Pharmacodynamic phase I study using FLT PET/CT in advanced solid malignancies treated with a sequential combination of X-82 and docetaxel.

Abstract

e14088 Background: Increased tumor proliferation has been observed during withdrawal of anti-angiogenic therapy, known as withdrawal flare, which has been demonstrated using [18-F] fluorothymidine [FLT] PET/CT . Sequencing chemotherapy may increase therapeutic window by better synchronizing treatment with tumor proliferation during the flare. This study utilizes FLT PET/CT to assess X-82, a novel VEGFR TKI, used in sequence with docetaxel. Methods: Pts with at least 1 lesion evaluable with FLT PET/CT underwent 21-day treatment cycles with X-82 daily on days 2-15. Starting in cycle 2 (C2), docetaxel was given on day 1 of each cycle. FLT PET/CTs were obtained on days 1 and 15 in cycles 1 and 2. Tumors were identified by a nuclear medicine physician and manually segmented. The maximum tumor FLT uptake SUVmax and the total tumor FLT uptake SUVtotal were extracted for each tumor. To quantify changes in tumor FLT uptake, SUVs were log transformed and included in mixed effects models with random effects accounting for intrapatient correlation of tumor responses. Results: 14 pts were treated with median 3.5 cycles (range 0-12). 4 pts with 13 metastatic tumors completed all PET scans and were included in the pharmacodynamic assessment. 1 pt had an unconfirmed PR and 7 pts had stable disease per RECIST 1.1. The mean percent (%) change in tumor SUV during C1 (X-82 monotherapy) was -13% for SUVmax (P = 0.04) and -17% for SUVtotal (P = 0.14). The mean % change in tumor SUV during C2 (X-82 + docetaxel) was -44% for SUVmax (P = 0.03) and -59% for SUVtotal (P < 0.01). There was a significantly greater decrease in SUV in C2 than in C1 for both SUVmax (P = 0.03) and SUVtotal(P = 0.02). Ten grade 3 AEs possibly related to X-82 were noted in 6 pts, including infections, cytopenias, and vascular complications. Conclusions: Diminished tumor proliferation was observed during X-82 treatment, indicating successful targeting of VEGFRs. Sequential combination of X-82 plus docetaxel showed greater decreases in tumor proliferation compared to X-82 monotherapy indicating value in sequencing chemotherapy during VEGFR TKI treatment breaks. There is evidence that combination therapy is both safe and effective. Clinical trial information: NCT 02146222.