This Phase 1, first-in-human, open-label, multicenter study follows a 3+3 ascending dose
escalation design to determine the MTD/RP2D and to characterize the safety, tolerability, PK,
and antitumor effects of LNS8801 in patients with advanced cancer. LNS8801 capsules or
tablets will be administered orally. Multiple dose regimens may be explored in this study.
LNS8801 will be administered for 3 (Day 1 to Day 3 or every day) or 7 consecutive days per
week (once or twice daily) for each 21 day cycle until disease progression or unacceptable
toxicity occurs. Up to 70 patients will be accrued for this study. Up to six study sites in
the United States will participate in the study.
In this Phase 1, first-in-human, open-label, multi-center study, cohorts will enroll at least
3 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), 2 cohorts may be expanded
to include 8 to 10 patients to further explore PK and pharmacodynamics. 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.
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.
After the RP2D of LNS8801 is identified, up to 27 patients who have previously had confirmed
clinical benefit from a PD-1/L1 therapy (defined by stable disease, partial response, or
complete response by RECIST v1.1 for at least 16 weeks) but have since relapsed on the same
PD-1/L1 therapy will be dosed in an expansion cohort. Up to 27 patients may be studied in
1. Has histopathologically confirmed locally advanced or metastatic cancer (solid tumor
or lymphoma) that has progressed after at least 1 line of therapy if a regulatory
approved or standard of care therapy exists and no other standard therapy with proven
clinical benefit is available or the patient declines further standard of care.
Note: Must have measurable disease per RECIST v1.1 as assessed by the local site
Investigator/radiologist. Lesions in a previously irradiated area are measurable if
progression has been demonstrated after radiation. Lesions must be measurable in at
least 2 dimensions in a spiral computed tomography (CT) or magnetic resonance imaging
(MRI) scan. For lymphoma patients only, the minimum measurement must be >15 mm on the
long axis and >10 mm on the short axis.
Must provide access to de-identified historical scans or scan reports for the
assessment of the patient's rate of progression on and after their previous regimen,
2. In anti-PD-1/L1 therapy refractory cohorts, patients must first have had a clinical
benefit (complete response, partial response, or stable disease for at least 16 weeks)
to anti-PD-1/L1 therapy and then must have progressed on anti-PD-1/L1 treatment as
defined by meeting all of the following criteria:
1. Has received anti-PD-1/L1 therapy at least twice if dosed every 4 weeks (q4w) or
longer, at least 3 times if dosed every 3 weeks (q3w), or at least 4 times if
dosed every 2 weeks (q2w).
2. Has demonstrated progressive disease (PD) after anti-PD-1/L1 therapy as defined
by RECIST v1.1.
3. First documented disease progression has been documented within 4 weeks or one
dosing cycle, whichever is longer, from the last dose of anti-PD-1/L1 therapy.
Note: Patients who have experienced Grade 3 immunological adverse events on previous
anti-PD-1/L1 therapy before 16 weeks may also be included.
3. Is an adult ≥18 years of age on day of signing informed consent.
4. Has an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
5. Has an estimated life expectancy of >3 months.
6. Patients who have surgically accessible lesions must agree to biopsies. If applicable,
patients must consent for the Sponsor to access historical biopsies.
7. Is able to swallow capsules and/or tablets.
8. Has adequate organ and bone marrow function defined by:
- Absolute neutrophil count ≥1.5 × 109/L (≥1500/mm3).
- Hemoglobin ≥9.0 g/dL or equivalent.
- Platelet count ≥75 × 109/L (≥75,000/mm3).
- Total bilirubin ≤1.5 × institutional upper limit of normal (ULN), unless known
Gilbert syndrome has been diagnosed.
- Measured or calculated creatinine clearance (glomerular filtration rate) ≥60
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN or
≤5 × ULN with cancer in the liver.
9. 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. If the urine test is positive or cannot be confirmed
negative, a serum pregnancy test will be required and must be negative for the patient
to be eligible.
10. Female patients must not be breastfeeding.
11. Female patients of childbearing potential must be willing to use a highly effective
contraception method before study entry, while on study drug, and for a period of at
least 4 months after the last dose of study drug.
Note: Women receiving estrogen-based contraceptives will be excluded from the study.
Note: A woman is considered of childbearing potential unless she is postmenopausal (≥1
year without menses and confirmed with a follicle-stimulating hormone test) or
surgically sterilized via bilateral oophorectomy, hysterectomy, bilateral tubal
ligation, or successful Essure® placement with a documented confirmation test at least
3 months after the procedure.
Male patients must be surgically sterile or willing to use a highly effective
double-barrier contraception method (eg, male condom with diaphragm or male condom
with cervical cap) upon study entry, while on study drug, and for a period of at least
4 months after the last dose of study drug.
(Highly effective contraception is defined as a method of contraception that has a <1%
failure rate when used consistently and correctly (as defined by the International
Council for Harmonization Guidance on Nonclinical Safety Studies for the Conduct of
Human Clinical Research M3 [R2]). These methods include implants, injectables,
combined hormonal contraceptives (eg, combined oral contraceptives [excluding
estrogen-based contraceptives], patch, and vaginal ring), some intrauterine devices
(IUDs) (eg, IUD or intrauterine system), sexual abstinence, or a monogamous
relationship with a vasectomized partner. True abstinence, when in line with the
preferred and usual lifestyle of the patient, is considered a highly effective method
only if defined as refraining from heterosexual intercourse during the entire period
of risk associated with the study drug (ie, 60 days after discontinuing study drug or
5 times the terminal elimination half-life, whichever is longer). Periodic abstinence
(eg, calendar, ovulation, symptothermal, or post ovulation methods) and withdrawal are
not acceptable methods of contraception.)
12. Is able to understand and voluntarily sign a written informed consent form and is
willing and able to comply with protocol requirements.
1. Has thyroid cancer or gall bladder cancer.
2. Has any cancer that is known to be estrogen receptor-positive (ERalpha+).
3. Received an anticancer therapy within 4 weeks (6 weeks for nitrosoureas or mitomycin
C) or 5 half-lives, whichever is shorter, before the first dose of study drug. except
in the anti-PD-1/L1 refractory cohort, in which patients may start LNS8801 therapy at
what would be the beginning of the next cycle of their immunotherapy (eg, LNS8801 may
be dosed 3 weeks after pembrolizumab, or 4 weeks after nivolumab, etc).
4. Has unresolved toxicities from previous anticancer therapy. Anticancer therapy
toxicities are defined as toxicities (other than alopecia) not yet resolved according
to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events
(CTCAE) v5.0 ≤ Grade 1, or baseline (participants with ≤ Grade 2 neuropathy may be
5. Patients must not be participating in another study of an investigational agent or
have used an investigational device within 4 weeks before the first dose of study
Note: Patients who have entered the follow-up phase of an investigational study may
participate as long as it has been 4 weeks after the last dose of the previous
6. Has a symptomatic primary central nervous system (CNS) tumor, symptomatic CNS
metastases, leptomeningeal carcinomatosis, or untreated spinal cord compression.
Note: Patients are eligible if neurologic symptoms and CNS imaging are stable and the
steroid dose is stable for 14 days before the first dose of study drug and no CNS
surgery or radiation has been performed for 28 days (14 days if stereotactic
7. 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
8. 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).
Note: Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal, thyroid, or pituitary insufficiency) is permitted.
9. Has a diagnosis of immunodeficiency, is on immunosuppressive therapy, or is receiving
chronic systemic or enteric steroid therapy (with doses exceeding 10 mg/day of
prednisone equivalent) or any other form of immunosuppressive therapy within 7 days
before the first dose of study drug.
Note: At screening and during study participation, patients may be using systemic
corticosteroids (dose ≤10 mg/day of prednisone or equivalent) or topical or inhaled
10. 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
11. Has had major surgery (excluding placement of vascular access) within 4 weeks before
the planned first dose of LNS8801.
12. 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 before the first dose of study drug. Participants must have recovered
from all radiation-related toxicities, not require corticosteroids, and not have had
13. Has evidence of pneumonitis or interstitial lung disease.
14. Has any of the following known infections:
1. 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]).
Note: Patients with a history of treated HBV infection who are antigen-negative
or patients with a history of treated HCV infection who are HCV RNA-undetectable
may be enrolled.
2. 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
15. Has active malabsorption syndrome or other condition likely to affect gastrointestinal
absorption of the study drug.
16. Has received a live vaccine within 30 days of the planned start of study drug.
17. 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.
Note: Isolated right bundle branch block and incomplete right bundle branch block and
left anterior hemiblock are acceptable.
18. 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.
19. Is using a strong inhibitor or inducer of cytochrome P450 1A2, 2C9, 2C19, 2D6, or 3A4.
20. Requires treatment with a proton pump inhibitor.
21. Has received estrogen treatment since cancer diagnosis or the presumed initiation of
their cancer, including estrogen-based contraceptives.
22. Has a cancer that was treated with estrogen hormone therapy.
23. Is currently using estrogen hormone replacement therapy, was diagnosed while on
estrogen hormone replacement therapy, or has used estrogen replacement therapy since
24. 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.
25. 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, present a low
risk for recurrence. These exceptions include, but are not limited to, basal or
squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the
prostate, cervix, or breast.
26. 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.
27. Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the study, interfere with the participant's
participation for the full duration of the study, or is not in the best interest of
the patient to participate, in the opinion of the treating Investigator.
28. Has a known psychiatric or substance abuse disorder that would interfere with the
participant's ability to cooperate with the requirements of the study.
29. Has received radiation therapy to the lung that is >30 Gy within 6 months of the first
dose of trial treatment for patients with non-small cell lung cancer.