Reid, Joel M.

PURPOSE: To compare the pharmacokinetics of continuous venous infusion (CVI) fluorouracil (5-FU) with that of oral eniluracil/5-FU and to describe toxicities and clinical activity of prolonged oral administration of eniluracil/5-FU. PATIENTS AND METHODS: A randomized, open-label, cross-over study compared CVI 5-FU to an oral 5-FU/eniluracil combination. Seventeen patients (arm A) were randomly assigned to receive eniluracil/5-FU combination tablets (10:1 mg/m 2 BID for 7 days) during the first study period, followed by 5-FU (300 mg/m 2 CVI for 7 days) during period 2, with a 14-day washout between periods. Sixteen patients (arm B) received treatment in the opposite sequence. In period 3, all patients received eniluracil/5-FU tablets BID for 28 days. Plasma levels of 5-FU during CVI and oral administration were analyzed in periods 1 and 2. Dihydropyrimidine dehydrogenase (DPD) activity was determined by measuring plasma uracil, urinary α–fluoro-β-alanine, and peripheral-blood mononuclear cell (PBMC) DPD activity. RESULTS: There were no grade 3 or 4 toxicities in either arm. Partial responses were observed in three patients. Another three patients had stable disease for ≥ 3 months. Eniluracil and 5-FU pharmacokinetics were similar to those observed in previous studies and were unaffected by administration sequence. The mean ± SD steady-state plasma concentration (C P ) and area under the curve (AUC) 144-168h for CVI 5-FU (104 ± 45 ng/mL and 2,350 ± 826 ng·h/mL, respectively) were three-fold greater than those for oral 5-FU (38.1 ± 7.7 ng/mL and 722 ± 182 ng·h/mL, respectively [P < .00001]). Individual 5-FU concentrations during CVI were highly variable, whereas those after eniluracil/5-FU were very reproducible. DPD activity in PBMCs before each study period was normal. CONCLUSION: Both CVI 5-FU and oral eniluracil/5-FU were well tolerated, with moderate activity in these heavily pretreated patients. However, 5-FU steady-state C P and AUCs achieved with oral eniluracil/5-FU were significantly less than with CVI 5-FU.

Abstract Background: The combination of a microtubule stabilizing agent and an mTOR inhibitor has been identified as a synergistic combination in preclinical models. Additional studies have further evaluated the impact of treatment sequence with paclitaxel and rapamycin where administration of rapamycin after paclitaxel was associated with synergy. In our preclinical studies, apoptosis was greater with the combination of ixabepilone and temsirolimus than with either single agent. Thus, a Phase I study of the combination of Ixabepilone (IXB) and Temsirolimus (TEM) was performed to determine the maximum tolerated dose (MTD), describe the toxicity profile and characterize the pharmacokinetics of each agent in patients with advanced cancer. Methods: Eligible patients included adults with a histologically confirmed solid tumor malignancy that was metastatic or unresectable who have received ≤ 2 chemotherapy regimens and had ECOG PS ≤ 2 with adequate bone marrow, renal and hepatic function. Using a standard 3+3 design, patients were treated with IXB IV over 3 hours on day 1 and TEM IV over 0.5 hours on days 2 and 9 (schedule A) or days 1 and 8 (schedule B) every 21 days. Pharmacokinetics (PK) was performed in patients on schedule B. Results: 22 evaluable patients were enrolled between August 24, 2011 and November 7, 2014. The final 7 patients were treated on schedule B. Patients were treated at 3 dose levels of IXB (mg/m2)/TEM (mg): DL1- 24/15 (A- 6 pts, B- 2 pts); DL2- 32/15 (A- 3 pts, B- 5 pts); DL3- 32/20 (A- 6 pts). One patient had DLT (grade 3 hypophosphatemia) and 1 patient expired due to disease progression in DL1A. No DLTs were seen in DL2A. The dose was escalated to DL3 and 1 patient had DLT (grade 3 hypokalemia). Following a change to schedule B, 5 patients were enrolled to DL2B and 1 experienced DLT (grade 4 neutropenia, grade 4 thrombocytopenia, grade 4 sepsis). The dose was reduced to DL1B and 2 more patients were enrolled, both of whom experienced DLTs (grade 5 bronchopulmonary hemorrhage and grade 4 neutropenia). Grade 4 events considered at least possibly related to treatment occurred in 6 of 22 patients (27%) and included cardiac arrest, dyspnea, hypokalemia, hypoxia, multi-organ failure, decreased platelets, acute renal failure, neutropenia, neutropenic fever, sepsis, and decreased WBCs. Patients received a median of 4 cycles (range, 1-10+). Partial response was noted in 1 patient and stable disease was noted in 11 patients. One patient remains on treatment after 11 cycles. IXB (plasma), TEM (whole blood) and sirolimus (whole blood) concentrations were measured by a sensitive, specific lc/ms/ms assay. A 24 and 32 mg/m2 IXB dose yields Cmax of 159 and 312 ng/ml, respectively. The IXB CLp and t1/2 values were 31 L/h and 76 h, respectively. The Cmax, Cl and t1/2 values after a 15 mg TEM dose were 518 ng/ml, 6.4 L/h and 11 h, respectively. The Cmax and t1/2 values of sirolimus after a 15 mg TEM dose were 37.6 ng/ml and 49 h, respectively. The PK of IXB and TEM in combination were similar to those reported for each drug alone. Conclusions: The reasons for the unpredictable, severe toxicity of the IXB/TEM combination are unclear. The MTD could not be determined, and enrollment was discontinued. This trial exemplifies challenges associated with development of drug combinations with mTOR inhibitors. Supported in part by UM1 CA186686 and P30 CA15083. Clinical trial information: NCT01375829 Citation Format: Joel M. Reid, Michael E. Menefee, Felix Boakye-Agyeman, Chad A. Walden, Charles Erlichman, Keith C. Bible. Phase I and pharmacokinetic study of ixabepilone and temsirolimus in adult patients with advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B113.

Abstract Antibody-directed chemotherapy (ADC) offers an advantage over conventional chemotherapy because it provides antibody-directed targeting, with resultant improvement in therapeutic efficacy and reduced toxicity. Despite extensive research, with notable exceptions, broad clinical application of ADC remains elusive; major hurdles include the instability of antibody–chemotherapy linkers and reduced tumor toxicity of the chemotherapy when bound to the antibody. To address these challenges, we have developed a platform technology that utilizes the nab-paclitaxel formulation of paclitaxel, Abraxane, in which hydrophobic paclitaxel is suspended in 130-nm albumin nanoparticles and thus made water-soluble. We have developed a method to noncovalently coat the Abraxane nanoparticle with recombinant mAbs (anti-VEGF, bevacizumab) and guide Abraxane delivery into tumors in a preclinical model of human A375 melanoma. Here, we define the binding characteristics of bevacizumab and Abraxane, demonstrate that the chemotherapy agent retains its cytotoxic effect, while the antibody maintains the ability to bind its ligand when the two are present in a single nanoparticle (AB160), and show that the nanoparticle yields improved antitumor efficacy in a preclinical human melanoma xenograft model. Further data suggest that numerous therapeutic monoclonal IgG1 antibodies may be utilized in this platform, which has implications for many solid and hematologic malignancies. Cancer Res; 76(13); 3954–64. ©2016 AACR.

AbstractThe population pharmacokinetic model reported here was developed using data from 2 phase 2 trials of irinotecan for treatment of malignant glioma to quantify the impact of concomitant therapy with enzyme‐inducing antiepileptic drugs (EIAEDs) on irinotecan pharmacokinetics. Patients received weekly irinotecan doses of 100 to 400 mg/m2, and plasma samples were collected and analyzed for irinotecan and its APC, SN‐38, and SN‐38G metabolites. Nonlinear mixed‐effects modeling was employed for population pharmacokinetic analysis. Concomitant therapy with phenytoin, phenobarbital, or carbamazepine increased the clearances of irinotecan, SN‐38, and SN‐38G but not APC. SN‐38 clearance was 2‐fold higher with concomitant EIAED use, resulting in 40% lower SN‐38 exposure. Evaluation of additional covariates revealed no clinically relevant effects of sex or concomitant corticosteroid use. The population pharmacokinetic model suggests that a 1.7‐fold increase in irinotecan dose may compensate for decreases in SN‐38 exposure in the presence of concomitant EIAEDs. Although slightly more conservative, this dose adjustment is consistent with those recommended based on increases in the maximally tolerated dose for malignant glioma patients receiving EIAEDs and may be an appropriate starting point for further investigation when extrapolating to other cancer types or alternative regimens.

Abstract Background: Breast cancer recurrence has been shown to differ based upon CYP2D6 genotype and endoxifen (Endx) exposure following treatment with tamoxifen (TAM) in the adjuvant setting. The average Endx Css is 29 nM (range, 2-80 nM) in TAM treated patients at a dose of 20 mg/day. Administration of Endx itself to patients is predicted to provide adequate, consistent, active drug levels in all treated patients, resulting in clinical benefit. As part of two phase 1 trials of oral Endx to determine the safety, tolerability, and MTD, we characterized the pharmacokinetics and in vivo metabolism of Endx. Methods: Patients were given escalating daily oral doses of Endx (28 day cycle) over the dose range of 20 - 160 mg/day in Phase I trials at the Mayo Clinic and NCI. Pharmacokinetics sampling was performed on days 1, 7, 14 and 28, and prior to subsequent cycles. Endx plasma concentrations and metabolite profiles were determined by HPLC and LC/MS/MS. Results: 44 patients with ECOG PS 0-1 have been enrolled to date encompassing 8 dose levels in the Mayo (25 women with AI refractory MBC; median age 58 yrs, range 41-83 yrs) and NCI (19 women with ovary (9), breast (4), desmoid (2), fallopian tube (2), endometrial cancer (2); median age 64 yrs, range 43-75 yrs) studies. Day 1 Endx peak concentrations (Cmax) were reached 4h after the Endx oral dose and mean values of Cmax, C24h, and AUC0-24h increased in proportion to dose. Css was achieved on day 7 and 3.5-fold accumulation (t1/2= 50.5 h) was observed on day 28. At the starting dose ( 20 mg/day) and highest dose level (160 mg/day), Endx Css values of 146 ng/ml (390 nM) and 1950 ng/ml (5200 nM), respectively, were achieved and maintained throughout the 28-day treatment. Endx Css values remained unchanged following continuous dosing for 8-10 months. The mean apparent steady-state clearance was 6.2 L/h. We also characterized the Endx metabolite profile in patient plasma and urine. Metabolites detected in plasma include nor-Endx, N-hydroxy-Endx, Endx-catechol, methoxy-Endx catechol, and Endx-glucuronide, and appear in amounts much lower compared to Endx. Like the parent drug, metabolites accumulated in plasma over the 28-day cycle. Characterization of the pharmacokinetics of Nor-Endx, a putative aromatase inhibitor, is ongoing and will be presented. Conclusion: In these ongoing Phase I studies, daily administration of Endx is well tolerated with Css consistently above those obtained following administration of standard dose tamoxifen. In the Mayo study, expansion at 20 and 100 mg/day has commenced to perform translational studies and further characterize Endx PK. In the NCI study, dose escalation continues to establish the maximum tolerated dose. Supported in part by R01CA 133049, U01 CA69912, P30CA 15083, P50CA 116201 and NCI Contracts CM52206 and HHSN261201100014C. Citation Format: Joel M. Reid, Matthew P. Goetz, Shivaani Kumar, Renee M. McGovern, Sarah A. Buhrow, Stephanie L. Safgren, Vera J. Suman, Travis J. Docktor, Charles Erlichman, Howard Streicher, James H. Doroshow, Jerry Collins, Matthew M. Ames. Pharmacokinetics and in vivo metabolism of Z-endoxifen: Results from two phase I studies in women with ER+ breast cancer, gynecologic malignancies and desmoids. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4631. doi:10.1158/1538-7445.AM2014-4631

BackgroundGiven the success of immunotherapeutic approaches in hematologic malignancies, the COG designed a phase I/II study to determine whether the addition of epratuzumab (anti‐CD22) to an established chemotherapy platform improves rates of second remission (CR2) in pediatric patients with B‐lymphoblastic leukemia (B‐ALL) and early bone marrow relapse.ProcedureTherapy consisted of three established blocks of re‐induction chemotherapy. Epratuzumab (360 mg/m2/dose) was combined with chemotherapy on weekly × 4 (B1) and twice weekly × 4 [eight doses] (B2) schedules during the first re‐induction block. Remission rates and minimal residual disease (MRD) status were compared to historical rates observed with the identical chemotherapy platform alone.ResultsCR2 was achieved in 65 and 66%, of the evaluable B1 (n = 54) and B2 patients (n = 60), respectively; unchanged from that observed historically without epratuzumab. Rates of MRD negativity (<0.01%) were 31% in B1 (P = 0.4128) and 39% in B2 patients (P = 0.1731), compared to 25% in historical controls. The addition of epratuzumab was well tolerated, with a similar toxicity profile to that observed with the re‐induction chemotherapy platform regimen alone.ConclusionsEpratuzumab was well tolerated in combination with re‐induction chemotherapy. While CR2 rates were not improved compared to historical controls treated with chemotherapy alone, there was a non‐significant trend towards improvement in MRD response with the addition of epratuzumab (twice weekly for eight doses) to re‐induction chemotherapy. Pediatr Blood Cancer 2015;62:1171–1175. © 2015 Wiley Periodicals, Inc.