RECRUITING

Ulixertinib in People With Histiocytic Neoplasms

Conditions

Histiocytic Neoplasms Ulixertinib (BVD-523)23-282 Mitogen-activated protein kinase

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Study Overview

This clinical trial focuses on testing the efficacy of different digital interventions to promote re-engagement in cancer-related long-term follow-up care for adolescent and young adult (AYA) survivors of childhood cancer.

Description

The researchers are doing this study is to find out whether ulixertinib is an effective and safe treatment for people with histiocytic neoplasms.

Official Title

Phase 2 Trial of Ulixertinib for Patients With Histiocytic Neoplasms

Quick Facts

Study Start:2024-05-07

Study Completion:2027-05

Study Type:Not specified

Phase:Not Applicable

Enrollment:Not specified

Status:RECRUITING

Study ID

NCT06411821

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Ages Eligible for Study:12 Years

Sexes Eligible for Study:ALL

Accepts Healthy Volunteers:No

Standard Ages:CHILD, ADULT, OLDER_ADULT

Inclusion Criteria	Exclusion Criteria
* Histologically confirmed histiocytic neoplasm or histologic findings consistent with histiocytic neoplasm with confirmatory radiologic or molecular findings. Pathologic examination can be performed at any of the enrolling institutions. This qualification is made because it is well known that biopsies of histiocytic neoplasms are variable and do not always demonstrate "typical" morphologic appearance with all of the classically described elements. As a result, histiocytic neoplasms are not exclusively pathologic diagnoses-rather, they are interpretations of histologic findings in a clinical and radiologic context. These criteria were applied in NCT02649972 and will be applied in this trial * Identified mutation in MAPK pathway genes, including but not limited to ARAF, BRAF, RAF1, NRAS, KRAS, MAP2K1, MAP2K2, and NF1 (primary cohort). Tumor mutation may be identified by tumor sequencing or cfDNA-based sequencing. Concordance between cfDNA and tumor sequencing for BRAFV600E and non-BRAF mutations in histiocytic neoplasms has been documented by our group and others * Measurable disease according to PRC, confirmed by an investigator radiologist * Age (a) ≥18 years prior to interim safety and efficacy analyses or (b) ≥12 years following the interim safety and efficacy analyses * The histiocytic neoplasm must be (a) disease that is recurrent/refractory/persistent despite local therapies, chemotherapy, immunosuppression, or BRAF/MEK inhibitors OR (b) multisystem disease OR (c) single-system disease that is causing end-organ dysfunction and is unlikely to benefit from local or conventional (chemotherapy or immunosuppressive) therapies on the basis of evidence-based guidelines (e.g. symptomatic neurologic-only LCH) * Prior treatment (chemotherapy, BRAF inhibitor, or MEK inhibitor) is required and the patient must have (a) progressive disease or persistent disease (i.e. having disease measurable by PRC) or (b) intolerance or contraindication to chemotherapy, BRAF inhibition, or MEK inhibition. * Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 (age ≥ 16) or Lansky 50-100 (age 12-15) * Adequate renal function (according to the Cockcroft-Gault equation; creatinine ≤1.5 times upper limit of normal \[ULN\] or a glomerular filtration rate of ≥50 mL/min) * Pediatric patients (\<18 years old) must have a creatinine clearance or radioisotope GFR ≥ 70 mL/min/1.73 m\^2 or serum creatinine based on age/gender as follows: * \< 13 years- 1.2 (Male),1.2 (Female) * 13 to \< 16 years- 1.5 (Male), 1.4 (Female) * The threshold creatinine values in this Table were derived from the Schwartz formula for estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing child length and stature data published by the CDC. * Patients with renal impairment deemed the direct result of disease and therefore amenable to improvement with Ulixertinib treatment may be enrolled at the discretion of the treating investigator * Adequate hepatic function (total bilirubin ≤1.5 times ULN, aspartate transaminase \[AST\] and- alanine transaminase \[ALT\] ≤3 times ULN or ≤5 times ULN if attributable to liver involvement by tumor). Patients with hepatic impairment deemed the direct result of disease and therefore amenable to improvement with Ulixertinib treatment may be enrolled at the discretion of the treating investigator. * Adequate bone marrow function (hemoglobin ≥9.0 g/dL, platelets ≥100 x 10\^9 cells/L, absolute neutrophil count ≥1.5 x 10\^9 cells/L). Patients with cytopenias deemed the direct result of disease and therefore amenable to improvement with Ulixertinib treatment may be enrolled at the discretion of the treating investigator. * Adequate cardiac function * Left ventricular ejection fraction \>50% as assessed by multi-gated acquisition or ultrasound or echocardiography and * Corrected QT interval (QTc) \<480 ms according to the Fridericia method (QTcF) * Contraception * For women: a negative pregnancy test for those of child-bearing potential, must be surgically sterile, postmenopausal (no menstrual cycle for at least 12 consecutive months), or compliant with a medically approved contraceptive regimen during and for 3 months after the treatment period * For men: must be surgically sterile or compliant with a medically approved contraceptive regimen during and for 3 months after the treatment period * For patients aged \<18 years who are not sexually active: abstinence is an acceptable form of contraception. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant. * Willing and able to participate in the trial and comply with all trial requirements * Patients with a prior or concurrent malignancy whose natural history or treatment * does not have the potential to interfere with the safety or efficacy assessment of * the investigational agent may be included at the discretion of the site PI	* Uncontrolled or severe intercurrent medical condition * Receipt of any histiocytic neoplasm-directed therapy (chemotherapy, targeted therapy, biologic) within 28 days or 5 half-lives (whichever is shorter) before the first dose of ulixertinib. Patients previously treated with radiotherapy must have recovered from acute toxicities associated with such treatment * Histiocytic neoplasm mandated for observation-only or first-line local therapy per established guidelines. Examples would include asymptomatic nodal RDD, asymptomatic osseous ECD, or limited cutaneous LCH * Major surgery within 4 weeks of the first dose of ulixertinib * Pregnant, lactating, or breast-feeding (for women) * Any evidence of serious active infections. Patients are allowed to enroll if they have been fever free for at least 48 h * History or current evidence of risk of retinal vein occlusion or central serous retinopathy. Examples of risk factors to be considered would include uncontrolled ocular hypertension or history of hyperviscosity. * Concurrent therapy with drugs known to be strong inhibitors or inducers of CYP1A2, CYP2D6, and CYP3A4 * Concurrent therapy with p-glycoprotein inhibitors and sensitive substrates of CYP1A2, CYP2B6, CYP2C8, and CYP3A4/5 with narrow therapeutic indices * Inability to swallow oral medications * Prior stomach or duodenal resection that, in the opinion of the site PI, would affect the breakdown and absorption of the study medications. Patients with a feeding tube will also be excluded, as ulixertinib tablets cannot be taken broken, cracked or otherwise not intact. Note: ulixertinib is primarily absorbed in the duodenum, and therefore the potential inclusion of a patient with any prior stomach or duodenal resection should be discussed with the MSK PI * Concurrent therapy with any investigational agent * Any use of an investigational drug within 28 days or 5 half-lives (whichever is shorter). In addition, any drug toxicities should have recovered to grade 1 or less before start of the trial medication

Inclusion Criteria

Exclusion Criteria

* Histologically confirmed histiocytic neoplasm or histologic findings consistent with histiocytic neoplasm with confirmatory radiologic or molecular findings. Pathologic examination can be performed at any of the enrolling institutions. This qualification is made because it is well known that biopsies of histiocytic neoplasms are variable and do not always demonstrate "typical" morphologic appearance with all of the classically described elements. As a result, histiocytic neoplasms are not exclusively pathologic diagnoses-rather, they are interpretations of histologic findings in a clinical and radiologic context. These criteria were applied in NCT02649972 and will be applied in this trial
* Identified mutation in MAPK pathway genes, including but not limited to ARAF, BRAF, RAF1, NRAS, KRAS, MAP2K1, MAP2K2, and NF1 (primary cohort). Tumor mutation may be identified by tumor sequencing or cfDNA-based sequencing. Concordance between cfDNA and tumor sequencing for BRAFV600E and non-BRAF mutations in histiocytic neoplasms has been documented by our group and others
* Measurable disease according to PRC, confirmed by an investigator radiologist
* Age (a) ≥18 years prior to interim safety and efficacy analyses or (b) ≥12 years following the interim safety and efficacy analyses
* The histiocytic neoplasm must be (a) disease that is recurrent/refractory/persistent despite local therapies, chemotherapy, immunosuppression, or BRAF/MEK inhibitors OR (b) multisystem disease OR (c) single-system disease that is causing end-organ dysfunction and is unlikely to benefit from local or conventional (chemotherapy or immunosuppressive) therapies on the basis of evidence-based guidelines (e.g. symptomatic neurologic-only LCH)
* Prior treatment (chemotherapy, BRAF inhibitor, or MEK inhibitor) is required and the patient must have (a) progressive disease or persistent disease (i.e. having disease measurable by PRC) or (b) intolerance or contraindication to chemotherapy, BRAF inhibition, or MEK inhibition.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 (age ≥ 16) or Lansky 50-100 (age 12-15)
* Adequate renal function (according to the Cockcroft-Gault equation; creatinine ≤1.5 times upper limit of normal \[ULN\] or a glomerular filtration rate of ≥50 mL/min)
* Pediatric patients (\<18 years old) must have a creatinine clearance or radioisotope GFR ≥ 70 mL/min/1.73 m\^2 or serum creatinine based on age/gender as follows:
* \< 13 years- 1.2 (Male),1.2 (Female)
* 13 to \< 16 years- 1.5 (Male), 1.4 (Female)
* The threshold creatinine values in this Table were derived from the Schwartz formula for estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing child length and stature data published by the CDC.
* Patients with renal impairment deemed the direct result of disease and therefore amenable to improvement with Ulixertinib treatment may be enrolled at the discretion of the treating investigator
* Adequate hepatic function (total bilirubin ≤1.5 times ULN, aspartate transaminase \[AST\] and- alanine transaminase \[ALT\] ≤3 times ULN or ≤5 times ULN if attributable to liver involvement by tumor). Patients with hepatic impairment deemed the direct result of disease and therefore amenable to improvement with Ulixertinib treatment may be enrolled at the discretion of the treating investigator.
* Adequate bone marrow function (hemoglobin ≥9.0 g/dL, platelets ≥100 x 10\^9 cells/L, absolute neutrophil count ≥1.5 x 10\^9 cells/L). Patients with cytopenias deemed the direct result of disease and therefore amenable to improvement with Ulixertinib treatment may be enrolled at the discretion of the treating investigator.
* Adequate cardiac function
* Left ventricular ejection fraction \>50% as assessed by multi-gated acquisition or ultrasound or echocardiography and
* Corrected QT interval (QTc) \<480 ms according to the Fridericia method (QTcF)
* Contraception
* For women: a negative pregnancy test for those of child-bearing potential, must be surgically sterile, postmenopausal (no menstrual cycle for at least 12 consecutive months), or compliant with a medically approved contraceptive regimen during and for 3 months after the treatment period
* For men: must be surgically sterile or compliant with a medically approved contraceptive regimen during and for 3 months after the treatment period
* For patients aged \<18 years who are not sexually active: abstinence is an acceptable form of contraception. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant.
* Willing and able to participate in the trial and comply with all trial requirements
* Patients with a prior or concurrent malignancy whose natural history or treatment
* does not have the potential to interfere with the safety or efficacy assessment of
* the investigational agent may be included at the discretion of the site PI

* Uncontrolled or severe intercurrent medical condition
* Receipt of any histiocytic neoplasm-directed therapy (chemotherapy, targeted therapy, biologic) within 28 days or 5 half-lives (whichever is shorter) before the first dose of ulixertinib. Patients previously treated with radiotherapy must have recovered from acute toxicities associated with such treatment
* Histiocytic neoplasm mandated for observation-only or first-line local therapy per established guidelines. Examples would include asymptomatic nodal RDD, asymptomatic osseous ECD, or limited cutaneous LCH
* Major surgery within 4 weeks of the first dose of ulixertinib
* Pregnant, lactating, or breast-feeding (for women)
* Any evidence of serious active infections. Patients are allowed to enroll if they have been fever free for at least 48 h
* History or current evidence of risk of retinal vein occlusion or central serous retinopathy. Examples of risk factors to be considered would include uncontrolled ocular hypertension or history of hyperviscosity.
* Concurrent therapy with drugs known to be strong inhibitors or inducers of CYP1A2, CYP2D6, and CYP3A4
* Concurrent therapy with p-glycoprotein inhibitors and sensitive substrates of CYP1A2, CYP2B6, CYP2C8, and CYP3A4/5 with narrow therapeutic indices
* Inability to swallow oral medications
* Prior stomach or duodenal resection that, in the opinion of the site PI, would affect the breakdown and absorption of the study medications. Patients with a feeding tube will also be excluded, as ulixertinib tablets cannot be taken broken, cracked or otherwise not intact. Note: ulixertinib is primarily absorbed in the duodenum, and therefore the potential inclusion of a patient with any prior stomach or duodenal resection should be discussed with the MSK PI
* Concurrent therapy with any investigational agent
* Any use of an investigational drug within 28 days or 5 half-lives (whichever is shorter). In addition, any drug toxicities should have recovered to grade 1 or less before start of the trial medication

Contacts and Locations

Study Contact

Eli Diamond, MD

CONTACT

212-610-0243

diamone1@mskcc.org

Rona Yaeger, MD

CONTACT

646-888-5109

Principal Investigator

Eli Diamond, MD

PRINCIPAL_INVESTIGATOR

Memorial Sloan Kettering Cancer Center

Study Locations (Sites)

Memorial Sloan Kettering Basking Ridge (Consent Only)

Basking Ridge, New Jersey, 07920

United States

Memorial Sloan Kettering Monmouth (Limited Protocol Activities)

Middletown, New Jersey, 07748

United States

Memorial Sloan Kettering Bergen (Consent Only)

Montvale, New Jersey, 07645

United States

Memorial Sloan Kettering Suffolk-Commack (Consent Only)

Commack, New York, 11725

United States

Memorial Sloan Kettering Westchester (Limited Protocol Activities)

Harrison, New York, 10604

United States

Memorial Sloan Kettering Cancer Center (All Protocol Activities)

New York, New York, 10065

United States

Memorial Sloan Kettering Nassau (Consent Only)

Uniondale, New York, 11553

United States

Collaborators and Investigators

Sponsor: Memorial Sloan Kettering Cancer Center

Eli Diamond, MD, PRINCIPAL_INVESTIGATOR, Memorial Sloan Kettering Cancer Center

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates

Study Start Date2024-05-07

Study Completion Date2027-05

Study Record Updates

Study Start Date2024-05-07

Study Completion Date2027-05

Terms related to this study

Keywords Provided by Researchers

Ulixertinib (BVD-523)
23-282
Mitogen-activated protein kinase

Additional Relevant MeSH Terms

Histiocytic Neoplasms