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Larotrectinib in Treating Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders with NTRK Fusions (A Pediatric MATCH Treatment Trial)

Status
Active
Cancer Type
Brain & Spinal Cord Tumor
Brain Tumor
Liver Cancer / Hepatoblastoma
Neuroblastoma
Non-Hodgkin Lymphoma
Sarcoma
Wilms Tumor
Trial Phase
Phase II
Eligibility
12 Months - 21 Years, Male and Female
Study Type
Treatment
NCT ID
NCT03213704
Protocol IDs
APEC1621A (primary)
APEC1621A
NCI-2017-01264
APEC1621A
Study Sponsor
Children's Oncology Group

Summary

This phase II Pediatric MATCH trial studies how well larotrectinib works in treating patients with solid tumors, non-Hodgkin lymphoma, or histiocytic disorders with NTRK fusions that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced) and have come back (relpased) or does not respond to treatment (refractory). Larotrectinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Objectives

PRIMARY OBJECTIVE:
I. To determine the objective response rate (ORR; complete response + partial response) in pediatric patients treated with larotrectinib sulfate (LOXO-101 [larotrectinib]) with advanced solid tumors (including central nervous system [CNS] tumors), non-Hodgkin lymphomas or histiocytic disorders harboring NTRK 1/2/3 fusions.

SECONDARY OBJECTIVES:
I. To estimate the progression free survival in pediatric patients treated with LOXO-101 (larotrectinib) with advanced solid tumors (including CNS tumors), non-Hodgkin lymphomas or histiocytic disorders with NTRK 1/2/3 fusions.
II. To obtain additional information about the tolerability of LOXO-101 (larotrectinib) in children with relapsed or refractory cancer.
III. To provide preliminary estimates of the pharmacokinetics of LOXO-101 (larotrectinib) in children 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 larotrectinib sulfate orally (PO) or via nasogastric (NG)- or gastric (G)-tube twice per day (BID) on days 1-28. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo a computed tomography (CT) scan, magnetic resonance imaging (MRI), an x-ray, bone scan, and/or iobenguane (MIBG) scintigraphy during screening and on study. Patients also undergo bone marrow aspiration and/or biopsy during screening and may undergo blood sample collection on study.

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

Eligibility

  1. APEC1621SC: Patient must have enrolled onto APEC1621SC and must have been given a treatment assignment to Molecular Analysis for Therapy Choice (MATCH) to APEC1621A based on the presence of an actionable mutation as defined in APEC1621SC
  2. Patients must be >= than 12 months and =< 21 years of age at the time of study enrollment
  3. Patients must have radiographically measurable disease at the time of study enrollment; patients with neuroblastoma who do not have measurable disease but have 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 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
  4. 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
  5. 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 time frame, 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; for agents not listed, the duration of this interval must be discussed with the study chair and the study-assigned research coordinator prior to enrollment ** >= 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; for agents not listed, the duration of this interval must be discussed with the study chair and the study-assigned research coordinator prior to enrollment * 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 leukocyte 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, 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 brain metastases (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 other NTRK inhibitors including but not limited to LOXO-101 (larotrectinib), entrectinib (RXDX-101), DS6051, PLX7486
  6. 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)
  7. 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
  8. Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 ml/min/1.73 m^2 (within 7 days prior to enrollment) or
  9. A serum creatinine based on age/gender as follows (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
  10. Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to enrollment)
  11. 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)
  12. Serum albumin >= 2 g/dL (within 7 days prior to enrollment)
  13. Patients with seizure disorder may be enrolled if on anti-convulsants and well controlled
  14. 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 reflect (DTR); any grade of DTR is eligible
  15. 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

Treatment Sites in Georgia

Aflac Cancer and Blood Disorders Center of Children’s at Egleston


1405 Clifton Road NE
3rd Floor
Atlanta, GA 30322
404-785-0853
www.choa.org

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