Ensartinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With ALK or ROS1 Genomic Alterations (A Pediatric MATCH Treatment Trial)

• ClinicalTrials.gov Identifier: NCT03213652
• Recruitment Status: Recruiting
• First Posted: July 11, 2017
• Last Update Posted: May 10, 2024
• Sponsor: National Cancer Institute (NCI)
• Collaborator: Children's Oncology Group
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Tracking Information

• First Submitted Date: July 10, 2017
• First Posted Date: July 11, 2017
• Last Update Posted Date: May 10, 2024
• Actual Study Start Date: April 17, 2018
• Estimated Primary Completion Date: September 30, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 25, 2019)

Objective response rate [ 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.

Original Primary Outcome Measures (submitted: July 10, 2017)

Objective response rate [ Time Frame: Up to 4 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.

Current Secondary Outcome Measures (submitted: December 2, 2022)

• 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.
• Progression free survival (PFS) [ Time Frame: From the initiation of protocol treatment to the occurrence of 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.
• Pharmacokinetic (PK) parameters [ Time Frame: Pre-dose, 1, 2, 4, 6-8, and 20-24 hours post day 1 dose and pre-dose, 1, 2, 4, and 6-8 hours post day 28 dose of cycle 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).

Original Secondary Outcome Measures (submitted: July 10, 2017)

• Incidence of toxicity evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 4 years ]
  All patients who receive at least one dose of protocol therapy will be considered in the evaluation of toxicity. Toxicity tables will be constructed to summarize the observed incidence by type of toxicity and grade. Toxicity information recorded will include the type, severity, time of onset, time of resolution, and the probable association with the study regimen.
• Progression free survival (PFS) [ Time Frame: From the initiation of protocol treatment to the occurrence of disease progression or disease recurrence or death from any cause, assessed up to 4 years ]
  PFS along with the confidence intervals will be estimated using the Kaplan-Meier method.

Current Other Pre-specified Outcome Measures (submitted: December 2, 2022)

• Biomarkers as predictors of response to ensartinib [ Time Frame: Up to 4 years ]
  Descriptive analysis will be performed and will be summarized with simple summary statistics.
• Changes in tumor genomic profile [ Time Frame: Up to 4 years ]
  Approaches to profiling changes in tumor genomics over time through evaluation of circulating tumor deoxyribonucleic acid will be explored. Descriptive analysis will be performed and will be summarized with simple summary statistics.

Original Other Pre-specified Outcome Measures (submitted: July 10, 2017)

• Biomarkers as predictors of response to ensartinib [ Time Frame: Up to 4 years ]
  Descriptive analysis will be performed and will be summarized with simple summary statistics.
• Changes in tumor genomic profile [ Time Frame: Up to 4 years ]
  Approaches to profiling changes in tumor genomics over time through evaluation of circulating tumor DNA will be explored. Descriptive analysis will be performed and will be summarized with simple summary statistics.
• Pharmacokinetic (PK) parameters [ Time Frame: Pre-dose, 1, 2, 4, 6-8, and 20-24 hours post day 1 dose and pre-dose, 1, 2, 4, and 6-8 hours post day 28 dose of course 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).

Descriptive Information

• Brief Title: Ensartinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With ALK or ROS1 Genomic Alterations (A Pediatric MATCH Treatment Trial)
• Official Title: NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice)- Phase 2 Subprotocol of Ensartinib in Patients With Tumors Harboring ALK or ROS1 Genomic Alterations
• Brief Summary: This phase II Pediatric MATCH trial studies how well ensartinib works in treating patients with solid tumors, non-Hodgkin lymphoma, or histiocytic disorders with ALK or ROS1 genomic alterations that have come back (recurrent) or does not respond to treatment (refractory) and may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced). Ensartinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description

PRIMARY OBJECTIVE:

I. To determine the objective response rate (ORR; complete response + partial response) in pediatric patients treated with ensartinib with advanced solid tumors (including central nervous system [CNS] tumors), non-Hodgkin lymphomas or histiocytic disorders that harbor ALK or ROS1 fusions or that harbor ALK missense mutations.

SECONDARY OBJECTIVES:

I. To estimate the progression free survival in pediatric patients treated with ensartinib with advanced solid tumors (including CNS tumors), non-Hodgkin lymphomas or histiocytic disorders that harbor ALK or ROS1 fusions or that harbor ALK missense mutations.

II. To obtain information about the tolerability of ensartinib in children with relapsed or refractory cancer.

III. To provide preliminary estimates of the pharmacokinetics of ensartinib in children with relapsed or refractory cancer.

EXPLORATORY OBJECTIVES:

I. To evaluate other biomarkers as predictors of response to ensartinib and specifically, whether tumors that harbor different missense mutations or fusions (including the crizotinib resistant F1174L ALK variant) will demonstrate differential response to ensartinib treatment.

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

OUTLINE:

Patients receive ensartinib orally (PO) once daily (QD) on days 1-28. Cycles repeat every 28 days for 2 years (up to 26 cycles) in the absence of disease progression or unacceptable toxicity. Patients undergo an x-ray, computed tomography (CT) scan, magnetic resonance imaging (MRI), positron emission tomography (PET) scan, radionuclide imaging, and/or bone scan, as well as a bone marrow aspiration and/or biopsy during screening and on study. Patients also undergo blood sample collection on study.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Advanced Malignant Solid Neoplasm
• Malignant Solid Neoplasm
• Recurrent Ependymoma
• Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor
• 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 Primary Central Nervous System Neoplasm
• Recurrent Rhabdoid Tumor
• Recurrent Rhabdomyosarcoma
• Recurrent Soft Tissue Sarcoma
• Refractory Ependymoma
• Refractory Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor
• 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 Primary Central Nervous System Neoplasm
• Refractory Rhabdoid Tumor
• Refractory Rhabdomyosarcoma
• Refractory Soft Tissue Sarcoma
• Wilms Tumor

Intervention

• Procedure: Biospecimen Collection
  Undergo blood sample collection
  Other Names:

  • Biological Sample Collection
  • Biospecimen Collected
  • Specimen Collection
• Procedure: Bone Marrow Aspiration and Biopsy
  Undergo a bone marrow aspiration and/or biopsy
• Procedure: Bone Scan
  Undergo a bone scan
  Other Name: Bone Scintigraphy
• Procedure: Computed Tomography
  Undergo a CT scan
  Other Names:

  • CAT
  • CAT Scan
  • Computed Axial Tomography
  • Computerized Axial Tomography
  • Computerized axial tomography (procedure)
  • Computerized Tomography
  • Computerized Tomography (CT) scan
  • CT
  • CT Scan
  • tomography
• Drug: Ensartinib
  Given PO
  Other Name: X-396
• Other: Laboratory Biomarker Analysis
  Correlative studies
• Procedure: Magnetic Resonance Imaging
  Undergo MRI
  Other Names:

  • Magnetic Resonance
  • Magnetic Resonance Imaging (MRI)
  • Magnetic resonance imaging (procedure)
  • Magnetic Resonance Imaging Scan
  • Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
  • MR
  • MR Imaging
  • MRI
  • MRI Scan
  • MRIs
  • NMR Imaging
  • NMRI
  • Nuclear Magnetic Resonance Imaging
  • sMRI
  • Structural MRI
• Other: Pharmacological Study
  Correlative studies
• Procedure: Positron Emission Tomography
  Undergo a PET scan
  Other Names:

  • Medical Imaging, Positron Emission Tomography
  • PET
  • PET Scan
  • Positron emission tomography (procedure)
  • Positron Emission Tomography Scan
  • Positron-Emission Tomography
  • proton magnetic resonance spectroscopic imaging
  • PT
• Procedure: Radionuclide Imaging
  Undergo radionuclide imaging
  Other Names:

  • NM
  • Nuclear Medicine
  • nuclear medicine scan
  • radioimaging
  • Radionuclide Scanning
  • Scan
  • Scintigraphy
• Procedure: X-Ray Imaging
  Undergo an x-ray
  Other Names:

  • Conventional X-Ray
  • Diagnostic Radiology
  • Medical Imaging, X-Ray
  • Plain film radiographs
  • Radiographic Imaging
  • Radiographic imaging procedure (procedure)
  • Radiography
  • RG
  • Static X-Ray
  • X-Ray

Study Arms

Experimental: Treatment (ensartinib)

Patients receive ensartinib PO QD on days 1-28. Cycles repeat every 28 days for 2 years (up to 26 cycles) in the absence of disease progression or unacceptable toxicity. Patients undergo an x-ray, CT scan, MRI, PET scan, radionuclide imaging, and/or bone scan, as well as a bone marrow aspiration and/or biopsy during screening and on study. Patients also undergo blood sample collection on study.

Interventions:

• Procedure: Biospecimen Collection
• Procedure: Bone Marrow Aspiration and Biopsy
• Procedure: Bone Scan
• Procedure: Computed Tomography
• Drug: Ensartinib
• Other: Laboratory Biomarker Analysis
• Procedure: Magnetic Resonance Imaging
• Other: Pharmacological Study
• Procedure: Positron Emission Tomography
• Procedure: Radionuclide Imaging
• Procedure: X-Ray Imaging

• Publications *: Baranowska-Kortylewicz J, Kortylewicz ZP, McIntyre EM, Sharp JG, Coulter DW. Multifarious Functions of Butyrylcholinesterase in Neuroblastoma: Impact of BCHE Deletion on the Neuroblastoma Growth In Vitro and In Vivo. J Pediatr Hematol Oncol. 2022 Aug 1;44(6):293-304. doi: 10.1097/MPH.0000000000002285. Epub 2021 Sep 6.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: July 10, 2017): 98
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: September 30, 2024
• Estimated Primary Completion Date: September 30, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Patient must have enrolled onto APEC1621SC and must have been given a treatment assignment to Molecular Analysis for Therapy Choice (MATCH) to APEC1621F based on the presence of an actionable mutation
• Patients must be >= than 12 months and =< 21 years of age at the time of study enrollment.
• Patients must have a body surface area >= 0.5 m^2 at enrollment

• Patients must have radiographically measurable disease at the time of study enrollment. Patients with neuroblastoma who do not have measurable disease but have iobenguane (MIBG) positive (+) 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 a standard MRI or 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 counts [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 none 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 ensartinib; prior treatment with other ALK inhibitors is permitted given that at least 5 half-lives or 21 days have elapsed since therapy discontinuation, whichever is greater

• For patients with solid tumors without known bone marrow involvement:

  • Peripheral absolute neutrophil count (ANC) >= 1000/mm^3 (within 7 days prior to enrollment)
  • Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment) (within 7 days prior to enrollment)
• Patients with known bone marrow metastatic disease will be eligible for study provided they meet the blood counts (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 as follows (within 7 days prior to enrollment):

  • Age 1 to < 2 years: maximum serum creatinine 0.6 mg/dL for male and 0.6 mg/dL for female
  • Age 2 to < 6 years: maximum serum creatinine 0.8 mg/dL for male and 0.8 mg/dL for female
  • Age 6 to < 10 years: maximum serum creatinine 1 mg/dL for male and 1 mg/dL for female
  • Age 10 to < 13 years: maximum serum creatinine 1.2 mg/dL for male and 1.2 mg/dL for female
  • Age 13 to < 16 years: maximum serum creatinine 1.5 mg/dL for male and 1.4 mg/dL for female
  • Age >= 16 years: maximum serum creatinine 1.7 mg/dL for male and 1.4 mg/dL for female
• Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to enrollment)
• Serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L (within 7 days prior to enrollment) (for the purpose of this study, the ULN for SGPT is 45 U/L)
• Serum albumin >= 2 g/dL (within 7 days prior to enrollment)
• Patients must be able to swallow intact capsules
• 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

Exclusion Criteria:

• Pregnant or breast-feeding women will not be entered on this study because there is currently 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 contraceptive method for the duration of study treatment and for one week after the last dose of ensartinib

• Concomitant medications

  • Corticosteroids: 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
  • Investigational drugs: patients who are currently receiving another investigational drug are not eligible
  • Anti-cancer agents: patients who are currently receiving other anti-cancer agents are not eligible
  • Anti-GVHD agents post-transplant: 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

  • CYP3A4 agents: patients who are currently receiving drugs that are strong inducers or strong inhibitors of CYP3A4 are not eligible; strong inducers or 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
• 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 12 Months to 21 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Listed Location Countries: Australia, Puerto Rico, United States

Administrative Information

• NCT Number: NCT03213652
• Other Study ID Numbers: NCI-2017-01243; NCI-2017-01243 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); APEC1621F ( Other Identifier: Children's Oncology Group ); APEC1621F ( Other Identifier: CTEP ); U10CA180886 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: National Cancer Institute (NCI)
• Original Responsible Party: Same as current
• Current Study Sponsor: National Cancer Institute (NCI)
• Original Study Sponsor: Same as current
• Collaborators: Children's Oncology Group

Investigators

• Principal Investigator: Meredith S Irwin; Children's Oncology Group

• PRS Account: National Cancer Institute (NCI)
• Verification Date: March 2024