Neoadjuvant Combination of Doxorubicin, Cisplatin and Methotrexate in Patients Aged 24-40 Years With Primary Bone Tumors

Neoadjuvant Three-component Chemotherapy Based on a Combination of Doxorubicin, Cisplatin and Methotrexate in Patients Aged 24-40 Years With Primary Bone Tumors to Increase the Response Rate Compared With Two-component Chemotherapy

Two cycles of neoadjuvant three-component chemotherapy according to the MAP prototoc: Doxorubicin 25 mg / m2 IV on days 1-3, Cisplatin 120 mg / m2 IV on day 1 against the background of hyperhydration. G-CSF support from 4 to 13 days. Methotrexate 12 g / m2 at 28 and 35 days IV with leucovorin 60 mg / m2 in the first 5 days after each administration of methotrexate. The interval between cycles is 42 days.

The advantage of this regimen is to use the three-component chemotherapy regimen, which should increase the degree of tumor necrosis and increase the rate of tumor response to treatment, which will further improve the disease prognosis. Currently, the use of such treatment for adult patients (over 24 years old) is controversial. Since it is believed that the elimination of methotrexate in adult patients is more delayed than in patients under 24 years old, and can lead to serious adverse events (SAE). However, the use of modern standard methods of hemodialysis makes it possible to avoid SAE.

Study Overview

• Status: Recruiting
• Conditions: Sarcoma; Neoplasms, Connective and Soft Tissue; Osteosarcoma; Neoplasms, Connective Tissue; Sarcoma of Bone
• Intervention / Treatment: Drug: Doxorubicin, Cisplatin, Methotrexate; Drug: Doxorubicin, Cisplatin

Detailed Description

The role of methotrexate in neoadjuvant chemotherapy for bone tumors is a topic for debate. However, the benefits of methotrexate have been confirmed in at least one phase II study showing better results with high doses of methotrexate in the context of triple chemotherapy. Moreover, many studies have shown a correlation between peak serum methotrexate levels, tumor response to chemotherapy, and treatment outcome. Thus, it is possible that the negative results of the effectiveness of methotrexate have been compromised due to the administration of insufficient doses or incorrect administration of the drug. The optimal regimen of methotrexate administration has not been established. However, the control group in the EURAMOS-1 study of the American Osteosarcoma Research Group (AOST) is considered as the standard. The main practical problem with the use of triple chemotherapy in a group of patients aged 24 and older is that the slow clearance of methotrexate can delay the administration of the next cycle of doxorubicin-cisplatin, thereby reducing the dose intensity and adversely affecting the outcome. Currently, there are both isolated clinical cases and observations of a small number of included patients. The use of three-component neoadjuvant chemotherapy for primary bone tumors will improve the rate of response to treatment, reduce the frequency of recurenses and disease progression.

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Anastasia Tararykova; Phone Number: +79175274287; Email: anastasiatararykova@gmail.com

Study Locations

• Russian Federation
  • Moscow, Russian Federation, 115478
    • Recruiting
    • Federal State Budgetary Institution "N.N. Blokhin National Medical Research Center of Oncology" оf the Ministry of Health of the Russian Federation
    • Contact: Anastasia Tararykova; Phone Number: 89175274287; Email: anastasiatararykova@gmail.com
    • Sub-Investigator: Anastasia Tararykova
    • Sub-Investigator: Andrei Konev
    • Principal Investigator: Beniamin Bokhyan, PhD
    • Principal Investigator: Aslan Valiev, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 24 years to 40 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Histologically confirmed diagnosis of primary bone tumor (osteosarcoma)

Age from 24 to 40 years

Operable process, possibility of performing resection R0-R1

ECOG performance score 0 or 1

Normal renal function (estimated creatinine clearance more than 60 ml / min)

Normal liver function (AST, ALT - no more than 3 norms)

Left ventricular ejection fraction> 55%

Adequate marrow function (hemoglobin level more than 9 g / dL, neutrophil count more than 1.5 thousand / μl, platelet number more than 100 thousand / μl)

Signed informed consent

Exclusion Criteria:

Children, women during pregnancy, childbirth, women during breastfeeding

Persons with mental disorders

The presence of an active viral infection with HIV, viral hepatitis B and C

Inoperable tumor

Morphologically confirmed diagnosis of GIST, Kaposi's sarcoma, alveolar or clear cell sarcoma, chondrosarcoma, chordoma, giant cell tumor, paraosal osteosarcoma, Ewing's sarcoma / PNET, rhabdomyosarcoma, G1 osteosarcoma

The presence of a second malignant neoplasm within the last 5 years before enrollment, other than cured basal cell or squamous cell carcinoma or cervical cancer in situ, prostate cancer

Clinically significant cardiovascular or cerebrovascular diseases within the last 6 months (acute myocardial infarction, unstable angina pectoris, significant ventricular arrhythmias, severe heart failure (NYHA class IV), stroke or uncontrolled arterial hypertension)

Renal failure (serum creatinine level more than 150 μmol / L), except for cases caused by lymphoid infiltration of the kidneys, and tumor disintegration syndrome

Hepatic failure (except for cases caused by leukemic / lymphoid organ infiltration), acute hepatitis (serum bilirubin level more than 2 norms, ALT and AST activity more than 4 norms, prothrombin index less than 50%)

Decompensated diabetes mellitus (blood serum glucose above 15 mmol / L)

Sepsis (septicopyemic foci, hemodynamic instability; ineffective antimicrobial therapy) or acute infectious diseases

Brain metastases

Life-threatening conditions (bleeding, tumor decay, etc.)

Hypersensitivity to the active substance of the investigational drugs or any of the auxiliary components or their intolerance

Surgical interventions less than 21 days before starting therapy

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Three-component chemotherapy; Doxorubicin 25 mg / m2 IV on days 1-3, Cisplatin 120 mg / m2 IV on day 1 against the background of hyperhydration. G-CSF support from 4 to 13 days. Methotrexate 12 g / m2 at 28 and 35 days IV with leucovorin 60 mg / m2 in the first 5 days after each administration of methotrexate. The interval between cycles is 42 days	Drug: Doxorubicin, Cisplatin, Methotrexate; IV; Other Names: MAP
Active Comparator: Two-component chemotherapy; Doxorubicin 25 mg / m2 IV on days 1-3, Cisplatin 120 mg / m2 IV on day 1 against the background of hyperhydration. G-CSF support from 4 to 13 days. The interval between cycles is 28 days	Drug: Doxorubicin, Cisplatin; IV; Other Names: AP

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate	Proportion of patients who have a partial or complete response to therapy	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison of tumor necrosis	Proportion of tumor necrosis after chemotherapy	6 months
Comparison of safety assessment	Adverse Event Assessment and Serious Adverse Event Assessment according to CTCAE 5.0	6 months

Collaborators and Investigators

• Sponsor: Blokhin's Russian Cancer Research Center
• Investigators: Principal Investigator: Beniamin Bokhyan, PhD, N.N. Blokhin NMRCO

Publications and helpful links

Helpful Links

• official site
• russian surcoma group site

Study record dates

Study Major Dates

• Study Start (Actual): January 10, 2022
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: September 7, 2021
• First Submitted That Met QC Criteria: September 15, 2021
• First Posted (Actual): September 27, 2021

Study Record Updates

• Last Update Posted (Actual): April 1, 2024
• Last Update Submitted That Met QC Criteria: March 29, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Bone sarcoma
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Connective Tissue Diseases; Neoplasms, Bone Tissue; Neoplasms; Sarcoma; Osteosarcoma; Neoplasms, Connective and Soft Tissue; Neoplasms, Connective Tissue; 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; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Dermatologic Agents; Antibiotics, Antineoplastic; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Cisplatin; Doxorubicin; Liposomal doxorubicin; Methotrexate
• Other Study ID Numbers: AMAP2021-7-2

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes