Docetaxel or Cabazitaxel with Clarithromycin in Treating Patients with Metastatic Castration-Resistant Prostate Cancer
- Men with metastatic castrate-resistant prostate cancer (prostate cancer progressing despite castrate levels of testosterone [< 50 ng/dL]), using standard measures of progression defined by Prostate Cancer Working Group 2 (PCWG2)
- Have received at least 4 cycles of docetaxel or cabazitaxel, and less than ten, with two consecutive rising PSA values, checked at least 7 days apart
- Radiographic progressive disease, irrespective of PSA changes, after receiving at least 4 cycles of docetaxel or cabazitaxel
- Bone disease documented by either: a positive bone scan, computed tomography (CT) scan, or magnetic resonance imaging (MRI); or biopsy proven bony metastases
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
- Absolute neutrophil count >= 1,500/mcL
- Platelets >= 100,000/mcL
- Total bilirubin within normal institutional limits
- Docetaxel: Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x upper limit of normal (ULN) (or =< 1.5 x ULN in conjunction with alkaline phosphatase (alk phos) > 2.5 x ULN
- Cabazitaxel: AST =< 1.5 x ULN
- Docetaxel: Creatinine clearance no minimum
- Cabazitaxel: Creatinine clearance >= 30 mL/min/1.73 m^2
- No evidence of clinical progression, in the form of increased lesions on cross-sectional imaging, or new cancer-attributable symptoms or worsening of existing symptoms
- Ability to understand and the willingness to sign a written informed consent document
- Patients who have residual toxicities > grade 2 attributed to taxane therapy, except for neuropathy, who are excluded if > grade 1
- Patients who are receiving any other investigational agents or have within the last 28 days
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to clarithromycin or taxanes
- Patients receiving any medications or substances that are inhibitors or inducers of CYP3A4 are ineligible; the subject requires concomitant treatment with the following inhibitors of CYP3A4: * Antibiotics: clarithromycin, erythromycin, telithromycin, troleandomycin; specifically, clarithryomycin is permitted for patients considered for this trial * Antifungals: itraconzaole, ketoconazole, voriconazole, fluconazole, posaconazole * Antidepressants: nefazodone * Antidiuretic: conivaptan * Antiretrovirals: delaviridine or protease inhibitors (ritonavir, indinavir, lopinavir/ritonavir, saquinavir, nelfinavir) or cobicistat-boosted antiretrovirals * Gastrointestinal (GI): cimetidine, aprepitant * Hepatitis C: boceprevir, telaprevir * Miscellaneous: Seville oranges, grapefruit, or grapefruit juice and/or pummelos, star fruit, exotic citrus fruits, or grapefruit hybrids)
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
- Received more than 10 cycles of docetaxel (for docetaxel cohort only) or 6 of cabazitaxel (for cabazitaxel cohort only)
- Last docetaxel or cabazitaxel dose > 6 weeks prior to enrollment
- Patients with a documented history of QT prolongation or ventricular cardiac arrhythmia, including torsades de pointes, or taking drugs that are known to prolong the QT
I. Define the safety and tolerability of docetaxel or cabazitaxel in combination with clarithromycin.
II. Determine the maximum tolerated dose and recommended phase 2 dose of docetaxel and of cabazitaxel when it is combined with clarithromycin.
I. Compare docetaxel OR cabazitaxel exposure (maximal [Cmax] and total [area under curve (AUC)]) when combined with the strong CYP3A4 inhibitor clarithromycin to historic controls.
II. To investigate anti-tumor activity of the strategy.
III. To assess the ability of CYP3A4 inhibition to alter both the systemic (secondary objective I) and microenvironmental exposure to chemotherapy.
OUTLINE: This is a dose-escalation study of docetaxel and cabazitaxel. Patients are assigned to 1 of 2 groups.
GROUP I: Patients receive clarithromycin orally (PO) twice daily (BID) on days -1 to 2 and docetaxel intravenously (IV) over 1 hour on day 1. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.
GROUP II: Patients receive clarithromycin PO BID on days -1 to 2 and cabazitaxel IV over 1 hour on day 1. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 30 days.
Trial Phase Phase I
Trial Type Treatment
Johns Hopkins University / Sidney Kimmel Cancer Center
Michael Anthony Carducci
- Primary ID J16144
- Secondary IDs NCI-2017-01675, IRB00117591, CRMS-65335
- Clinicaltrials.gov ID NCT03043989