Summary:We report a patient with pre-existing end-stage renal disease (ESRD) who underwent successful matched related donor allogeneic bone marrow transplantation for AML in second complete remission (CR2) using conditioning with high-dose cyclophosphamide (CY, 60 mg/kg/day ؋ 2) and TBI (165 cGy twice daily ؋ 4 days). The timing of hemodialysis after high-dose CY was extrapolated from available data on the pharmacokinetics of high-dose CY and hemodialysis clearance of conventional dose CY and its metabolites. Pharmacokinetic analyses indicated that the elimination of highdose CY and its alkylating metabolites is impaired in ESRD but is cleared with hemodialysis. The patient's early post-transplant course was uncomplicated, and WBC and platelet engraftment occurred by day ؉22. Bone marrow examination on day ؉25 showed trilineage engraftment with no AML; cytogenetics showed 100% donor karyotype. The patient remains in remission with 100% donor karyotype at 3 years post transplant. Clinical results indicate that the administration of high-dose CY is feasible with hemodialysis support for patients with ESRD. Keywords: allogeneic BMT; renal disease; cyclophosphamide; AML; pharmacokinetics; hemodialysis High-dose chemotherapy with BMT is considered to be contraindicated in patients with severe renal dysfunction since it is often assumed that the pharmacokinetics and/or pharmacodynamics of high-dose chemotherapy are significantly altered. High-dose cyclophosphamide (CY) is a common component of preparative regimens. The effect of renal dysfunction on the pharmacokinetics of high-dose CY is not known although pharmacokinetic models suggest that Correspondence: Dr JJ Perry, Section of Hematology/Oncology, Department of Internal Medicine, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina, USA 27157 Received 9 July 1998; accepted 12 November 1998 clearance of two important CY metabolites, 4-OH CY and aldophosphamide, may be reduced if severe renal impairment is present.1 The pharmacokinetics of conventionaldose CY and its alkylating metabolites are altered in patients with renal insufficiency.2,3 However, the toxicity profile has not been reported to be different from patients with normal renal function 4 leading some authors to suggest that conventional doses of CY do not require modification in patients with renal dysfunction. 5 In this report, we describe the clinical BMT course of a patient with endstage renal disease (ESRD) (on chronic hemodialysis) and AML in CR2 who received high-dose CY. The pharmacokinetics of high-dose CY and CY-alkylating metabolites are also presented. Case reportA 42-year-old male was diagnosed with AML (subtype FAB-M2) in January 1994. He achieved CR after treatment with daunorubicin 45 mg/m 2 i.v. × 3 days and cytarabine 100 mg/m 2 /day by continuous i.v. infusion (CIVI) ϫ 7 days. He was given four courses of post-remission therapy using daunorubicin 45 mg/m 2 i.v. ϫ 2 days and cytarabine 100 mg/m 2 /day CIVI ϫ 5 days, completed in July 1994. ...

Background: Seviteronel (Sevi), a CYP17-lyase (L) inhibitor (reduces testosterone (T) and estradiol (E2) biosynthesis) and a competitive AR antagonist, has activity in castration resistant prostate cancer at a dose of 600mg nightly. Sevi potently inhibits the growth of ER(+)/AR(+) MCF7, tamoxifen-resistant (TAMR) MCF7, and ER(-)/AR(+) MDA-MB-453 cells. In a TAMR xenograft BC model, Sevi decreases tumor growth greater than enzalutamide (Enza), an AR antagonist (Ellison et al, SABCS 2015). Nearly all subtypes of BC, including AR(+) TNBC, are potential targets for Sevi based on its mechanism of action (MOA). Phase (Ph) 1 of this study established the recommended Ph 2 dose (RP2D) of Sevi in women with BC as 450mg once nightly, based upon preliminary tolerability and pharmacokinetics (PK) (Bardia et al, ASCO 2016). The primary objective of Ph 2 is to estimate the activity of Sevi, as measured by clinical benefit rate (CBR) at 16 and 24 weeks (wks) for AR(+) TNBC and ER(+) BC, respectively. The secondary objectives include an estimation of Sevi tolerability and pharmacodynamics (PD) (NCT02580448). Methods: Women with advanced AR(+) TNBC (stratified by prior Enza use) or ER(+) BC were enrolled using 3 parallel Simon's 2-stage designs powered to evaluate CBR. ER(+) BC patients must have had ≥1 prior line of endocrine therapy; no limit to prior treatment for TNBC. AR(+) status was confirmed using central IHC analysis in all patients, with a ≥10% tumor cell nuclear staining cutoff for evaluable TNBC patients. Sevi was administered once nightly with dinner at 450mg (28d cycle). Tumor and blood samples were collected for PK and PD analysis (circulating tumor cells, ctDNA, sex steroids). Response was assessed every 8 wks for 52 wks, then every 12 wks thereafter. Current tolerability and PD results are presented herein for this ongoing Ph 2 study. Results: As of June 7, 2016, 17 patients received Sevi at 450mg nightly between Ph1 and Ph2 with 10 in screening. 14 patients are currently on study in Cycles 1-6. The most common adverse events (AEs > 10% regardless of causality or grade) were tremor (24%), pain (18%), fatigue (18%) and dyspnea (18%), nausea (12%), AST increase (12%), ALT increase (12%) and abdominal pain (12%), all of which were Grade 1 or 2 except for Grade 3 dyspnea (n=1; unrelated). No dose reductions were reported and there were no drug-related discontinuations. Nine patients underwent central AR testing (4 AR(+) of 6 TNBC; 3 AR(+) of 3 ER(+) BC). Median AR tumor cell nuclear staining was 90% (15-100%). Preliminary sex steroid analyses from 6 Ph 1 patients receiving Sevi at 450, 600, or 750mg nightly (n=2 at each dose) for 1 cycle showed a median decline in E2 concentration of 52% (-29 to -87%) to 12.4pmol/L (4 to 33pmol/L) from baseline. There was a similar magnitude of decline for T. Conclusions: Sevi was well-tolerated at 450mg nightly with exposures similar to the RP2D in men (600mg nightly). The CYP17-L inhibition activity of Sevi was demonstrated with an early and potent reduction in E2 and T. Sevi's unique CYP17-L and AR antagonist MOA may provide a new novel treatment option for AR(+) TNBC or ER(+) BC. Citation Format: Gucalp A, Bardia A, Gabrail N, DaCosta N, Danso M, Elias AD, Ali H, Lemon SJ, Riley EC, Eisner JR, Fleming RA, Kurman MR, Moore WR, Traina TA. Phase 1/2 study of oral seviteronel (VT-464), a dual CYP17-lyase inhibitor and androgen receptor (AR) antagonist, in patients with advanced AR positive triple negative (TNBC) or estrogen receptor (ER) positive breast cancer (BC) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-08-04.

#3121 Background: Lapatinib is a selective and highly potent dual, competitive inhibitor of erbB1 and erbB2 tyrosine kinases with clinical activity in erbB2-positive metastatic breast cancer (MBC). The combination of carboplatin, paclitaxel, and trastuzumab has been shown to have significant clinical activity in MBC as well as in the adjuvant setting. Given the synergy of dual inhibition with trastuzumab and lapatinib observed in both the preclinical and clinical settings, we assessed the feasibility, safety, and early clinical activity of paclitaxel, carboplatin, lapatinib with and without trastuzumab in patients (pts) with MBC.
 Methods: MBC pts previously untreated with trastuzumab or cytotoxic chemotherapy for metastatic or locally recurrent disease were enrolled into either Group (Grp) A (erbB2 positive) or B (erbB2 positive or negative). Escalating doses of lapatinib (planned range of 750-1500 mg/d) were administered in combination with (Grp A) or without (Grp B) trastuzumab (4 mg/kg followed by weekly 2 mg/kg infusions). Paclitaxel (80 mg/m2) and carboplatin (AUC 2 mg/ml*min) were administered on days 1, 8, 15 with cycles repeated every 28 days. Starting doses of lapatinib were 750 mg in Grp A and 1000 mg in Grp B. A standard 3 + 3 Phase I design is being used until the optimally tolerated regimen (OTR) dose level is determined. An additional 14 - 17 pts will be enrolled into each grp at the OTR dose level to further assess safety and tolerability.
 Results: Fourteen pts (Grp A n=8, Grp B n=6) have been enrolled in the study (median age 42 yrs, range 27-66). A median of 5.5 cycles (range 4-17) in Grp A and 3.5 (range 1-7) in Grp B have been administered. All pts had at least one adverse event (AE). In Grp A, grade 3 toxicities include neutropenia (50%), diarrhea (38%), rash (25%), vomiting (13%), hypokalemia (13%), and syncope (13%). No grade 4 toxicities were reported. In Grp B, grade 3 toxicities include fatigue (33%), hyponatremia (17%), menorrhagia (17%), dermatitis (17%), and rash (17%). One pt (in Grp B) had grade 4 neutropenia. No febrile neutropenia was observed. In Grp A, there was one DLT (Gr 3 diarrhea) at lapatinib 1000 mg. In Grp B, one DLT (Gr 4 neutropenia) at lapatinib 1000 mg has been observed. Clinical activity to date includes 8/8 objective responses in Grp A, (1 CR, 7 PR) and 2/6 objective responses (2 PR) in Grp B (all pts in Grp B were erbB2 negative). Dose escalation continues in both grps.
 Conclusions: Lapatinib may be administered safely in combination with carboplatin, paclitaxel, with and without trastuzumab at known effective doses for each. Clinical activity has been observed. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3121.

2579 Background: CapOx is a standard treatment for patients (pts) with metastatic colorectal cancer (mCRC) and has been shown to be equivalent to FOLFOX in a phase III study. L is a tyrosine kinase inhibitor with targeting of the EGF and Her-2 receptors. Preclinical data suggest there may be synergy between L and Cap as well as L and Ox. This phase I study was designed to determine the maximum tolerated dose (MTD) of CapOx and L. Methods: Pts eligible for treatment included those with advanced or metastatic cancers, ECOG PS 2 or less, adequate renal and liver function, and ≤ 3 prior chemotherapy regimens. Treatment over a 21-day cycle was as follows: Ox, single IV infusion on Day 1; Cap, twice-daily oral administration on Days 1 through 14; L, continuous once-daily oral administration. Pts were treated with escalating doses of L (starting at 1000 mg daily) and Cap (starting at 1500 mg/m2/day), while Ox was kept at 130 mg/m2. The primary endpoint was determination of MTD. Results: Ten pts (9/10 female, median age 62 yrs.) were enrolled. One pt had breast cancer and the remainder had non- colorectal GI malignancies (esophagus, hepatobiliary, and pancreas). One pt at dose level 0 experienced dose-limiting toxicity (DLT) (dehydration, elevated bilirubin, hypokalemia). Two pts at dose level 1 (L 1000, Ox 130, Cap 2000) had DLTs of hypokalemia and diarrhea. At an intermediate dose level of L 1000, Cap 1700, Ox 130, two pts experienced DLTs (grade 2 fatigue/anorexia, grade 3 fatigue and dizziness). The MTD was determined to be L 1000 mg daily, Cap 1500 mg/m2/day, Ox 130 mg/m2. There were no treatment-related grade 4 toxicities. The most common grade 3 toxicity was diarrhea (4 pts). There were no grade 3 neuropathies, hematologic toxicities, or rash, and only one case of grade 3 fatigue. One pt with pancreatic cancer had a confirmed partial response (PR) to treatment, and 3 others had stable disease for > 90 days. Conclusions: The regimen of CapOx and L has efficacy in the treatment of solid tumors with established responsiveness to fluoropyrimidines or Ox. The MTD was L 1000 mg daily, Ox 130 mg/m2, and Cap 1500 mg/m2/day. This regimen will be investigated further in a Phase II study involving pts with mCRC. [Table: see text]