MAPAC: Comparison of MAPI+Camrelizumab Versus API+Apatinib Versus MAPI in Patients With a Poor Response to Preoperative Chemotherapy for Newly Diagnosed High-grade Osteosarcoma

Sponsor

Peking University People's Hospital (Other)

Overall Status

Recruiting

CT.gov ID

NCT04351308

Collaborator

Chinese Sarcoma Study Group (Other)

Enrollment

Location

Arms

Anticipated Duration (Months)

1.9

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Treatment strategies for high-grade osteosarcoma with multidrug chemotherapy and resection result in 3-year event-free survival of 60-70%. The most common factors predicting survival are presence of metastases, histological response to preoperative chemotherapy and complete surgical resection. Four of the active drugs in osteosarcoma include cisplatin, doxorubicin, high-dose methotrexate and ifosfamide and this combination (MAPI), given preoperatively and postoperatively, is widely used for the treatment of osteosarcoma in China. Apatinib also has activity in advanced setting and when incorporated into the treatment of patients with metastatic disease seemed to improve progression-free survival. Combination of apatinib and camrelizumab resulted in durable therapuetic effect in selected cases. Though EURAMOUS-1 suggested that changing chemotherapy postoperatively on the basis of histological response did not improve outcomes. The exploratory study with radomised design to compare combination of chemotherapy with target drug or combination of chemotherapy with anti-PD-1 antibody versus standard chemotherapy has not been tried yet. Thus we aim to investigate the efficacy and toxicity of these combiantions versus standard chemotherapy in this study.

Condition or Disease	Intervention/Treatment	Phase
Osteosarcoma Survival Chemotherapy Effect Toxicity, Drug	Drug: MAPI chemotherapy Drug: Apatinib Mesylate Drug: Camrelizumab	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

60 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Randomized Trial of Comparison of MAPI+Camrelizumbab Verus API+Apatinib Versus MAPI in Patients With a Poor Response to Preoperative Chemotherapy for Newly Diagnosed High-grade Osteosarcomaies : an Open-label, Exploratory Study

Actual Study Start Date :

May 1, 2020

Anticipated Primary Completion Date :

Sep 1, 2022

Anticipated Study Completion Date :

Dec 31, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: API+apatinib AP = Doxorubicin (Adriamycin) 20 mg/m2/day * 2 day (total/cycle 40 mg/m²) + Cisplatin 100 mg/m2/course (total/cycle 120 mg/m²); I = Ifosfamide 2000 mg/m2/day *5 day (total/cycle 10000 mg/m²); apatinib = 500 mg QD;	Drug: MAPI chemotherapy AP = Doxorubicin (Adriamycin) 37.5 mg/m2/day * 2day (total/cycle 75 mg/m²) + Cisplatin 120 mg/m2/course (total/cycle 120 mg/m²) ; M = Methotrexate 12000 mg/m2 (total/cycle 12000 mg/m²) with leucovorin rescue; I = Ifosfamide 2400 mg/m2/day 5day (total/cycle 12000 mg/m²) Drug: Apatinib Mesylate* anti-angiogenesis tyrosine kinase inhibitors 500 mg orally daily
Experimental: MAPI+camrelizumab AP = Doxorubicin (Adriamycin) 37.5 mg/m2/day * 2day (total/cycle 75 mg/m²) + Cisplatin 120 mg/m2/course (total/cycle 120 mg/m²); M = Methotrexate 12000 mg/m2 (total/cycle 12000 mg/m²) with leucovorin rescue; I = Ifosfamide 2400 mg/m2/day *5day (total/cycle 12000 mg/m²); camralizumab = 200mg ivgtt. Q2W;	Drug: MAPI chemotherapy AP = Doxorubicin (Adriamycin) 37.5 mg/m2/day * 2day (total/cycle 75 mg/m²) + Cisplatin 120 mg/m2/course (total/cycle 120 mg/m²) ; M = Methotrexate 12000 mg/m2 (total/cycle 12000 mg/m²) with leucovorin rescue; I = Ifosfamide 2400 mg/m2/day 5day (total/cycle 12000 mg/m²) Drug: Camrelizumab* anti-PD-1 antibody 200mg ivgtt. Q2W
Active Comparator: MAPI AP = Doxorubicin (Adriamycin) 37.5 mg/m2/day * 2day (total/cycle 75 mg/m²) + Cisplatin 120 mg/m2/course (total/cycle 120 mg/m²); M = Methotrexate 12000 mg/m2 (total/cycle 12000 mg/m²) with leucovorin rescue; I = Ifosfamide 2400 mg/m2/day *5day (total/cycle 12000 mg/m²);	Drug: MAPI chemotherapy AP = Doxorubicin (Adriamycin) 37.5 mg/m2/day * 2day (total/cycle 75 mg/m²) + Cisplatin 120 mg/m2/course (total/cycle 120 mg/m²) ; M = Methotrexate 12000 mg/m2 (total/cycle 12000 mg/m²) with leucovorin rescue; I = Ifosfamide 2400 mg/m2/day *5day (total/cycle 12000 mg/m²)

Arm

Intervention/Treatment

Experimental: API+apatinib

AP = Doxorubicin (Adriamycin) 20 mg/m2/day * 2 day (total/cycle 40 mg/m²) + Cisplatin 100 mg/m2/course (total/cycle 120 mg/m²); I = Ifosfamide 2000 mg/m2/day *5 day (total/cycle 10000 mg/m²); apatinib = 500 mg QD;

Drug: MAPI chemotherapy

AP = Doxorubicin (Adriamycin) 37.5 mg/m2/day * 2day (total/cycle 75 mg/m²) + Cisplatin 120 mg/m2/course (total/cycle 120 mg/m²) ; M = Methotrexate 12000 mg/m2 (total/cycle 12000 mg/m²) with leucovorin rescue; I = Ifosfamide 2400 mg/m2/day *5day (total/cycle 12000 mg/m²)

Drug: Apatinib Mesylate

anti-angiogenesis tyrosine kinase inhibitors 500 mg orally daily

Experimental: MAPI+camrelizumab

AP = Doxorubicin (Adriamycin) 37.5 mg/m2/day * 2day (total/cycle 75 mg/m²) + Cisplatin 120 mg/m2/course (total/cycle 120 mg/m²); M = Methotrexate 12000 mg/m2 (total/cycle 12000 mg/m²) with leucovorin rescue; I = Ifosfamide 2400 mg/m2/day *5day (total/cycle 12000 mg/m²); camralizumab = 200mg ivgtt. Q2W;

Drug: MAPI chemotherapy

Drug: Camrelizumab

anti-PD-1 antibody 200mg ivgtt. Q2W

Active Comparator: MAPI

AP = Doxorubicin (Adriamycin) 37.5 mg/m2/day * 2day (total/cycle 75 mg/m²) + Cisplatin 120 mg/m2/course (total/cycle 120 mg/m²); M = Methotrexate 12000 mg/m2 (total/cycle 12000 mg/m²) with leucovorin rescue; I = Ifosfamide 2400 mg/m2/day *5day (total/cycle 12000 mg/m²);

Drug: MAPI chemotherapy

Outcome Measures

Primary Outcome Measures

event-free survival rate [2 years]
from initial treatment after definitive surgery to progression/death/ last follow up

Secondary Outcome Measures

overall survival rate [5 years]
from initial treatment after definitive surgery to death/ last follow up

Eligibility Criteria

Criteria

Ages Eligible for Study:

12 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically confirmed high-grade osteosarcoma, including second malignancies
Tumor (primary, metastatic, or both) resectable OR is expected to become resectable after neoadjuvant induction chemotherapy
Suitable for neoadjuvant chemotherapy and adjuvant chemotherapy
Performance status - Lansky 50-100% (for patients under 16 years of age); Performance status - WHO or ECOG 0-2 with a life expectancy >3 months
normal cardiac function (shortening fraction >28%), normal hearing, normal bone marrow as shown by an absolute neutrophil count of at least 1·5 × 10⁹ cells per L (or a white blood cell count of at least 3 × 10⁹ cells per L if neutrophil count is not available), and a platelet count of at least 100 000 platelets per μL
Patients were also required to have a serum bilirubin concentration of at most less than 1·5 times the upper limit of normal and a normal creatinine concentration for their age as per protocol
Women of child-bearing potential had to take adequate contraceptive measures and have a negative pregnancy test within 7 days of study entry.

Exclusion Criteria:

patients who have recieved anti-angiogenic TKIs or anti-PD-1/PD-L1 antibodies
allergy to chemotherapy or apatinib or camrelizumab
other severe illness (eg, psychosis or previous history of cardiovascular disease)
symptomatic or known CNS metastases
previous or concurrent second primary malignant tumours
had uncontrolled complications such as diabetes mellitus, coagulation disorders, urine protein ≥ ++, and so on
had other infections or wounds
pregnant or breastfeeding.