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

Primary Purpose

Prostate Cancer

Status

Terminated

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Docetaxel

Cabazitaxel

Clarithromycin

About this trial

This is an interventional treatment trial for Prostate Cancer focused on measuring docetaxel, cabazitaxel, phase 1b, castration-resistant, bone metastasis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)MaleDoes not accept healthy volunteers

Inclusion Criteria:

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
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
Bone disease documented by either: a positive bone scan, CT scan, or MRI; or biopsy-proven bony metastases
Age ≥18 years
ECOG performance status ≤ 2 (Karnofsky ≥ 60%)
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
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

Exclusion Criteria:

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 day.
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
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

Sites / Locations

Johns Hopkins Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Arm Label

Docetaxel and clarithromycin combination

Cabazitaxel and clarithromycin combination

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

Escalate dose up the maximum tolerated dose achieved, and initiate this as the recommended phase 2 dose of docetaxel and of cabazitaxel when it is combined with clarithromycin.

Secondary Outcome Measures

Compare docetaxel OR cabazitaxel exposure (maximal [Cmax] when combined with the strong CYP3A4 inhibitor clarithromycin to historic controls.

Compare docetaxel OR cabazitaxel exposure ( total [AUC]) when combined with the strong CYP3A4 inhibitor clarithromycin to historic controls.

Full Information

NCT ID

NCT03043989

First Posted

January 26, 2017

Last Updated

February 13, 2020

Sponsor

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Collaborators

Maryland Technology Development Corporation

1. Study Identification

Unique Protocol Identification Number

NCT03043989

Brief Title

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

Official Title

Two Independent Phase 1b Cohorts of Docetaxel or Cabazitaxel in Combination With the Potent CYP3A4 Inhibitor, Clarithromycin

Study Type

Interventional

2. Study Status

Record Verification Date

February 2020

Overall Recruitment Status

Terminated

Why Stopped

Low accrual

Study Start Date

March 21, 2017 (Actual)

Primary Completion Date

July 26, 2019 (Actual)

Study Completion Date

July 26, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Collaborators

Maryland Technology Development Corporation

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Prostate Cancer

Keywords

docetaxel, cabazitaxel, phase 1b, castration-resistant, bone metastasis

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

4 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Docetaxel and clarithromycin combination

Arm Type

Active Comparator

Arm Description

Arm Title

Cabazitaxel and clarithromycin combination

Arm Type

Active Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Docetaxel

Intervention Description

6 infusions of Docetaxel with 18 doses clarithromycin

Intervention Type

Drug

Intervention Name(s)

Cabazitaxel

Other Intervention Name(s)

JEVTANA

Intervention Description

6 infusions of Cabazitaxel with 18 doses clarithromycin

Intervention Type

Drug

Intervention Name(s)

Clarithromycin

Intervention Description

18 doses of clarithromycin with either Docetaxel or Cabazitaxel

Primary Outcome Measure Information:

Title

Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

Time Frame

3 years

Title

Escalate dose up the maximum tolerated dose achieved, and initiate this as the recommended phase 2 dose of docetaxel and of cabazitaxel when it is combined with clarithromycin.

Time Frame

3 years

Secondary Outcome Measure Information:

Title

Compare docetaxel OR cabazitaxel exposure (maximal [Cmax] when combined with the strong CYP3A4 inhibitor clarithromycin to historic controls.

Time Frame

3 years

Title

Compare docetaxel OR cabazitaxel exposure ( total [AUC]) when combined with the strong CYP3A4 inhibitor clarithromycin to historic controls.

Time Frame

3 years

10. Eligibility

Sex

Male

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 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 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 Bone disease documented by either: a positive bone scan, CT scan, or MRI; or biopsy-proven bony metastases Age ≥18 years ECOG performance status ≤ 2 (Karnofsky ≥ 60%) 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 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 Exclusion Criteria: 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 day. 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 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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Michael A Carducci, MD

Organizational Affiliation

Johns Hopkins University

Official's Role

Principal Investigator

Facility Information:

Facility Name

Johns Hopkins Hospital

City

Baltimore

State/Province

Maryland

ZIP/Postal Code

21231

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

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

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