RMB (RENCA Macrobead) therapy in advanced mCRC: Phase IIb preliminary multi-site survival findings; correlation &amp; combination with Phase I and IIa data including imaging and lab profiles [U.S.FDA BB-IND 10091]
Authors: A. Nazarian, Z. Andrada, J. Thomas, S. Sureshbabu, N. Berman, D. Wolf, L. Gazda, T. Fahey, A. Ocean, B. Smith
Journal: Annals of Oncology (2018)

Introduction: Because cancer can be considered as a complex, biological-systems disease, we have explored a cell-based systems therapeutic approach based on this concept. We report ongoing human experience using mouse renal adenocarcinoma cells (RENCA) entrapped in agarose macrobeads (RMB) for late-stage mCRC therapy (Chin J Cancer Res 2018;30(1):72-83). Such cells undergo genomic changes that release multiple anti-neoplastic factors (> ten). One or more achieve 40% of their tumor-cell inhibitory effect via MEF-2 regulation. (Cancer Res. 2011;71(3): 716–724;725–735). Other pathways are currently under study with Lund University. Phase I and IIa RMB trials provided evidence of survival and quality of life benefit in treatment-resistant, late-stage mCRC patients (Cancer Growth Metastasis.2016;9:9–20). Here, we report the combined findings of the P I/IIa, along with new preliminary survival and other-benefit findings from a PIIb multi-site trial. Methods: Eighty-nine mCRC patients who failed all available cancer treatments underwent laparoscopic intraperitoneal implantation of RMBs up to 4 times in these open-label PI/IIa/IIb trials. The PIIb multi-site trial (40 patients), closed for enrollment, currently includes four in LTFU and one patient undergoing a fourth implantation. OS was the primary endpoint, with serial physical examinations, lab profiles and PET-CT imaging performed pre- and three months post-implantation to further evaluate safety/efficacy in all three trials. Survival was measured from time of study entry until death. The P I/IIA trials differed from IIb in that none of their patients had been treated with regorafenib or trifluridine/tipiracil. Results: Mean survival for 84/89 patients (all three trials) was 41 weeks [median survival=33 weeks; SD +/-37.5 wks]. For all patients in Phase IIb only (n = 36/41), preliminary analysis indicates mean survival of 34 weeks [median, 29.5 wks; SD +/-24 wks]. For patients who received regorafenib and/or trifluridine/tipiracil prior to RMBs in this trial (n = 12/13), mean survival was 26.5 weeks [median survival=21wks; SD+/-23 wks]. For the patients not receiving either (n = 23/36), mean survival was 37wks [median survival=35wks; SD+/-25 wks]. In all three trials, the ancillary testing described in Methods indicated that there were responders (R), as well as non-responders (NR) to the RMB. For the combined PI/IIa data, two groups of patients: R (n = 25) and NR (n = 9) were defined by their LDH values at days 30 and 60 after first implantation (D30, mean R value 305.92+/-284.76 vs. NR, 649.33+/- 363.60; p < 0.0070), D60 (R, 333.88+/-445.89 vs. NR, 1278.50+/- 761.9; p < 0.0001). These correlated with CEA and/or CA19-9 decreases (≥20%), and with the PET-CT SUVmax findings. Eighty-four FDG-positive mCRC lesions were detected in 26/34 patients at D90. Of the 25 LDH responders, 14 showed stable or decreased SUVmax values; seven an increase (4 non-evaluable) (doi:10.3252/pso.eu.19wcgic.2017). Parallel data from PIIb will be presented at WCGIC 2018. Conclusion: Taken together, the PI/IIa/IIb trial data are encouraging in indicating improved survival of late-stage mCRC patients with RMB treatment. The laboratory data (LDH levels, CEA and CA19-9) decreases, as well as PET-CT imaging (decreased SUVmax) support this. The data to date merit development of a Phase III randomized trial of RMB vs. standard therapy to further assess the effectiveness of the RMB in late-stage mCRC.