Carolyn Sidor

A Phase II Multicenter, Randomized, Double-Blind, Safety Trial Assessing the Pharmacokinetics, Pharmacodynamics, and Efficacy of Oral 2-Methoxyestradiol Capsules in Hormone-Refractory Prostate Cancer

Purpose: To determine whether the preclinical antitumor and antiangiogenic activity of 2-methoxyestradiol can be translated to the clinic. Experimental Design: Men with hormone-refractory prostate cancer were enrolled into this phase II randomized, double-blind trial of two doses of oral 2-methoxyestradiol capsules (400 and 1,200 mg/d) given in 4-week cycles. Pharmacokinetic sampling was done on day 1 of cycles 1 and 2 and trough samples were obtained weekly. Results: Thirty-three men were accrued between February and September 2001. The notable toxicity related to therapy was one grade 2 and two grade 3 episodes of liver transaminase elevation, which resolved with continued treatment in two patients. There were two cases of deep venous thromboses. The drug had nonlinear pharmacokinetic, rapid conversion to 2-methoxyestrone and ∼85% conjugation. Trough plasma levels of unconjugated 2-methoxyestradiol and 2-methoxyestrone were ∼4 and 40 ng/mL, respectively. Prostate-specific antigen declines between 21% and 40% were seen in seven patients in the 1,200 mg group and in one patient in the 400 mg group. The higher-dose group showed significantly decreased prostate-specific antigen velocity (P = 0.037) and compared with the 400 mg dose had a longer median time to prostate-specific antigen progression (109 versus 67 days; P = 0.094) and time on study (126 versus 61 days; P = 0.024). There was a 2.5- and 4-fold increase in sex hormone-binding globulin for the 400 and 1,200 mg dose levels, respectively, at days 28 and 56. Conclusion: 2-Methoxyestradiol is well tolerated and, despite suboptimal plasma levels and limited oral bioavailability with this capsule formulation, still showed some anticancer activity at 1,200 mg/d.

Novel therapy with 2-methoxyestradiol for the treatment of relapsed and plateau phase multiple myeloma.

Purpose: 2-Methoxyestradiol (2ME2) is an endogenous product of estradiol metabolism with antiangiogenic and antineoplastic properties. We report on the first phase II trial of 2ME2 in multiple myeloma. Experimental Design: 2ME2 was administered orally at a dose of 1,000 mg daily. Sixty patients (31 men and 29 women) were treated. After 39 patients were accrued, the dose was increased to 800 mg twice daily for the remaining patients. Results: Thirty-one patients had relapsed or refractory multiple myeloma, and 29 had plateau phase multiple myeloma. Median age was 60 years (range, 27-84 years). Therapy was well tolerated. Common adverse events included anemia (35%), fatigue (35%), nausea (25%), diarrhea (20%), hot flushes (20%), headache (17%), muscle cramps (15%), and upper respiratory tract infection (15%). Most adverse events were mild (grade 1-2); 12% experienced grade 3-4 adverse events. Median time to progression was 3.8 months, with 5.6 months for plateau phase disease and 2.3 months for relapsed multiple myeloma. Estimated progression-free survival rates for all patients at 1, 2, and 3 years were 24%, 17%, and 11%, respectively. Three patients, all with plateau phase disease, have been on study for over 4 years without progression at 50, 60, and 63 months, respectively. Minor response was noted in 2 patients. Conclusions: Although no partial responses have been seen thus far, the minor responses and prolonged stable disease seen with 2ME2 therapy are promising. Plasma levels indicate that the dose of 2ME2 was inadequate. A new formulation with better bioavailability will be tested soon in multiple myeloma.

Phase I Safety, Pharmacokinetic, and Pharmacodynamic Study of ENMD-2076, a Novel Angiogenic and Aurora Kinase Inhibitor, in Patients with Advanced Solid Tumors

Purpose: ENMD-2076 is a unique orally bioavailable Aurora kinase and VEGFR inhibitor. The purpose of this phase 1 study of ENMD-2076 was to determine the MTD, pharmacokinetic, and pharmacodynamic profiles and preliminary antitumor activity. Experimental Design: Patients with refractory advanced solid malignancies were treated with ENMD-2076 orally with continuous once daily dosing. Doses from 60 to 200 mg/m2 were evaluated using a standard 3 (to 4) + 3 design. Pharmacokinetic parameters were studied on days 1, 28, and 30 to 35 of cycle 1. Expanded MTD cohorts included patients with ovarian cancer, colorectal cancer, and refractory solid tumors. Results: A total of 67 patients (46 F, 21M; ages 30–76) entered the study. Dose levels of 60, 80, 120, 200, and 160 mg/m2 were evaluated. Two patients experienced grade 3 hypertension at 200 mg/m2, and additional grade 3 neutropenia events limited tolerability at this dose. An intermediate dose of 160 mg/m2 was determined to be the MTD. The most common drug-related adverse events included hypertension, nausea/vomiting, and fatigue. The pharmacokinetics of ENMD-2076 were characterized by a rapid absorption phase (Tmax 3–7.8 hours), a t1/2 of 27.3 to 38.3 hours after a single dose, and dose proportional exposure. Decreased plasma sVEGFR2 was observed posttreatment. Two patients with platinum refractory/resistant ovarian cancer had RECIST partial responses. Conclusions: ENMD-2076 was well tolerated, had a linear pharmacokinetic profile, and showed promising antitumor activity, particularly in ovarian cancer. The recommended phase 2 dose of ENMD-2076 is 160 mg/m2 administered orally once daily with continuous dosing. Clin Cancer Res; 17(4); 849–60. ©2010 AACR.

ENMD-2076, an oral inhibitor of angiogenic and proliferation kinases, has activity in recurrent, platinum resistant ovarian cancer

PURPOSE The purpose was to assess the activity and side effect profile of ENMD-2076, an oral anti-angiogenic and anti-proliferative kinase inhibitor, in platinum-resistant recurrent epithelial ovarian cancer (EOC), fallopian tube or peritoneal cancer. Archival tumour tissue was obtained for correlative analyses. EXPERIMENTAL DESIGN This was an open-label single-arm Phase II study of single agent ENMD-2076 taken daily orally (PO). The primary objective was to determine the progression free survival (PFS) rate at 6 months of ENMD-2076 in platinum-resistant cancer based on RECIST v1.1. Secondary objectives included response rate (RR), duration of response, overall survival (OS) and safety. An exploratory analysis of archival tissue for mitotic index and angiogenesis was conducted in an attempt to identify a sensitive or resistant patient phenotype. RESULTS 64 patients were enrolled, and the PFS rate at 6 months was 22% with a median time to progression of 3.6 months. The median number of prior regimens was 2. The most common adverse events were fatigue, hypertension and diarrhoea with the most common Grade 3/4 events being hypertension and fatigue. None of the markers of mitotic index or angiogenesis evaluated in the archival tissue samples were predictive of greater benefit or resistance to ENMD-2076 treatment. CONCLUSIONS ENMD-2076 has activity in platinum-resistant ovarian cancer, and observed toxicities were similar to other PO kinase inhibitors. Additional studies with ENMD-2076 are warranted, especially in combination with active chemotherapeutic agents in platinum-resistant patients. Further work to determine appropriate biomarkers for ENMD-2076 should be incorporated into new clinical studies.

Preclinical activity of a novel multiple tyrosine kinase and aurora kinase inhibitor, ENMD-2076, against multiple myeloma.

ENMD‐2076 is a novel, orally‐active molecule that has been shown to have significant activity against aurora and multiple receptor tyrosine kinases. We investigated the activity of ENMD‐2076 against multiple myeloma (MM) cells in vitro and in vivo. ENMD‐2076 showed significant cytotoxicity against MM cell lines and primary cells, with minimal cytotoxicity to haematopoietic progenitors. ENMD‐2076 inhibited the phosphoinositide 3‐kinase/AKT pathway and downregulated survivin and X‐linked inhibitor of apoptosis as early as 6 h after treatment. With longer treatment (24–48 h), ENMD‐2076 also inhibited aurora A and B kinases, and induced G2/M cell cycle arrest. In non‐obese diabetic/severe combined immunodeficient mice implanted with H929 human plasmacytoma xenografts, oral treatment with ENMD‐2076 (50, 100, 200 mg/kg per day) resulted in a dose‐dependent inhibition of tumour growth. Immunohistochemical staining of excised tumours showed significant reduction in phospho‐Histone 3 (pH3), Ki‐67, and angiogenesis, and also a significant increase in cleaved caspase‐3 at all dose levels compared to tumours from vehicle‐treated mice. In addition, a significant reduction in p‐FGFR3 was observed on Western blot. ENMD‐2076 shows significant activity against MM cells in vitro and in vivo, and acts on several pathways important for myeloma cell growth and survival. These results provide preclinical rationale for clinical investigation of ENMD‐2076 in MM.

Phase I study of continuous MKC-1 (cMKC-1) in patients (pts) with advanced or metastatic solid malignancies using a modified time-to-event continual reassessment method (TITE-CRM) for dose assignment.

e13001 Background: MKC-1 is an oral cell-cycle inhibitor amenable to a variety of dosing schedules. Previous clinical trials used intermittent dosing schedules with modest activity for doses of 225 mg/d averaged over 28 days. Preclinical data suggested continuous drug would be more efficacious. The primary objectives were the maximum tolerated dose (MTD) and response rate (RR) of cMKC-1. Secondary objectives included characterizing the dose-limiting toxicities (DLTs) and pharmacokinetics (PK). Methods: Pts with solid malignancies were eligible, if they had measurable disease, ECOG PS ≤1, and adequate organ function. Exclusions included brain metastases and inability to receive oral drug. MKC-1 was dosed twice-daily, continuously for 28 days. Other medications were eliminated if there were possible drug interactions. Doses were assigned using a TITE- CRM algorithm after the first 3 pts. Disease response was assessed every 8 weeks. Results: Between 5/08-9/09, 24 pts enrolled (15 M/9 F, median 58 yo). Pts 1-...