A Multicenter Study to Assess the Safety, Tolerability, Pharmacokinetics, and Preliminary Anti-tumor Activity of LNS8801 in Patients With Advanced Cancer

This Phase 1, first-in-human, open-label, multi-center study follows a 3+3 ascending dose escalation design to determine the MTD/RP2D and to characterize the safety, tolerability, PK, and anti-tumor effects of LNS8801. LNS8801 will be administered for three consecutive days per week (Day 1 to Day 3 of each week) for each 21 day cycle until disease progression or unacceptable toxicity occurs.

Cohorts will enroll at least three patients in accordance with a traditional 3+3 design, and the study will determine the MTD/RP2D. With permission from the Safety Review Committee (SRC), two cohorts may be expanded to include 8 to 10 patients to further explore PK and pharmacodynamics.

Safety assessments will be performed on all patients at screening, throughout their participation in the study, and for 30 days following the last dose of study drug. Throughout the study, imaging of tumors for evidence of tumor response and/or progression will be performed; biopsies will be performed on accessible lesions.

Up to 50 patients will be accrued for this study. LNS8801 capsules will be administered orally. There are up to five study sites in the United States.

Inclusion Criteria:

1. Has histopathologically confirmed locally advanced or metastatic cancer (solid tumor or lymphoma) that has progressed following at least one line of therapy, and no other standard therapy with proven clinical benefit is available or the patient declines further standard of care.
2. Is an adult 18 years of age or older.
3. Has an Eastern Cooperative Oncology Group Performance Status of 0 or 1.
4. Has an estimated life expectancy of greater than three months.
5. Patients who have surgically accessible lesions must agree to biopsies. If applicable, patients must consent for Sponsor to access historical biopsies.
6. Is able to swallow capsules.
7. Has adequate organ and bone marrow function defined by:
   • Absolute neutrophil count >=1.5 x 10e9/ L.
   • Hemoglobin >=9.0 g/dL or equivalent.
   • Platelet count >=75 x 10e9/L.
   • Total bilirubin <=1.5 x institutional upper limit of normal (ULN), unless known Gilbert syndrome has been diagnosed.
   • Measured or calculated glomerular filtration rate >=60 mL/min/1.73 m2.
   • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <=2.5 times ULN or <=5 x ULN with cancer in the liver.
8. Female patients of childbearing potential must have a negative serum pregnancy test at screening and a negative (serum or urine) pregnancy test within 72 hours before the first dose of study drug.
9. Female patients of childbearing potential must be willing to use a highly effective contraception method prior to study entry, while on study drug, and for a period of at least 4 months following the last dose of study drug. Male patients must be surgically sterile or willing to use a highly effective double-barrier contraception method.
10. Is able to understand and voluntarily sign a written informed consent form and is willing and able to comply with protocol requirements.

Exclusion Criteria:

1. Has thyroid cancer.
2. Has any cancer that is known to be ER+ (estrogen receptor-positive).
3. Received an anticancer therapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) before the first dose of study drug or has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to the NCI CTCAE v5.0 <=Grade 1, or baseline.
4. Has a symptomatic primary central nervous system (CNS) tumor, symptomatic CNS metastases, leptomeningeal carcinomatosis, or untreated spinal cord compression. Patients are eligible if neurological symptoms and CNS imaging are stable and steroid dose is stable for 14 days prior to the first dose of study drug and no CNS surgery or radiation has been performed for 28 days (14 days if stereotactic radiosurgery).
5. Requires the use of antitumor necrosis factor (anti-TNF) therapies, such as infliximab, or has received treatment with anti-TNF therapies within 5 half-lives of that therapy.
6. Has an active autoimmune disease that required systemic treatment in the past 2 years (ie, with use of disease-modifying antirheumatic agents or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal, thyroid, or pituitary insufficiency) is permitted.
7. Has ongoing immunosuppressive therapy, including systemic and enteric corticosteroids. Patients may be using systemic corticosteroids (dose <=10 mg/day of prednisone or equivalent) or topical or inhaled corticosteroids.
8. Is receiving any other investigational agent(s) or has received an investigational agent within 30 days or 5 half-lives, whichever is shorter, of the first dose of study drug.
9. Has had major surgery (excluding placement of vascular access) within 4 weeks prior to planned start of LNS8801.
10. Has had radiotherapy with a limited field for palliation within 1 week of the first dose of study drug, with the exception of patients receiving radiation to more than 30% of the bone marrow or with a wide field of radiation, which must be completed at least 4 weeks prior to the first dose of study drug.
11. Has evidence of pneumonitis or interstitial lung disease.
12. Has any of the following known infections:
    • Human immunodeficiency virus (HIV), hepatitis B virus (HBV) (ie, hepatitis B surface antigen-positive), or hepatitis C virus (HCV) (ie, detectable HCV ribonucleic acid [RNA]).
    • Active infections (including asymptomatic infections with positive virus titers and the Investigator's judgment that worsening of the condition is likely with study drug or the condition would impair or prohibit a patient's participation in the study).
13. Has active malabsorption syndrome or other condition likely to affect gastrointestinal absorption of the study drug.
14. Has received a live vaccine within 30 days of the planned start of study drug.
15. Has a corrected QT interval (QTc) by Fridericia method >450 msec for male patients or >470 msec for female patients, or a history or risk factors for or use of medications known to prolong the QTc or that may be associated with torsades de pointes within 7 days of the first dose of study drug.
16. Has had any prior treatment for the present solid malignancy with GPER agonists (eg, tamoxifen, raloxifene, or estrogen hormone replacement therapy). History of oral contraceptive use is permissible.
17. Is using a strong inhibitor or inducer of cytochrome P450 1A2, 2C9, 2C19, 2D6, or 3A4.
18. Requires treatment with a proton pump inhibitor (PPI).
19. Has had a recent (diagnosed within 2 years) cancer that was treated with estrogen hormone therapy.
20. Is currently using estrogen hormone replacement therapy, was diagnosed while on estrogen hormone replacement therapy, or has used estrogen replacement therapy since diagnosis.
21. Is pregnant, lactating, has been pregnant within the last 2 years, or is planning to attempt to become pregnant or impregnate someone during this study or within 90 days after dosing of study drug.
22. Has a history of another active malignancy (a second cancer) within the previous 2 years except for localized cancers that are not related to the current cancer being treated, are considered cured, and, in the opinion of the Investigator, presents a low risk of recurrence.
23. Has an uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, hypertension, unstable angina pectoris, cardiac arrhythmia, autoimmune or inflammatory diseases, or psychiatric illness/social situations that would limit compliance with study requirements.