Nelfinavir Mesylate and Bortezomib in Treating Patients With Relapsed or Progressive Advanced Hematologic Cancer

Study Overview
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Brief Summary
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RATIONALE: Nelfinavir mesylate and bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Bortezomib may also stop the growth of hematologic cancer by blocking blood flow to the cancer. Giving nelfinavir mesylate together with bortezomib may kill more cancer cells. PURPOSE: This phase I trial is studying the side effects and best dose of nelfinavir mesylate when given together with bortezomib in treating patients with relapsed or progressive advanced hematologic cancer.

Detailed Description
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OBJECTIVES: To assess the safety of nelfinavir mesylate in combination with bortezomib in patients with relapsed or progressive, advanced hematologic malignancies. To establish the phase II recommended dose of nelfinavir mesylate in these patients. OUTLINE: This is a multicenter, dose-escalation study of nelfinavir mesylate. Patients receive oral nelfinavir mesylate twice daily on days 1-21 and bortezomib IV on days 8, 11, 15, and 18 in course 1. Course 1 has a duration of 28 days. Beginning in course 2, patients receive oral nelfinavir mesylate twice daily on days 1-14 and bortezomib IV on days 1, 4, 8, and 11. Treatment repeats every 21 days for 2 courses. Patients with responding disease may continue to receive nelfinavir mesylate and bortezomib for up to 4 additional courses. After completion of study treatment, patients are followed for 30 days.

Official Title
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Phase I Trial of Nelfinavir and Bortezomib in Advanced Hematologic Malignancies

Conditions
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Leukemia, Lymphoma, Mature T-cell and Nk-cell Neoplasms, Multiple Myeloma and Plasma Cell Neoplasm

Intervention / Treatment
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* Drug: bortezomib
* Drug: nelfinavir mesylate


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosed with advanced hematologic malignancies meeting the following criteria: Multiple myeloma Received ≥ 2 lines of prior chemotherapy (induction chemotherapy followed by high-dose chemotherapy and autologous stem cell transplant with or without maintenance therapy is considered one line of therapy) Acute myeloid leukemia Acute lymphoblastic leukemia Diffuse large B-cell lymphoma Hodgkin lymphoma Mantle cell lymphoma Mature T- and NK-cell neoplasms restricted to the following WHO-defined entities: T-cell prolymphocytic leukemia T-cell large granular lymphocytic leukemia Aggressive NK-cell leukemia Adult T-cell leukemia/lymphoma Extranodal NK/T-cell lymphoma (nasal type) Mycosis fungoides Sézary syndrome Primary CD30-positive T-cell lymphoproliferative disorders Primary cutaneous anaplastic large cell lymphoma Primary cutaneous gamma-delta T-cell lymphoma Peripheral T-cell lymphoma (not otherwise specified) Angioimmunoblastic T-cell lymphoma Anaplastic large cell lymphoma (ALK-positive/ALK-negative) Grade 3B follicular lymphoma Relapsed following or progressed during standard therapy Meeting the following criteria: Standard intensive therapy is not feasible Current disease state for which there is no standard effective therapy Refused standard therapy where no curative option exists Measurable disease, defined as the following: Myeloma: measurable serum monoclonal protein > 1 g/dL for IgG, or > 0.5 g/dL for IgA, IgM or IgD, or difference between involved and uninvolved free light chain levels in serum > 100 mg/L Lymphoma: must have ≥ 1 lesion measurable by CT (longest diameter ≥ 15 mm) Acute leukemia: ≥ 20% blasts in bone marrow or in peripheral blood (≥ 200/mL blasts in peripheral blood) No HIV-associated lymphoma PATIENT CHARACTERISTICS: WHO performance status 0-2 Absolute neutrophil count ≥ 1,500/mm³ Platelet count ≥ 75,000/mm³ (if bone marrow impairment, ≥ 20,000/mm^3) Hemoglobin > 80 g/L (if considered to be caused by the underlying hematologic malignancy or bone marrow impairment, > 80 g/L after transfusion) Bilirubin ≤ 1.5 times upper limit of normal (ULN) (if suspected hemolysis, direct bilirubin ≤ 1.5 times ULN) ALT ≤ 2.5 times ULN Calculated creatinine clearance > 30 mL/min Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for 12 months after completion of study treatment Willing and capable to comply with an oral regimen Capable of understanding information given by the investigator on the trial Able to adhere and remain in geographic proximity to allow proper staging, treatment, and followup No other non-hematologic malignancy within the past 5 years, except adequately treated cervical carcinoma in situ or localized nonmelanoma skin cancer No known chronic hepatitis B or C infection or known HIV infection No serious underlying medical condition (at the judgment of the investigator) which would impair the ability of the patient to participate in the trial, including any of the following: Active autoimmune disease Uncontrolled diabetes Ongoing or active infection Symptomatic congestive heart failure Unstable angina pectoris Cardiac arrhythmia Psychiatric disorder No myocardial infarction within the past 6 months No polyneuropathy > grade 1 significantly interfering with activities of daily living or painful polyneuropathy No known hypersensitivity to trial drugs or hypersensitivity to any other component of the trial drugs PRIOR CONCURRENT THERAPY: See Disease Characteristics No more than 4 prior lines of chemotherapeutic regimens (induction chemotherapy followed by high-dose chemotherapy and autologous stem cell transplant with or without maintenance therapy is considered one line of therapy) More than 30 days since prior treatment in a clinical trial More than 30 days since prior and no concurrent chemotherapy or biologic agents For patients with acute leukemia, hydroxyurea may be given up to 48 hours before first administration of the trial treatment, and low dose cytarabine (up to 20 mg/m^2) and mitoxantrone up to 20 mg up to 14 days before first dosing At least 1 week since prior and no concurrent CYP3A4 modulators No concurrent other experimental drugs No concurrent radiotherapy No concurrent antineoplastic therapy with chemotherapeutic or biologic agents

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: bortezomib + nelfinavir<br>escalation 3 by 3 cohorts | Drug: bortezomib<br>* Bortezomib i.v., day 8, 11, 15, 18; 1.3 mg/m2<br>* Other names: Velcade;Drug: nelfinavir mesylate<br>* p.o., days 1 to 21; dose level: (625), 1250, 1875, or 2500 mg, 2x/d<br>* Other names: Viracept;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose limiting toxicity |  | during first cycle | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response |  | during treatment | 
| Adverse events according to NCI CTCAE v.4.0 |  | during treatment + 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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refractory multiple myeloma, recurrent adult acute myeloid leukemia, recurrent adult acute lymphoblastic leukemia, recurrent adult diffuse large cell lymphoma, recurrent adult Hodgkin lymphoma, recurrent mantle cell lymphoma, recurrent adult T-cell leukemia/lymphoma, adult nasal type extranodal NK/T-cell lymphoma, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma, T-cell large granular lymphocyte leukemia, anaplastic large cell lymphoma, recurrent grade 3 follicular lymphoma, recurrent cutaneous T-cell non-Hodgkin lymphoma, recurrent mycosis fungoides/Sezary syndrome, aggressive NK-cell 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, stage III adult diffuse large cell lymphoma, stage IV adult diffuse large cell lymphoma, stage III adult Hodgkin lymphoma, stage IV adult Hodgkin lymphoma, stage III mantle cell lymphoma, stage IV mantle cell lymphoma, stage III adult T-cell leukemia/lymphoma, stage IV adult T-cell leukemia/lymphoma, stage III grade 3 follicular lymphoma, stage IV grade 3 follicular lymphoma, stage III mycosis fungoides/Sezary syndrome, stage IV mycosis fungoides/Sezary syndrome, stage III cutaneous T-cell non-Hodgkin lymphoma, stage IV cutaneous T-cell non-Hodgkin lymphoma, prolymphocytic leukemia