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

Phase 1
18 Years
Not Enrolling
Gastrointestinal Stromal Tumor, Recurrent Adult Soft Tissue Sarcoma, Stage IV Adult Soft Tissue Sarcoma

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Trial Information

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


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.


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.

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

- 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

- 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

- No concurrent combination antiretroviral therapy for HIV-positive patients

- No other concurrent investigational agents

- No other concurrent anticancer therapy

Type of Study:


Study Design:

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

Outcome Measure:

MTD of alvocidib when given every three weeks in conjunction with doxorubicin hydrochloride

Outcome Description:

Defined as the dose level immediately preceding the dose where 2 or more patients experienced DLT.

Outcome Time Frame:

Course 1

Safety Issue:


Principal Investigator

David D'Adamo

Investigator Role:

Principal Investigator

Investigator Affiliation:

Memorial Sloan-Kettering Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

October 2004

Completion Date:

Related Keywords:

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



Memorial Sloan Kettering Cancer Center New York, New York  10021