Fractionated Docetaxel and Radium 223 in Metastatic Castration-Resistant Prostate Cancer

March 21, 2024 updated by: Tufts Medical Center

A Phase I Trial of Fractionated Docetaxel and Radium 223 in Metastatic Castration-Resistant Prostate Cancer (CRPC)

The objective of this study is to determine the maximum safe dose of Ra-223 in combination with fractionated (split doses) docetaxel when given to subjects and to determine the best administering dose. The study will look at side effects that may happen while taking the combination treatment. A total of approximately 18 subjects will take part in the dose escalation part of the study and an additional 25 subjects will participate in the expansion cohort. This study will be conducted across four centers in the United States.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

Detailed Description

The primary objective of this study is to assess the safety and toxicity of a fractionated docetaxel schedule in combination with standard Ra-223.

Secondary Objectives include: assessment of progression-free survival, time to treatment failure, overall survival, ability of subjects to complete 6 cycles of the combination therapy, assessment of Prostate Specific Antigen (PSA) kinetics and objective responses (measurable disease), assessment of quality of life and assessment of bone bio-marker outcomes.

The study features a 4-week lead-in period with docetaxel monotherapy to assess for docetaxel intolerance. The lead-in period is then followed by combination therapy with Ra-223 every 4 weeks for 6 cycles in a traditional Phase I dose-escalation design.

A provision has been made to include prophylactic granulocyte colony stimulating factor (G-CSF) cohorts after the lead-in period if neutropenia is the dose limiting toxicity at either dose level.

The investigators hypothesize that the fractionated dosing of docetaxel will significantly mitigate the hematologic toxicity, preserve antineoplastic activity and allow for maintenance of the 4-weekly Ra-223 schedule.

Study Type

Interventional

Enrollment (Actual)

43

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • United States
    • Massachusetts
      • Boston, Massachusetts, United States, 02111
        • Tufts Medical Center
      • Boston, Massachusetts, United States, 01805
        • Lahey Hospital & Medical Center
    • Michigan
      • Detroit, Michigan, United States, 48202
        • Henry Ford Health System
    • Ohio
      • Columbus, Ohio, United States, 43210
        • Ohio State University Comprehensive Cancer Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Histologically or cytologically confirmed adenocarcinoma of the prostate
  2. Documented metastatic castration resistant disease with PSA progression, radiographic progression, or both, despite medical or surgical castration
  3. Two or more bone metastases detected on skeletal scintigraphy
  4. Eligible for docetaxel chemotherapy
  5. ECOG Performance Status 0-2

  6. Adequate organ function:

    1. Hemoglobin > 10 g/dL
    2. Absolute Neutrophil Count ≥ 1,500 K/mL
    3. Platelet count ≥ 150,000 x 10^9/L
    4. Total bilirubin ≤ 1.5x upper limit of normal range, excluding Gilbert syndrome
    5. Serum AST ≤ 1.5 x upper limit of normal range
    6. Serum ALT ≤ 1.5 x upper limit of normal range
  7. Estimated glomerular filtration rate (GFR) > 30mL/min
  8. Ongoing castration (androgen deprivation therapy or prior orchiectomy)
  9. Male subjects with female sexual partners of childbearing potential must agree to use at least one highly effective methods of birth control.
  10. Ability to understand and willingness to sign an informed consent form prior to initiation of any study procedures.
  11. Age ≥ 18 years

Exclusion Criteria:

  1. Prior radionuclide therapy for CRPC
  2. Prior docetaxel for CRPC. (Permitted if given for castration sensitive disease > 6 months prior).
  3. Antiandrogen therapy within 4 weeks of enrollment. However, patients with primary failure of secondary anti-androgen therapy OR symptomatic progression, objective progression and/or biochemical evidence of rising PSA less than 4 weeks after discontinuation of anti-androgen therapy will not have anti-androgen withdrawal responses and will not be excluded.
  4. Preexisting peripheral neuropathy grade 2 or higher.
  5. Other serious medical condition as judged by the investigator.
  6. Active second malignancy that requires therapy.
  7. Known brain or leptomeningeal metastases
  8. Concurrent enrollment in any other investigational anticancer therapy
  9. Treatment with any myelosuppressive agent within 30 days of enrollment

  10. Presence of bulky visceral metastases, defined as any of the following:

    1. ≥ 4 lung lesions (at least 1cm each in size in the longest diameter) or pulmonary lymphangitic metastasis
    2. Liver metastases with sum of lesion diameters totaling ≥ 5cm
  11. Evidence of neuroendocrine or small cell differentiation on prior biopsy
  12. History of severe hypersensitivity reactions to docetaxel or to drugs formulated with polysorbate 80

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Sequential Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Dose escalation

There are four dose cohorts (1, 1a, 2, 2a) in this arm and two dose levels of docetaxel (40mg/m^2 [level 1] and 50mg/m^2 [level 2]). Dosing of Radium 223 remains the same in all cohorts (55 KBq/kg given every 28 days for 6 cycles).

Maximum tolerated dose (MTD) of docetaxel will be assessed. MTD is defined as the highest dose-level, among those tested, associated with a rate of less than a 33% dose limiting toxicity (DLT).
Drug: Docetaxel
Docetaxel will be administered every 2 weeks (on Day 1 and Day 15 of a 28 day cycle). Fractionated dosing dependent on cohort.
Other Names:
  • Fractionated Docetaxel
Radiation: Radium 223
Radium 223 will be delivered every 28 days (on day 1) for 6 cycles.
Other Names:
  • Ra-223
Experimental: Dose expansion
If the maximum tolerated dose (MTD) of docetaxel is found in arm 1, this dose level will be expanded to include an additional 25 subjects to confirm the safety and explore the preliminary anti-cancer effect. If the MTD is not identified, the study will be stopped and the expansion cohort will not be accrued.
Drug: Docetaxel
Docetaxel will be administered every 2 weeks (on Day 1 and Day 15 of a 28 day cycle). Fractionated dosing dependent on cohort.
Other Names:
  • Fractionated Docetaxel
Radiation: Radium 223
Radium 223 will be delivered every 28 days (on day 1) for 6 cycles.
Other Names:
  • Ra-223

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidence of Dose Limiting Toxicities (DLT)
Time Frame: Up to 29 Days
DLT is defined as a subject in any cohort experiencing any of the following adverse events during cycle 1 of treatment, until cycle 2 day 1 of treatment: Thrombocytopenia (platelets < 75 x 10^9/L on C1D15 or < 100 x 10^9/L on C2D1), Neutropenia (ANC < 1000 K/mL on C1D15 or ANC < 1500 K/mL on C2D1), Grade 3 (by CTCAE v4) fatigue lasting ≥ 7 days, other non-hematologic toxicity ≥ grade 3, lasting ≥ 48 hours at least possibly related to treatment, or any toxicity (non-hematologic or hematologic) at least possibly related to treatment requiring dose reduction or dose interruption.
Up to 29 Days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Efficacy, assessed as non-progression/progression rate according to prostate cancer working group (PCWG2) criteria
Time Frame: From date of randomization until the date of first documented progression or death from any cause, whichever came first, assessed up to 25 years
Time to progression of disease, calculated as a time-to-event endpoint
From date of randomization until the date of first documented progression or death from any cause, whichever came first, assessed up to 25 years
Progression Free Survival (PFS)
Time Frame: Up to 25 years
Progression free survival is defined as the interval from first dose date of study drug to the earlier of the first documentation of definitive disease progression (assessed per PCWG2) or death from any cause
Up to 25 years
Time to Treatment Failure (TTTF)
Time Frame: Up to 25 years
A measurement from the date of randomization to the first event which meets the criteria for disease progression (assessed per PCWG2 criteria) or death from any cause
Up to 25 years
Overall Survival
Time Frame: Up to 25 years
Overall survival is defined as the interval from first dose date of study drug to death from any cause.
Up to 25 years
Proportion of Randomized Subjects to Complete Combination Therapy on Schedule per Protocol
Time Frame: Up to 28 weeks
The number of subjects who were able to receive both lead-in doses of docetaxel and all 6 cycles of combination docetaxel and Ra223 on time (+/- 7 days).
Up to 28 weeks
Response to treatment, as assessed by prostate-specific antigen (PSA) Kinetics and Objective Responses
Time Frame: From date of randomization until the date of first documented progression or death from any cause, whichever came first, assessed up to 25 years
Measurable disease calculated at each time point in which the data is collected. We will use mixed effect models to explore the temporal trajectories for the outcome changes over time in response to the treatment.
From date of randomization until the date of first documented progression or death from any cause, whichever came first, assessed up to 25 years
Satisfaction, as assessed by Quality of Life Questionnaires
Time Frame: From date of randomization until the date of first documented progression or death from any cause, whichever came first, assessed up to 25 years
Measured by the Brief Pain Inventory (BPI) and Functional Assessment of Cancer Therapy (FACT-G) Questionnaires
From date of randomization until the date of first documented progression or death from any cause, whichever came first, assessed up to 25 years
Response to Treatment, as assessed by Bone Bio-marker Outcomes
Time Frame: Up to 28 weeks
Measurement of bone-specific alkaline phosphatase and urine N-telopeptides (laboratory testing)
Up to 28 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Tufts Medical Center

Collaborators

Bayer
Ohio State University Comprehensive Cancer Center
Lahey Clinic
Henry Ford Hospital

Investigators

  • Principal Investigator: Paul Mathew, MD, Tufts Medical Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 30, 2018

Primary Completion (Estimated)

December 31, 2024

Study Completion (Estimated)

December 31, 2025

Study Registration Dates

First Submitted

October 25, 2018

First Submitted That Met QC Criteria

November 7, 2018

First Posted (Actual)

November 9, 2018

Study Record Updates

Last Update Posted (Actual)

March 22, 2024

Last Update Submitted That Met QC Criteria

March 21, 2024

Last Verified

March 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IIR-US-2016-3279

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

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.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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