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

Phase I Trial of Nelfinavir and Bortezomib in Advanced Hematologic Malignancies

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.

Study Overview

• Status: Completed
• Conditions: Lymphoma; Leukemia; Multiple Myeloma and Plasma Cell Neoplasm; Mature T-cell and Nk-cell Neoplasms
• Intervention / Treatment: Drug: bortezomib; Drug: nelfinavir mesylate

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 1

Contacts and Locations

Study Locations

• Switzerland
  • Bern, Switzerland, CH-3010
    • Inselspital Bern
  • Chur, Switzerland, CH-7000
    • Kantonsspital Graubuenden
  • Lausanne, Switzerland, CH-1011
    • Centre Hospitalier Universitaire Vaudois
  • St. Gallen, Switzerland, CH-9007
    • Kantonsspital - St. Gallen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Dose limiting toxicity	during first cycle

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Swiss Group for Clinical Cancer Research
• Investigators: Study Chair: Christoph Driessen, MD, Cantonal Hospital of St. Gallen; Principal Investigator: Dagmar Hess, MD, Cantonal Hospital of St. Gallen; Principal Investigator: Roger von Moos, MD, Kantonsspital Graubuenden; Principal Investigator: Thomas Pabst, MD, University Hospital Inselspital, Berne

Publications and helpful links

General Publications

• Driessen C, Kraus M, Joerger M, Rosing H, Bader J, Hitz F, Berset C, Xyrafas A, Hawle H, Berthod G, Overkleeft HS, Sessa C, Huitema A, Pabst T, von Moos R, Hess D, Mey UJ. Treatment with the HIV protease inhibitor nelfinavir triggers the unfolded protein response and may overcome proteasome inhibitor resistance of multiple myeloma in combination with bortezomib: a phase I trial (SAKK 65/08). Haematologica. 2016 Mar;101(3):346-55. doi: 10.3324/haematol.2015.135780. Epub 2015 Dec 11.

Study record dates

Study Major Dates

• Study Start: July 1, 2010
• Primary Completion (Actual): July 1, 2012
• Study Completion (Actual): November 1, 2013

Study Registration Dates

• First Submitted: July 16, 2010
• First Submitted That Met QC Criteria: July 16, 2010
• First Posted (Estimate): July 19, 2010

Study Record Updates

• Last Update Posted (Actual): May 15, 2019
• Last Update Submitted That Met QC Criteria: May 14, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Keywords: stage III adult diffuse large cell lymphoma; stage IV grade 3 follicular lymphoma; stage IV adult diffuse large cell lymphoma; recurrent grade 3 follicular lymphoma; recurrent adult diffuse large cell lymphoma; 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; recurrent adult acute myeloid leukemia; recurrent adult Hodgkin lymphoma; stage III grade 3 follicular lymphoma; stage III mantle cell lymphoma; stage IV mantle cell lymphoma; recurrent mantle cell lymphoma; stage III adult Hodgkin lymphoma; stage IV adult Hodgkin lymphoma; stage III cutaneous T-cell non-Hodgkin lymphoma; stage IV cutaneous T-cell non-Hodgkin lymphoma; recurrent cutaneous T-cell non-Hodgkin lymphoma; stage III adult T-cell leukemia/lymphoma; stage IV adult T-cell leukemia/lymphoma; recurrent adult T-cell leukemia/lymphoma; angioimmunoblastic T-cell lymphoma; anaplastic large cell lymphoma; stage III mycosis fungoides/Sezary syndrome; stage IV mycosis fungoides/Sezary syndrome; recurrent mycosis fungoides/Sezary syndrome; adult nasal type extranodal NK/T-cell lymphoma; refractory multiple myeloma; recurrent adult acute lymphoblastic leukemia; prolymphocytic leukemia; peripheral T-cell lymphoma; T-cell large granular lymphocyte leukemia; aggressive NK-cell leukemia
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Neoplasms; Lymphoma; Multiple Myeloma; Neoplasms, Plasma Cell; Leukemia; Plasmacytoma; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Antineoplastic Agents; Protease Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Bortezomib; Nelfinavir
• Other Study ID Numbers: SAKK 65/08; SWS-SAKK-65/08; EU-21051; SWS-SAKK-JC26866138LYM1005; CDR0000681442 (Registry Identifier: CDR0000681442)