17-N-Allylamino-17-Demethoxygeldanamycin and Bortezomib in Treating Patients With Relapsed or Refractory Hematologic Cancer

June 3, 2013 updated by: National Cancer Institute (NCI)

A Phase I Study of PS-341 (Velcade, Bortezomib) in Combination With 17-allylamino-17-demethoxygeldanamycin (17-AAG) in Patients With Relapsed or Refractory Hematologic Malignancies

This phase I trial is studying the side effects and best dose of 17-N-allylamino-17-demethoxygeldanamycin and bortezomib in treating patients with relapsed or refractory hematologic cancer. Drugs used in chemotherapy, such as 17-N-allylamino-17-demethoxygeldanamycin, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving 17-N-allylamino-17-demethoxygeldanamycin together with bortezomib may kill more cancer cells.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of PS-341 (Velcade, Bortezomib) in combination with 17-allyamino-17-demethoxygeldanamycin (17-AAG) in patients with relapsed or refractory acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL).

II. To determine the MTD of PS-341 in combination with 17-AAG in patients with relapsed or refractory chronic lymphocytic leukemia (CLL), and non-Hodgkin's lymphoma (NHL).

III. To define the specific toxicities and the dose limiting toxicity (DLT) of PS-341 in combination with 17-AAG in the treatment of patients with relapsed or refractory hematologic malignancies.

SECONDARY OBJECTIVES:

I. To determine the pharmacokinetics of 17-AAG alone and in combination with PS-341 in patients with AML, ALL, CLL, and NHL.

II. To evaluate 20S proteasome inhibition following combination therapy with 17-AAG and PS-341 in patients with AML, ALL, CLL, and NHL.

III. To assess the relationship between FLT3 mutational status and leukemic cell response to PS-341 and 17-AAG in patients with AML.

IV. To assess the relationship between Bcl-2 over-expression and response to 17-AAG and PS-341 in patients with AML and NHL.

V. To evaluate the effects of the combination of PS-341 and 17-AAG on Hsp90 and NF-kappaB and their downstream targets including Hsp70, Akt, phosphorylated Akt, p21, and caspases 3 and 9 in patient-derived primary AML and NHL cells.

OUTLINE: This is a dose-escalation study. Patients are stratified according to diagnosis (acute myeloid leukemia [AML] or acute lymphoblastic leukemia vs chronic lymphoctyic leukemia or non-Hodgkin's lymphoma [NHL]).

Patients receive 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) intravenously (IV) over 1-6 hours on days 1, 4, 8, and 11 and bortezomib IV over 3-5 seconds on days 4, 8, and 11 of course 1 and on days 1, 4, 8, and 11 of all subsequent courses.

Treatment repeats every 21 days for 3-12 courses provided patient is receiving clinical benefit. Patients achieving objective response may discontinue therapy to undergo stem cell transplantation.Cohorts of 3-6 patients with receive escalating doses of 17-AAG and bortezomib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

After the MTD is determined, an additional 20 patients (10 per stratum with AML or follicular NHL) are enrolled and receive 17-AAG and bortezomib as above at the MTD.

Study Type

Interventional

Enrollment (Actual)

74

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Ohio
      • Columbus, Ohio, United States, 43210
        • Ohio State University Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Histologically or cytologically confirmed diagnosis of 1 of the following hematologic malignancies:

    • Acute myeloid leukemia or acute lymphoblastic leukemia

      • Not a candidate for potentially curative therapy
      • WBC ≤ 10,000/mm^3 OR WBC ≤ 40,000/mm^3 that is stable for 5 days (hydroxyurea allowed)
      • No acute promyelocytic leukemia

    • Non-Hodgkin's lymphoma (NHL), including 1 of the following subtypes:

      • Small lymphocytic lymphoma
      • Marginal zone lymphoma
      • Lymphoplasmacytic lymphoma
      • Follicular lymphoma
      • Mantle cell lymphoma
      • Diffuse large B-cell lymphoma
      • Anaplastic large cell lymphoma
      • Peripheral T-cell lymphoma
      • Extranodal NK/T cell lymphoma (nasal and nasal type)
      • Enteropathy-type T-cell lymphoma
      • Hepatosplenic T-cell lymphoma
      • Angioimmunoblastic T-cell lymphoma
      • Subcutaneous panniculitis-like T-cell lymphoma
    • Chronic lymphocytic leukemia (CLL)

  • Patients with NHL or CLL must meet the following criteria:

    • Ineligible for, or refused potentially curative stem cell transplantation
    • Transformed lymphoma/Richter's transformation, defined as the transformation of low-grade lymphoma, including follicular lymphoma, CLL, or small lymphocytic lymphoma to high-grade lymphoma (i.e., diffuse large cell lymphoma) allowed at time of transformation
    • Evidence of ≥ 50% bone marrow involvement at the time of enrollment OR tumor tissue accessible for biopsy (for patients enrolled after the maximum tolerated dose [MTD] is determined)
    • Absolute neutrophil count ≥ 1,000/mm^3
    • Platelet count ≥ 100,000/mm^3
  • Relapsed or refractory disease
  • Willing to undergo serial bone marrow biopsy (for patients enrolled after the MTD is determined)
  • No untreated or active CNS leukemia or lymphoma
  • Performance status - ECOG 0-2
  • At least 12 weeks
  • Bilirubin ≤ 1.5 mg/dL
  • AST and ALT ≤ 2.5 times upper limit of normal
  • Creatinine ≤ 2.0 mg/dL
  • No uncontrolled cardiac disease
  • No New York Heart Association class III-IV symptomatic congestive heart failure
  • No unstable angina pectoris
  • No serious ventricular arrhythmia (i.e., ventricular tachycardia or ventricular fibrillation > 3 beats in a row) within the past 6 months
  • No other uncontrolled cardiac arrhythmia or requiring antiarrhythmic drugs
  • No myocardial infarction within the past year
  • No active ischemic heart disease within the past year
  • No congenital long QT syndrome
  • No left bundle branch block
  • QTc ≥ 450 msec (for men) or 470 (for women) on ECG/EKG
  • No history of LVEF < 50% by MUGA or echocardiogram
  • Resting ejection fraction ≥ 50% by MUGA or echocardiogram
  • No prior history of cardiac toxicity after receiving anthracycline therapy (e.g., doxorubicin hydrochloride, daunorubicin hydrochloride, or mitoxantrone hydrochloride)
  • No uncontrolled pulmonary disease
  • No symptomatic pulmonary disease requiring oxygen or medications
  • DLCO (i.e., oxygen diffusion capacity) ≥ 80% on pulmonary function testing
  • Resting and exercise oxygen saturation ≥ 90% by pulse oximetry

  • No ongoing pulmonary symptoms ≥ grade 2 including any of the following:

    • Dyspnea on or off exertion
    • Paroxysmal nocturnal dyspnea
    • Significant pulmonary disease including chronic obstructive or restrictive pulmonary disease
    • No prior history of pulmonary toxicity after bleomycin or carmustine
  • No Medicare requirement for home oxygen (e.g., Resting O_2 saturation ≥ 90% or desaturation to ≥ 90% with exertion)
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • HIV negative
  • No preexisting sensory or motor peripheral neuropathy ≥ grade 2
  • No history of allergic reaction to eggs
  • No ongoing or active infection
  • No psychiatric illness or social situation that would preclude study compliance
  • No other uncontrolled illness
  • Prior stem cell transplantation for relapsed or refractory disease allowed
  • At least 2 weeks since prior immunotherapy and recovered
  • At least 2 weeks since prior chemotherapy (excluding hydroxyurea) and recovered
  • No other concurrent chemotherapy
  • No concurrent routine corticosteroids except for treatment of other medical problems (e.g., pulmonary, rheumatologic, or adrenal disorders)
  • At least 2 weeks since prior radiotherapy and recovered
  • No prior radiotherapy that potentially included the heart in the field (e.g., mantle)
  • No prior history of chest radiation
  • No concurrent palliative radiotherapy
  • At least 2 weeks since prior investigational therapy
  • Prior bortezomib allowed
  • No other concurrent commercial or investigational agents or therapies for the malignancy

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Treatment (17-AAG and bortezomib)

Patients receive 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) IV over 1-6 hours on days 1, 4, 8, and 11 and bortezomib IV over 3-5 seconds on days 4, 8, and 11 of course 1 and on days 1, 4, 8, and 11 of all subsequent courses.

Treatment repeats every 21 days for 3-12 courses provided patient is receiving clinical benefit. Patients achieving objective response may discontinue therapy to undergo stem cell transplantation.
Drug: tanespimycin
Given IV
Other Names:
  • 17-AAG
Drug: bortezomib
Given IV
Other Names:
  • MLN341
  • LDP 341
  • VELCADE

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Maximum tolerated dose (MTD) of bortezomib) in combination with 17-AAG)
Time Frame: Day 21
Defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.
Day 21

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Cancer Institute (NCI)

Investigators

  • Principal Investigator: Kristie Blum, Ohio State University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

April 1, 2005

Primary Completion (Actual)

April 1, 2008

Study Registration Dates

First Submitted

February 7, 2005

First Submitted That Met QC Criteria

February 7, 2005

First Posted (Estimate)

February 8, 2005

Study Record Updates

Last Update Posted (Estimate)

June 4, 2013

Last Update Submitted That Met QC Criteria

June 3, 2013

Last Verified

June 1, 2013

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NCI-2012-01463
  • U01CA076576 (U.S. NIH Grant/Contract)
  • OSU 0448
  • NCI-6520
  • CDR0000409584
  • OSU-2004C0084
  • OSU-0448

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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