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
brief summary
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
detailed description
Dose-Escalation:
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 mutated WHO grade 3 /4 glioma patients will be added. The starting dose of JBI-778 is 40 mg orally, once daily in 21-day treatment cycles using a 3+3 design. Dose escalation will be 100% until dose level 3 (i.e., 160 mg) afterwards, a maximum of 33%-75% dose increment will be implemented (up to 75% dose increment if no dose limiting toxicity (DLT), but 33% dose increment if one DLT is observed in the previous dose level, applicable to any dose level not just after 160mg), rounded up or down based on capsule strength. With these restrictions, the next dose to be studied will be determined by the sponsor with approval by the Safety Review Committee (SRC). In the event that any DLTs occur at the starting dose in 2 patients, and with the approval of the SRC, a 20 mg once daily dose level will be evaluated using a 3+3 design. If 20 mg once daily is not tolerated, no further patients will be recruited, and the study will be terminated. In addition to the PK evaluation, patients in dose-escalation will provide pre-treatment and on treatment tissue and/or liquid biopsies to aid in the assessment.
In the 3+3 design, if 3 patients at a dose level complete the DLT evaluation period with no DLT, that dose level of JBI-778 will be deemed safe, and another 3 patients will be treated at the next higher dose level. If 1 of the first 3 patients experience a DLT, 3 more patients will be treated at the same JBI-778 dose level. If 2 or more of the 3 to 6 patients in any dose level experience a DLT, dosing will stop at that level, and either the previous dose level will be considered the Maximum Tolerated Dose (MTD) or intermediate doses may be explored to determine MTD, especially if the difference between the non-tolerated dose and the previous dose is \> 50%.
Dose-escalation will continue until any of the following events occur:
* The highest planned dose level is determined to be safe and tolerable (Minimum of 6 DLT evaluable patients). * An MTD is identified. Additional dose levels may be explored based on emerging data (Additional patients (up to 6 patients may be enrolled in 1 or more dose levels that have been shown to be safe and tolerable, defined as backfill enrolment). This backfill enrolment will be done to better estimate the RP2D and to better characterize the safety, efficacy, PK and pharmacodynamics (PD) for JBI 778 and may be concurrent with dose-escalation to identify the MTD. Study patients who do not complete the DLT period for reasons other than study drug toxicity will be replaced. All patients will be assessed for a response using relevant RECIST 1.1 and RANO criteria. Clinical status will be assessed by the NANO instrument. Intra-patient dose-escalations are allowed in this study. Patients who complete the DLT period, tolerate the dose, and have been on the treatment for ≥ 2 cycles without significant toxicities may proceed to a higher dose level for the following treatment cycle if the next dose cohort is deemed safe (For both acute and cumulative toxicities) at that time by the Safety Review Committee (SRC), and after consultation with the Sponsor if the patient has not experienced any ≥ Grade 2 adverse events (deemed treatment-related by the Investigator) during entire prior treatment. The maximum Intra-patient Dose-Escalation level should be one level below the current actively enrolling dose level if tolerability based on the protocol defined criteria have not yet been established. Patients who do not proceed to a higher dose may continue to receive additional cycles at their original dose, based on the decision of the investigator and concurrence by the SRC. An SRC will have oversight of safety and will meet at the end of each cohort and approximately quarterly and as needed during the dose-escalation phase to review cumulative toxicity data, make recommendations to the Sponsor regarding ongoing safety and dose-escalations. The SRC may recommend protocol amendments to maintain patient safety at any stage. In addition, any serious adverse events (SAEs) will be forwarded to the SRC upon occurrence. Safety and tolerability of JBI-778 will be characterized by adverse event and serious adverse event type, severity (graded using the National Cancer Institute Common Terminology Criteria for Adverse Events \[NCI CTCAE\] Version 5.0), timing, and relationship to study therapy, and laboratory abnormalities in the first and in subsequent cycles. Administration of JBI-778 may continue until evidence of disease progression, intolerance to study medication, or withdrawal of consent. Stable or responding patients who experience DLTs may continue therapy once DLTs have resolved.
official title
A Phase 1, Multicenter, 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, Isocitrate Dehydrogenase (IDH) Mutated WHO Grade 3/4 Recurrent Glioma and Adenoid Cystic Carcinoma (ACC)