On August 15, 2018 Adaptimmune Therapeutics plc (Nasdaq:ADAP), a leader in T-cell therapy to treat cancer, reported a favorable review of safety data from the second dose cohort of patients who received one billion transduced SPEAR T‑cells targeting MAGE-A4 in the ongoing basket study in nine solid tumor indications (Press release, Adaptimmune, AUG 15, 2018, View Source;p=RssLanding&cat=news&id=2363723 [SID1234528864]). Based on these data, the Safety Review Committee (SRC) has endorsed dose escalation to the third dose cohort of 1.2 to 6 billion cells.
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To date, three patients have received 100 million transduced MAGE‑A4 SPEAR T-cells in the first dose cohort, and three patients received one billion cells in the second cohort. No evidence of toxicity related to off-target binding or alloreactivity has been reported. Most adverse events were consistent with those typically experienced by cancer patients undergoing cytotoxic chemotherapy or other cancer immunotherapies.
"In Cohorts 1 and 2, we have observed cell expansion consistent with the doses administered. We are initiating dosing with 1.2 to 6 billion cells in the MAGE-A10 and MAGE-A4 studies. We have a number of patients whose cell products have been manufactured and these cells can be used when patients are ready for therapy. We remain on track to deliver initial data on response assessments from these cohorts during the second half of 2018," said Rafael Amado, Adaptimmune’s President of Research & Development.
Overview of Study Design MAGE-A4 Pilot Study
This is a first-in-human, open-label study utilizing a modified 3+3 design in up to 36 patients with escalating doses of 100 million (Cohort 1), 1 billion (Cohort 2), and 1.2‑6 billion (Cohort 3) transduced SPEAR T-cells to evaluate safety, including dose limiting toxicities (DLTs) followed by a possible expansion phase with doses of up to 10 billion SPEAR T-cells
This active trial is being evaluated across nine solid tumor indications including urothelial, melanoma, head and neck, ovarian, NSCLC, esophageal, and gastric cancers; as well as synovial sarcoma and myxoid/round cell liposarcoma (MRCLS)
Patients are screened under a separate protocol (Screening Protocol: NCT02636855) to identify those who have the relevant HLA-A*02 alleles and MAGE-A4 tumor expression
There was a 21-day stagger between patients in Cohort 1, with this stagger dropping to 7 days in Cohorts 2, and 3. There is no pre-determined stagger in the potential expansion phase
Cohorts 1-3 were intended to enroll 3 patients each with an expansion to 6 patients if DLTs were observed
The expansion phase can enroll up to 30 patients
The lymphodepletion regimen are:
Cohorts 1 and 2 – fludarabine (flu) (30mg/m2/day) and cyclophosphamide (cy) (600 mg/m2/day) for 3 days
Cohorts 3 and expansion phase – flu (30mg/m2/day) for 4 days and cy (600 mg/m2/day) for 3 days
Efficacy is assessed by overall response rate, time to response, duration of response, progression-free survival, and overall survival at weeks 4, 8, and 12, month 6, and then every 3 months until confirmation of disease progression
Adaptimmune’s Pipeline
Adaptimmune’s proprietary technology enables the Company to consistently generate affinity enhanced T-cell receptors (TCRs) that address intracellular targets on solid tumors that may not be accessible to certain other immunotherapy treatment modalities. Adaptimmune has three wholly owned SPEAR T‑cells in active clinical trials, with additional first and next generation SPEAR T‑cells being evaluated by means of Adaptimmune’s proprietary preclinical testing platform in advance of proceeding to the clinic.
Adaptimmune’s wholly owned SPEAR T-cells targeting MAGE‑A10, MAGE‑A4, and AFP are being evaluated in four active clinical trials across ten solid tumor indications:
MAGE-A10: Two active trials, one in NSCLC, and a triple tumor study in urothelial (bladder), melanoma, and head & neck cancers
MAGE-A4: One active trial across nine solid tumor indications including urothelial, melanoma, head and neck, ovarian, NSCLC, esophageal, and gastric cancers; as well as synovial sarcoma and myxoid/round cell liposarcoma (MRCLS)
AFP: One active study in hepatocellular (liver) cancer
Patients are receiving doses of 1.2-6 billion SPEAR T-cells across all the MAGE-A4 and MAGE‑A10 trials as there has been no evidence of off-target toxicity, to date, which has supported dose escalation