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

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.

• Docetaxel (Drug), also known as Fractionated Docetaxel: Docetaxel will be administered every 2 weeks (on Day 1 and Day 15 of a 28 day cycle). Fractionated dosing dependent on cohort.
• Radium 223 (Radiation), also known as Ra-223: Radium 223 will be delivered every 28 days (on day 1) for 6 cycles.

Primary outcomes

• Incidence of Dose Limiting Toxicities (DLT) [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.

Secondary outcomes

• Efficacy, assessed as non-progression/progression rate according to prostate cancer working group (PCWG2) criteria [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) [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) [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 [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 [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 [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 [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 [Up to 28 weeks]: Measurement of bone-specific alkaline phosphatase and urine N-telopeptides (laboratory testing)

Sex: All, ages: 18 Years to any

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

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• Study Protocol (PDF, 2018-10-02)
• Statistical Analysis Plan (PDF, 2018-04-17)

• Paul Mathew, MD, Principal investigator, Tufts Medical Center