Feasibility Study of Interval Compressed Regimen Using Four-drugs for Osteosarcoma

The aim of the study is to test the feasibility of four-drug, interval-compressed regimen in osteosarcoma.

Primary objective is to explore the toxicity and mortality related to treatment. Secondary objectives are to examine tumor necrosis rates after neoadjuvant chemotherapy, and to evaluate the usefulness of circulating cell-free DNA, survivin, or transforming growth factor-beta1 levels as well as programmed cell death ligand 1 expression in tumor specimen as a predictive or prognostic biomarker in osteosarcoma patients.

Study Overview

• Status: Unknown
• Conditions: Feasibility; Osteosarcoma; Biomarker; Treatment Response
• Intervention / Treatment: Drug: Poor responder group adjuvant chemotherapy; Drug: Good responder group adjuvant chemotherapy

Detailed Description

In this study, the investigators will investigate the feasibility of interval compressed regimen using four-drugs in newly-diagnosed osteosarcoma patients. Four drugs will be adriamycin, high-dose methotrexate, cisplatin, ifosfamide. All these drugs will be given preoperatively in an interval-compressed schedule, but postoperatively at a regular interval. Neoadjuvant therapy will be composed of two courses, and adjuvant therapy of two or three courses depending on necrosis rates following neoadjuvant therapy.

• Study Type: Interventional
• Enrollment (Anticipated): 23
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Byung-Kiu Park, M.D., Ph.D.; Phone Number: 82-31-920-1240; Email: bkpark@ncc.re.kr

Study Locations

• Korea, Republic of
  • Gyeonggi
    • Goyang-si, Gyeonggi, Korea, Republic of, 10408
      • National Cancer Center
      • Contact: Byung-Kiu Park, M.D., Ph.D.; Phone Number: 82-31-920-1240; Email: bkpark@ncc.re.kr
      • Contact: Mi Mi Kwon, RN; Phone Number: 82-31-920-1240; Email: rnjsalal@ncc.re.kr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 40 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Newly diagnosed osteosarcoma patients under age 40 years.

Exclusion Criteria:

• Patients who don't meet the organ function criteria as follows;

  1. renal function : CCr or GFR or eGFR ≥ 70 mL/min/1.73 m2
  2. liver function : AST/ALT ≤ 5 x upper limit, total bilirubin ≤ 1.5 x upper limit of normal for age
  3. cardiac function : shortening fraction ≥ 24% or ejection fraction ≥ 50% (Echo)
  4. lung function : No dyspnea on rest, If dyspnea exists, SpO2 95% or more in room air by pulse oximetry,
  5. hematologic : ANC ≥ 750/uL and platelet ≥ 75,000/uL

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: four-drug interval-compressed regimen; Interventions for 'four-drug interval-compressed regimen': Drug: methotrexate, cisplatin, doxorubicin, ifosfamide. Newly diagnosed oseteosarcoma patients under 40 years are eligible. Neoadjuvant chemotherapy with four drugs in an interval-compressed schedule will be done as a single arm. Duration of neoadjuvant chemotherapy will be 10 weeks like that of conventional three-drug regimen, although four-drugs are employed in the current protocol. After tumor resection operation, participants will be divided to poor responder group and good responder group based on 90% necrosis rate of a tumor specimen. Poor responder group and will be assigned to 'Poor responder group adjuvant chemotherapy' and good responder will be assigned to 'Good responder group adjuvant chemotherapy'.

Drug: Poor responder group adjuvant chemotherapy; Poor responder group (necrosis ≤ 90%) : week 0, 7 and 14, doxorubicin; week 2, 9 and 16, ifosfamde, week 4, 11, 18 and 19, methotrexate; wk 5, 12 and 20 B. Resection of tumor C. Adjuvant chemotherapy; Poor responder group (necrosis ≤ 90%)week 0, 7 and 14, doxorubicin; week 2, 9 and 16, ifosfamde, week 4, 11, 18 and 19, methotrexate; wk 5, 12 and 20; Good responder group (necrosis > 90%)week 0 and 8, doxorubicin; week 2 and 10, ifosfamide; week 4, 5, 12 and 13, methotrexate; week 6 and 14, cisplatin; Other Names: PR adjuvant four-drug interval-compressed regimen; Drug: Good responder group adjuvant chemotherapy; Good responder group (necrosis > 90%) : week 0 and 8, doxorubicin; week 2 and 10, ifosfamide; week 4, 5, 12 and 13, methotrexate; week 6 and 14, cisplatin; Other Names: GR adjuvant four-drug interval-compressed regimen

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Toxicity determined according to CTCAE	treatment-related toxicity (organ dysfunction, neutropenic fever, infection, mortality, et al.)	Until study completion, an average of 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
tumor necrosis rate	necrosis rate of the excised tumor after neoadjuvant chemotherapy	Until study completion, an average of 3years
Predictive or prognostic biomarker	Usefulness of circulating cell-free DNA, survivin, transforming growth factor-beta1 levels and programmed cell death 1 expression in tumor specimen as a biomarker	Until study completion, an average of 3 years

Collaborators and Investigators

• Sponsor: Byung-Kiu Park
• Collaborators: Samsung Medical Center; Chungnam National University Hospital
• Investigators: Principal Investigator: Byung-Kiu Park, M.D., Ph.D., National Cancer Center

Publications and helpful links

General Publications

• Marina NM, Smeland S, Bielack SS, Bernstein M, Jovic G, Krailo MD, Hook JM, Arndt C, van den Berg H, Brennan B, Brichard B, Brown KLB, Butterfass-Bahloul T, Calaminus G, Daldrup-Link HE, Eriksson M, Gebhardt MC, Gelderblom H, Gerss J, Goldsby R, Goorin A, Gorlick R, Grier HE, Hale JP, Hall KS, Hardes J, Hawkins DS, Helmke K, Hogendoorn PCW, Isakoff MS, Janeway KA, Jurgens H, Kager L, Kuhne T, Lau CC, Leavey PJ, Lessnick SL, Mascarenhas L, Meyers PA, Mottl H, Nathrath M, Papai Z, Randall RL, Reichardt P, Renard M, Safwat AA, Schwartz CL, Stevens MCG, Strauss SJ, Teot L, Werner M, Sydes MR, Whelan JS. Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomised controlled trial. Lancet Oncol. 2016 Oct;17(10):1396-1408. doi: 10.1016/S1470-2045(16)30214-5. Epub 2016 Aug 25.
• Lewis IJ, Nooij MA, Whelan J, Sydes MR, Grimer R, Hogendoorn PC, Memon MA, Weeden S, Uscinska BM, van Glabbeke M, Kirkpatrick A, Hauben EI, Craft AW, Taminiau AH; MRC BO06 and EORTC 80931 collaborators; European Osteosarcoma Intergroup. Improvement in histologic response but not survival in osteosarcoma patients treated with intensified chemotherapy: a randomized phase III trial of the European Osteosarcoma Intergroup. J Natl Cancer Inst. 2007 Jan 17;99(2):112-28. doi: 10.1093/jnci/djk015.

Study record dates

Study Major Dates

• Study Start (Anticipated): February 1, 2018
• Primary Completion (Anticipated): December 31, 2020
• Study Completion (Anticipated): December 31, 2020

Study Registration Dates

• First Submitted: December 11, 2017
• First Submitted That Met QC Criteria: December 28, 2017
• First Posted (Actual): January 5, 2018

Study Record Updates

• Last Update Posted (Actual): January 9, 2018
• Last Update Submitted That Met QC Criteria: January 5, 2018
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Keywords: four-drugs, interval-compression
• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Sarcoma; Osteosarcoma
• Other Study ID Numbers: NCC-OSA-1601

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Clinical data of individual participants can be shared without personal information. Each participating center will submit the clinical data to the principal investigation center, after eliminating personal data.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No