MC# 17-39 - A Phase I, Open-Label Study of GSK1795091 Administered in Combination with Immunotherapies in Participants with Advanced Solid Tumors

  • Agent(s): GSK1795091, GSK3174998, GSK3359609
  • Disease Type(s): Bladder, Breast, Cervical, Colorectal, Endometrial, Esophageal, Gastric, Head and Neck, Hepatocellular, Lung-NSCLC, Lung-SCLC, Lymphoma, Melanoma, Mesothelioma, Neuroendocrine, Ovarian, Pancreatic, Prostate, Renal, Sarcoma, Solid Tumor, Squamous Cell, Thyroid, Cholangiocarcinoma
  • Phase(s): I
  • Drug Classification(s): Targeted Therapy, Immunotherapy, Monoclonal Antibody
  • Molecular Target(s): OX40, TLR4, ICOS

Mechanism of Action

  • GSK1795091 is an agonist of TLR4 that induces immunologic responses in vitro and in vivo -- stimulates cytokine production, changes in immune cell populations, and generates fever response.
  • GSK3174998 is a humanized wild-type IgG1 anti-OX40 agonistic mAb that works by promoting effector CD4+ T-cell proliferation, inhibiting the induction of IL-10-producing CD4+ Type 1 regulatory cells and blocking the suppressive function of natural Tregs, and binding to the fragment crystallizable region receptor, which is anticipated to augment OX40 signaling via cross-linking of the antibody via the Fc domain on FcR positive cells.
  • GSK3359609, an anti-ICOS agonist antibody, targets and binds to ICOS expressed on tumor infiltrating CD4-positive T cells. This stimulates ICOS-positive T-cell proliferation, enhances cytotoxic T-lymphocyte (CTL) survival and increases CTL-mediated immune responses against tumor cells.

Purpose

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

  • How much of the study drugs can be given with an acceptable level of side effects
  • The effects of the study drugs (good and bad)
  • How much of the study drugs are absorbed into the blood and how fast they are removed
Inclusion Criteria

Age

  • Participant must be > 18 years of at the time of signing the informed consent.

Type of Participant and Disease Characteristics

  • Histological documentation of advanced solid tumor, other than TNBC (defined per ASCO/CAP guidelines).
  • Archival tumor tissue obtained at any time from the initial diagnosis to study entry. Although a fresh biopsy obtained during screening is preferred, archival tumor specimen is acceptable if it is not feasible to obtain a fresh biopsy.

Note: Participants enrolled in a PK/Pharmacodynamic Cohort must provide a fresh biopsy of a tumour lesion not previously irradiated during the screening period and must agree to provide at least one additional on-treatment biopsy.

  • Disease that has progressed after standard therapies or for which standard therapy is otherwise unsuitable (e.g., intolerance).
  • Measurable disease, i.e., presenting with at least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST version 1.1).
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1.
  • Life expectancy of at least 12 weeks.
  • Adequate organ function defined as:
System Laboratory Values
 Hematologic  
   ANC 1.5 x 109/ L
   Hemoglobina > 9 g/dL
   Plateletsa > 100 x 109/L

   PT/INR and PTT

   (unless participant is receiving anticoagulant)

< 1.5 x ULN
 Hepatic  

   Total Bilirubin

   For participants with Gilbert's Syndrome

   (only if direct bilirubin < 35%)

< 1.5 x ULN

< 3.0 x ULN

 

   ALT < 1.5 x ULN
 Renal  
   Calculated CrClb > 50 mL/min
 Endocrine  
   TSHc WNL
 Cardiac  
   Ejection Fraction > 50 % by echocardiogramd

 

 

 

 

 

 

 

 

 

 

 

a Participants must maintain haemoglobin and/or platelet values for at least 2 weeks without transfusion or growth factor support.

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

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

d Multigated acquisition scan (MUGA) is acceptable if echocardiography is not available

Sex

  •  Male or female

Female participants:

A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least 1 of the following conditions applies:

  • Not a woman of childbearing potential (WOCBP)      OR
  • A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 120 days after the last dose of study treatment.

Informed Consent

  • Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

Additional Inclusion Criteria for Patients in Parts 2a and 2b

  • Histological or cytological documentation of SCCHN (oral cavity, oropharynx, hypopharynx, or larynx) that is recurrent, locally advanced, or metastatic.
  • No more than 3 prior lines of systemic therapy for metastatic disease.

Additional Inclusion Criteria for Patients in Part 2c

  • Histological or cytological documentation of SCCHN (oral cavity, oropharynx, hypopharynx, or larynx) that is recurrent, locally advanced, or metastatic and is not amenable to curative treatment options, surgery or definitive chemoradiation therapy.
  • Received or ineligible for platinum-based therapy.
  • Received no more than 2 prior lines of systemic therapy for metastatic disease.
Exclusion Criteria

Medical Conditions

  • Malignancy other than disease under study with the exception of those from which the participant has been disease-free for more than 2 years and not expected to affect the safety of the participant or the endpoints of the trial.
  • Active autoimmune disease that has required systemic disease modifying or immunosuppressive treatment within the last 2 years.
  • Symptomatic central nervous system (CNS) metastases or asymptomatic CNS metastases that have required steroids within 2 weeks prior to first dose of study treatment.

Note: Replacement therapy (e.g., thyroxine or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is permitted.

  • Concurrent medical condition requiring the use of systemic immunosuppressive treatment within 28 days before the first dose of study treatment.
  • Current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, persistent jaundice, or cirrhosis.
  • Known human immunodeficiency virus infection.

Note: Stable chronic liver disease (including Gilbert’s syndrome or asymptomatic gallstones) or hepatobiliary involvement of malignancy is acceptable if participant otherwise meets entry criteria.

  • Presence of Hepatitis B surface antigen (HBsAg) at screening or within 3 months prior to first dose of study treatment
  • Positive Hepatitis C test result at screening or within 3 months prior to first dose of study treatment.

Note: Participants with positive Hepatitis C antibody due to prior resolved disease can be enrolled, only if a confirmatory negative Hepatitis C RNA test is obtained. Participants with negative Hepatitis C antibody test are not required to also undergo Hepatitis C RNA testing

  • QTcF >450 msec or QTcF >480 msec for participants with bundle branch block

The QTcF is the QT interval corrected for heart rate according to Fridericia’s formula, machine-read or manually over-read.

  • Recent history (within the past 6 months) of acute diverticulitis, inflammatory bowel disease, intra-abdominal abscess, or gastrointestinal obstruction.
  • Recent history of allergen desensitization therapy within 4 weeks of starting study treatment.
  • History of severe hypersensitivity to mAbs.
  • History or evidence of cardiovascular (CV) risk including any of the following:
    • Recent (within the past 6 months) history 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 the past 6 months before enrollment.
    • Congestive heart failure (Class II, III, or IV) as defined by the New York Heart Association functional classification system.
    • Recent (within the past 6 months) history of symptomatic pericarditis.
  • History of idiopathic pulmonary fibrosis, pneumonitis, interstitial lung disease, or organizing pneumonia, or evidence of active, non-infectious pneumonitis. Note: post-radiation changes in the lung related to prior radiotherapy and/or asymptomatic radiation-induced pneumonitis not requiring treatment may be permitted if agreed by the investigator and Sponsor.
  • Recent history (within 6 months) of uncontrolled symptomatic ascites or pleural effusions.
  • 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 to the study procedures.
  • Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or child) who is investigational site or sponsor staff directly involved with this trial, unless prospective Institutional Review Board (IRB) approval (by chair or designee) is given allowing exception to this criterion for a specific participant.

Prior/Concomitant Therapy

  • Prior treatment with the following agents:
    • Tumor necrosis factor receptor (TNFR) agonists, including OX40, CD27, CD137 (4-1BB), CD357 (glucocorticoid-induced TNFR family-related gene) at any time.
    • TLR4 agonist at any time.
    • Anticancer therapy or investigational therapy within 30 days or 5 half-lives of the drug, whichever is shorter.
    • Prior radiation therapy: permissible if at least 1 non-irradiated measurable lesion is available for assessment according to RECIST version 1.1 or if a solitary measurable lesion was irradiated, objective progression is documented. A wash out of at least 14 days before start of study treatment for radiation of any intended use to the extremities for bone metastases and 28 days for radiation to the chest, brain, or visceral organs is required.
  • Prior allogeneic or autologous bone marrow transplantation or other solid organ transplantation.
  • Toxicity from previous treatment including:
    • Toxicity Grade ≥3 related to prior immunotherapy and that lead to study treatment discontinuation.
    • Toxicity related to prior treatment has not resolved to Grade > 1 (except alopecia, or endocrinopathy managed with replacement therapy).
  • Received transfusion of blood products (including platelets or red blood cells) or administration of colony stimulating factors (including G-CSF, granulocyte- macrophage colony-stimulating factor, and recombinant erythropoietin) within 2 weeks before the first dose of study treatment.

Additional Exclusion Criteria for Patients in Part 2c

  • Received prior PD-1/PD-L1 therapy.

Other Exclusions

  • Major surgery < 4 weeks before the first dose of study treatment. Participants must have also fully recovered from any surgery (major or minor) and/or its complications before initiating study treatment.
  • Known drug or alcohol abuse.
  • Receipt of any live vaccine within 4 weeks.

Location

  • Dallas, TX - Mary Crowley Cancer Research - Medical City
More Info: https://clinicaltrials.gov/ct2/show/NCT03447314?term=NCT03447314&rank=1

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Re: MC# 17-39