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Phase I/II Trial of Epothilone Analog BMS-247550 (Ixabepilone), Mitoxantrone, and Prednisone in Hormone Refractory Prostate Cancer Patients Previously Treated With Chemotherapy


Phase 1/Phase 2
18 Years
N/A
Not Enrolling
Male
Adenocarcinoma of the Prostate, Recurrent Prostate Cancer, Stage IV Prostate Cancer

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Trial Information

Phase I/II Trial of Epothilone Analog BMS-247550 (Ixabepilone), Mitoxantrone, and Prednisone in Hormone Refractory Prostate Cancer Patients Previously Treated With Chemotherapy


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.


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

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

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)

Outcome Description:

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.

Outcome Time Frame:

Every 21 days

Safety Issue:

Yes

Principal Investigator

Andrea Harzstark

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of California San Francisco Medical Center-Mount Zion

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2009-00155

NCT ID:

NCT00331344

Start Date:

April 2006

Completion Date:

Related Keywords:

  • Adenocarcinoma of the Prostate
  • Recurrent Prostate Cancer
  • Stage IV Prostate Cancer
  • Adenocarcinoma
  • Adenocarcinoma, Mucinous
  • Prostatic Neoplasms

Name

Location

University of Wisconsin Hospital and ClinicsMadison, Wisconsin  53792-0001
UCSF Helen Diller Family Comprehensive Cancer CenterSan Francisco, California  94115