On January 7, 2020 Leap Therapeutics, Inc. (Nasdaq: LPTX), a biotechnology company focused on developing targeted and immuno-oncology therapeutics, reported the closing of its previously announced equity financing to issue 1,421,801 shares of newly designated Series A mandatorily convertible preferred stock to a lead institutional investor, at a price of $10.54 per share, and an aggregate of 1,137,442 shares of newly designated Series B mandatorily convertible preferred stock to BeiGene and Perceptive Advisors, at a price of $10.55 per share (Press release, Leap Therapeutics, JAN 7, 2020, View Source [SID1234553263]). The preferred stock price reflects a common stock equivalent price of $1.055 per share, the closing price for Leap’s common stock on the Nasdaq Global Market on the day of pricing, January 2, 2020 and, in the case of the Series A mandatorily convertible preferred stock, reflects a per share reduction equal to the exercise price of the pre-funded warrant issued upon conversion of the Series A mandatorily convertible preferred stock. The holder of Series A mandatorily convertible preferred stock also received a share of a newly designated special voting preferred stock that will entitle it to elect one member of Leap’s Board of Directors.

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Upon approval by the stockholders of Leap, the Series A mandatorily convertible preferred stock will automatically convert into pre-funded warrants to purchase 14,218,010 shares of common stock and the Series B mandatorily convertible preferred stock will automatically convert into 11,374,420 shares of common stock, plus that number of additional shares of common stock representing payment of an 8% per annum accruing dividend on each share of preferred stock as of the conversion date. Upon stockholder approval and conversion of the preferred stock, the investors will also receive warrants to purchase up to an equal number of shares of common stock at an exercise price of $2.11 per share. The aggregate gross proceeds to Leap from this offering are approximately $27 million, before deducting placement agent fees and estimated offering expenses payable by Leap, and excluding proceeds from the exercise of any warrants.

Raymond James & Associates, Inc. was the placement agent for the equity financing.

The securities sold in the private placement have not been registered under the Securities Act of 1933, as amended, or state securities laws and may not be offered or sold in the United States absent registration with the Securities and Exchange Commission (SEC) or an applicable exemption from such registration requirements. Leap has agreed to file a registration statement with the SEC covering the resale of the shares of common stock issuable upon conversion of the preferred stock and exercise of the warrants issued in the private placement.

This press release does not constitute an offer to sell or the solicitation of an offer to buy the securities, nor shall there be any sale of the securities in any state in which such offer, solicitation or sale would be unlawful prior to the registration or qualification under the securities laws of such state.

On January 7, 2020 ECOG-ACRIN reported that the antibody-drug conjugate ado-trastuzumab emtansine (T-DM1) has promising activity in HER2 amplified salivary gland tumors, according to data published in the Annals of Oncology (Press release, ECOG-ACRIN, JAN 7, 2020, View Source [SID1234553261]). The publication is for ‘Arm Q,’ which is one of nearly 40 single-arm phase two treatments in the NCI-Molecular Analysis for Therapy Choice (NCI-MATCH or EAY131) trial. NCI-MATCH is being co-led by the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) and the National Cancer Institute (NCI), part of the National Institutes of Health.

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"We saw that two of the three NCI-MATCH patients with salivary gland tumors had significant tumor shrinkage by at least 30% with T-DM1 treatment, and this benefit lasted," said lead researcher Komal Jhaveri, MD, FACP, a medical oncologist and early-phase clinical trials specialist at Memorial Sloan Kettering Cancer Center in New York. "The benefit lasted two years in the patient with squamous cell cancer of the parotid gland, and nine months in the case of mucoepidermoid carcinoma of the parotid gland."

"This is a hint of activity that needs to become the focus of a larger trial," said Dr. Jhaveri.

Another recent T-DM1 trial (not part of the NCI-MATCH trial) reported interim results at the 2019 annual meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper). In that trial (NCT02675829), nine of the 10 patients with salivary gland cancers treated with T-DM1 responded either with tumor shrinkage by computed tomography (CT) scan or as assessed by positron emission tomography (PET). As a result, that trial has since been expanded to enroll additional patients.

T-DM1 is a targeted therapy that contains the monoclonal antibody trastuzumab, which binds to the HER2 protein found on some cancer cells. It also contains the cytotoxic drug DM1, which inhibits tumor cell division. Unlike chemotherapy, antibody-drug conjugates like T-DM1 are intended to target and kill tumor cells while sparing healthy cells. T-DM1 has improved overall survival and led to a new standard of care in HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane.

The primary objective of each arm in NCI-MATCH is to estimate the proportion of patients who had an objective response (OR). Under predefined criteria, an OR rate greater than 16% in a given NCI-MATCH arm would warrant further study of the agent(s).

Although the results from Arm Q did not meet these criteria, the signal in salivary gland tumors is important.

"We are excited about the prospect of this and other upcoming MATCH arms to shed new light on responsive tumor types, as there is far less data available in rare and uncommon disease types from previously conducted trials," said Keith T. Flaherty, MD, a medical oncologist at Massachusetts General Hospital Cancer Center in Boston and ECOG-ACRIN study chair for the overall NCI-MATCH trial. "Salivary cancer is a particularly understudied area and seeing evidence of benefit for a molecularly targeted approach strongly supports further focus on this cancer type."

Patients received T-DM1 at 3.6 mg/kg intravenously every three weeks until toxicity or disease progression.

Of the 38 patients enrolled in Arm Q, 36 were included in the efficacy analysis. Overall, this was a heavily pretreated group of patients with multiple unique histologies (excluding breast and gastric). Seventeen patients (47%) had stable disease with median duration of 4.6 months, including eight of 10 patients with ovarian and uterine carcinomas. The six-month progression-free survival rate was 23.6%. Common toxicities were fatigue, anemia, fever and thrombocytopenia. However, this arm did not find any new toxicities for T-DM1.

There was a trend for tumor shrinkage with higher levels of gene copy number as determined by the tumor sequencing assay. The median HER2 copy number was 17 (range: seven-139). Notably, the patient with squamous cell cancer of the parotid gland had a HER2 gene copy number of 129 and the patient with mucoepidermoid carcinoma of the parotid gland had a copy number of 21.

"NCI-MATCH seeks to determine whether matching certain drugs or drug combinations in adults whose tumors have specific gene abnormalities will effectively treat their cancer, regardless of their cancer type," said Lyndsay Harris, MD, Associate Director, Cancer Diagnosis Program, NCI, and co-PI of the NCI-MATCH trial. "In certain studies, such as this, we also saw benefit in rare tumor types. Such discoveries could be eligible to move on to larger, more definitive trials."

The publication (Annals of Oncology, Volume 30, Issue 11, November 2019) marks a milestone for the NCI-MATCH trial, being the first results manuscript to appear in print. The manuscript was previously published online ahead of print (View Source).

Genentech Inc. provided ado-trastuzumab emtansine for Arm Q under a Clinical Trial Participation Agreement between NCI and Genentech.

NCI-MATCH treatment arms are posted at View Source

On January 7, 2020 Genomic Testing Cooperative, LCA announced that the Medicare Administrative Contractor Palmetto GBA (MolDx) has established coverage for its solid tumor molecular profile. The GTC-Solid Tumor Profile provides a comprehensive evaluation of the abnormalities in the entire coding sequence of 434 genes in various types of solid tumors (Press release, Genomic Testing Cooperative, JAN 7, 2020, View Source [SID1234553222]). This decision of covering solid tumors along with the previous coverage decision of two GTC hematology profiles allows GTC to offer comprehensive genomic profiling with next-generation sequencing (NGS) for patients with all types of cancer including a liquid biopsy for hematologic neoplasms.
Laboratories and hospitals that are members of the cooperative group as well as non-member medical professionals will have immediate access to these Medicare-covered tumor profiling tests.

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Dr. Maher Albitar, GTC Chief Executive Officer and Chief Medical Officer, stated "We are delighted that Palmetto GBA now covers our hematology and solid tumor profiles. This full coverage along with our unique business model as a cooperative company will allow us to fulfill our mission in democratizing comprehensive molecular profiling of cancer and making it available and affordable for every patient with cancer." Dr Albitar added "We believe that this coverage by Medicare will help other Co-op member laboratories and large oncology practice groups obtain coverage when they adapt and or internalize our highly validated comprehensive molecular profiling tests. This will not only improve patient care, but also reduce costs and deliver better standardized Precision Medicine."
It is estimated that approximately 1.74 million Americans will be diagnosed with cancer every year and more than 14 million people are living with a diagnosis of cancer in the US. Cancer is currently the second leading cause of death in the US.

On January 7, 2020 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) reported how resistance to a promising targeted drug develops in patients with a rare, lethal cancer of the bile ducts called cholangiocarcinoma (Press release, The Ohio State University Comprehensive Cancer Center, JAN 7, 2020, View Source [SID1234553217]).

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The study, reported in the journal Molecular Cancer Therapeutics, also suggests that adding another drug at the time of progression might re-sensitize tumor cells to the initial drug, called an FGFR inhibitor.

"While the majority of patients with FGFR-positive cholangiocarcinoma benefit from new FGFR inhibitors in clinical trials, most patients unfortunately develop cancers resistant to the drugs," says study leader Sameek Roychowdhury, MD, PhD, a medical oncologist and researcher at the OSUCCC – James. "We believe that this study is an important step in understanding drug resistance and improving the treatment of this and other cancers caused by abnormal FGFR gene mutations."

Findings also suggest that monitoring fragments of circulating tumor DNA for acquired mutations that cause resistance to FGFR inhibitors may reveal the presence of resistance mutations and mark the time a patient should begin taking the additional drug, an mTOR inhibitor.

The successful treatment of cholangiocarcinoma is challenging because the disease is usually diagnosed at an advanced stage that has a five-year survival rate of 2%. Patients diagnosed earlier also have low, five-year survival due to high rates of disease recurrence. Abnormal activation of the FGFR gene happens in 15 to 20% of people with cholangiocarcinoma, and FGFR inhibitors show effectiveness in 70 to 80% of those patients until resistance develops. There are six studies of FGFR inhibitors in clinical trials at the OSUCCC – James.

"A better understanding of how treatment resistance develops and how to prevent it is critical for improving the treatment of cholangiocarcinoma and other cancers caused by FGFR mutations," says first author Melanie Krook, PhD, a postdoctoral fellow in Roychowdhury’s lab.

"Our findings suggest that cholangiocarcinoma patients treated with an FGFR targeted therapy could potentially benefit from combination therapies with other drugs such as mTOR inhibitors. Additional laboratory studies are needed to identify the optimal lead strategies for this combination," she adds.

For this study, Roychowdhury, Krook and colleagues examined the FGFR (fibroblast growth factor receptor) gene in the cancer cells of a cholangiocarcinoma patient who died after experiencing disease progression and developing resistance to the FGFR inhibitor infigratinib.

The researchers identified two acquired FGFR mutations in the patient’s tumor cells that conferred resistance to FGFR inhibitors. They then used cancer cell lines to learn that the mutations led to activation of the mTOR biochemical pathway. This enabled the cancer cells to grow even in the presence of FGFR inhibitors. Adding an mTOR inhibitor to the cells restored their sensitivity to FGFR inhibitors.

Key findings:

Two acquired FGFR2 mutations, p.E565A and p.L617M, were shown to drive resistance to the FGFR inhibitor infigratinib.

The p.E565A mutation upregulates the mTOR signaling pathway, which desensitizes cholangiocarcinoma cell lines to infigratinib and other FGFR inhibitors.

A drug that inhibited the mTOR pathway restored the sensitivity of the cells to infigratinib and other FGFR inhibitors.

"Overall, our findings suggest that an mTOR inhibitor administered at the time of progression may re-sensitize tumor cells to an FGFR inhibitor in patients who develop resistance to these agents," Roychowdhury says.

This study was supported by grants from the American Cancer Society (MRSG-12-194-01-TBG), the Prostate Cancer Foundation, the National Institutes of Health (HG006508, CA202971, CA216432), the American Lung Association and Pelotonia.

Other researchers involved in this study were Alexandria Lenyo, Max Wilberding, Hannah Barker, Mikayla Dantuono, Hui-Zi Chen, Julie W. Reeser, Michele R. Wing, Jharna Miya, Eric Samorodnitsky, Amy M. Smith, Thuy Dao, Dorrelyn M. Martin, John L. Hays and Aharon G. Freud, The Ohio State University; Kelly M. Bailey, University of Pittsburgh; and Kristen K. Ciombor, Vanderbilt University.

On January 7, 2020 Verastem presented the corporate presentation (Presentation, Verastem, JAN 7, 2020, View Source [SID1234553058]).

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