NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice) - Phase 2 Subprotocol of AG-120 (Ivosidenib) in Patients With Tumors Harboring IDH1 Mutations

STATUS

Recruiting
End date

Dec 31, 2025
participants needed

49
sponsor

National Cancer Institute (NCI)

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Updated on 23 October 2022

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nervous system disorders

ag-120

Summary

This phase II Pediatric MATCH trial studies how well ivosidenib works in treating patients with solid tumors that have spread to other places in the body (advanced), lymphoma, or histiocytic disorders that have IDH1 genetic alterations (mutations). Ivosidenib may block the growth of cancer cells that have specific genetic changes in an important signaling pathway called the IDH pathway.

Description

PRIMARY OBJECTIVE:

I. To determine the objective response rate (ORR; complete response + partial response) in pediatric patients treated with AG-120 (ivosidenib) with advanced solid tumors (including central nervous system [CNS] tumors), lymphomas or histiocytic disorders that harbor activating genetic alterations in the IDH1 pathway.

SECONDARY OBJECTIVES:

I. To estimate the progression free survival in pediatric patients treated with AG-120 (ivosidenib) with advanced solid tumors (including CNS tumors), lymphomas or histiocytic disorders that harbor activating genetic alterations in the IDH1 pathway.

II. To obtain information about the tolerability of AG-120 (ivosidenib) in children and adolescents with relapsed or refractory cancer.

III. To provide preliminary estimates of the pharmacokinetics and pharmacodynamics of AG-120 (ivosidenib) in children and adolescents with relapsed or refractory cancer.

EXPLORATORY OBJECTIVES:

I. To evaluate other biomarkers as predictors of response to AG-120 (ivosidenib) and specifically, whether tumors that harbor different missense mutations or fusions will demonstrate differential response to AG-120 (ivosidenib) treatment.

II. To explore approaches to the profiling changes in tumor genomics over time through evaluation of circulating tumor deoxyribonucleic acid (DNA).

OUTLINE

Patients receive ivosidenib orally (PO) once daily (QD). Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically.

Details

Condition	Recurrent Ependymoma, Recurrent Ewing Sarcoma, Recurrent Hepatoblastoma, Recurrent Langerhans Cell Histiocytosis, Recurrent Malignant Germ Cell Tumor, Recurrent Malignant Glioma, Recurrent Malignant Solid Neoplasm, Recurrent Medulloblastoma, Recurrent Neuroblastoma, Recurrent Non-Hodgkin Lymphoma, Recurrent Osteosarcoma, Recurrent Peripheral Primitive Neuroectodermal Tumor, Recurrent Rhabdoid Tumor, Recurrent Rhabdomyosarcoma, Recurrent Soft Tissue Sarcoma, Recurrent WHO Grade 2 Glioma, Refractory Ependymoma, Refractory Ewing Sarcoma, Refractory Hepatoblastoma, Refractory Langerhans Cell Histiocytosis, Refractory Malignant Germ Cell Tumor, Refractory Malignant Glioma, Refractory Malignant Solid Neoplasm, Refractory Medulloblastoma, Refractory Neuroblastoma, Refractory Non-Hodgkin Lymphoma, Refractory Osteosarcoma, Refractory Peripheral Primitive Neuroectodermal Tumor, Refractory Rhabdoid Tumor, Refractory Rhabdomyosarcoma, Refractory Soft Tissue Sarcoma, Refractory WHO Grade 2 Glioma, Wilms Tumor
Treatment	Ivosidenib
Clinical Study Identifier	NCT04195555
Sponsor	National Cancer Institute (NCI)
Last Modified on	23 October 2022

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Eligibility		Yes	No	Not Sure
Inclusion Criteria
	Patient must have enrolled onto APEC1621SC and must have been given a treatment assignment to MATCH to APEC1621K based on the presence of an actionable mutation as defined in APEC1621SC
	Patients must have a body surface area >= 0.78 m^2 at enrollment
	Patients must be >= than 12 months and =< 21 years of age at the time of study enrollment
	Patients must be able to swallow intact tablets
	Patients must have radiographically measurable disease at the time of study enrollment. Patients with neuroblastoma who do not have measurable disease but have metaiodobenzylguanidine (MIBG)+ evaluable disease are eligible. Measurable disease in patients with CNS involvement is defined as any lesion that is at minimum 10 mm in one dimension on standard magnetic resonance imaging (MRI) or computed tomography (CT)
	Note: The following do not qualify as measurable disease
	Malignant fluid collections (e.g., ascites, pleural effusions)
	Bone marrow infiltration except that detected by MIBG scan for neuroblastoma
	Lesions only detected by nuclear medicine studies (e.g., bone, gallium or positron emission tomography [PET] scans) except as noted for neuroblastoma
	Elevated tumor markers in plasma or cerebrospinal fluid (CSF)
	Previously radiated lesions that have not demonstrated clear progression post radiation
	Leptomeningeal lesions that do not meet the measurement requirements for Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
	Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment. If after the required timeframe, the numerical eligibility criteria are met, e.g. blood count criteria, the patient is considered to have recovered adequately
	Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 for patients =< 16
	Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive. >= 21 days after the last dose of cytotoxic or myelosuppressive chemotherapy (42 days if prior nitrosourea)
	years of age. Note: Neurologic deficits in patients with CNS tumors must have
	Anti-cancer agents not known to be myelosuppressive (e.g. not associated with reduced platelet or absolute neutrophil count [ANC] counts): >= 7 days after the last dose of agent
	been relatively stable for at least 7 days prior to study enrollment. Patients
	Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade =< 1
	who are unable to walk because of paralysis, but who are up in a wheelchair
	will be considered ambulatory for the purpose of assessing the performance
	Corticosteroids: If used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid
	score
	Hematopoietic growth factors: >= 14 days after the last dose of a long-acting growth factor (e.g. pegfilgrastim) or 7 days for short-acting growth factor. For growth factors that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair and the study-assigned research coordinator
	Interleukins, interferons and cytokines (other than hematopoietic growth factors): >= 21 days after the completion of interleukins, interferon or cytokines (other than hematopoietic growth factors)
	Stem cell infusions (with or without total body irradiation [TBI])
	Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem cell infusion including donor lymphocyte infusion (DLI) or boost infusion: >= 84 days after infusion and no evidence of graft versus host disease (GVHD)
	Autologous stem cell infusion including boost infusion: >= 42 days
	Radiation therapy (XRT)/external beam Irradiation including protons: >= 14 days after local XRT; >= 150 days after TBI, craniospinal XRT or if radiation to >= 50% of the pelvis; >= 42 days if other substantial bone marrow (BM) radiation
	Note: Radiation may not be delivered to "measurable disease" tumor site(s) being used to follow response to subprotocol treatment
	Patients must not have received prior exposure to AG-120 (ivosidenib) or other IDH1 inhibitors
	Cellular Therapy: >= 42 days after the completion of any type of cellular therapy
	For patients with solid tumors without known bone marrow involvement: Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
	(e.g. modified T cells, natural killer [NK] cells, dendritic cells, etc.)
	Patients with known bone marrow metastatic disease will be eligible for study provided they meet the blood count (may receive transfusions provided they are not known to be refractory to red cell or platelet transfusions). These patients will not be evaluable for hematologic toxicity
	Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 ml/min/1.73 m^2 (within 7 days prior to enrollment), or
	A serum creatinine based on age/gender (within 7 days prior to enrollment)
	Age 1 to < 2 years, maximum serum creatinine (mg/dL) male 0.6, female 0.6
	Radiopharmaceutical therapy (e.g., radiolabeled antibody, 131I-MIBG): >= 42 days
	Age 2 to < 6 years, maximum serum creatinine (mg/dL) male 0.8, female 0.8
	after systemically administered radiopharmaceutical therapy
	Age 6 to < 10 years, maximum serum creatinine (mg/dL) male 1, female 1
	For patients with solid tumors without known bone marrow involvement: Peripheral
	Age 10 to < 13 years, maximum serum creatinine (mg/dL) male 1.2, female 1.2
	absolute neutrophil count (ANC) >= 1000/mm^3 (within 7 days prior to
	Age 13 to < 16 years, maximum serum creatinine (mg/dL) male 1.5, female 1.4
	enrollment)
	Age >= 16 years, maximum serum creatinine (mg/dL) male 1.7, female 1.4
	Serum glutamate-pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L. (For the purpose of this study, the ULN for SGPT is 45 U/L) (within 7 days prior to enrollment)
	Serum albumin >= 2 g/dL (within 7 days prior to enrollment)
	Corrected QT (QTc )interval =< 450 milliseconds (within 7 days prior to enrollment)
	Note: Patients should avoid concomitant medication known or suspected to prolong QTc interval or cause Torsades de Pointes. Patients who are receiving drugs that prolong the QTc are eligible if the drug is necessary and no alternatives are available
	Nervous system disorders (Common Terminology Criteria for Adverse Events [CTCAE] version [v]5.0) resulting from prior therapy must be =< grade 2, with the exception of decreased tendon reflex (DTR). Any grade of DTR is eligible
	All patients and/or their parents or legally authorized representatives must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines
	Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for
	age (within 7 days prior to enrollment)
	Patients with seizure disorder may be enrolled if on anticonvulsants and well
	controlled
Exclusion Criteria
	Pregnant or breast-feeding women will not be entered on this study due to risks because there is yet no available information regarding human fetal or teratogenic toxicities. Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use an effective non-hormonal contraceptive method for the duration of study treatment and for at least 1 month after last dose of AG-120 (ivosidenib). Since AG-120 (ivosidenib) may decrease concentrations of hormonal contraceptives, hormonal contraceptives are not considered effective contraception when co-administered with AG-120 (ivosidenib)
	Patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible. If used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid
	Patients who are currently receiving another investigational drug are not eligible
	Patients who are currently receiving other anti-cancer agents are not eligible
	Patients who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post bone marrow transplant are not eligible for this trial
	Patients who are currently receiving drugs that are strong inducers or moderate to strong inhibitors of CYP3A4 are not eligible. Strong inducers or moderate to strong inhibitors of CYP3A4 should be avoided from 14 days prior to enrollment to the end of the study. Note: CYP3A4 inducing anti-epileptic drugs and dexamethasone for CNS tumors or metastases, on a stable dose, are allowed. In addition, patients receiving sensitive or narrow therapeutic range substrates of CYP3A4 are not eligible
	Patients with a history of progressive multifocal leukoencephalopathy are not eligible
	Patients who have an uncontrolled infection are not eligible
	Patients who have received a prior solid organ transplantation are not eligible
	Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible

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NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice) - Phase 2 Subprotocol of AG-120 (Ivosidenib) in Patients With Tumors Harboring IDH1 Mutations