Doxorubicin Hydrochloride and Alvocidib in Treating Patients With Metastatic or Recurrent Sarcoma That Cannot Be Removed By Surgery

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00098579
First received: December 7, 2004
Last updated: March 18, 2013
Last verified: March 2013
  Purpose

This phase I trial is studying the side effects and best dose of alvocidib when given with doxorubicin hydrochloride in treating patients with metastatic or recurrent sarcoma that cannot be removed by surgery. Drugs used in chemotherapy, such as doxorubicin hydrochloride and alvocidib, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Alvocidib may also help doxorubicin hydrochloride work better by making tumor cells more sensitive to the drug. Giving more than one drug may kill more tumor cells


Condition Intervention Phase
Gastrointestinal Stromal Tumor
Recurrent Adult Soft Tissue Sarcoma
Stage IV Adult Soft Tissue Sarcoma
Drug: alvocidib
Drug: doxorubicin hydrochloride
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I Trial of Doxorubicin and Alvocidib (Flavopiridol; NCI Supplied Agent, NSC 649890) in the Treatment of Metastatic Sarcoma

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • MTD of alvocidib when given every three weeks in conjunction with doxorubicin hydrochloride [ Time Frame: Course 1 ] [ Designated as safety issue: Yes ]
    Defined as the dose level immediately preceding the dose where 2 or more patients experienced DLT.


Secondary Outcome Measures:
  • Dose limiting toxicity [ Time Frame: Weekly during course 1 at initiation of each course thereafter ] [ Designated as safety issue: Yes ]
    Defined as the occurrence of Grade 4 hematologic toxicity 21 days after treatment, Grade 4 hematologic toxicity lasting 7 days or longer, Grade 3 or 4 non-hematologic toxicity, or any delay in treatment of more than two weeks. Evaluated using the National Cancer Institute (NCI) Common Toxicity Criteria. Graded using the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.

  • Clinical pharmacokinetics of the regimen [ Time Frame: Week 1 ] [ Designated as safety issue: No ]
    Biopsies will be performed by Tru-Cut or CT guidance. The material obtained will be examined for p21, p53 and pRb expression by immunohistochemistry (IHC) as well as measurements of apoptosis by terminal deoxynucleotidyl transferase (TdT)- mediated dUTP nick end labeling (TUNEL).

  • Therapeutic activity of alvocidib in combination with doxorubicin hydrochloride in patients with advanced solid tumors [ Time Frame: Every 2 courses for the first 6 courses and every 3 courses thereafter ] [ Designated as safety issue: Yes ]
    Evaluated using the new international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee.


Enrollment: 36
Study Start Date: October 2004
Primary Completion Date: July 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (chemotherapy)
Patients receive doxorubicin hydrochloride IV over 5-10 minutes and alvocidib IV over 1 hour on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients reaching a cumulative doxorubicin dose of 600 mg/m^2 or experiencing cardiotoxicity may receive alvocidib alone at the discretion of the investigator. Cohorts of 3-6 patients receive escalating doses of alvocidib 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. Ten additional patients receive treatment at the MTD. Patients are followed every 3 months for 1 year.
Drug: alvocidib
Given IV
Other Names:
  • FLAVO
  • flavopiridol
  • HMR 1275
  • L-868275
Drug: doxorubicin hydrochloride
Given IV
Other Names:
  • ADM
  • ADR
  • Adria
  • Adriamycin PFS
  • Adriamycin RDF

Detailed Description:

PRIMARY OBJECTIVE:

I. Determine the maximum tolerated dose of flavopiridol (alvocidib) when administered with a fixed dose of doxorubicin (doxorubicin hydrochloride) in patients with unresectable metastatic or locally recurrent sarcoma.

SECONDARY OBJECTIVES:

I. Determine the clinical pharmacokinetics of this regimen in these patients. II. Determine, preliminarily, the therapeutic activity of this regimen in these patients.

III. Correlate pRb, p53, and p21 protein levels with treatment response and apoptosis in patients treated with this regimen.

IV. Correlate NMR biochemical patterns with response in patients treated with this regimen.

OUTLINE: This is an open-label, dose-escalation study of alvocidib.

Patients receive doxorubicin hydrochloride intravenously (IV) over 5-10 minutes and alvocidib IV over 1 hour on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients reaching a cumulative doxorubicin dose of 600 mg/m^2 or experiencing cardiotoxicity may receive alvocidib alone at the discretion of the investigator. Cohorts of 3-6 patients receive escalating doses of alvocidib 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. Ten additional patients receive treatment at the MTD. Patients are followed every 3 months for 1 year.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically or cytologically confirmed soft-tissue sarcoma*

    • Unresectable disease
    • Locally recurrent or metastatic disease
  • Disease amenable to biopsy (patients treated at the maximum tolerated dose only)
  • No known prior or concurrent brain metastases
  • Performance status - Karnofsky 60-100%
  • Performance status - ECOG 0-2
  • Absolute neutrophil count ≥ 1,500/mm^3
  • Platelet count ≥ 100,000/mm^3
  • Bilirubin ≤ 1.5 mg/dL
  • AST and ALT ≤ 2.5 times upper limit of normal
  • Creatinine ≤ 1.5 mg/dL
  • Creatinine clearance ≥ 60 mL/min
  • Ejection fraction ≥ 50% by MUGA or echocardiogram
  • No uncontrolled hypertension
  • No myocardial infarction
  • No New York Heart Association class II-IV congestive heart failure
  • No unstable angina
  • No serious cardiac arrhythmia requiring medication
  • No peripheral vascular disease ≥ grade 2 within the past year
  • No other clinically significant cardiac disease
  • No prior deep vein thrombosis
  • No other prior vascular thrombus
  • No prior pulmonary embolism
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • No symptomatic peripheral neuropathy ≥ grade 2
  • No other malignancy within the past 5 years except adequately treated basal cell skin cancer or carcinoma in situ of the cervix

    • Carcinoma in situ not considered a second malignancy
  • No history of allergic reaction attributed to compounds of similar chemical or biologic composition to study drugs
  • No psychiatric illness or social situation that would preclude study compliance
  • No ongoing or active infection
  • No other uncontrolled illness
  • See Chemotherapy
  • At least 3 weeks since prior immunotherapy and recovered
  • At least 3 weeks since prior chemotherapy (6 weeks for carmustine or mitomycin) and recovered
  • No more than 2 prior cytotoxic chemotherapy regimens

    • Peroxisome proliferator-activated receptor (PPAR)-gamma agonists, thalidomide, or targeted therapy (i.e., tyrosine kinase inhibitors including imatinib mesylate, sorafenib, or sunitinib malate) do not count as a prior chemotherapy regimen
  • No prior anthracyclines
  • At least 3 weeks since prior radiotherapy and recovered
  • No prior extensive radiotherapy to bone marrow-producing sites (e.g., radiotherapy to both the pelvis and spine)
  • At least a 1 week washout period since prior tyrosine kinase inhibitors or other targeted therapy
  • Concurrent low-dose warfarin (1 mg per day) to prevent thrombus of a central line allowed
  • No concurrent combination antiretroviral therapy for HIV-positive patients
  • No other concurrent investigational agents
  • No other concurrent anticancer therapy
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00098579

Locations
United States, New York
Memorial Sloan Kettering Cancer Center
New York, New York, United States, 10065
Sponsors and Collaborators
Investigators
Principal Investigator: David D'Adamo Memorial Sloan-Kettering Cancer Center
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00098579     History of Changes
Obsolete Identifiers: NCT01645488
Other Study ID Numbers: NCI-2009-00048, 04-075A, U01CA069856
Study First Received: December 7, 2004
Last Updated: March 18, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Sarcoma
Gastrointestinal Stromal Tumors
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Connective Tissue
Gastrointestinal Neoplasms
Digestive System Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Doxorubicin
Liposomal doxorubicin
Alvocidib
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Growth Inhibitors
Growth Substances
Physiological Effects of Drugs
Protein Kinase Inhibitors

ClinicalTrials.gov processed this record on September 16, 2014