On September 11, 2017 Ignyta, Inc. (Nasdaq:RXDX), a biotechnology company focused on precision medicine in oncology, provided an update on entrectinib—an orally bioavailable, CNS-active tyrosine kinase inhibitor being developed in tumors that harbor NTRK fusions or ROS1 fusions, currently being studied in a registration-enabling Phase 2 clinical trial known as STARTRK-2—and RXDX-105—an investigational, VEGFR-sparing, potent RET inhibitor (Press release, Ignyta, SEP 11, 2017, View Source [SID1234520465]).

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"Building on last week’s announcement of the completion of enrollment of the entrectinib efficacy data set for NDA submission in ROS1 fusion-positive non-small cell lung cancer, we are equally excited to also have completed enrollment of the efficacy data set for NDA submission in the NTRK tissue-agnostic indication," said Jonathan Lim, M.D., chairman and CEO of Ignyta. "We look forward to dual registration submissions in 2018 for these two independent, high unmet need, molecularly defined populations."

Entrectinib program updates:

Based on written feedback from the FDA, Ignyta confirms completion of enrollment of the efficacy data sets for both the NTRK tissue-agnostic (i.e., fusion-positive solid tumor) cohort and the ROS1 NSCLC cohort to support dual NDA submissions in 2018.
No additional studies were requested for these submissions.
Entrectinib was intentionally designed to cross the blood-brain barrier and has demonstrated CNS activity. Specific guidance was provided by FDA on inclusion of entrectinib CNS efficacy data in future prescribing information for both NTRK and ROS1.
An update on data from STARTRK-2 on entrectinib in ROS1 NSCLC, including an additional six months of follow-up, will be presented at the International Association for the Study of Lung Cancer (IASLC) 18th World Conference on Lung Cancer (WCLC) in Yokohama, Japan October 18, 2017. Previous interim data were shared in an investor update call in April 2017.
Additionally, a recent joint meeting with the Center for Devices and Radiological Health (CDRH) and the Center for Drug Evaluation Research (CDER) on companion diagnostic strategy for entrectinib confirms the premarket approval submission plan and timeline for Trailblaze Pharos are tracking with the dual NDA submissions in NTRK and ROS1.
RXDX-105 program updates:

New Phase 1b clinical data on RXDX-105 presented this week at the ESMO (Free ESMO Whitepaper) 2017 Congress in Madrid, Spain demonstrated clinical activity in RET fusions and compelling response rate in an ultra-rare lung cancer population.

Safety –

A total of 152 patients, with a range of solid tumors, have been treated in the Phase 1/1b clinical trial, including 74 patients treated at the recommended Phase 2 dose of 275mg daily in the fed state, and 43 patients treated at a dose of 350mg daily in the fed state.
RXDX-105 continues to be well tolerated, with the most common treatment-related adverse events Grade 1 or 2 and reversible with dose modifications. The most common Grade 3 treatment-related adverse events ( > 5 percent) were rash (10 percent), hypophosphatemia (7 percent) and elevated ALT (7 percent).
Importantly, toxicities commonly associated with VEGFR inhibition, such as hypertension, hypothyroidism, proteinuria and neurotoxicity were rarely observed ( < 5 percent); and RXDX-105 was not associated with Qt/QTc prolongation.
Efficacy –

Of those treated, 22 patients had NSCLC harboring RET fusions and were RET inhibitor naïve, making them evaluable for response.
A preliminary objective response rate of 75 percent was observed in patients with non-KIF5B-RET fusions, with six of eight patients achieving a confirmed partial response. In contrast, those with KIF5B-RET fusions (14 patients) did not demonstrate a RECIST response. These data are consistent with previous studies that suggest that KIF5B-RET fusions may be less susceptible to RET inhibition.
The longest duration of response (DOR) in a responding patient with non-KIF5B-RET fusion was 10.2 months and ongoing; two-thirds of responding patients currently continue on treatment in active response; median DOR therefore has not yet been reached.
Development plan –

This robust clinical trial design has employed next generation sequencing to identify the precise patient populations most likely to benefit from RXDX-105 – those with non-KIF5B-RET fusions – which is estimated to be approximately 800 new patients per year in the United States.
The RXDX-105 Phase 1b study will be concluded with no further enrollment. Those currently receiving treatment will remain on study.
Ignyta will continue discussing RXDX-105 with potential partners and will provide an update on this program in the first half of 2018.

On September 11, 2017 DelMar Pharmaceuticals (Nasdaq: DMPI) ("DelMar" and "the Company"), a biopharmaceutical company focused on the development of new cancer therapies, reported the initiation of a Phase 2 clinical trial for its lead agent VAL-083 in newly diagnosed MGMT-unmethylated glioblastoma multiforme (GBM) (Press release, DelMar Pharmaceuticals, SEP 11, 2017, View Source [SID1234520461]). The biomarker-driven clinical trial will explore safety and efficacy of chemoradiation with VAL-083 as an alternative to standard-of-care temozolomide in patients with MGMT-unmethylated GBM.

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"This small trial has the ability to pave the way for a significant treatment paradigm change for patients with newly diagnosed GBM. Positive data from this study will serve as a lead-in to a randomized global trial and set the stage for VAL-083 to potentially become the standard of care for approximately two-thirds of newly diagnosed GBM patients," commented Jeffrey Bacha, Chief Executive Officer of DelMar Pharmaceuticals.

The trial, which is being funded under the terms of DelMar’s collaboration with Guangxi Wuzhou Pharmaceutical Group Co. Ltd. (Guangxi Wuzhou Pharma), is being conducted at Sun Yat-sen University Cancer Center (SYUCC) in Guangzhou, China under the direction of Prof. Zhong-ping Chen, M.D., Ph.D. Prof. Chen is the Chair of the Department of NeuroSurgery/Neuro-Oncology at SYUCC and a member of the editorial board of the Journal of NeuroOncology.

The study will enroll 20-30 newly diagnosed GBM patients whose tumors exhibit high-expression of the DNA-repair enzyme O6-methylguanine methyltransferase (MGMT) and will be treated with VAL-083 in combination with radiotherapy to examine the safety and efficacy of VAL-083 in this population. MGMT methylation status will be used as a biomarker for patient selection and only patients whose tumors are MGMT-unmethylated will be enrolled.

GBM patients with MGMT-unmethylated tumors exhibit a high expression of the MGMT enzyme. MGMT expression is correlated with resistance to temozolomide, the current front-line chemotherapy used in the treatment of GBM. MGMT-unmethylated patients have particularly poor patient outcomes and significantly reduced survival compared to MGMT-methylated patients. VAL-083 has demonstrated anti-cancer activity independent of MGMT expression against multiple GBM cell lines in vitro.

The primary efficacy endpoint of this trial is progression free survival (PFS). Based on enrollment projections, it is expected that safety/tolerability and primary efficacy (PFS) data from this trial will become available within 9 months and 15 months, respectively from start of enrollment. Results will be used to guide the design of global randomized studies, which if successful, will position VAL-083 as a potential replacement for the current standard-of-care (chemoradiation with temozolomide) in newly diagnosed GBM patients, particularly for the approximately 2/3 of patients whose tumors feature MGMT-unmethylated GBM. Further details of the trial can be found at clinicaltrials.gov (Identifier Number: NCT03050736)

About VAL-083

VAL-083 (dianhydrogalactitol) is a "first-in-class", DNA-targeting agent that introduces interstrand DNA cross-links at the N7-position of guanine leading to DNA double-strand breaks and cancer cell death. VAL-083 has demonstrated clinical activity against a range of cancers including GBM in historical clinical trials sponsored by the U.S. National Cancer Institutes (NCI).

VAL-083 has been granted an orphan drug designation by the U.S. FDA Office of Orphan Products for the treatment of glioma, medulloblastoma and ovarian cancer, and in Europe for the treatment of malignant gliomas.

DelMar has demonstrated that VAL-083’s anti-tumor activity against GBM is unaffected by the expression of MGMT in vitro. Further details regarding these studies can be found at View Source

The Company’s recent outcomes in Phase 1-2 clinical trials suggested that VAL-083 may offer a clinically meaningful survival benefit for patients with recurrent GBM following treatment with both TMZ and bevacizumab. A well-tolerated dosing regimen of 40mg/m2/day on days 1, 2, and 3 of a 21-day cycle was selected for study in subsequent GBM clinical trials.

Overall VAL-083’s clinical activity as a potential treatment for GBM has been established by DelMar’s recent clinical trials in refractory GBM and historical trials conducted by the NCI. In prior NCI trials, VAL-083 combined with radiotherapy in newly diagnosed GBM (all MGMT status) demonstrated superior benefit versus radiotherapy alone (8.3 months) in comparison to similar studies involving temozolomide or nitrosoureas (1.2 – 2.5 months).

Based on these results, DelMar has embarked on human clinical trials for VAL-083 across multiple lines of GBM therapy. These trials include, i) an ongoing single-arm, biomarker driven, Phase 2 study to determine if VAL-083 treatment of MGMT-unmethylated adult GBM patients at first recurrence/progression, prior to bevacizumab, improves overall survival, compared to historical control with lomustine (clinicaltrials.gov identifier: NCT02717962); ii) a pivotal, randomized Phase 3 study in temozolomide-Avastin Recurrent GBM ("STAR-3") to evaluate overall survival versus salvage chemotherapy (clinicaltrials.gov identifier: NCT03149575); iii) a single arm, biomarker driven, Phase 2 study to confirm the tolerability and efficacy of VAL-083 in combination with radiotherapy in newly diagnosed MGMT-unmethylated GBM patients whose tumors are known to express high MGMT levels (clinicaltrials.gov identifier: NCT03050736). The results of these studies may support a new treatment paradigm in chemotherapeutic regimens for the treatment of GBM.

About Glioblastoma Multiforme (GBM)

Glioblastoma Multiforme (GBM) is the most common and aggressive primary brain cancer. Approximately 18,000 patients are diagnosed with GBM in the United States and 25,000 in Europe each year. Current standard of care includes surgery, radiation and treatment with temozolomide (TMZ), however nearly all tumors recur and the prognosis for recurrent GBM is dismal. Approximately two-thirds of newly diagnosed GBM patients have tumors characterized by an unmethylated promoter for O6-methylguanine methyltransferase (MGMT); a validated biomarker for TMZ-resistance. Second-line treatment with anti-angiogenic agent bevacizumab has not improved overall survival (OS) and 5-year survival is less than 3%.

On September 11, 2017 Curis, Inc. (NASDAQ:CRIS), a biotechnology company focused on the development and commercialization of innovative and effective therapeutics for the treatment of cancer, reported preliminary data from the initial 34 patients with cancer treated in the dose escalation stage of the Phase 1 trial of CA-170 conducted in the U.S., South Korea and Spain, at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2017 Congress (Press release, Curis, SEP 11, 2017, View Source [SID1234520460]). As a result of the initial safety data and preliminary evidence of clinical benefit observed in the trial, Curis’s collaborator and discoverer of CA-170, Aurigene Discovery Technologies Limited, a specialized biotechnology company engaged in discovery and early clinical development of novel and best-in-class therapies to treat cancer and inflammatory diseases, reported plans to initiate a Phase 2 trial of CA-170 to be conducted at sites in India.

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"We are pleased with these early results. Based on evidence of tumor shrinkage, multiple patients remaining on drug treatment for extended periods, and compelling signals for biomarkers of immune modulation in patient blood and tumor samples, we remain highly confident that the CA-170 program is moving in the right direction. We plan to continue with the dose escalation and continued analysis of patient biopsy samples in the Phase 1 trial," said Ali Fattaey, Ph.D., President and Chief Executive Officer of Curis. "We expect to provide additional updates at upcoming conferences including the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) annual meeting in November."

"The ability for cancer patients to administer a potential checkpoint inhibitor on their own as a once daily oral drug is a significant and unique opportunity in our field," added Adil Daud, M.D., investigator in the CA-170 Phase 1 trial and director of Melanoma Clinical Research at the UCSF Helen Diller Family Comprehensive Cancer Center. "These initial clinical results are encouraging and merit continued development."

"These results are consistent with the observations made in the preclinical setting and further affirm CA-170’s mechanism of action as an oral small molecule checkpoint inhibitor," commented Mr. CSN Murthy, Chief Executive Officer of Aurigene. "Based on these initial clinical results, we are excited for the opportunity to expand testing of CA-170, possibly in earlier lines of treatment and in a greater number of immunotherapy treatment-naïve cancer patients." Added Mr. Murthy, "Together with Curis, we have designed a Phase 2 trial in selected populations of patients of interest to be treated at major cancer centers in India. Aurigene’s decision to sponsor and fund this trial is further affirmation of our commitment to CA-170 and a reflection of the successful collaboration we have with Curis in multiple development programs."

CA-170 is an oral small molecule targeting the immune checkpoints PDL1 and VISTA. Data presented at the ESMO (Free ESMO Whitepaper) 2017 conference represent the initial 34 patients treated to date in the dose escalation Phase 1 trial. 30 patients were naïve to prior immunotherapy treatment, while four patients had experienced prior treatment with approved anti-checkpoint antibodies. No dose limiting toxicities were observed at doses ranging from 50 mg to 800 mg once daily dosing examined thus far. CA-170 demonstrated good oral bioavailability and plasma drug levels were shown to increase in a near-linear manner with increasing doses. Evidence of immune modulation, including an increase in activated CD8+ T cells, was observed in patient blood and tumor biopsy samples examined following treatment. Of the 21 patients evaluable for disease assessment, 13 patients experienced disease stabilization. Four immunotherapy treatment-naïve patients treated with CA-170 experienced shrinkage of their tumors. Six patients remained on drug treatment beyond three months, including all four patients with tumor shrinkages. In addition, seven of the 34 patients remain on study and are continuing with treatment.

On September 11, 2017 Cascadian Therapeutics, Inc. (NASDAQ:CASC), a clinical-stage biopharmaceutical company, reported tucatinib data in multiple tumor types were presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2017 Congress being held September 8-12, 2017 in Madrid, Spain (Press release, Cascadian Therapeutics, SEP 11, 2017, View Source [SID1234520458]). Results from the pooled analysis of Phase 1b combination studies support the potential utility of tucatinib for patients with HER2-positive (HER2+) metastatic breast cancer with brain metastases, including untreated or progressive brain metastases after radiation therapy. HER2 disease has been associated with shorter survival times as well as a higher risk of recurrence and brain metastases.

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"Approximately 30-to-50 percent of patients with metastatic HER2+ breast cancer will develop brain metastases over time and, historically, patients with HER2+ brain metastases have had poorer outcomes compared to those without," said Stacy L. Moulder, MD, Associate Professor, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. "The results from this pooled analysis of tucatinib combination studies suggesting that patients with HER2+ brain metastases, including those with untreated or progressing disease, have similar progression-free survival compared to those without brain metastases is promising and supports inclusion of patients with brain metastases into ongoing clinical trials. There remains a clinical need for safe and effective HER2-targeted therapies that are active both systemically and in the brain."

Luke Walker, MD, Senior Vice President, Clinical Development of Cascadian Therapeutics, added, "These data from our Phase 1b trials further support the inclusion of patients with brain metastases in our ongoing registrational trial of tucatinib in combination with capecitabine and trastuzumab. This trial, known as HER2CLIMB, is enrolling patients with all types of brain metastases, including untreated, previously treated or progressing brain metastases. Approximately half of patients enrolled in HER2CLIMB to date have had brain metastases at study entry, which will allow us to assess activity in that subpopulation in a statistically meaningful way."

Progression-free survival (PFS) and site of first progression in HER2+ metastatic breast cancer patients with or without brain metastases: A pooled analysis of tucatinib phase I studies (Poster 264)

In this poster (264), data from two Phase 1b combination studies of tucatinib were pooled to analyze baseline characteristics and outcomes of patients with and without brain metastases: 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), and tucatinib in combination with T-DM1 (ONT-380-004). Of the 77 patients in the pooled analysis, 47 percent (n=36) of patients are without brain metastases and 53 percent (n=41) with brain metastases, including patients with untreated or progressive brain metastases after radiation therapy. Four subgroups were identified retrospectively based on historical data and then compared with respect to baseline characteristics, progression-free survival and site of progression. Data from pooled tucatinib studies suggest the PFS of patients with and without brain metastases were similar, regardless of whether brain metastases were untreated or progressed after radiation therapy.

In addition, the following nonclinical poster supports the clinical evaluation of tucatinib for the treatment of other HER2+ tumor types.

Tucatinib, a HER2 selective kinase inhibitor, is active in patient derived xenograft (PDX) models of HER2-amplified colorectal, esophageal and gastric cancer (Poster 1639)

In this poster, data are presented that show tucatinib is active as a single agent in nonclinical models of HER2+ gastrointestinal cancers, including colorectal, esophageal and gastric cancers. The data also demonstrate that tucatinib combined with trastuzumab displayed superior anti-tumor activity compared with either single agent, producing a higher proportion of partial and complete tumor regressions. These nonclinical data support the clinical evaluation of tucatinib for the treatment of HER2+ gastrointestinal cancers. Tucatinib is currently being evaluated in an open label Phase 2 study combining tucatinib with trastuzumab in HER2+/RAS wild type metastatic colorectal cancer (MOUNTAINEER: NCT03043313).

Scott Peterson, Ph.D., Chief Scientific Officer of Cascadian Therapeutics, commented, "We are pleased to share this update regarding the potential versatility of tucatinib in combination for other tumor types beyond breast cancer."

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.