Study of LP-184 in Patients with Advanced Solid Tumors

Eligibility Criteria

• 1. ≥18 years of age at the time of consent
• 2. Provided signed written ICF and voluntary consent prior to any mandatory study-specific procedures, sampling, and analyses.
• 3. Have a histologically or cytologically documented advanced solid tumor that has relapsed from or is refractory to standard treatment, or for which no standard treatment is available.
• 4. ECOG performance status 0-1 or Karnofsky performance scale \>60 for GBM patients.
• 5. Patients must have measurable disease per RECIST 1.1 or RANO 2.0 criteria as applicable.
• 6. Patients must have life expectancy \>3 months.
• 7. Adequate organ function at screening defined as:
• * AST, ALT ≤3 x ULN or \<5 x ULN in cases of documented liver metastases or involvement of liver in the disease process.
• * Total serum bilirubin ≤1.5 x ULN or \<5 x ULN if secondary to Gilbert's syndrome or documented liver metastases or involvement of liver in the disease process.
• * Serum creatinine clearance ≥60 mL/min either measured or calculated using standard Cockcroft-Gault formula.
• * Serum electrolyte (potassium, calcium, and magnesium) levels within the normal reference range (may be supplemented according to institutional standard).
• * ANC ≥1500/μL.
• * Hemoglobin ≥8 g/dL (The use of transfusion or other intervention to achieve hemoglobin ≥8 g/dL is acceptable. For those patients undergoing RBC transfusion, hemoglobin must be evaluated at least 14 days after the last RBC transfusion).
• * Platelet count ≥100,000/μL (assessed ≥7 days following last platelet transfusion in patients with thrombocytopenia requiring platelets).
• 8. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within 3 days of first dose of LP-184. A woman is of child-bearing potential unless she:
• * has had a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy;
• * is age ≥60 years and is amenorrhoeic; or
• * is age \<60 years and has been amenorrhoeic for ≥12 months (including no irregular menses or spotting) in the absence of any medication which induces a menopausal state and has documented ovarian failure by serum estradiol and follicle-stimulating hormone levels within the institutional laboratory postmenopausal range).
• 9. WOCBP or must agree to use highly effective contraceptive methods and avoid egg donation during the study treatment and for 6 months after the last dose of LP-184.
• 10. Men of reproductive potential agree to use highly effective contraceptive methods and avoid sperm donation during the study treatment and for 3 months after the last dose of LP-184. A man is of child-producing potential unless he has had a bilateral vasectomy with documented aspermia or a bilateral orchiectomy.
• 11. Is willing to provide archived samples (blocks and/or slides) for comprehensive DDR genomic analyses and/or PTGR1 expression profiling and/or other genomic alterations if the patient has a PR/CR.
• 12. Regarding brain metastases, based on screening contrast brain MRI, patients must have 1of the following:
• * No evidence of brain metastases
• * Untreated brain metastases not requiring immediate local therapy. For patients with untreated CNS lesions \>2.0 cm on screening contrast brain MRI, discussion with and approval from the Medical Monitor is required prior to enrollment.
• * Previously treated brain metastases that are either stable for at least 4 weeks since last treatment or progressed since prior local CNS therapy and not requiring immediate re-treatment with local therapy in the opinion of the investigator.
• 1. Exposure to anti-cancer therapy within 2 weeks or within at least 5 half-lives of the anticancer agent whichever is shorter; or 4 weeks from any biologics/immunotherapies or any investigational therapy prior to the first dose of LP-184.
• 2. Any history of retinopathy and/or macular degeneration (without specifications or grades).
• 3. Has received radiation within 4 weeks of Cycle 1 Day 1. Unless the tumor at the site of treatment continues to increase in size after the patient has completed radiotherapy treatment.
• 4. Infection requiring antibiotics, antivirals, or antifungals within 1 week prior to first dose of study drug, unless such infection is adequately controlled (defined as exhibiting no ongoing signs/symptoms related to the infection and with clinical improvement). In the case of prophylactic use of these agents, discussion with the Medical Monitor is required prior to enrollment.
• 5. Hepatitis B and/or hepatitis C infection (as detected by positive testing for hepatitis B surface antigen \[HbsAg\] or antibody to hepatitis C virus with confirmatory testing) or known seropositivity for or history of active viral infection with human immunodeficiency virus (HIV).
• 6. Are pregnant or breastfeeding. (NOTE: breast milk cannot be stored for future use while the mother is being treated on study).
• 7. Have clinically significant cardiac disease including:
• * New York Heart Association Class IV heart failure.
• * Myocardial infarction or stroke ≤3 months prior to the first dose of LP-184.
• * Unstable angina within ≤12 weeks prior to the first dose of LP-184 unless the underlying disease has been corrected by procedural intervention e.g., stent, bypass.
• * Severe aortic stenosis.
• * Uncontrolled arrhythmia. Sponsor approval of patients with arrhythmia is required.
• * QTc \>470 ms by Fredericia criteria.
• * Congenital long QT syndrome, or a QT interval corrected by Fridericia's formula (QTcF) \>470 ms (average of triplicate ECGs) at Screening and/or on Cycle 1 Day 1 (pre-dose) except for a documented bundle branch block or unless secondary to pacemaker. In the case of a documented bundle branch block or a pacemaker, discussion with the medical monitor is required prior to enrollment.
• 8. Have clinically significant AEs that have not returned to baseline or ≤Grade 1 based on NCI-CTCAE prior to first dose of study drug, unless approved by the sponsor. Patients with chronic Grade 2 toxicities may be eligible per the discretion of the investigator and sponsor (e.g., Grade 2 chemotherapy-induced neuropathy, alopecia, or hypothyroidism from prior immunotherapy treatment).
• 9. Have had major surgery (requiring general anesthesia) within ≤4 weeks of first dose of LP-184.
• 10. Have any other serious medical condition which, in the opinion of the investigator, would preclude the patient from study participation.
• 11. Have clinically active brain metastases, defined as untreated and symptomatic, or requiring therapy with steroids at a dose \> 2 mg of dexamethasone or equivalent or anticonvulsants to control associated symptoms. Patients with treated brain metastases that are no longer symptomatic and who require no treatment with steroids may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 4 weeks must have elapsed between the end of whole brain radiotherapy and study enrollment (1 week for stereotactic radiotherapy).
• 12. For patients with suspected or known CNS metastatic disease, based on screening brain MRI, patients must not have:
• 13. Male patients with partners currently pregnant, or male patients able to father children, and female patients of childbearing potential who are unwilling or unable to use highly effective methods of contraception as outlined in this protocol for the duration of the study and for at least 3 months (male) or 6 months (female) after last dose of study drug