Safety
encephalopathy, early-onset, ischemic cerebrovascular accident, Toxicities, tremor, cytopenias, skin rashes, NSCLC, ovarian cancer, TEAEsDuration/dose, myelodysplastic syndrome, neurotoxicity, DLTs, Skin rashes, mg/mEighteen deaths, cytopenia, aplastic anemia, headache, deaths
DISEASE PROGRESSION, OVARIAN CANCER, BRAIN METASTASIS, MYELODYSPLASTIC SYNDROME, CYTOPENIAS, CYTOMEGALOVIRUS INFECTION, CYTOKINE RELEASE SYNDROME, ENCEPHALOPATHY, CEREBROVASCULAR ACCIDENT, CYTOPENIA, APLASTIC ANEMIA, NSCLC, IMMUNE EFFECTOR CELL-ASSOCIATED NEUROTOXICITY SYNDROME, EVENTS
Toxicities determined by the Safety Review Committee as DLTs occurred in six patients and included cytopenias (four), aplastic anemia (one) and cerebrovascular accident (one); all DLTs occurred in the expansion group (median dose, 7.85 × 10Incidence of TEAEsDuration/dose increases of the fludarabine and cyclophosphamide components of LD chemotherapy were made per the absence of DLTs. An additional day of fludarabine 30 mg/mEighteen deaths were reported due to disease progression (14), AEs (three, two possibly treatment-related AEs) or comorbidities (one). Both treatment-related deaths were among the seven patients in the expansion group who received the highest LD dose regimen. The first was a 77-year-old patient with SS, heavily pre-treated with chemotherapy, who died of aplastic anemia on day 55 of the study. Grade 3 cytopenia developed in this patient from day −5 (LD chemotherapy day 3) and worsened after afami-cel infusion. Bone marrow biopsy on day 38 did not detect myelodysplastic syndrome, cytomegalovirus infection, enrichment of transduced T cells or MAGE-A4 antigen. The second was a 71-year-old patient with ovarian cancer who died of an ischemic cerebrovascular accident on day 17 after a Grade 3 neurotoxicity. Because of these two treatment-related fatalities, the maximum age at screening was reduced to 75 years, and the high-dose cyclophosphamide LD regimen was discontinued. The subsequent 22 patients in the expansion group reverted to the lower cyclophosphamide regimen.Twenty-one patients (55%) had cytokine release syndrome (CRS)—ten (58%) Grade 1, nine (24%) Grade 2, one (3%) Grade 3 and one (3%) Grade 4; all events resolved (Supplementary Table Two patients (5%) had treatment-emergent, low-grade, early-onset, immune effector cell-associated neurotoxicity syndrome (ICANS)/encephalopathy, which was reversible and lasted 3 days or less: Grade 1 ICANS on day 3 in a patient with NSCLC with known brain metastasis and Grade 2 encephalopathy on day 8 in a patient with ovarian cancer without baseline brain metastasis. Six additional patients had other possible treatment-related neurological AEs, including tremor or headache. Nine expansion group patients had skin rashes possibly related to afami-cel, including three with Grade 3 severity. Skin rashes were typically reversible with supportive care and/or topical corticosteroids. Two patients with SS received a second afami-cel infusion after progressing from partial responses (PRs) achieved with the first afami-cel treatment. No new clinically important TEAEs developed after administration of a second round of LD chemotherapy followed by a second afami-cel infusion compared with their first LD chemotherapy/afami-cel infusion schedules (Supplementary Table 