NRG Oncology CC003: A randomized phase II/III trial of prophylactic cranial irradiation with or without hippocampal avoidance for small cell lung cancer.

TPS8578 Background: Multiple clinical trials have shown that prophylactic cranial irradiation (PCI) prevents brain metastases and may prolong survival in small cell lung cancer (SCLC). However,prophylactic cranial irradiation can lead to decline in cognitive function. Preclinical evidence suggests that the pathogenesis of this toxicity includes inflammatory injury to proliferating neuronal progenitor cells in the peri-hippocampal stem cell niches. We hypothesized that conformal avoidance of the hippocampal neural stem cell compartment during brain irradiation using intensity-modulated radiotherapy (IMRT) would decrease the likelihood and/or severity of this toxicity. This hypothesis was recently validated by positive results from NRG Oncology CC001, a phase III trial of hippocampal avoidance during whole-brain radiotherapy for patients with brain metastases. NRG Oncology CC003 is an ongoing randomized phase II/III trial of hippocampal avoidance during prophylactic cranial irradiation (HA-PCI) for small cell lung cancer, conducted in parallel with NRG Oncology CC001. Methods: The primary endpoints of the phase IIR and III components are 12-month intracranial relapse rate and 6-month deterioration in Hopkins Verbal Learning Test-Revised (HVLT-R) Delayed Recall, respectively. This is a seamless phase IIR/III trial, with the phase IIR designed to demonstrate non-inferiority. If the non-inferiority margin of the phase IIR component is not exceeded, then the trial would transition to the phase III component. Following accrual of 182 of planned 172 patients on the phase IIR component, the trial closed to accrual on 10/13/17 to assess the phase IIR primary endpoint. The DSMB evaluated the IIR outcomes, and on 1/9/19, the trial was reactivated to accrue an additional 122 patients to the phase III component. Eligibility criteria include: 1) small cell lung cancer with at least partial response to chemotherapy; 2) contrast-enhanced thin-slice volumetric MRI scan; and, 3) Zubrod performance status 0-2. Supported by grant UG1CA189867 (NCORP) from the National Cancer Institute. Clinical trial information: NCT02635009.