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)

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.

• Biospecimen Collection (Procedure), also known as Biological Sample Collection, Biospecimen Collected, Sample Collection, Specimen Collection: Undergo blood sample collection
• Bone Marrow Aspiration and Biopsy (Procedure): Undergo a bone marrow aspiration and/or biopsy
• Bone Scan (Procedure), also known as Bone Scintigraphy: Undergo a bone scan
• Computed Tomography (Procedure), also known as CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, Computerized Tomography (CT) scan, CT, CT Scan, Diagnostic CAT Scan, Diagnostic CAT Scan Service Type, tomography: Undergo a CT scan
• Larotrectinib Sulfate (Drug), also known as ARRY 470 Sulfate, LOXO 101 Sulfate, LOXO-101 Sulfate, Vitrakvi: Given PO or via nasogastric- or gastric-tube
• Magnetic Resonance Imaging (Procedure), also known as 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: Undergo MRI
• Radionuclide Imaging (Procedure), also known as Gamma Scan, NM, Nuclear Medicine, nuclear medicine scan, radioimaging, Radionuclide Scanning, Scan, Scintigraphy: Undergo a MIBG scintigraphy
• X-Ray Imaging (Procedure), also known as 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: Undergo an x-ray

Primary outcomes

• Objective Response Rate [Up to 2 years from study entry]: 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. The revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) was used to determine response and progression in this study, with specific criteria outlined for the different subtypes of tumors (e.g., 2-dimensional measurements for central nervous system (CNS) tumors).

Secondary outcomes

• Progression Free Survival (PFS) [Up to 6 months from study entry]: The Kaplan-Meier method will be used to estimate the 6 month PFS. PFS is defined as time from initiation of protocol treatment to disease progression, recurrence, death from any cause, or date of last contact.
• Percentage of Patients Experiencing Grade 3 or Higher Adverse Events [Up to 2 years from study entry]: 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.

Other outcomes

• Pharmacokinetics of Larotrectinib [Pre-dose, 1, 2, 4, and 6-8 hours after morning dose of day 1 cycle 1 and pre-dose of day 1 cycle 2]: A descriptive analysis of pharmacokinetic parameters of LOXO-101 (larotrectinib) will be performed to define systemic exposure, drug clearance, and other pharmacokinetic parameters. The pharmacokinetic parameters will be summarized with simple summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit). All these analyses will be descriptive and exploratory and hypotheses generating in nature.
• Ability to Detect NTRK Fusions in Circulating Cell-free Tumor Deoxyribonucleic Acid in Plasma [Up to 5 years]: A descriptive analysis of the exploratory aims will be performed and will be summarized with simple summary statistics. All of these analyses will be descriptive in nature.

Sex: All, ages: 12 Months to 21 Years

Inclusion Criteria:

* 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
* Patients must be >= than 12 months and =< 21 years of age at the time of study enrollment
* 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
* 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 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
* 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 (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 (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 with seizure disorder may be enrolled if on anti-convulsants 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 reflect (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

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 an effective contraceptive method for the duration of study treatment
* 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 (GVHD) 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
* Patients who have received prior therapy with a specific inhibitor of TRK (including but not limited to entrectinib \[RXDX-101\], DS-6051b, and PLX7486) 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

Participant flow

Outcome results

• Objective Response Rate (Primary), Number, percentage of participants: Treatment (Larotrectinib Sulfate) 33 (14.2 to 60.2)
• Progression Free Survival (PFS) (Secondary), Number, percentage of participants: Treatment (Larotrectinib Sulfate) 76 (33.2 to 93.5)
• Percentage of Patients Experiencing Grade 3 or Higher Adverse Events (Secondary), Number, percentage of participants: Treatment (Larotrectinib Sulfate) 44 (13.7 to 78.8)
• Pharmacokinetics of Larotrectinib (Other pre specified)
• Ability to Detect NTRK Fusions in Circulating Cell-free Tumor Deoxyribonucleic Acid in Plasma (Other pre specified)

Adverse events

Time frame: Adverse Events monitored/assessed from enrollment to 30 days after the end of treatment, up to 2 years. All-Cause Mortality monitored/assessed up to 5 years

Serious adverse events by term

Other adverse events by term

24 more terms not shown.

24 more sites not listed.

• Study Protocol and Statistical Analysis Plan (PDF, 2022-10-28)
• Informed Consent Form (PDF, 2022-10-28)

• Katherine A Janeway, Principal investigator, Children's Oncology Group

NIH grants: U10CA180886