IN10018 in Combination With Dalpiciclib for Progressive Meningiomas

An Open-Label Phase Ib Clinical Study Evaluating the Safety, Tolerability, and Efficacy of IN10018 in Combination With Dalpiciclib in Participants With Progressive Meningiomas

This open-label Phase Ib study will evaluate the safety, tolerability, and preliminary effectiveness of IN10018 in combination with dalpiciclib in adults with progressive meningiomas. Progressive meningiomas are tumors arising from the membranes surrounding the brain that have continued to grow or have returned after previous treatment.

Participants will receive both study drugs by mouth in 28-day treatment cycles. IN10018 will be taken once daily throughout each cycle, and dalpiciclib will be taken once daily for 21 days followed by 7 days without dalpiciclib. Treatment may continue until the tumor progresses, unacceptable side effects occur, or another reason for stopping treatment applies.

The study includes a dose-confirmation phase and a dose-expansion phase. The main goals are to evaluate side effects and determine a recommended dose of the combination for further study. Researchers will also assess whether the treatment can shrink tumors or delay tumor growth, measure how the drugs are processed in the body, and explore tumor and blood biomarkers that may be associated with treatment response.

Inclusion Criteria:

Inclusion Criteria:

Participants must be able to understand and willing to sign a written informed consent form and agree to comply with all study requirements. Written informed consent must be obtained before any study-related examination or procedure is performed.

Aged 18 years or older, male or female.

Histologically confirmed meningioma meeting at least one of the following conditions:

1. World Health Organization (WHO) Grade 2 or Grade 3 meningioma; or
2. WHO Grade 1 meningioma that has recurred after surgery or radiotherapy and demonstrates clear radiographic or clinical progression, as determined by the investigator.

No available standard treatment option, or failure of standard treatment, including surgery, radiotherapy, or other systemic therapy.

At least 24 weeks must have elapsed since completion of radiotherapy, including external beam radiation therapy, brachytherapy, or radiosurgery such as Gamma Knife or CyberKnife.

At least one measurable lesion according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), as confirmed by the investigator.

Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. Estimated life expectancy of at least 3 months, as determined by the investigator.

Adverse effects caused by previous treatments must have recovered to Grade 1 or lower according to the Common Terminology Criteria for Adverse Events (CTCAE), except for alopecia and fatigue.

The dose of corticosteroids or other hormonal treatment must have been stable for at least 4 days before enrollment.

Adequate hematologic and organ function, based on laboratory tests performed within 7 days before the first dose, as follows:

Hematologic function:

1. Hemoglobin of at least 100 g/L, without dependence on red blood cell transfusion or erythropoietin.

2. Platelet count of at least 100 × 10^9/L, without dependence on platelet transfusion.

3. Absolute neutrophil count of at least 1.5 × 10^9/L, without the use of colony-stimulating factors.

   Hepatic function:

4. Total bilirubin no greater than the upper limit of normal.

5. Alanine aminotransferase and aspartate aminotransferase no greater than 2.5 times the upper limit of normal.

   Renal function:

6. Serum creatinine no greater than 1.5 times the upper limit of normal.

7. Either creatinine clearance calculated using the Cockcroft-Gault formula of at least 60 mL/min or estimated glomerular filtration rate calculated using the Modification of Diet in Renal Disease formula of at least 60 mL/min/1.73 m².

   Urinary protein and coagulation function:

8. Urine protein negative or trace. Participants with urine protein of 1+ must have a morning spot urine protein-to-creatinine ratio of less than 0.5 or 24-hour urinary protein of less than 0.5 g/24 hours.

9. International normalized ratio no greater than 1.5 and activated partial thromboplastin time no greater than 1.5 times the upper limit of normal.

Female participants must not be pregnant or breastfeeding and must meet one of the following conditions:

1. Not be a woman of childbearing potential; or
2. If a woman of childbearing potential, agree to follow the protocol-specified contraceptive requirements during study treatment and for 3 months after the last dose.

Exclusion Criteria:

Major surgery or major trauma within 28 days before the first dose, or diagnostic biopsy within 14 days before the first dose.

Receipt of systemic anticancer treatment, including an investigational drug, within the protocol-specified washout period, including chemotherapy or targeted therapy within 14 days or 5 half-lives before the first dose, whichever is shorter, or immunotherapy within 28 days before the first dose.

Previous treatment with a focal adhesion kinase inhibitor or a cyclin-dependent kinase 4/6 inhibitor, including dalpiciclib.

A serious cardiovascular event or clinically significant cardiovascular condition within 6 months before initiation of study treatment, including but not limited to:

1. Left ventricular ejection fraction below 50%;
2. Corrected QT interval greater than 480 milliseconds;
3. New York Heart Association functional class 2 or higher;
4. History of serious arrhythmia or cardiomyopathy. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage. Participants with small-volume effusions detectable only by imaging may be considered eligible.

Malabsorption syndrome or inability to take oral medication. Serious gastrointestinal disease, including uncontrolled inflammatory gastrointestinal disease, active Crohn disease, active ulcerative colitis, or uncontrolled gastrointestinal bleeding.

Active infection that is not adequately controlled by systemic treatment. Known human immunodeficiency virus infection. Human immunodeficiency virus testing is not required during screening unless mandated by local regulations or institutional policy.

Known active hepatitis B virus or hepatitis C virus infection. Hepatitis B virus and hepatitis C virus testing is not required during screening unless mandated by local regulations or institutional policy.

Any medical history, treatment, laboratory abnormality, or other condition that, in the investigator's judgment, could confound interpretation of the study results, interfere with participant compliance, or compromise the participant's safety or interests.

Known psychiatric illness or substance abuse that could interfere with compliance with study requirements.

Known hypersensitivity to IN10018, dalpiciclib, or any component of either study drug.

Systemic treatment with a strong inhibitor or inducer of CYP3A4, CYP2D6, or P-glycoprotein within 14 days before the first dose, or anticipated need for such treatment during the study treatment period.