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Array BioPharma Announces FDA Acceptance For Review Of Binimetinib And Encorafenib New Drug Applications For Patients With Advanced BRAF-mutant Melanoma

On September 12, 2017 Array BioPharma (Nasdaq: ARRY) reported that the U.S. Food and Drug Administration (FDA) has accepted for review its New Drug Applications (NDAs) to support use of the combination of binimetinib 45 mg twice daily and encorafenib 450 mg once daily (COMBO450) for the treatment of patients with BRAF-mutant advanced, unresectable or metastatic melanoma (Press release, Array BioPharma, SEP 12, 2017, View Source [SID1234520479]). The FDA set a target action date under the Prescription Drug User Fee Act (PDUFA) of June 30, 2018 for both applications. In addition, the FDA informed Array that based on their preliminary review of the applications they have not identified any potential review issues, and that they are not currently planning to hold an advisory committee meeting to discuss these NDAs. Array completed its NDA submissions at the end of June 2017 based on findings from the pivotal Phase 3 COLUMBUS trial.

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"We look forward to working with the FDA and EMA as they review our New Drug Applications for binimetinib and encorafenib," said Ron Squarer, Chief Executive Officer. "The robust PFS benefit together with the attractive tolerability profile demonstrated in COLUMBUS suggest the combination represents a potentially important addition to the MEK/BRAF treatment landscape for patients with BRAF-mutant melanoma."

COLUMBUS Results
As presented at the 2016 Society for Melanoma Research Annual Congress, results from Part 1 of the COLUMBUS study showed that COMBO450 significantly extend PFS in patients with advanced BRAF-mutant melanoma, with a PFS of 14.9 months compared with 7.3 months observed with vemurafenib [hazard ratio (HR) 0.54, (95% CI 0.41-0.71, P<0.001)]. As part of the trial design, the primary analysis was based on a Blinded Independent Central Review (BICR) of patient scans, while results by local review at the investigative site were also analyzed. The table below outlines the median PFS (mPFS) results, as determined by both assessments, for COMBO450 versus vemurafenib, COMBO450 versus encorafenib, and encorafenib versus vemurafenib:

mPFS BICR

mPFS Local Review
COMBO450 vs. Vemurafenib

COMBO450
Vemurafenib

14.9 months
7.3 months

14.8 months
7.3 months

HR (95% CI): 0.54 (0.41-0.71); P<0.001

HR (95% CI): 0.49 (0.37-0.64); P<0.001

COMBO450 vs. Encorafenib

COMBO450
Encorafenib

14.9 months
9.6 months

14.8 months
9.2 months

HR (95% CI): 0.75 (0.56-1.00); P=0.051

HR (95% CI): 0.68 (0.52-0.90); P=0.006

Encorafenib vs. Vemurafenib

Encorafenib
Vemurafenib

9.6 months
7.3 months

9.2 months
7.3 months

HR (95% CI): 0.68 (0.52-0.90); P=0.007

HR (95% CI): 0.70 (0.54-0.91); P=0.008
In this study, COMBO450 was generally well-tolerated, with a median duration of treatment of 51 weeks and median relative dose intensity for encorafenib and binimetinib of 100% and 99.6%, respectively. Grade 3/4 adverse events (AEs) that occurred in more than 5% of patients receiving COMBO450 were increased gamma-glutamyltransferase (GGT) (9%), increased blood creatine phosphokinase (CK) (7%) and hypertension (6%). The incidence of selected any grade AEs of special interest, defined based on toxicities commonly associated with commercially available MEK+BRAF-inhibitor treatments for patients receiving COMBO450 included: rash (23%), pyrexia (18%), retinal pigment epithelial detachment (13%) and photosensitivity (5%). Full safety results of COLUMBUS Part 1 were presented at the 2016 Society for Melanoma Research Annual Congress.

COLUMBUS Part 2 was designed specifically to assess the contribution of binimetinib to the combination of binimetinib and encorafenib by reducing the dose of encorafenib to 300mg in the combination arm to allow for a comparison of equal doses across arms. In COLUMBUS Part 2, the primary analysis compared PFS in patients treated with binimetinib 45mg twice daily plus encorafenib 300mg daily (COMBO300) to patients treated with encorafenib 300mg daily as a single agent. Top-line results showed the mPFS for patients treated with COMBO300 was 12.9 months compared to 9.2 months for patients treated with single agent encorafenib, with HR of 0.77 [95% CI 0.61-0.97, p=0.029]. COMBO300 was generally well-tolerated and reported dose intensity and AEs were consistent with COMBO450 results in COLUMBUS Part 1. Results of COLUMBUS Part 2 were presented at the 2017 European Society for Medical Oncology Congress.

About the Phase 3 COLUMBUS Study
The COLUMBUS trial, (NCT01909453), is a two-part, international, randomized, open label Phase 3 study evaluating the efficacy and safety of the combination of binimetinib plus encorafenib to vemurafenib and encorafenib monotherapy in 921 patients with locally advanced, unresectable or metastatic melanoma with BRAF V600 mutation. Prior immunotherapy treatment was allowed. Over 200 sites across North America, Europe, South America, Africa, Asia and Australia participated in the study. Patients were randomized into two parts:

In Part 1, 577 patients were randomized 1:1:1 to receive 45mg binimetinib plus 450mg encorafenib (COMBO450), 300mg encorafenib alone, or 960mg vemurafenib alone. The dose of encorafenib in the combination arm is 50% higher than the single agent maximum tolerated dose of 300mg. A higher dose of encorafenib was possible due to improved tolerability when combined with binimetinib. The primary endpoint for the COLUMBUS trial was a PFS comparison of COMBO450 versus vemurafenib. PFS is determined based on tumor assessment (RECIST version 1.1 criteria) by a Blinded Independent Central Review (BICR). Secondary endpoints include a comparison of the PFS of encorafenib monotherapy to that of COMBO450 and a comparison of overall survival (OS) for COMBO450 to that of vemurafenib alone.
In Part 2, 344 patients were randomized 3:1 to receive 45mg binimetinib plus 300mg encorafenib or 300mg encorafenib alone. Part 2 is designed to provide additional data to help evaluate the contribution of binimetinib to the combination of binimetinib and encorafenib. As the comparison of COMBO450 to encorafenib in Part 1 did not achieve statistical significance, analyses of other endpoints including the statistical analysis conducted in Part 2 is descriptive.
About Melanoma
Metastatic melanoma is the most serious and life-threatening type of skin cancer and is associated with low survival rates[1],[2]. There are about 200,000 new cases of melanoma diagnosed worldwide each year, approximately half of which have BRAF mutations, a key target in the treatment of metastatic melanoma[1],[3],[4].

About Binimetinib and Encorafenib
MEK and BRAF are key protein kinases in the MAPK signaling pathway (RAS-RAF-MEK-ERK). Research has shown this pathway regulates several key cellular activities including proliferation, differentiation, survival and angiogenesis. Inappropriate activation of proteins in this pathway has been shown to occur in many cancers, such as melanoma, colorectal and thyroid cancers. Binimetinib is a late-stage small molecule MEK inhibitor and encorafenib is a late-stage small molecule BRAF inhibitor, both of which target key enzymes in this pathway. Binimetinib and encorafenib are being studied in clinical trials in advanced cancer patients, including the Phase 3 BEACON CRC trial with encorafenib in combination with cetuximab with or without binimetinib in patients with BRAF V600E-mutant colorectal cancer.

Binimetinib and encorafenib are investigational medicines and are not currently approved in any country.

Array BioPharma retains exclusive rights to binimetinib and encorafenib in key markets including the U.S., Canada and Israel. Array has granted Ono Pharmaceutical exclusive rights to commercialize both products in Japan and South Korea and Pierre Fabre exclusive rights to commercialize both products in all other countries, including Europe, Asia and Latin America.

Aptose Biosicences and CrystalGenomics Announce Issuance of U.S. Patent for CG’806

On September 12, 2017 Aptose Biosciences Inc. ("Aptose" or the "Company") (NASDAQ:APTO) (TSX:APS), a clinical-stage company developing highly differentiated therapeutics targeting the underlying mechanisms of cancer, reported that the United States Patent and Trademark Office has issued US Patent 9,758,508 entitled "2,3-DIHYDRO-ISOINDOLE-1-ON DERIVATIVE AS BTK KINASE SUPPRESSANT, AND PHARMACEUTICAL COMPOSITION INCLUDING SAME" (Press release, Aptose Biosciences, SEP 12, 2017, View Source [SID1234520478]). The patent claims numerous compounds, including the CG’806 compound, pharmaceutical compositions comprising the CG’806 compound, and methods of treating various diseases. The patent is expected to provide protection until the end of 2033.

"This newly issued patent represents a major step in protecting the unique structural properties and potentially broad applications of CG’806," stated Dr. William G. Rice, Chairman, President and Chief Executive Officer of Aptose. "In addition to being developed as an orally bioavailable first-in-class multi-targeted pan-FLT3/BTK inhibitor, it has been shown to impact other relevant oncogenic targets. We look forward to bolstering the patent portfolio through additional findings and applications."

"Following the execution of the License Agreement, our two organizations have become close allies to ensure the expeditious development of CG’806, and we look forward to continuous progress towards the upcoming IND application," stated Joong Myung Cho, Ph.D., Chairman and Chief Executive Officer of CrystalGenomics.

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 AML tumors in the absence of toxicity in murine xenograft models, and represents a potential best-in-class therapeutic for patients with FLT3-driven AML. Likewise, CG’806 demonstrates potent, non-covalent inhibition of the wild type and Cys481Ser mutant of the BTK enzyme, as well as other oncogenic kinases 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 pre-clinical development in partnership with CrystalGenomics.

About the License Agreement
As previously announced on June 8, 2016, Aptose and CrystalGenomics, Inc. entered into an exclusive global option and license agreement focused on the development of CG026806 (CG’806). Aptose is currently undertaking Investigational New Drug (IND) enabling studies and expects to exercise its option to develop and commercialize CG’806 under the agreement and initiate a phase 1 clinical trial by mid 2018. The potential option exercise would occur prior to submission of an IND application in the U.S and, upon exercise, Aptose would have to pay US $2.0 million in cash or in a combination of cash and common shares. Upon exercise of the option, Aptose would own global rights to develop and commercialize the program outside of Korea and China.

Deciphera Pharmaceuticals Reports Updated Data from Ongoing Phase 1 Clinical Study of DCC-2618 at the European Society of Medical Oncology 2017 Congress

On September 11, 2017 Deciphera Pharmaceuticals, a clinical-stage biopharmaceutical company focused on addressing key mechanisms of tumor drug resistance, reported the presentation of updated data from its ongoing Phase 1 clinical trial of DCC-2618, the Company’s pan-KIT and PDGFRα inhibitor, in patients with gastrointestinal stromal tumors (GIST) (Press release, Deciphera Pharmaceuticals, SEP 11, 2017, View Source [SID1234520498]). The data were presented in an oral presentation at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2017 Congress on September 9, 2017, in Madrid, Spain. This expands upon data from the same trial presented at the ASCO (Free ASCO Whitepaper) meeting in June 2017, providing further validation of the clinical benefit of DCC-2618 with more patients continuing on therapy out to 12 and 24 weeks. The data showed that in heavily pretreated patients with GIST, treatment with DCC-2618 at >100 mg daily resulted in disease control rates of 76% at 12 weeks and 57% at 24 weeks.

"The clinical activity observed to date, which includes durable responses in patients who were resistant to other kinase inhibitors, supports the planned evaluation of DCC-2618 in a placebo-controlled randomized, pivotal Phase 3 trial in patients with GIST who have previously received approved therapies," said Michael D. Taylor, Ph.D., President and Chief Executive Officer of Deciphera Pharmaceuticals. "In addition to this initial Phase 3 trial in fourth-line GIST patients, where there are no approved therapies, we plan to initiate a second pivotal Phase 3 trial in second-line GIST patients comparing DCC-2618 to sunitinib."

"DCC-2618 continues to demonstrate good tolerability and clinical activity in heavily pretreated patients with GIST," said Oliver Rosen, M.D., Chief Medical Officer of Deciphera Pharmaceuticals. "The extensive reductions in KIT mutant allele frequencies observed across the spectrum of exons 9, 11, 13, 14, 17 and 18 mutations supports the pan-KIT activity of DCC-2618 in these patients."

In an oral presentation, titled "Encouraging activity of novel pan-KIT and PDGFRα inhibitor DCC-2618 in patients (pts) with gastrointestinal stromal tumor (GIST)," Filip Janku, M.D., Ph.D., The University of Texas MD Anderson Cancer Center, presented data from 57 heavily pretreated GIST patients. As of July 28, 2017, data showed:

At daily doses of 100 mg or greater, GIST patients with KIT or PDGFRα driven disease on DCC-2618 showed a disease control rate (DCR) of 76% at 12 weeks (n=25) and a DCR of 57% at 24 weeks (n=21). DCR is defined as patients with stable disease, partial response or complete response as assessed by Response Evaluation Criteria in Solid Tumors, or RECIST.
Treatment with DCC-2618 resulted in reductions in cfDNA KIT mutant allele frequencies (MAF) compared to baseline values (n=19), suggesting pan-KIT activity across the spectrum of exons 9, 11, 13, 14, 17 and 18 mutations.
DCC-2618 was generally well-tolerated at all dose levels studied, and a dose of 150 mg once per day was selected for the expansion cohorts and planned Phase 3 pivotal trials.

Details for the presentation are as follows:

Title: Encouraging activity of novel pan-KIT and PDGFRα inhibitor DCC-2618 in patients (pts) with gastrointestinal stromal tumor (GIST).
Author: Filip Janku, M.D., Ph.D., The University of Texas MD Anderson Cancer Center
Session: Sarcoma: Proffered Paper Sarcoma Session
Chair: Sebastian Bauer, M.D., West German Cancer Center, University of Essen
Abstract #: 14730
Date and Time: Saturday, September 9, 2017, 11:00 AM – 12:30 PM (CEST)

About DCC-2618
DCC-2618 is currently in a first-in-human Phase 1 clinical trial. DCC-2618 is a pan-KIT and PDGFRα kinase switch control inhibitor in clinical development for the treatment of KIT and/or PDGFRα-driven cancers, including gastrointestinal stromal tumors, glioblastoma multiforme and systemic mastocytosis.

RX Therapeutics Presents Positive IRX-2 Phase 2a Head and Neck Squamous Cell Carcinoma Clinical Results at the European Society for Medical Oncology Annual Congress 2017

On September 11, 2017 IRX Therapeutics, Inc. (IRX) reported results from a Phase 2a clinical trial of IRX-2, the company’s lead drug candidate, in head and neck squamous cell carcinoma (SCCHN) at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Annual Congress 2017 (Press release, IRX Therapeutics, SEP 11, 2017, View Source [SID1234520497]).

"The results presented today demonstrate that IRX-2, a primary cell-derived biologic, drives intratumoral immune infiltration of T cells, B cells and dendritic cells, promoting their activation. This increase in lymphocyte infiltration was associated with reductions in tumor size and an overall survival rate of 65% at 5 years in patients with head and neck squamous cell carcinoma," said Gregory T. Wolf, M.D., Professor Emeritus, Department of Otolaryngology-Head and Neck Surgery, University of Michigan Comprehensive Cancer Center. "These data demonstrate that IRX-2 modulates the tumor microenvironment in cancer cells and may improve patient outcomes in this difficult-to-treat patient population."

In a subset study of 7 patients, the study also demonstrated that IRX-2 upregulates immune checkpoint markers, including PDL1 and CTLA4 expression, suggesting that the effects of IRX-2 treatment may be enhanced by combination therapy with checkpoint inhibitors. The clinical trial also demonstrated that IRX-2 promotes expression of chemokine pathway genes (CCLs, CCRs, CXCLs and CXCRs), which are chemoattractants whose expression may result in increased lymphocyte infiltration.

"The data presented provides evidence that IRX-2 offers a durable improvement in head and neck cancer patient outcomes and has a unique mechanism of action that suggests restored immune function and activation in the tumor microenvironment," said Mark Leuchtenberger, President and Chief Executive Officer of IRX Therapeutics. "Based on these encouraging results, we are currently conducting a Phase 2b multicenter, randomized trial (INSPIRE) in neoadjuvant SCCHN. We are also collaborating with investigators and companies with checkpoint inhibitors to assess IRX-2 as treatment for breast cancer (NCT02950259) and in multiple other tumor types with and without checkpoint inhibitors. We believe that IRX-2 has the potential to enhance patient outcomes across a variety of cancer indications and may also improve outcomes when used in combination with checkpoint inhibitors."

About IRX Therapeutics and IRX-2

IRX Therapeutics is a clinical-stage company developing novel immunotherapies focused on reducing the immune suppression that is seen in the cancer tumor micro-environment, restoring immune function, and activating a coordinated immune response against the tumor.

The lead candidate, IRX-2 is a proprietary therapeutic containing numerous active cytokine components, which data suggests may restore and activate multiple immune cell types, including T cells, dendritic cells, and natural killer cells, that are known to recognize and attack tumors. IRX-2 is a primary cell-derived biologic of produced by stimulation of human peripheral blood mononuclear cells (PBMCs) obtained from heathy donor whole blood. Data collected to date suggest that IRX-2 reduces the immune suppression that is often seen in the cancer tumor microenvironment. This immunomodulatory activity appears to occur through the restoration of immune function and activation of a coordinated immune response against the tumor.

Currently, IRX-2 is being studied in an ongoing Phase 2b clinical trial in patients with newly diagnosed Stage II, III, and IVA squamous cell carcinoma of the head and neck (SCCHN) (INSPIRE) View Source (clinicaltrials.gov NCT02609386) and in pre-operative early stage breast cancer (ESBC) (clinicaltrials.gov NCT02950259).
For more information about the Company and its clinical programs, please visit www.IRXTherapeutics.com.
Contacts

MacDougall Biomedical Communications
Rob Kloppenburg or Kara Mazey, 781-235-3060
[email protected] or [email protected]
IRX Therapeutics to Present IRX-2 Clinical and Biomarker Updates at Upcoming Medical Conferences

— IRX-2 multiyear event free survival and overall survival Phase 2a clinical trial results to be presented at ESMO (Free ESMO Whitepaper) 2017 —
— INSPIRE Phase 2b head and neck cancer trial in progress to be presented at ICIC 2017 —
NEW YORK – August 2, 2017 – IRX Therapeutics, Inc. (IRX) reported that a poster featuring clinical and biomarker results from a Phase 2a head and neck cancer clinical trial of IRX-2, the company’s lead drug candidate, will be presented on September 10, 2017 at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Annual Congress in Madrid, Spain. In addition, a trial in progress poster of the Phase 2b INSPIRE clinical trial of IRX-2, in head and neck cancer, will be presented at the International Cancer Immunotherapy Conference (CIMT) (Free CIMT Whitepaper) (ICIC) in Mainz, Germany on September 8, 2017.
IRX will present the following poster presentation at ESMO (Free ESMO Whitepaper):
Poster title: Immune profile analysis of head and neck squamous cell carcinoma before and after neoadjuvant treatment with the IRX-2 regimen
Date and Time: Sunday, September 10 from 13:15-14:15 (GMT+2)
Presentation number: 1062P
Full session details and data presentation listings for ESMO (Free ESMO Whitepaper) 2017 Congress can be found at View Source
IRX will present the following poster presentation at ICIC:
Poster title: INSPIRE: A multicenter randomized trial of neoadjuvant and adjuvant therapy with the IRX-2 regimen in patients with newly diagnosed stage II, III, or IVa squamous cell carcinoma of the oral cavity
Date and Time: Friday, September 8 from 18:15-20:15 (UTC+2)
Presentation number: B164
Full session details and data presentation listings for ICIC 2017 Conference can be found at View Source

Initial Clinical Trial Data for Combination of X4P-001-IO and Inlyta® (Axitinib) Demonstrate Encouraging Disease Control Rates and Durable Clinical Responses in Patients with Clear Cell Renal Cell Carcinoma (ccRCC)

On September 11, 2017 X4 Pharmaceuticals, a clinical stage biotechnology company developing a novel CXCR4 inhibitor drug to improve immune cell trafficking to treat cancer and rare diseases, reported Phase 1 results from the company’s ongoing Phase 1/2 study of X4P-001-IO (Press release, X4 Pharmaceuticals, SEP 11, 2017, View Source [SID1234520496]). The data were presented at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) 2017 Congress being held September 8-12 in Madrid, Spain.

Results from the 16 patients with advanced ccRCC enrolled in the dose escalation part of the ongoing Phase 1/2 study as of the data cutoff date were presented at the ESMO (Free ESMO Whitepaper) 2017 Congress on Sunday, September 10. All patients had received at least one prior line of therapy and 69 percent of patients have received at least two prior lines of therapy. Highlights of the poster presentation include:

In the evaluable patient population, the combination of X4P-001-IO and Inlyta produced a disease control rate (DCR) and objective response rate (ORR) of 92 percent (11/12) and 25 percent (3/12), respectively, including 3 partial responses (PRs).
The median duration on treatment was 14.7 weeks and 43 percent of patients had been exposed to study treatment for at least 24 weeks.
X4P-001-IO in combination with Inlyta was generally well tolerated. The most frequent treatment-related adverse events (AEs) in patients receiving X4P-001-IO at 200 mg twice daily, 400 mg once daily, or 600 mg once daily were diarrhea, hypertension, fatigue, nausea, headache, decreased appetite, and vomiting. No grade 4 or 5 AEs occurred.
A dose of 400 mg X4P-001-IO once daily with 5 mg Inlyta twice daily has been selected for the Phase 2 portion of the ongoing Phase 1/2 study.
"The high disease control rate and clinical responses in previously treated patients with late-stage clear cell renal cell carcinoma underscore the rationale for investigating the therapeutic potential of CXCR4 inhibition plus VEGFR inhibition," said Michael Atkins, MD, Deputy Director, Georgetown-Lombardi Comprehensive Cancer Center in Washington, DC and William M. Scholl Professor of, Oncology at Georgetown University School of Medicine. "The preliminary results shown in this clinical study are very encouraging and support continued investigation of this approach."

"By leveraging data from prior clinical studies, we were able to quickly reach the recommended Phase 2 dose of X4P-001-IO, and the combination has demonstrated good tolerability with early signs of clinical activity," said Sudha Parasuraman, MD, Chief Medical Officer of X4. "We look forward to presenting the full results of this study in 2018."

The Phase 2 portion of the study continues to enroll patients to evaluate the clinical efficacy of X4P-001-IO as measured by objective response rate (ORR), duration of response (DOR), and progression free survival (PFS), as well as exploring the correlation of biomarkers with efficacy.

About X4P-001-IO in Cancer

X4P-001-IO is an investigational selective, oral, small molecule inhibitor of CXCR4 (C-X-C receptor type 4) that regulates the tumor microenvironment thereby enhancing endogenous anti-tumor responses. CXCR4 is a chemokine receptor that modulates immune function and angiogenesis through the trafficking of key immune cells such as T- cells, dendritic cells, and myeloid derived suppressor cells. CXCR4 signaling is disrupted in a broad range of cancers, facilitating tumor growth by allowing cancer cells to evade immune detection and creating a pro-tumor microenvironment.

About Renal Cell Carcinoma

Kidney cancer is among the ten most common cancers in both men and women with more than 60,000 new diagnoses each year in the United States.1 Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer, and advanced ccRCC accounts for approximately 20% of the patient population. Therapies for advanced ccRCC include immunotherapies, mammalian target of rapamycin (mTOR) kinase inhibitors, and angiogenesis inhibitors, such as vascular endothelial growth factor (VEGF) inhibitors.2 There continue to be unmet medical needs with advanced ccRCC because durable responses remain a serious clinical challenge for patients with advanced disease.