publication date: Jul. 27, 2018

Clinical Roundup

UCLA’s Yang receives $1.4M to develop cellular therapy using blood stem cells

Lili Yang, a researcher at the UCLA Jonsson Comprehensive Cancer Center and the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, has received a Quest Discovery Program award totaling approximately $1.4 million from the California Institute for Regenerative Medicine.

CIRM, a state stem cell agency, established the program to support the development of promising novel stem cell-based technologies that will be ready for translational studies within two years.

The award will fund Yang’s efforts to develop a cellular therapy that could potentially be used to treat multiple cancers including solid tumors (melanoma, colon, lung, breast, and head and neck cancers) and blood cancers (such as leukemia, multiple myeloma, and myelodysplastic syndromes).

Yang’s novel approach will genetically modify blood-forming stem cells—which produce every type of blood cell, including the immune cells that can fight disease—to create large supplies of invariant natural killer T cells, a powerful subset of immune cells that have the remarkable capacity to target a broad range of cancers.

To date, the clinical applications of iNKT cells have been greatly limited because they don’t naturally exist in high numbers in the body; one drop of human blood contains around 10 million total blood cells but only around 10 iNKT cells; cancer patients typically have even less iNKT cells.

Using blood-forming stem cells from healthy donors, Yang’s approach will first genetically modify the cells in two ways:

  • One genetic modification will insert a receptor that will prompt the blood-forming stem cells to create only iNKT cells and not any other kind of T cell.

  • The second genetic modification will remove specific molecules from the blood-forming stem cells, prompting the stem cells to create iNKT cells that won’t cause rejection when transplanted into a patient. This means the cells could come from any donor but still be universally compatible with any patient.

The genetically modified blood-forming stem cells will then be put into an artificial thymic organoid in collaboration with Gay Crooks, a professor of pathology and laboratory medicine and of pediatrics and co-director of the UCLA Broad Stem Cell Research Center, whose lab developed the organoid.

This organoid mimics the natural functions of the thymus, which turns blood-forming stem cells into immune cells within the body. After 8 weeks, the blood-forming stem cells will produce iNKT cells that will be multiplied in the lab, tested for safety and then frozen.

Using this method, Yang and the research team estimate that about 1,000 to 10,000 doses of iNKT cells can be produced from a single blood stem cell donor.

The team plans to test the effectiveness of the iNKT cells in preclinical animal models of various types of human cancer. If the method proves successful, the team hopes to take the concept to clinical trials in the future and ultimately create a lasting supply of iNKT cells that are readily available to treat a large population of cancer patients.


Takeda’s Alunbrig meets PFS primary endpoint

The global, randomized, phase III ALTA-1L trial met its primary endpoint at the first pre-specified interim analysis, with Alunbrig (brigatinib) demonstrating a statistically significant improvement in progression-free survival compared to crizotinib in adults with anaplastic lymphoma kinase-positive locally advanced or metastatic non-small cell lung cancer who had not received a prior ALK inhibitor.

Takeda Pharmaceutical Company Limited sponsors this drug.

The trial was designed to assess the efficacy and safety of ALUNBRIG in comparison to crizotinib based on evaluation of the primary endpoint of PFS, or length of time from the start of treatment that a patient lives without the disease getting worse. Alunbrig is currently not approved as frontline therapy.

The safety profile associated with Alunbrig from the ALTA-1L (ALK in Lung Cancer Trial of AP26113 in 1st Line) trial was generally consistent with the existing prescribing information, with no new safety concerns.

The results from this interim analysis will be submitted for presentation at an upcoming medical meeting.

The phase III ALTA-1L (ALK in Lung Cancer Trial of AP26113 in 1st Line) trial of Alunbrig in adults is a global, ongoing, randomized, open-label, comparative, multicenter trial, which enrolled 275 patients with ALK+ locally advanced or metastatic NSCLC who have not received prior treatment with an ALK inhibitor.

Patients received either Alunbrig, 180 mg once daily with seven-day lead-in at 90 mg once daily, or crizotinib, 250 mg twice daily. Independent Review Committee-assessed progression-free survival was the primary endpoint.

Secondary endpoints included objective response rate per RECIST v1.1, intracranial ORR, intracranial PFS, overall survival, safety and tolerability. A total of approximately 198 PFS events are planned at the final analysis of the primary endpoint in order to demonstrate a minimum of six months PFS improvement over crizotinib.

The trial is designed with two pre-specified interim analyses for the primary endpoint—one at 50 percent of planned PFS events and one at 75 percent of planned PFS events.

Alunbrig is a targeted cancer medicine discovered by Ariad Pharmaceuticals Inc., which was acquired by Takeda in February 2017. In April 2017, Alunbrig received Accelerated Approval from the FDA for ALK+ metastatic NSCLC patients who have progressed on or are intolerant to crizotinib.

This indication is approved under Accelerated Approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Alunbrig received Breakthrough Therapy Designation from the FDA for the treatment of patients with ALK+ NSCLC whose tumors are resistant to crizotinib and was granted Orphan Drug Designation by the FDA for the treatment of ALK+ NSCLC, ROS1+ and EGFR+ NSCLC.

A Marketing Authorization Application for Alunbrig was submitted to the European Medicines Agency in Feb 2017.

The brigatinib clinical development program further reinforces Takeda’s ongoing commitment to developing innovative therapies for people living with ALK+ NSCLC worldwide and the healthcare professionals who treat them.

The comprehensive program includes the following clinical trials:

  • Phase I/II trial, which was designed to evaluate the safety, tolerability, pharmacokinetics and preliminary anti-tumor activity of Alunbrig.

  • Pivotal phase II ALTA trial investigating the efficacy and safety of Alunbrig at two dosing regimens in patients with ALK+ locally advanced or metastatic NSCLC who had progressed on crizotinib

  • Phase IIII ALTA-1L trial assessing the efficacy and safety of Alunbrig in comparison to crizotinib in patients with ALK+ locally advanced or metastatic NSCLC who have not received prior treatment with an ALK inhibitor

  • Phase II single-arm, multicenter study in Japanese patients with ALK+ NSCLC, focusing on patients who have progressed on alectinib

  • Phase II global study evaluating Alunbrig in patients with advanced ALK+ NSCLC who have progressed on alectinib or ceritinib

Copyright (c) 2018 The Cancer Letter Inc.