Two phase 2A clinical trials to evaluate the safety and efficacy of IMSA101 in combination with radiotherapy and checkpoint inhibitors in oligometastatic and oligoprogressive solid tumor malignancies.

TPS2685 Background: The innate immune system plays a pivotal role in detecting cancer-induced DNA damage and signaling the adaptive immune system to initiate tumor-targeted immune response. However, many cancer cells develop mechanisms to evade immunosurveillance. IMSA101 augments tumor detection and killing via the cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS)-stimulator of interferon genes (STING) pathway. Pre-clinical data suggests that IMSA101, combined with DNA-damage inducing personalized ultra-fractionated stereotactic adaptive radiation (PULSAR) therapy and PD-1-targeted immunotherapy (IO), can synergistically optimize anti-cancer response. A recently concluded phase 1 clinical trial demonstrated the safety and efficacy of IMSA101 administered both as monotherapy and in combination with IO. Methods: IMSA101-102 and IMSA101-103 are phase 2 randomized clinical trials, partially funded by a State of Texas, Cancer Prevention and Research Institute of Texas (CPRIT) grant, comparing the safety and efficacy of a PULSAR-IO doublet administered with or without IMSA101 in patients (pts.) with oligometastatic non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC)(102 study) and oligoprogressive solid tumor malignancies (103 study, see Figure 2). Both ongoing studies are being run at U.S. cancer centers and commence with an ascending dose level, safety lead-in component in which pts. receive PULSAR-IO + IMSA101 administered at either 800mcg or 1200mcg. Upon completion of the safety lead-in period, approximately 34 and 39 pts. respectively will be randomized to receive either the experimental triplet or the PULSAR-IO control arm. In both studies, the experimental treatment regimen will consist of 3 doses of PULSAR spaced 1 month apart, either Nivolumab or Pembrolizumab IO therapy per FDA product label and 5 intra-tumoral injections of IMSA101 over a 60-day period. All pts. will be assessed for RECIST-based anti-tumor efficacy at screening, prior to the end of cycle 3 and at 8-week intervals thereafter. A FACT-G quality-of-life assessment will additionally be performed for all evaluable pts. OMD Study: 40 OMD NSCLC and RCC patients, randomized 1:1 to control arm vs. experimental arm (control: PULSAR + PD-1 Ab, experimental arm: PULSAR + PD-1 Ab + IMSA 101). Primary endpoint: Progression-free rate at 18 months. OPD Study: 45 OPD solid tumor patients, randomized 1:2 to control arm vs. experimental arm (control: PULSAR + PD1 Ab, experimental arm: PULSAr + PD-1 Ab + IMSA 101). Primary endpoint: Progression-free rate at 12 months. Clinical trial information: NCT05846646 and NCT05846659 .