On June 20, 2016 Cellectis (Alternext: ALCLS – Nasdaq: CLLS), a biopharmaceutical company focused on developing immunotherapies based on gene edited CAR T-cells (UCART), reported that the first patient has been treated in the Phase I study of UCART19 in pediatric acute B lymphoblastic leukemia (B-ALL) at the University College of London (UCL) (Press release, Cellectis, JUN 20, 2016, View Source [SID:1234513467]). This UCART19 clinical trial is sponsored by Servier in close collaboration with Pfizer.

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The pediatric Phase I is an open label, non-comparative, monocenter study to evaluate the safety and ability of UCART19 to induce molecular remission in pediatric patients with relapsed or refractory CD19 positive B-cell acute lymphoblastic leukemia ahead of planned allogeneic haematopoeitic stem cell transplantation (allo-HSCT).

Cellectis will receive a milestone payment from Servier of an undisclosed amount.

About UCART19

UCART19 is an allogeneic CAR T-cell product candidate developed for treatment of CD19-expressing hematological malignancies, gene edited with TALEN. UCART19 is initially being developed in chronic lymphocytic leukemia (CLL) and acute lymphoblastic leukemia (ALL). Cellectis’ approach with UCART19 is based on the preliminary positive results from clinical trials using autologous products based on the CAR technology, and has the potential to overcome the limitation of the current autologous approach by providing an allogeneic, frozen, "off-the-shelf" T cell based medicinal product.

In November 2015, Servier acquired the exclusive rights to UCART19 from Cellectis. Following further agreements, Servier and Pfizer began collaborating on a joint clinical development program for this cancer immunotherapy. Pfizer has exclusive rights from Servier to develop and commercialize UCART19 in the United States, while Servier retains exclusive rights for all other countries.

On June 20, 2016 Hutchison China MediTech Limited ("Chi-Med") (AIM/Nasdaq: HCM) reported the initiation of a Phase II expansion of the ongoing TATTON trial (NCT02143466) to evaluate the selective c-Met inhibitor savolitinib (AZD6094) in epidermal growth factor receptor ("EGFR") mutant non-small cell lung cancer ("NSCLC") patients (Press release, Hutchison Medipharma, JUN 20, 2016, http://www.chi-med.com/savolitinib-global-phase-ii-trial-initiated-in-egfr-mutant-non-small-cell-lung-cancer/ [SID:1234513466]).

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Savolitinib has the potential to address major unmet medical needs in c-Met-driven subsets of NSCLC, a disease that is estimated to afflict approximately 1.7 million new patients annually worldwide.

The trial is a single-arm global Phase II study of savolitinib in combination with Tagrisso (osimertinib/AZD9291) in advanced NSCLC patients who have developed resistance to approved EGFR tyrosine kinase inhibitors ("TKIs"). This expansion was initiated following encouraging early data from a number of patients enrolled in the TATTON study who received savolitinib in combination with Tagrisso.

The initiation of the expanded Phase II study has triggered a US$10 million milestone payment to Hutchison MediPharma Limited ("HMP") (a 99.8% held subsidiary of Chi-Med) under the terms of the agreement with AstraZeneca PLC ("AstraZeneca") signed in December 2011. HMP and AstraZeneca are conducting Phase II studies in NSCLC with savolitinib in monotherapy, as well as in combination with either Tagrisso or Iressa (gefitinib). AstraZeneca continues to lead and invest in the global NSCLC development program for savolitinib.

Susan Galbraith, Senior Vice President, Head of Oncology Innovative Medicines, AstraZeneca, said: "Savolitinib is a highly selective c-Met inhibitor that is being investigated in a number of cancers including in patients with lung cancer whose disease is driven by aberrant c-Met / HGF signaling. We are extremely excited by the data we have seen for savolitinib when used in combination with our EGFR tyrosine kinase inhibitors. We are committed to advancing research to develop a broad range of potential treatment options for patients with lung cancer."

Christian Hogg, Chief Executive Officer of Chi-Med, said: "We estimate that the annual incidence of patients with MET-driven NSCLC in the U.S., European Union and Japan totals about 40,000-50,000 in all treatment settings. This is an important unmet medical need and one that we believe savolitinib is well suited to address because of its very high selectivity. This allows for effective target coverage of c-Met, as well as safe and tolerable combinations with other oncology agents. We believe that savolitinib either as a monotherapy in first-line NSCLC, or in proprietary combinations with AstraZeneca’s Iressa and Tagrisso in second- and third-line NSCLC, will address the key genetic drivers of cancer cell proliferation in these very difficult-to-treat NSCLC patients. We are hopeful about proceeding into Phase III in 2017 based on future data from this study."

NSCLC DEVELOPMENT PROGRAM HIGHLIGHTS

Savolitinib continues to be explored in a range of MET-driven NSCLC settings including:

Savolitinib in combination with Tagrisso or Iressa in Phase II expansions of ongoing studies in advanced EGFR mutant NSCLC
Savolitinib + Tagrisso combination Phase II study in third-line NSCLC (for patients progressing on T790M-directed therapies)
Savolitinib monotherapy Phase II study in NSCLC
Savolitinib is in clinical development in multiple MET-driven solid tumor indications including NSCLC, kidney, gastric and colorectal cancer. For a detailed summary of all current savolitinib clinical trials covering multiple patient populations, please click here.



NOTES TO EDITORS
About NSCLC and TKIs to address MET-driven and EGFR-driven NSCLC

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-third of all cancer deaths, and more than breast, prostate and colorectal cancers combined. TKIs are used in many cancer therapies and act by blocking the cell signaling pathways that drive the growth of tumor cells.

Around 4-5% of first-line NSCLC patients have MET-driven NSCLC, including approximately 3-4% with MET Exon-14 mutations and approximately 1-2% with c-Met gene amplification, and are generally sensitive to treatment with selective c-Met inhibitors such as savolitinib. Currently there are no approved selective c-Met TKIs for these NSCLC patients.

Separately, patients who have the EGFR mutation form of NSCLC, which occurs in an estimated 10-15% of NSCLC patients in 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, with median progression-free periods of approximately nine months. Among NSCLC patients treated with the approved EGFR-TKIs Iressa, Tarceva (erlotinib) or Gilotrif (afatinib), who build resistance to EGFR-TKIs and thus become second-line patients, approximately half of this resistance is driven by T790M, and approximately one-fifth is driven by c-Met gene amplification.

In third-line NSCLC patients treated with EGFR T790M mutation-positive TKIs, resistance pathways are only beginning to emerge as more patients are being treated with TKIs in clinical trials and Tagrisso was approved in the U.S., European Union, Japan and South Korea. Data is limited, but as patients become resistant to Tagrisso (median progression-free survival of nine months), c-Met gene amplification is emerging as a resistance pathway of significant interest.



About savolitinib, a uniquely selective c-Met inhibitor

Savolitinib is a potential global first-in-class inhibitor of c-Met (also known as mesenchymal epithelial transition factor) receptor tyrosine kinase, an enzyme which has been shown to function abnormally in many types of solid tumors. It was developed as a potent and highly selective oral inhibitor specifically designed to address issues observed in the clinic with first-generation c-Met inhibitors, including renal toxicity.



About Tagrisso, a selective inhibitor against EGFR and T790M mutations

Tagrisso (osimertinib) 80mg once-daily tablet, developed by AstraZeneca, is the first medicine indicated for the treatment of adult patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC. Non-clinical in vitro studies have demonstrated that osimertinib has high potency and inhibitory activity against mutant EGFR phosphorylation across the range of clinically relevant EGFRm and T790M mutant NSCLC cell lines, with significantly less activity against EGFR in wild-type cell lines.

Tagrisso is being compared with platinum-based doublet chemotherapy in the confirmatory AURA3 Phase III study in patients with EGFR T790M-positive, locally advanced or metastatic NSCLC who have progressed after EGFR-TKI therapy. It is also being investigated in the adjuvant and metastatic first-line settings, including in patients with and without brain metastases, in leptomeningeal disease, and in combination treatment.

About Iressa, an EGFR mutation inhibitor

Iressa (gefitinib) is a targeted monotherapy developed by AstraZeneca for the treatment of patients with advanced or metastatic EGFR 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. EGFR mutations occur in approximately 10-15% of NSCLC Caucasian patients and 30-40% of NSCLC patients in Asia. Iressa is approved in 91 countries worldwide.

On June 20, 2016 Unum Therapeutics reported that the investigational new drug (IND) application for ACTR087 for the treatment of adult patients with relapsed/refractory CD20-positive B-cell non-Hodgkin lymphoma, is now active (Press release, Unum Therapeutics, JUN 20, 2016, View Source!2016jun20-unum-therapeutics-announces-ac/vrn7q [SID:1234513465]).

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The IND, which the Company had filed in the United States with the Food and Drug Administration, enables Unum to initiate a multi-center, Phase 1 trial to evaluate the use of ACTR087 in combination with rituximab in this patient population. This trial will be the first U.S.-based clinical program for Unum Therapeutics.
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"This is an important milestone in our strategy to identify and develop ACTR T-cell immunotherapies to combat a broad range of cancers," said Michael Vasconcelles, MD, Unum’s Chief Medical Officer. "We are eager to explore the potential of ACTR087 to become an important new treatment option for underserved patients with relapsed/refractory B-cell non-Hodgkin lymphoma. We’re excited to be working with experienced clinical investigators at several leading U.S. academic medical centers in this trial."

Site initiation activities are currently underway and the Company anticipates that study enrollment will begin in the second half of 2016. ACTR087, Unum’s most advanced product candidate, combines the Company’s proprietary Antibody-Coupled T-cell Receptor (ACTR), with rituximab, an anti-CD20 antibody. By binding to tumor cells, rituximab effectively targets the tumor for destruction by the genetically modified ACTR087 T-cells.

"ACTR087 is Unum’s first product candidate with an active IND. This marks an important step as we advance our clinical efforts and continue developing a broad pipeline of novel product candidates based on our universal ACTR technology," said Charles Wilson, PhD, Unum’s President and Chief Executive Officer.

This trial will be an open label Phase 1 dose-escalating study using three doses of genetically modified ACTR T-cells in combination with rituximab in patients with relapsed or refractory CD20-positive B-cell non-Hodgkin lymphoma. The primary objective of this trial is to evaluate the safety and tolerability of ACTR087 in patients with relapsed or refractory CD20-positive B-cell lymphoma. Secondary objectives will include the assessment of efficacy of ACTR087 and measurements of durability and persistence of ACTR087 in the blood. The study will be conducted at several clinical sites in the U.S. and is planned to enroll approximately 45 patients.
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About Antibody-Coupled T-cell Receptor (ACTR) Technology and ACTR087

Unum’s proprietary ACTR is a chimeric protein that combines components from receptors normally found on two different human immune cell types – natural killer (NK) cells and T-cells – to create a novel cancer cell killing activity. T-cells bearing the ACTR receptor protein can be directed to attack a tumor by combining with a monoclonal antibody that binds antigens on the cancer cell surface.

In contrast to other T-cell therapy approaches for cancer that are limited to a single cancer cell surface target and, therefore, treat a narrow set of tumors, Unum’s approach is not restricted by a specific tumor cell antigen and, thus, may have applications for treating many different types of cancers when combined with the right antibody.

Unum is developing ACTR in combination with a range of tumor-targeting antibodies for use in both hematologic and solid tumor indications. ACTR087, Unum’s most advanced product candidate, combines Unum’s proprietary ACTR, with rituximab, an anti-CD20 antibody. The ACTR087 study will be the first clinical trial using a viral vector to permanently insert the ACTR gene into the genome of patient T-cells.

About B-cell non-Hodgkin Lymphoma
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B-cell non-Hodgkin lymphoma, a collection of many distinct forms of cancer arising from specific immune cells called B lymphocytes, is one of the most common cancers in the United States. The American Cancer Society estimates that in 2016 alone, approximately 72,000 people will be diagnosed with this disease.[i] Though B-cell non-Hodgkin lymphoma is treatable with a variety of available cancer medicines, and some forms of the disease may be curable with initial chemotherapy-based treatment, patients whose disease relapses after treatment or is refractory to available therapies face limited treatment options, and historically their outcomes are poor.

On June 20, 2016 Kite Pharma, Inc. (Nasdaq: KITE), a clinical-stage biopharmaceutical company focused on developing engineered autologous T-cell therapy (eACT) products for the treatment of cancer, reported the official opening of its new commercial manufacturing facility in El Segundo, California (Press release, Kite Pharma, JUN 20, 2016, View Source [SID:1234513463]).

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Over 300 employees, investors and company partners attended the unveiling of the 43,500-square-foot, state-of-the-art plant. The facility has been designed to produce chimeric antigen receptor (CAR) and T-cell receptor (TCR) product candidates for clinical trials, as well as for the potential launch and commercialization of Kite’s lead CAR T-cell product candidate, KTE-C19, which is in clinical study for the treatment of chemorefractory diffuse large B-cell lymphoma (DLBCL) and other B-cell malignancies. Kite anticipates commercial launch of KTE-C19 in 2017.

The facility is estimated to have the capacity to produce up to 5,000 patient therapies per year. The plant’s location, adjacent to Los Angeles International Airport, is intended to expedite receipt and shipment of engineered T-cells from and to patients across the United States and Europe.

"Establishing world-class manufacturing capability has always been a priority for Kite," said Timothy Moore, Kite’s Executive Vice President of Technical Operations. "Through our continuous efforts to optimize manufacturing, supply chain and quality control, our proprietary process now reduces the time from when a patient’s materials are shipped to our facility to when the engineered T cells are returned to the patient to approximately 14 days, one of the fastest in the industry."

Underscoring the company’s focus on execution and commitment to the future delivery of immuno-oncology therapies, the El Segundo facility is expected to be operational by the end of this year for clinical production, less than two years after the site groundbreaking in February 2015. The El Segundo facility will complement Kite’s existing clinical manufacturing facilities in Santa Monica, California, that are currently producing therapies for Kite’s ongoing clinical trials.

"We are excited and proud to celebrate the opening of our El Segundo manufacturing facility, the latest milestone in our mission to deliver a potentially transformative therapy to patients with a significant unmet need," said Arie Belldegrun, M.D., FACS, Kite’s Chairman, President and Chief Executive Officer. "If approved by the FDA, this site will become a model factory serving patients all over the country. We will also continue to innovate and introduce next generation manufacturing technologies at our facility."

About Kite’s ZUMA Clinical Programs for KTE-C19

KTE-C19 is an investigational therapy in which a patient’s T-cells are genetically modified to express a CAR that is designed to target the antigen CD19, a protein expressed on the cell surface of B-cell lymphomas and leukemias. Kite is currently enrolling four pivotal studies (also known as ZUMA studies) for KTE-C19 in patients with various B-cell malignancies.


Study Phase Indication Status
ZUMA-1 Phase 2 Pivotal
NCT02348216 (N=112) Chemorefractory DLBCL, PMBCL, TFL Phase 2 enrolling
ZUMA-2 Phase 2 Pivotal
NCT02601313 (N=70) Relapsed/refractory MCL Phase 2 enrolling
ZUMA-3 Phase 1/2 Pivotal
NCT02614066 (N=75) Relapsed/refractory Adult ALL Phase 1/2 enrolling
ZUMA-4 Phase 1/2 Pivotal
NCT02625480 (N=75) Relapsed/refractory Pediatric ALL Phase 1/2 enrolling

DLBCL = diffuse large B-cell lymphoma
PMBCL = primary mediastinal B-cell lymphoma
TFL = transformed follicular lymphoma
MCL = mantle cell lymphoma
ALL = acute lymphoblastic leukemia