IRB Study Number 23-079
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objectives
Determine the MTD, select an RP2D, and evaluate safety and tolerability of PC14586
Secondary Objectives
Characterize the PK of PC14586 when administered orally
Describe the concentrations of PC14586 and major metabolite (M1) when PC14586 is administered orally
Evaluate the preliminary efficacy of PC14586 using tumor response criteria
Inclusion Criteria
Patient is at least 18 years of age, or 12 to 17 years of age under the following condition: patients 12 to 17 years of age and ≥ 40 kg may enroll in the study during the mTPI portion of Phase 1 and Phase 2 upon SRC approval, which may occur only after at least 3 adult patients have been treated with PC14586 for a minimum of one 21-day treatment cycle, including at least one adult patient treated with PC14586 for at least one treatment cycle at the same dose of PC14586 proposed for the adolescent.
Patient understands the study procedures and agrees to participate by giving written, signed, and dated informed consent or assent if < 18 years of age, prior to any mandatory study-specific procedures, sampling, or analysis.
• For adolescent patients aged 12 to 17 years, a parent/guardian or legally authorized representative must understand the study procedures and agree to the adolescent patient’s participation in the study by giving written, signed, and dated informed consent to accompany the patient’s assent, before initiation of any protocol-related procedures.
Patient has an ECOG status of 0 or 1 (Section 12.1.8).
Patient has a histologically or cytologically confirmed advanced solid malignancy with a TP53 Y220C mutation identified through Sponsor-approved NGS molecular test performed at a CLIA certified (or equivalent) laboratory.
Patients must have been previously treated with one or more lines of standard of care (SOC) anticancer therapy and have documented disease progression during or after their most recent line of anticancer therapy. In addition, either there is no SOC therapy for the patient or SOC therapies are deemed unlikely to be tolerated or result in clinically meaningful benefit by the Investigator. Typical therapies for certain tumor types are listed in Section 8.3.
Patients with CRPC must have ongoing androgen deprivation therapy with a gonadotropin-releasing hormone analog or inhibitor, or orchiectomy (medical or surgical castration).
Patient has adequate organ function as defined as:
• Hepatic: total bilirubin ≤ 1.5 x upper limit of normal (ULN) or direct bilirubin ≤ 1.5 x ULN for patients with Gilbert’s syndrome, ALT and AST ≤ 3.0 x ULN for patients without liver metastasis and ≤ 5.0 x ULN for patients with liver metastasis;
• Renal: Estimated creatinine clearance must be ≥ 30 mL/min (calculated by using the Cockcroft-Gault equation for adults and adolescents);
• Bone marrow: ANC ≥ 1.5 x 109/L, platelet count ≥ 100 x 109/L, and hemoglobin ≥ 8 g/dL.
• Serum potassium, calcium, magnesium, and phosphorus within normal limits or ≤ Grade 1. If values are low on the initial screening assessment, supplements may be given and values repeated to confirm within normal limits or ≤ Grade 1.
- Female patients of childbearing potential must have a negative urine or serum pregnancy test within 3 days prior to first dose of study drug or be of non-childbearing potential. Non-childbearing potential is defined as:
• Postmenopausal, defined as no menses for 12 months without an alternative medical cause. A follicle-stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormone replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.
• Surgically sterile.
• Adolescents aged 12 to 17 who are Tanner Stage I or Stage II and are premenarchal.
Patients who are females of childbearing potential must use a highly effective method of contraception for the course of the study, or agree to be abstinent, from 14 days prior to the first dose of study drug through 3 months after the last dose of study drug. Highly effective methods of contraception include (1) oral, injected, or implanted hormonal methods of contraception, (2) intrauterine device, (3) intrauterine hormone-releasing system, (4) bilateral tubal occlusion, (5) vasectomized partner with verified absence of sperm in ejaculate post-vasectomy. Barrier contraception (including male and female condoms with or without spermicide) is not considered a highly effective method of contraception. If used, this method must be used in combination with another acceptable method listed above.
Patients who are males and have a female partner of childbearing potential must agree to use a highly effective method of contraception as described in inclusion criterion 9, starting with the first dose of study drug through 3 months after the last dose of study drug, unless confirmed to be azoospermic (vasectomized or secondary to medical cause), or agree to be abstinent.
Patients must be willing to undergo a tumor biopsy during screening for NGS if an archival tumor specimen is not available and if the procedure is in line with standard of care (i.e., of low risk and the tumor is of sufficient size to be biopsied).
Patients in Phase 2 Cohort A must meet the following additional criterion:
- Measurable disease per RECIST v1.1 (Eisenhauer, 2009) as assessed by the Investigator, with the last imaging performed within 28 days before C1D1.
Adolescent Patients
Patients who are 12-17 years of age and ≥ 40 kg are eligible for enrollment in the mTPI portion of Phase 1 and Phase 2 with SRC approval, and only after at least 3 adult patients have completed at least one 21-day treatment cycle of PC14586, and only after at least one adult patient has been treated with PC14586 for at least one 21-day treatment cycle at the same dose of PC14586 proposed for the adolescent. In addition, a pediatric oncologist will join the SRC prior to enrollment of a patient 12 to 17 years of age.
Before any protocol-related procedures are performed, adolescent patients must have a parent/guardian or legally authorized representative who understands the study procedures and agrees to the adolescent patient’s participation in the study give written, signed, and dated informed consent to accompany the patient’s assent.
Exclusion Criteria
Patient has received prior chemotherapy, targeted therapy, immunotherapy, or treatment with an investigational anticancer agent within 21 days or 5 half-lives (if half-life is known), whichever is shorter, before receiving their first dose of study drug.
Patient has received radiotherapy within 28 days.
Patient has a primary CNS tumor. Exception: Patients with primary CNS tumors are permitted in Phase 2 Cohort B if they are neurologically stable and do not require steroids to treat associated neurological symptoms.
Patient has history of leptomeningeal disease or spinal cord compression.
Patient has brain metastases. Exception: Patients with brain metastases are permitted if they are neurologically stable and do not require steroids to treat associated neurological symptoms.
Patient has had a stroke or transient ischemic attack within 6 months prior to screening.
Patient has had one or more of the following cardiac criteria:
• Unstable angina
• Myocardial infarction within 6 months prior to screening
• New York Heart Association Class II or greater congestive heart failure (Appendix 1)
• QT interval corrected (QTc) using Fridericia’s formula (QTcF) > 470 msec obtained as the mean from 3 consecutive resting ECGs. Exception: A QTcF value corrected for wide QRS > 120 msec (QTcFBBB) should be used in place of QTcF for patients with non-clinically significant wide QRS > 120 msec due to a pacemaker or bundle branch block.as described in Section 12.1.7.
• Clinically significant abnormalities in rhythm, conduction, or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block)
• Congenital long QT syndrome
• Uncontrolled hypertension.
- Patient treated with any of the following medications prior to receiving PC14586 within the below time windows:
• Strong CYP3A4 inhibitors or inducers within 14 days of first dose of PC14586
• Inhibitors of P-gp or BCRP within 7 days of first dose of PC14586
• Medications with a known risk of QT/QTc prolongation within 7 days or 5 half-lives of the first dose of PC14586, whichever is shorter
• Proton pump inhibitors within 2 days of first dose of PC14586.
Patient has a history of GI disease that may interfere with absorption of study drug (e.g., ulcerative colitis, Crohn’s disease, inflammatory bowel disease, frequent vomiting, severe diarrhea, malabsorption syndrome, or small bowel/gastric resection), or patients unable to take oral medication.
Patient has a history of prior organ transplant.
Patient has any medical condition that would, in the Investigator’s judgment, prevent the patient’s participation in the clinical study due to safety concerns or compliance with clinical study procedures.
Patient has any other known, active malignancy, except for treated cervical intraepithelial neoplasia, or non-melanoma skin cancer.
Patient has a known, active uncontrolled Hepatitis B infection (i.e., viral load above the limit of quantification), Hepatitis C infection (i.e., viral load above the limit of quantification), or human immunodeficiency virus infection (viral load > 400 copies/mL). Patients whose viral load is controlled should be on established non-CYP3A4 mediated antiretroviral therapy for at least 4 weeks prior to receiving their first dose of PC14586.
Female patients that are breastfeeding or bottle feeding with their breast milk.
Patient has any unresolved toxicities from prior therapy greater than Grade 1 at the time of starting PC14586 treatment with the exception of alopecia and Grade 2 prior chemotherapy induced neuropathy.
Patient has had major surgery within 2 weeks prior to the planned start of PC14586 treatment.
