Phase II study of 2-methoxyestradiol NanoCrystal dispersion (2ME2) alone and in combination with sunitinib (SU) in patients with metastatic renal cell carcinoma (mRCC) progressing on SU

Abstract

e16116 Background: Panzem NCD (2ME2) is a non-estrogenic derivative of estradiol with antiproliferative and antiangiogenic activity that downregulates HIF-1α. One mechanism of VEGFR TKI failure may be upregulation of HIF-1α. We hypothesized that 2ME2 may have single-agent activity in pts who previously progressed on SU and that addition of 2ME2 may restore response in pts progressing on SU. Methods: Pts with clear cell mRCC who had previously received or were currently receiving SU with disease progression were eligible. Pts who had previously received SU were treated with 2ME2 alone (arm A). Pts currently on SU continued on the 4:2 schedule, with the addition of 2ME2 (arm B). All pts received 2ME2 at 1,500 mg PO TID, repeated in 6 wk cycles. The primary endpoint was objective response (OR) rate by RECIST. An exploratory endpoint was metabolic response on FDG-PET. Simon optimal 2-stage design was used with plans to enroll 21 pts/arm, and if activity was seen to continue enrollment for a total of 41 pts/arm. Results: 17 pts were enrolled (A: 10; B: 7). Median number of cycles on study was 1 (range <1 to 5). A pt remains on study in cycle 8. Adverse events (AE) of grade 3 or greater occurred in 4 pts (29%). Most frequent AE were: fatigue (71%), diarrhea (50%), dysgeusia (29%), anemia or decreased hemoglobin (29%), and anorexia (21%). Reasons for treatment discontinuation include: disease progression (7), pt/doctor discretion (3), AE (3), and noncompliance (1). No ORs by RECIST were seen. Conclusions: 2ME2 appears to have some single-agent activity, with an MR in a pt removed from study due to AE and a metabolic PR (ΔSUVmax -84%) in a pt with SD by RECIST. With 6/17 pts discontinuing therapy before meeting any OR endpoint, 2ME2 was not tolerable in this population. The study was closed to accrual knowing that a more promising 2ME2 analog is currently under development for oncologic use. The rationale to target HIF-1α after (and during) SU therapy remains of interest. This study design provides a unique way to assess both single-agent and rational combination strategies in pts with mRCC and should be utilized with other agents to seek evidence for clinical activity. [Table: see text]