Phase I Study of Weekly Intravenous PS-341 (Bortezomib) Plus Mitoxantrone - Full Text View

Sponsor:	M.D. Anderson Cancer Center
Collaborators:	Millennium Pharmaceuticals, Inc. National Cancer Institute (NCI)
Information provided by (Responsible Party):	M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier:	NCT00059631

Purpose

Primary Objective:

-Establish the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of weekly mitoxantrone in combination with weekly PS-341 in patients with advanced AI-PCa.

Secondary objectives:

Evaluate the effect of bortezomib and mitoxantrone in combination on PSA levels among patients with baseline PSA levels >/=5 ng/mL who are treated near the maximum tolerated dose.
Monitor the effect of escalating doses of bortezomib combined with mitoxantrone on selected parameters of clinical benefit (i.e. performance status, tumor-related symptoms, measurable disease response).

Condition	Intervention	Phase
Prostate Cancer	Drug: Mitoxantrone (Novantrone) Drug: Bortezomib (PS-341)	Phase I

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Phase I Study of Weekly Intravenous PS-341 (Bortezomib) Plus Mitoxantrone in Patients With Advanced Androgen-Independent Prostate Cancer (AI-PCa)

Resource links provided by NLM:

MedlinePlus related topics: Cancer Prostate Cancer

Drug Information available for: Mitoxantrone Mitoxantrone hydrochloride Bortezomib

U.S. FDA Resources

Further study details as provided by M.D. Anderson Cancer Center:

Primary Outcome Measures:

Maximum Tolerated Dose (MTD) of Novantrone (Mitoxantrone) combined with PS-341 (Bortezomib) [ Time Frame: Continual reassessment method, with each 5 week cycle ] [ Designated as safety issue: Yes ]
A single-course MTD is defined as the dose level having mean posterior dose limiting toxicity probability closest to 25%.

Secondary Outcome Measures:

Activity of drug's biochemical target, the 20S proteasome, in peripheral blood white cells [ Time Frame: 7 Years ] [ Designated as safety issue: No ]

Estimated Enrollment:	42
Study Start Date:	March 2003
Estimated Primary Completion Date:	March 2013 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Bortezomib + Mitoxantrone	Drug: Mitoxantrone (Novantrone) Starting dose of 2 mg/m^2, four weekly intravenous injections (on Days 1, 8, 15 and 22) over eight 5 week cycles. Drug: Bortezomib (PS-341) Starting Dose of 1.4 mg/m^2, four weekly intravenous injections (on Days 1, 8, 15, and 22) over eight 5 week cycles. Other Names: Velcade LDP-341 MLN341

Detailed Description:

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 multiply.

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 it.

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 .

Eligibility

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

Criteria

Inclusion Criteria:

Patient has given voluntary written informed consent before performance of any study-related procedure not part of standard medical care.
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).
Patient has progressive measurable or evaluable disease, defined as meeting at least one of the three criteria, described in protocol section 4.1.
Zubrod performance status of </= 2 (Appendix B).
Resting Left Ventricular Ejection Fraction (LEVF) >/= 50%.
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 </=1.5 x the upper limit of normal (ULN). ALT or AST </= 2.5 x the ULN, or, if the patient has liver metastases, </= 5 x the ULN. Creatinine </= 2 mg/dL. Serum testosterone </= 50 ng/mL.

Exclusion Criteria:

Patient has received chemotherapy (including thalidomide or ketoconazole) within four weeks, nitrosoureas within six weeks, or antibody therapy within eight weeks of enrollment.
Patient has received radiation therapy or Samarium-153 within four weeks of enrollment, or Strontium-89 within 12 weeks of enrollment.
Patient has not recovered from all serious toxic effects of previous chemotherapy or radiation or antibody therapy.
Patient received treatment with flutamide within four weeks of enrollment or nilutamide or bicalutamide within six weeks of enrollment.
Patient has had any major surgery within four weeks of enrollment.
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 5.1.4.1).
Patient has a history of severe hypersensitivity reaction to mitoxantrone or other agents formulated with polysorbate 80.
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)
Patients who have received > equivalent to 180 mg/m^2 of Doxorubicin cumulative dose.
Patients with diabetes mellitus requiring insulin, or those that have required pharmacologic intervention for diabetes mellitus for greater than 5 years
Patient has uncontrolled brain metastases or central nervous system disease.
Patient has >/= Grade 2 peripheral neuropathy (per NCI CTC v.2).
Patient has an uncontrolled intercurrent illness (e.g., active infection).
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.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00059631

Locations

United States, Texas
UT MD Anderson Cancer Center
Houston, Texas, United States, 77030

Sponsors and Collaborators

M.D. Anderson Cancer Center

Millennium Pharmaceuticals, Inc.

National Cancer Institute (NCI)

Investigators

Principal Investigator:

Arlene Siefker-Radtke, MD

UT M.D. Anderson Cancer Center

More Information

Additional Information:

UT MD Anderson Cancer Center website This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party:	M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier:	NCT00059631 History of Changes
Obsolete Identifiers:	NCT00082680
Other Study ID Numbers:	ID02-227, P50CA090270, P30CA016672, MDA-ID-02227, CDR0000355822
Study First Received:	April 29, 2003
Last Updated:	September 1, 2011
Health Authority:	United States: Food and Drug Administration

Keywords provided by M.D. Anderson Cancer Center:

Prostate Cancer
Advanced Androgen-Independent Prostate Cancer
AI-PCa
Advanced Prostate Cancer
Novantrone
Mitoxantrone

PS-341
Bortezomib
Velcade
LDP-341
MLN341
20S proteasome

Additional relevant MeSH terms:

Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Genital Diseases, Male
Prostatic Diseases
Androgens
Bortezomib
Mitoxantrone
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists

Physiological Effects of Drugs
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Central Nervous System Agents
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on February 09, 2012