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

Primary Purpose

Leukemia, Lymphoma, Mature T-cell and Nk-cell Neoplasms

Status
Completed
Phase
Phase 1
Locations
Switzerland
Study Type
Interventional
Intervention
bortezomib
nelfinavir mesylate
Sponsored by
Swiss Group for Clinical Cancer Research
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Leukemia focused on measuring 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

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Inselspital Bern
  • Kantonsspital Graubuenden
  • Centre Hospitalier Universitaire Vaudois
  • Kantonsspital - St. Gallen

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

bortezomib + nelfinavir

Arm Description

escalation 3 by 3 cohorts

Outcomes

Primary Outcome Measures

Dose limiting toxicity

Secondary Outcome Measures

Objective response
Adverse events according to NCI CTCAE v.4.0

Full Information

First Posted
July 16, 2010
Last Updated
May 14, 2019
Sponsor
Swiss Group for Clinical Cancer Research
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1. Study Identification

Unique Protocol Identification Number
NCT01164709
Brief Title
Nelfinavir Mesylate and Bortezomib in Treating Patients With Relapsed or Progressive Advanced Hematologic Cancer
Official Title
Phase I Trial of Nelfinavir and Bortezomib in Advanced Hematologic Malignancies
Study Type
Interventional

2. Study Status

Record Verification Date
May 2019
Overall Recruitment Status
Completed
Study Start Date
July 2010 (undefined)
Primary Completion Date
July 2012 (Actual)
Study Completion Date
November 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Swiss Group for Clinical Cancer Research

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Leukemia, Lymphoma, Mature T-cell and Nk-cell Neoplasms, Multiple Myeloma and Plasma Cell Neoplasm
Keywords
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
18 (Actual)

8. Arms, Groups, and Interventions

Arm Title
bortezomib + nelfinavir
Arm Type
Experimental
Arm Description
escalation 3 by 3 cohorts
Intervention Type
Drug
Intervention Name(s)
bortezomib
Other Intervention Name(s)
Velcade
Intervention Description
Bortezomib i.v., day 8, 11, 15, 18; 1.3 mg/m2
Intervention Type
Drug
Intervention Name(s)
nelfinavir mesylate
Other Intervention Name(s)
Viracept
Intervention Description
p.o., days 1 to 21; dose level: (625), 1250, 1875, or 2500 mg, 2x/d
Primary Outcome Measure Information:
Title
Dose limiting toxicity
Time Frame
during first cycle
Secondary Outcome Measure Information:
Title
Objective response
Time Frame
during treatment
Title
Adverse events according to NCI CTCAE v.4.0
Time Frame
during treatment + 30 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Christoph Driessen, MD
Organizational Affiliation
Cantonal Hospital of St. Gallen
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Dagmar Hess, MD
Organizational Affiliation
Cantonal Hospital of St. Gallen
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Roger von Moos, MD
Organizational Affiliation
Kantonsspital Graubuenden
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Thomas Pabst, MD
Organizational Affiliation
Insel Gruppe AG, University Hospital Bern
Official's Role
Principal Investigator
Facility Information:
Facility Name
Inselspital Bern
City
Bern
ZIP/Postal Code
CH-3010
Country
Switzerland
Facility Name
Kantonsspital Graubuenden
City
Chur
ZIP/Postal Code
CH-7000
Country
Switzerland
Facility Name
Centre Hospitalier Universitaire Vaudois
City
Lausanne
ZIP/Postal Code
CH-1011
Country
Switzerland
Facility Name
Kantonsspital - St. Gallen
City
St. Gallen
ZIP/Postal Code
CH-9007
Country
Switzerland

12. IPD Sharing Statement

Citations:
PubMed Identifier
26659919
Citation
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.
Results Reference
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Nelfinavir Mesylate and Bortezomib in Treating Patients With Relapsed or Progressive Advanced Hematologic Cancer

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