First-in-Human Phase II Clinical Trial of Multiplex IntraTumoral Immunotherapy (MITI) in Patients with Metastatic...

Background/Objectives: Little is known about the synergy between intratumoral immunotherapy and cancer ablation. We conducted a Phase II Trial (Abscopal 5001 trial; NCT04713371) in patients with metastatic solid cancer to assess the safety and efficacy of cryoablation with concurrent injection of RPT-01-5001 (combination of low-dose checkpoint inhibitors and cyclophosphamide), a treatment process referred to as Multiplex Intratumoral Immunotherapy (MITI^TM). Methods: Twelve patients with metastatic cancer who had failed standard therapy and one with sacral chordoma received at least one intratumoral treatment of MITI preceded by 3-5 days of oral low-dose cyclophosphamide. MITI consisted of CT-guided cryoablation followed by intratumoral injection of RPT-01-5001. GM-CSF was subcutaneously administered daily for four weeks. Treatment was repeated every four weeks if the tumor burden remained stable or reduced, as noted by the iRECIST criteria. These criteria were modified when follow-up biopsies revealed pathology with minimal or no cancer, despite persistent suspicious masses on imaging. Results: Cancers included prostate (four patients), sarcoma (two), and one each of breast, colon, bladder, uterine cervix, tongue, kidney, and sacral chordoma. Eight patients received three cycles of treatment, two received two, and three received one. All patients tolerated the procedure well and were discharged within 2 h. The adverse event rate was 69%, all of which were grade 1 or 2, except for two grade 3 cases with delayed cryosurgical complications (15%). At completion of up to three cycles of treatment, a complete response (iCR) was observed in one patient (7.7%), partial response (iPR) in four patients (30.8%), and stable disease (iSD) in five (38.5%), with a disease control rate (iDCR) of 77%. Disparity between post-treatment imaging and pathologic findings was observed in four patients (positive vs. negative, respectively), requiring modification of the iRECIST criteria in favor of pathology. The best response ranged from 0 to 91%, with a mean for responding patients of 38%. Median progression-free survival (PFS) and 95% confidence intervals (95% CI) were 5.4 months (1.8 to 23.1 months); and median overall survival (OS) was 20.9 months (9.1 to 22.8 months). The injection site cancer response was observed in nine (69%) patients, and the distal abscopal effect was seen in four (31%), including one sarcoma patient with a complete abscopal response of lung metastases and one bladder cancer patient with biopsy-confirmed complete resolution of lung and liver metastases. Conclusions: MITI with RPT-01-5001 is safe and highly feasible, providing 77% disease control and 31% of the abscopal effect in patients with metastatic cancer who have failed standard therapies.