objectives related to assessing activity in brain metastases include a key secondary endpoint of PFS in a subset of patients with brain metastases. All patients will be followed for overall survival. HER2CLIMB is currently enrolling patients in the United States, Canada, Western Europe and Australia. Additional information is available at www.HER2CLIMB.com.

About HER2+ Metastatic Breast Cancer

Patients with HER2+ breast cancer have tumors with high levels of a protein called human epidermal growth factor receptor 2 (HER2), which promotes the aggressive spread of cancer cells. The American Cancer Society estimates that 20-25 percent of the approximately 246,660 annual new cases of breast cancer diagnoses in the U.S. are HER2+. Historically, HER2 disease has been associated with shorter survival times as well as a higher risk of recurrence and CNS disease (brain metastases). Up to 50 percent of patients with HER2+ metastatic breast cancer experience brain metastases over time.3 Over the past two decades, the approvals of four targeted treatments (trastuzumab, pertuzumab, lapatinib, and T-DM1) have led to improved time to progression and survival rates of patients with HER2+ breast cancer. Despite these advances, there is still a significant need for new therapies that can impact metastatic disease, including brain metastases, and be tolerated for longer periods of time.

Syros Presents New Preclinical Data on SY-1365, Its First-in-Class Selective CDK7 Inhibitor, and Discovery of Potential New Drug Targets in Triple Negative Breast Cancer at San Antonio Breast Cancer Symposium

On December 7, 2017 Syros Pharmaceuticals (NASDAQ: SYRS), a biopharmaceutical company pioneering the discovery and development of medicines to control the expression of disease-driving genes, reported that new preclinical data on SY-1365, its first-in-class selective cyclin-dependent kinase 7 (CDK7) inhibitor currently in a Phase 1 clinical trial in advanced solid tumors, demonstrate anti-tumor activity across a broad panel of breast cancer cell lines and point to potential biomarkers predictive of response (Press release, Syros Pharmaceuticals, DEC 7, 2017, View Source [SID1234522431]). The Company also announced its identification of key genes driving relapse and metastasis in triple negative breast cancer (TNBC), pointing to potential new drug targets. These data were presented at the San Antonio Breast Cancer Symposium (SABCS).

"These data speak to the power of our gene control platform to provide a new lens for understanding disease with important implications for developing much-needed therapies in defined subsets of patients," Eric R. Olson, Ph.D., Chief Scientific Officer of Syros. "Despite advances in the treatment of certain cancers, two of the biggest challenges in cancer treatment remain the ability to pair the right patients with the right drugs and to prevent the emergence of drug resistance in response to targeted therapies. By analyzing regulatory regions of the genome, we discovered potential biomarkers of response to SY-1365 within heterogeneous patient populations that we can further explore during clinical development. Separately, using our platform, we also identified new potential points of therapeutic intervention in TNBC with the potential to thwart the mechanisms cancer uses to become resistant to therapy and spread to other parts of the body."

New Preclinical Data on SY-1365
Syros scientists analyzed the anti-tumor activity of SY-1365 across a panel of more than 400 cancer cell lines, including 19 TNBC cell lines and 21 ER-positive, PR-positive and HER2-positive cells lines. They then grouped the cell lines according to sensitivity to SY-1365 and looked for markers of response using Syros’ gene control platform to analyze regulatory regions of the genome. The data showed:

SY-1365 induced cell death in 15 out of the 19 TNBC cell lines and 17 of the 21 ER-positive, PR-positive and HER2-positive cells lines.
Sensitivity to SY-1365 in these breast cancer cell lines was associated with a super-enhancer, a highly specialized regulatory region of the genome, that drives increased expression of the known oncogene MYC.
Sensitivity to SY-1365 was also associated with low expression of the mitochondrial apoptosis antagonist BCL2L1 in these cell lines.
Lowered expression of MCL1, a gene in the mitochondrial apoptosis pathway known to inhibit apoptosis, was associated with SY-1365 target engagement and anti-tumor activity in cell lines and a cell-derived xenograft model of TNBC.
The Phase 1 trial of SY-1365 is a multi-center, open-label trial enrolling 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 and expected to enroll approximately 35 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 transcriptionally driven tumors 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 expects to present initial clinical data from this study in 2018.

Mechanisms of Relapse and Metastasis in TNBC
Using its gene control platform, Syros scientists, in collaboration with the lab of Robert Weinberg, Ph.D. at the Whitehead Institute, analyzed regulatory regions of the genome in cancer-stem cell enriched TNBC cell lines. Cancer stem cells (CSCs) are known to be involved in resistance to chemotherapies, relapse of disease and development of metastasis. The analysis revealed key genes that may be involved in driving disease relapse and metastasis, with implications for the discovery and development of novel therapies for TNBC. Notably, TP73 was found to be a core driver of transcriptional circuitry in CSCs, controlling super-enhancer associated genes involved in cell migration, signal transduction and developmental processes. TP73 is a gene that encodes a DNA-binding transcription factor called p73. The set of TP73-controlled genes provide new leads for drug discovery and development with potential to yield much-needed new therapies for TNBC patients.