Ixabepilone, Mitoxantrone Hydrochloride, and Prednisone in Treating Patients With Metastatic Prostate Cancer That Did Not Respond to Hormone Therapy and Chemotherapy

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00331344
First received: May 30, 2006
Last updated: September 19, 2012
Last verified: September 2012
  Purpose

This phase I/II trial is studying the side effects and best dose of ixabepilone and mitoxantrone hydrochloride when given together with prednisone and to see how well they work in treating patients with metastatic prostate cancer that did not respond to hormone therapy and chemotherapy. Drugs used in chemotherapy, such as ixabepilone, mitoxantrone hydrochloride, and prednisone, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells


Condition Intervention Phase
Adenocarcinoma of the Prostate
Recurrent Prostate Cancer
Stage IV Prostate Cancer
Drug: mitoxantrone hydrochloride
Drug: ixabepilone
Drug: prednisone
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I/II Trial of Epothilone Analog BMS-247550 (Ixabepilone), Mitoxantrone, and Prednisone in Hormone Refractory Prostate Cancer Patients Previously Treated With Chemotherapy

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Safety of the combination of ixabepilone, mitoxantrone hydrochloride, and prednisone in patients with hormone-refractory metastatic prostate cancer that progressed during or after taxane-based chemotherapy (phase I) [ Time Frame: Every 21 days ] [ Designated as safety issue: Yes ]
    This study will utilize the Common Terminology Criteria for Adverse Events (CTCAE) v3.0 for adverse event monitoring and reporting. Toxicities will be tabulated by grade for each dose cohort and overall for all patients accrued to the phase I study.

  • Maximum tolerated dose of the combination of ixabepilone, mitoxantrone hydrochloride, and prednisone in patients with hormone-refractory metastatic prostate cancer that progressed during or after taxane-based chemotherapy (phase I) [ Time Frame: Course 1 (first 21 days) ] [ Designated as safety issue: Yes ]
    Cohorts of 3 patients will be enrolled at each dose level; if 1 DLT is observed then the cohort will be expanded to 6 patients. If a second DLT is observed, the previous dose level will be considered the MTD. If all observed DLT are due to neuropathy (specific to ixabepilone), then we would consider the previous dose level of Ixabepilone the MTD for that drug, and escalate mitoxantrone hydrochloride as described above to a maximum dose of 12 mg/m^2. Toxicities will be tabulated by grade for each dose cohort and overall for all patients accrued to the phase I study.

  • Proportion responding to treatment with of the combination of ixabepilone and mitoxantrone hydrochloride with prednisone in HRPC patients who have had prior taxane chemotherapy based upon a PSA decline of > 50% (phase II) [ Time Frame: Every 3 courses ] [ Designated as safety issue: No ]
    Descriptive statistics will be calculated to characterize the disease and treatment factors including the proportion responding with a 95% confidence interval. If accrual is completed and more than 15 of 58 patients show > 50% PSA declines after 3 courses, then the null hypothesis of a 20% response proportion will be rejected. PSA declines for individual patients will be plotted in the form of a waterfall diagram of maximal PSA declines.


Secondary Outcome Measures:
  • Time to progression (phase II) [ Time Frame: Every 3 months ] [ Designated as safety issue: Yes ]
    Estimated using the Kaplan-Meier product limit method.


Enrollment: 106
Study Start Date: April 2006
Primary Completion Date: November 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (combination chemotherapy)
Patients receive mitoxantrone hydrochloride IV over 30 minutes and ixabepilone IV over 3 hours on day 1 and oral prednisone twice daily on days 1-21. Treatment repeats every 21 days for ≥ 3 courses in the absence of disease progression or unacceptable toxicity.
Drug: mitoxantrone hydrochloride
Given IV
Other Names:
  • CL 232315
  • DHAD
  • DHAQ
  • Novantrone
Drug: ixabepilone
Given IV
Other Names:
  • BMS-247550
  • epothilone B lactam
  • Ixempra
Drug: prednisone
Given orally
Other Names:
  • DeCortin
  • Deltra

Detailed Description:

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose (MTD) and dose-limiting toxicities of the combination of ixabepilone, mitoxantrone hydrochloride, and prednisone in patients with hormone-refractory metastatic prostate cancer that progressed during or after taxane-based chemotherapy. (Phase I) II. Assess the efficacy, as measured by reduction in prostate-specific antigen, of this regimen in these patients. (Phase II)

SECONDARY OBJECTIVES:

I. Evaluate the overall safety of this regimen as second-line chemotherapy in these patients.

II. Evaluate the objective response rate in patients treated with this regimen.

OUTLINE: This is a multicenter, phase I, open label, dose-escalation study of mitoxantrone hydrochloride and ixabepilone followed by a phase II study.

PHASE I: Patients receive mitoxantrone hydrochloride intravenously (IV) over 30 minutes and ixabepilone IV over 3 hours on day 1 and oral prednisone twice daily on days 1-21. Treatment repeats every 21 days for ≥ 3 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of mitoxantrone hydrochloride and ixabepilone until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity.

PHASE II: Patients receive mitoxantrone hydrochloride and ixabepilone at the MTD determined in phase I and prednisone as in phase I.

After completion of study treatment, patients are followed every 3 months.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically confirmed adenocarcinoma of the prostate
  • Progressive metastatic disease (i.e., positive bone scan or measurable disease) despite castrate levels of testosterone (either from orchiectomy or luteinizing hormone-releasing hormone [LHRH] agonist therapy)

    • Progressive disease after discontinuing hormonal therapy
    • Progressive disease is based on any of the following*:

      • Transaxial imaging
      • Rise in prostate-specific antigen (PSA)
      • Radionuclide bone scan (must show new metastatic lesions)
  • Nonmeasurable or measurable disease

    • For measurable disease, progression is defined by RECIST criteria
    • Positive bone scan and elevated PSA required for nonmeasurable disease

      • PSA evidence of progressive prostate cancer during or after first-line chemotherapy consists of a PSA level ≥ 2 ng/mL that has risen on ≥ 2 successive occasions ≥ 1 week apart
  • Received ≥ 3 prior courses of paclitaxel- or docetaxel-based therapy, with disease progression documented during therapy or after cessation of therapy

    • No more than 1 prior chemotherapy regimen
    • Re-treatment with the same taxane-based regimen allowed
    • Changes in prior chemotherapy regimen (addition of other agents) for disease progression are considered 2 chemotherapy regimens, and are not allowed
  • PSA ≥ 2 ng/mL
  • Testosterone < 50 ng/dL

    • Patients must continue primary androgen deprivation with LHRH analogue if they have not undergone orchiectomy
  • No known active brain metastases
  • ECOG performance status 0-2
  • Life expectancy ≥ 12 weeks
  • Creatinine ≤ 1.5 times upper limit of normal (ULN) OR creatinine clearance > 40 mL/min
  • ALT and AST < 2.5 times ULN
  • Granulocyte count ≥ 2,000/mm³
  • Platelet count ≥ 100,000/mm³
  • Bilirubin < 1.5 times ULN
  • Ejection fraction normal by MUGA scan or echocardiogram
  • No significant cardiovascular disease, including any of the following:

    • Congestive heart failure (New York Heart Association class III-IV heart disease)
    • Active angina pectoris
    • Myocardial infarction within the past 6 months
  • No serious infections or nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by study therapy
  • No psychiatric illness or social situation that would preclude study compliance
  • No pre-existing motor or sensory peripheral neuropathy > grade 1
  • No known prior severe hypersensitivity reactions to agents containing Cremophor® EL
  • No "currently active" second malignancy other than nonmelanoma skin cancer

    • Patients are not considered to have a "currently active" malignancy if they have completed therapy and are considered to be at < 30% risk of relapse
  • Fertile patients must use effective contraception prior to, during, and for 3 months after completion of study treatment
  • See Disease Characteristics
  • No prior mitoxantrone hydrochloride, ixabepilone, or other epothilones
  • At least 4 weeks since prior hormonal therapy (i.e., any dose of megestrol, finasteride, or any herbal product known to decrease PSA levels [e.g., saw palmetto or PC-SPES]) other than LHRH agonist or a stable dose of corticosteroids from a prior chemotherapy regimen
  • More than 4 weeks since other prior systemic therapies for prostate cancer
  • At least 4 weeks since prior radiation therapy
  • More than 8 weeks since prior radiopharmaceuticals (e.g., strontium chloride Sr 89 or samarium Sm 153 lexidronam pentasodium)
  • No concurrent moderate to strong CYP3A4 inhibitors
  • No concurrent prophylactic colony-stimulating factors
  • No concurrent radiotherapy
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00331344

Locations
United States, California
UCSF Helen Diller Family Comprehensive Cancer Center
San Francisco, California, United States, 94143-0875
United States, Wisconsin
University of Wisconsin Hospital and Clinics
Madison, Wisconsin, United States, 53792
Sponsors and Collaborators
Investigators
Principal Investigator: Andrea Harzstark University of California San Francisco Medical Center-Mount Zion
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00331344     History of Changes
Obsolete Identifiers: NCT01648374
Other Study ID Numbers: NCI-2009-00155, 055513, CDR0000481121, N01CM62202
Study First Received: May 30, 2006
Last Updated: September 19, 2012
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Adenocarcinoma
Prostatic Neoplasms
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Genital Diseases, Male
Prostatic Diseases
Epothilone B
Mitoxantrone
Prednisone
Epothilones
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Central Nervous System Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Anti-Inflammatory Agents
Tubulin Modulators
Antimitotic Agents

ClinicalTrials.gov processed this record on April 23, 2014