Clinical Trials /

Phase 1 Study to Determine the MTD, Safety, Tolerability, PK and Preliminary Anti-tumor Effects of LNS8801

NCT04130516

Description:

LNS-101 is a multi-center 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 is designed to determine the maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D). LNS8801 will be administered until disease progression or unacceptable toxicity.

Related Conditions:
  • Lymphoma
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Phase 1 Study to Determine the MTD, Safety, Tolerability, PK and Preliminary Anti-tumor Effects of LNS8801
  • Official Title: A Multicenter Study to Assess the Safety, Tolerability, Pharmacokinetics, and Preliminary Anti-tumor Activity of LNS8801 in Patients With Advanced Cancer

Clinical Trial IDs

  • ORG STUDY ID: LNS-101
  • NCT ID: NCT04130516

Conditions

  • Solid Tumor, Adult
  • Lymphoma

Interventions

DrugSynonymsArms
Small molecule, orally bioavailable, selective agonist of GPERActive

Purpose

LNS-101 is a multi-center 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 is designed to determine the maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D). LNS8801 will be administered until disease progression or unacceptable toxicity.

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
ActiveOtherPhase 1 open-label
  • Small molecule, orally bioavailable, selective agonist of GPER

Eligibility Criteria

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:The primary outcome is the determination of the MTD or RP2D of LNS8801 based on safety and tolerability.
Time Frame:Duration of study, approximately 24 months
Safety Issue:
Description:

Secondary Outcome Measures

Measure:LNS8801 plasma exposures as measured by Area Under the Curve (AUC)
Time Frame:Three consecutive days during initial dosing, then weekly for the next three weeks, then every three weeks through study completion, which is estimated as 24 months
Safety Issue:
Description:
Measure:LNS8801 plasma exposures as measured by maximum plasma concentration (Cmax)
Time Frame:Three consecutive days during initial dosing, then weekly for the next three weeks, then every three weeks through study completion, which is estimated as 24 months
Safety Issue:
Description:
Measure:Overall response rate (ORR) by RECIST v1.1
Time Frame:Tumor response will be assessed every 8 weeks for the first year, every 12 weeks through study completion, which is estimated to be up to 24 months for ORR rate evaluation over time
Safety Issue:
Description:
Measure:Progression-free survival (PFS) by RECIST v1.1.
Time Frame:PFS will be assessed from the date of first dose until the end of the study, which is estimated to be 24 months
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Linnaeus Therapeutics, Inc.

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