Bortezomib in Treating Patients With Advanced or Metastatic Sarcoma

A Multi-Institutional, Open-Label, Two-Group, Phase II Study of PS-341 (LDP-341, NSC #681239) in Patients With Advanced or Metastatic Sarcoma

RATIONALE: Bortezomib may stop the growth of cancer by blocking the enzymes necessary for tumor cell growth.

PURPOSE: Phase II trial to study the effectiveness of bortezomib in treating patients who have advanced or metastatic sarcoma.

OBJECTIVES:

• Determine the response rate in patients with advanced or metastatic sarcoma treated with bortezomib.
• Correlate levels of cyclins D1, E, p21 (WAF1), p27 (Kip1), mdm^2, p53, and Ki67 with response in patients treated with this drug.

OUTLINE: This is an open-label, multicenter study. Patients are stratified according to disease (stratum I: soft tissue sarcoma not specified in stratum II, osteogenic sarcoma arising from soft tissues, or gastrointestinal stromal tumor vs stratum II: Ewing's sarcoma of soft tissue or bone, rhabdomyosarcoma, or osteogenic sarcoma of bone). (Stratum I closed to accrual as of 10/17/03.)

Patients receive bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Patients are followed every 3 months for 1 year.

PROJECTED ACCRUAL: A total of 21-41 patients will be accrued for stratum I within 5-11 months and 21-41 patients will be accrued for stratum II within 10.5-22 months. (Stratum I closed to accrual as of 10/17/03.)

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed sarcoma

• Soft tissue metastasis or locally recurrent disease

• Stratum I (closed to accrual as of 10/17/03):

  • Soft tissue sarcoma not specified in stratum II
  • Osteogenic sarcoma arising from soft tissue or gastrointestinal stromal tumor (GIST)

• Stratum II:

  • Ewing's sarcoma of soft tissue or bone (if measurable soft tissue metastasis is present)
  • Rhabdomyosarcoma
  • Osteogenic sarcoma of bone (if measurable soft tissue metastasis is present)

• At least 1 unidimensionally measurable lesion

  • At least 20 mm by conventional techniques OR at least 10 mm by spiral CT scan

• Disease progression within the past 3 months

• No prior or active known brain metastases

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• Karnofsky 80-100% OR
• ECOG 0-1

Life expectancy:

• Not specified

Hematopoietic:

• Absolute neutrophil count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3

Hepatic:

• Bilirubin no greater than 1.5 mg/dL
• AST/ALT no greater than 2.5 times upper limit of normal

Renal:

• Creatinine no greater than 1.5 mg/dL OR
• Creatinine clearance greater than 60 mL/min

Cardiovascular:

• No peripheral vascular disease requiring surgical management
• No history of congestive heart failure even if it is medically controlled
• No angina pectoris even if it is medically controlled
• No myocardial infarction within the past year
• No cardiac arrhythmias
• No prior cerebrovascular event
• No prior transient ischemic attack
• No EKG evidence of acute ischemia or conduction abnormality (e.g., bifascicular block [left anterior hemiblock in the presence of right bundle branch block] or second or third degree atrioventricular block)
• No history of orthostatic hypotension

Other:

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No prior allergic reaction to compounds of similar chemical or biological composition to study drug
• No other uncontrolled concurrent illness
• No ongoing or active infection
• No psychiatric illness or social situation that would preclude study compliance
• No other malignancy within the past 5 years except adequately treated basal cell skin cancer or carcinoma in situ of the cervix
• No symptomatic peripheral neuropathy greater than grade 1

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• At least 4 weeks since prior immunotherapy and recovered
• No concurrent biological or immunological agents

Chemotherapy:

• Stratum I (closed to accrual as of 10/17/03):

  • At least 1 year since prior chemotherapy in the adjuvant or neoadjuvant setting
  • No other prior chemotherapy

• Stratum II:

  • No more than 1 prior chemotherapy regimen

• No concurrent chemotherapy

Endocrine therapy:

• Not specified

Radiotherapy:

• At least 4 weeks since prior radiotherapy and recovered
• No concurrent radiotherapy

Surgery:

• Not specified

Other:

• Prior imatinib mesylate for GIST (stratum I closed to accrual as of 10/17/03) allowed
• No other concurrent investigational agents
• No concurrent commercial anticancer agents or therapies
• No concurrent combination antiretroviral therapy for HIV-positive patients