Clinical Trials /

Phase 1 Study to Determine the MTD, Safety, Tolerability, PK and Preliminary Anti-tumor Effects of LNS8801alone and in Combination With Pembrolizumab

NCT04130516

Description:

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 alone and in combination with pembrolizumab. The study will include a dose escalation and a dose expansion phase. Up to 100 patients will be accrued for this study. Up to ten study sites in the United States will participate in the study.

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

Recruiting

Phase:

Phase 1/Phase 2

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

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.

Detailed Description

      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
      this cohort.
    

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 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,
             if available.

          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
                  mL/min/1.73 m2.

               -  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.

        Exclusion Criteria:

          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
             eligible).

          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
             drug.

             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
             investigational agent.

          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
             radiosurgery).

          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
             that therapy.

          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
             corticosteroids.

         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
             drug.

         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
             radiation pneumonitis.

         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
                  the study).

         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
             diagnosis.

         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.
      
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:
Measure:Clinical benefit rate (CBR)
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 CBR rate evaluation over time
Safety Issue:
Description:

Details

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

Last Updated

August 7, 2020