Tanespimycin and Bortezomib in Treating Patients With Advanced Solid Tumors or Lymphomas

February 21, 2014 updated by: National Cancer Institute (NCI)

A Phase I Trial Of 17-Allylaminogeldanamycin (17-AAG) And PS341 In Advanced Malignancies

This phase I trial is studying the side effects and best dose of giving tanespimycin together with bortezomib in treating patients with advanced solid tumors or lymphomas. (Accrual for lymphoma patients closed as of 11/27/09) Drugs used in chemotherapy, such as tanespimycin, work in different ways to stop cancer cells from dividing so they stop growing or die. Bortezomib may stop the growth of cancer cells by blocking the enzymes necessary for their growth. It may also increase the effectiveness of tanespimycin by making cancer cells more sensitive to the drug. Combining tanespimycin with bortezomib may kill more cancer cells.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

OBJECTIVES:

I. Determine the dose-limiting toxicity and maximum tolerated dose of 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) (tanespimycin) and bortezomib in patients with advanced solid tumors or lymphomas (Accrual for Lymphoma Patients Closed as of 11/27/09).

II. Determine changes in biomarkers (e.g., HSP70, client proteins, and ubiquitination of proteins) in peripheral blood mononuclear cells and tumor specimens from patients with advanced solid tumors or lymphomas (Accrual for Lymphoma Patients Closed as of 11/27/09) treated with this regimen.

III. Determine responses in patients treated with this regimen. IV. Determine the toxic effects of this regimen in these patients.

OUTLINE: This is a dose-escalation, multicenter study.

Patients receive tanespimycin intravenously (IV) over 1-2 hours and bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tanespimycin 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. Once the MTD is determined, at least 12 additional patients are treated as above* at the MTD.

NOTE: *Bortezomib is not administered on day 1 of course 1 only. Patients are followed at 3 months.

Study Type

Interventional

Enrollment (Actual)

36

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
    • Minnesota
      • Rochester, Minnesota, United States, 55905
        • Mayo Clinic

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 confirmed solid tumor or lymphomas (Accrual for Lymphoma Patients Closed as of 11/27/09)
  • Refractory to standard treatment OR no standard treatment that is potentially curative or capable of prolonging life expectancy exists
  • Tumor amenable to biopsy (patients accrued at the MTD only)
  • No CNS metastases
  • Performance status - ECOG 0-2
  • At least 12 weeks
  • Absolute neutrophil count ≥ 1,500/mm^3
  • Platelet count ≥ 100,000/mm^3
  • Hemoglobin ≥ 9.0 g/dL
  • Bilirubin ≤ 2 times upper limit of normal (ULN)
  • AST ≤ 2.5 times ULN
  • Alkaline phosphatase ≤ 2 times ULN (5 times ULN if due to liver involvement)
  • Creatinine ≤ 2 times ULN
  • QTc < 500 msec for men (470 msec for women)
  • LVEF > 40% by echocardiogram
  • Ejection fraction normal by echocardiogram (for patients who have received prior anthracycline therapy)
  • No cardiac symptoms ≥ grade 2
  • No New York Heart Association class III or IV heart failure
  • 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
  • No history of uncontrolled dysrhythmias or requiring antiarrhythmic drugs
  • No history of cardiac toxicity after receiving anthracyclines (e.g., doxorubicin hydrochloride, daunorubicin hydrochloride, mitoxantrone hydrochloride, bleomycin, or carmustine)
  • No poorly controlled angina
  • No history of serious ventricular arrhythmia (ventricular tachycardia or ventricular fibrillation ≥ 3 beats in a row)
  • No other significant cardiac disease
  • Pulse oximetry at rest and exercise < 88% (per Medicare guidelines)
  • No pulmonary symptoms ≥ grade 2
  • No significant pulmonary disease requiring oxygen supplementation or causing a severe limitation in activity

  • No symptomatic pulmonary disease requiring medication including any of the following:

    • Dyspnea on or off exertion
    • Paroxysmal nocturnal dyspnea
    • Oxygen requirement and significant pulmonary disease, including chronic obstructive/restrictive pulmonary disease
  • No home oxygen use that meets the Medicare criteria
  • No history of pulmonary toxicity after receiving anthracyclines (e.g., doxorubicin hydrochloride, daunorubicin hydrochloride, mitoxantrone hydrochloride, bleomycin, or carmustine)
  • No seizure disorder
  • No sensory peripheral neuropathy > grade 1

  • No neuropathic pain of any etiology

    • Patients with residual peripheral neuropathy ≤ grade 1 due to oxaliplatin therapy allowed
  • No uncontrolled infection
  • No prior serious allergic reaction to eggs
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • Willing to return to Mayo Clinic Rochester, Mayo Clinic Arizona, or Mayo Clinic Florida for follow up
  • More than 4 weeks since prior immunotherapy or biologic therapy
  • No concurrent prophylactic colony-stimulating factors
  • No concurrent immunotherapy, biologic therapy, or gene therapy
  • More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin)
  • No other concurrent chemotherapy
  • Concurrent steroids (at a stable dose for ≥ 4 weeks) for comorbid conditions (e.g., adrenal insufficiency or rheumatoid arthritis) allowed
  • More than 4 weeks since prior radiotherapy
  • No prior radiotherapy that potentially included the heart in the field (e.g., mantle) or chest
  • No prior radiotherapy to > 25% of bone marrow
  • No prior radiopharmaceuticals
  • No concurrent radiotherapy
  • Recovered from prior therapy
  • More than 8 weeks since prior UCN-01

  • No concurrent warfarin

    • Low molecular weight heparin allowed
  • No concurrent medications that prolong or may prolong QTc interval
  • No other concurrent investigational therapy

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 (chemotherapy and enzyme inhibitor therapy)

Patients receive tanespimycin IV over 1-2 hours and bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tanespimycin and bortezomib until the 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. Once the MTD is determined, at least 12 additional patients are treated as above* at the MTD.

NOTE: *Bortezomib is not administered on day 1 of course 1 only. Patients are followed at 3 months.
Other: laboratory biomarker analysis
Correlative studies
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
MTD of tanespimycin in combination with bortezomib in the treatment of solid tumors
Time Frame: At 3 weeks
Defined as the dose level below the lowest dose that induces dose-limiting toxicity in at least one-third of the solid tumor patients (at least 2 of a maximum of 6 new patients).
At 3 weeks
Toxicity of tanespimycin in combination with bortezomib in the treatment of solid tumors
Time Frame: At 3 weeks
Defined by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 as adverse events that are classified as either possibly, probably, or definitely related to study treatment. Non-hematologic toxicities will be evaluated via the ordinal common toxicity criteria (CTC) standard toxicity grading. Hematologic toxicity measures of thrombocytopenia, neutropenia, and leukopenia will be assessed using continuous variables as the outcome measures (primarily nadir) as well as categorization via CTC standard toxicity grading.
At 3 weeks
Changes in biomarkers in peripheral blood mononuclear cells and tumor specimens from patients with advanced solid tumors or lymphomas
Time Frame: Baseline, days 4, 8, and 11 of course 1, and at the end of treatment study
Changes in the levels of expressions of HSP70, client proteins, and ubquitination of proteins in PBMC at the different dose levels as well as at the different time points will be descriptively summarized. The degree of proteasome inhibition will be quantitated whenever possible and the results will be displayed graphically and analyzed using simple descriptive statistics.
Baseline, days 4, 8, and 11 of course 1, and at the end of treatment study
Responses in patients treated with this regimen
Time Frame: Every 6 weeks
Evaluated using the modified Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Summarized by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease (overall and by tumor group).
Every 6 weeks
Time until hematologic nadirs (WBC, ANC, platelets)
Time Frame: Days 4, 8, and 11 of course 1 and then every 21 days
Days 4, 8, and 11 of course 1 and then every 21 days
Time to progression
Time Frame: Every 6 weeks
Every 6 weeks
Time to treatment failure
Time Frame: At 3 weeks and every 6 weeks
Defined as the time from registration to documentation of progression, unacceptable toxicity, or refusal to continue participation by the patient.
At 3 weeks and every 6 weeks

Collaborators and Investigators

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

Sponsor

National Cancer Institute (NCI)

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

November 1, 2004

Primary Completion (Actual)

March 1, 2010

Study Registration Dates

First Submitted

November 9, 2004

First Submitted That Met QC Criteria

November 8, 2004

First Posted (Estimate)

November 9, 2004

Study Record Updates

Last Update Posted (Estimate)

February 24, 2014

Last Update Submitted That Met QC Criteria

February 21, 2014

Last Verified

October 1, 2011

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NCI-2009-00043 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
  • P30CA015083 (U.S. NIH Grant/Contract)
  • U01CA069912 (U.S. NIH Grant/Contract)
  • MAYO-MC0214
  • NCI-6121
  • CDR0000391837
  • MC0214 (Other Identifier: Mayo Clinic)
  • 6121 (Other Identifier: CTEP)

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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