Prospective Clinical Trial Evaluating Metronomic Chemotherapy in Patients With High-grade, Operable, Non-metastatic Osteosarcoma of the Extremity

Preclinical models show that a daily antiangiogenic regimen at low-dose may be effective against chemotherapy-resistant tumors. The aim of this study is to evaluate the efficacy of maintenance therapy with continuous oral cyclophosphamide and methotrexate in patients with high grade, operable, non-metastatic osteosarcoma (OST) of the extremities. The primary end point is event-free survival (EFS) from randomization.

Study Overview

• Status: Unknown
• Conditions: High Grade Osteosarcoma
• Intervention / Treatment: Drug: continuous oral cyclophosphamide and methotrexate

Detailed Description

The study design includes a backbone of 10 weeks of preoperative therapy using MAP (High-dose methotrexate, cisplatin, and doxorubicin). Following surgery, non-metastatic patients were randomized by blocks to complete 31 weeks of MAP or to receive 73 weeks of maintenance therapy following MAP; while metastatic patients received maintenance therapy in combination with MAP since the beginning of treatment.

• Study Type: Interventional
• Enrollment (Anticipated): 738
• Phase: Phase 2

Contacts and Locations

Study Locations

• Brazil
  • SP
    • São Paulo, SP, Brazil, 04023-062
      • Recruiting
      • GRAACC- Institute of Pediatric Oncology
      • Contact: Antônio Sérgio Petrilli, MD; Phone Number: 55-11-5080-8494; Email: sergiopetrilli@graacc.org.br
      • Principal Investigator: Antônio Sérgio Petrilli, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 day to 30 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patients with high-grade malignancy osteosarcoma , biopsy-proven , newly diagnosed , previously untreated . Patients with osteosarcoma as a second malignancy should also be eligible .
2. Patients with any primary site , with or without metastases at diagnosis , will be accepted and treated.
3. Patients < 30 years.
4. Patients must have normal body function and adequate renal function defined as serum creatinine < 1.5 x the normal value or creatinine clearance > 60ml/min/1 ,73m2 .
5. Patients must have adequate hepatic function, defined as total bilirubin < 1.5 x normal, aspartate aminotransferase (AST or SGOT) and alanine aminotransferase (ALT or SGPT) < 2.5 x normal.
6. Patients must have adequate cardiac function defined by a shortening fraction > 27 % by echocardiogram or ejection fraction > 47 % by radioisotopic angiogram .

7. If pre- chemotherapy amputation is necessary, the patient is included in the study and eligible to survival analyzes, however the pathological analyze response will be not performed.

   Obtain material for pathological and molecular study is recommended .

8. Whenever possible a central catheter should be placed against the intensity of chemotherapy and need for forced hydration .
9. Patient or legal guardian must sign a consent form which will be explain the type of treatment and procedures that the patient will be submitted .
10. Time > than 4 weeks between biopsy and initiation of treatment - Restaging

Exclusion Criteria:

1. Disease progression ( increase of at least 20% of the extent of the lesion, taking as reference the smallest measurement recorded from the start of treatment, or the appearance of one or more lesions );
2. Any properly documented clinical situation , which at the discretion of the attending physician , patient can not follow with chemotherapy , for safety reasons ;
3. The evaluation of cardiac aspects will be done carefully , so will exclude patients with 20% reduction in the ejection fraction of the left ventricle compared to baseline or with a ventricular ejection fraction < 45 % regardless of baseline;
4. The patient refusal to continue treatment ;
5. Nephrotoxicity , neurotoxicity and ototoxicity grade 4 ;
6. Delay greater than 40 days for the realization of the next treatment cycle , not related to toxicity;
7. Refusal of surgery ; 8 . Variation above 20% of the recommended dose without justification.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Maintenance therapy; 73 weeks of continuous oral low dose chemotherapy with cyclophosphamide (CPM) and methotrexate (MTX) following 31 weeks of MAP.	Drug: continuous oral cyclophosphamide and methotrexate
No Intervention: Control; 31 weeks of MAP.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event-Free Survival	AT 5 YEARS	EFS AT 5 YEARS

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	AT 5 YEARS	OS AT 5 YEARS

Collaborators and Investigators

• Sponsor: Grupo de Apoio ao Adolescente e a Crianca com Cancer

Study record dates

Study Major Dates

• Study Start: May 1, 2006
• Primary Completion (Actual): June 1, 2013

Study Registration Dates

• First Submitted: July 7, 2014
• First Submitted That Met QC Criteria: October 23, 2014
• First Posted (Estimate): October 24, 2014

Study Record Updates

• Last Update Posted (Estimate): February 11, 2016
• Last Update Submitted That Met QC Criteria: February 10, 2016
• Last Verified: February 1, 2016

More Information

Terms related to this study

• Keywords: of the extremity
• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Sarcoma; Osteosarcoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Dermatologic Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Cyclophosphamide; Methotrexate
• Other Study ID Numbers: GLATO 2006