IRB Study Number 25-358
Status Recruiting
Phase Phase 1
Location Cleveland Clinic Main Campus
Institute Taussig Cancer Institute
Description
Primary Objectives
To determine the MTD of JAB-23E73 monotherapy.
To evaluate the overall safety and tolerability of JAB-23E73.
Secondary Objectives
To evaluate preliminary antitumor activity of various dose levels of JAB-23E73 in participants with advanced solid tumors.
To characterize the PK profile of JAB-23E73.
Inclusion Criteria
Written informed consent form (ICF), according to local guidelines, signed and dated by the participant or legally authorized representative prior to the performance of any study-specific procedures, sampling, or analyses.
Participant must be ≥18 years of age at the time of signature of the informed consent form.
Histologically or cytologically confirmed locally advanced or metastatic solid tumors that are not suitable for curative interventions (surgery, radiation or chemotherapy). Prior treatment must meet the following criteria,
Dose Escalation Phase (Phase 1a)
− Advanced or metastatic solid tumors that have exhausted all standard therapeutic options or will not benefit from standard therapy at the discretion of the investigator.
Dose Expansion/Optimization Phase (Phase 1b)
− Advanced or metastatic NSCLC that have progressed after at least one available standard therapy or are intolerant to the standard therapy, or lack of standard therapy, or will not benefit from standard therapy at the discretion of the investigator.
Indication Expansion Phase (Phase2a)
− Cohort C1: participants with CRC who have received at least therapies for advanced or metastatic disease including fluoropyrimidine-, oxaliplatin-, and irinotecan-based regimens.
− Cohort C2: PDAC participants who have received at least 1 prior regimen for advanced or metastatic disease including either gemcitabine-based treatment or FOLFIRINOX or mFOLFIRINOX or NALIRIFOX.
− Cohort C3: Other advanced or metastatic solid tumors that have progressed after at least one available standard therapy or are intolerant to the standard therapy, or lack of standard therapy, or will not benefit from standard therapy at the discretion of the investigator.
Participants must have KRAS alterations. Eligible alterations include G12X, G13D, Q61H mutations, and wild-type amplification (defined as the copy number of KRAS gene ≥4 by next-generation sequencing or the ratio of KRAS to CEP12 ≥2 by fluorescence in situ hybridization). Documentation of these alterations must be provided by prior test results (either from tissue testing or blood testing) or prospective test results from the central laboratory prior to enrollment. Participants with other gene alterations may be enrolled at the sponsor's discretion.
Participants are required to provide an archived tumor sample (formalin-fixed, paraffin embedded [FFPE] sample collected within 3 years). If archival tumor tissue is not available, tumor tissue from a newly obtained tumor biopsy (within 28 days of C1D1) will be optional if deemed safe and accessible by the investigator.
Participants with a life expectancy ≥3 months.
ECOG performance status score of 0 or 1.
Participants must have at least one measurable lesion as defined by RECIST v1.1.
Note: Selected target lesions should have not been treated with local therapy, or if the selected target lesion is in an area previously treated with local therapy, then it should have documented disease progression after treatment with local therapy according to RECIST v1.1.
- Participant whose laboratory data must meet the following criteria:
a) Absolute neutrophil count ≥ 1.5×109/L
b) Hemoglobin ≥ 9 g/dL
c) Platelets ≥ 100×109/L
d) Serum bilirubin ≤ 1.5× upper limit of normal (ULN), or ≤ 2.0 × ULN for participants with Gilbert’s syndrome and a direct bilirubin ≤ 1.5× ULN.
e) AST and ALT ≤ 1.5×ULN (with presence of liver metastases, ≤ 3×ULN)
f) International normalization ratio (INR) <1.5 if the participant is not on anticoagulants, or INR <3 if the participant is on anticoagulants.
g) Estimated glomerular filtration rate (eGFR) ≥60mL/min (see Appendix 5 for details).
Women of childbearing potential (WOCBP) must have a negative serum pregnancy test prior to study entry. Women of non-childbearing potential will have had at least 12 continuous months of natural (spontaneous) amenorrhea, and an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms), or have had surgical bilateral oophorectomy, hysterectomy, or bilateral tubal ligation >6 weeks prior to screening.
Male or female participants: Male participants with female partners of childbearing potential and female participants of childbearing potential are required to use 2 forms of acceptable contraception, including 1 barrier method, during their participation in the study and for 3 months following last dose. Male participants must also refrain from donating sperm during their participation in the study until 3 months after their last dose of investigational product.
Exclusion Criteria
Medical Conditions
Inability to swallow oral medications, or presence of gastrointestinal dysfunction or gastrointestinal disorders that may significantly alter the absorption of the investigational product (e.g., active inflammatory bowel disease, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome).
History (≤2years) of solid tumor or hematological malignancy that is histologically distinct from the cancers under study, except for cervical carcinoma in situ, superficial non-invasive bladder tumors, or curatively treated Stage I non-melanoma skin cancer or other tumors that have been cured with recurrence of less than 10% within 3 years and agreed by investigator or medical monitor.
Participants who have previously been treated with KRAS G12C inhibitors, KRAS G12D inhibitors, or pan/multi-KRAS inhibitors, as well as similar compounds, are not eligible for the study.
Known serious allergy to JAB-23E73 or excipient.
Participants with primary central nervous system tumors.
Participants with active central nervous system (CNS) metastases are generally excluded, with the following exceptions:
a. Participants who have received adequate prior therapy (radiation or surgery) for CNS metastases, demonstrate radiographic stability for at least 4 weeks, and are free of neurological clinical symptoms are eligible for enrollment.
b. Enrollment is permitted for participants with newly identified CNS metastases at screening if they have undergone radiation therapy or surgery, are clinically stable or asymptomatic for at least 2 weeks post-treatment, and do not require steroid therapy.
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures or medical intervention (clinically significant recurrence requiring additional intervention within 2 weeks of intervention).
Presence of infection requiring systemic antibacterial, antifungal or antiviral treatment ≤7 days prior to the first dose.
Known current infection or history of human immunodeficiency virus (HIV).
Participants with hepatitis B virus (HBV) infection and HBV-DNA levels above the upper limit of normal at their site, or those with active hepatitis C virus (HCV) infection.
Participants who are inactive HBV carriers or have stable disease after receiving appropriate treatment, with detectable hepatitis B surface antigen (HBsAg) but HBV DNA levels below the upper limit of normal at their site, or those with inactive HCV infection, may be enrolled. Prophylactic antiviral therapy should be administered in accordance with local guidelines. Participants with controlled viral infections must undergo regular monitoring of HBV DNA and HCV RNA levels by their treating physician.
- Participants who have impaired cardiac function or vascular dysfunction, or clinically significant cardiac diseases, including any of the following:
a. History (≤ 6 months before the start of the investigational products) of diseases including acute myocardial infarction, unstable angina pectoris, or cerebrovascular accident.
b. Clinically significant ventricular or supraventricular arrhythmias (participants with sinus arrhythmia or rate-controlled atrial fibrillation in the absence of other cardiac abnormalities are eligible).
c. Left ventricular ejection fraction (LVEF) ≤ 50% assessed by echocardiogram (ECHO) or multigated acquisition scan (MUGA).
d. Resting bradycardia (<50 beats per minute) determined as the mean of 3 heart rate values from the screening triplicate 12-lead ECGs obtained.
e. Other clinically significant heart disease such as heart failure with a New York Heart Association Class > class II (see Appendix 6 for New York Heart Association Functional Classification).
Participants with QT interval >470 msec at Screening using Fridericia’s formula (QTcF), determined as the mean of 3 QTcF values from the screening triplicate ECG.
Participants experiencing unresolved Grade >1 toxicity before the start of investigational product except for hair loss (alopecia), Grade 2 peripheral neuropathy, hemoglobin 9 to 10 g/dL, and hypothyroidism that requires thyroid hormone supplements but is asymptomatic under stable therapy, adrenocortical hypofunction managed with a stable dose of hormone replacement therapy, controlled type 1 diabetes mellitus, and Grade >1 abnormal laboratory results which are not considered clinically significant by the investigator and medical monitor.
Women who are pregnant or breast-feeding.
Participants with current alcohol or substance abuse, or psychiatric disorders that interfere with compliance or the accuracy of study results.
Participants with interstitial lung disease (ILD) requiring steroid therapy, prior history of radiation pneumonia, or evidence of clinically active ILD.
Prior and Concomitant Therapy
History of an allogeneic bone marrow or solid organ transplant.
Use of anticancer agent is prohibited ≤28 days for biologics and other investigational drugs, or ≤14 days or 5 half-lives (whichever is longer) for small molecule targeted drugs, chemotherapy and other medicines (except for hormonal therapy for prostate cancer and breast cancer, and therapy for bone metastases or cancer-related hypercalcemia), prior to the first dose of JAB-23E73.
Participants who have received radiation therapy ≤28 days prior to the first dose or are scheduled to receive radiation therapy during the study are not allowed, except for those received palliative radiation therapy limited to non-target lesions ≥14 days prior to the first dose.
20.History (≤28 days before the start of investigational product) of major surgery or trauma or likelihood to require significant surgery at any time until the permanent discontinuation of treatment (the significance will be determined by the investigator after consultation with the medical monitor).
21.Participants who received erythropoietin (EPO), granulocyte colony-stimulating factor (G-CSF), or thrombopoietin (TPO) or thrombopoietin receptor agonist (TPO-RA) ≤14 days before start of investigational product.
22.History of transfusion of whole blood, red blood cells or platelet packets ≤14 days before start of investigational product.
23.Use of drugs known to be strong inhibitors or strong inducers of CYP3A, or sensitive CYP3A substrates, or CYP3A substrates with a narrow therapeutic index within 14 days or 5 half-lives, whichever is longer, prior to first dose, and throughout the trial, and until 14 days or 5 half-lives (whichever is longer) after the last dose (see Appendix 7).
24.Use of drugs known to be inhibitors of P-gp and BCRP within 14 days or 5 half-lives(whichever is longer) prior to first dose, throughout the trial, and until 14 days or 5 half-lives (whichever is longer) after the last dose (see Appendix 7).
25.Use of drugs known to be H2-receptor antagonists and PPIs within 3 days or 5 half-lives(whichever is longer) prior to start of treatment, throughout the trial, and until 3 days or 5 half-lives (whichever is longer) after the last dose (see Appendix 8).
26.History (≤14 days before the start of the investigational products) of medications with known risk of Torsades de Pointes.
27.Other conditions that are judged by the investigator to be ineligible for enrollment.
