Clinical trial NCT00237627: Doxorubicin Hydrochloride Liposome and Bortezomib in Treating Patients With Refractory Hematologic Cancer or Malignant Solid Tumor or Metastatic Breast Cancer
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Breast Cancer
Leukemia
Lymphoma
Multiple Myeloma and Plasma Cell Neoplasm
Ovarian Cancer
Unspecified Adult Solid Tumor, Protocol Specific
Keywords: stage IIIA breast cancer
stage IIIB breast cancer
stage IIIC breast cancer
stage IV breast cancer
male breast cancer
recurrent ovarian epithelial cancer
stage III ovarian epithelial cancer
stage IV ovarian epithelial cancer
recurrent adult acute lymphoblastic leukemia
recurrent adult acute myeloid leukemia
adult acute myeloid leukemia with 11q23 (MLL) abnormalities
adult acute myeloid leukemia with inv(16)(p13;q22)
adult acute myeloid leukemia with t(15;17)(q22;q12)
adult acute myeloid leukemia with t(16;16)(p13;q22)
adult acute myeloid leukemia with t(8;21)(q22;q22)
secondary acute myeloid leukemia
mast cell leukemia
stage III chronic lymphocytic leukemia
stage IV chronic lymphocytic leukemia
refractory chronic lymphocytic leukemia
T-cell large granular lymphocyte leukemia
atypical chronic myeloid leukemia
accelerated phase chronic myelogenous leukemia
blastic phase chronic myelogenous leukemia
chronic phase chronic myelogenous leukemia
meningeal chronic myelogenous leukemia
relapsing chronic myelogenous leukemia
chronic myelomonocytic leukemia
refractory hairy cell leukemia
progressive hairy cell leukemia, initial treatment
stage III adult T-cell leukemia/lymphoma
stage IV adult T-cell leukemia/lymphoma
recurrent adult T-cell leukemia/lymphoma
stage III adult Hodgkin lymphoma
stage IV adult Hodgkin lymphoma
recurrent adult Hodgkin lymphoma
anaplastic large cell lymphoma
angioimmunoblastic T-cell lymphoma
stage III cutaneous T-cell non-Hodgkin lymphoma
stage IV cutaneous T-cell non-Hodgkin lymphoma
stage III mycosis fungoides/Sezary syndrome
stage IV mycosis fungoides/Sezary syndrome
recurrent cutaneous T-cell non-Hodgkin lymphoma
recurrent mycosis fungoides/Sezary syndrome
adult grade III lymphomatoid granulomatosis
adult nasal type extranodal NK/T-cell lymphoma
Waldenstrom macroglobulinemia
extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
splenic marginal zone lymphoma
stage III adult Burkitt lymphoma
stage III adult diffuse large cell lymphoma
stage III adult diffuse mixed cell lymphoma
stage III adult diffuse small cleaved cell lymphoma
stage III adult immunoblastic large cell lymphoma
stage III adult lymphoblastic lymphoma
stage III grade 1 follicular lymphoma
stage III grade 2 follicular lymphoma
stage III grade 3 follicular lymphoma
stage III mantle cell lymphoma
stage III marginal zone lymphoma
stage III small lymphocytic lymphoma
stage IV adult Burkitt lymphoma
stage IV adult diffuse large cell lymphoma
stage IV adult diffuse mixed cell lymphoma
stage IV adult diffuse small cleaved cell lymphoma
stage IV adult immunoblastic large cell lymphoma
stage IV adult lymphoblastic lymphoma
stage IV grade 1 follicular lymphoma
stage IV grade 2 follicular lymphoma
stage IV grade 3 follicular lymphoma
stage IV mantle cell lymphoma
stage IV marginal zone lymphoma
stage IV small lymphocytic lymphoma
recurrent adult Burkitt lymphoma
recurrent adult diffuse large cell lymphoma
recurrent adult diffuse mixed cell lymphoma
recurrent adult diffuse small cleaved cell lymphoma
recurrent adult grade III lymphomatoid granulomatosis
recurrent adult immunoblastic large cell lymphoma
recurrent adult lymphoblastic lymphoma
recurrent grade 1 follicular lymphoma
recurrent grade 2 follicular lymphoma
recurrent grade 3 follicular lymphoma
recurrent mantle cell lymphoma
recurrent marginal zone lymphoma
recurrent small lymphocytic lymphoma
intraocular lymphoma
primary central nervous system lymphoma
stage III multiple myeloma
stage II multiple myeloma
refractory multiple myeloma
cutaneous B-cell non-Hodgkin lymphoma
recurrent ovarian germ cell tumor
stage III ovarian germ cell tumor
stage IV ovarian germ cell tumor
unspecified adult solid tumor, protocol specific
recurrent breast cancer
nodal marginal zone B-cell lymphoma
Lead sponsor: UNC Lineberger Comprehensive Cancer Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2005-10-12
Enrollment: 107
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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 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.

Eligibility 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

Primary outcomes:
measure: Maximum tolerated dose (MTD) of PS-341 in combination with Doxil (Phase I)
timeFrame: 1 year
measure: Response rate of the combination of Velcade and Doxil in patients with metastatic breast cancer
timeFrame: every 42 days
Secondary outcomes:
Other outcomes:
Locations:
city: Chapel Hill
country: United States
facility: Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
state: North Carolina
Study officials:
affiliation: UNC Lineberger Comprehensive Cancer Center
name: Elizabeth C. Dees, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: UNC Lineberger Comprehensive Cancer Center
name: Robert Z. Orlowski, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Dees EC, O'Neil BH, Lindley CM, Collichio F, Carey LA, Collins J, Riordan WJ, Ivanova A, Esseltine D, Orlowski RZ. A phase I and pharmacologic study of the combination of bortezomib and pegylated liposomal doxorubicin in patients with refractory solid tumors. Cancer Chemother Pharmacol. 2008 Dec;63(1):99-107. doi: 10.1007/s00280-008-0716-8. Epub 2008 Mar 8.