IRB Study Number 24-531
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objectives
To evaluate the safety and tolerability, and to determine the MTD of JAB-30355 monotherapy administered in participants with advanced solid tumors harboring TP53 Y220C mutation.
Secondary Objectives
To characterize the pharmacokinetic (PK) profiles of JAB-30355 after a single dose and at steady state after multiple doses.
To evaluate preliminary antitumor activity of various dose levels JAB-30355 monotherapy in participants with advanced solid tumors harboring TP53 Y220C mutation.
To characterize the effect of food on JAB-30355.
Inclusion Criteria
Written informed consent, according to local guidelines, must be signed and dated by the participant prior to the performance of any study-specific procedures, sampling, or analyses.
Participant must be ≥18 years of age at the time of signing the Informed Consent Form (ICF).
Participant has an ECOG performance status score of 0 or 1.
Participant must have a life expectancy ≥3 months.
Participant is required to provide an archived tumor sample (formalin-fixed, paraffin embedded [FFPE] sample collected within 5 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.
Participant has histologically or cytologically confirmed metastatic or locally advanced solid tumor that is not a candidate for curative intervention.
Has been treated with at least one line of systemic therapy for that tumor type and stage.
Have documentation of confirmed TP53 Y220C mutation (blood and/or tissue tests are acceptable).
TP53 treatment naïve (Dose Expansion/Phase 2a only).
Have confirmed KRAS wild type tumor (Dose Expansion/Phase 2a only).
Specific inclusion criteria for food effect assessment cohort only:
a. Must be able to eat a standardized high fat, high caloric meal within 30 minutes.
b. Must be able to fast for at least 10 hours.
c. Must be able to handle urine collection over a 24-hour period.
Participants must have at least 1 measurable lesion as defined by RECIST v1.1. Tumor lesions that have been irradiated ≥4 weeks before the start of treatment, and have subsequently had documented progression, may be chosen as target lesions in the absence of measurable lesions that have not been irradiated (see Appendix 13.5).
Participants must have laboratory data that meet the following criteria:
a. Absolute neutrophil count ≥1.5 × 109/L
b. Platelet count ≥100 × 109/L
c. Hemoglobin ≥9 g/dL
d. Albumin ≥3.0 g/dL
e. Total bilirubin ≤1.5 × ULN (with Gilbert’s syndrome, ≤2.0 × ULN)
f. AST and ALT ≤1.5 × ULN (with presence of liver metastases, ≤3 × ULN)
g. PT and PTT <1.5 × ULN and INR <1.5 if the participant is not on anticoagulants, or INR <3 after dose titration has been completed if the participant is on anticoagulants
h. Adequate kidney function with estimated creatinine clearance of > 60 mL/min (measured using Cockcroft-Gault equation; see Appendix 13.4).
Women of childbearing potential must have a negative serum pregnancy test prior to study entry. Women of nonchildbearing potential must 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 the last dose of JAB-30355. Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study intervention. Male participants must also refrain from donating sperm during their participation in the study and for 3 months following the last dose of JAB-30355 (see
Appendix 13.7).
- Participants must be able to swallow and retain orally administered medication.
Exclusion Criteria
Participant has a history (≤2 years) of solid tumor or hematological malignancy that is histologically distinct from the cancers under study, except for cervical carcinoma in situ, superficial noninvasive bladder tumors, breast ductal carcinoma in situ, prostatic intraepithelial neoplasia without evidence of prostate cancer, or curatively treated Stage I nonmelanoma skin cancer.
Participant has known serious allergy to JAB-30355 or their components.
Participant has brain or spinal metastases except if treated by surgery, surgery plus radiotherapy or radiotherapy alone, with no evidence of radiographic progression or hemorrhage for at least 28 days before the start of treatment with the study drug.
Participants with symptomatic/neurologic dysfunction that would inhibit evaluation of neurological and/or other AEs.
Diagnosis of primary CNS tumor.
History of spinal cord compression or leptomeningeal disease.
Active infection requiring systemic treatment within 7 days of the first study treatment in this trial.
Known human immunodeficiency virus (HIV) infection or positivity on immunoassay.
Note: Testing for seropositive status during Screening will be at the discretion of the investigator in participants without previously reported results.
Has active infection of hepatitis B virus (HBV) or hepatitis C virus (HCV). Note: Participants will be tested for HCV antibody and HBV surface antigen at Screening. Additional HBV and HCV serological testing will be done at the discretion of the investigator. Note: Participants with HBV who have controlled infection (serum HBV DNA PCR that is below the limit of detection) are permitted. Participants with controlled infections must undergo periodic monitoring of HBV DNA. Note: Participants who are HCV antibody positive who have controlled infection (undetectable HCV RNA by PCR either spontaneously or in response to a successful prior course of anti-HCV therapy) may be enrolled into the study. Participants with controlled infections must undergo periodic monitoring of HCV RNA by their treating physician.
History (≤6 months before the start of treatment) of any severe and/or uncontrolled medical conditions or other conditions that, in the opinion of the investigator and sponsor, could affect the participant’s participation in the study such as the following:
a. Nonmalignant illnesses that are uncontrolled or whose control may be jeopardized by this study drug.
b. Nonmalignant decompensated liver disease
c. Significant gastrointestinal abnormalities or a chronic condition, including delayed gastric emptying, chronic active Crohn’s disease that requires steroid therapy at any dose, refractory nausea, vomiting, and/or prior surgical procedures affecting absorption or requirement for IV alimentation.
History (≤6 months before the start of treatment with the study drugs) of any of the following: acute myocardial infarction, unstable angina pectoris, coronary artery bypass graft, or cerebrovascular accident (except for asymptomatic lacunar infarction or transient ischemic attack).
Participants who have impaired cardiac function or clinically significant cardiac diseases, including any of the following:
a. Significant ventricular or supraventricular arrhythmias (participants with sinus arrhythmia or chronic rate-controlled atrial fibrillation in the absence of other cardiac abnormalities are eligible)
b. Left ventricular ejection fraction (LVEF) ≤50% assessed by ECHO or MUGA within 6 months before the start of treatment with the study drug and at Screening.
c. Other clinically significant heart disease such as congestive heart failure New York Heart Association Class III-IV
Participants with QT interval >470 msec at Screening using QTcF, determined as the mean of 3 QTcF values from the screening triplicate ECG.
Participants experiencing unresolved Grade >1 toxicity secondary to prior systemic treatment before the first dose of JAB-30355 except for hair loss (alopecia), stable Grade 2 neuropathy, and ongoing stable Grade 2 endocrinopathies secondary to prior systemic treatment, other stable immune related AEs, and Grade >1 abnormal lab results which are not considered clinically significant by the Investigator and Medical Monitor, may be allowed after discussion with and approval from the medical monitor.
Electrolyte abnormalities ≥ Grade 3 (potassium, sodium, calcium, magnesium) that have not been corrected within 3 days prior to the first dose.
Women who are pregnant or breast-feeding.
Has received or will receive a live vaccine within 30 days prior to the first administration of study medication. Seasonal flu vaccines that do not contain live vaccine are permitted.
Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
Prior and Concomitant Therapy
History of an allogeneic bone marrow or solid organ transplant.
Use of systemic anticancer agent or investigational drug is prohibited ≤21 days prior to the first dose of JAB-30355 for all solid tumors.
History of therapeutic radiation therapy ≤28 days, or palliative radiation therapy ≤14 days prior to the first dose of study drug.
Prophylactic administration of agents for hematopoietic support such as granulocyte colony stimulating factor (G-CSF), filgrastim, pegfilgrastim, blood transfusion, platelet packets, erythropoietin, thrombopoietin, interleukin-11, etc., are not allowed during ≤2 weeks before the start of treatment and during Cycle 1 of the Dose Escalation Phase (Phase 1; limited to DLT evaluable participants only).
Use of drugs known to be moderate or strong CYP3A4 inhibitors or inducers or sensitive CYP3A4 substrates or CYP3A4 substrates with a narrow therapeutic index is prohibited ≤14 days or 5 half-lives, whichever is longer, before the start of treatment with the study drug until end of treatment (EOT). Some of these medications may be allowed at the investigator’s discretion after approval by the medical monitor (see Appendix 13.8).
Use of herbal drugs and supplements known to be moderate or strong CYP3A4 inhibitors or inducers or sensitive CYP3A4 substrates or CYP3A4 substrates with a narrow therapeutic index, or have another potential for clinically significant interaction with JAB-30355 are prohibited ≤14 days or 5 half-lives, whichever is longer, before the start of treatment with the study drug until EOT (see Appendix 13.8). These herbal medications include but are not limited to St John’s wort, grapefruit and products, cannabis (including “medical marijuana”), kava, ephedra (ma huang), gingko biloba, DHEA, yohimbe, saw palmetto, black cumin, and ginseng.
History (14 days or five half-lives, whichever is longer, before the start of treatment with the study drug) of use with medications that are known to be inhibitors or inducers of P-gp (see Appendix 13.8).
History (≤28 days before the start of treatment with the study drugs) of major surgery or trauma or likelihood to require surgery at any time until the permanent discontinuation of treatment (the significance will be determined by the investigator after consultation with the medical monitor).
History (14 days or 5 half-lives, whichever is longer, before the start of treatment with the study drugs) of medications with known risk of Torsades de Pointes (cardiac arrhythmia due to drug-induced QTc prolongation) (see Appendix 13.9).
Use of agents that suppress gastric acidity (H2-receptor antagonists, proton pump inhibitors, and/or intraluminal antacids) and agents that delay gastric emptying within 3 days or 5 half-lives (whichever is longer) prior to start of treatment (see Appendix 13.10).
