On December 19, 2018 MiNA Therapeutics, the pioneer in RNA activation therapeutics, reported that enrolment of the first patients treated with MTL-CEBPA in combination with Sorafenib in OUTREACH, the multi-centre Phase 1b clinical trial in patients with advanced liver cancer (Press release, MiNA Therapeutics, DEC 19, 2018, View Source [SID1234532155]). The study is designed to assess the safety, tolerability and clinical activity of MTL-CEBPA in combination with Sorafenib. OUTREACH is currently being conducted at multiple clinical trials sites in the United Kingdom, Singapore and Taiwan.

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Evaluation of MTL-CEBPA in combination with Sorafenib follows the evaluation of MTL-CEBPA as a single agent in 38 patients with advanced liver cancer. Preliminary clinical results of MTL-CEBPA as a single agent presented in June 2018 at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting showed encouraging safety, pharmacology and clinical activity. Furthermore in September 2018 at the International Liver Cancer Association (ILCA) Conference, investigators reported complete tumour responses in patients off-study when subsequently administered Sorafenib. Sorafenib is the standard of care for first line treatment of advanced liver cancer.

Robert Habib, CEO of MiNA Therapeutics, commented, "We are encouraged by our initial clinical evaluation of MTL-CEBPA as a single agent and are excited about its potential in combination with approved therapies that on their own have demonstrated only modest benefit to patients. We look forward to continue to collaborate with our clinical investigators and evaluating the combination of MTL-CEBPA and Sorafenib into the expansion of the OUTREACH trial."

MTL-CEBPA consists of a double stranded RNA formulated in a liposomal nanoparticle and is designed to activate the CEBPA gene. The CEBPA gene encodes CCAAT/enhancer binding protein alpha (C/EBP-α), a transcription factor that acts as a master regulator of cell lineage determination and differentiation in several tissues including myeloid cells, liver cells and adipose tissue. In cancer, C/EBP-α plays important roles in regulating both tumour growth and the tumour immune microenvironment.

On December 19, 2018 Chugai Pharmaceutical Co., Ltd. (TOKYO: 4519) reported that it filed a new drug application to the Ministry of Health, Labour and Welfare (MHLW) for a ROS1/TRK inhibitor entrectinib for the treatment of NTRK fusion-positive solid tumors (Press release, Chugai, DEC 19, 2018, View Source [SID1234532139]). Entrectinib received Sakigake designation and orphan drug designation from MHLW.

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"Entrectinib obtained the first Sakigake designation for Chugai. Entrectinib demonstrated efficacy across tumor types in extremely rare NTRK fusion-positive solid tumors in the global studies," said Dr. Yasushi Ito, Chugai’s Executive Vice President, Co-Head of Project & Lifecycle Management Unit. "Chugai is committed to seek approval of entrectinib so that we may contribute to advancing personalized healthcare which may enable the most optimal treatment decision for patients based on genetic profiles of individual tumors."

This application for approval is based on an integrated analysis of an open-label, multicenter, global phase II study (the STARTRK-2 study) and three overseas phase I studies (the STARTRK-NG study, the STARTRK-1 study and the ALKA-372-001 study). Efficacy was evaluated in 54 patients with untreated NTRK fusion-positive solid tumors while safety assessment was conducted with 355 patients registered in the four trials.

[Reference information]
About the integrated analysis results
Media release issued by Roche on October 21, 2018
Title: Roche’s investigational personalised medicine entrectinib shrank tumours in people with NTRK fusion-positive solid tumours
View Source

Entrectinib has been granted Breakthrough Therapy Designation (BTD) by the U.S. Food and Drug Administration (FDA) in May 2017, Priority Medicines (PRIME) designation by the European Medicines Agency (EMA) in October 2017 for the treatment of NTRK fusion-positive, locally advanced or metastatic solid tumors in adult and pediatric patients who have either progressed following prior therapies or have no acceptable standard therapies.

As the top pharmaceutical company in the field of oncology in Japan, Chugai will work for the early approval to provide entrectinib as a new treatment option for patients and medical professionals.

About entrectinib
Entrectinib is an investigational, oral medicine in development for the treatment of locally advanced or metastatic solid tumors that harbor NTRK1/2/3 or ROS1 gene fusions. It is a selective, CNS-active tyrosine kinase inhibitor designed to inhibit the kinase activity of the TRK A/B/C and ROS1 proteins, whose activating fusions drive proliferation in certain types of cancer. Entrectinib can block ROS1 and NTRK kinase activity and inhibit proliferation of cancer cells with ROS1 or NTRK gene fusions. Entrectinib is being investigated across a range of solid tumor types, including breast, cholangiocarcinoma, colorectal, gynaecological, neuroendocrine, non-small cell lung, salivary gland, pancreatic, sarcoma and thyroid cancers.

About NTRK fusion gene positive cancer
NTRK fusion gene is an abnormal gene that can be formed by fusing the NTRK genes (NTRK1, NTRK2, NTRK3 encode TRKA, TRKB, TRKC protein, respectively) and other genes (ETV6, LMNA, TPM3, etc.) as a result of chromosomal translocation. The TRK fusion kinase made from NTRK fusion gene is thought to promote cancer cell proliferation. There is very rare expression of NTRK fusion but in various adult and pediatric solid tumors, including appendiceal cancer, breast cancer, cholangiocarcinoma, colorectal cancer, gastrointestinal stromal tumor (GIST), infantile fibrosarcoma, lung cancer, mammary analogue secretory carcinoma of the salivary gland, melanoma, pancreatic cancer, thyroid cancer, and various sarcomas.

On December 19, 2018 Kyn Therapeutics, a biotechnology company advancing new immunometabolism therapies for treating cancer, reported the initiation of two clinical trials of ARY-007 (also known as Grapiprant), an EP4 receptor antagonist, in collaboration with Merck (known as MSD outside the United States and Canada) (Press release, KYN Therapeutics, DEC 19, 2018, View Source [SID1234532156]). ARY-007 will be assessed in combination with Merck’s anti-PD-1 therapy, KEYTRUDA (pembrolizumab) in checkpoint-refractory and -resistant solid tumors, an area of high unmet medical need.

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Prostaglandin E2 (PGE2) has been shown to contribute to an immunosuppressive environment in cancer by enhancing the activity of regulatory immune cells and suppressing the activity of effector immune cells. EP4 is a high-affinity receptor of PGE2 and is known to facilitate these immunosuppressive activities. ARY-007 is an oral, potent and highly selective antagonist of EP4. In preclinical models, EP4 inhibition leads to antitumor activity and also significantly enhances the antitumor activity of checkpoint inhibitors. While in development for a non-oncology indication, ARY-007 was found to be well-tolerated in multiple studies which enrolled approximately 1000 human subjects.

The Phase 1b/2 multicenter, open-label, single arm clinical trials are designed to assess the safety and efficacy of ARY-007 in combination with pembrolizumab in patients with advanced or progressive Microsatellite Stable (MSS) Colorectal Cancer (CRC), and with advanced or metastatic PD-1/L1 refractory Non-Small Cell Lung Cancer (NSCLC) adenocarcinoma. MSS CRC is inherently resistant to anti-PD-1 therapies – these agents have only shown activity in the microsatellite instability-high (MSI-H) subset of CRC. The NSCLC study is enrolling patients who have progressed while on PD-1 or PD-L1 therapy. Both studies incorporate a robust translational biomarker strategy.

"The Kyn team believes immunometabolism pathways hold great promise as therapeutics that could deliver breakthrough improvements for patients non-responsive to immunotherapy regimens. We believe EP4 is the right target and ARY-007 is the right molecule for overcoming the immunosuppressive effects of PGE2 in these cancers where increased pathway expression is associated with poor outcome," said Mark Manfredi, Ph.D., president and chief executive officer of Kyn Therapeutics. "We welcome the opportunity to collaborate with Merck as we initiate clinical studies."

About ARY-007
ARY-007 is an orally available, potent and highly selective antagonist of the EP4 receptor, a component of the prostaglandin E2 (PGE2) pathway which significantly influences the composition of the tumor microenvironment. In preclinical studies, inhibition of EP4 has been shown to boost the immune response through modulation of multiple immune cell types, and in combination with checkpoint inhibitors has yielded significant reduction in tumor growth relative to either agent alone.

On December 19, 2018 Anixa Biosciences, Inc. (NASDAQ: ANIX), a biotechnology company focused on using the body’s immune system to fight cancer, reported that it completed a Pre-Submission (Pre-Sub) meeting with the US FDA on December 17, 2018 (Press release, Anixa Biosciences, DEC 19, 2018, View Source [SID1234532175]).

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The meeting was focused on discussing Anixa’s Cchek test, an artificial intelligence (AI) based liquid biopsy for the early detection of cancer. Specifically, the discussion focused on using Cchek for prostate cancer testing, as prostate cancer will be the first commercial application.

Dr. Amit Kumar, President and CEO of Anixa Biosciences said, "The meeting was very positive and productive, with discussions that included the intended use of the test, the path for regulatory approval, and the use of AI. We are eager to move Cchek-Prostate towards commercialization." Dr. Kumar continued, "Standard of care for screening for prostate cancer includes a prostate specific antigen (PSA) measurement, followed by a digital rectal exam (DRE). It is well known that these current tests are imperfect, and cause hundreds of thousands of men to undergo painful, expensive and risk-laden biopsies that are negative and may be unnecessary. Our preliminary data, which we presented to the FDA, demonstrates that Cchek-Prostate could potentially eliminate a large number of these unnecessary procedures. The FDA was very supportive and appreciated us initiating the dialogue with them. As we continue through the regulatory process, we anticipate additional productive meetings and submissions with the FDA."

Anixa Biosciences expects the official minutes of the Pre-Sub meeting to be available in January. On January 24, 2019 Anixa plans to hold a conference call where it will discuss the commercialization path and timeline for Cchek-Prostate, as well as an update on its CAR-T therapeutics program. The details of the conference call will be provided at a later date.

On December 19, 2018 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) reported that the first patient has been dosed in the first novel-novel combination study evaluating two investigational agents within its AML Franchise (Press release, Daiichi Sankyo, DEC 19, 2018, View Source [SID1234532207]). The phase 1 study will evaluate the safety and activity of the combination of a FLT3 inhibitor, quizartinib, and an MDM2 inhibitor, milademetan (DS-3032), in patients with relapsed/refractory FLT3-ITD acute myeloid leukemia (AML) or newly-diagnosed FLT3-ITD AML unfit for intensive chemotherapy, a very aggressive form of the disease associated with poor prognosis.

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"We have initiated this combination study of quizartinib and milademetan in order to determine the safety and tolerability of the combination and if the addition of the MDM2 inhibitor milademetan may potentially further improve the outcomes of patients with relapsed/refractory FLT3-ITD AML beyond what has been previously reported with single agent quizartinib," said Arnaud Lesegretain, Vice President, Oncology R&D and Head, AML Franchise, Daiichi Sankyo. "In this study, we also are exploring the potential of the combination of quizartinib and milademetan in patients with newly-diagnosed FLT3-ITD AML who are unfit for intensive chemotherapy. This study is the first of several planned studies that will evaluate the potential of novel combinations within our investigational AML Franchise, as we are committed to continuously improving the standard of care for patients with AML."

Quizartinib is the first FLT3 inhibitor to demonstrate a survival benefit as an oral, single agent compared to chemotherapy in a randomized, phase 3 study (QuANTUM-R) in patients with FLT3-ITD AML, which was refractory or relapsed within six months of first remission, and single agent milademetan has demonstrated preliminary clinical activity in AML and myelodysplastic syndrome (MDS) in a phase 1 study.1,2 Additionally, preclinical research has shown that the combination of quizartinib and milademetan has greater activity in FLT3-ITD AML cells compared to the respective single agent treatments.3

In the QuANTUM-R study, the median treatment duration with quizartinib was 4 cycles of 28 days each versus 1 cycle in the salvage chemotherapy arm. Incidence of treatment-emergent adverse events was comparable between patients who received single agent quizartinib and those who received salvage chemotherapy. The most common adverse drug reactions (>30 percent, any Grade) in patients treated with quizartinib included infections, bleeding, nausea, asthenic conditions, pyrexia, febrile neutropenia and vomiting, and the most common Grade ≥ 3 adverse drug reactions (>20 percent) were infection and febrile neutropenia. The most common laboratory adverse reactions (incidence >50 percent) were decreased white blood cell count, decreased lymphocyte count, decreased hemoglobin, decreased neutrophil count and decreased platelet count. The safety profile observed in QuANTUM-R appears consistent with that observed at similar doses in the quizartinib clinical development program.

In addition to the quizartinib and milademetan combination study, an ongoing phase 1 study of milademetan has been expanded to include evaluation of milademetan in combination with the hypomethylating agent 5-azacitidine, an inhibitor of DNA methylation, in patients with newly-diagnosed AML unfit for intensive chemotherapy, relapsed/refractory AML or high-risk MDS.

About the Quizartinib/Milademetan Combination Study

The multi-center, non-randomized, phase 1, open-label, two-part study is investigating the safety and efficacy of the combination of quizartinib and milademetan in patients with relapsed/refractory FLT3-ITD AML or newly-diagnosed FLT3-ITD AML unfit for intensive chemotherapy. The first part of the study (dose escalation) will assess the safety and tolerability of the combination to determine the dosing schedule, maximum tolerated dose and recommended dose for expansion. The second part of the study (dose expansion) will confirm the safety and tolerability at the recommended dose for expansion of the combination and will identify a recommended phase 2 dose. The primary objective of the study is safety. Secondary objectives include evaluation of pharmacokinetics and preliminary efficacy. The study is expected to enroll approximately 110 patients in the U.S., EU and Japan. For more information about the study, visit ClinicalTrials.gov.

About the Milademetan/5-Azacitidine Combination Study

The multi-center, non-randomized, phase 1, open-label, two-part study is investigating the safety and efficacy of milademetan as a single agent and in combination with the hypomethylating agent 5-azacitidine. The first part of the study (dose escalation) will evaluate the safety and tolerability and identify the maximum tolerated dose and recommended dose for expansion of milademetan as a single agent and in combination with 5-azacitidine in patients with relapsed/refractory AML or high-risk MDS. The second part of the study (dose expansion) will confirm the safety and tolerability at the recommended dose of milademetan in combination with 5-azacitidine and will identify a recommended phase 2 dose in patients with relapsed/refractory AML, newly-diagnosed AML unfit for intensive chemotherapy or high-risk MDS. The primary objectives of the study are safety and tolerability, maximum tolerated dose, recommended dose for expansion and response to treatment. Key secondary objectives include evaluation of pharmacokinetics and pharmacodynamic effects. The study is expected to enroll up to 200 patients in the U.S. For more information about the study, visit ClinicalTrials.gov.

About Acute Myeloid Leukemia and Myelodysplastic Syndrome

AML is an aggressive blood and bone marrow cancer that causes uncontrolled growth and accumulation of malignant white blood cells that fail to function normally and interfere with the production of normal blood cells.4 In the U.S. this year, it is estimated that there will be more than 19,000 new diagnoses of AML and more than 10,000 deaths from AML.5 The five-year survival rate of AML reported from 2007 to 2013 was approximately 27 percent, which was the lowest of all leukemias.4

FLT3 gene mutations are one of the most common genetic abnormalities in AML.6 FLT3-ITD is the most common FLT3 mutation, affecting approximately one in four patients with AML.7,8,9,10 FLT3-ITD is a driver mutation that presents with high leukemic burden and has poor prognosis and a significant impact on disease management for patients with AML.8,11 Patients with FLT3-ITD AML have a worse overall prognosis, including an increased incidence of relapse, an increased risk of death following relapse and a higher likelihood of relapse following hematopoietic stem cell transplantation as compared to those without this mutation.12,13

MDS is a type of cancer that can occur when blood-forming cells in the bone marrow become abnormal.14 There were over 14,000 new cases of MDS diagnosed each year from 2010 to 2014.4 In about one in three patients, MDS progresses to AML.14

About Quizartinib

Quizartinib, the lead investigational agent in the AML Franchise of the Daiichi Sankyo Cancer Enterprise, is an oral selective type II FLT3 inhibitor currently in phase 3 development for relapsed/refractory FLT3-ITD AML (QuANTUM-R) in the U.S. and EU; phase 3 development for newly-diagnosed FLT3-ITD AML (QuANTUM-First) in the U.S., EU and Japan; phase 2 development for relapsed/refractory FLT3-ITD AML in Japan; and phase 1 development in combination with an investigational agent, milademetan, for relapsed/refractory FLT3-ITD AML and newly-diagnosed FLT3-ITD AML unfit for intensive chemotherapy in the U.S., EU and Japan.

Quizartinib has been granted Priority Review and Breakthrough Therapy designation for the treatment of adult patients with relapsed/refractory FLT3-ITD AML, and Fast Track designation for the treatment of relapsed/refractory AML by the U.S. Food and Drug Administration (FDA). Quizartinib also has been granted accelerated assessment by the European Medicines Agency (EMA) for the treatment of adults with relapsed or refractory AML, which is FLT3-ITD positive, and granted Orphan Drug designation by both the FDA and the European Commission (EC) for the treatment of AML and by the Japan Ministry of Health, Labour and Welfare (MHLW) for the treatment of FLT3-mutated AML.

About Milademetan

Milademetan (DS-3032) is an oral selective MDM2 inhibitor currently in phase 1 clinical development for solid and hematologic malignancies, including a combination study with quizartinib in relapsed/refractory FLT3-ITD AML or newly-diagnosed FLT3-ITD AML unfit for intensive chemotherapy in the U.S., EU and Japan; a single agent and combination study with 5-azacitidine in newly-diagnosed AML unfit for intensive chemotherapy, relapsed/refractory AML or high-risk MDS in the U.S.; and two single agent studies in lymphomas and solid tumors in the U.S. and Japan.

Quizartinib and milademetan are investigational agents that have not been approved for any indication in any country. Safety and efficacy of these investigational agents have not been established.