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

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ClinicalTrials.gov Identifier: NCT03043989
Recruitment Status : Recruiting
First Posted : February 6, 2017
Last Update Posted : April 20, 2018
Sponsor:
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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.


Condition or disease Intervention/treatment Phase
Prostate Cancer Drug: Docetaxel Drug: Cabazitaxel Drug: Clarithromycin Phase 1

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 35 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Two Independent Phase 1b Cohorts of Docetaxel or Cabazitaxel in Combination With the Potent CYP3A4 Inhibitor, Clarithromycin
Actual Study Start Date : March 21, 2017
Estimated Primary Completion Date : February 15, 2020
Estimated Study Completion Date : February 15, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: 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.

Drug: Docetaxel
6 infusions of Docetaxel with 18 doses clarithromycin

Drug: Clarithromycin
18 doses of clarithromycin with either Docetaxel or Cabazitaxel

Active Comparator: 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.

Drug: Cabazitaxel
6 infusions of Cabazitaxel with 18 doses clarithromycin
Other Name: JEVTANA

Drug: Clarithromycin
18 doses of clarithromycin with either Docetaxel or Cabazitaxel




Primary Outcome Measures :
  1. Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: 3 years ]
  2. 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 Measures :
  1. Compare docetaxel OR cabazitaxel exposure (maximal [Cmax] when combined with the strong CYP3A4 inhibitor clarithromycin to historic controls. [ Time Frame: 3 years ]
  2. Compare docetaxel OR cabazitaxel exposure ( total [AUC]) when combined with the strong CYP3A4 inhibitor clarithromycin to historic controls. [ Time Frame: 3 years ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03043989


Contacts
Contact: Michael A Carducci, MD 410-614-3977 carducci@jhmi.edu

Locations
United States, Maryland
Johns Hopkins Hospital Recruiting
Baltimore, Maryland, United States, 21231
Contact: Michael A Carducci, MD    410-614-3977    carducci@jhmi.edu   
Contact: Rana Sullivan, RN    410-614-6337    tomalra@jhmi.edu   
Principal Investigator: Michael A Carducci, MD         
Sponsors and Collaborators
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Investigators
Principal Investigator: Michael A Carducci, MD Johns Hopkins University

Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
ClinicalTrials.gov Identifier: NCT03043989     History of Changes
Other Study ID Numbers: J16144
IRB00117591 ( Other Identifier: JHM IRB )
First Posted: February 6, 2017    Key Record Dates
Last Update Posted: April 20, 2018
Last Verified: April 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins:
docetaxel
cabazitaxel
phase 1b
castration-resistant
bone metastasis

Additional relevant MeSH terms:
Docetaxel
Clarithromycin
Cytochrome P-450 CYP3A Inhibitors
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Anti-Bacterial Agents
Anti-Infective Agents
Protein Synthesis Inhibitors
Enzyme Inhibitors
Cytochrome P-450 Enzyme Inhibitors