Cixutumumab and Temsirolimus in Treating Patients With Locally Recurrent or Metastatic Breast Cancer

Recurrent Breast Carcinoma Clinical Trial

Official title:

Phase I/II Trial of IMC-A12 in Combination With Temsirolimus in Patients With Metastatic Breast Cancer

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00699491
• Other study ID #: NCI-2009-00284
• Secondary ID: NCI-2009-00284CD
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: October 31, 2008
• Est. completion date: February 14, 2018

Study information

• Verified date: May 2018
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This phase I/II trial is studying the side effects and best dose of cixutumumab when given together with temsirolimus and to see how well they work in treating patients with breast cancer that has recurred (come back) at or near the same place as the original (primary) tumor or has spread to other places in the body. Monoclonal antibodies, such as cixutumumab, can block tumor growth in different ways by targeting certain cells. Temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving cixutumumab together with temsirolimus may be a better treatment for breast cancer.

Description:

PRIMARY OBJECTIVES:

I. To establish the recommended dose level for the phase II trial. (Phase I) II. To examine the safety profile of this combination in patients with metastatic breast cancer. (Phase I) III. To assess the anti-tumor activity (in terms of overall response rate) and toxicity profile of IMC-A12 (cixutumumab) in combination with temsirolimus in patients with metastatic breast cancer. (Phase II)

SECONDARY OBJECTIVES:

I. To estimate the progression-free survival (PFS) and overall survival distributions (as well as the 6-month PFS rate).

II. To evaluate the in vivo mechanisms of action of temsirolimus in combination with IMC-A12 and to examine potential biomarker predictors of treatment response.

OUTLINE: This is a phase I, dose-escalation study of cixutumumab followed by a phase II study.

Patients receive temsirolimus intravenously (IV) over 30 minutes and cixutumumab IV over 60 minutes on days 1, 8, 15, and 22 (cixutumumab is given on days 8, 15, and 22 of course 1 only). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically for up to 2 (phase I) or 5 (phase II) years.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 48
• Est. completion date: February 14, 2018
• Est. primary completion date: September 9, 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Histologically confirmed diagnosis of breast cancer with diagnosis of metastatic or locally recurrent disease (locally recurrent disease should be stage IV e.g. chest wall involvement)

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1 (Karnofsky >= 80%)

• Life expectancy of > 12 weeks

• Capable of understanding investigational nature, potential risks and benefits of the study and able to provide written informed consent

• Negative serum pregnancy test =< 7 days of registration for women of childbearing potential:

• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) for the duration of study therapy and for 3 months after the last dose of IMC-A12 and CCI-779 (temsirolimus)

• Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately

• Nursing women must be willing to discontinue nursing; NOTE: breastfeeding should be discontinued if the mother is treated with CCI-779 and IMC-A12

• Absolute neutrophil count >= 1,500/mcL

• Hemoglobin >= 8.5 g/dL

• Platelets >= 100,000/mcL

• Total bilirubin =< 1.5 X institutional upper limit of normal (ULN)

• Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional ULN (=< 5 X institutional ULN if liver function test [LFT] elevations due to liver metastases)

• Creatinine =< 1.5 X institutional ULN OR creatinine clearance >= 60 mL/min/1.73^2 for patients with creatinine > institutional ULN

• Fasting serum cholesterol =< 350 mg/dL (9.0 mmol/L)

• Fasting triglycerides =< 400 mg/dL (4.56 mmol/L)

• Albumin >= 3.4 mg/dL

• Fasting or non fasting serum glucose < 120 mg/dL

• Hemoglobin A1c (HbA1c) (for all patients with a history of diabetes mellitus) < 8%

• Phase I only: Any number of prior therapy regimens is allowed

• Phase II only: Measurable disease is required for the Phase II portion of the study; measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 20 mm with conventional techniques (computed tomography [CT], magnetic resonance imaging [MRI], x-ray) or as >= 10 mm with spiral CT scan

• Phase II only: =< two and at least one prior chemotherapy regimens in the setting of metastatic or locally recurrent (stage IV chest wall involvement) disease are required

Exclusion Criteria:

• Phase I patients only: Patients with base line diabetes requiring oral hypoglycemics or insulin

• Phase II patients only: Poorly controlled diabetes mellitus; NOTE: patients with a history of diabetes mellitus on oral hypoglycemics or insulin are allowed to participate, provided that their fasting blood glucose is < 120 mg/dL and that they are on a stable dietary or therapeutic regimen for this condition

• Any of the following:

• Pregnant women

• Nursing women

• Men or women of childbearing potential who are unwilling to employ adequate contraception (hormonal agents are not allowed and oral contraceptives are not acceptable for contraception)

• Receiving hormonal agents used for the treatment of breast cancer with the exception that premenopausal women who have been on a gonadotropin-releasing hormone (GnRH) agonist and subsequently progressed may, at the discretion of the treating physician, continue on the GnRH agonist

• Any of the following prior therapies:

• Systemic anti-cancer therapy =< 3 weeks prior to registration

• Radiation therapy =< 2 weeks prior to registration

• Prior invasive non-breast malignancy, except for adequately treated basal or squamous cell carcinoma of the skin or other cancer from which the patient has been disease free for >= 5 years

• Known hypersensitivity reactions to macrolide antibiotics (such as erythromycin, clarithromycin, and azithromycin); allergic reactions attributed to compounds of similar chemical or biologic composition to IMC-A12, or temsirolimus

• Prior treatment with agents targeting the insulin-like growth factor-I receptor (IGF-IR)/insulin-like growth factors (IGFs) or phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PI3K)/v-akt murine thymoma viral oncogene homolog 1 (Akt)/mechanistic target of rapamycin (mTOR) pathway

• Receiving any other investigational agents or herbal preparations

• Patients may not be taking oral corticosteroids except for replacement for adrenal insufficiency

• Uncontrolled brain metastases; Note: brain metastases are not permitted on study unless the metastases have been treated by surgery or radiotherapy, and the patient has been neurologically stable and off of steroids for >= 12 weeks

• Known human immunodeficiency virus (HIV)-positive patients who have cluster of differentiation (CD)4 counts below the normal range or who are on anti-retroviral therapy that may interfere with the metabolism of temsirolimus

• Uncontrolled intercurrent illness including, but not limited to:

• Ongoing or active infection

• Symptomatic congestive heart failure

• Unstable angina pectoris

• Uncontrolled symptomatic cardiac arrhythmia

• Psychiatric illness/social situations that would limit compliance with study requirements

• Receiving enzyme-inducing antiepileptic drugs (EIAEDs; e.g., phenytoin, carbamazepine, phenobarbital) or any other cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inducer such as rifampin or St. John's wort

Related Conditions & MeSH terms

• Breast Neoplasms
• Breast Neoplasms, Male
• Carcinoma
• Male Breast Carcinoma
• Recurrent Breast Carcinoma
• Stage IV Breast Cancer AJCC v6 and v7

Intervention

Biological:
• Cixutumumab
Given IV

Other:
• Laboratory Biomarker Analysis
Correlative studies
• Pharmacological Study
Correlative studies

Drug:
• Temsirolimus
Given IV

Locations

Country	Name	City	State
United States	Hawaii Oncology Inc-Pali Momi	'Aiea	Hawaii
United States	Pali Momi Medical Center	'Aiea	Hawaii
United States	Bixby Medical Center	Adrian	Michigan
United States	Hickman Cancer Center	Adrian	Michigan
United States	Michigan Cancer Research Consortium NCORP	Ann Arbor	Michigan
United States	Saint Joseph Mercy Hospital	Ann Arbor	Michigan
United States	Randolph Hospital	Asheboro	North Carolina
United States	Rush - Copley Medical Center	Aurora	Illinois
United States	The Medical Center of Aurora	Aurora	Colorado
United States	Mid Dakota Clinic	Bismarck	North Dakota
United States	Saint Alexius Medical Center	Bismarck	North Dakota
United States	Sanford Bismarck Medical Center	Bismarck	North Dakota
United States	Illinois CancerCare-Bloomington	Bloomington	Illinois
United States	Saint Joseph Medical Center	Bloomington	Illinois
United States	Saint Alphonsus Cancer Care Center-Boise	Boise	Idaho
United States	Boulder Community Hospital	Boulder	Colorado
United States	Toledo Clinic Cancer Centers-Bowling Green	Bowling Green	Ohio
United States	Cooper Hospital University Medical Center	Camden	New Jersey
United States	Graham Hospital Association	Canton	Illinois
United States	Illinois CancerCare-Canton	Canton	Illinois
United States	Illinois CancerCare-Carthage	Carthage	Illinois
United States	Memorial Hospital	Carthage	Illinois
United States	University of Chicago Comprehensive Cancer Center	Chicago	Illinois
United States	Weiss Memorial Hospital	Chicago	Illinois
United States	Adena Regional Medical Center	Chillicothe	Ohio
United States	Penrose-Saint Francis Healthcare	Colorado Springs	Colorado
United States	Columbus NCI Community Oncology Research Program	Columbus	Ohio
United States	Doctors Hospital	Columbus	Ohio
United States	Grant Medical Center	Columbus	Ohio
United States	John B Amos Cancer Center	Columbus	Georgia
United States	Mount Carmel Health Center West	Columbus	Ohio
United States	Riverside Methodist Hospital	Columbus	Ohio
United States	Dayton NCI Community Oncology Research Program	Dayton	Ohio
United States	Good Samaritan Hospital - Dayton	Dayton	Ohio
United States	Grandview Hospital	Dayton	Ohio
United States	Miami Valley Hospital	Dayton	Ohio
United States	Samaritan North Health Center	Dayton	Ohio
United States	Beaumont Hospital-Dearborn	Dearborn	Michigan
United States	Heartland Cancer Research NCORP	Decatur	Illinois
United States	Grady Memorial Hospital	Delaware	Ohio
United States	Colorado Cancer Research Program NCORP	Denver	Colorado
United States	Porter Adventist Hospital	Denver	Colorado
United States	Presbyterian - Saint Lukes Medical Center - Health One	Denver	Colorado
United States	Rose Medical Center	Denver	Colorado
United States	SCL Health Saint Joseph Hospital	Denver	Colorado
United States	Saint John Hospital and Medical Center	Detroit	Michigan
United States	Essentia Health Cancer Center	Duluth	Minnesota
United States	Essentia Health Saint Mary's Medical Center	Duluth	Minnesota
United States	Miller-Dwan Hospital	Duluth	Minnesota
United States	Union Hospital of Cecil County	Elkton	Maryland
United States	Hematology Oncology Center Incorporated	Elyria	Ohio
United States	Mercy Cancer Center-Elyria	Elyria	Ohio
United States	Swedish Medical Center	Englewood	Colorado
United States	Green Bay Oncology - Escanaba	Escanaba	Michigan
United States	Eureka Hospital	Eureka	Illinois
United States	Illinois CancerCare-Eureka	Eureka	Illinois
United States	Blanchard Valley Hospital	Findlay	Ohio
United States	Genesys Hurley Cancer Institute	Flint	Michigan
United States	Genesys Regional Medical Center-West Flint Campus	Flint	Michigan
United States	Hurley Medical Center	Flint	Michigan
United States	Atrium Medical Center-Middletown Regional Hospital	Franklin	Ohio
United States	Fredericksburg Oncology Inc	Fredericksburg	Virginia
United States	Illinois CancerCare-Galesburg	Galesburg	Illinois
United States	Glens Falls Hospital	Glens Falls	New York
United States	Wayne Memorial Hospital	Goldsboro	North Carolina
United States	Altru Cancer Center	Grand Forks	North Dakota
United States	Benefis Healthcare- Sletten Cancer Institute	Great Falls	Montana
United States	North Colorado Medical Center	Greeley	Colorado
United States	Green Bay Oncology at Saint Vincent Hospital	Green Bay	Wisconsin
United States	Green Bay Oncology Limited at Saint Mary's Hospital	Green Bay	Wisconsin
United States	Saint Vincent Hospital Cancer Center at Saint Mary's	Green Bay	Wisconsin
United States	Saint Vincent Hospital Cancer Center Green Bay	Green Bay	Wisconsin
United States	Cone Health Cancer Center	Greensboro	North Carolina
United States	Wayne Hospital	Greenville	Ohio
United States	Legacy Mount Hood Medical Center	Gresham	Oregon
United States	Smilow Cancer Hospital Care Center at Saint Francis	Hartford	Connecticut
United States	Ingalls Memorial Hospital	Harvey	Illinois
United States	Illinois CancerCare-Havana	Havana	Illinois
United States	Mason District Hospital	Havana	Illinois
United States	Margaret R Pardee Memorial Hospital	Hendersonville	North Carolina
United States	Hawaii Cancer Care Inc-POB II	Honolulu	Hawaii
United States	Hawaii Oncology Inc-Kuakini	Honolulu	Hawaii
United States	Kapiolani Medical Center for Women and Children	Honolulu	Hawaii
United States	Queen's Medical Center	Honolulu	Hawaii
United States	Straub Clinic and Hospital	Honolulu	Hawaii
United States	University of Hawaii Cancer Center	Honolulu	Hawaii
United States	Franciscan Health Indianapolis	Indianapolis	Indiana
United States	Green Bay Oncology - Iron Mountain	Iron Mountain	Michigan
United States	Allegiance Health	Jackson	Michigan
United States	Castle Medical Center	Kailua	Hawaii
United States	Heartland Hematology and Oncology Associates Incorporated	Kansas City	Missouri
United States	North Kansas City Hospital	Kansas City	Missouri
United States	Research Medical Center	Kansas City	Missouri
United States	Saint Luke's Hospital of Kansas City	Kansas City	Missouri
United States	Kettering Medical Center	Kettering	Ohio
United States	Illinois CancerCare-Kewanee Clinic	Kewanee	Illinois
United States	Gundersen Lutheran Medical Center	La Crosse	Wisconsin
United States	Saint Anthony Hospital	Lakewood	Colorado
United States	Fairfield Medical Center	Lancaster	Ohio
United States	Sparrow Hospital	Lansing	Michigan
United States	Saint Luke's East - Lee's Summit	Lee's Summit	Missouri
United States	Beebe Medical Center	Lewes	Delaware
United States	Wilcox Memorial Hospital and Kauai Medical Clinic	Lihue	Hawaii
United States	Lima Memorial Hospital	Lima	Ohio
United States	Nebraska Cancer Research Center	Lincoln	Nebraska
United States	Saint Mary Mercy Hospital	Livonia	Michigan
United States	Sky Ridge Medical Center	Lone Tree	Colorado
United States	Longmont United Hospital	Longmont	Colorado
United States	McKee Medical Center	Loveland	Colorado
United States	Illinois CancerCare-Macomb	Macomb	Illinois
United States	Mcdonough District Hospital	Macomb	Illinois
United States	Holy Family Memorial Hospital	Manitowoc	Wisconsin
United States	Marietta Memorial Hospital	Marietta	Ohio
United States	Bay Area Medical Center	Marinette	Wisconsin
United States	Toledo Clinic Cancer Centers-Maumee	Maumee	Ohio
United States	Toledo Radiation Oncology at Northwest Ohio Onocolgy Center	Maumee	Ohio
United States	Holy Family Medical Center	Monmouth	Illinois
United States	Illinois CancerCare-Monmouth	Monmouth	Illinois
United States	Mercy Memorial Hospital	Monroe	Michigan
United States	Toledo Clinic Cancer Centers-Monroe	Monroe	Michigan
United States	Knox Community Hospital	Mount Vernon	Ohio
United States	Christiana Care Health System-Christiana Hospital	Newark	Delaware
United States	Licking Memorial Hospital	Newark	Ohio
United States	Bromenn Regional Medical Center	Normal	Illinois
United States	Community Cancer Center Foundation	Normal	Illinois
United States	Illinois CancerCare-Community Cancer Center	Normal	Illinois
United States	Green Bay Oncology - Oconto Falls	Oconto Falls	Wisconsin
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Alegent Health Bergan Mercy Medical Center	Omaha	Nebraska
United States	Alegent Health Immanuel Medical Center	Omaha	Nebraska
United States	Alegent Health Lakeside Hospital	Omaha	Nebraska
United States	Creighton University Medical Center	Omaha	Nebraska
United States	Missouri Valley Cancer Consortium	Omaha	Nebraska
United States	Saint Charles Hospital	Oregon	Ohio
United States	Toledo Clinic Cancer Centers-Oregon	Oregon	Ohio
United States	Florida Hospital Orlando	Orlando	Florida
United States	Illinois CancerCare-Ottawa Clinic	Ottawa	Illinois
United States	Ottawa Regional Hospital and Healthcare Center	Ottawa	Illinois
United States	Menorah Medical Center	Overland Park	Kansas
United States	Saint Luke's South Hospital	Overland Park	Kansas
United States	Palo Alto Medical Foundation Health Care	Palo Alto	California
United States	Illinois CancerCare-Pekin	Pekin	Illinois
United States	OSF Saint Francis Radiation Oncology at Pekin Cancer Treatment Center	Pekin	Illinois
United States	Illinois CancerCare-Peoria	Peoria	Illinois
United States	Methodist Medical Center of Illinois	Peoria	Illinois
United States	OSF Saint Francis Medical Center	Peoria	Illinois
United States	Proctor Hospital	Peoria	Illinois
United States	Illinois CancerCare-Peru	Peru	Illinois
United States	Illinois Valley Hospital	Peru	Illinois
United States	Valley Medical Oncology Consultants	Pleasanton	California
United States	Saint Joseph Mercy Oakland	Pontiac	Michigan
United States	Lake Huron Medical Center	Port Huron	Michigan
United States	Legacy Good Samaritan Hospital and Medical Center	Portland	Oregon
United States	Southern Ohio Medical Center	Portsmouth	Ohio
United States	Kansas City NCI Community Oncology Research Program	Prairie Village	Kansas
United States	Illinois CancerCare-Princeton	Princeton	Illinois
United States	Perry Memorial Hospital	Princeton	Illinois
United States	Saint Mary Corwin Medical Center	Pueblo	Colorado
United States	Annie Penn Memorial Hospital	Reidsville	North Carolina
United States	Reid Health	Richmond	Indiana
United States	Mayo Clinic	Rochester	Minnesota
United States	Saint Mary's of Michigan	Saginaw	Michigan
United States	Coborn Cancer Center at Saint Cloud Hospital	Saint Cloud	Minnesota
United States	Saint Cloud Hospital	Saint Cloud	Minnesota
United States	Saint Joseph Oncology Inc	Saint Joseph	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	HSHS Saint Nicholas Hospital	Sheboygan	Wisconsin
United States	Mercy Medical Center-Sioux City	Sioux City	Iowa
United States	Saint Luke's Regional Medical Center	Sioux City	Iowa
United States	Siouxland Regional Cancer Center	Sioux City	Iowa
United States	Illinois CancerCare-Spring Valley	Spring Valley	Illinois
United States	Springfield Regional Medical Center	Springfield	Ohio
United States	Green Bay Oncology - Sturgeon Bay	Sturgeon Bay	Wisconsin
United States	Flower Hospital	Sylvania	Ohio
United States	Mercy Hospital of Tiffin	Tiffin	Ohio
United States	Mercy Saint Anne Hospital	Toledo	Ohio
United States	Saint Vincent Mercy Medical Center	Toledo	Ohio
United States	The Toledo Hospital/Toledo Children's Hospital	Toledo	Ohio
United States	Toledo Clinic Cancer Centers-Toledo	Toledo	Ohio
United States	Toledo Community Hospital Oncology Program CCOP	Toledo	Ohio
United States	University of Toledo	Toledo	Ohio
United States	Upper Valley Medical Center	Troy	Ohio
United States	Legacy Meridian Park Hospital	Tualatin	Oregon
United States	Natalie Warren Bryant Cancer Center at Saint Francis	Tulsa	Oklahoma
United States	Carle Cancer Center	Urbana	Illinois
United States	Legacy Salmon Creek Hospital	Vancouver	Washington
United States	Saint John Macomb-Oakland Hospital	Warren	Michigan
United States	Fulton County Health Center	Wauseon	Ohio
United States	Saint Ann's Hospital	Westerville	Ohio
United States	SCL Health Lutheran Medical Center	Wheat Ridge	Colorado
United States	Greene Memorial Hospital	Xenia	Ohio
United States	Genesis Healthcare System Cancer Care Center	Zanesville	Ohio

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Recommended Dose Level for Phase II Testing (RPTD) (Phase I)	The RPTD is defined as the highest dose level at which at most one of 6 patients develops a dose limiting toxicity (DLT) during the first course of treatment and the next highest dose level has 2 or more DLTs. The number of patients in each cohort reporting a DLT is reported.; Dose-limiting toxicities (DLTs) are defined as any of the following adverse events (AEs) that are related to study agent with an attribution of possible, probably, or definite and fulfilling one of the following criteria: Any grade 4 hematologic toxicity; Hyperglycemia that cannot be stably controlled with diabetic medication; Any grade 3 or 4 non-hematologic toxicity (except asymptomatic medically manageable laboratory abnormalities such as hyperlipidemia, hypophosphatemia, and hypokalemia)	During first course
Primary	Tumor Response Rate (TRR) (Complete Response [CR] or Partial Response [PR]) by the Response Evaluation Criteria in Solid Tumors (RECIST) (Phase II)	A response is defined as a disease burden that meets the RECIST criteria for Complete Response (CR) or Partial Response (PR) on 2 consecutive evaluations at least 6-8 weeks apart.; Complete Response (CR): All of the following must be true: Disappearance of all target and non-target lesions.; Each target lymph node must have reduction in short axis to <1.0 cm.; Partial Response (PR): At least a 30% decrease in PBSD (sum of the longest diameter for all target lesions plus the sum of the short axis of all the target lymph nodes at current evaluation) taking as reference the baseline measures.; The rate is calculated by dividing the number of patients with a CR or PR by the number of evaluable patients. A ninety percent confidence interval for the true tumor response rate will be calculated using the Duffy-Santer approach.	Up to 5 years
Secondary	Adverse Events Graded Using the NCI CTCAE Version. 3 (Phase II)	Adverse events will be graded using the NCI-CTCAE v3.0 coding scheme. The maximum grade for each adverse event considered to be 'at least possibly related to treatment' will be recorded. Frequency tables will be constructed and the number of patients reporting an adverse event of grade 3 or higher at least possibly related to treatment will be reported.	Up to 5 years
Secondary	Duration of Response (Phase II)	Duration of response is defined for all evaluable patients with changes in disease burden that met the RECIST criteria for CR or PR on 2 consecutive evaluations at least 6-8 weeks apart as the date at which the CR or PR to the date progression is documented. The distribution of response durations will be estimated using the Kaplan-Meier method.	Up to 5 years
Secondary	Progression Free Survival (PFS) (Phase II)	Progression free survival is defined as the time from registration to documentation of disease progression. If a patient dies without a documentation of disease progression, the patient will be considered to have had tumor progression at the time of their death unless there is sufficient documented evidence to conclude no progression occurred prior to death. If the patient is declared to be a major treatment violation, the patient will be censored on the date the treatment violation was declared to have occurred. In the case of a patient starting treatment and then never returning for any evaluations, the patient will be censored for progression on the last day of therapy was administered. The distribution of progression-free survival times will be estimated using the Kaplan-Meier method.The distribution of PFS times will be estimated using the Kaplan-Meier method.	Time from registration to documentation of disease progression, up to 5 years
Secondary	Progression Free Survival Rate	Progression free survival (PFS) is defined as the time from registration to documentation of disease progression. A point and interval estimate of the 6 month PFS rate will be obtained using the Kaplan-Meier method.	At 6 months
Secondary	Survival Time (Phase II)	Survival time is defined as the time from registration to death due to any cause. The distribution of survival time will be estimated using the method of Kaplan-Meier.	Time from registration to death due to any cause