Clinical Trials /

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

NCT03737370

Description:

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.

Related Conditions:
  • Prostate Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: IIR-US-2016-3279
  • NCT ID: NCT03737370

Conditions

  • Metastatic Castrate Resistant Prostate Cancer

Interventions

DrugSynonymsArms
DocetaxelFractionated DocetaxelDose escalation

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Dose escalationExperimentalThere 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).
  • Docetaxel
Dose expansionExperimentalIf 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.
  • Docetaxel

Eligibility Criteria

        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. No more than one prior second generation androgen receptor inhibitor

          5. Eligible for docetaxel chemotherapy

          6. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2

          7. 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 aspartate aminotransferase (AST) < 1.5 x upper limit of normal range

               6. Serum alanine aminotransferase (ALT) < 1.5 x upper limit of normal range

               7. Calculated creatinine clearance > 30mL/min

          8. Age ≥ 18 years

          9. Ongoing castration (androgen deprivation therapy or prior orchiectomy)

         10. Male subjects with female sexual partners of childbearing potential must agree to use
             at least one highly effective methods of birth control.

         11. Ability to understand and willingness to sign an informed consent form prior to
             initiation of any study procedures.

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of Dose Limiting Toxicities (DLT)
Time Frame:Up to 29 Days
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure: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
Safety Issue:
Description:Time to progression of disease, calculated as a time-to-event endpoint
Measure:Progression Free Survival (PFS)
Time Frame:Up to 25 years
Safety Issue:
Description: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
Measure:Time to Treatment Failure (TTTF)
Time Frame:Up to 25 years
Safety Issue:
Description: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
Measure:Overall Survival
Time Frame:Up to 25 years
Safety Issue:
Description:Overall survival is defined as the interval from first dose date of study drug to death from any cause.
Measure:Proportion of Randomized Subjects to Complete Combination Therapy on Schedule per Protocol
Time Frame:Up to 28 weeks
Safety Issue:
Description: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).
Measure: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
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description:Measured by the Brief Pain Inventory (BPI) and Functional Assessment of Cancer Therapy (FACT-G) Questionnaires
Measure:Response to Treatment, as assessed by Bone Bio-marker Outcomes
Time Frame:Up to 28 weeks
Safety Issue:
Description:Measurement of bone-specific alkaline phosphatase and urine N-telopeptides (laboratory testing)

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Tufts Medical Center

Trial Keywords

  • Prostate Cancer

Last Updated

May 1, 2019