MC# 20-15 - A Phase 1 First-Time-in-Human, Open-Label Study of GSK6097608 Administered as Monotherapy and in Combination with Anticancer Agents in Participants with Advanced Solid Tumors

  • Agent(s): GSK6097608 & Dostarlimab
  • Disease Type(s): Bladder, Cervical, Colorectal, Esophageal, Gastric, Head and Neck, Hepatocellular, Melanoma, Ovarian, Solid Tumor, Renal, Lung-NSCLC, MSI-H Solid Tumors
  • Phase(s): I
  • Drug Classification(s): Monoclonal Antibody
  • Molecular Target(s): PD-1, CD96

Mechanism of Action

  • Dostarlimab, an anti-PD-1 monoclonal antibody, binds to and inhibits PD-1 and its downstream signaling pathways.
  • GSK6097608 is a monoclonal antibody that inhibits CD96.

Purpose

In this study, the sponsor and investigators want to learn:

  • About the safety and tolerability of GSK6097608 alone and in combination with dostarlimab
  • How proteins that indicate the status of your disease are affected with use of GSK6097608 alone and in combination with dostarlimab
  • If GSK6097608 alone or in combination with dostarlimab prevents or delays tumor growth or shrinks existing tumors
  • How quickly GSK6097608 and dostarlimab are removed from your bloodstream
  • If research tests can be used in the future to predict who will benefit from GSK6097608 and dostarlimab
Inclusion Criteria
  1. Provide signed informed consent.  Participant must be capable of providing informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
  2. Male or female participants ≥18 years of age at the time of signing the ICF
    • A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least 1 of the following conditions applies:
      • Is not a woman of childbearing potential (WOCBP) OR
      • Is a WOCBP and using a contraceptive method that is highly effective with a failure rate of <1% per year during the intervention period and for at least 15 weeks after the last dose of GSK6097608 or 150 days after the last dose of dostarlimab, corresponding to time needed to eliminate study interventions (ie, at least 5 terminal half-lives).  The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention.
      • A WOCBP must have a negative serum pregnancy test within 7 days before the first dose of study intervention
    • The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy
  3. Histological or cytological documentation of locally advanced, recurrent, or metastatic solid malignancy
    • Participants in PK/PD cohorts must have histologically or cytologically confirmed diagnosis of one of the following: NSCLC, HNSCC, or an alternative immunogenic tumor type with medical monitor approval
  4. Disease that has progressed after standard therapy for the specific tumor type, or for which standard therapy has proven to be ineffective, intolerable, or is considered inappropriate, or if no further standard therapy exists
    • Participants whose cancers harbor molecular alterations for which targeted therapy is standard of care should have received local health authority-approved appropriate targeted therapy for their tumor type(s) prior to enrollment
    • Participants in the PK/PD cohorts with NSCLC must have received a platinum- containing chemotherapy regimen and an anti-PD(L)1 mAb-containing regimen
  5. Excepting cases in which biopsy requirements are waived by the medical monitor due to safety considerations, participants must provide a tumor biopsy during the Screening period from a tumor lesion not previously irradiated and agree to an additional on-treatment biopsy approximately 6 weeks after first dose of study intervention.  (Note: The biopsy must be collected from a tumor lesion not previously irradiated and tumor lesions planned for biopsy must not be followed as target lesions for disease assessment.  Participants with only 1 target lesion that is also the only lesion available for biopsy are not eligible unless biopsy requirements are waived by the medical monitor.)
  6. Measurable disease per RECIST 1.1
  7. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1
  8. Life expectancy of at least 12 weeks
  9. Adequate organ function, as defined in

Table 12  Definitions for Adequate Organ Function

System Laboratory Values
Hematologica  
ANC ≥1.5x109/L
Hemoglobin  ≥9 g/dL
Platelets ≥100x109/L
PT/INR and PTT (unless participant is receiving anticoagulant therapy, in which case PT/INR or PTT must be within therapeutic range of intended use of anticoagulants) <1.5x ULN
Hepatic  

Total bilirubin

For participants with Gilbert’s Syndrome (only if direct bilirubin ≤35%)

≤1.5x ULN

≤3.0x ULN

ALT and AST

For participants with liver metastases/tumor infiltration/HCC

≤2.5x ULN

≤5x ULN
Renal  

Serum Creatinine OR

Estimated GFRb

≤1.5x ULN

>60 mL/min/1.73m2

Endocrine  
TSHc WNL
Cardiac  
Ejection Fraction ≥50% by echocardiogram

Abbreviations: ALT = alanine aminotransferase; ANC = Absolute neutrophil count; AST = aspartate aminotransferase; G-CSF = granulocyte-colony stimulating factor; GFR = glomerular filtration rate; HCC = hepatocellular carcinoma; INR = international normalized ratio; PT = prothrombin time; PTT = partial thromboplastin time; TSH = thyroid stimulating hormone; ULN = upper limit of normal; WNL = within normal limits.

a. Hematologic criteria must be met without transfusion of blood products (including platelets or red blood cells) or administration of G-CSF for at least 14 days prior to sample collection.

b. Estimated GFR to be calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula.

c. If TSH is not within institutional normal limits at baseline, the participant may still be eligible if total T3 or free T3 and free T4 are within normal limits.

Exclusion Criteria
  1. Prior treatment with the following therapies (from last dose of prior treatment to first dose of GSK6097608):
    • Any therapy directed against CD96 (eg, anti-CD96 mAb) at any time
    • Immune-checkpoint inhibitors, including PD-1, PD-L1, and CTLA-4 inhibitors, within 4 weeks
    • Other anticancer therapy, including chemotherapy, targeted therapy, and biological therapy: within 4 weeks or 5 half-lives of the drug, whichever is shorter.  Prior radiation therapy is permissible if at least 1 nonirradiated measurable lesion is available for assessment via RECIST 1.1.  A washout between radiation and the start of study intervention is required as follows: 1) at least 2 weeks for palliative radiation to the extremities for osseous bone metastases; 2) at least 4 weeks for radiation to the chest, brain, or visceral organs is required; and 3) at least 6 weeks for large-field radiation.
    • Investigational therapy: if the participant has participated in a clinical study and has received an investigational product within 4 weeks or 5 half-lives of the investigational product (whichever is shorter)
  2. Prior allogenic or autologous bone marrow transplantation or other solid organ transplantation
  3. Toxicity from previous anticancer treatment, including
    • ≥ Grade 3 immune-mediated toxicity considered related to prior immunotherapy and that led to treatment discontinuation; or
    • Toxicity related to prior treatment that has not resolved to Grade 1 (except alopecia, hearing loss, vitiligo, endocrinopathy managed with replacement therapy, and Grade 2 neuropathy)
  4. Participant has a known additional malignancy that progressed or required active treatment within the last 2 years.  Participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen may be included only after approval from the medical monitor.
  5. Uncontrolled or symptomatic central nervous system (CNS) metastases and/or carcinomatous meningitis.  Note: Participants with previously treated brain metastases may participate provided they are asymptomatic (any neurologic symptoms have returned to baseline [participants may be receiving stable doses of anticonvulsants]), radiographically stable (without evidence of progression by imaging for at least 4 weeks prior to the first dose of study treatment), have no evidence of new or enlarging brain metastases, and are clinically stable off steroids for at least 2 weeks prior to study treatment.  Participants with carcinomatous meningitis or leptomeningeal spread are excluded regardless of clinical stability.
  6. Active autoimmune disease that has required systemic disease-modifying or immunosuppressive treatment within the last 2 years. (Note: Stable, medically managed autoimmune endocrinopathies are acceptable if participant otherwise meets entry criteria.)
  7. Concurrent medical condition requiring the use of systemic immunosuppressive treatment within 28 days before the first dose of study intervention. Physiologic doses of corticosteroids for treatment of endocrinopathies or steroids with minimal systemic absorption, including topical, inhaled, or intranasal corticosteroids may be continued if the participant is on a stable dose. (Note: Corticosteroid premedication for contrast allergy is permitted.)
  8. Cirrhosis or current unstable liver or biliary disease per investigator assessment, defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice
    • Stable noncirrhotic chronic liver disease (including Gilbert’s syndrome or asymptomatic gallstones) is acceptable if participant otherwise meets entry criteria
    • Participants with HCC may be eligible if participant otherwise meets entry criteria unless any of the following are present:
      • Encephalopathy in the last 6 months.  Participants on rifaximin or lactulose to control their encephalopathy are not allowed;
      • Esophageal or gastric variceal bleeding within the last 6 months;
      • Child-Pugh Class B or Class C, assessed during Screening;
      • Portal vein invasion at the main portal branch (Vp4), inferior vena cava, or cardiac involvement of HCC based on imaging;
      • Clinically significant ascites evident on imaging (more than trace) and/or clinical examination
  9. Active infection requiring systemic treatment, known human immunodeficiency virus infection, or positive test for hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV).  Participants who test positive for HCV antibodies are eligible if HCV RNA is undetectable.
  10. QTcF >450 msec for male participants, >470 msec for female participants, or >480 msec for participants with bundle branch block. QTcF is QT corrected for heart rate according to Fridericia’s formula and can be machine calculated or manually over-read
  11. Allergen desensitization therapy within 4 weeks of starting study intervention
  12. History of hypersensitivity to mAbs. For Arm B, history of hypersensitivity to dostarlimab or its excipients
  13. History or evidence of cardiovascular (CV) risk including any of the following:
    • Recent history (within 6 months) of serious uncontrolled cardiac arrhythmia or clinically significant ECG abnormalities including second degree (Type II) or third-degree atrioventricular block
    • Cardiomyopathy, myocardial infarction, acute coronary syndromes (including unstable angina pectoris), coronary angioplasty, stenting, or bypass grafting within 6 months
    • Congestive heart failure (Class II, III, or IV) as defined by the New York Heart Association Functional Classification System
    • Recent history (within 6 months) of symptomatic pericarditis
  14. Recent history (within 6 months) of uncontrolled symptomatic ascites or pleural effusions
  15. History of idiopathic pulmonary fibrosis; interstitial lung disease; organizing pneumonia; noninfectious pneumonitis that required steroids, or evidence of active, noninfectious pneumonitis.  (Note: postradiation changes in the lung related to prior radiotherapy and/or asymptomatic radiation induced pneumonitis not requiring treatment may be permitted if agreed by investigator and sponsor.)
  16. Any serious and/or unstable pre-existing medical, psychiatric disorder, or other condition that could interfere with the participant’s safety, obtaining informed consent, or compliance with the study procedures
  17. Pregnant or lactating woman 
  18. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or child) who is study site or sponsor staff directly involved with this study, unless prospective Institutional Review Board (IRB) approval (by chair or designee) is given allowing exception to this criterion for a specific participant
  19. Receipt of live vaccine within 30 days of the start of study intervention
  20. Receipt of transfusion of blood products (including platelets or red blood cells) or administration of colony-stimulating factors (including granulocyte-colony stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor, and recombinant erythropoietin) within 14 days before the first dose of study intervention
  21. Major surgery less than 4 weeks before the first dose of study intervention.  Participants must have also fully recovered from any surgery (major or minor) and/or its complications before initiating study intervention.
  22. Known drug or alcohol abuse

Location

  • Dallas, TX - Mary Crowley Cancer Research - Medical City
More Info: https://www.clinicaltrials.gov/ct2/show/NCT04446351

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Re: MC# 20-15