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 LNS8801alone and in Combination With Pembrolizumab
  • Official Title: A Multicenter Study to Assess the Safety, Tolerability, Pharmacokinetics, and Antitumor Activity of LNS8801 in Patients With Advanced Cancer Including Immunotherapy Refractory Expansion Cohorts With and Without Pembrolizumab

Clinical Trial IDs

  • ORG STUDY ID: LNS-101
  • SECONDARY ID: MK3475-B47
  • NCT ID: NCT04130516

Conditions

  • Solid Tumor, Adult
  • Lymphoma

Interventions

DrugSynonymsArms
LNS8801 -Small molecule, orally bioavailable, selective agonist of GPERActive
Pembrolizumab - anti-PD-1 antibodyKeytruda, PembrolizumabActive

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 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.

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 dose escalation 3+3 design, and the study will
      determine the MTD/RP2D of LNS8801. 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. LNS8801 will be administered 3 days/week or once or twice a day during 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 (90 days in combination cohorts) 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 and the safety of dosing LNS8801 with pembrolizumab
      has been established, 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 expansion cohorts.

      The expansion cohorts will determine the effects of LNS8801 alone and in combination with
      pembrolizumab. LNS8801 capsules or tablets will be administered orally for 3 (Day 1 to Day 3)
      or 7 consecutive days per week (once or twice daily) for each 21 day cycle until disease
      progression or unacceptable toxicity occurs. Pembrolizumab will be dosed at 200 mg every 3
      weeks with the first combination cohort to receive LNS8801 starting at the RP2D or one dose
      level below the MTD/RP2D determined in the monotherapy cohort. In the monotherapy expansion
      cohort, patients with a grade 3 immune related adverse event to prior immunotherapy will also
      be eligible for inclusion. Up to 100 patients will be accrued for this study at up to ten
      study sites in the United States.
    

Trial Arms

NameTypeDescriptionInterventions
ActiveOtherPhase 1 open-label
  • LNS8801 -Small molecule, orally bioavailable, selective agonist of GPER
  • Pembrolizumab - anti-PD-1 antibody

Eligibility Criteria

        Inclusion Criteria:

          1. Has histopathologically confirmed locally advanced or metastatic cancer (solid tumor
             or lymphoma) that has progressed following 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 or RANO 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 CT scan or MRI. For lymphoma patients only, the minimum
             measurement must be >15 mm on the long axis and >10 mm on the short axis.

               1. 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. Must provide access to existing formalin-fixed biopsy tissue or slides for
                  histology assessments if a pretreatment biopsy is not performed or unsuccessful
                  for any reason.

          2. In the anti-PD-1/L1 therapy refractory cohorts, patients must have first had a
             clinical benefit from (confirmed complete response, partial response, or stable
             disease for at least 16 weeks) and then progressed on or after anti-PD1/L1 treatment
             administered as monotherapy or in combination with other checkpoint inhibitors or
             other therapies and with no intervening systemic therapy before starting on this
             study. Progression is 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, 3 times if dosed every 3 weeks (q3w) or 4 times if dosed every 2 weeks
                  (q2w).

               2. Has demonstrated progressive disease (PD) while on or after anti-PD-1/L1 therapy
                  as defined by RECIST v1.1 or RANO.

          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 from
             nonirradiated tumor lesions or irradiated tumor lesions that have shown progression
             since irradiation. If no surgically accessible lesions exist, patients must consent
             for Sponsor to access historical biopsies.

             a. For lymphoma patients only: patients must be able to provide a core or excisional
             lymph node biopsy for biomarker analysis from a newly obtained biopsy prior to drug
             treatment.

          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.

               -  For cohorts receiving LNS8801/pembrolizumab combination therapy with
                  pembrolizumab, prothrombin time (PT) or activated partial thromboplastin time
                  (aPTT) must be ≤1.5 × ULN. If a participant is receiving anticoagulant therapy,
                  PT or aPTT must be within therapeutic range of intended use of anticoagulants.

          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).

               -  Note: Patients in an LNS8801/pembrolizumab combination cohort must not have
                  undergone prior allogeneic hematopoietic stem cell transplantation within the
                  last 5 years. (Participants who have had a transplant greater than 5 years ago
                  are eligible as long as there are no symptoms of acute graft versus host disease
                  [GVHD])

          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. Note: a. For pembrolizumab
             combination cohorts, has a history of (noninfectious) pneumonitis that required
             steroids or has current pneumoniti

         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 (120 days for pembrolizumab combination cohorts).

         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.

         30. In the pembrolizumab combination cohorts, has severe hypersensitivity (≥ Grade 3) to
             pembrolizumab and/or any of its excipients.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:The primary objective of this study is to determine the MTD or RP2D of LNS8801 based on safety and tolerability. PK and PD parameters will also be considered in determining the RP2Ds.
Time Frame:Duration of study, approximately 24 months
Safety Issue:
Description:

Secondary Outcome Measures

Measure:To assess the Cmax of ascending doses of LNS8801
Time Frame:During first 23 days of dosing
Safety Issue:
Description:
Measure:To assess the AUC of ascending doses of LNS8801
Time Frame:During first 23 days of dosing
Safety Issue:
Description:
Measure:To assess accumulation of LNS8801 during ascending doses
Time Frame:Duration of study, approximately 24 months
Safety Issue:
Description:
Measure:To assess the number of participants with treatment related adverse events assessed by CTCAE v4.0 dosed with LNS8801 alone.
Time Frame:Duration of study, approximately 24 months
Safety Issue:
Description:
Measure:To assess the number of participants with treatment related adverse events assessed by CTCAE v4.0 dosed with LNS8801 and pembrolizumab.
Time Frame:Duration of study, approximately 24 months
Safety Issue:
Description:
Measure:To assess the clinical benefit of LNS8801 in patients with locally advanced or metastatic cancer based on RECIST V1.1 criteria
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:To assess the preliminary clinical benefit of LNS8801 in patients with locally advanced or metastatic cancer who have previously responded to and then progressed on a PD-1 or PD-L1 therapy based on RECIST V1.1 criteria
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:To assess the preliminary clinical benefit of LNS8801 and pembrolizumab dosed as a combination in patients with cancer who have previously responded to and then progressed on PD-1/L1 therapy based on RECIST V1.1 criteria
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/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Linnaeus Therapeutics, Inc.

Last Updated

September 25, 2020