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

Gastrointestinal Stromal Tumor Clinical Trial

Official title:

Phase I Trial of Doxorubicin and Alvocidib (Flavopiridol; NCI Supplied Agent, NSC 649890) in the Treatment of Metastatic Sarcoma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00098579
• Other study ID #: NCI-2009-00048
• Secondary ID: 04-075AU01CA0698
• Status: Completed
• Phase: Phase 1
• First received: December 7, 2004
• Last updated: March 18, 2013
• Start date: October 2004

Study information

• Verified date: March 2013
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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

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.

Other known NCT identifiers

• NCT01645488

Recruitment information / eligibility

• Status: Completed
• Enrollment: 36
• Est. primary completion date: July 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Gastrointestinal Stromal Tumor
• Gastrointestinal Stromal Tumors
• Recurrent Adult Soft Tissue Sarcoma
• Sarcoma
• Stage IV Adult Soft Tissue Sarcoma

Intervention

Drug:
• alvocidib
Given IV
• doxorubicin hydrochloride
Given IV

Locations

Country	Name	City	State
United States	Memorial Sloan Kettering Cancer Center	New York	New York

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	MTD of alvocidib when given every three weeks in conjunction with doxorubicin hydrochloride	Defined as the dose level immediately preceding the dose where 2 or more patients experienced DLT.	Course 1	Yes
Secondary	Dose limiting toxicity	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.	Weekly during course 1 at initiation of each course thereafter	Yes
Secondary	Clinical pharmacokinetics of the regimen	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).	Week 1	No
Secondary	Therapeutic activity of alvocidib in combination with doxorubicin hydrochloride in patients with advanced solid tumors	Evaluated using the new international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee.	Every 2 courses for the first 6 courses and every 3 courses thereafter	Yes