On November 10, 2015 The U.S. Food and Drug Administration reported that it approved Cotellic (cobimetinib) to be used in combination with vemurafenib to treat advanced melanoma that has spread to other parts of the body or can’t be removed by surgery, and that has a certain type of abnormal gene (BRAF V600E or V600K mutation) (Press release, , NOV 10, 2015, View Source [SID:1234508187]).
Melanoma is the most aggressive and dangerous form of skin cancer in the United States. It forms in the skin cells that develop the skin’s pigment and if not diagnosed early, the cancer is likely to spread to other parts of the body. The National Cancer Institute estimates that 73,870 Americans will be diagnosed with melanoma and 9,940 will die from the disease this year.

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"As we continue to advance our knowledge of tumor biology, we have learned that cancer cells have a remarkable ability to adapt and become resistant to targeted therapies. Combining two or more treatments addressing different cancer-causing targets may help to address this challenge," said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. "Today’s approval provides a new targeted treatment that, when added to vemurafenib, demonstrates greater benefit than vemurafenib alone in patients with BRAF mutation-positive melanoma."

Cotellic works by blocking the activity of an enzyme known as MEK, which is part of a larger signaling pathway. Abnormal activity of signaling pathways can lead to cancer. Cotellic prevents or slows cancer cell growth. Vemurafenib, marketed in the U.S. as Zelboraf, is a BRAF inhibitor that affects a different part of the same pathway and was approved in 2011 to treat patients with melanoma that has spread to other parts of the body or cannot be removed by surgery, whose tumors express a gene mutation called BRAF V600E, as detected by an FDA approved test. Health care providers should confirm the presence of BRAF V600 E or V600K mutation in their patients’ tumor specimens using one of the available FDA approved tests prior to starting treatment with Cotellic in combination with vemurafenib.

The safety and efficacy of Cotellic taken in combination with vemurafenib were demonstrated in a randomized clinical study of 495 patients with previously untreated, BRAF V600 mutation-positive melanoma that is advanced or cannot be removed by surgery. All study participants received vemurafenib and were then randomly selected to also take either Cotellic or a placebo. On average, patients taking Cotellic plus vemurafenib experienced a delay in the amount of time it took for their disease to worsen (approximately 12.3 months after starting treatment) compared to approximately 7.2 months after starting treatment for those taking vemurafenib only. In addition, patients taking Cotellic plus vemurafenib lived longer, with approximately 65 percent of patients alive 17 months after starting treatment as compared to half of those taking vemurafenib only. Additionally, 70 percent of those taking Cotellic plus vemurafenib experienced complete or partial shrinkage of their tumors, compared to 50 percent among those taking vemurafenib plus placebo.

The most common side effects of treatment with Cotellic in combination with vemurafenib are diarrhea, sensitivity to ultraviolet (UV) light (photosensitivity reaction), nausea, fever (pyrexia) and vomiting.

Cotellic may cause severe side effects including damage to the heart muscle (cardiomyopathy) or to other muscles (rhabdomyolysis), new skin tumors (primary cutaneous malignancies), eye disease (retinal detachment), severe skin rash, liver damage (hepatotoxicity), hemorrhage and severe skin rash due to increased sensitivity to sunlight (photosensitivity). People taking Cotellic should avoid sun exposure, wear protective clothing, and a broad spectrum ultraviolet A/ultraviolet B sunscreen to protect against sunburn. Women taking Cotellic should use effective contraception, as the medication can cause harm to a developing fetus.

Cotellic was reviewed under the FDA’s priority review program that provides for an expedited six-month review of drugs that, at the time the application was submitted, have the potential to be a significant improvement in safety or effectiveness in the treatment of a serious condition. Cotellic also received orphan drug designation, which provides incentives such as tax credits, user fee waivers and eligibility for orphan drug exclusivity to assist and encourage the development of drugs for rare diseases.

Cotellic and Zelboraf are both marketed by Genentech of San Francisco, California.

On November 10, 2015 Delcath Systems, Inc. (NASDAQ: DCTH), a specialty pharmaceutical and medical device company focused on oncology with an emphasis on the treatment of primary and metastatic liver cancers, reported financial results for the three and nine months ended September 30, 2015 (Press release, Delcath Systems, NOV 10, 2015, View Source;p=RssLanding&cat=news&id=2110968 [SID:1234508184]).

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Financial and other highlights for the third quarter of 2015 and recent weeks included:

84% increase in total revenue compared with the third quarter of 2014
23% decrease in total operating expenses compared with the third quarter of 2014
Establishment of national reimbursement coverage for CHEMOSAT procedures in Germany
Treatment of first patient in the intrahepatic cholangiocarcinoma (ICC) cohort of the Global Phase 2 HCC/ICC trial program
Acceptance for publication of prior Melanoma Phase 3 trial results in the Annals of Surgical Oncology
Presentation of data supporting Delcath’s Hepatic CHEMOSAT Delivery System at the CIRSE, ECCO and EADO annual meetings
Appointment of Jennifer Simpson, Ph.D., MSN, CRNP, President and CEO of Delcath to the Company’s Board of Directors
"Our performance in the third quarter and recent weeks was strong, with significant achievements in all of our commercial and clinical priorities," said Dr. Simpson. "Highlighting the period was the establishment of ZE reimbursement for CHEMOSAT procedures in Germany beginning in 2016, which represents our first national reimbursement mechanism and an important step towards increasing commercialization of CHEMOSAT in Europe. We also continued to drive commercial adoption of CHEMOSAT in other European markets, as evidenced by a nearly 84% increase in third quarter revenue compared with last year. In fact, our year-to-date revenue has already exceeded full-year 2014 revenue. This performance was achieved while maintaining disciplined expense management, which allowed us to beat our operating expense guidance of $4-5 million per quarter."

"During the period we also continued to advance our clinical development program, with the first treatment performed in the ICC cohort of our Global Phase 2 HCC/ICC trial program in October and data supporting CHEMOSAT presented at three major medical conferences. Adding to this growing body of evidence will be data from our prior U.S. Phase 3 clinical trial, which will published in the Annals of Surgical Oncology in the coming weeks. Publication of these results will be an important tool that will enhance our efforts to expand reimbursement in certain European countries, and will also help increase awareness of the value of this therapy in Europe."

"We held a productive meeting with the U.S. Food and Drug Administration regarding our plans for a global pivotal Phase 3 clinical trial in patients with ocular melanoma (OM) that has metastasized to the liver, with overall survival as the primary endpoint. The dialogue was constructive and the FDA is working with Delcath to advance the initiation of this important trial."

"Our team is executing our plan and entirely focused on delivering value for shareholders. We look forward to continuing this momentum through to the end of 2015 and beyond," concluded Dr. Simpson.

Third Quarter Financial Results

Total revenue for the third quarter of 2015 of $0.4 million increased 83.9% from $0.2 million for the third quarter of 2014. Selling, general and administrative expenses during the third quarter were $2.3 million, a decrease of $2.2 million or 48.9% from $4.5 million for the same period in 2014.

Total operating expenses for the third quarter of 2015 decreased by 23.1% to $4.0 million from $5.2 million for the same period in 2014. This decrease reflects a reduction in severance and compensation-related expenses following significant workforce restructurings throughout 2014 and into 2015, as well as a reduction in facility expenses.

The Company recorded a net loss for the third quarter of 2015 of $2.4 million, or $0.12 per share, a decrease of $2.2 million or 47.8%, compared with a net loss of $4.6 million, or $0.48 per share, for the same period in 2014. This decrease is primarily due to a $1.2 million reduction in operating expenses, a $0.1 million improvement in gross profit and a $0.8 million change in the fair value of the warrant liability, a non-cash item.

Nine Month Financial Results

Total revenue for the first nine months of 2015 of $1.3 million increased 62.5% from $0.8 million for the first nine months of 2014. Selling, general and administrative expenses during the first nine months of 2015 were $7.8 million, a decrease of $5.2 million or 40.0% from $13.0 million for the same period in 2014.

Total operating expenses for the first nine months of 2015 decreased by 27.7% to $12.0 million from $16.6 million for the same period in 2014. This decrease reflects a reduction in severance and compensation-related expenses following significant workforce restructurings throughout 2014 and into 2015, as well as a reduction in facility expenses.

The Company recorded a net loss for the first nine months of 2015 of $9.6 million, or $0.67 per share, a decrease of $4.8 million or 33.3% compared with a net loss of $14.4 million, or $1.54 per share, for the same period in 2014. This decrease is primarily due to a $4.7 million reduction in operating expenses, a $0.4 million improvement in gross profit and a $0.2 million change in the fair value of the warrant liability, a non-cash item.

Balance Sheet Highlights

Cash and cash equivalents as of September 30, 2015 were $16.7 million, compared with $20.5 million as of December 31, 2014. During the first nine months of 2015, net cash used in operating activities was $12.2 million.

On November 10, 2015 Tokai Pharmaceuticals Inc. (NASDAQ: TKAI), a biopharmaceutical company focused on developing and commercializing innovative therapies for prostate cancer and other hormonally driven diseases, reported results for the quarter ended September 30, 2015 (Press release, Tokai Pharmaceuticals, NOV 10, 2015, View Source;p=RssLanding&cat=news&id=2110919 [SID:1234508183]).

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"This was an important quarter of progress for Tokai," said Jodie Morrison, President and Chief Executive Officer of Tokai. "Active screening of patients in our ARMOR3-SV pivotal trial is underway, and we expect to report top-line results by the end of 2016. In parallel, under the experienced leadership of Lisa Taylor, we are making substantial progress in shaping our go-to-market strategy and engaging with clinical leaders throughout the world who recognize the significant need for new treatment options for patients who are unresponsive to existing therapies."

Recent highlights include:

Pivotal ARMOR3-SV Trial Underway: During the quarter, Tokai began screening patients for participation in ARMOR3-SV, the company’s pivotal Phase 3 clinical trial of galeterone, the first Androgen Receptor Degrader in clinical testing. ARMOR3-SV, the first pivotal trial in prostate cancer employing a precision medicine approach for patient selection, is evaluating whether administration of galeterone results in a statistically significant increase in radiographic progression-free survival as compared to Xtandi (enzalutamide) in 148 treatment-naïve metastatic castration-resistant prostate cancer (mCRPC) patients whose prostate tumor cells express the androgen receptor splice variant-7 (AR-V7). AR-V7 is a truncated form of the androgen receptor that has been associated with non-response to commonly used oral therapies for mCRPC. The design of ARMOR3-SV is aligned with feedback obtained from the U.S. Food and Drug Administration (FDA) and the European Medicines Agency, and top-line data for the trial are expected by the end of 2016.

Expanded the Executive Team’s Commercial Expertise: Tokai continued to prepare its growing commercial organization for the anticipated launch of galeterone. Lisa Taylor joined the company during the quarter as Senior Vice President, Commercial Development, a newly created role. Ms. Taylor brings over two decades of experience in biopharmaceutical marketing, and was a member of the launch team for Xtandi (enzalutamide) at Medivation Inc.

Financial Results:

Cash and investments at September 30, 2015 were $73.1 million, compared to $105.3 million at December 31, 2014. Tokai believes that its existing cash and investments will be sufficient to enable the company to conduct ARMOR3-SV, fund the development of a companion diagnostic test for use with galeterone, conduct other clinical trials and nonclinical studies necessary to support the submission of an initial NDA to the FDA for galeterone, as well as to continue funding its operating expenses and capital expenditure requirements into the first half of 2017.

Research and development expense was $8.5 million and $24.9 million for the three and nine months ended September 30, 2015, respectively, as compared to $2.8 million and $10.8 million for the corresponding periods in 2014. The increases in research and development expense in both periods were primarily attributable to start-up costs for the ARMOR3-SV clinical trial and the development of the AR-V7 clinical trial assay, and costs associated with other clinical trial and manufacturing activities to support the submission of a new drug application for galeterone.

General and administrative expense was $3.4 million and $9.3 million for the three and nine months ended September 30, 2015, respectively, as compared to $3.6 million and $6.4 million for the corresponding periods in 2014. The increase in general and administrative expense for the nine month period primarily relates to increased headcount in general and administrative functions, increased legal and patent expenses and costs associated with operating as a public company since September 2014.
Net loss was $11.9 million and $34.1 million for the three- and nine-month periods ended September 30, 2015, respectively, as compared to $6.4 million and $17.1 million for the corresponding periods in 2014.

On November 10, 2015 DelMar Pharmaceuticals, Inc. (OTCQX: DMPI) ("DelMar" and the "Company"), a biopharmaceutical company focused on the development and commercialization of new cancer therapies, reported the presentation by its collaborators from the University of British Columbia (UBC) and Vancouver Prostate Centre (VPC) of additional data on the unique molecular signaling events responsible for VAL-083 (dianhydrogalactitol) activity against cancer (Press release, DelMar Pharmaceuticals, NOV 10, 2015, View Source [SID:1234508180]).

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"We continue to demonstrate the therapeutic potential of VAL-083 both as a single-agent and in combination with other treatments," stated Jeffrey Bacha, DelMar’s president and CEO. "We have previously shown that VAL-083’s anti-tumor activity is unaffected by the expression of MGMT, a DNA repair enzyme that is implicated in chemotherapy resistance. To further understand the unique anti-cancer mechanism of VAL-083, we collaborated with researchers from UBC and VPC to study VAL-083’s anti-cancer activity on a molecular level."

These new data were presented on November 9th by UBC and VPC researchers in a poster entitled, "Exploring the Molecular Mechanisms of Dianhydrogalactitol (VAL-083) in Cancer Treatment," at the 2015 Canadian Cancer Research Conference of the Canadian Cancer Research Alliance (CCRA).

"The study results show a pattern of durability in the DNA lesions caused by VAL-083 which indicate its unique mechanism and potential superiority versus other chemotherapeutic agents. This suggests that VAL-083 is effective at modifying tumor cells and may halt tumor progression by inhibiting natural cellular repair processes," added Mr. Bacha.

"VAL-083’s broad anti-cancer activity was established in prior clinical trials sponsored by the U.S. National Cancer Institutes (NCI). Employing modern biological tools to differentiate the mechanisms involved in VAL-083’s anti-cancer activity from other chemotherapies provides a basis for future combination treatments as well as guidance for our drug development efforts to concentrate on tumor-types representing significant unmet medical needs," Mr. Bacha stated.

VAL-083 is a bi-functional alkylating agent causing N7-guanine methylation and interstrand DNA crosslinks and is approved in China as a chemotherapeutic drug for the treatment of chronic myelogenous leukemia and lung cancer. Preclinical studies and clinical trial data suggest that VAL-083 may be active against a range of tumor types via a novel mechanism of action that could provide improved treatment options for patients.

The goal of this study was to further understand the detailed molecular mechanisms mediating VAL-083 sensitivity or resistance in cancer by investigating the signaling events responsible for VAL-083 activity against cancer. The study confirmed a four-fold hypotheses:

VAL-083 induces DNA double-strand breaks (DSBs).

VAL-083 cytotoxicity is due to cell cycle arrest and apoptosis resulting from DNA cross-linking lesions accumulating in S- and G2-phases of the cell cycle.
The antineoplastic effect of VAL-083 is dependent on cancer cells’ ability to repair the VAL-083-induced DNA damage.
Alterations in DNA damage repair signaling pathway lead to VAL-083 sensitivity or resistance in tumor cells.
Results indicate that treatment of cancer cells by VAL-083 induces phosphorylation of H2AX, a hallmark of double-strand DNA breaks. H2AX is a histone involved in the CHK2 checkpoint activation pathway, a key component of the body’s immune response to DNA damage resulting in down-stream signaling ultimately resulting in apoptosis.

"We will continue to explore the signaling pathways involved in VAL-083 for the treatment of cancer," added Mr. Bacha. "The further elucidation of these molecular mechanisms will help to focus our drug development efforts on patients with cancer who would most benefit from VAL-083 treatment. This ‘personalized-medicine’ approach leverages significant historical clinical data from prior NCI-sponsored studies; which, when juxtaposed against new understanding of VAL-083’s biological mechanism, provides an opportunity to accelerate the development of VAL-083 as a new therapy for cancer patients with limited treatment options."

The research presented at the 2015 Cancer Research Conference was funded in part by financial contributions from Canada’s National Research Council’s Industrial Research Assistance Program (NRC-IRAP) and Mitacs, a Canadian Network of Centres of Excellence, dedicated to supporting scientific and industrial research.

The poster on the molecular mechanisms of VAL-083 may be found on DelMar’s website under View Source

About VAL-083

VAL-083 is a "first-in-class," small-molecule chemotherapeutic. In more than 40 Phase I and II clinical studies sponsored by the U.S. National Cancer Institute, VAL-083 demonstrated clinical activity against a range of cancers including lung, brain, cervical, ovarian tumors and leukemia both as a single-agent and in combination with other treatments. VAL-083 is approved in China for the treatment of chronic myelogenous leukemia (CML) and lung cancer, and has received orphan drug designation in Europe and the U.S. for the treatment of malignant gliomas.

DelMar has demonstrated that VAL-083’s anti-tumor activity is unaffected by the expression of MGMT, a DNA repair enzyme that is implicated in chemotherapy resistance and poor outcomes in GBM patients following standard front-line treatment with Temodar (temozolomide).

DelMar recently announced the completion of enrollment in a Phase II clinical trial of VAL-083 in refractory GBM. Patients have been enrolled at five clinical centers in the United States: Mayo Clinic (Rochester, MN); UCSF (San Francisco, CA) and three centers associated with the Sarah Cannon Cancer Research Institute (Nashville, TN, Sarasota, FL and Denver, CO).

In the Phase I dose-escalation portion of the study, VAL-083 was well tolerated at doses up to 40mg/m2 using a regimen of daily x 3 every 21 days. Adverse events were typically mild to moderate; no treatment-related serious adverse events reported at doses up to 40 mg/m2. Dose limiting toxicity (DLT) defined by thrombocytopenia (low platelet counts) was observed in two of six (33%) of patients at 50 mg/m2. Generally, DLT-related symptoms resolved rapidly and spontaneously without concomitant treatment, although one patient who presented with hemorrhoids received a platelet transfusion as a precautionary measure.

Sub-group analysis of data from the Phase I dose-escalation portion of the study suggested a dose-dependent and clinically meaningful survival benefit following treatment with VAL-083 in GBM patients whose tumors had progressed following standard treatment with temozolomide, radiotherapy, bevacizumab and a range of salvage therapies.

Patients in a low dose (≤5mg/m2) sub-group had a median survival of approximately five (5) months versus median survival of approximately nine (9) months for patients in the therapeutic dose (30mg/m2 & 40mg/m2) sub-group following initiation of VAL-083 treatment. DelMar reported increased survival at 6, 9 and 12 months following initiation of treatment with VAL-083 in the therapeutic dose sub-group compared to the low dose sub-group.

On November 10, 2015 Celator Pharmaceuticals, Inc. (Nasdaq: CPXX) reported the presentation of positive results from its CombiPlex technology platform applied to drug combinations incorporating molecularly targeted agents (MTAs) 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) (Press release, Celator Pharmaceuticals, NOV 10, 2015, View Source [SID:1234508179]).

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CombiPlex is Celator’s proprietary technology that uses nano-scale drug carriers to ensure the optimal ratio of anticancer drugs are simultaneously delivered and selectively exposed to tumor cells for prolonged periods of time while reducing drug exposure and toxicity to normal tissues. The technology addresses difficulties often experienced with conventional MTA combination regimens, where significant toxicities and/or incomplete target inhibition can lead to sub-optimal patient outcomes.

Pre-clinical data presented at the conference demonstrated the broad applicability of Celator’s hydrophobic prodrug nanoparticle (HPN) delivery technology to MTAs from diverse classes, including inhibitors of MEK, Akt, HSP90, B-Raf and FGFR. In all cases, Celator’s proprietary HPN delivery eliminated the early drug distribution phase observed for conventional formulations of these agents, which historically has been associated with significant exposure and toxicity to normal tissues. In fact, HPN co-formulated combinations of docetaxel plus the HSP90 inhibitor AUY922, and the MEK:Akt inhibitor combination of selumetinib plus ipatasertib, could be administered at much higher drug exposure with maintained improvements in safety while also resulting in increased efficacy.

The largest improvements were observed in tumor models known to be more resistant to conventional dosing forms of the two combinations. Optimal efficacy was achieved at drug ratios of 1:2 and 2:1, respectively. In the case of docetaxel:AUY922, the conventional formulation provided negligible tumor growth delay at the maximum tolerated dose (MTD) in the OVCAR-8 human ovarian xenograft model with tumors reaching 1 gram in size in approximately 25 days. In contrast, dosing with Celator’s proprietary HPN formulation at MTD, tumors grew to only half that size after 50 days demonstrating potent tumor growth inhibition.

"As an oncologist who has personally experienced the challenges with combining conventional formulations of molecularly targeted agents in a clinical setting, I am very encouraged by the results Celator has generated using its CombiPlex technology," said Dr. Tony Tolcher, director of clinical research at South Texas Accelerated Research Therapeutics. "This approach could provide an important breakthrough in our ability to optimize the therapeutic index and patient outcomes for many molecularly targeted agent combinations."

Once HPN formulation conditions were optimized for these initial combinations, the approach was readily extended to the B-Raf inhibitor GDC0879 and the FGFR inhibitor LY2874455 and both were successfully co-formulated with the MEK inhibitor selumetinib resulting in coordinated drug exposure in the plasma. In addition, the drug components could be "mixed and matched," and this versatility was then taken one step further by generating a 3-drug combination, co-formulating selumetinib, AUY922 and docetaxel into a single HPN that exhibited a plasma half-life in the range of 10 hours in mice with no early distribution phase.

"The CombiPlex technology platform continues to deliver on its promise to optimize the efficacy of a wide range of anticancer drug combinations," said Dr. Lawrence Mayer, president and chief scientific officer at Celator. "The successful application of this technology to molecularly targeted agents across a wide range of drug classes makes a compelling data package that we believe will be instrumental in attracting R&D collaborations with pharmaceutical companies."