Clinical trial NCT00331344: Treating Patients With Metastatic Prostate Cancer Not Responding to Hormone and Chemotherapy
Official title: Phase I/II Trial of Epothilone Analog BMS-247550 (Ixabepilone), Mitoxantrone, and Prednisone in Hormone Refractory Prostate Cancer (HRPC) Patients Previously Treated With Chemotherapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Adenocarcinoma of the Prostate
Recurrent Prostate Cancer
Stage IV Prostate Cancer
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2006-05-31
Enrollment: 100
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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

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 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

Primary outcomes:
measure: Proportion Responding to Treatment With of the Combination of Ixabepilone and Mitoxantrone Hydrochloride With Prednisone in Hormone Refractory Prostate Cancer Patients Who Have Had Prior Taxane Chemotherapy Based Upon a PSA Decline of > 50% (Phase II)
timeFrame: Every 3 courses until cancer progression/excessive toxicity or death
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)
timeFrame: Every 21 days until cancer progression/excessive toxicity or death
measure: Dose Limiting Toxicities for Each Dose Level of Ixabepilone, Mitoxantrone Hydrochloride, and Prednisone in Patients With Hormone-refractory Metastatic Prostate Cancer That Progressed During or After Taxane-based Chemotherapy (Phase I).
timeFrame: Course 1 (first 21 days)
Secondary outcomes:
measure: Time to Progression (Phase II)
timeFrame: Every 3 months until cancer progression/excessive toxicity or death
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: UCSF Helen Diller Family Comprehensive Cancer Center
state: California
city: Madison
country: United States
facility: University of Wisconsin Hospital and Clinics
state: Wisconsin
Study officials:
affiliation: University of California San Francisco Medical Center-Mount Zion
name: Andrea Harzstark
role: PRINCIPAL_INVESTIGATOR
References:
citation: Rosenberg JE, Ryan CJ, Weinberg VK, Smith DC, Hussain M, Beer TM, Ryan CW, Mathew P, Pagliaro LC, Harzstark AL, Sharib J, Small EJ. Phase I study of ixabepilone, mitoxantrone, and prednisone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel-based therapy: a study of the department of defense prostate cancer clinical trials consortium. J Clin Oncol. 2009 Jun 10;27(17):2772-8. doi: 10.1200/JCO.2008.19.8002. Epub 2009 Apr 6.
citation: Harzstark AL, Rosenberg JE, Weinberg VK, Sharib J, Ryan CJ, Smith DC, Pagliaro LC, Beer TM, Liu G, Small EJ. Ixabepilone, mitoxantrone, and prednisone for metastatic castration-resistant prostate cancer after docetaxel-based therapy: a phase 2 study of the Department Of Defense Prostate Cancer Clinical Trials Consortium. Cancer. 2011 Jun 1;117(11):2419-25. doi: 10.1002/cncr.25810. Epub 2010 Dec 29.