A Study of JZP815 Oral Capsules in Adult Participants With Advanced or Metastatic Solid Tumors Harboring Mitogen Activated Protein Kinase (MAPK) Pathway Alterations to Investigate the Safety, Dosing, and Antitumor Activity of JZP815

Официальное название

Phase 1, FIH, Open-label, Nonrandomized, Multicenter Study of JZP815 in Participants With Advanced or Metastatic Solid Tumors Harboring Alterations in the MAPK Pathway

Обзор

This phase 1 study will investigate the safety, dosing, and initial antitumor activity of JZP815 in participants with advanced or metastatic solid tumors harboring alterations in the MAPK pathway.

Подробное описание

This first-in-human study will consist of two parts: Part A and Part B.

Part A will characterize the safety and tolerability of JZP815, assess pharmacokinetics (PK) profile, and determine a recommended phase 2 dose (RP2D) to be further investigated in the Expansion phase (Part B).

Part B will further investigate the RP2D determined in Part A, and assess antitumor activity in various subsets of disease (based on mutation and/or tumor type) in which the mechanism of action of JZP815 is applicable.

Вмешательства

• Препарат JZP815
  JZP815 will be administered as oral capsules to participants BID approximately 12 hours apart, in the morning and in the evening. QD dosing may also be investigated, if supported by PK data.

Первичные конечные точки

• Number of Participants With Dose-Limiting Toxicities (Part A) [Срок оценки: Baseline until death, withdrawal of consent, or lost to follow-up, up to 18 months after last participant starts study intervention]
• Number of Participants With Treatment-emergent Adverse Events and Serious Adverse Events (Part A and B) [Срок оценки: Baseline until death, withdrawal of consent, or lost to follow-up, up to 18 months after last participant starts study intervention]
• Change From Baseline in Hemoglobin (Part A and B) [Срок оценки: Baseline until death, withdrawal of consent, or lost to follow-up, up to 18 months after last participant starts study intervention]
• Change From Baseline in Absolute Neutrophil Count (Part A and B) [Срок оценки: Baseline until death, withdrawal of consent, or lost to follow-up, up to 18 months after last participant starts study intervention]
• Change From Baseline in Platelets (Part A and B) [Срок оценки: Baseline until death, withdrawal of consent, or lost to follow-up, up to 18 months after last participant starts study intervention]
• Change From Baseline in Hematocrit (Part A and B) [Срок оценки: Baseline until death, withdrawal of consent, or lost to follow-up, up to 18 months after last participant starts study intervention]
• Change From Baseline in Aspartate Aminotransferase (Part A and B) [Срок оценки: Baseline until death, withdrawal of consent, or lost to follow-up, up to 18 months after last participant starts study intervention]
• Change From Baseline in Alanine Aminotransferase (Part A and B) [Срок оценки: Baseline until death, withdrawal of consent, or lost to follow-up, up to 18 months after last participant starts study intervention]
• Change From Baseline in Creatinine (Part A and B) [Срок оценки: Baseline until death, withdrawal of consent, or lost to follow-up, up to 18 months after last participant starts study intervention]
• Change From Baseline in Total Bilirubin (Part A and B) [Срок оценки: Baseline until death, withdrawal of consent, or lost to follow-up, up to 18 months after last participant starts study intervention]

Вторичные конечные точки (11)

• Pharmacokinetic Parameter Maximum Plasma Concentration (Cmax) Levels of JZP815 and its Metabolites (Part A) [Срок оценки: MTD determination cohorts, Cycle 1 Days 1 and 15: predose and 0.25,0.5,1,2,3,4,6, 8 hours (hr) postdose; 24, 48 and 72 hr postdose relative to 1st dose given on Cycle 1 Day 1; Others, Cycle 1 Days 1, 15 or 22: predose and 0.25,0.5,1,2,3,4,6,8 hr postdose]
• Pharmacokinetic Parameter Time to Maximum Plasma Concentration (Tmax) of JZP815 and its Metabolites (Part A) [Срок оценки: MTD determination cohorts, Cycle 1 Days 1 and 15: predose and 0.25,0.5,1,2,3,4,6, 8 hours (hr) postdose; 24, 48 and 72 hr postdose relative to 1st dose given on Cycle 1 Day 1; Others, Cycle 1 Days 1, 15 or 22: predose and 0.25,0.5,1,2,3,4,6,8 hr postdose]
• Pharmacokinetic Parameter Area Under the Concentration-Time Curve (AUC) of JZP815 and its Metabolites (Part A) [Срок оценки: MTD determination cohorts, Cycle 1 Days 1 and 15: predose and 0.25,0.5,1,2,3,4,6, 8 hours (hr) postdose; 24, 48 and 72 hr postdose relative to 1st dose given on Cycle 1 Day 1; Others, Cycle 1 Days 1, 15 or 22: predose and 0.25,0.5,1,2,3,4,6,8 hr postdose]
• Pharmacokinetic Parameter Apparent Terminal Elimination Half-life (t1/2) of JZP815 and its Metabolites (Part A) [Срок оценки: MTD determination cohorts, Cycle 1 Days 1 and 15: predose and 0.25,0.5,1,2,3,4,6, 8 hours (hr) postdose; 24, 48 and 72 hr postdose relative to 1st dose given on Cycle 1 Day 1; Others, Cycle 1 Days 1, 15 or 22: predose and 0.25,0.5,1,2,3,4,6,8 hr postdose]
• Pharmacokinetic Parameter Clearance (CL/F) of JZP815 (Part A) [Срок оценки: MTD determination cohorts, Cycle 1 Days 1 and 15: predose and 0.25,0.5,1,2,3,4,6, 8 hours (hr) postdose; 24, 48 and 72 hr postdose relative to 1st dose given on Cycle 1 Day 1; Others, Cycle 1 Days 1, 15 or 22: predose and 0.25,0.5,1,2,3,4,6,8 hr postdose]
• Pharmacokinetic Parameter Accumulation Ratio of JZP815 and its Metabolites (Part A) [Срок оценки: MTD determination cohorts, Cycle 1 Days 1 and 15: predose and 0.25,0.5,1,2,3,4,6, 8 hours (hr) postdose; 24, 48 and 72 hr postdose relative to 1st dose given on Cycle 1 Day 1; Others, Cycle 1 Days 1, 15 or 22: predose and 0.25,0.5,1,2,3,4,6,8 hr postdose]
• Pharmacokinetic Parameter Apparent Volume of Distribution During Terminal Phase (Vz/F) of JZP815 (Part A) [Срок оценки: MTD determination cohorts, Cycle 1 Days 1 and 15: predose and 0.25,0.5,1,2,3,4,6, 8 hours (hr) postdose; 24, 48 and 72 hr postdose relative to 1st dose given on Cycle 1 Day 1; Others, Cycle 1 Days 1, 15 or 22: predose and 0.25,0.5,1,2,3,4,6,8 hr postdose]
• Pharmacokinetic Parameter Metabolite to Parent Ratio of JZP815 and its Metabolites (Part A) [Срок оценки: MTD determination cohorts, Cycle 1 Days 1 and 15: predose and 0.25,0.5,1,2,3,4,6, 8 hours (hr) postdose; 24, 48 and 72 hr postdose relative to 1st dose given on Cycle 1 Day 1; Others, Cycle 1 Days 1, 15 or 22: predose and 0.25,0.5,1,2,3,4,6,8 hr postdose]
• Objective Response Rate (as Defined by RECIST v1.1) (Part A) [Срок оценки: Baseline until death, withdrawal of consent, or lost to follow-up, up to 18 months after last participant starts study intervention]
• Progression-free Survival (Part B) [Срок оценки: Baseline until death, withdrawal of consent, or lost to follow-up, up to 18 months after last participant starts study intervention]
• Overall Survival (Part B) [Срок оценки: Baseline until death, withdrawal of consent, or lost to follow-up, up to 18 months after last participant starts study intervention]

Критерии участия

Критерии включения

• Participant must be ≥ 18 years of age, at the time of signing the informed consent
• Participants who have histological or cytological diagnosis of an advanced or metastatic solid tumor carrying a documented, clinically significant, MAPK pathway alteration
• Participants must have exhausted all available standard of care therapies, or in the opinion of the investigator would be unlikely to tolerate or derive clinically meaningful benefit from available standard of care therapy
• Performance status (ECOG) of 0 or 1, measured within 72 hours before start of treatment. For Arm 7 (NRAS Q61 mutated anaplastic thyroid cancer) in Part B (Expansion), ECOG of 0 to 2, measured within 72 hours before the start of treatment.
• Must have measurable disease by RECIST v1.1
• Tumor must be safely amenable to core needle or excisional biopsy (applies only to participants enrolled in Pre-Expansion cohorts)
• Adequate organ function
• Expected life expectancy of at least 12 weeks
• For each arm in Part B (Expansion), participants must be diagnosed with the tumor type(s) carrying the mutation(s) specified and meet protocol specified requirements for prior therapy
• Male participants must agree to refrain from donating sperm plus either be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent or must agree to use contraception
• Female participants are eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies: is a women of nonchildbearing potential (WONCBP) or is a women of childbearing potential (WOCBP) and using a contraceptive method that is highly effective during the study intervention period and for at least 3 months after the last dose of study intervention and agrees not to donate eggs
• A WOCBP must have a negative highly sensitive pregnancy test (urine or serum) within 3 days before the first dose of study intervention
• Capable of giving signed informed consent

Критерии исключения

• Known uncontrolled brain metastases. Stable brain metastases either treated or being treated with a stable dose of steroids/anticonvulsants, with no dose change in the previous 4 weeks, are permitted
• Active fungal, bacterial and/or known viral infection including HIV or Hepatitis A, B, C
• Concomitant malignancies or previous malignancies with less than 2 years disease-free interval at the time of enrollment, with the exception of non-metastatic, non-melanomatous skin cancers, carcinoma in-situ, melanoma in-situ, prostate cancer with undetectable PSA, indolent thyroid cancer that are adequately treated
• Has clinically significant (ie, active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (> New York Heart Association Classification Class II), QTc ≥ 470 msec, or serious cardiac arrhythmia requiring medication
• Uncontrolled or severe intercurrent medical condition
• Gastrointestinal condition that could impair absorption of study intervention or inability to ingest study intervention
• In the judgement of the investigator, any important medical illness or abnormal laboratory finding that would increase the risk of participating in this study
• Received any cancer directed therapy (chemotherapy, hormonal therapy, biologic, etc.) within 28 days or 5 half-lives (whichever is shorter) of starting study intervention. For Arm 7 (NRAS Q61 mutated anaplastic thyroid cancer) in Part B (Expansion), participants who have received radio-sensitizing chemotherapy (low-dose chemotherapy) are permitted a wash-out period of 7 days or 5 half-lives, whichever is shorter (a discussion with the sponsor is required). Participants who have received radiotherapy must have recovered from acute toxicities associated with treatment.
• Use of any products or medicines known to be strong or moderate inducers or inhibitors of CYP3A4, which cannot be discontinued at least 4 weeks or 5 half-lives (whichever is shorter) before starting study intervention, or planned use at any time during the study
• Use of proton pump inhibitors (eg, omeprazole) and histamine-2 receptor antagonists (eg, famotidine), which cannot be discontinued at least 2 weeks before first dose, or planned use at any time during the study
• Concurrent therapy with any other investigational agent

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Последовательный дизайн

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 15 центров

• Valkyrie Clinical Trials — Los Angeles
• SCRI HealthOne — Denver
• Florida Cancer Specialists - Lake Nona — Orlando
• Florida Cancer Specialists - Sarasota — Sarasota
• University of Chicago — Chicago
• NYU Langone Health — New York
• Icahn School of Medicine at Mount Sinai — New York
• Oklahoma University — Oklahoma City
• … и ещё 7 центров

Идентификаторы

NCT: NCT05557045 · JZP815-101

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗