First in Human Multicenter Open Name Dose-increase, Consolidation Method to Study Safety Drug-level in Blood & Drug Metabolism Clinical Activity of Oral JBI-778 in Lung Cancer Patients With, Without Brain Metastasis IDH Mutated WHO Grade 3,4 Recurrent Glioma, Salivary Glands Tumor

This is a phase 1, multicentre, first-in-human, open-label, dose-escalation/consolidation study to investigate the safety, pharmacokinetics, pharmacodynamics, and clinical activity of orally administered JBI-778 in EGFR mutated lung cancer patients with or without brain metastasis, IDH mutated WHO grade 3 /4 recurrent glioma and ACC with evidence of recurrent, metastatic or advanced, incurable disease arising from any primary site. A total of 42 patients will be recruited in the study. The initial dose escalation up to cohort 3 (estimate to be 160mg) or until the pharmacologically active dose is reached, whichever comes first as determined by the safety committee will be performed only in EGFR mutant NSCLC patients with or without stable cerebral metastases and ACC patients. Once this dose level is reached IDH mutant WHO grade 3 /4 glioma patients will be added. Once the RP2D is determined following dose escalation, additional patients, up to 12, will be treated at that dose to obtain further safety data and preliminary efficacy. Approximately 4 to 6 sites are anticipated for the dose-escalation/consolidation, additional sites will be evaluated as needed. Study will be initiated only after receipt of regulatory and ethics committee (EC) approval. After signing the informed consent form, the patients will undergo screening assessments to confirm eligibility. Eligible patients will be considered first for initial dose escalation and once the RP2D is determined following dose escalation, additional patients, up to 12, will be treated at that dose to obtain further safety data and preliminary efficacy. The RP2D will be establish after a detailed analysis of the totality of dose escalation data, including PK, safety, efficacy, CNS penetration based on CSF sample for study drug presence, analysis of PD markers in peripheral blood and both pre-treatment and on treatment tumor biopsies. The duration of participation for each patient will be as follows: Screening: - Up to 21 days (-21 to 1 days); Treatment period: Treatment cycle of 21-day each. Treatment may continue for up to 2 years from the start of treatment, provided that the patient experiences clinical benefit in the opinion of the Investigator and shows no signs or symptoms of unequivocal progression of the disease, unacceptable toxicity, or other reasons for study discontinuation. End of treatment (EOT)/ Early termination (ET) visit Safety Follow-up: 30 days after last dose Survival: Every 3 months

Sex

All

Minimum age

18 Years

Inclusion Criteria:

1. Male or female participants aged ≥18 years.
2. Histologically or cytologically confirmed:

   1. EGFR-mutated non-small cell lung cancer (NSCLC) with or without brain metastases previously treated with an EGFR inhibitor; or
   2. IDH-mutated WHO Grade 3/4 recurrent glioma; or
   3. Adenoid cystic carcinoma (ACC) with recurrent, metastatic, or advanced incurable disease.
3. At least one measurable lesion according to RECIST v1.1 and/or RANO criteria, as applicable.
4. ECOG performance status ≤2.
5. Adequate hematologic, hepatic, renal, and coagulation function.
6. Resolution of clinically significant toxicities from prior therapy to Grade 0 or 1, except permitted residual toxicities.
7. Life expectancy of at least 3 months.
8. Able to swallow oral medication.
9. Availability of tumor tissue and/or liquid biopsy suitable for next-generation sequencing.
10. Willing to use highly effective contraception during study participation and for at least 3 months after the last dose of study treatment.
11. Able and willing to provide written informed consent.

Exclusion Criteria:

1. Systemic anticancer therapy or investigational therapy within 2 weeks or 5 half-lives prior to study treatment.
2. Major surgery within 21 days before study treatment.
3. Radiotherapy within 4 weeks for brain metastases or within 2 weeks for other disease sites.
4. Significant uncontrolled cardiovascular, metabolic, psychiatric, or other serious medical conditions.
5. QTcF \>450 msec in males or \>470 msec in females.
6. History of optic neuritis or optic neuropathy.
7. Active HIV infection or active hepatitis B or C infection.
8. Active infection requiring systemic antibiotic therapy.
9. Use of strong CYP3A inhibitors or inducers within protocol-specified washout periods.
10. Gastrointestinal conditions that may significantly affect drug absorption.
11. Pregnancy or breastfeeding.
12. Participation in another interventional clinical study.
13. Previous treatment with JBI-778.
14. Any condition that, in the opinion of the investigator, would place the participant at unacceptable risk or interfere with study participation.