Protocol Number: 09-C-0104

Title:

A Randomized, Double-Blinded, Placebo-Controlled, Multi-Institutional, Phase II.5 Study of AZDO53O, a Selective Src Kinase Inhibitor, in Patients with Recurrent Osteosarcoma Localized to the Lung

Number:

09-C-0104

Summary:

Background:

-AZDO53O is a potent and selective Src kinase inhibitor.

-In vitro studies demonstrate that 95% of patients with osteosarcoma have activation of Src, or one of its substrates.

-A Phase I study of AZDO53O, given daily, in adult patients with advanced solid malignancies, has identified 175 mg as the maximum tolerated dose.

Primary Objective:

-To determine if the addition of AZDO53O to pulmonary metastasectomy, versus placebo and pulmonary metastasectomy, results in an increase in progression free survival.

Secondary Objectives:

-To determine if the addition of AZDO53O to pulmonary metastasectomy, versus placebo and pulmonary metastasectomy, results in an increase in overall survival.

-To determine if the addition of AZDO53O to pulmonary metastasectomy, versus placebo and pulmonary metastasectomy, results in an increase in the time to treatment failure, defined as a composite endpoint measuring time from randomization to discontinuation of treatment for any reason, including disease progression, treatment toxicity, or death.

-To perform microarray analysis of tumor samples to identify a gene signature that predicts for recurrence of osteosarcoma.

-To evaluate tumor samples for biomarkers related to activation of Src and Src substrates.

-To establish cell lines and murine xenografts from recurrent tumor samples.

Eligibility:

-Patients 15 and less than 75 years of age with recurrent osteosarcoma, localized to the lung, who have had complete surgical removal of all lung nodules, or who are deemed fully resectable, will be enrolled.

Design:

-Only after complete resection of all lung nodules, patients will be randomized to treatment with AZDO53O or placebo. Eighty-eight patients will be randomized, 44 patients in each arm of the study. This will be a multi-institutional study.

-AZDO53O, or placebo, will be administered as a once daily, oral dose of 175 mg, for a 28-day cycle, with no breaks between cycles. The duration of treatment with

AZDO53O or placebo will be 13 cycles (364 days total).

-Patients will begin cycle 1 after complete surgical resection.

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Participants currently recruited/enrolled

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): None

Eligibility Criteria:

INCLUSION CRITERIA:

Patients who have recurrence of osteosarcoma, localized to the lungs, who have had complete surgical removal of all lung nodules, or who are deemed fully resectable, are eligible for enrollment.

Other inclusion criteria are as follows:

a. Histological diagnosis of osteosarcoma of the recurrent sample (histology types must be osteoblastic, chondroblastic, fibroblastic or telangiectatic)

b. Recurrence of osteosarcoma in the lung following standard chemotherapy including: adriamycin, cisplatin, ifosphamide and methotrexate (or provide justification why any of these agents were not received)

c. Age greater than or equal to 15 and less than 75 years of age

d. Weight greater than 34 kg

e. ECOG performance score of 0, 1 or 2 (0 equals asymptomatic, 1 equals symptomatic but fully ambulatory, 2 equals symptomatic in bed less than 50% of the day)

f. Adequate bone marrow function (ANC greater than or equal to 1500/uL, Hb greater than or equal to 9.0 g/dL, platelets greater than or equal to 100,000IuL)

g. Adequate renal function (serum creatinine less than or equal to 1.5 or a creatinine clearance greater than or equal to 50 mL/min/l.73m(2)

h. Adequate hepatic function (ALT/AST less than or equal to 2.5 X normal, total bilirubin less than or equal to 2 mgldl with the exception of patients with Gilbert's syndrome)

i. Adequate cardiac function (ECHO or MUGA with shortening fraction greater than or equal to 27% or ejection fraction greater than or equal to 45%) and (EKG with QTc less than or equal to 480 msec)

j. Negative pregnancy test for women of childbearing potential, less than or equal to 7 days prior to enrollment, and the willingness to use an acceptable method of contraception during participation in the study and for 3 months after the last dose

k. Randomization must occur less than or equal to 6 weeks after complete surgical resection of all tumor nodules

l. Informed consent: all patients, or their legal guardian if the patient is less than 18 years of age, must sign a document of informed consent indicating their awareness of the investigational nature and the risks of this study

EXCLUSION CRITERIA:

a. Presence of metastatic disease in other locations in addition to the lung

b. Disruption of the lung pleura by tumor

c. Paget's disease

d. Current use, or previous use within the specified time period, of medications that are potent inducers, inhibitors or substrates of CYP3A4

e. Known hypersensitivity to other Src/Abl non-receptor kinase inhibitors

f. Any evidence of interstitial lung disease (bilateral, diffuse, parenchymal lung disease)

g. Any concurrent condition which in the investigator's opinion makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the protocol. These include conditions that are severe and/or inadequately uncontrolled, such as severe or worsening hepatic, respiratory and cardiac impairment.

h. Myocardial infarction within one year prior to study entry

i. Bleeding diathesis, resulting in symptomatic bleeding

j. Pregnant women or breast-feeding or nursing women

k. Any agent (chemotherapy, biological or investigational) administered 28 days prior to enrollment

1. Unresolved toxicity greater than or equal to CTCAEv3 grade 2 (except alopecia) from previous agents

The reasoning for the above criteria is that patients who meet exclusion criteria a-c have an extremely poor five-year survival rate. Since some patients will meet one of the above criteria, it is possible that a true survival advantage with adjuvant AZDO53O treatment may go undetected if the above patients are included.

Special Instructions:

Currently Not Provided

Keywords:

Osteosarcoma

Lung Metastasis

AZD 0530

Src Kinase Inhibitor

Recruitment Keyword(s):

None

Condition(s):

Osteosarcoma

Lung Metastasis

AZD 0530

Src Kinase Inhibitor

Investigational Drug(s):

AZD0530

Investigational Device(s):

None

Intervention(s):

Drug: AZD0530

Supporting Site:

National Cancer Institute

Contact(s):

NCI Referral Office
National Institute of Health Clinical Center (CC), 9000 Rockville Pike, Bethesda, Maryland 20892, United States: NCI Clinical Trials Referral Office
Phone: 1-888-NCI-1937
Fax: Not Listed
Electronic Address: ncicssc@mail.nih.gov

Citation(s):

Meyers PA, Schwartz CL, Krailo M, Kleinerman ES, Betcher D, Bernstein ML, Conrad E, Ferguson W, Gebhardt M, Goorin AM, Harris MB, Healey J, Huvos A, Link M, Montebello J, Nadel H, Nieder M, Sato J, Siegal G, Weiner M, Wells R, Wold L, Womer R, Grier H. Osteosarcoma: a randomized, prospective trial of the addition of ifosfamide and/or muramyl tripeptide to cisplatin, doxorubicin, and high-dose methotrexate. J Clin Oncol. 2005 Sep 10;23(26):6437-8. J Clin Oncol. 2008 Jun 20;26(18):3102-3; author reply 3104-5. J Clin Oncol. 2008 Jun 20;26(18):3103-4; author reply 3104-5.

Bielack SS, Kempf-Bielack B, Delling G, Exner GU, Flege S, Helmke K, Kotz R, Salzer-Kuntschik M, Werner M, Winkelmann W, Zoubek A, JŸrgens H, Winkler K. Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol. 2002 Feb 1;20(3):627-9. J Clin Oncol. 2002 Jun 15;20(12):2910; author reply 2910-1.

Kempf-Bielack B, Bielack SS, JŸrgens H, Branscheid D, Berdel WE, Exner GU, Gšbel U, Helmke K, Jundt G, Kabisch H, Kevric M, Klingebiel T, Kotz R, Maas R, Schwarz R, Semik M, Treuner J, Zoubek A, Winkler K. steosarcoma relapse after combined modality therapy: an analysis of unselected patients in the Cooperative Osteosarcoma Study Group (COSS). J Clin Oncol. 2005 Jan 20;23(3):559-68.

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