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Phase I Study of Weekly Intravenous PS-341 (Bortezomib) Plus Mitoxantrone in Patients With Advanced Androgen-Independent Prostate Cancer (AI-PCa)

Phase 1
18 Years
Open (Enrolling)
Prostate Cancer

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Trial Information

Phase I Study of Weekly Intravenous PS-341 (Bortezomib) Plus Mitoxantrone in Patients With Advanced Androgen-Independent Prostate Cancer (AI-PCa)

Mitoxantrone is used to treat bone pain in advanced prostate cancer and inhibits many
proteins that the cancer cells need to multiply.

Bortezomib is a member of a new class of drugs that possess powerful and broad-spectrum
anti-tumor activity and inhibit many proteins that the cancer cells need to survive and

Pre-study testing will include brief physical examination, vital signs (weight, height,
temperature, pulse, respiratory and blood pressure), chest x-ray, EKG (test to measure the
electrical activity of the heart), echocardiogram, blood test, urine tests, and depending on
the stage of the disease, a CT scan and/or bone scan.

During treatment, the participants will receive one dose of Mitoxantrone combined with one
dose of Bortezomib every week for 4 weeks in a row followed by 2 weeks of rest; this is
called a course. If side effects are not too severe, Mitoxantrone and Bortezomib will be
infused rapidly into a vein while participants will be receiving normal saline ("salt in
water solution") at a rate of 100ml/hour. They will receive the salt solution the entire
time they are in the treatment area.

Participants will have their vital signs (temperature, pulse, breathing, blood pressure)
taken before and one hour after treatment. All side effects during course one will be
reviewed and, if no serious side effects took place, the participant may have additional
courses. A pill may be given by mouth every day to decrease the risk of clot formation or a
pill for diarrhea, nausea, and/or vomiting if the doctor believes that participants may need

Also during treatment, participants will have a complete physical examination by a physician
or their designated representative (such as a nurse or physician assistant) each week of
treatment. Bone Scan and/or CT Scan will be done if necessary. Participants will have
blood tests done every week during study. A special blood test, called the 20S proteosome,
will be done weekly during Cycles 1 and 2 to evaluate the activity of the drugs. Blood will
be collected before you receive treatment and then at 1-2 hours afterward. About 2 teaspoons
of blood will be collected each time for this. Bone scan, chest x-ray and/or CT scans will
be repeated during the study every other course.

Participants will be taken off study if the disease gets worse or intolerable side effects
occur. Side effects that are thought to be related to the study drug are renal failure
resulting in death, and a grade 3 rash requiring treatment with steroids that recurred with
subsequent treatments.

The maximum amount of time that participants can remain on the study is 8 courses of
treatment. Long term follow-up of participants will include a phone call every 6 months.

This is an investigational study. Bortezomib has been approved by the FDA for
investigational use only. Mitoxantrone has been approved by the FDA for treatment of
symptoms in advanced prostate cancer. Only Mitoxantrone is commercially available. About 42
participants will take part in this study. All will be enrolled at M.D. Anderson .

Inclusion Criteria:

1. Patient has given voluntary written informed consent before performance of any
study-related procedure not part of standard medical care.

2. Patient has histologically-confirmed advanced and/or metastatic AI-PCa requiring
anti-neoplastic treatment. Patients should continue on LHRH analog therapy throughout
the study period, if this is their mode of androgen suppression therapy. Patients
should have discontinued anti-androgen therapy for >/= than 4 weeks (for flutamide)
or >/= 6 weeks (for bicalutamide and nilutamide).

3. Patient has progressive measurable or evaluable disease, defined as meeting at least
one of the three criteria, described in protocol section 4.1.

4. Zubrod performance status of
5. Resting Left Ventricular Ejection Fraction (LEVF) >/= 50%.

6. Patient has all of the following pretreatment laboratory data within 14 days (except
for serum testosterone which may be done within 28 days prior to registration) before
the first study drug dose: Absolute neutrophil count (ANC) >/= 1,500/mm^3. Platelets
>/= 100,000/mm^3. Hemoglobin >8.0 g/dL. Total bilirubin normal (ULN). ALT or AST
Exclusion Criteria:

1. Patient has received chemotherapy (including thalidomide or ketoconazole) within four
weeks, nitrosoureas within six weeks, or antibody therapy within eight weeks of

2. Patient has received radiation therapy or Samarium-153 within four weeks of
enrollment, or Strontium-89 within 12 weeks of enrollment.

3. Patient has not recovered from all serious toxic effects of previous chemotherapy or
radiation or antibody therapy.

4. Patient received treatment with flutamide within four weeks of enrollment or
nilutamide or bicalutamide within six weeks of enrollment.

5. Patient has had any major surgery within four weeks of enrollment.

6. Patient has a history of allergic reactions to anti-diarrheal medications or
anti-emetics suggested to be administered in conjunction with study drug (see Section

7. Patient has a history of severe hypersensitivity reaction to mitoxantrone or other
agents formulated with polysorbate 80.

8. Patients with significant atherosclerotic disease, as defined by: a) myocardial
infarction within six months of enrollment, uncontrolled / unstable angina pectoris
or electrocardiographic evidence of acute ischemia b) clinically significant
ventricular arrhythmias, c) symptomatic congestive heart failure d) significant
conduction abnormalities: 2nd or 3rd degree AV blocks, bifascicular block (defined as
Left Anterior Hemiblock in the presence of Right Bundle Branch Block), e)
claudication limiting activity and f) history of cerebrovascular events within the
last year (including TIA)

9. Patients who have received > equivalent to 180 mg/m^2 of Doxorubicin cumulative dose.

10. Patients with diabetes mellitus requiring insulin, or those that have required
pharmacologic intervention for diabetes mellitus for greater than 5 years

11. Patient has uncontrolled brain metastases or central nervous system disease.

12. Patient has >/= Grade 2 peripheral neuropathy (per NCI CTC v.2).

13. Patient has an uncontrolled intercurrent illness (e.g., active infection).

14. Patient has another serious medical or psychiatric illness that could, in the
investigator's opinion, potentially interfere with the patient's ability to provide
informed consent or with the completion of treatment according to this protocol.

Type of Study:


Study Design:

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

Outcome Measure:

Maximum Tolerated Dose (MTD) of Novantrone (Mitoxantrone) combined with PS-341 (Bortezomib)

Outcome Description:

A single-course MTD is defined as the dose level having mean posterior dose limiting toxicity probability closest to 25%.

Outcome Time Frame:

Continual reassessment method, with each 5 week cycle

Safety Issue:


Principal Investigator

Arlene Siefker-Radtke, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

UT M.D. Anderson Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

March 2003

Completion Date:

Related Keywords:

  • Prostate Cancer
  • Prostate Cancer
  • Advanced Androgen-Independent Prostate Cancer
  • AI-PCa
  • Advanced Prostate Cancer
  • Novantrone
  • Mitoxantrone
  • PS-341
  • Bortezomib
  • Velcade
  • LDP-341
  • MLN341
  • 20S proteasome
  • Prostatic Neoplasms



UT MD Anderson Cancer Center Houston, Texas  77030