Clinical Trials

Date: 2018-01-08

Type of information: Interim results

phase: 1-2

Announcement: interim results

Company: Adaptimmune (UK)

Product: MAGE A10c796T - autologous genetically modified T-cells expressing enhanced T cell receptors (TCRs) specific for MAGE A10

Action mechanism:

•  cell therapy/immunotherapy product. MAGE-A10 (melanoma antigen family A10) is a member of the MAGE-A family of cancer/testis tumor associated antigens. It is believed to be expressed in approximately 30 percent of lung (squamous cell carcinoma), bladder and skin melanomas, and at a lower incidence in many other cancers.
• Adaptimmune’s proprietary technology enables the Company to genetically optimize T-cell receptors (TCR) in an effort to equip them to recognize and bind cancer antigens that are presented in small quantities on the surface of a cancer cell, whether of intracellular or extracellular origin, thus initiating cell death. The company’s differentiated, proprietary technology allows it to reliably generate parental TCRs to naturally presented targets, affinity optimize its TCRs to bind cancer proteins from solid and hematologic cancers that are generally unavailable to naturally occurring TCRs, and to significantly reduce the risk of side effects resulting from off-target binding of healthy tissues.

Disease: locally advanced or metastatic (Stage IIIb or IV) non-small cell lung cancer (NSCLC)

Therapeutic area: Cancer - Oncology

Country: USA

Trial details:

• This phase 1-2 dose escalation open label clinical trial is evaluating the safety and the efficacy of  MAGE A10^c796T  in Subjects With Stage IIIb or Stage IV Non-Small Cell Lung Cancer (NSCLC). This first time in human study is intended for men and women at least 18 years of age who have advanced lung cancer which has grown or returned after being treated. In particular, it is a study for subjects who have a blood test positive for HLA-A*0201 and/or HLA-A*0206 protein and a tumor test positive for MAGE A10 expression (protein or gene). The study will take the subject's T cells, which are a natural type of immune cell in the blood, and send them to a laboratory to be modified. The changed T cells used in this study will be the subject's own T cells that have been genetically changed with the aim of attacking and destroying cancer cells. The manufacturing of T cells takes about 1 month to complete. The T cells will be given back to the subject through an intravenous infusion. The purpose of this study is to test the safety of genetically changed T cells and find out what effects, if any, they have in subjects with lung cancer. The study will evaluate three different cell dose levels in order to find out the target cell dose. Once the target cell dose is determined, additional subjects will be enrolled to further test the safety and effects at this cell dose. Subjects will be seen frequently by the Study Physician right after receiving their T cells back. Subjects will then be entered into a long-term follow up in order to monitor the subject. Subjects will be seen every 6 months by their Study Physician for the first 5 years after the T cell infusion. If the T cells are found in the blood at five years, then the subjects will continue to be seen once a year until the T cells are no longer found in the blood for a maximum of 15 years. If the T cells are no longer found in the blood at 5 years, then the subject will be contacted by the Study Physician for the next 10 years. (NCT02592577)
• There are two ongoing clinical trials with SPEAR T-cells targeting MAGE-A10; one in non-small cell lung cancer (NSCLC), and a triple tumor study in bladder, melanoma, and head & neck cancers. Both studies are dose escalation trials that evaluate three doses of transduced SPEAR T-cells, administered after a lymphodepleting chemotherapy regimen. The three doses being evaluated are 100 million, 1 billion and 1 to 5 billion transduced SPEAR T-cells.
• NSCLC study: In this study, five patients have received SPEAR T-cells in the first group of Cohort 1 (1a without fludarabine) 2, and there was one report of Grade 4 CRS that resolved with treatment.
• Triple Tumor Study: Three patients have been dosed in the first cohort. There were no reports of CRS greater or equal to Grade 3, and all cases resolved with supportive treatment.

Latest news:

• • On January 8, 2018, Adaptimmune Therapeutics announced initial safety data from its two ongoing pilot studies of SPEAR T-cells targeting MAGE-A10, one in non-small cell lung cancer (NSCLC) and a triple tumor study in bladder, melanoma, and head & neck cancers.
• To date, 8 patients have each received 100 million transduced MAGE?A10 SPEAR T-cells in the first dose cohorts of both studies. No evidence of toxicity related to off-target binding or alloreactivity has been observed. There have been no reports of neurotoxicity safety events similar to CAR?T cell-related encephalopathy syndrome (CRES). In the NSCLC study, there has been one serious adverse event of cytokine release syndrome (CRS), a Grade 4 event that resolved with treatment. This event led to cohort 1 expansion from 3 to 6 patients. No dose limiting toxicities were observed in cohort 1 of the triple tumor study.
• Following review by the independent safety review committee (SRC), the decision has been made to escalate to the next dose of 1 billion transduced MAGE-A10 SPEAR T-cells in the triple tumor study. This was the therapeutic threshold dose observed with SPEAR T?cells targeting NY-ESO in the synovial sarcoma pilot study. The decision to escalate in the NSCLC cohort will be reviewed by the SRC following dosing of the 6th patient.
• • On June 5, 2017, Adaptimmune announced a poster presentation on updated data from  the open-label study of  MAGE A-10 SPEAR T-cells in patients with non-small cell lung cancer at the American Society of Clinical Oncology (ASCO) Annual Meeting.  The MAGE-A10 trial is a first-in-human study utilizing a modified 3+3 design in up to 28 patients with escalating doses of 0.1, 1.0 and 1-6 x10⁹ transduced T-cells to evaluate safety, including dose limiting toxicities (DLTs). The DLT observation period will be during the first 30 days following SPEAR T-cell infusion for each patient in all groups. Subjects are screened under a separate protocol (Screening Protocol: NCT02636855) to identify those who have the relevant HLA-A*02 alleles and MAGE-A10 tumor expression. Subjects must have Stage IIIb or IV NSCLC, have failed at least one platinum-containing regimen (may have received CPIs), have measurable disease, ECOG 0-1, adequate organ function, and be without brain metastases, history of severe autoimmune disease or current uncontrolled illness. The lymphodepletion regimen for the first group is cyclophosphamide alone : cyclophosphamide (1800 mg/m2/day) for 2 days; subsequent groups will receive fludarabine (30mg/m2/day) and cyclophosphamide (600 mg/m2/day) for 3 days. Efficacy assessed by response rate, duration of response, progression-free survival, and overall survival at weeks 4, 8, and 12, month 6, and then every 3 months (for 2 years) and then every 6 months until confirmation of disease progression. The study is currently active and enrolling; as of May 18, 2017, 2 subjects have been enrolled in the MAGE-A10 study.
• • On December 17, 2015, Adaptimmune  announced that it has initiated a Phase I/II study of its affinity enhanced T-cell therapy targeting the MAGE-A10 cancer antigen in patients with locally advanced or metastatic (Stage IIIb or IV) non-small cell lung cancer (NSCLC), the most prevalent type of lung cancer representing approximately 85 percent of lung cancers. This will be the first study of Adaptimmune’s unpartnered affinity enhanced T-cell therapy targeting MAGE-A10, a highly immunogenic member of the MAGE-A family of cancer testis antigens. MAGE-A10 is expressed in a number of solid tumor cell types, and the immunogenicity of the MAGE-A10 antigen has been robustly established. Cancer testis antigen expression in cancer is often associated with higher grade tumors.This is an open label, 3+3 dose escalation study of autologous T-cells genetically engineered with an affinity optimized MAGE-A10 TCR in HLAA*0201 and HLA-A*0206 positive patients with stage IIIb or stage IV NSCLC expressing the MAGE-A10 antigen. Though the prevalence of HLA sub-types varies from population to population, the most common in the western world is HLA-A2. Among the HLA-A2 variants, the most prevalent are HLA-A*0201 and HLA-A*0206. The study is intended to enroll up to 32 patients in leading clinical centers located in the United States and Europe and will assess the safety and tolerability of Adaptimmune’s affinity enhanced T-cell therapy targeting MAGE-A10. Secondary objectives will include the assessment of clinical efficacy, measurements of durability of persistence of MAGE-A10 T-cells in the blood, and exploratory tumor biomarker studies and evaluations of the phenotype and functionality of MAGE-A10 T-cells.
• • On July 2, 2015, Adaptimmune Therapeutics announced that the FDA has accepted the Company’s investigational new drug (IND) application for autologous genetically modified T-cells expressing enhanced T cell receptors (TCRs) specific for MAGE A10 (MAGE-A10 T) in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC), and that the IND is now active. The acceptance of this IND allows Adaptimmune to initiate an open label Phase I/II study designed to evaluate its wholly-owned MAGE-A10 T therapeutic candidate in NSCLC. Site initiation activities are now underway, and the Company anticipates that enrollment will begin in 2015. The trial will be an open label phase I/II dose escalating study of three doses of genetically engineered MAGEA10 T-cells in HLAA*0201 and HLA-A*02:06 patients with advanced (stage IIIB or stage IV) NSCLC whose tumors express this antigen.

Is general: Yes