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Gefitinib, Trametinib, Disulfiram, and Sunitinib in Addition to Standard Chemotherapy for the Treatment of Metastatic, Unresectable or Relapsed Osteosarcoma, OstEvo Trial
Trial Status: active
This phase II trial tests compares the effect of gefitinib, trametinib, disulfiram and sunitinib in combination with standard chemotherapy to standard chemotherapy alone in treating patients with osteosarcoma that is newly diagnosed, that has spread from where it first started (primary site) to other places in the body (metastatic), that cannot be removed by surgery (unresectable), or that has come back after a period of improvement (relapsed). Gefitinib, a type of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, blocks certain proteins made by the EGFR gene, which may help keep tumor cells from growing. It may also prevent the growth of new blood vessels that tumors need to grow. Trametinib, a mitogen-activated protein kinase (MEK) inhibitor, targets and blocks proteins called MEK1 and MEK2, which are found on tumor cells and play a roll in tumor growth and survival. By blocking these proteins, trametinib may help slow or stop the growth of tumors. Disulfiram blocks an enzyme called aldehyde dehydrogenase (ALDH). This enzyme may be too active or found at high levels in some types of tumor cells. By blocking, ALDH, disulfiram may help slow or stop the growth of tumors. Sunitinib, a type of tyrosine kinase inhibitor, vascular endothelial growth factor receptor inhibitor and a type of angiogenesis inhibitor, blocks certain proteins, which may help keep tumor cells from growing. It may also prevent the growth of new blood vessels that tumors need to grow. Standard of care chemotherapy may include methotrexate, doxorubicin and cisplatin (MAP) or ifosfamide. Methotrexate is in a class of medications called antimetabolites. It is also a type of antifolate. Methotrexate stops cells from using folic acid to make deoxyribonucleic acid (DNA) and may kill tumor cells. Chemotherapy drugs, such as doxorubicin and ifosfamide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Cisplatin is in a class of medications known as platinum-containing compounds. It works by killing, stopping or slowing the growth of cancer cells. Adding gefitinib, trametinib, disulfiram, and sunitinib to standard of care chemotherapy may be safe, tolerable, and or effective than standard chemotherapy alone in treating patients with newly diagnosed, metastatic, unresectable, or relapsed osteosarcoma.
Inclusion Criteria
COHORT 1 ONLY NEWLY DIAGNOSED, METASTATIC OSTEOSARCOMA: For study entry, the suspected diagnosis of osteosarcoma may be based on clinical judgement. Biopsy confirmation is required for treatment but as this protocol has biologic aims from serial tumor samples, some patients will be enrolled prior to open biopsy. Patients must have a histologic new diagnosis of metastatic high-risk osteosarcoma to start OstEvo systemic therapy. For purposes of this protocol, newly diagnosed, high-risk metastatic osteosarcoma includes:
* Having at least 1 extrapulmonary metastasis, radiographic confirmation of metastasis is adequate, and/or
* Unresectable metastases at diagnosis as determined by the investigator
COHORT 1 ONLY NEWLY DIAGNOSED, METASTATIC OSTEOSARCOMA: Patients may have started systemic conventional chemotherapy but must enroll on this study prior to day 29 of chemotherapy initiation. Having received a single standard MAP cycle (doxorubicin and cisplatin [AP] x 1 and high dose methotrexate [HDMTX] up to 2 times) of chemotherapy prior to enrollment is acceptable
COHORT 2 ONLY RELAPSED, METASTATIC OSTEOSARCOMA: Patients must have achieved a radiographically confirmed complete response as determined by the investigator from initial therapy and then relapsed with metastatic high-risk osteosarcoma. No strict size criteria of pulmonary or additional nodules for eligibility are required. For purposes of this protocol, relapsed, metastatic, high-risk osteosarcoma includes:
* First relapse within 24 months of start of first chemotherapy or
* First relapse involving more than one lung nodule, or the lung and any extrapulmonary sites or
* First relapse with pleural disruption at relapse as determined by the investigator which can be determined by CT scan and/or
* Multiply relapsed patients are eligible provided the current relapse is in the context of a radiographically confirmed complete response on the scans preceding the relapse making them potentially eligible for OstEvo
COHORT 2 ONLY RELAPSED, METASTATIC OSTEOSARCOMA: Patients may have received only a single cycle of ifosfamide-containing conventional chemotherapy ever and included for the relapse making them eligible for OstEvo, but must enroll on this study prior to day 22 of the first cycle post-relapse
COHORT 3 ONLY: Patients with newly diagnosed osteosarcoma who are not eligible for Cohorts 1 or 2
COHORT 3 ONLY: Diagnostic biopsy has insufficient material for research
COHORT 3 ONLY: Must be enrolled on Memorial Sloan Kettering (MSK) institutional review board (IRB) 12-245, biospecimen research protocol, with oncologic surgeries planned to be performed at MSK
COHORT 3 ONLY: Orthopedic surgeon assessment is that a research biopsy will not increase the risk of local recurrence
COHORT 3 ONLY: Patients must be willing to assent, and consenting party must consent to the single research biopsy prior to the initiation of chemotherapy. Patients over 18 must consent to research biopsies at study entry
COHORTS 1 AND 2 ONLY: Patient must be > 6 and < 50 years of age at the time of study enrollment
COHORTS 1 AND 2 ONLY: Metastatic high-risk osteosarcoma with cohort specific criteria above
COHORTS 1 AND 2 ONLY: Karnofsky ≥ 50% for patients > 16 years of age and Lansky ≥ 50 for patients ≤ 16 years of age within 28 days prior to enrollment
COHORTS 1 AND 2 ONLY: Patients must be able to swallow oral medications as whole tablets/capsule form if a commercially available oral suspension is not available or if tablet dissolution is not stated in the protocol
COHORTS 1 AND 2 ONLY: May use creatinine clearance (estimated or by cystatin C) or radioisotope glomerular filtration rate (GFR) ≥ 70 mL/min/1.73m^2 or estimated GFR (eGFR) in pediatric patients
* A serum creatinine based on age/sex as follows:
** 6 to < 10 years: Male 1; female 1
** 10 to < 13 years: Male 1.2; female 1.2
** 13 to < 16 years: Male 1.5; female 1.4
** ≥ 16 years: Male 1.7; female 1.4
COHORTS 1 AND 2 ONLY: Total bilirubin < 1.5 x upper limit of normal (ULN) for age
COHORTS 1 AND 2 ONLY: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x ULN for age
COHORTS 1 AND 2 ONLY: No history of congenital prolonged corrected QT interval (QTc) syndrome
COHORTS 1 AND 2 ONLY: Correct QT (using Fridericia’s correction [QTcF]) interval < 480 msec.
* QTcF = QT/RR^(0.33), where RR = 60/heart rate in beats per minute (bpm)
COHORTS 1 AND 2 ONLY: Left ventricular ejection fraction (LVEF) ≥ 55 % on echocardiogram or multigated acquisition scan (MUGA)
COHORTS 1 AND 2 ONLY: Patients at least 7 years old and less than 18 years old must be willing to assent, and consenting party must consent to research biopsies in Cohort 1. Patients 18 years and older must consent to research biopsies at study entry. All patients and/or their parents or legal guardians must have the ability to understand and the willingness to sign a written informed consent or assent document
COHORTS 1 AND 2 ONLY: Patients must have adequate biopsy tumor tissue, or the patient is willing to undergo a pretreatment research biopsy. A research biopsy following cycles 1 and 2 of treatment done with the thoracotomy procedure will be required. Availability of these paired biopsies will be informative to understanding mechanisms of response and resistance to initial therapy in osteosarcoma and may benefit future patients with this rare cancer
COHORTS 1 AND 2 ONLY: Must be enrolled on MSK IRB 12-245, biospecimen research protocol, with oncologic surgeries planned to be performed at MSK
COHORTS 1 AND 2 ONLY: The effects of the chemotherapeutic agents in OstEvo on the developing human fetus are unknown. For this reason and because OstEvo agents as well as other therapeutic agents used in this trial are known to be teratogenic, participants of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) during study therapy and for 12 months following the completion of study therapy. Should a participant become pregnant or suspect pregnancy while participating in this study, they should inform their treating physician immediately
COHORTS 1 AND 2 ONLY: Women of childbearing potential should adhere to contraception from enrollment through 12 months after completion of systemic chemotherapy administration. Men who are sexually active with women of childbearing potential should adhere to contraception from enrollment through 12 months after completion of systemic chemotherapy administration
COHORTS 1 AND 2 ONLY: Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and evaluations
Exclusion Criteria
COHORTS 1 AND 2 ONLY: Patients who are receiving any other investigational agents for osteosarcoma therapy are ineligible
COHORTS 1 AND 2 ONLY: Patient with an uncontrolled chronic or active infection or another condition where any component of OstEvo therapy would be contraindicated
COHORTS 1 AND 2 ONLY: Patients with a history of heart disease including, but not limited to: uncontrolled hypertension within 12 months prior to enrollment; ongoing cardiac dysrhythmias ≥ grade 2 or atrial fibrillation of any grade; unstable angina, symptomatic congestive heart failure, or prior myocardial infarction
COHORTS 1 AND 2 ONLY: Patients must not be receiving any additional medicines being given for the specific purpose of treating cancer. Alternative medications including, but not limited to cannabis-based products would not be a reason for exclusion
COHORTS 1 AND 2 ONLY: Patients with any medical or surgical conditions that would interfere with gastrointestinal absorption of oral agents
COHORTS 1 AND 2 ONLY: Patients may not have received prior cardiac irradiation
COHORT 2 ONLY: Patients must not have previously been enrolled in OstEvo
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT07477457.
Locations matching your search criteria
United States
New Jersey
Basking Ridge
Memorial Sloan Kettering Basking Ridge
Status: Active
Contact: Damon Russell Reed
Phone: 347-971-4412
Middletown
Memorial Sloan Kettering Monmouth
Status: Active
Contact: Damon Russell Reed
Phone: 347-971-4412
Montvale
Memorial Sloan Kettering Bergen
Status: Active
Contact: Damon Russell Reed
Phone: 347-971-4412
New York
Commack
Memorial Sloan Kettering Commack
Status: Active
Contact: Damon Russell Reed
Phone: 347-971-4412
New York
Memorial Sloan Kettering Cancer Center
Status: Active
Contact: Damon Russell Reed
Phone: 347-971-4412
Uniondale
Memorial Sloan Kettering Nassau
Status: Active
Contact: Damon Russell Reed
Phone: 347-971-4412
West Harrison
Memorial Sloan Kettering Westchester
Status: Active
Contact: Damon Russell Reed
Phone: 347-971-4412
PRIMARY OBJECTIVES:
I. Evaluate the 12-month progression free survival (PFS) in prespecified cohort sizes to improve from a 30% PFS rate at 12 months to 45% in newly diagnosed, high risk, metastatic osteosarcoma patients. (Cohort 1)
II. Evaluate the 24-month overall survival (OS) in prespecified cohort sizes to improve from a 20% OS rate at 24 months to 35% in relapsed, high risk, metastatic osteosarcoma patients. (Cohort 2)
III. Describe resistant osteosarcoma cells during MAP chemotherapy through a research only diagnostic biopsy for patients with newly diagnosed osteosarcoma not eligible for Cohorts 1 or 2 and without sufficient diagnostic material. (Cohort 3)
SECONDARY OBJECTIVES:
I. Evaluate progression-free survival and overall survival in cohorts 1 and 2.
II. Describe grade 3 and higher adverse events at least possibly related to the novel agents utilized in the osteosarcoma evolves (OstEvo) strategies in cohorts 1 and 2.
III. Describe mechanisms of resistance to chemotherapy and compare biomarkers and phenotypes of sensitivity to therapies through proteomics, DNA and bulk/single ribonucleic acid (RNA) sequencing, peripheral blood markers, radiologic imaging parameters, and pathology.
OUTLINE: Patients with newly diagnosed metastatic or unresectable osteosarcoma are assigned to Cohort 1. Patients with relapsed osteosarcoma are assigned to Cohort 2. Patients with newly diagnosed osteosarcoma who do not meet the requirements of the other cohorts are assigned to Cohort 3.
COHORT 1:
CYCLES 1-3 (WEEKS 1-12): Patients receive methotrexate intravenously (IV) over 4 hours on day 1 of cycles 1-3, cisplatin IV over 4 hours and doxorubicin IV over 15-30 minutes on days 8 and 9 of cycles 1-3. Patients also receive gefitinib orally (PO) once daily (QD) on days 15-28 of cycles 2 and 3. Cycles repeat every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo standard thoracotomy with research biopsy of primary site prior to starting cycle 2.
CYCLES 4-6 (WEEKS 14-25): Patients receive methotrexate IV over 4 hours on day 1 of cycles 4-6, cisplatin IV over 4 hours and doxorubicin IV over 15-30 minutes on days 8 and 9 of cycles 4-6 of each cycle. Patients also receive gefitinib PO QD 15-28 of cycle 4 of cycle 4, disulfiram PO on days 15-28 of cycles 4 and 5 and sunitinib PO QD on days 15-28 of cycles 5. Cycles repeat every 28 days for cycles 4-6 in the absence of disease progression or unacceptable toxicity. After week 24, patients may also undergo radiation therapy to affected sites if indicated.
Additionally, patients undergo echocardiography (ECHO), magnetic resonance imaging (MRI), computed tomography (CT) chest, positron emission tomography (PET), research biopsies and blood sample collection throughout the study.
COHORT 2:
CYCLES 1-3 (WEEKS 1-9): Patients receive ifosfamide IV on days 1-5 of cycles 1-3, gefitinib PO QD on days 8-21 of cycle 1, trametinib PO QD on days 8-21 of cycle 2. Cycles repeat every 21 days for cycles 1-3 in the absence of disease progression or unacceptable toxicity. Patients also undergo standard thoracotomy after cycles 1 and 2
CYCLES 4-6 (WEEKS 10-18): Patients receive ifosfamide IV on days 1-5 of cycles 4-6, sunitinib PO QD on days 8-21 of cycles 4 and 6, gefitinib PO QD on days 8-21 of cycle 5, and disulfiram PO QD on days 8-21 of cycle 5. Cycles repeat every 21 days for cycles 4-6 in the absence of disease progression or unacceptable toxicity. After cycle 4, patients may undergo standard of care radiation therapy.
Additionally, patients undergo blood sample collection, MRI or x-ray, CT chest, and PET throughout the study.
COHORT 3: Patients undergo research biopsy prior to starting standard of care therapy.
After completion of study treatment, patients in Cohorts 1 and 2 are followed up at 10 days, then every 3 months for up to 3 years.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationMemorial Sloan Kettering Cancer Center
