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

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 I) 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.

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