Michael C. Cox

Influence of Garlic (Allium sativum) on the Pharmacokinetics of Docetaxel

Purpose: The herbal supplement garlic (Allium sativum) is commonly used by cancer patients. Preclinical studies have shown that allicin, a major component of garlic, may affect cytochrome P450 3A4 (CYP3A4) activity. This study examines the influence of garlic supplementation on the pharmacokinetics of docetaxel, a CYP3A4 substrate. Experimental Design: Women with metastatic breast cancer were treated with docetaxel (30 mg/m2) given weekly for 3 of 4 weeks. Three days after the initial dose of docetaxel, patients received 600 mg of garlic twice daily for 12 consecutive days. Docetaxel pharmacokinetics were assessed during the first three administrations. Results: In 10 evaluable patients, the mean baseline clearance of docetaxel was 30.8 L/h/m2 [95% confidence intervals (95% CI), 16.7-44.9]. Coadministration of garlic reduced mean clearance of docetaxel to 23.7 L/h/m2 (95% CI, 15.5-31.8) and 20.0 L/h/m2 (95% CI, 13.3-26.7) on days 8 and 15, respectively (P = 0.17). Additional pharmacokinetic variables of docetaxel, including peak concentration (P = 0.79), area under the curve (P = 0.36), volume of distribution (P = 0.84), and half-life (P = 0.36), were also not statistically significantly different. The mean area under the curve ratio between day 15 and day 1 was 3.74 in three individuals with the CYP3A5*1A/*1A genotype (all African American) compared with 1.02 in six individuals with the CYP3A5*3C/*3C genotype (all Caucasian). Conclusions: This study indicates that garlic does not significantly affect the disposition of docetaxel. However, it cannot be excluded that garlic decreases the clearance of docetaxel in patients carrying a CYP3A5*1A allele.

Pharmacogenetic associations of CYP2C19 genotype with in vivo metabolisms and pharmacological effects of thalidomide.

Thalidomide requires cytochrome P450 (CYP)-catalyzed biotransformation for its antiangiogenic property, and CYP2C19 is responsible for 5-hydroxylation and 5’-hydroxylation of thalidomide in human. This study explored a hypothesis that patients with poor metabolizing phenotype of CYP2C19 receive little benefit from thalidomide treatment and that the poor metabolizer genotype is associated with lower ability to form the metabolites. A case-control study was conducted with 63 patients with prostate cancer who had been enrolled in a randomized phase II trial of thalidomide monotherapy (200 to 1,200 mg/day). CYP2C19 polymorphism (CYP2C19*2, CYP2C19*3, CYP2C19*4) was compared with clinical events (prostate-specific antigen (PSA) decline) and formations of the hydroxylated metabolites. Two patients were homozygous for the variant CYP2C19*2 allele (poor metabolizing phenotype). Both of these were included in the 25 patients whose PSA failed to demonstrate a decline. While 32% and 48% of the patients had quantifiable levels of 5-hydroxythalidomide and cis-5’-hydroxythalidomide, respectively, these metabolite were below quantification in both poor metabolizing patients. None had CYP2C19*3 or CYP2C19*4 alleles. Although this study had no power to detect the statistical significance of the CYP2C19 genotype, the findings were consistent with our hypothesis. The role of CYP2C19 polymorphism in thalidomide treatments remains to be elucidated.

Thalidomide metabolism and hydrolysis: mechanisms and implications.

Despite its controversial past, thalidomide is currently under investigation for the treatment of several disease types, ranging from inflammatory conditions to cancer. The mechanism of action of thalidomide is complex and not yet fully understood, but there is some evidence to suggest that metabolism may play a role. Consequently, there has been a considerable effort to characterize the metabolism of thalidomide in recent years. Thalidomide undergoes biotransformation by non-enzymatic hydrolysis and enzyme-mediated hydroxylation to form a multitude of metabolites. Metabolite identification and reaction phenotyping studies have been performed and will be discussed in this review in addition to interspecies differences in thalidomide metabolism.

Clinical Pharmacology of Flavopiridol following a 72-Hour Continuous Infusion

Background Flavopiridol, a novel flavone derivative, inhibits cyclin-dependent kinase-1. We initiated a Phase I trial in patients with refractory solid tumors to determine the maximum tolerated dose and characterize the adverse effect profile. Objective To characterize the clinical pharmacology of flavopiridol. Methods Serial plasma samples were collected and analyzed by HPLC using electrochemical detection. The pharmacokinetics were analyzed by noncompartmental analysis. Enterohepatic recirculation was studied by analyzing fecal samples, with an attempt to correlate cholecystokinin and post-infusional peak concentrations. The plasma protein binding was studied using equilibrium dialysis. Results Seventy-six patients were treated with flavopiridol at 13 dose levels for a total of 504 cycles of treatment. The average steady-state concentration was 26.5 and 253 nM at 4 and 122.5 mg/m2, respectively. The clearance ranged from 49.9 to 2943 mL/min, with nonlinearity at doses >50 mg/m2/d. A post-infusional increase in plasma flavopiridol concentrations was noted in a subset of patients and generally occurred between 3 and 24 hours after the end of infusion. Flavopiridol was found in fecal matter, suggesting enterohepatic recirculation. There was nonsaturable plasma protein binding of flavopiridol (fu = 6%). Conclusions The dose-limiting toxicity for the Phase I trial of flavopiridol was secretory diarrhea. We failed to identify a clear relationship between dose or concentration and diarrhea. At 50 and 78 mg/m2/d, the mean steady-state plasma concentrations were 278 and 390 nM. These concentrations were well above those noted for in vitro antiproliferative activity. Nonlinear elimination was observed at doses above 50 mg/m2/d, and postinfusional peaks appear to be related to enterohepatic recirculation.

Infantile Fibrosarcoma With NTRK3–ETV6 Fusion Successfully Treated With the Tropomyosin-Related Kinase Inhibitor LOXO-101

Infantile fibrosarcoma (IFS) is a rare pediatric cancer typically presenting in the first 2 years of life. Surgical resection is usually curative and chemotherapy is active against gross residual disease. However, when recurrences occur, therapeutic options are limited. We report a case of refractory IFS with constitutive activation of the tropomyosin‐related kinase (TRK) signaling pathway from an ETS variant gene 6–neurotrophin 3 receptor gene (ETV6–NTRK3) gene fusion. The patient enrolled in a pediatric Phase 1 trial of LOXO‐101, an experimental, highly selective inhibitor of TRK. The patient experienced a rapid, radiographic response, demonstrating the potential for LOXO‐101 to provide benefit for IFS harboring NTRK gene fusions.

Prostate‐specific antigen velocity and survival for patients with hormone‐refractory metastatic prostate carcinoma

The authors investigated whether prostate‐specific antigen (PSA) velocity was associated significantly with the time to death after randomization among patients with hormone‐refractory metastatic prostate carcinoma (HRMPC) who were treated with cytotoxic, cytotatic, or combination therapy.

Leuprolide acetate given by a subcutaneous extended-release injection: less of a pain?

Androgen deprivation therapy is a mainstay for the treatment of advanced prostate cancer. Hormonal therapy commonly consists of injection of gonadotropin hormone-releasing hormone agonists. Based on the need for improved convenience of administration, a novel formulation of leuprolide acetate (Eligard®; Atrix Laboratories Inc. & Sanofi Aventis) which incorporates a mixture of selected polymers and solvents to achieve sustained drug delivery after subcutaneous injection, was developed. The US Food and Drug Administration has approved 1-, 3-, 4- and 6-month formulations of leuprolide acetate. In clinical trials, leuprolide acetate achieves sustained suppression of serum testosterone to castration levels (≤50 ng/dl). The adverse-event profile is consistent with the effects of testosterone suppression. This novel delivery system in addition to the availability of a 6-month formulation of leuprolide acetate, offers patients the option of a convenient twice-yearly injection schedule.

Abstract PR13: Clinical safety and activity from a phase 1 study of LOXO-101, a selective TRKA/B/C inhibitor, in solid-tumor patients with NTRK gene fusions

Background: Gene fusions involving the NTRK1, 2 and 3 genes result in constitutively-active TRKA, -B, and -C kinases that are prevalent in a wide array of tumor types, including lung adenocarcinoma, thyroid, head and neck cancer, sarcoma, and other tumors. LOXO-101 is an orally bioavailable, potent, ATP-competitive, selective inhibitor of TRKA, TRKB, and TRKC being studied in a Phase 1 dose escalation trial. In pre-clinical in vivo xenograft mouse models bearing NTRK-fusions LOXO-101 demonstrated potent tumor growth inhibition and regression. Here, we report updated PK and safety data on 24 patients (pts). Methods: In this on-going open-label, multicenter, 3+3 dose escalation Phase I study of LOXO-101, 24 pts with solid tumors refractory to standard therapy, normal hematopoietic and major organ function have been enrolled. LOXO-101 is administered orally as a single dose, followed by QD or BID doses for continuous 28-day cycles. Response is measured by RECIST Criteria, version 1.1. Serum is collected for pharmacokinetic analysis on Cycle 1 Day 1 and Day 8. Safety information is collected on all patients and the definition of dose-limiting toxicity applies to adverse events regardless of relationship to investigational product. Nude mice were injected with CUTO3.29 (MPRIP-NTRK1, lung adenocarcinoma) or MO-91 (ETV6-NTRK3, acute myeloid leukemia) cell lines and then administered LOXO-101 orally at 60 or 200mg/kg daily for 2 weeks. Results: As of September 3, 2015, 24 pts have been treated at each of the first five dose levels (50mg QD, 100mg QD, 200mg QD, 100mg BID, and 150mg BID). LOXO-101 has been well tolerated; the MTD has not been reached and the most common adverse events are Grade 1 and 2 fatigue (42%), dizziness (29%) and anemia (21%). Two pts have had grade 3 AEs leading to dose cohort expansions: elevated AST, grade 3 (Dose Level 150mg BID) and delirium, grade 3 (Dose Level 100mg BID). Each case was subsequently deemed unrelated to study drug by the treating investigator, and the pts remained on study at reduced doses without recurrence. PK analysis showed maximum plasma concentrations of LOXO-101 were reached 30-60 minutes following dosing. The unbound drug levels of LOXO-101 appear sufficient for approximately 98% inhibition of TRKA/B/C at peak concentrations at all dose levels. All three pts with NTRK-fusions enrolled have achieved a PR: an undifferentiated sarcoma with an LMNA-NTRK1 fusion (59% decrease; 7 cycles+), a c-kit-negative GI Stromal Tumor (GIST) with an ETV6-NTRK3 fusion (30% decrease; 2 cycles+), and a mammary analogue secretory carcinoma of the salivary glands with an ETV6-NTRK3 fusion (64% decrease; 2 cycles+). These patients were treated at either 100 or 150 mg BID. These data are supported by in vivo tumor regression in xenograft mouse models of NTRK1 and NTRK3 fusion bearing tumor cells of different histologies in the presence of clinically achievable concentrations of LOXO-101. Conclusions: LOXO-101 has been well tolerated and has sufficient systemic exposure for robust tumor responses in 3 of 3 (100%) of NTRK-fusion pts enrolled on study. These data further validate this molecular target as an oncogenic driver across diverse tumor histologies and support the exploration of TRK inhibition in cancer pts with NTRK-fusions. Citation Format: David S. Hong, Marcia S. Brose, Robert C. Doebele, Alice T. Shaw, Afshin Dowlati, Todd M. Bauer, Anna F. Farago, Adriana Estrada-Bernal, Anh T. Lee, Michael C. Cox, Nisha Nanda, Jennifer A. Low, Howard A. Burris, III. Clinical safety and activity from a phase 1 study of LOXO-101, a selective TRKA/B/C inhibitor, in solid-tumor patients with NTRK gene fusions. [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 PR13.

Emerging drugs to replace current leaders in first-line therapy for breast cancer.

Increasing knowledge of drug resistance and side effects of currently approved agents, and of the biology of breast cancer, has given way to new treatment options that improve on previously available agents, or medications that target specific kinases and proteins associated with an oncogenic phenotype. This paper discusses new agents, including improved formulations of paclitaxel and epothilones, and molecularly targeted agents such as bevacizumab, sunitinib malate, pertuzumab, lapatinib, the mTOR inhibitors and farnesyl transferase inhibitors. Although endocrine therapy is a targeted therapy, it is not covered in this paper. These agents have increased excitement in the treatment of breast cancer and stand on the forefront of a potential improvement in quality of life and treatment options for patients afflicted with this deadly disease.

Abstract CT008: Clinical safety and activity from a phase I study of LOXO-101, a selective TRKA/B/C inhibitor, in solid-tumor patients with NTRK gene fusions

Background: NTRK1, 2 and 3 gene fusions occur across a wide array of tumor types and can lead to constitutively-active TRKA, B, and C kinases. LOXO-101 is an orally bioavailable, potent, ATP-competitive, selective pan-TRK inhibitor. Here, we report response and durability data for patients with NTRK fusions enrolled in an ongoing Phase I dose escalation trial. Updated pharmacokinetic (PK) and safety data for all 41 enrolled patients (pts) are also reported. Methods: This is an ongoing, open-label, multicenter, 3+3 dose escalation Phase I study. LOXO-101 is administered orally as a one- or twice-daily dose for continuous 28-day cycles. Response is measured by RECIST guideline, version 1.1, criteria. Plasma is obtained for PK analysis on Cycle 1 Day 1 and Day 8. Safety information is collected on all patients and adverse events are reported regardless of their attribution to the study drug. Results: As of February 16, 2016, 41 pts with solid tumors refractory to available therapies have been enrolled, including seven pts with NTRK fusions across five different tumor types: sarcoma (1), papillary thyroid cancer (1), mammary analog secretory carcinoma (MASC) of the salivary glands (3), non-small cell lung cancer (1) and GI stromal tumor (1). Collectively, these seven patients harbor gene fusions involving both NTRK1 and NTRK3, with a variety of fusion partners. Six of the seven patients with NTRK fusions were evaluable for response evaluation at the time of data cutoff, and all six have demonstrated a clinical response to LOXO-101. Five of the six patients have achieved confirmed RECIST partial responses, while the sixth patient has exhibited a 21% tumor regression. All seven patients remain on study with no evidence of progressive disease. For these seven patients, duration of therapy ranges from one to thirteen cycles. No objective anti-tumor activity has been observed in treated patients without an NTRK fusion. In total, 41pts have been treated on the Phase I study, across five dose levels (50mg QD, 100mg QD, 200mg QD, 100mg BID, and 150mg BID). Maximum plasma concentrations of LOXO-101 were reached 30-60 minutes following dosing. The unbound drug levels of LOXO-101 appear sufficient for approximately 98% inhibition of TRKA/B/C at peak concentrations at all dose levels. LOXO-101 has been well tolerated. The maximum tolerated dose has not been reached, and the most common adverse events are Grade 1 and 2 fatigue (29%), dizziness (24%) and nausea (20%). Conclusions: LOXO-101 has been well tolerated and has shown promising and broad anti-tumor activity in patients with NTRK fusions. All patients with NTRK fusions have experienced objective tumor reductions, with 5/6 (83%) exhibiting confirmed RECIST partial responses. All of these patients remain on study without disease progression. These data suggest that a LOXO-101 dose of 100mg BID is well-tolerated and capable of inducing durable disease control in patients with NTRK gene fusions, supporting the design of the ongoing LOXO-101 Phase 2 basket trial. Citation Format: David S. Hong, Anna F. Farago, Marcia S. Brose, Howard A. Burris, Afshin Dowlati, Todd M. Bauer, Matthew Taylor, Alice T. Shaw, Adriana Estrada-Bernal, Anh T. Lee, Nisha Nanda, Michael C. Cox, Robert C. Doebele. Clinical safety and activity from a phase I study of LOXO-101, a selective TRKA/B/C inhibitor, in solid-tumor patients with NTRK gene fusions. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT008.