Jennifer Heideman

Potential cytochrome P-450 drug–drug interactions in adults with metastatic solid tumors and effect on eligibility for Phase I clinical trials

PURPOSE Potential cytochrome P-450 (CYP) drug-drug interactions in adults with metastatic solid tumors and their effect on eligibility for Phase I clinical trials were characterized. METHODS This study included adult patients with metastatic solid tumors seen by a medical oncologist from January 2008 through July 2011. The medications used by these patients were identified. Each medications potential for interacting with CYP isozymes was also characterized. Medication changes required to meet Phase I trial eligibility criteria were also reviewed. RESULTS Data from 1773 patients were analyzed: 1489 were not enrolled in a Phase I trial and 284 were enrolled in a Phase I trial. Polypharmacy was significantly more prevalent in the group enrolled in a Phase I trial compared with those not enrolled (95% versus 80%, p < 0.001). The majority of patients not enrolled in a Phase I trial were taking at least one CYP isozyme inhibitor (87%) and at least one CYP isozyme inducer (45%). In a separate analysis, four Phase I trials were evaluated. Of 295 screened patients, 3.2% could not enroll due to concurrent medications. Charts from 74 enrolled patients revealed 655 concurrent medications—93 medications required further review for eligibility involving 51 (69%) of patients. Of the 93 medications, 38 (41%) were stopped and 41 (44%) were changed for the study. CONCLUSION Polypharmacy and the use of medications that interact with CYP isoyzmes were common in adult patients with metastatic solid tumors. Patients enrolling in Phase I studies often require medication changes to meet eligibility requirements.

A Phase 1, Multi-Center, Open-Label, Dose-Escalation Study of 131I-CLR1404 in Subjects with Relapsed or Refractory Advanced Solid Malignancies.

This study explores the imaging and therapeutic properties of a novel radiopharmaceutical, 131I-CLR1404. Phase 1a data demonstrated safety and tumor localization by SPECT-CT. This 1b study assessed safety, imaging characteristics, and possible antineoplastic properties and provided further proof-of- concept of phospholipid ether analogues’ retention within tumors. A total of 10 patients received 131I-CLR1404 in an adaptive dose-escalation design. Imaging characteristics were consistent with prior studies, showing tumor uptake in primary tumors and metastases. At doses of 31.25 mCi/m2 and greater, DLTs were thrombocytopenia and neutropenia. Disease- specific studies are underway to identify cancers most likely to benefit from 131I-CLR1404 monotherapy.

Abstract P5-19-20: A phase I study of MK-2206 in combination with lapatinib in patients with advanced solid tumors followed by dose-expansion in advanced HER2+ breast cancer

Background : AKT mediates signaling in the human epidermal growth factor receptor-2 (HER2) pathway. HER2 inhibition can result in feedback regulation of signaling, leading to high AKT activity. Preclinical studies demonstrate activity of combined HER2 and AKT inhibition. MK-2206 is an oral selective inhibitor of AKT. This study was designed to determine the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), adverse events (AEs), clinical activity, pharmacokinetic (PK) parameters and explore potential biomarkers of the combination of MK-2206 with lapatinib. Methods : The dose escalation cohort included adult patients (pts) with solid tumors treated with MK-2206 (30-60 mg qod) and lapatinib (1000-1500 mg qd) continuously. Cycles were 28 days, except cycle 1 (35 days), due to a 1 week MK-2206 lead-in to evaluate for PK interactions. MK-2206 plasma concentrations were evaluated on day 1, 9 (steady state) and 15 (steady state in combination with lapatinib). Lapatinib plasma concentrations were evaluated on day 9 (first dose) and day 15 (steady state in combination with MK-2206). Both used a validated LC-MSMS assay. Pharmacokinetic parameters were calculated using non-compartmental methods with WinNonLin Phoenix version. The dose expansion cohort included women with advanced HER2+ breast cancer treated at the MTD. Peripheral blood mononuclear cells (PBMCs) and archived tumor samples were collected for all pts. Results : In the dose escalation cohort, 23 pts (median age 59 [range 22-72];15 female:8 male) were enrolled. Cancers were colorectal (8 pts), lung (4 pts), breast (3 pts) and other (8 pts). 19 evaluable pts were treated a median of 8 weeks (range 3-35). At dose level four, 1 pt had grade 4 hyponatremia, grade 3 rash and hypocalcemia and 1 pt had intolerable grade 2 mucositis with delivery of Conclusions : Continuous dosing of MK-2206 in combination with lapatinib is well-tolerated. Preliminary results of pharmacokinetic analysis indicate a potential for a drug interaction. Clinical benefit was seen in patients with HER2+ breast cancer. Citation Format: Moniba Nazeef, Amye J Tevaarwerk, Jens Eickhoff, Mark E Burkard, Jennifer Heideman, Glenn Liu, Chris Flynn, Jill M Kolesar, Kari B Wisinski. A phase I study of MK-2206 in combination with lapatinib in patients with advanced solid tumors followed by dose-expansion in advanced HER2+ breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-19-20.

Abstract P6-12-02: Use of cytochrome P450 interacting medications in the setting of adjuvant therapy for breast cancer.

Background: In the current era of personalized medicine, oral targeted therapies are increasingly used in cancer treatment. In breast cancer, oral anti-estrogen agents have historically been part of standard treatment for hormone receptor positive disease. More recently, other targeted agents have been introduced in the metastatic setting, and are being evaluated as adjuvant therapies. Many oral medications, including anticancer therapies, are metabolized by cytochrome P450 (CYP450) enzymes raising possibility of drug-drug interactions that may affect toxicities or breast cancer outcomes. We sought to evaluate concomitant CYP450 medication use among women seeing a medical oncologist to discuss adjuvant systemic therapy for breast cancer. Methods: We performed an electronic medical record database extraction. Adult women diagnosed with breast cancer from 1/2008-7/2011 were identified from the University of Wisconsin Hospital and Clinics Cancer Registry. Medication lists were extracted from the first encounter with a medical oncologist after the initial breast cancer diagnosis. Non-systemic medications were excluded. Cytochrome P450 (CYP450) enzyme-interacting medications were categorized as inhibitors, inducers, and/or substrates of specific enzymes including CYP1A2, CYP2A6, CYP2B6, CYP2C19, CYP2C8, CYP2C9, CYP2D6, CYP2E1, and CYP3A4. CYP450 inhibitors and inducers were further characterized as strong, moderate or weak acting. Results: A total of 455 women with non-metastatic breast cancer were identified. Mean age was 56.6 years (range of 23–90) and 413 (91%) were Caucasian. Polypharmacy, defined as use of 3–5 medications, was seen in 123 (27.0%) women. A total of 236 (51.9%) women were on 0–4; 109 (24.0%) on 5–10; and 13 (2.9%) on > 10 medications at the time of first encounter with a medical oncologist after a breast cancer diagnosis. 23 (5.05%) women were on strong CYP450 enzyme inhibitors while 72 (15.8%) were on strong inducers. CYP450 enzymes most commonly affected were CYP3A4, CYP2C9, and CYP2D6. Among medications taken on a fixed schedule, levothyroxine and simvastatin were the most commonly used, while simvastatin and ranitidine were the most common CYP450 interacting medications. Further classification of potential CYP450 interactions is ongoing. Conclusions: A significant proportion of patients were on one or more CYP450 interacting medications in the setting of adjuvant therapy for breast cancer. Given the number of new oral cancer agents that are also CYP450 interacting, the potential for drug interactions should be recognized and appropriate management strategies implemented. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-12-02.