Doxorubicin Hydrochloride Liposome and Bortezomib in Treating Patients With Refractory Hematologic Cancer or Malignant Solid Tumor or Metastatic Breast Cancer

Sponsor

UNC Lineberger Comprehensive Cancer Center (Other)

Overall Status

Completed

CT.gov ID

NCT00237627

Collaborator

National Cancer Institute (NCI) (NIH)

107

Enrollment

Location

Arms

104

Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy, such as doxorubicin hydrochloride liposome, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving doxorubicin hydrochloride liposome together with bortezomib may kill more cancer cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of bortezomib when given together with doxorubicin hydrochloride liposome and to see how well they work in treating patients with refractory hematologic cancer or malignant solid tumor or metastatic breast cancer.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer Leukemia Lymphoma Multiple Myeloma and Plasma Cell Neoplasm Ovarian Cancer Unspecified Adult Solid Tumor, Protocol Specific	Drug: PS-341 Drug: Doxil Drug: Velcade	Phase 1/Phase 2

Detailed Description

OBJECTIVES:

Primary

Determine the maximum tolerated dose of bortezomib when administered with pegylated doxorubicin hydrochloride liposome in patients with refractory hematologic or solid tumor malignancies. (Phase I [closed to accrual as of 10/15/2007])
Determine the dose-limiting toxicity of this regimen in these patients. (Phase I [closed to accrual as of 10/15/2007])
Determine the response rate in patients with metastatic breast cancer treated with this regimen. (Phase II)

Secondary

Determine the response in patients with hematologic or solid tumor malignancies treated with this regimen. (Phase I [closed to accrual as of 10/15/2007])
Determine the time to disease progression in patients with metastatic breast cancer treated with this regimen. (Phase II)
Obtain further evidence of the safety of this regimen in patients with metastatic breast cancer. (Phase II)

OUTLINE: This is a phase I (closed to accrual as of 10/15/2007), dose-escalation study of bortezomib followed by a phase II study.

Phase I (closed to accrual as of 10/15/2007): Patients receive bortezomib IV on days 1, 4, 8, and 11 and pegylated doxorubicin hydrochloride liposome IV over 1 hour on day 4. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.
Phase II: Patients receive bortezomib (at the maximum tolerated dose determined in phase

and pegylated doxorubicin hydrochloride liposome as in phase I.

After completion of study therapy, patients are followed at 1 week.

PROJECTED ACCRUAL: A total of 72 patients will be accrued for the phase I portion of the study and 40 for the phase II portion.

Study Design

Study Type:

Interventional

Actual Enrollment :

107 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase I Evaluation of the Combination of Pegylated Liposomal Doxorubicin (Doxil®) With PS-341 in Patients With Refractory Hematologic and Solid Malignancies

Study Start Date :

May 1, 2001

Actual Primary Completion Date :

Dec 1, 2006

Actual Study Completion Date :

Jan 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Part 1 Doxil + PS-341	Drug: PS-341 PS-341 will be administered as an intravenous push into a side arm of either a peripheral or central intravenous line infusing normal saline at 100 ml/hr. Patients will be treated twice weekly for two weeks, followed by a one week rest period, such that the typical days of treatment will be days 1, 4, 8, 11 of each three-week cycle. The initial dose level for PS-341 will be 0.9 mg/m2/dose intravenously, while subsequent dose levels will be determined according to a modified Fibonacci schema Drug: Doxil Doxil will be administered at a dose of 30 mg/m2 as a 1 hour infusion through either a peripheral or central intravenous line every 3 weeks (on day 4 of each 21 day cycle) Other Names: pegylated liposomal doxorubicin
Experimental: Part 2 Doxil + Velcade	Drug: Doxil Doxil will be administered at a dose of 30 mg/m2 as a 1 hour infusion through either a peripheral or central intravenous line every 3 weeks (on day 4 of each 21 day cycle) Other Names: pegylated liposomal doxorubicin Drug: Velcade Velcade will be adminstered intravenously at 1.3 mg/m2 days 1, 4, 8, 11 every 3 weeks Other Names: Bortezomib

Arm

Intervention/Treatment

Experimental: Part 1

Doxil + PS-341

Drug: PS-341

PS-341 will be administered as an intravenous push into a side arm of either a peripheral or central intravenous line infusing normal saline at 100 ml/hr. Patients will be treated twice weekly for two weeks, followed by a one week rest period, such that the typical days of treatment will be days 1, 4, 8, 11 of each three-week cycle. The initial dose level for PS-341 will be 0.9 mg/m2/dose intravenously, while subsequent dose levels will be determined according to a modified Fibonacci schema

Drug: Doxil

Doxil will be administered at a dose of 30 mg/m2 as a 1 hour infusion through either a peripheral or central intravenous line every 3 weeks (on day 4 of each 21 day cycle)

Other Names:

pegylated liposomal doxorubicin

Experimental: Part 2

Doxil + Velcade

Drug: Doxil

Doxil will be administered at a dose of 30 mg/m2 as a 1 hour infusion through either a peripheral or central intravenous line every 3 weeks (on day 4 of each 21 day cycle)

Other Names:

pegylated liposomal doxorubicin

Drug: Velcade

Velcade will be adminstered intravenously at 1.3 mg/m2 days 1, 4, 8, 11 every 3 weeks

Other Names:

Bortezomib

Outcome Measures

Primary Outcome Measures

Maximum tolerated dose (MTD) of PS-341 in combination with Doxil (Phase I) [1 year]
When the current dose level exceeds the MTD, the preceding dose-level will be considered to be the MTD if there have been six patients treated at that dose level. Otherwise, 3 additional patients will be treated at the presumed MTD. No further dose escalation will occur. MTD, like dose limiting toxicity (DLT), will be defined based on toxicities seen within the first cycle. Among the additional 3 patients enrolled in a cohort, if one or more DLT is observed, the MTD will be considered to have been exceeded
Response rate of the combination of Velcade and Doxil in patients with metastatic breast cancer [every 42 days]
Radiographic response will be measured using RECIST criteria

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

DISEASE CHARACTERISTICS:

Phase I (closed to accrual as of 10/15/2007)

Histologically or cytologically confirmed solid tumor or hematologic malignancy, including, but not limited to, any of the following:
Breast cancer
Ovarian cancer
Myeloid or lymphoid leukemia
Hodgkin or non-Hodgkin lymphoma
Multiple myeloma
Measurable or evaluable disease
Must meet 1 of the following criteria:
Refractory to at least one prior conventional treatment regimen
Not a candidate for conventional therapy
No conventional therapy exists
No clinically or radiographically significant pleural or pericardial effusion
Patients with ascites may be eligible at the discretion of the investigator
Previously treated central nervous system disease allowed provided it has been stable for > 3 months and it is not the only site of measurable disease
Not eligible for a higher priority protocol

Phase II

Diagnosis of breast cancer
Metastatic disease
Measurable disease by RECIST criteria
No symptomatic brain metastases
Patients with treated brain metastases that have been stable for > 3 months and does not require chronic steroids are eligible
Hormone receptor status not specified

PATIENT CHARACTERISTICS:

Phase I (closed to accrual as of 10/15/2007)

Karnofsky performance status 60-100%
Life expectancy ≥ 2 months
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
WBC ≥ 2,000/mm³
ANC ≥ 1,500/mm³ (≥ 1,000/mm³ for patients with marrow infiltration)
Platelet count ≥ 100,000/mm³ (≥ 50,000/mm³ for patients with marrow infiltration)
Hemoglobin ≥ 8 g/dL
Creatinine ≤ 2.5 mg/dL OR creatinine clearance ≥ 30 mL/min
AST and ALT < 2.5 times upper limit of normal (ULN)
Total bilirubin < 1.2 times ULN
Prothrombin time (PT) and activated partial thromboplastin time (aPTT) < 1.5 times ULN
Patients receiving warfarin or heparin therapy for a history of thrombosis, embolism, or other indication must have PT and/or aPTT within the accepted therapeutic ranges for those indications
Patients with a history of reactions to other liposomal drug formulations that are not due to the liposome itself may be eligible at the discretion of the investigator
No known HIV seropositivity
No known active hepatitis A, B, or C viral infection
No New York Heart Association class III or IV congestive heart failure
LVEF ≥ 45% by 2-D ECHO or MUGA
No acute ischemia or new conduction system abnormality by EKG
No conduction system abnormality (e.g., left bundle branch block) by EKG that would preclude the ability to detect new ischemic episodes
No myocardial infarction within the past 6 months
No significant comorbidity, such as poorly controlled hypertension, diabetes mellitus, or other serious medical or psychiatric illness that, in the opinion of the investigator, might compromise any aspect of the study
No uncontrolled infection
Patients may have febrile episodes up to 38.5°C if these are felt to be due to tumor fever and the possibility of infection has been ruled out by evaluation
No prior hypersensitivity reaction to pegylated doxorubicin hydrochloride liposome or doxorubicin hydrochloride
Patients with a history of reactions to other liposomal drug formulations and/or to the liposome itself, as opposed to the encapsulated agent, may be excluded at the discretion of the investigator

Phase II

Female or male
Menopausal status not specified
Karnofsky performance status 70-100%
Life expectancy ≥ 3 months
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception during and for 3 months after completion of study therapy
ANC ≥ 1,500/mm³
Platelet count ≥ 100,000/mm³
Hemoglobin ≥ 9.0 g/dL
Creatinine ≤ 2.5 mg/dL (≤ 200 µmol/L)
AST and ALT ≤ 2 times ULN
Alkaline phosphatase ≤ 2 times ULN (unless attributed to tumor)
Bilirubin ≤ ULN
Cardiac ejection fraction > 50% by MUGA or 2-D ECHO
No clinical evidence of congestive heart failure
No New York Heart Association class II-IV cardiac disease
No myocardial infarction within the past 6 months
No uncontrolled angina
No severe uncontrolled ventricular arrhythmias
No evidence of acute ischemia or active conduction system abnormalities by EKG
Any EKG abnormality at screening must be documented by the investigator as not medically relevant
No grade 2 peripheral neuropathy within the past 14 days
No significant comorbidity that would impair compliance with study therapy or interpretation of study results
No history of hypersensitivity reactions attributed to a conventional formulation of doxorubicin hydrochloride or the components of pegylated doxorubicin hydrochloride liposome
No hypersensitivity to bortezomib, boron, or mannitol
No serious medical or psychiatric illness likely to interfere with participation in this study

PRIOR CONCURRENT THERAPY:

Phase I (closed to accrual as of 10/15/2007)

More than 3 weeks since prior major surgery
More than 3 weeks since prior and no concurrent radiotherapy
More than 4 weeks since prior and no concurrent immunotherapy (i.e., interferon, interleukin, or other cytokine-based treatment)
More than 3 weeks since prior and no concurrent participation in another therapeutic clinical trial with an experimental drug
More than 3 weeks since prior and no other concurrent chemotherapy
No prior doxorubicin dose > 400 mg/m²
No other concurrent antineoplastic therapy

Phase II

More than 6 months since prior anthracyclines
More than 14 days since other prior investigational drugs
No more than 300 mg/m² of prior doxorubicin or 540 mg/m² of prior epirubicin
No more than two prior chemotherapy regimens for metastatic disease
No other concurrent antineoplastic therapy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill	Chapel Hill	North Carolina	United States	27599-7295

Sponsors and Collaborators

UNC Lineberger Comprehensive Cancer Center
National Cancer Institute (NCI)

Investigators

Principal Investigator: Elizabeth C. Dees, MD, UNC Lineberger Comprehensive Cancer Center
Principal Investigator: Robert Z. Orlowski, MD, PhD, UNC Lineberger Comprehensive Cancer Center