Hormone Ablation Therapy, Doxorubicin, and Zoledronate With or Without Strontium 89 in Treating Patients With Androgen-Dependent Prostate Cancer and Bone Metastases

Phase 2

Completed

• Conditions: Metastatic Cancer; Prostate Cancer
• Interventions: Drug: Doxorubicin hydrochloride; Drug: Goserelin acetate; Drug: Leuprolide acetate; Drug: Zoledronic acid; Procedure: orchiectomy; Radiation: strontium chloride Sr

• Registration Number: NCT00081159
• Lead Sponsor: M.D. Anderson Cancer Center

Brief Summary

RATIONALE: Androgens can stimulate the growth of prostate cancer cells. Drugs such as goserelin and leuprolide may fight prostate cancer by stopping the adrenal glands from producing androgens. Drugs used in chemotherapy such as doxorubicin work in different ways to stop tumor cells from dividing so they stop growing or die. Zoledronate may prevent bone loss and stop the growth of tumor cells in bone. Radioactive substances such as strontium-89 may relieve bone pain associated with prostate cancer. It is not yet known whether hormone (androgen) ablation therapy and chemotherapy combined with zoledronate is more effective with or without strontium-89 in treating prostate cancer and bone metastases.

PURPOSE: This randomized phase II trial is studying giving hormone ablation therapy, doxorubicin, and zoledronate together with strontium-89 to see how well it works compared to hormone ablation therapy, doxorubicin, and zoledronate alone in treating patients with androgen-dependent prostate cancer and bone metastases.

Detailed Description

OBJECTIVES:

Primary

* Compare the clinical efficacy of hormonal ablative therapy combined with doxorubicin and zoledronate with or without strontium chloride Sr 89, in terms of progression-free survival, in patients with androgen-dependent prostate cancer and bone metastases.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to the number of bony metastases (≤ 6 versus \> 6). Patients are randomized to 1 of 2 treatment arms.

* Arm I: Patients receive hormonal ablative therapy comprising luteinizing hormone-releasing hormone agonist (e.g., leuprolide or goserelin) continuously during study treatment OR bilateral orchiectomy. Patients also receive doxorubicin intravenously (IV) on days 1, 8, and 15 every 28 days for 2 courses; zoledronate IV over 15 minutes on day 1 every 28 days for 6 courses; and a single dose of strontium chloride Sr 89 IV over 1-2 minutes on day 1.

* Arm II: Patients receive hormonal ablative therapy, doxorubicin, and zoledronate as in arm I.

In both arms, treatment continues in the absence of disease progression or unacceptable toxicity.

Patients are followed every 3 months.

PROJECTED ACCRUAL: A total of 80 patients (40 per treatment arm) will be accrued for this study within 20 months.

Study Timeline

• Study First Submitted: 2004-04-07
• Study First Submitted QC: 2004-04-07
• Study First Posted: 2004-04-08
• Study Start: 2004-07
• Primary Completion: 2014-09
• Study Completion: 2014-09
• Status Verified: 2016-09
• Results First Submitted: 2016-09-22
• Results First Submitted QC: 2016-09-22
• Last Update Submitted: 2016-09-22
• Results First Posted: 2016-11-10
• Last Update Posted: 2016-11-10

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Male
• Target Recruitment: 80

Inclusion Criteria

1. Histologically or cytologically confirmed prostate carcinoma.
2. Osteoblastic metastases on bone scan or computed tomography (CT) scan.
3. Initiation of hormonal ablative therapy within 3 months of registration.
4. Prior neoadjuvant, concurrent, or intermittent hormonal ablative therapy of less than 3 years duration and completed at least 3 years prior to entry into this study.
5. The Eastern Cooperative Oncology Group (ECOG) performance status <3 (Karnofsky >40%)
6. Patients must have normal organ and marrow function as defined: leukocytes: >3,000/mL; absolute neutrophil count: >1,500/mL; platelets: >100,000/mL; total bilirubin within normal institutional limits; alanine transaminase (ALT)(SGPT)/aspartate aminotransferase (AST)(SGOT): <2.5 * institutional upper limit of normal; creatinine: < or = 3.0; left ventricular ejection fraction: >45%
7. The effects of strontium-89 and zoledronic acid on the developing human fetus at the recommended therapeutic dose are unknown. Even though all patients are castrated during this study, men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should the spouse of a patient become pregnant or suspect she is pregnant while participating in this study, she/he should inform the treating physician immediately.
8. Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria

1. More than one prior chemotherapy regimen. Prior doxorubicin treatment is permitted. However patient's with >250 mg/m2 cumulative dosage are excluded.
2. Prior radioisotope treatment consisting of strontium-89 or samarium-153.
3. Zoledronic acid treatment for more than 3 months duration prior to registration. Other bisphosphonate treatments are permitted.
4. Corrected serum calcium level less than 8 mg/dL.
5. Patients may not be receiving any other investigational agents.
6. Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
7. History of allergic reactions attributed to compounds of similar chemical or biologic composition to zoledronic acid or other agents used in the study
8. Patients with the following atypical presentations should have a biopsy: those with small cell carcinoma, purely lytic bone metastases, or bulky (i.e. 5 cm) visceral or nodal disease in the absence of bone involvement are not eligible.
9. Symptomatic bulky lymphadenopathy causing scrotal or pedal edema or significant local invasive disease in bladder invasion.
10. History of other malignancies other than nonmelanoma skin cancer, unless in complete remission and off therapy for that disease for at least 5 years.
11. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, history of congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
12. Because patients with immune deficiency are at increased risk of lethal infections when treated with marrow-suppressive therapy, HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with strontium-89 or other agents administered during the study. Appropriate studies will be undertaken in patients receiving combination anti-retroviral therapy when indicated.
13. Evidence or suspicion of myelodysplastic syndrome by complete blood test (CBC) must be confirmed by bone marrow biopsy.
14. Untreated symptomatic spinal cord compressions.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
HAT, Doxorubicin + Zoledronate	Goserelin acetate	Arm II: HAT, doxorubicin, and zoledronate as in arm I. HAT comprising luteinizing hormone-releasing hormone agonist (e.g., leuprolide or goserelin) continuously during study treatment OR bilateral orchiectomy; doxorubicin IV on days 1, 8, and 15 every 28 days for 2 courses; zoledronate IV over 15 minutes on day 1 every 28 days for 6 courses.
HAT, Doxorubicin, Zoledronate + Strontium chloride	strontium chloride Sr	Arm I: Hormonal ablative therapy (HAT) comprising luteinizing hormone-releasing hormone agonist (e.g., leuprolide or goserelin) continuously during study treatment OR bilateral orchiectomy; doxorubicin IV on days 1, 8, and 15 every 28 days for 2 courses; zoledronate IV over 15 minutes on day 1 every 28 days for 6 courses; and a single dose of strontium chloride Sr 89 IV over 1-2 minutes on day 1.
HAT, Doxorubicin + Zoledronate	Leuprolide acetate	Arm II: HAT, doxorubicin, and zoledronate as in arm I. HAT comprising luteinizing hormone-releasing hormone agonist (e.g., leuprolide or goserelin) continuously during study treatment OR bilateral orchiectomy; doxorubicin IV on days 1, 8, and 15 every 28 days for 2 courses; zoledronate IV over 15 minutes on day 1 every 28 days for 6 courses.
HAT, Doxorubicin + Zoledronate	orchiectomy	Arm II: HAT, doxorubicin, and zoledronate as in arm I. HAT comprising luteinizing hormone-releasing hormone agonist (e.g., leuprolide or goserelin) continuously during study treatment OR bilateral orchiectomy; doxorubicin IV on days 1, 8, and 15 every 28 days for 2 courses; zoledronate IV over 15 minutes on day 1 every 28 days for 6 courses.
HAT, Doxorubicin, Zoledronate + Strontium chloride	Goserelin acetate	Arm I: Hormonal ablative therapy (HAT) comprising luteinizing hormone-releasing hormone agonist (e.g., leuprolide or goserelin) continuously during study treatment OR bilateral orchiectomy; doxorubicin IV on days 1, 8, and 15 every 28 days for 2 courses; zoledronate IV over 15 minutes on day 1 every 28 days for 6 courses; and a single dose of strontium chloride Sr 89 IV over 1-2 minutes on day 1.
HAT, Doxorubicin, Zoledronate + Strontium chloride	Leuprolide acetate	Arm I: Hormonal ablative therapy (HAT) comprising luteinizing hormone-releasing hormone agonist (e.g., leuprolide or goserelin) continuously during study treatment OR bilateral orchiectomy; doxorubicin IV on days 1, 8, and 15 every 28 days for 2 courses; zoledronate IV over 15 minutes on day 1 every 28 days for 6 courses; and a single dose of strontium chloride Sr 89 IV over 1-2 minutes on day 1.
HAT, Doxorubicin, Zoledronate + Strontium chloride	orchiectomy	Arm I: Hormonal ablative therapy (HAT) comprising luteinizing hormone-releasing hormone agonist (e.g., leuprolide or goserelin) continuously during study treatment OR bilateral orchiectomy; doxorubicin IV on days 1, 8, and 15 every 28 days for 2 courses; zoledronate IV over 15 minutes on day 1 every 28 days for 6 courses; and a single dose of strontium chloride Sr 89 IV over 1-2 minutes on day 1.
HAT, Doxorubicin, Zoledronate + Strontium chloride	Doxorubicin hydrochloride	Arm I: Hormonal ablative therapy (HAT) comprising luteinizing hormone-releasing hormone agonist (e.g., leuprolide or goserelin) continuously during study treatment OR bilateral orchiectomy; doxorubicin IV on days 1, 8, and 15 every 28 days for 2 courses; zoledronate IV over 15 minutes on day 1 every 28 days for 6 courses; and a single dose of strontium chloride Sr 89 IV over 1-2 minutes on day 1.
HAT, Doxorubicin, Zoledronate + Strontium chloride	Zoledronic acid	Arm I: Hormonal ablative therapy (HAT) comprising luteinizing hormone-releasing hormone agonist (e.g., leuprolide or goserelin) continuously during study treatment OR bilateral orchiectomy; doxorubicin IV on days 1, 8, and 15 every 28 days for 2 courses; zoledronate IV over 15 minutes on day 1 every 28 days for 6 courses; and a single dose of strontium chloride Sr 89 IV over 1-2 minutes on day 1.
HAT, Doxorubicin + Zoledronate	Doxorubicin hydrochloride	Arm II: HAT, doxorubicin, and zoledronate as in arm I. HAT comprising luteinizing hormone-releasing hormone agonist (e.g., leuprolide or goserelin) continuously during study treatment OR bilateral orchiectomy; doxorubicin IV on days 1, 8, and 15 every 28 days for 2 courses; zoledronate IV over 15 minutes on day 1 every 28 days for 6 courses.
HAT, Doxorubicin + Zoledronate	Zoledronic acid	Arm II: HAT, doxorubicin, and zoledronate as in arm I. HAT comprising luteinizing hormone-releasing hormone agonist (e.g., leuprolide or goserelin) continuously during study treatment OR bilateral orchiectomy; doxorubicin IV on days 1, 8, and 15 every 28 days for 2 courses; zoledronate IV over 15 minutes on day 1 every 28 days for 6 courses.

Primary Outcome Measures

Name	Time	Method
Progression Free Survival (PFS)	Up to 90 months with evaulation in 4 week intervals for up to 6 months of treatment, then follow up until disease progression	Study's primary endpoint of PFS duration/time to progression was defined as the time from the date of randomization to the date of first evidence of disease progression or patient death. Prostate-specific antigen (PSA) progression is usually the first evidence of progression. PSA progression is defined as a 25% increase over the baseline or the nadir provided that the increase is a minimum of 1 ng/ml.

Secondary Outcome Measures

Name	Time	Method
Major Bone Scan Response	Week 13	Bone scan performed at baseline and at Week 13 provided if baseline scan was positive for metastases. A major bone scan response was considered with a substantial resolution of participant bone metastases on the bone scans, i.e. complete resolution of the osseous metastases on the bone scan.

Trial Locations

Locations (4)

M.D. Anderson Cancer Center at Orlando; 🇺🇸 Orlando, Florida, United States

M.D. Anderson Cancer Center at University of Texas; 🇺🇸 Houston, Texas, United States

CCOP - Marshfield Clinic Research Foundation; 🇺🇸 Marshfield, Wisconsin, United States

CCOP - Wichita; 🇺🇸 Wichita, Kansas, United States