Neoplasms

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Thyroid Diseases

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All Drugs and Chemicals

Amino Acids

Entrectinib

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

Arm closed for further enrollment

ROS1, ALK non-gene fusion molecular alterations

Oral entrectinib (RXDX-101)

Arm closed for further enrollment

molecular alterations, including gene fusions

Oral entrectinib (RXDX-101)

Arm closed for further enrollment

Oral entrectinib (RXDX-101)

Arm closed for further enrollment

harboring - NTRK1/2/3, ROS1, ALK gene fusions

Oral entrectinib (RXDX-101)

Arm closed for further enrollment

Any participant who otherwise meet all other eligibility criteria

Oral entrectinib (RXDX-101)

gene fusions

Oral entrectinib (RXDX-101)

NTRK 1,2,3 and ROS1 fusions

Oral entrectinib (RXDX-101)

Clinical Trials

This is an open-label, Phase 1/2 multicenter dose escalation study in pediatric patients with relapsed or refractory extracranial solid tumors (Phase 1), with additional expansion cohorts (Phase 2) in patients with primary brain tumors harboring NTRK1/2/3 or ROS1 gene fusions, and extracranial solid tumors harboring NTRK1/2/3 or ROS1 gene fusions.

Study Of Entrectinib (Rxdx-101) in Children and Adolescents With Locally Advanced Or Metastatic Solid Or Primary CNS Tumors And/Or Who Have No Satisfactory Treatment Options

A Phase 1/2, Open-Label, Dose-Escalation And Expansion Study Of Entrectinib (Rxdx-101) In Pediatrics With Locally Advanced Or Metastatic Solid Or Primary CNS Tumors And/Or Who Have No Satisfactory Treatment Options

Assessed by National Cancer Institute Common Terminology for Adverse Events Criteria (NCI CTCAE v4.03)

AE, ECG and Labs assessed by NCI CTCAE v4.03

Assessed by plasma concentrations obtained on Days 1, 2, 8, 15, 22 (Cycle 1), Days 1, 2 (Cycle 2) and on Day 1 of every cycle thereafter

Assessed by RECIST v1.1 per the BICR and investigator

Assessed by RANO per the BICR and investigator

Assessed by the Curie scale per the BICR and investigator

Assessed by RECIST v1.1 per the investigator

Hoffmann-La Roche

Blood and Lymph Conditions

Recurrence

Leukemia

Acute Disease

Neoplasms by Histologic Type

Hematologic Diseases

Disease Attributes

Neoplasms, Fibrous Tissue

Neoplasms, Connective Tissue

Neoplasms, Connective and Soft Tissue

Acute Graft Versus Host Disease

Patients receive larotrectinib PO or by NG or G-tube BID on days 1-28. Treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity, or complete surgical resection of tumor.

Larotrectinib Sulfate

Theodore W Laetsch

This phase II trial studies the side effects and how well larotrectinib works in treating patients with previously untreated TRK fusion solid tumors and TRK fusion acute leukemia that has come back. Larotrectinib may stop the growth of cancer cells with TRK fusions by blocking the TRK enzymes needed for cell growth.

PRIMARY OBJECTIVE:

I. To determine the objective response rate (ORR) of children with infantile fibrosarcoma (IFS) treated with neoadjuvant larotrectinib prior to local control.

SECONDARY OBJECTIVES:

I. To determine event-free survival (EFS), overall survival (OS), and duration of response (DoR) of children with IFS treated with neoadjuvant larotrectinib prior to local control.

II. To determine the ORR, EFS, OS, and DoR of children with newly diagnosed TRK fusion solid tumors other than IFS treated with neoadjuvant larotrectinib prior to local control.

III. To describe the toxicity of larotrectinib in children with solid tumors and acute leukemia.

IV. To determine the percentage of patients with TRK fusion solid tumors with detectable circulating tumor deoxyribonucleic acid (DNA) at baseline and after 2 weeks, 4 weeks, 24 weeks of treatment, at the time of discontinuation of larotrectinib therapy, and at progression.

EXPLORATORY OBJECTIVES:

I. To determine the EFS, OS, and DoR of children with TRK fusion solid tumors other than IFS treated with adjuvant larotrectinib following upfront surgery with positive margins after neoadjuvant larotrectinib.

II. To determine the EFS, OS, and DoR of children with TRK fusion solid tumors who experience a complete response to larotrectinib and subsequently discontinue larotrectinib therapy.

III. To determine the remission induction rate for patients with recurrent/refractory TRK fusion leukemia when treated with larotrectinib.

IV. To evaluate the surgical morbidity and extent of resection of initially unresectable tumors in patients with TRK fusion solid tumors who undergo surgical resection following neoadjuvant larotrectinib.

V. To evaluate mechanisms of response and resistance to larotrectinib in children with TRK fusion cancers.

VI. To evaluate the morphologic features of TRK fusion solid tumors at time of initial biopsy to further define criteria for pathologic diagnosis of these tumors.

VII. To evaluate immunohistochemistry for pan-TRK as a screening method for TRK fusion tumors and in resection specimens following neoadjuvant treatment with larotrectinib.

VIII. To evaluate the histologic response to larotrectinib in resection specimens following neoadjuvant treatment.

IX. To evaluate circulating tumor DNA for the detection of the emergence of resistance mutations and recurrence in patients with TRK fusion solid tumors treated with larotrectinib.

X. To evaluate the ratio of cerebrospinal fluid (CSF) to concurrent plasma concentrations of larotrectinib in patients with leukemia.

XI. To evaluate the change in neurocognitive/behavioral functioning over time between baseline and 2 years post-diagnosis of patients treated on this protocol using parent-reported adaptive functioning (Adaptive Behavior Assessment System \[ABAS\]-III General Adaptive Composite), executive function (Behavior Rating Inventory of Executive Function Scales-Preschool Version \[BRIEF-P\] or BRIEF-2 Global Executive Composite Score), psychosocial functioning (Behavior Assessment System for Children \[BASC\]-3 Internalizing, Externalizing and Behavioral Symptoms Indices) and quality of life (Pediatric Quality of Life Inventory \[PedsQL\] Total score).

OUTLINE:

Patients receive larotrectinib orally (PO) or by nasogastric (NG) or gastric tube (G-tube) twice daily (BID) on days 1-28. Treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity. Patients whose tumors shrink sufficiently while taking larotrectinib may undergo surgical resection of their tumor while on study.

After completion of study treatment, patients are followed up at 3, 6, 12, 18, 24, 30, 36, and 48 months and annually thereafter for up to 5 years from the date of study entry.

Larotrectinib in Treating Patients With Previously Untreated TRK Fusion Solid Tumors and TRK Fusion Relapsed Acute Leukemia

Larotrectinib (LOXO-101, NSC# 788607) for Previously Untreated TRK Fusion Pediatric Solid Tumors and TRK Fusion Relapsed Pediatric Acute Leukemias

Response rates will be calculated as the percent of evaluable patients who are responders, and confidence intervals will be constructed accounting for the two-stage design.

Will be computed one year after the last enrollment in a stratum.

Will be computed one year after the last enrollment in a stratum. Will be defined among patients with a confirmed best response of either PR and CR.

Per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. 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 attribution(s) to the study regimen.

The percentage of ctDNA and frequency with which patients have detectable ctDNA prior to the start of therapy and at times during therapy when subsequent serial samples are obtained will be summarized with simple summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit). In cases of treatment resistance, we will also perform exploratory deep sequencing of ctDNA to determine whether this method can detect the emergence of resistance mutations.

National Cancer Institute (NCI)

Children's Oncology Group

Pediatric patients with IFS harboring an NTRK gene fusion who have been enrolled in the SCOUT study.

Pediatric patients with IFS harboring an NTRK gene fusion in the eligible external cohort(s).

Pediatric patients with IFS harboring an NTRK gene fusion.

Larotrectinib (Vitrakvi, BAY2757556)

Standard of care for the patients from the eligible external cohorts.

Standard of Care

This is an observational study in which data from the past of children and young people with a specific cancer, called NTRK gene fusion positive infantile fibrosarcoma (IFS) is studied.

IFS is a rare type of childhood cancer that commonly affects legs and arms. IFS cancers typically have specific changes in their building plans (genes) called NTRK gene fusion. NTRK stands for the specific gene that has been altered, the neurotrophic tyrosine kinase (NTRK) gene.

This change to the building plan leads to the creation of an altered protein known as a TRK fusion protein, which can cause cancer cells to grow and to survive. The specific cancer is therefore also called TRK (tropomyosin receptor kinase) fusion-positive IFS.

The study drug, larotrectinib (also called BAY2757556) works by blocking the altered TRK fusion protein. Larotrectinib is already available in Europe and in many other countries and is approved for doctors to prescribe to patients with NTRK gene fusion cancer which has spread to nearby tissues and/or lymph nodes or to other parts of the body.

In France, HAS (the French authority in charge of evaluating health products and technologies) gave a positive opinion for the reimbursement of larotrectinib but only in the pediatric patients with IFS or another STS harboring a NTRK gene fusion, which is locally advanced or metastatic, and refractory or in relapse mainly due to the lack of comparative evidence.

The main purpose of this study is to collect more data to learn how well larotrectinib works compared with current standard of care chemotherapy in people up to 21 years of age with NTRK gene fusion positive IFS that has spread to nearby tissues and/or lymph nodes (locally advanced) or other parts of the body (metastatic).

To see how well larotrectinib works, researchers will make a comparison between

* how long larotrectinib works well and
* how long the standard of care works well.

Working well means that the treatments can prevent the following from happening:

* need for a new treatment for the cancer
* need for radiation therapy for the cancer
* need for surgery to treat the cancer, but which causes major damage to body parts
* death.

In addition to the above, data about medical problems related to the treatments in both groups and that may have required to stop the treatment will be compared.

The data for the comparison will come from

* an ongoing international study called SCOUT which was started in December 2015 (larotrectinib group)
* international databases (standard of care chemotherapy group). Data will be from the year 2000 up to the present.

There will be no required visits with a study doctor or required tests in this study.

A Study Called EPI VITRAKVI to Compare Treatment Results in Patients With Infantile Fibrosarcoma (IFS), a Type of Connective Soft Tissue Cancer, Who Received a Treatment Called Larotrectinib From a Study Called SCOUT With Patient Data From an External Database

A Comparison of Clinical Outcomes in Infantile Fibrosarcoma (IFS) Patients Treated With Larotrectinib in the Phase I/II SCOUT Study Versus (an) External Historical Cohort(s)

Availability of this study's data will later be determined according to Bayer's commitment to the EFPIA/PhRMA "Principles for responsible clinical trial data sharing". This pertains to scope, timepoint and process of data access. As such, Bayer commits to sharing upon request from qualified researchers patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials in patients for medicines and indications approved in the US and EU as necessary for conducting legitimate research. This applies to data on new medicines and indications that have been approved by the EU and US regulatory agencies on or after January 01, 2014.

Interested researchers can use www.vivli.org to request access to anonymized patient-level data and supporting documents from clinical studies to conduct research. Information on the Bayer criteria for listing studies and other relevant information is provided in the member section of the portal.

Defined as the time (months) from the start of treatment to the date of the following events, whichever comes first: subsequent systemic treatment, radiation therapy, mutilating surgery or death due to any cause.

Calculated from the start date of larotrectinib treatment for the SCOUT study and start date of chemotherapy (first line) for the external historical control cohort(s) to the start date of a post-treatment systemic anti-cancer therapy, if any.

Calculated from the start date of larotrectinib treatment for the SCOUT study and start date of chemotherapy (first line) for the external historical control cohort(s) to the date of a post-treatment mutilating surgery including limb amputation, if any.

Calculated from the start date of larotrectinib treatment for the SCOUT study and start date of chemotherapy (first line) for the external historical control cohort(s) to the start date of a post-treatment radiation therapy, if any.

Calculated from the start date of larotrectinib treatment for the SCOUT study and start date of chemotherapy (first line) for the external historical control cohort(s) to the date of a post-treatment complete surgical resection (excluding amputation), if any.

Start date of larotrectinib treatment for the SCOUT study and start date of chemotherapy (first line) for the external historical control cohort(s), Date of death due to any cause, if applicable, or, Last date of patient follow-up for patients alive and lost to follow-up, if applicable.

Larotrectinib treatment for the SCOUT study and chemotherapy (first line) for the external historical control cohort(s).

Bayer

Respiratory Tract (Lung and Bronchial) Diseases

Digestive System Diseases

Nutritional and Metabolic Diseases

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Carcinoma

Adenoma

Colonic Neoplasms

Lung Diseases

Head and Neck Neoplasms

Endocrine Gland Neoplasms

Protein-Energy Malnutrition

Respiratory Tract Diseases

Thoracic Neoplasms

Respiratory Tract Neoplasms

Bronchial Neoplasms

Carcinoma, Bronchogenic

Endocrine System Diseases

Myofibromatosis

Adenocarcinoma

Adenocarcinoma, Papillary

Neoplasms, Glandular and Epithelial

Thyroid Cancer, Medullary

Infantile Myofibromatosis

Herbal and Botanical

Cola

Phase 1- Dose Escalation and determination of MTD; multiple dose levels of LOXO-292 to be evaluated; Phase 2 - The MTD/recommended dose from Phase 1

LOXO-292

There may be multiple sites in this clinical trial. 1-877-CTLILLY (1-877-285-4559) or

Leo Mascarenhas

Margaret Macy

Ramamoorthy Nagasubramanian

Steven DuBois

Emily Greengard

Julia Glade Bender

Brian Turpin

Frank Balis

Alberto Pappo

Tanya Watt

Stephanie Fetzko

Douglas Hawkins

David Ziegler

Martin Campbell

Daniel Alexander Morgenstern

Karstend Nysom

Charlotte Rigaud

Cornelis Van Tilburg

Michela Casanova

Atushi Manabe

Ayumu Arakawa

Shuhei Karakawa

Katsutsugu Umeda

HyoungJin Kang

Raquel Hladun

Sara Stoneham

Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST)

This is an open-label, multi-center Phase 1/2 study of oral LOXO-292 in pediatric participants with an activating rearranged during transfection (RET) alteration and an advanced solid or primary CNS tumor.

This study includes 2 parts: phase 1 (dose escalation) and phase 2 (dose expansion). In phase 1, participants will be enrolled using a rolling 6 dose escalation scheme. The starting dose of LOXO-292 is equivalent to the adult recommended phase 2 dose of 160 milligrams (mg) twice a day (BID). Once the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) is identified, participants will be enrolled to one of four phase 2 dose expansion cohorts depending on tumor histology and tumor genotype. Cycle length will be 28 days.

A Study of Oral LOXO-292 (Selpercatinib) in Pediatric Participants With Advanced Solid or Primary Central Nervous System (CNS) Tumors

A Phase 1/2 Study of the Oral RET Inhibitor LOXO 292 in Pediatric Patients With Advanced RET-Altered Solid or Primary Central Nervous System Tumors

Tumor stage is described according to the Tumor, Node, Metastasis (TNM)Classification of malignant tumors of the Union for International Cancer Control (UICC)

Tumor margins after surgery are classified into four groups using the International Cancer Control (UICC)-R classification and the Intergroup Rhabdomyosarcoma Staging (IRS) systems: 1) Complete tumor resection with histologically free margins, 2) Macroscopic resection but invaded margins on histology, 3)Macroscopic residual tumor and 4) Distant metastatic tumor.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study Of Entrectinib (Rxdx-101) in Children and Adolescents With Locally Advanced Or Metastatic Solid Or Primary CNS Tumors And/Or Who Have No Satisfactory Treatment Options	NCT02650401	Solid Tumors CNS Tumors	Entrectinib	0 Years - 18 Years	Hoffmann-La Roche
Larotrectinib in Treating Patients With Previously Untreated TRK Fusion Solid Tumors and TRK Fusion Relapsed Acute Leukemia	NCT03834961	Central Nervous... Infantile Fibro... Recurrent Acute... Refractory Acut... Solid Neoplasm	Larotrectinib S...	- 30 Years	Children's Oncology Group
A Study Called EPI VITRAKVI to Compare Treatment Results in Patients With Infantile Fibrosarcoma (IFS), a Type of Connective Soft Tissue Cancer, Who Received a Treatment Called Larotrectinib From a Study Called SCOUT With Patient Data From an External Database	NCT05236257	Locally Advance... Infantile Fibro...	Larotrectinib (... Standard of Car...	- 21 Years	Bayer
A Study of Oral LOXO-292 (Selpercatinib) in Pediatric Participants With Advanced Solid or Primary Central Nervous System (CNS) Tumors	NCT03899792	Medullary Thyro... Infantile Myofi... Infantile Fibro... Papillary Thyro... Soft Tissue Sar...	LOXO-292	6 Months - 21 Years	Eli Lilly and Company
A Study of Oral LOXO-292 (Selpercatinib) in Pediatric Participants With Advanced Solid or Primary Central Nervous System (CNS) Tumors	NCT03899792	Medullary Thyro... Infantile Myofi... Infantile Fibro... Papillary Thyro... Soft Tissue Sar...	LOXO-292	6 Months - 21 Years	Eli Lilly and Company
Study Of Entrectinib (Rxdx-101) in Children and Adolescents With Locally Advanced Or Metastatic Solid Or Primary CNS Tumors And/Or Who Have No Satisfactory Treatment Options	NCT02650401	Solid Tumors CNS Tumors	Entrectinib	0 Years - 18 Years	Hoffmann-La Roche

Spots Global Cancer Trial Database for infantile fibrosarcoma