Ivosidenib in Treating Patients With Advanced Solid Tumors, Lymphoma, or Histiocytic Disorders With IDH1 Mutations (A Pediatric MATCH Treatment Trial)
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|ClinicalTrials.gov Identifier: NCT04195555|
Recruitment Status : Recruiting
First Posted : December 12, 2019
Last Update Posted : March 10, 2023
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|Condition or disease||Intervention/treatment||Phase|
|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||Drug: Ivosidenib||Phase 2|
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.
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.
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).
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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||49 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice) - Phase 2 Subprotocol of AG-120 (Ivosidenib) in Patients With Tumors Harboring IDH1 Mutations|
|Actual Study Start Date :||June 8, 2020|
|Estimated Primary Completion Date :||December 31, 2025|
|Estimated Study Completion Date :||December 31, 2025|
Experimental: Treatment (ivosidenib)
Patients receive ivosidenib PO QD. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.
- Objective response rate (ORR; complete response + partial response) in pediatric patients treated with ivosidenib [ Time Frame: From enrollment to the end of treatment, up to 2 years ]A responder is defined as a patient who achieves a best response of partial response or complete response on the study. Response rates will be calculated as the percent of evaluable patients who are responders, and confidence intervals will be constructed using the Wilson score interval method.
- Progression free survival (PFS) [ Time Frame: From the initiation of protocol treatment to the occurrence of any of the following events: disease progression or disease recurrence or death from any cause, assessed up to 5 years ]Progression free survival will be defined as time from the initiation of protocol treatment to the occurrence of any of the following events: disease progression or disease recurrence or death from any cause. PFS along with the confidence intervals will be estimated using the Kaplan-Meier method.
- Percentage of patients experiencing grade 3 or higher adverse events [ Time Frame: From enrollment to the end of treatment, up to 2 years ]Percentage of patients experiencing grade 3 or higher adverse events will be evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. All patients who receive at least one dose of protocol therapy will be considered in the evaluation of toxicity.
- Preliminary estimates of the pharmacokinetics (PK) of ivosidenib in children and adolescents with relapsed or refractory cancer [ Time Frame: Pre-dose, 1, 2, 3, 4, and 6-8 hours after dose on cycle 1, day 1; pre-dose on cycle 1, day 2; pre-dose, 1, 2, 3, 4, and 6-8 hours after dose on cycle 1, day 15; and pre-dose on cycle 2, day 1 and cycle 4, day 1 ]A descriptive analysis of PK parameters will be performed to define systemic exposure, drug clearance, and other pharmacokinetic parameters. The PK parameters will be summarized with simple summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit).
- Preliminary estimates of the pharmacodynamics (PD) of ivosidenib in children and adolescents with relapsed or refractory cancer [ Time Frame: Pre-dose, 1, 2, 3, 4, and 6-8 hours after dose on cycle 1, day 1; pre-dose on cycle 1, day 2; pre-dose, 1, 2, 3, 4, and 6-8 hours after dose on cycle 1, day 15; and pre-dose on cycle 2, day 1 and cycle 4, day 1 ]
- Biomarker analysis [ Time Frame: Up to 5 years ]Will evaluate other biomarkers as predictors of response to ivosidenib and whether tumors that harbor different missense mutations or fusions will demonstrate differential response to treatment. A descriptive analysis will be performed and will be summarized with simple summary statistics. All of these analyses will be descriptive in nature.
- Profiling changes in tumor genomics [ Time Frame: Baseline up to 5 years ]Will explore approaches to the profiling changes in tumor genomics over time through evaluation of circulating tumor deoxyribonucleic acid. A descriptive analysis will be performed and will be summarized with simple summary statistics.
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|Ages Eligible for Study:||12 Months to 21 Years (Child, Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
- 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 be >= than 12 months and =< 21 years of age at the time of study enrollment
- Patients must have a body surface area >= 0.78 m^2 at 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.
- Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 for patients =< 16 years of age. Note: Neurologic deficits in patients with CNS tumors must have been relatively stable for at least 7 days prior to study enrollment. Patients 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 score.
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
- 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)
- 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
- 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
- Corticosteroids: If used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid
- 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
- Cellular Therapy: >= 42 days after the completion of any type of cellular therapy (e.g. modified T cells, natural killer [NK] cells, dendritic cells, etc.)
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
- Radiopharmaceutical therapy (e.g., radiolabeled antibody, 131I-MIBG): >= 42 days after systemically administered radiopharmaceutical therapy
- Patients must not have received prior exposure to AG-120 (ivosidenib) or other IDH1 inhibitors
- For patients with solid tumors without known bone marrow involvement: Peripheral absolute neutrophil count (ANC) >= 1000/mm^3 (within 7 days prior to enrollment)
- 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)
- 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
- Age 2 to < 6 years, maximum serum creatinine (mg/dL) male 0.8, female 0.8
- Age 6 to < 10 years, maximum serum creatinine (mg/dL) male 1, female 1
- Age 10 to < 13 years, maximum serum creatinine (mg/dL) male 1.2, female 1.2
- Age 13 to < 16 years, maximum serum creatinine (mg/dL) male 1.5, female 1.4
- Age >= 16 years, maximum serum creatinine (mg/dL) male 1.7, female 1.4
- Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to enrollment)
- 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
- Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled
- 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
- 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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04195555
|Principal Investigator:||Elizabeth D Alva||Children's Oncology Group|
|Responsible Party:||National Cancer Institute (NCI)|
|Other Study ID Numbers:||
NCI-2019-08098 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
APEC1621K ( Other Identifier: Children's Oncology Group )
APEC1621K ( Other Identifier: CTEP )
U10CA180886 ( U.S. NIH Grant/Contract )
|First Posted:||December 12, 2019 Key Record Dates|
|Last Update Posted:||March 10, 2023|
|Last Verified:||December 2022|
|Individual Participant Data (IPD) Sharing Statement:|
|Plan to Share IPD:||Yes|
|Plan Description:||NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.|
|Studies a U.S. FDA-regulated Drug Product:||Yes|
|Studies a U.S. FDA-regulated Device Product:||No|
Neoplasms, Germ Cell and Embryonal
Neuroectodermal Tumors, Primitive
Neuroectodermal Tumors, Primitive, Peripheral
Neoplasms by Histologic Type
Immune System Diseases
Neoplasms, Connective and Soft Tissue