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

Inclusion Criteria

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