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Selpercatinib for the Treatment of Advanced Solid Tumors, Lymphomas, or Histiocytic Disorders With Activating RET Gene Alterations, a Pediatric MATCH Treatment Trial

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ClinicalTrials.gov Identifier: NCT04320888
Recruitment Status : Recruiting
First Posted : March 25, 2020
Last Update Posted : November 24, 2020
Sponsor:
Collaborator:
Children's Oncology Group
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE March 24, 2020
First Posted Date  ICMJE March 25, 2020
Last Update Posted Date November 24, 2020
Actual Study Start Date  ICMJE September 14, 2020
Estimated Primary Completion Date September 30, 2027   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 7, 2020)
Objective response rate (complete response + partial response) in pediatric patients treated with selpercatinib (LOXO-292) [ Time Frame: Up to 2 years ]
Will be determined by Response Evaluation Criteria in Solid Tumors. 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  ICMJE
 (submitted: March 24, 2020)
Objective response rate (complete response + partial response) in pediatric patients treated with selpercatinib (LOXO-292) [ Time Frame: Up to completion of Pediatric MATCH Screening Trial (APEC1621) ]
Will be determined by Response Evaluation Criteria in Solid Tumors. 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.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 7, 2020)
  • Progression-free survival (PFS) [ Time Frame: From the initiation of subprotocol (APEC1621N) treatment to the occurrence of any of the following events: disease progression or disease recurrence or death from any cause, assessed up to 2 years ]
    PFS along with the confidence intervals will be estimated using the Kaplan-Meier method.
  • Percentage of patients experiencing grade 3 or 4 adverse events [ Time Frame: Up to 2 years ]
    Evaluated by Common Terminology Criteria for Adverse Events version 5. Any eligible patient who receives at least one dose of protocol therapy will be considered in the evaluation of toxicity.
Original Secondary Outcome Measures  ICMJE
 (submitted: March 24, 2020)
  • Progression-free survival (PFS) [ Time Frame: From the initiation of subprotocol (APEC1621N) treatment to the occurrence of any of the following events: disease progression or disease recurrence or death from any cause, assessed up to completion of Pediatric MATCH Screening Trial (APEC1621) ]
    PFS along with the confidence intervals will be estimated using the Kaplan-Meier method.
  • Incidence of adverse events [ Time Frame: Up to completion of Pediatric MATCH Screening Trial (APEC1621) ]
    Evaluated by Common Terminology Criteria for Adverse Events version 5. Toxicity tables will be constructed to summarize the observed incidence by type of toxicity and grade. A patient will be counted only once for a given toxicity for the worst grade of that toxicity reported for that patient. Toxicity information recorded will include the type, severity, time of onset, time of resolution, and the probable association with the study regimen.
Current Other Pre-specified Outcome Measures
 (submitted: March 24, 2020)
Profiling changes in tumor genomics [ Time Frame: Up to time of disease progression or end of protocol therapy ]
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. All of these analyses will be descriptive in nature.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Selpercatinib for the Treatment of Advanced Solid Tumors, Lymphomas, or Histiocytic Disorders With Activating RET Gene Alterations, a Pediatric MATCH Treatment Trial
Official Title  ICMJE NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice) - Phase 2 Subprotocol of LOXO-292 in Patients With Tumors Harboring RET Gene Alterations
Brief Summary This phase II pediatric MATCH trial studies how well selpercatinib works in treating patients with solid tumors that have spread to other places in the body (advanced), lymphomas, or histiocytic disorders that have activating RET gene alterations. Selpercatinib may block the growth of cancer cells that have specific genetic changes in an important signaling pathway (called the RET pathway) and may reduce tumor size.
Detailed Description

PRIMARY OBJECTIVE:

I. To determine the objective response rate (ORR; complete response + partial response) in pediatric patients treated with selpercatinib (LOXO-292) with advanced solid tumors (including central nervous system [CNS] tumors), lymphomas or histiocytic disorders that harbor activating genetic alterations in the RET pathway.

SECONDARY OBJECTIVES:

I. To estimate the progression free survival in pediatric patients treated with LOXO-292 with advanced solid tumors (including CNS tumors), lymphomas or histiocytic disorders that harbor activating genetic alterations in the RET pathway.

II. To obtain information about the tolerability of LOXO-292 in children and adolescents with relapsed or refractory cancer.

EXPLORATORY OBJECTIVE:

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

OUTLINE:

Patients receive selpercatinib orally (PO) twice daily (BID) on days 1-28. Treatment repeats every 28 days for up to 26 cycles (2 years) in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed for 30 days, then periodically thereafter.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Hematopoietic and Lymphoid Cell Neoplasm
  • Recurrent Ependymoma
  • Recurrent Ewing Sarcoma
  • Recurrent Hepatoblastoma
  • Recurrent Histiocytic and Dendritic Cell Neoplasm
  • Recurrent Langerhans Cell Histiocytosis
  • Recurrent Lymphoma
  • 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 II Glioma
  • Refractory Ependymoma
  • Refractory Ewing Sarcoma
  • Refractory Hepatoblastoma
  • Refractory Histiocytic and Dendritic Cell Neoplasm
  • Refractory Langerhans Cell Histiocytosis
  • Refractory Lymphoma
  • 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 II Glioma
  • Wilms Tumor
Intervention  ICMJE Drug: Selpercatinib
Given PO
Other Names:
  • LOXO-292
  • RET Kinase Inhibitor LOXO-292
  • Retevmo
  • WHO 10967
Study Arms  ICMJE Experimental: Treatment (selpercatinib)
Patients receive selpercatinib PO BID on days 1-28. Treatment repeats every 28 days for up to 26 cycles (2 years) in the absence of disease progression or unacceptable toxicity.
Intervention: Drug: Selpercatinib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 24, 2020)
49
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 30, 2027
Estimated Primary Completion Date September 30, 2027   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patient must have enrolled onto APEC1621SC and must have been given a treatment assignment to MATCH to APEC1621N based on the presence of an actionable mutation
  • 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) positive (+) evaluable disease are eligible. Measurable disease in patients with CNS involvement is defined as tumor that is measurable in two perpendicular diameters on magnetic resonance imaging (MRI) and visible on more than one slice

    • 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 cerebral spinal 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 [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 LOXO-292 or other specific RET inhibitors
  • For patients with solid tumors without known bone marrow involvement (within 7 days prior to enrollment):

    • Peripheral absolute neutrophil count (ANC) >= 1000/mm^3
  • For patients with solid tumors without known bone marrow involvement (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)
  • 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: Maximum serum creatinine (mg/dL)

      • 1 to < 2 years: male (0.6), female (0.6)
      • 2 to < 6 years: male (0.8), female (0.8)
      • 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)
  • 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. (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)
  • Corrected QT (QTc) interval =< 480 milliseconds (within 7 days prior to enrollment)
  • 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 due to risks of fetal and teratogenic adverse events as seen in animal/human studies. 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 two (2) highly effective contraceptive method for the duration of study treatment and for at least 3 months after the last dose of LOXO-292. Male study participants are to refrain from sperm donation during treatment and for 6 months after the last dose of LOXO-292
  • 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 moderate or strong inducers or 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
  • Concomitant use of proton pump inhibitors (PPI)s during LOXO-292 therapy is prohibited. PPIs are to be discontinued at least 1 week prior to the start of protocol therapy
  • Patients who have major surgery within 14 days prior to cycle 1 day 1 (C1D1) are not eligible. (Central line placement or subcutaneous port placement is not considered major surgery)
  • Patients with known clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal absorption of LOXO-292 are excluded
  • Patients with known hypersensitivity to any of the components of the investigational agent, LOXO 292 are excluded
  • Patients with uncontrolled hypertension are excluded
  • Patients with uncontrolled symptomatic hyperthyroidism and hypothyroidism (i.e. the patient required a modification to current thyroid medication in 7 days prior to enrollment) are excluded
  • Patients with uncontrolled symptomatic hypercalcemia and hypocalcemia are excluded
  • 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  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 12 Months to 21 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE Puerto Rico,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04320888
Other Study ID Numbers  ICMJE NCI-2020-01756
NCI-2020-01756 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
APEC1621N ( Other Identifier: Children's Oncology Group )
APEC1621N ( Other Identifier: CTEP )
U10CA180886 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
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  ICMJE
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.
URL: https://grants.nih.gov/policy/sharing.htm
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Children's Oncology Group
Investigators  ICMJE
Principal Investigator: Andrea T Franson Children's Oncology Group
PRS Account National Cancer Institute (NCI)
Verification Date September 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP