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Chi-Med Presents Phase I/II Clinical Data for Selective VEGFR Inhibitor Fruquintinib at the 2017 Gastrointestinal Cancers Symposium

On January 16, 2017 Hutchison China MediTech Limited ("Chi-Med") (AIM/Nasdaq: HCM) reported that data from the ongoing Phase I/II clinical trial of fruquintinib in combination with paclitaxel (Taxol) in second-line patients with advanced gastric cancer will be presented at the 2017 Gastrointestinal Cancers Symposium sponsored by the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) ("ASCO-GI"), being held in San Francisco, California from January 19 to 21, 2017 (Press release, Hutchison China MediTech, JAN 16, 2017, http://www.chi-med.com/chi-med-presents-phase-iii-clinical-data-for-selective-vegfr-inhibitor-fruquintinib-at-the-2017-gastrointestinal-cancers-symposium/ [SID1234517411]). Fruquintinib is a highly selective and potent oral inhibitor of vascular endothelial growth factor receptors ("VEGFR").

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Chi-Med completed a Phase Ib dose finding study of fruquintinib in combination with paclitaxel, which established a combination regimen that was well tolerated, and continued to enroll patients in this trial to expand the data-set. Additional details about this study may be found at clinicaltrials.gov, using identifier NCT02415023.

The most recent results of the study will be presented in detail as follows:

Presentation Title:

A Phase I/II trial of Fruquintinib in Combination with Paclitaxel for Second-line Treatment in Patients with Advanced Gastric Cancer

Authors:
Ruihua Xu, Dongsheng Zhang, Lin Shen, Jin Li, Jing Huang, Yang Zhang, Jifang Gong, Weijian Guo, Songhua Fan, Ke Li, Ye Hua and Weiguo Su

Abstract No:

128

Session:

Poster Session A: Cancers of the Esophagus and Stomach

Date & Time: Thursday, January 19, 2017, 12:30 PM-6:30 PM (PST)
Once presented, the presentation will be available at www.chi-med.com/news. Further information about ASCO (Free ASCO Whitepaper)-GI is available at gicasym.org.

ABSTRACT
A Phase I/II Trial of Fruquintinib in Combination with Paclitaxel for Second-line Treatment in Patients with Advanced Gastric Cancer

Ruihua Xu, Dongsheng Zhang, Lin Shen, Jin Li, Jing Huang, Yang Zhang, Jifang Gong, Weijian Guo, Songhua Fan, Ke Li, Ye Hua and Weiguo Su

Background

Advanced gastric cancer is a major public health problem, particularly in Asian countries. The treatment options are limited in patients who failed standard first-line chemotherapy. This Phase I/II study is aimed to evaluate the tolerability, pharmacokinetics ("PK") and preliminary efficacy of fruquintinib, a selective oral VEGFR inhibitor, combined with paclitaxel as second-line therapy in Chinese patients with advanced gastric cancer.

Patients and methods

This open arm Phase I/II trial (NCT02415023) consisted of dose finding and dose expansion stages. In the dose finding stage, three dose levels of fruquintinib (2, 3, 4mg once daily; three-weeks-on and one-week-off) were evaluated in combination with standard 80mg/m2 paclitaxel (once weekly on day 1, 8 and 15) in a 28-day cycle until the maximum tolerated dose ("MTD") or recommended phase II dose ("RP2D") was reached. Additional patients were enrolled at dose expansion phase with fruquintinib RP2D regimen to assess further the efficacy, safety and PK profile.

Results

As of September 10, 2016, a total of 32 patients were enrolled and dosed with fruquintinib in combination with weekly paclitaxel. The RP2D of fruquintinib was determined to be 4 mg daily.

Two patients at 4 mg experienced dose-limiting toxicity, both with febrile neutropenia. Grade 3 or 4 treatment emergent adverse events ("TEAE") were neutropenia (40.6%), leukopenia (28.1%), decreased hemoglobin (6.25%), hand-foot skin reaction (6.25%), neurophlegmon (6.25%), and hypertension (6.25%), with higher frequencies in the 4mg cohort as compared with lower doses.

At steady state, fruquintinib drug exposure, i.e. the area under the curve (AUCss), increased dose-proportionally and was within the same range as given as a single agent. Paclitaxel exposure at fruquintinib RP2D (4mg) however, increased by approximately 30% as compared to that of single agent.

28 of 32 patients were evaluable for tumor response, and of these, 10 patients achieved confirmed partial response (objective response rate, ("ORR") = 35.7%), 9 patients experienced stable disease for at least 8 weeks (disease control rate, ("DCR") = 67.9%). At fruquintinib RP2D, ≥16w progression free survival ("PFS") = 50% and ≥7m overall survival ("OS") = 50%.

Conclusion

Combination therapy of fruquintinib and paclitaxel appeared to be generally well-tolerated with promising tumor response in the second-line setting in advanced gastric cancer. Further evaluation of fruquintinib in a randomized control trial is warranted.

About Gastric Cancer
Every year, it is estimated that approximately one million new patients around the world are diagnosed with gastric cancer, according to Frost & Sullivan, and in 2015 China represented approximately 44% of all newly diagnosed gastric cancer cases worldwide. The very high prevalence of gastric cancer in China as compared to the rest of the world is thought to be linked in part to food preparation habits, such as the use of certain preservatives. In 2015 there were an estimated 679,100 incidence gastric cancer cases and 498,000 mortality cases in China, according to the National Central Cancer Registry of China.

Gastric cancer is the third of most lethal cancer worldwide. As it is often diagnosed at an advanced stage, prognosis is poor with a median OS of less than 12 months. Although targeted therapy is under development in China, chemotherapy remains the mainstay of treatment for gastric cancer patients and confers only a moderate survival advantage. Accordingly, we see a high medical need for new targeted treatment options.

About Fruquintinib
Fruquintinib (HMPL-013) is a highly selective small molecule drug candidate that has been shown to inhibit VEGFR 24 hours a day via an oral dose, without known off-target toxicities. It is currently under the joint development in China by Chi-Med and its partner Eli Lilly and Company. Two late-stage, pivotal Phase III registration studies are ongoing in colorectal cancer (FRESCO) and lung cancer (FALUCA) along with the currently reported gastric cancer trial.

Colorectal: The FRESCO trial is a randomized, double-blind, placebo-controlled, multicenter, Phase III pivotal trial in patients with locally advanced or metastatic colorectal cancer who have failed at least two prior systemic antineoplastic therapies, including fluoropyrimidine, oxaliplatin and irinotecan. Enrollment was completed in May 2016. 416 patients were randomized at a 2:1 ratio to receive either: 5mg of fruquintinib orally once per day, on a three-weeks-on / one-week-off cycle, plus best supportive care ("BSC"); or placebo plus BSC. The primary endpoint is OS, with secondary endpoints including PFS, ORR, DCR and duration of response. Additional details of the FRESCO study may be found at clinicaltrials.gov, using identifier NCT02314819.

Lung: The FALUCA trial is a randomized, double-blind, placebo-controlled, multi-center, Phase III registration study targeted at treating patients with advanced non-squamous NSCLC, who have failed two lines of systemic chemotherapy. Enrollment began in December 2015. Patients are randomized at a 2:1 ratio to receive either: 5mg of fruquintinib orally once per day, on a three-weeks-on / one-week-off cycle, plus BSC; or placebo plus BSC. The primary endpoint is OS, with secondary endpoints including PFS, ORR, DCR and duration of response. Chi-Med plans to enroll approximately 520 patients in about 45 centers across China. Additional details about this study may be found at clinicaltrials.gov, using identifier NCT02691299.

Cancer Research Technology and Varleigh Dx (UK) Ltd launch test to support diagnosis of pancreatic cancer

On January 16, 2017 Cancer Research Technology (CRT), Cancer Research UK’s commercial arm, and Varleigh Dx (UK) Ltd, a clinical diagnostics development company, reported they have jointly launched a new test as an aid in the diagnosis of patients with pancreatic cancer (Press release, Cancer Research Technology, 16 16, 2017, View Source [SID1234523173]).

This test is now CE marked, conforming to the European IVD Directive, and available for diagnostic use across the UK*.

The launch coincides with research published in the British Journal of Cancer ** showing that the test, which detects a protein called MCM5 involved in cell replication, can aid in the diagnosis of pancreatic cancer, supporting traditional cytological methods. The test is performed on samples which are routinely taken as part of the current pancreatic cancer management pathway.

Standard cytology tests, which look at cells collected from the tumour are sometimes not sufficiently sensitive to provide an accurate diagnosis. Often several repeat procedures are required to obtain a definitive diagnosis. The researchers showed that using the MCM5 test alongside standard cytology testing helped support the diagnosis of patients who had received unclear results from repeat cytological tests***.

The new laboratory test uses a simple colourimetric test to measure the concentration of antibodies bound to the MCM5 protein, which is present at higher levels in cells that are dividing rapidly, such as those found in malignant tumours.

Clive Richardson, Director of Varleigh Dx said: "This test for pancreatic cancer is the first of a number of new tests for MCM5 technology that we are developing to assist in the early detection of cancer."

The rights to commercialise the MCM5 assay – also known as the ELISA test – were licensed to Varleigh Dx by CRT after the protein biomarker was first identified as a cancer biomarker by Cancer Research UK-funded researchers at the University of Cambridge.

Professor Nick Coleman, who lead on this earlier work, added: "It’s great news that our research has led to new routes to translate these biological markers into ways to improve early diagnosis, for such an aggressive cancer."

Dr Phil L’Huillier, Cancer Research Technology’s director of business development, said: "It’s always hugely satisfying to see discoveries originally made in the lab by Cancer Research UK scientists and licenced by CRT now reaching the stage where they can benefit patients and we’re delighted to have worked with Varleigh Dx to have made this possible.

"This should mean that more patients with this aggressive form of cancer can be diagnosed at the earliest possible stage, without having to undergo multiple invasive procedures."

Chi-Med Initiates a Phase II Combination Study of Fruquintinib with Iressa® (gefitinib) in First-Line Non-Small Cell Lung Cancer

On January 16, 2017 Hutchison China MediTech Limited ("Chi-Med") (AIM/Nasdaq:HCM) reported that it has initiated a Phase II study of a combination therapy using fruquintinib and Iressa in the first-line setting for patients with advanced or metastatic non-small cell lung cancer ("NSCLC") in China (Press release, Hutchison China MediTech, JAN 16, 2017, http://www.chi-med.com/chi-med-initiates-a-phase-ii-combination-study-of-fruquintinib-with-iressa-gefitinib-in-first-line-non-small-cell-lung-cancer/ [SID1234517415]). Fruquintinib is a highly selective and potent oral inhibitor of vascular endothelial growth factor receptors ("VEGFR"). The first drug dose was administered on January 9, 2017.

This Phase II combination therapy study is a multi-center, single-arm, open-label study. The objectives are to evaluate the safety and tolerability as well as preliminary efficacy of the combination therapy in the first-line setting for advanced or metastatic non-squamous NSCLC patients with epidermal growth factor receptor ("EGFR") activating mutations. Treatment will be continued until disease progression or intolerable toxicity occurs. Additional details about this study may be found at clinicaltrials.gov, using identifier NCT02976116.

About NSCLC and Tyrosine Kinase Inhibitors ("TKIs") to address EGFR-driven NSCLC
At an advanced stage, tumors secrete large amounts of vascular endothelial growth factors ("VEGF"), which are protein ligandsthat stimulate formation of excessive vasculature (angiogenesis) around the tumor in order to provide greater blood flow, oxygen, and nutrients to the tumor. VEGF and VEGFR play a pivotal role in tumor-related angiogenesis. Inhibition of the VEGF/VEGFR pathway represents an important therapeutic strategy in blocking the development of new blood vessels essential for tumors to grow and invade.

Every year, it is estimated that approximately 1.7 million new patients around the world are diagnosed with NSCLC, according to Frost & Sullivan. Lung cancer is the leading cause of cancer death among both men and women, accounting for about one-quarter of all cancer deaths (American Cancer Society), and more than breast, prostate and colorectal cancers combined.

NSCLC patients with EGFR activating mutations, which are an estimated 10-15% of NSCLC patients in the United States and Europe and 30-40% of NSCLC patients in Asia, are particularly sensitive to treatment with currently available EGFR-TKIs. However, tumors almost always develop resistance to treatment leading to disease progression. Combining therapies that inhibit different signaling pathways has the potential to be more effective than inhibition of a single pathway and to overcome tumor resistance.

About Fruquintinib
Fruquintinib (HMPL-013) is a highly selective small molecule drug candidate that has been shown to inhibit VEGFR 24 hours a day via an oral dose without known off-target toxicities. It is currently under the joint development in China by Chi-Med and its partner Eli Lilly and Company. Two late-stage, pivotal Phase III registration studies are ongoing in colorectal cancer (FRESCO) and lung cancer (FALUCA). In addition, fruquintinib is also in clinical development for gastric cancer.

Colorectal: The FRESCO trial is a randomized, double-blind, placebo-controlled, multi-center, Phase III pivotal trial in patients with locally advanced or metastatic colorectal cancer who have failed at least two prior systemic antineoplastic therapies, including fluoropyrimidine, oxaliplatin and irinotecan. Enrollment was completed in May 2016. 416 patients were randomized at a 2:1 ratio to receive either: 5 mg of fruquintinib orally once per day, on a three-weeks-on / one-week-off cycle, plus best supportive care ("BSC"); or placebo plus BSC. The primary endpoint is overall survival ("OS"), with secondary endpoints including progression free survival ("PFS"), objective response rate, disease control rate and duration of response. Additional details of the FRESCO study may be found at clinicaltrials.gov, using identifier NCT02314819.

Lung: The FALUCA trial is a randomized, double-blind, placebo-controlled, multi-center, Phase III registration study targeted at treating patients with advanced non-squamous NSCLC, who have failed two lines of systemic chemotherapy. Enrollment began in December 2015. Patients are randomized at a 2:1 ratio to receive either: 5 mg of fruquintinib orally once per day, on a three-weeks-on / one-week-off cycle, plus BSC; or placebo plus BSC . The primary endpoint is OS, with secondary endpoints including PFS, ORR, DCR and duration of response. Chi-Med plans to enroll approximately 520 patients in about 45 centers across China. Additional details about FALUCA study may be found at clinicaltrials.gov, using identifier NCT02691299.

Gastric: Chi-Med completed a Phase Ib dose finding study of fruquintinib in combination with paclitaxel, which established a combination regimen that was well tolerated. Additional details about this study may be found at clinicaltrials.gov, using identifier NCT02415023.

About Iressa, an EGFR-TKI
Iressa (gefitinib) is a targeted monotherapy developed by AstraZeneca for the treatment of patients with advanced or metastatic EGFR activating mutation positive NSCLC. Iressa acts by inhibiting the tyrosine kinase enzyme in the EGFR, thus blocking the transmission of signals involved in the growth and spread of tumors. Iressa is approved in 91 countries worldwide.

Chi-Med Initiates a Phase II Study of Sulfatinib in Second-line Biliary Tract Cancer in China

On January 16, 2017 Hutchison China MediTech Limited ("Chi-Med") (AIM/Nasdaq: HCM) reported that it has initiated a Phase II study of sulfatinib in second-line biliary tract cancer ("BTC") patients in China (Press release, Hutchison China MediTech, JAN 16, 2017, http://www.chi-med.com/chi-med-initiates-a-phase-ii-study-of-sulfatinib-in-second-line-biliary-tract-cancer-in-china/ [SID1234517412]). Sulfatinib is an oral, novel angio-immunokinase inhibitor that selectively targets vascular endothelial growth factor receptor ("VEGFR"), fibroblast growth factor receptor ("FGFR") and colony-stimulating factor-1 receptor ("CSF-1R"), three key tyrosine kinase receptors involved in tumor angiogenesis and immune evasion. The first drug dose was administered on January 9, 2017.

This Phase II study is a multi-center, single-arm, open-label study to evaluate the efficacy and safety of sulfatinib as a monotherapy in treating advanced or metastatic BTC patients who failed one prior systemic therapy. The primary endpoint is progression free survival ("PFS") at 16 weeks, with secondary endpoints including objective response rate ("ORR"), disease control rate ("DCR"), duration of response, PFS, overall survival ("OS") and safety. Additional details about this study may be found at clinicaltrials.gov, using identifier NCT02966821.

Hope Biosciences Licenses nuc-Gemcitabine, A ‘Trojan Horse’ Anti-nucleolin-Gemcitabine Aptamer Drug Conjugate Against Cancer

On January 13, 2017 HOPE BIOSCIENCES reported that it has acquired the exclusive rights to develop and commercialize nuc-gemcitabine (APTA-12/HOPE-888) through a licensing agreement with AptaBio Therapeutics, a Korean pharmaceutical company (Press release, Hope Biosciences, JAN 13, 2017, View Source [SID1234609541]).

nuc-Gemcitabine consists of Antisoma’s AS1411*, a clinically-tested DNA aptamer against surface nucleolin found on many cancer cells, and dFdCMP, an activated form of gemcitabine. Unlike ADCs (antibody drug conjugates) or SMDCs (small molecule drug conjugates), which require ‘linker’ conjugation of the cytotoxic payload to the drug, nuc-gemcitabine is created by incorporating a single activated gemcitabine molecule in lieu of a thymidine molecule during the one-step solid phase synthesis of the DNA aptamer.

Clinical trials in over 80 cancer patients showed AS1411 to have modest anti-cancer activity and a favorable safety profile. nuc-Gemcitabine is 100-1,000x more potent compared to AS1411 or conventional gemcitabine (Gemzar) in pre-clinical studies. Composition of matter patent has been granted in major countries, including the United States.

"Nucleolin is constantly and abundantly expressed on the cell surface of tumor cells where it serves as a binding protein for a variety of ligands implicated in cancer growth and angiogenesis," said Dr. SungHwan Moon, President and Chief Scientific Officer of AptaBio. "High nucleolin expression is correlated with decreased survival. nuc-Gemcitabine binds to surface nucleolin with high specificity and affinity, leading to internalization of the aptamer-drug into tumor cells, where it mediates cell death. We have demonstrated significantly greater anti-cancer activity at low doses of nuc-gemcitabine containing the equivalent of 3 mg/kg gemcitabine versus 80-100 mg/kg of Gemzar in gemcitabine-resistant pancreatic cancer xenograft mouse models."

"HOPE-888 has demonstrated impressive anti-cancer activity in preclinical models. It could truly be a game changing treatment strategy for pancreatic cancer and other difficult-to-treat malignancies," said George Uy, CEO and Founder of HOPE. "Our goal is to file IND application in the next 12-18 months and bring it into the clinic soon thereafter. We intend to truly personalize nuc-gemcitabine therapy by screening patients for nucleolin-expression with a biomarker kit."