Bevacizumab and Combination Chemotherapy in Treating Patients With Peripheral T-Cell Lymphoma or Natural Killer Cell Neoplasms

OBJECTIVES:

Primary

• Determine the 12-month progression-free survival of patients with peripheral T-cell or natural killer cell neoplasms treated with bevacizumab and combination chemotherapy comprising cyclophosphamide, doxorubicin, vincristine, and prednisone (A-CHOP).

Secondary

• Determine the overall response rate (complete remission [CR, unconfirmed CR, or functional CR] and partial remission) in these patients after courses 3, 6, and 8 of this treatment regimen.
• Determine the overall survival of patients treated with this regimen.
• Determine the toxicity of this regimen in these patients.

OUTLINE: This is a multicenter study.

Patients receive 6-8 cycles of A-CHOP followed by 8 cycles of maintenance bevacizumab (MA), as outlined below. Bevacizumab 15 mg/kg is administered on day 1 over 90 min (first cycle), 60 min (second cycle) and 30 min for the subsequent cycles. CHOP (cyclophosphamide 750 mg/m 2 ; doxorubicin 50 mg/m 2 ; vincristine 1.4 mg/m2 [max. 2 mg]; prednisone 100 mg daily on days 1-5) is administered on day 1 of a 21-day cycle. Radiographic response is assessed after cycles 3, 6 and 8 of ACHOP and after cycle 8 of MA. Patients receive six cycles of ACHOP if they achieve a complete response (CR) after three cycles, eight cycles if they achieve a partial response (PR) after three cycles. Non-responders are removed from the study. ACHOP responders receive maintenance bevacizumab 15 mg/kg every 21 days for eight cycles.

After completion of study treatment, patients are followed every 3 months for 2 years, and then every 6 months for up to 5 years.

PROJECTED ACCRUAL: A total of 43 patients will be accrued for this study within 22 months.

ACTUAL ACCRUAL: 46

Inclusion criteria

• Diagnosis of peripheral T-cell or natural killer cell neoplasm

• Any stage disease allowed
• HTLV-positive tumors allowed
• At least one objective measurable disease parameter. Abnormal positron emission tomography scans are not considered evidence of measurable disease unless results are confirmed by CT scan or other appropriate imaging techniques
• Age 18 and over
• ECOG Performance status 0-2
• Absolute neutrophil count ≥ 1,000/mm^3(500/mm^3 if due to bone marrow involvement with lymphoma)
• Platelet count ≥ 100,000/mm^3(50,000/mm^3 if due to bone marrow involvement with lymphoma)
• Bilirubin ≤ 2.0 mg/dL (≤ 3 times upper limit of normal [ULN] if due to hepatic involvement with lymphoma)
• AST ≤ 2 times ULN (5 times ULN if due to hepatic involvement with lymphoma)
• PT, INR, and PTT ≤ 1.5 times normal
• Creatinine ≤ 2.0 mg/dL
• Urinary protein:creatinine ratio ≤ 1
• History of deep venous thrombosis allowed provided patient is on a stable dose of anticoagulants for at least 2 weeks prior to study entry
• LVEF ≥ 50%
• History of pulmonary embolism allowed provided patient is on a stable dose of anticoagulants for at least 2 weeks prior to study entry
• One prior cycle of CHOP for PTCL allowed
• More than 4 weeks since prior major invasive surgery or open biopsy
• At least 7 days since prior minor surgery. Peripheral lymph node core biopsy, bone marrow biopsy, fine needle aspiration, skin biopsy, or central line placement are not considered minor surgical procedures
• More than 7 days since prior and no concurrent anti-platelet drugs (e.g., ticlopidine, clopidogrel, or cilostazol) except aspirin or other nonsteroidal anti-inflammatory drugs
• Concurrent anticoagulants allowed provided patient is on a stable dose

• INR must be stable for at least 2 weeks prior to study entry
• PT/INR and/or PTT must be closely monitored and levels kept within acceptable range for underlying thrombotic disease
• Concurrent heparin flush for maintenance of central line patency allowed

Exclusion criteria

• Anaplastic lymphoma kinase (ALK)-positive T-cell large cell lymphoma. ALK-negative T-cell large cell lymphoma allowed
• Cutaneous T-cell lymphoma
• History of or current radiographic evidence of CNS metastasis, including previously treated, resected, or asymptomatic brain lesions or leptomeningeal involvement
• Evidence of bleeding diathesis or coagulopathy
• Cerebrovascular accident within the past 6 months
• Myocardial infarction within the past 6 months
• Unstable angina within the past 6 months
• New York Heart Association class II-IV congestive heart failure
• Uncontrolled hypertension (i.e., systolic blood pressure [BP] > 150 mm Hg or diastolic BP > 100 mm Hg)
• Other clinically significant cardiovascular or peripheral vascular disease
• Abdominal fistula within the past 6 months
• Gastrointestinal perforation within the past 6 months
• Intra-abdominal abscess within the past 6 months
• Concurrent major surgery
• Pregnant or nursing. Female patients must have negative pregnancy test. Fertile patients must use effective contraception
• History of active seizures
• Significant traumatic injury within the past 4 weeks
• Non-healing ulcer (unless involved with lymphoma)
• Bone fracture
• Active infection requiring parenteral antibiotics
• HIV positivity
• Other active malignancy within the past 6 months except carcinoma in situ of the cervix or basal cell carcinoma of the skin