MC# 21-29 - A Phase I Study to Evaluate the Safety and Tolerability of GS-1811, an Afucosylated Anti-CCR8 Monoclonal Antibody, as Monotherapy and in Combination with Pembrolizumab in Adults with Advanced Solid Tumors

  • Agent(s): GS-1811
  • Disease Type(s): Breast, Gastric, Head and Neck, Solid Tumor, Lung-NSCLC, Gastroesophageal Junction
  • Phase(s): I
  • Drug Classification(s): Targeted Therapy, Monoclonal Antibody
  • Molecular Target(s): CCR8

Mechanism of Action

GS-1811 is a monoclonal antibody that is designed to selectively bind to CCR8.  It is thought to target Tumor-Infiltrating T Regulatory cells for depletion by enhancing an antibody-dependent cellular cytotoxicity mechanism.

Purpose

In this study, the sponsor and investigators want to learn as the safety and efficacy have not been demonstrated:

  • How much of GS-1811 when given alone or in combination with Pembrolizumab can be given with an acceptable level of side effects
  • About the safety and tolerability of GS-1811 when given alone or in combination with Pembrolizumab
  • How much of GS-1811 is absorbed into the blood and how fast it is removed
  • If research tests can be used in the future to predict who will benefit from GS-1811
Inclusion Criteria
  1. Able and willing to participate and comply with all study requirements and provide signed and dated informed consent prior to initiation of any study procedures
  2. Disease:
    1. Part A: Histologically or cytologically confirmed advanced solid tumors.  Participant must have received, been intolerant to, or been ineligible for all treatment known to confer clinical benefit.
    2. Part B: Histologically or cytologically confirmed advanced solid tumors.  Participant must have received, been intolerant to, or been ineligible for all treatment known to confer clinical benefit.  Tumor types include histologically or cytologically confirmed advanced HNSCC, NSCLC, gastric and EGJ adenocarcinoma, and breast cancer.
    3. Part C: Participants with histologically or cytologically confirmed advanced solid tumors, whose disease is indicated for pembrolizumab monotherapy or who have received, been intolerant to, or been ineligible for all treatment known to confer clinical benefit
  3. Measurable disease, according to RECIST v1.1 or evidence of evaluable disease radiographically assessable by the investigator and with approval from the sponsor
  4. Age ≥ 18 years
  5. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2
  6. Have adequate organ function as indicated by the following screening laboratory values:

System

Laboratory Valuea

Hematologicalb

Absolute neutrophil count (ANC)

≥ 1.5 x 109/L

Platelets

≥ 100 x 109/L

Hemoglobin

≥ 9 g/dL

Renal

 

Creatinine Clearance

≤ 1.5 x ULN or ≥50mL/min by the Cockcroft-Gault method

Hepatic

Total bilirubin

≤ 1.5 x ULN OR ≤ 3 x ULN in participants with liver metastases, biliary tract cancer, or Gilbert’s syndrome or a genetic equivalent

AST (SGOT) and ALT (SGPT)

≤ 2.5 x ULN OR ≤ 5 x ULN in participants with liver metastases

Coagulationc

International Normalized ration (INR) or Prothrombin time (PT)

≤1.5 x ULN, unless the participant is receiving anticoagulant therapy

Activated Partial Thromboplastin time (aPTT)

≤1.5 x ULN, unless the participant is receiving anticoagulant therapy

ALT = alanine aminotransferase; AST = aspartate aminotransferase; SGOT = serum glutamic-oxaloacetic transaminase; SGPT = serum glutamic-pyruvic transaminase; ULN = upper limit of normal

aAll screening laboratory tests must be reviewed by the investigator and be acceptable prior to enrollment

bHematologic laboratory values must be met at the screening visit and maintained without transfusion or growth factors prior to the first study drug dose

cParticipants on full-dose oral anticoagulation must be on a stable dose (minimum duration 14 days).  Participants on low molecular weight heparin will be allowed. In participants receiving warfarin, the recommended INR is ≤ 3.0 with no active bleeding (ie, no bleeding within 14 days prior to first dose of study drug).

  1. Male participants and female participants of childbearing potential who engage in heterosexual intercourse must agree to use protocol-specified method(s) of contraception
  2. Tissue requirement:
    1. Part A and Part C: Participants must have available sufficient and adequate formalin-fixed tumor tissue sample (as specified in the Laboratory Manual), preferably from a biopsy of a tumor lesion obtained either at the time of or after the diagnosis of advanced disease has been made and from a site not previously irradiated.  Alternatively, participants must agree to have a biopsy taken prior to enrollment to provide adequate tissue.  Fine needle aspirates are not acceptable.  Core needle, excisional biopsy, or resected tissue is required.
    2. Part B: Participants must have an accessible tumor lesion that biopsies can be obtained from prior to treatment and on treatment and from a site not previously irradiated.  The biopsies for each participant should be taken from the same lesion, if feasible.  Fine needle aspirates are not acceptable.  Core needle biopsy, excisional biopsy, or resected tissue is required.
Exclusion Criteria
  1. Concurrent anticancer treatment, either FDA-approved, palliative treatment for tumor debulking, or investigational for the cancer being evaluated in this study or for other cancers (with the exceptions listed in exclusion criterion 3e for other cancers)
  2. Prior infusion of GS-1811 or other CCR8 directed therapy
  3. The therapies listed below within the specified timeframe or ongoing toxicity attributed to prior therapy that was > Grade 1 according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. Exceptions: > Grade 1 toxicities that, in the opinion of the investigator, should not exclude the participant (eg, alopecia, Grade 2 neuropathy, hypo- or hyperthyroidism or other endocrinopathies that are well-controlled with hormone replacement) and are approved by the medical monitor.
    1. Major surgery (excluding minor procedures, eg, placement of vascular access, gastrointestinal/biliary stent, biopsy) < 4 weeks prior to planned Cycle 1, Day 1
    2. Immunotherapy or biologic therapy < 28 days prior to planned Cycle 1, Day 1
    3. Chemotherapy < 21 days prior to planned Cycle 1, Day 1, or < 42 days for mitomycin or nitrosoureas
    4. Targeted small molecule therapy < 14 days prior to planned Cycle 1, Day 1
    5. Hormonal or other adjunctive therapy for cancers other than the cancer under evaluation in this study that started < 14 days prior to planned Cycle 1, Day 1 are not permitted.  Exceptions: antiestrogen therapy, bisphosphonates, somatostatin analogues, and leuprolide are permitted if started ≥ 14 days prior to Cycle 1, Day 1.
    6. Radiation therapy < 21 days prior to planned Cycle 1, Day 1.  Exception: limited (eg, pain palliation) radiation therapy is allowed prior to and during study drug administration as long as there are no acute toxicities, any AE due to prior radiation therapy has recovered to < Grade 2, and the radiation is not administered to a target lesion.
    7. Any prior allogeneic tissue/solid organ transplantation, including allogeneic stem cell transplantation
  4. Concurrent active malignancy other than nonmelanoma skin cancer, carcinoma in situ of the cervix, or superficial bladder cancer after undergoing potentially curative therapy with no evidence of disease.  Participants with other previous malignancies are eligible if disease-free for > 2 years.
  5. History of intolerance, hypersensitivity, or treatment discontinuation due to severe irAEs on prior immunotherapy
  6. Diagnosis of immunodeficiency, either primary or acquired, or treatment with immunosuppressive levels of systemic corticosteroids or any other form of immunosuppressive therapy within 7 days prior to planned Cycle 1, Day 1.  Exceptions: intraocular, intranasal, intra-articular, inhaled, and/or topical corticosteroids, or systemic corticosteroids (prednisone at doses of up to 10 mg per day or equivalent, or at doses intended for adrenal replacement), and one-time doses of immunosuppressive agents used prophylactically for contrast allergies are permitted in the absence of active autoimmune disease.
  7. History of autoimmune disease or active autoimmune disease that has required systemic treatment within 2 years prior to the start of study treatment (ie, with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs).  Note: Participants with diabetes type 1, vitiligo, psoriasis, hypothyroid disease, or hyperthyroid disease not requiring immunosuppressive treatment are eligible
  8. Known severe intolerance or life-threatening hypersensitivity reactions to humanized mAbs or IV Ig preparations; any history of anaphylaxis; history of human anti-human antibody response; known allergy to any of the study medications, their analogues, or excipients
  9. Untreated brain metastases, leptomeningeal disease, or spinal cord compression not definitively treated with surgery or radiation.  (Participants with brain metastases that are stable and asymptomatic after prior treatment and are not on high dose steroids will be allowed.)
  10. Active and clinically relevant bacterial, fungal, or viral infection that is not controlled or requires IV antibiotics
  11. Active hepatitis B virus (HBV) and/or hepatitis C virus (HCV), and/or HIV
    1. Participants must be negative for hepatitis B surface antigen (HBsAg).  For participants with positive anti-HBc, HBV DNA by quantitative polymerase chain reaction (PCR) will be required.
    2. For participants with positive HCV antibody, HCV RNA by quantitative PCR will be required
    3. Participants must also be negative for HIV at screening
  12. Receipt of live vaccines within 30 days prior to planned Cycle 1, Day 1 (inactivated, viral vector vaccines, and mRNA vaccines are allowed; seasonal vaccines should be up to date prior to planned Cycle 1, Day 1)
  13. Positive serum pregnancy test
  14. Breastfeeding female
  15. History of pneumonitis requiring treatment with corticosteroids, interstitial lung disease, or severe radiation pneumonitis (excluding localized radiation pneumonitis)
  16. Symptomatic ascites or pleural effusion
  17. Symptomatic cardiac or cerebrovascular disease; cerebral vascular accident/stroke or myocardial infarction within 6 months of enrollment, unstable angina, congestive heart failure (New York Heart Association class ≥ III), or serious uncontrolled cardiac arrhythmia requiring medication; has a mean QT interval corrected for heart rate (QTc) using the Fridericia formula (QTcF) ≥ 470 ms
  18. Medical or social condition that, in the opinion of the investigator, might place the participant at increased risk, adversely affect compliance, or confound safety or other clinical study data interpretation

Location

  • Dallas, TX - Mary Crowley Cancer Research - Medical City
More Info: https://clinicaltrials.gov/ct2/show/NCT05007782

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Re: MC# 21-29