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

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. Identifier: NCT04130516
Recruitment Status : Recruiting
First Posted : October 17, 2019
Last Update Posted : August 11, 2020
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 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.

Condition or disease Intervention/treatment Phase
Solid Tumor, Adult Lymphoma Drug: Small molecule, orally bioavailable, selective agonist of GPER Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 21 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 Preliminary Anti-tumor Activity of LNS8801 in Patients With Advanced Cancer
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
Phase 1 open-label
Drug: Small molecule, orally bioavailable, selective agonist of GPER

Primary Outcome Measures :
  1. 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 ]

Secondary Outcome Measures :
  1. 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 ]
  2. 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 ]
  3. 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 ]
  4. 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 ]
  5. 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 ]

Other Outcome Measures:
  1. Overall survival [ 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

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.

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 identifier (NCT number): NCT04130516

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Contact: Tina Garyantes, PhD (908) 420-1159
Contact: Jessica Faso, MBA (513) 497-9835

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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   
United States, Connecticut
Yale Cancer Center Recruiting
New Haven, Connecticut, United States, 06519
Contact: Ingrid Palma, MHS    203-737-5342   
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   
United States, Texas
MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Jordi Rodon, MD    713-563-1930   
The START Center for Cancer Care Recruiting
San Antonio, Texas, United States, 78229
Contact: Isabel Jimenez, RN, MSN    210-593-5265   
Sponsors and Collaborators
Linnaeus Therapeutics, Inc.
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Study Director: Tina Garyantes, PhD Linnaeus Therapeutics, Inc.
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Responsible Party: Linnaeus Therapeutics, Inc. Identifier: NCT04130516    
Other Study ID Numbers: LNS-101
First Posted: October 17, 2019    Key Record Dates
Last Update Posted: August 11, 2020
Last Verified: October 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No