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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04130516
Recruitment Status : Recruiting
First Posted : October 17, 2019
Last Update Posted : September 25, 2020
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Linnaeus Therapeutics, Inc.

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Solid Tumor, Adult Lymphoma Drug: LNS8801 -Small molecule, orally bioavailable, selective agonist of GPER Biological: Pembrolizumab - anti-PD-1 antibody Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 67 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : October 21, 2019
Estimated Primary Completion Date : October 30, 2021
Estimated Study Completion Date : November 30, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active
Phase 1 open-label
Drug: LNS8801 -Small molecule, orally bioavailable, selective agonist of GPER
LNS8801 -Small molecule, orally bioavailable, selective agonist of GPER

Biological: Pembrolizumab - anti-PD-1 antibody
pembrolizumab- anti-PD-1 antibody
Other Names:
  • Keytruda
  • Pembrolizumab




Primary Outcome Measures :
  1. 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 ]
  2. The primary objective of this study is to determine the MTD or RP2D of LNS8801 dosed in combination with pembrolizumab 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 ]

Secondary Outcome Measures :
  1. To assess the Cmax of ascending doses of LNS8801 [ Time Frame: During first 23 days of dosing ]
  2. To assess the AUC of ascending doses of LNS8801 [ Time Frame: During first 23 days of dosing ]
  3. To assess accumulation of LNS8801 during ascending doses [ Time Frame: Duration of study, approximately 24 months ]
  4. 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 ]
  5. 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 ]
  6. 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 ]
  7. 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. ]
  8. 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 ]

Other Outcome Measures:
  1. To assess prolactin levels as a potential biomarker of GPER target engagement. [ Time Frame: 24 months or until study completion ]
  2. To assess c-myc staining as potential biomarkers of GPER target engagement and of anti-tumor activity. [ Time Frame: 24 months or until study completion ]
  3. To assess overall survival following initiation of LNS8801 therapy [ Time Frame: Overall survival will be assessed from the date of first dose until the end of the study, which is estimated to be 24 months ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04130516


Contacts
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Contact: Tina Garyantes, PhD (908) 420-1159 tgaryantes@linnaeustx.com
Contact: Jessica Faso, MBA (513) 497-9835 j.faso@medpace.com

Locations
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United States, California
Cedars-Sinai Medical Center Recruiting
Los Angeles, California, United States, 90048
Contact: Kari Kayser, RN, BSN, CCRP    (310) 967-0694    kari.kayser@cshs.org   
United States, Connecticut
Yale Cancer Center Recruiting
New Haven, Connecticut, United States, 06519
Contact: Ingrid Palma, MHS    203-737-5342    ingrid.palma@yale.edu   
United States, New Mexico
University of New Mexico Comprehensive Cancer Center Recruiting
Albuquerque, New Mexico, United States, 87106
Contact: Carolyn Muller, MD         
United States, Pennsylvania
Thomas Jefferson University, Sidney Kimmel Cancer Center Recruiting
Philadelphia, Pennsylvania, United States, 19107
Contact: Dorit Arditti-Falk, MSN, RN       Dorit.Arditti-Falk@jefferson.edu   
United States, Texas
MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Jordi Rodon, MD    713-563-1930    jrodon@mdanderson.org   
The START Center for Cancer Care Recruiting
San Antonio, Texas, United States, 78229
Contact: Isabel Jimenez, RN, MSN    210-593-5265    isabel.jimenez@startsa.com   
Sponsors and Collaborators
Linnaeus Therapeutics, Inc.
Merck Sharp & Dohme Corp.
Investigators
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Study Director: Tina Garyantes, PhD Linnaeus Therapeutics, Inc.
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Responsible Party: Linnaeus Therapeutics, Inc.
ClinicalTrials.gov Identifier: NCT04130516    
Other Study ID Numbers: LNS-101
MK3475-B47 ( Other Identifier: Merck, Sharpe and Dohme Corp. )
First Posted: October 17, 2019    Key Record Dates
Last Update Posted: September 25, 2020
Last Verified: September 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Pembrolizumab
Antibodies
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Immunological
Antineoplastic Agents