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

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ClinicalTrials.gov Identifier: NCT03737370
Recruitment Status : Recruiting
First Posted : November 9, 2018
Last Update Posted : February 1, 2021
Sponsor:
Collaborators:
Bayer
Lahey Clinic
Henry Ford Hospital
Ohio State University Comprehensive Cancer Center
Information provided by (Responsible Party):
Tufts Medical Center

Tracking Information
First Submitted Date  ICMJE October 25, 2018
First Posted Date  ICMJE November 9, 2018
Last Update Posted Date February 1, 2021
Actual Study Start Date  ICMJE January 30, 2018
Estimated Primary Completion Date March 31, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 7, 2018)		 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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 7, 2018)
  • 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
  • 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
  • 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
  • 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.
  • 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).
  • 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.
  • 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
  • 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)
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Fractionated Docetaxel and Radium 223 in Metastatic Castration-Resistant Prostate Cancer
Official Title  ICMJE A Phase I Trial of Fractionated Docetaxel and Radium 223 in Metastatic Castration-Resistant Prostate Cancer (CRPC)
Brief Summary 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.
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  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Metastatic Castrate Resistant Prostate Cancer
Intervention  ICMJE
  • 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 Name: Fractionated Docetaxel
  • Radiation: Radium 223
    Radium 223 will be delivered every 28 days (on day 1) for 6 cycles.
    Other Name: Ra-223
Study Arms  ICMJE
  • 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).

    Interventions:
    • Drug: Docetaxel
    • Radiation: Radium 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.
    Interventions:
    • Drug: Docetaxel
    • Radiation: Radium 223
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 7, 2018)		 25
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE October 31, 2022
Estimated Primary Completion Date March 31, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Latoya Lashley, MPH 617-636-5409 llashley@tuftsmedicalcenter.org
Contact: Christian Lawlor 617-636-8897 clawlor3@tuftsmedicalcenter.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03737370
Other Study ID Numbers  ICMJE IIR-US-2016-3279
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Tufts Medical Center
Study Sponsor  ICMJE Tufts Medical Center
Collaborators  ICMJE
  • Bayer
  • Lahey Clinic
  • Henry Ford Hospital
  • Ohio State University Comprehensive Cancer Center
Investigators  ICMJE
Principal Investigator: Paul Mathew, MD Tufts Medical Center
PRS Account Tufts Medical Center
Verification Date January 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP