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

Study Overview
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Brief Summary
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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

Detailed Description
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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.

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

Conditions
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Gastrointestinal Stromal Tumor, Recurrent Adult Soft Tissue Sarcoma, Stage IV Adult Soft Tissue Sarcoma

Intervention / Treatment
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* Drug: alvocidib
* Drug: doxorubicin hydrochloride


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (chemotherapy)<br>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<br>* Given IV<br>* Other names: L-868275;Drug: doxorubicin hydrochloride<br>* Given IV<br>* Other names: Adriamycin RDF;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 |