Cohorts of Docetaxel or Cabazitaxel in Combination With the Potent CYP3A4 Inhibitor, Clarithromycin

NCT ID: NCT03043989

Last Updated: 2020-02-17

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1
• Total Enrollment: 4 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-03-21
• Study Completion Date: 2019-07-26

Brief Summary

This clinical trial is being conducted to recommend a safe and tolerable phase 2 dose of docetaxel or cabazitaxel when combined with clarithromycin in men who have developed castrate-resistant prostate cancer.

In the castrate-resistant setting, resistance to taxane therapy inevitably develops. Men who develop resistance to taxanes have a very poor prognosis, and few treatment options.

It is believed that CYP enzymes contribute to docetaxel and cabazitaxel resistance in metastatic prostate cancer, and this resistance can be mitigated through pharmacologic CYP inhibition. In this study a potent CYP3A inhibitor, clarithromycin, will be co-administered concurrently with either docetaxel or cabazitaxel, whose systemic metabolism is dependent of CYP3A4, with the intent to overcome resistance to taxanes.

Detailed Description

This is a dose-escalation study designed to determine the maximum tolerated dose of docetaxel or cabazitaxel when given in combination with clarithromycin. Eligible patients will be assigned to docetaxel or cabazitaxel, based on which drug they were previously administered prior to study entry. Enrollment to dose levels will be in a 3+3 cohort design until the maximum tolerated dose is achieved.

Docetaxel or cabazitaxel will be administered on day 1 of each (3 week) cycle for a total of 6 cycles. Subjects in both arms will be administered clarithromycin on days -1, 1 and 2 of each 3 week cycle.

Conditions

Prostate Cancer

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Docetaxel and clarithromycin combination

Docetaxel will be administered by intravenous infusion over 1 hour every 3 weeks on day 1 of each (3 week) cycle for a total of 18 weeks.

Clarithromycin will be administered orally at 500mg twice a day for 3 days per cycle on days -1, 1, and 2.

Group Type: ACTIVE_COMPARATOR

Docetaxel

Intervention Type: DRUG

6 infusions of Docetaxel with 18 doses clarithromycin

Clarithromycin

Intervention Type: DRUG

18 doses of clarithromycin with either Docetaxel or Cabazitaxel

Cabazitaxel and clarithromycin combination

Cabazitaxel will be administered by intravenous infusion over 1 hour every 3 weeks on day 1 of each (3 week) cycle for a total of 18 weeks.

Clarithromycin will be administered orally at 500mg twice a day for 3 days per cycle on days -1, 1, and 2.

Group Type: ACTIVE_COMPARATOR

Cabazitaxel

Intervention Type: DRUG

6 infusions of Cabazitaxel with 18 doses clarithromycin

Clarithromycin

Intervention Type: DRUG

18 doses of clarithromycin with either Docetaxel or Cabazitaxel

Interventions

Docetaxel

6 infusions of Docetaxel with 18 doses clarithromycin

Intervention Type: DRUG

Cabazitaxel

6 infusions of Cabazitaxel with 18 doses clarithromycin

Intervention Type: DRUG

Clarithromycin

18 doses of clarithromycin with either Docetaxel or Cabazitaxel

Intervention Type: DRUG

Other Intervention Names

JEVTANA

Eligibility Criteria

Inclusion Criteria

1. 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 PCWG2

2. 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. No PSA decline in last 42 day

3. Bone disease documented by either: a positive bone scan, CT scan, or MRI; or biopsy-proven bony metastases

4. Age ≥18 years

5. ECOG performance status ≤ 2 (Karnofsky ≥ 60%)

6. Have normal organ and marrow function defined as:

• absolute neutrophil count ≥1,500/mcL
• platelets ≥100,000/mcL
• total bilirubin (within normal institutional limits)
• AST/ALT ≤ 2.5 × ULN (or ≤ 1.5 x ULN in conjunction with alk phos >2.5 x ULN for Docetaxel
• AST ≤ 1.5 x ULN for Cabazitaxel
• creatinine clearance-no minimum for Docetaxel
• creatinine clearance- ≥ 30 mL/min/1.73 m2 for Cabazitaxel

7. 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

8. Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

1. Patients who have residual toxicities > Grade 2 attributed to taxane therapy, except for neuropathy, who are excluded if > grade 1

2. Patients who are receiving any other investigational agents or have within the last 28 day.

3. History of allergic reactions attributed to compounds of similar chemical or biologic composition to clarithromycin or taxanes

4. Patients receiving any medications or substances that are inhibitors or inducers of CYP3A4 are ineligible

5. 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.

6. Received more than 10 cycles of docetaxel [for docetaxel cohort only] or 6 of cabazitaxel [for cabazitaxel cohort only]

7. Last docetaxel or cabazitaxel dose > 6 weeks prior to enrollment

8. 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: No

Sponsors

Maryland Technology Development Corporation

UNKNOWN

Sponsor Role: collaborator

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Michael A Carducci, MD

Role: PRINCIPAL_INVESTIGATOR

Johns Hopkins University

Locations

Johns Hopkins Hospital

Baltimore, Maryland, United States

Countries

United States

Other Identifiers

IRB00117591

Identifier Type: OTHER

Identifier Source: secondary_id

J16144

Identifier Type: -

Identifier Source: org_study_id