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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

NCT04320888

Description:

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.

Related Conditions:
  • Histiocytosis
  • Lymphoma
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Selpercatinib for the Treatment of Advanced Solid Tumors, Lymphomas, or Histiocytic Disorders With Activating RET Gene Alterations, a Pediatric MATCH Treatment Trial
  • Official Title: NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice) - Phase 2 Subprotocol of LOXO-292 in Patients With Tumors Harboring RET Gene Alterations

Clinical Trial IDs

  • ORG STUDY ID: NCI-2020-01756
  • SECONDARY ID: NCI-2020-01756
  • SECONDARY ID: APEC1621N
  • SECONDARY ID: APEC1621N
  • SECONDARY ID: U10CA180886
  • NCT ID: NCT04320888

Conditions

  • 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

Interventions

DrugSynonymsArms
SelpercatinibLOXO-292, RET Kinase Inhibitor LOXO-292, Retevmo, WHO 10967Treatment (selpercatinib)

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (selpercatinib)ExperimentalPatients 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.
  • Selpercatinib

Eligibility Criteria

        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 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
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:12 Months
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate (complete response + partial response) in pediatric patients treated with selpercatinib (LOXO-292)
Time Frame:Up to 2 years
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure: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
Safety Issue:
Description:PFS along with the confidence intervals will be estimated using the Kaplan-Meier method.
Measure:Percentage of patients experiencing grade 3 or 4 adverse events
Time Frame:Up to 2 years
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

October 7, 2020