Safety and Efficacy of DAY101 in Patients With Relapsed/Refractory LCH

• Status: Not yet recruiting
• Trial end date: 2025-05-29
• Target enrollment: 0
• Participant gender: All

Summary

This trial is an open-label, multi-center Phase 2 study to evaluate the safety and efficacy of the pan-RAF inhibitor DAY101 in patients with relapsed/refractory LCH with pathologic somatic mutations in genes encoding tyrosine kinase receptors, RAS or RAF. DAY101 will be given orally at the recommended phase 2 dose (RP2D). The primary end point will be the overall response rate. Disease-free, progression-free, and overall survival will be assessed as secondary end points. Tumor biopsies and serial blood specimens will be collected for correlative biology.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Children's Oncology Group

Criteria

Inclusion Criteria:

• Patients with multifocal progressive, relapsed, or recurrent LCH with evaluable disease at study entry.

• Patients must have had histologic verification of LCH (from either original diagnosis or relapse/progression) at the time of study entry.

1. Tissue confirmation of relapse is recommended but not required.

2. Pathology report must be submitted for central confirmation of diagnosis within 7 days of enrollment.

3. FFPE blocks or unstained slides (initial diagnosis and/or subsequent biopsies) will be required for retrospective central confirmation of diagnosis and molecular studies.

4. Patients with mixed histiocytic disorders (e.g. LCH with juvenile xanthogranuloma) may be included.

• Patients must have measurable disease, documented by radiographic imaging (LCH-specific RESIST/PERSIST criteria, See Section 10.0).

• Patients must have progressive or refractory disease or experience relapse after at least one previous systemic chemotherapy treatment strategy.

• Pathogenic somatic mutation detected in genes encoding tyrosine kinase receptors (CSFR1, ERBB3 or ALK), RAS or RAF (may be from original or subsequent biopsy or peripheral blood/bone marrow aspirate). Clinical mutation reports may include quantitative PCR (e.g. BRAFV600E) and/or Sanger or Next Generation sequencing. Immunohistochemistry (e.g. VE1 antibody for BRAFV600E) alone is not sufficient. Please note that activating mutations in MAP2K1 are not eligible for this study due to drug target specificity. Mutation status will be submitted to study team within 7 days of enrollment.

• Participant must be able to take an enteral dose and formulation of medication. Study medication is only available as an oral suspension or tablet, which may be taken by mouth or other enteral route such as nasogastric or gastric tube.

• Performance Level Karnofsky ≥50% for patients > 16 years of age and Lansky ≥ 50% for patients ≤ 16 years of age.

• Patients must have a performance status corresponding to ECOG scores of 0, 1 or 2. Use Karnofsky for patients > 16 years of age and Lansky for patients ≤ 16 years of age. See "Performance Status Scales Scoring".

• Patients must have a life expectancy of ≥ 8 weeks.

• Myelosuppressive chemotherapy: Patients must not have received within 28 days of entry onto this study.

• Investigational agent or any other anticancer therapy not defined above: Patients must not have received any investigational agent for at least 4 weeks prior to planned start of DAY101.

• Radiation therapy (RT): Patient must not have received RT within 2 weeks after the last dose fraction of RT.

• Patient should not have received any prior MAPK pathway inhibitor therapy.

• Patients must have fully recovered from any prior surgery.

• Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy with toxicities reduced to Grade 1 or less ((CTCAE) version 5.0).

• Ongoing retinopathy must be ≤ Grade 2

• Concomitant Medications Restrictions

1. Steroids: <0.5 mg/kg/day of prednisone equivalent averaged during the month prior to study enrollment is permissible but must be discontinued fourteen (14) days prior to study enrollment. Patients with documented brain lesions receiving corticosteroids for management of cerebral edema must be on a stable dose for fourteen (14) days prior to study enrollment.

2. Strong or moderate inducers of CYP2C8, CYP2C9, CYP2C19 and CYP3A4/5 enzymes and strong or moderate inhibitors of CYP2C8 are prohibited for 14 days before the first dose of DAY101 and for the duration of study participation.

• Adequate Bone Marrow Function Defined As:

• Peripheral absolute neutrophil count (ANC) ≥750/µL unless secondary to bone marrow involvement, in such cases bone marrow involvement must be documented.

• Platelet count ≥75,000/µL (unsupported/without transfusion within the past 7 days).

• Patients with marrow disease must have platelet count of ≥75,000/µL (transfusion support allowed) and must not be refractory to platelet transfusions. Bone marrow involvement must be documented.

• Hemoglobin ≥8 g/dL (unsupported/without transfusion within the past 7 days). Patients with marrow disease must have hemoglobin ≥8 g/dL (transfusion support allowed). Bone marrow involvement must be documented.

• Hematopoietic growth factors: At least 14 days after the last dose of a long-acting growth factor (e.g., Neulasta®) or 7 days for short-acting growth factor

• Adequate Renal Function Defined As:

• A serum creatinine based on age/gender OR - a 24 hour urine Creatinine clearance ≥ 70 mL/min/1.73 m2

OR - a GFR ≥ 70 mL/min/1.73 m2. GFR must be performed using direct measurement with a nuclear blood sampling method OR direct small molecule clearance method (iothalamate or other molecule per institutional standard).

Note: Estimated GFR (eGFR) from serum creatinine, cystatin C or other estimates are not acceptable for determining eligibility.

• Adequate Liver Function Defined As:

• Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of normal (ULN) for age

• ALT ≤ 5x ULN for age.

• Serum albumin ≥2 g/dl For patients with liver disease caused by histiocytic disorder (as evaluated on radiographic imaging or biopsy): Patients may be enrolled with abnormal bilirubin, AST, ALT and albumin with documentation of histiocytic liver disease.

• Adequate Cardiac Function Defined As:

a. Fractional shortening (FS) of > 25% or ejection fraction of > 50%, as determined by echocardiography or multigated acquisition scan (MUGA) within 28 days prior to study enrollment. Depending on institutional standard, either FS or left ventricular ejection fraction (LVEF) is adequate for enrollment if only one value is measured; if both values are measured, then both values must meet criteria above

• Adequate Pulmonary Function Defined As:

No evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry > 94% if there is clinical indication for determination; unless it is due to underlying pulmonary LCH

• Central Nervous System Function Defined As:

1. Patients with seizure disorder may be enrolled if on NON-enzyme inducing anticonvulsants and well controlled. Please see Appendix IX for recommended non-enzyme inducing anticonvulsants.

2. CNS toxicity ≤ Grade 2.

Exclusion Criteria:

• LCH arising along with other hematologic malignancy (e.g. mixed LCH with acute lymphoblastic leukemia) or any history of non-histiocytic malignancy.

• Disease scenarios as below will be excluded

1. Skin-limited disease

2. Single bone lesion

3. GI tract involvement only (those that have disease that can be determined by endoscopic biopsies only)

4. LCH-associated neurodegeneration (LCH-ND without parenchymal lesions or other systemic lesions)

• Exclusions for other illness

• Refractory nausea and vomiting, malabsorption, or external biliary shunt that would preclude adequate absorption of DAY101.

• Uncontrolled systemic bacterial, viral, or fungal infection.

• Major surgical procedure or significant traumatic injury within 14 days prior to study enrollment, or anticipation of need for major surgical procedure during the course of the study. Placement of a vascular access device or minor surgery is permitted within fourteen (14) days of study enrollment (provided that the wound has healed).

• History of significant bowel resection that would preclude adequate absorption or other significant malabsorptive disease.

• Ophthalmologic considerations: Patients with known significant ophthalmologic conditions or known risk factors for retinal vein occlusion (RVO) or central serous retinopathy (CSR) are not eligible.

• History of solid organ or hematopoietic bone marrow transplantation

• Clinically significant active cardiovascular disease, or history of myocardial infarction, or deep vein thrombosis/pulmonary embolism within 6 months prior to enrollment, ongoing cardiomyopathy, or current prolonged QT interval > 440 ms based on triplicate ECG average.

• History of Grade ≥ 2 CNS hemorrhage or history of any CNS hemorrhage within 28 days of study entry.

• Treatments and/or medications patient is receiving that would make her/him ineligible.

a. Cytotoxic chemotherapy

• Pregnancy and Breastfeeding

• Female patients who are pregnant are ineligible. A pregnancy test is required for female patients of childbearing potential.

• Lactating females who plan to breastfeed their infants are ineligible.

• Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation are ineligible. Participants (male and female) who are sexually active must use two forms of an acceptable method of birth control (for men, one form must be a barrier method) from start of therapy through 120 days following last dose of DAY101.

• All patients and/or their parents or legal guardians must sign a written informed consent.

• All institutional, FDA, and NCI requirements for human studies must be met.