Clinical Trials /

Study of a Combination of GSK1795091 and Immunotherapies in Subjects With Advanced Solid Tumors

NCT03447314

Description:

GSK1795091 is being developed for administration in combination with other immune system modulators for the treatment of cancers. The study will be conducted in two parts. In Part 1, dose escalation will be performed to identify combination dose levels comprising GSK1795091 with either 24 milligrams (mg) GSK3174998 (Part 1a), 80 mg GSK3359609 (Part 1b), or 200 mg pembrolizumab (Part 1c). One dose level of GSK3174998, GSK3359609, or pembrolizumab with up to 5 dose levels of GSK1795091 are planned for evaluation. In Part 2 (dose-expansion), subjects will receive a single dose level of GSK1795091 as identified based on data from Part 1, in combination with either GSK3174998, GSK3359609, or pembrolizumab.

Related Conditions:
  • Breast Carcinoma
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Study of a Combination of GSK1795091 and Immunotherapies in Subjects With Advanced Solid Tumors
  • Official Title: A Phase I, Open-Label Study of GSK1795091 Administered in Combination With Immunotherapies in Participants With Advanced Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: 204686
  • NCT ID: NCT03447314

Conditions

  • Neoplasms

Interventions

DrugSynonymsArms
GSK1795091Part 1c: pembrolizumab 200 mg
GSK3174998Part 1: PK/Pharmacodynamic cohort
GSK3359609Part 2b: GSK3359609 80 mg
PembrolizumabPart 1c: pembrolizumab 200 mg

Purpose

GSK1795091 is being developed for administration in combination with other immune system modulators for the treatment of cancers. The study will be conducted in two parts. In Part 1, dose escalation will be performed to identify combination dose levels comprising GSK1795091 with either 24 milligrams (mg) GSK3174998 (Part 1a), 80 mg GSK3359609 (Part 1b), or 200 mg pembrolizumab (Part 1c). One dose level of GSK3174998, GSK3359609, or pembrolizumab with up to 5 dose levels of GSK1795091 are planned for evaluation. In Part 2 (dose-expansion), subjects will receive a single dose level of GSK1795091 as identified based on data from Part 1, in combination with either GSK3174998, GSK3359609, or pembrolizumab.

Trial Arms

NameTypeDescriptionInterventions
Part 1a: GSK3174998 24 mgExperimentalIn Part 1, subjects with advanced solid tumors will be enrolled. Part 1a will have up to five dose escalation cohorts to investigate the safety and tolerability of escalating doses of GSK1795091 in combination with GSK3174998 24 mg.
  • GSK1795091
  • GSK3174998
Part 1b: GSK3359609 80 mgExperimentalIn Part 1, subjects with advanced solid tumors will be enrolled. Part 1b will have up to five dose escalation cohorts to investigate the safety and tolerability of escalating doses of GSK1795091 in combination with GSK3359609 80 mg.
  • GSK1795091
  • GSK3359609
Part 1c: pembrolizumab 200 mgExperimentalIn Part 1, subjects with advanced solid tumors will be enrolled. Part 1c will have up to five dose escalation cohorts to investigate the safety and tolerability of escalating doses of GSK1795091 in combination with pembrolizumab 200 mg.
  • GSK1795091
  • Pembrolizumab
Part 1: PK/Pharmacodynamic cohortExperimentalSubjects will be enrolled into PK/PD cohort to collect additional data on safety, PK, and pharmacodynamic endpoints. Subjects will be enrolled at previously completed dose levels following dose escalation.
  • GSK1795091
  • GSK3174998
  • GSK3359609
  • Pembrolizumab
Part 2a: GSK3174998 24 mgExperimentalIn Part 2, subjects with recurrent, locally advanced or metastatic SCCHN will be included. Subjects will be administered GSK1795091 at a dose identified in Part 1 along with GSK3174998 24 mg.
  • GSK1795091
  • GSK3174998
Part 2b: GSK3359609 80 mgExperimentalIn Part 2, subjects with recurrent, locally advanced or metastatic SCCHN will be included. Subjects will be administered GSK1795091 at a dose identified in Part 1 along with GSK3359609 80 mg.
  • GSK1795091
  • GSK3359609
Part 2c: pembrolizumab 200 mgExperimentalIn Part 2, subjects with recurrent, locally advanced or metastatic SCCHN will be included. Subjects will be administered GSK1795091 at a dose identified in Part 1 along with pembrolizumab 200 mg.
  • GSK1795091
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          -  Subject must be >=18 years of at the time of signing the informed consent.

          -  Histological documentation of advanced solid tumor.

          -  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. Subjects
             enrolled in a PK/Pharmacodynamic Cohort must provide a fresh biopsy of a tumor 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 (example, intolerance).

          -  Measurable disease, that is, 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.

          -  In France, a subject will be eligible for inclusion in this study only if either
             affiliated to or a beneficiary of a social security category.

          -  Male or female subjects will be included. A female subject is eligible to participate
             if she is not pregnant, not breastfeeding, and at least 1 of the following conditions
             applies: a) Not a woman of childbearing potential (WOCBP) OR b). 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.

          -  Capable of giving signed informed consent which includes compliance with the
             requirements and restrictions specified.

        Additional Inclusion criteria for Subjects in Part 2a (GSK3174998 expansion) and Part 2b
        (GSK3359609 expansion):

          -  Histological or cytological documentation of squamous cell carcinoma of the head and
             neck (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 and Programmed death receptor-1
             (PD-1)/programmed death-ligand 1 (PD-L1) therapy

          -  Received no more than 3 prior lines of systemic therapy for metastatic disease.

        Additional Inclusion Criteria for Subjects in Part 2c (pembrolizumab expansion):

          -  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:

          -  Malignancy other than disease under study with the exception of those from which the
             subject has been disease-free for more than 2 years and not expected to affect the
             safety of the subject or the endpoints of the trial.

          -  Symptomatic central nervous system (CNS) metastases or asymptomatic CNS metastases
             that have required steroids within 2 weeks prior to first dose of study treatment.

          -  Active autoimmune disease that has required systemic disease modifying or
             immunosuppressive treatment within the last 2 years. Replacement therapy (example,
             thyroxine or physiologic corticosteroid replacement therapy for adrenal or pituitary
             insufficiency) is permitted.

          -  Concurrent medical condition requiring the use of systemic immunosuppressive treatment
             within 28 days before the first dose of study treatment.

          -  Known human immunodeficiency virus infection.

          -  Current unstable liver or biliary disease per investigator assessment defined by the
             presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or
             gastric varices, persistent jaundice, or cirrhosis.

          -  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.

          -  QT interval corrected for heart rate according to Fridericia's formula (QTcF) >450
             milliseconds (msec) or QTcF >480 msec for subjects with bundle branch block

          -  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 monoclonal antibodies (mAbs).

          -  History or evidence of cardiovascular (CV) risk including any of the following: a)
             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. b) Cardiomyopathy, myocardial infarction, acute
             coronary syndromes (including unstable angina pectoris), coronary angioplasty,
             stenting, or bypass grafting within the past 6 months before enrollment. c) Congestive
             heart failure (Class II, III, or IV) as defined by the New York Heart Association
             (NYHA) functional classification system. d) 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.

          -  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 subject's safety, obtaining informed consent,
             or compliance to the study procedures.

          -  Is or has an immediate family member (example, 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 subject.

          -  Prior treatment with the following agents: a) Tumor necrosis factor receptor (TNFR)
             agonists, including OX40, cluster of differentiation (CD)27, CD137 (4-1BB), CD357
             (glucocorticoid-induced TNFR family-related gene) at any time. b) Prior systemic or
             intratumoral therapy with TLR agonist. c) Anticancer therapy or investigational
             therapy within 30 days or 5 half-lives of the drug, whichever is shorter. d) 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: a) Toxicity Grade >=3 related to prior
             immunotherapy and that lead to study treatment discontinuation. b) 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 granulocyte colony-stimulating
             factor [G-CSF], granulocyte macrophage colony-stimulating factor, and recombinant
             erythropoietin) within 2 weeks before the first dose of study treatment.

          -  Major surgery <=4 weeks before the first dose of study treatment. Subjects 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.

        Additional Exclusion Criteria for Subjects in Part 2c

          -  Received prior PD-1/PD-L1 therapy.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of subjects with adverse events (AEs) and serious adverse events (SAEs)
Time Frame:Up to 2 years
Safety Issue:
Description:AEs will be assessed at each visit from first dose until the treatment discontinuation visit (TDV) and until 90 days after last dose for adverse events of special interest (AESI) and SAEs.

Secondary Outcome Measures

Measure:Objective response rate
Time Frame:Up to 2 years
Safety Issue:
Description:Objective response rate is defined as percentage of subjects with complete response (CR) or partial response (PR). Objective response rate will be evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
Measure:Disease control rate
Time Frame:Up to 2 years
Safety Issue:
Description:Disease control rate is defined as percentage of subjects with CR or PR or at least 12 weeks of stable disease. Disease control rate will be evaluated according to RECIST 1.1.
Measure:Time to response
Time Frame:Up to 2 years
Safety Issue:
Description:Time to response is defined as the time from the date of first dose to the date of the first documented evidence of response (PR or CR).
Measure:Duration of response
Time Frame:Up to 2 years
Safety Issue:
Description:Duration of response is defined as the time from first documented evidence of CR or PR until disease progression or death due to any cause among subjects who achieve an overall response (that is, unconfirmed or confirmed CR or PR)
Measure:Number of subjects with progression-free survival (PFS)
Time Frame:Up to 2 years
Safety Issue:
Description:PFS is defined as time from the date of first dose to the date of disease progression according to clinical or radiological assessment or death due to any causes, whichever occurs earliest.
Measure:Number of subjects with overall survival
Time Frame:Up to 2 years
Safety Issue:
Description:Overall survival is defined as time from the date of first dose to the date of death due to any cause.
Measure:Plasma concentration of GSK1795091-Part 1
Time Frame:Day15 (pre-dose,10minutes,4hours post-dose),Day16 (24hours post-dose),Day22 (pre-dose),Day57 (pre-dose,10minutes,4hours post-dose),Day58 (24hours post-dose), Day64 (pre-dose,10minutes post-dose),10minutes post-dose on Day78 and every 12weeks for 2years
Safety Issue:
Description:Blood samples will be collected at indicated time points for the determination of plasma concentration of GSK1795091. Pre-dose indicates the blood sample will be collected within 60 minutes before the start of the GSK3174998, GSK3359609, or pembrolizumab infusion.
Measure:Plasma concentration of GSK1795091-Part 2
Time Frame:Day1 (pre-dose, 10minutes, 2, 4, 6hours post-dose), Day8 (pre-dose), Day22 (10minutes post-dose), Day43 (pre-dose, 10minutes, 4 hours post-dose), Day50 (pre-dose, 10minutes post-dose), 10minutes post-dose on Day64, Day85 and then every 12weeks for 2years
Safety Issue:
Description:Blood samples will be collected at indicated time points for the determination of plasma concentration of GSK1795091. Pre-dose indicates the blood sample will be collected within 60 minutes before the start of the GSK3174998, GSK3359609, or pembrolizumab infusion. For Days 8 and 50, pre-dose indicates the blood sample will be collected within 60 minutes before the start of the GSK1795091 injection.
Measure:Maximum plasma concentration (Cmax) of GSK1795091-Part 1
Time Frame:Day15 (pre-dose,10minutes,4hours post-dose),Day16 (24hours post-dose),Day22 (pre-dose),Day57 (pre-dose,10minutes,4hours post-dose),Day58 (24hours post dose), Day64 (pre-dose,10minutes post-dose),10minutes post-dose on Day78 and every 12weeks for 2years
Safety Issue:
Description:Blood samples will be collected at indicated time points for determination of Cmax. Pre-dose indicates the blood sample will be collected within 60 minutes before the start of the GSK3174998, GSK3359609, or pembrolizumab infusion.
Measure:Cmax of GSK1795091-Part 2
Time Frame:Day1 (pre-dose, 10minutes, 2, 4, 6hours post-dose), Day8 (pre-dose), Day22 (10minutes post-dose), Day43 (pre-dose, 10minutes, 4 hours post-dose), Day50 (pre-dose, 10minutes post-dose), 10minutes post-dose on Day64, Day85 and then every 12weeks for 2years
Safety Issue:
Description:Blood samples will be collected at indicated time points for determination of Cmax. Pre-dose indicates the blood sample will be collected within 60 minutes before the start of the GSK3174998, GSK3359609, or pembrolizumab infusion. For Days 8 and 50, pre-dose indicates the blood sample will be collected within 60 minutes before the start of the GSK1795091 injection.
Measure:Area under the concentration-time curve over the dosing interval (AUC [0-tau]) GSK1795091-Part 1
Time Frame:Day15 (pre-dose,10minutes,4hours post-dose),Day16 (24hours post-dose),Day22 (pre-dose),Day57 (pre-dose,10minutes,4hours post-dose),Day58 (24hours post-dose), Day64 (pre-dose,10minutes post-dose),10minutes post-dose on Day78 and every 12weeks for 2years
Safety Issue:
Description:Blood samples will be collected at indicated time points for determination of AUC (0-tau). Pre-dose indicates the blood sample will be collected within 60 minutes before the start of the GSK3174998, GSK3359609, or pembrolizumab infusion.
Measure:AUC (0-tau) of GSK1795091-Part 2
Time Frame:Day1 (pre-dose, 10minutes, 2, 4, 6hours post-dose), Day8 (pre-dose), Day22 (10minutes post-dose), Day43 (pre-dose, 10minutes, 4 hours post-dose), Day50 (pre-dose, 10minutes post-dose), 10minutes post-dose on Day64, Day85 and then every 12weeks for 2years
Safety Issue:
Description:Blood samples will be collected at indicated time points for determination of AUC (0-tau). Pre-dose indicates the blood sample will be collected within 60 minutes before the start of the GSK3174998, GSK3359609, or pembrolizumab infusion. For Days 8 and 50, pre-dose indicates the blood sample will be collected within 60 minutes before the start of the GSK1795091 injection.
Measure:Trough plasma concentrations (Ctrough) of GSK1795091-Part 1
Time Frame:Day15 (pre-dose,10minutes,4hours post-dose),Day16 (24hours post-dose),Day22 (pre-dose),Day57 (pre-dose,10minutes,4hours post-dose),Day58 (24hours post-dose), Day64 (pre-dose,10minutes post-dose),10minutes post-dose on Day78 and every 12weeks for 2years
Safety Issue:
Description:Blood samples will be collected at indicated time points for determination of Ctrough. Pre-dose indicates the blood sample will be collected within 60 minutes before the start of the GSK3174998, GSK3359609, or pembrolizumab infusion.
Measure:Ctrough of GSK1795091-Part 2
Time Frame:Day1 (pre-dose, 10minutes, 2, 4, 6hours post-dose), Day8 (pre-dose), Day22 (10minutes post-dose), Day43 (pre-dose, 10minutes, 4 hours post-dose), Day50 (pre-dose, 10minutes post-dose), 10minutes post-dose on Day64, Day85 and then every 12weeks for 2years
Safety Issue:
Description:Blood samples will be collected at indicated time points for determination of Ctrough. Pre-dose indicates the blood sample will be collected within 60 minutes before the start of the GSK3174998, GSK3359609, or pembrolizumab infusion. For Days 8 and 50, pre-dose indicates the blood sample will be collected within 60 minutes before the start of the GSK1795091 injection.
Measure:Number of subjects who develop detectable antidrug antibody (ADA) against GSK3174998
Time Frame:Up to 2 years
Safety Issue:
Description:Serum samples will be collected and tested for the presence of antibodies that bind to GSK3174998.
Measure:Number of subjects who develop ADA against GSK3359609
Time Frame:Up to 2 years
Safety Issue:
Description:Serum samples will be collected and tested for the presence of antibodies that bind to GSK3359609.
Measure:Number of subjects who develop ADA against pembrolizumab
Time Frame:Up to 2 years
Safety Issue:
Description:Serum samples will be collected and tested for the presence of antibodies that bind to pembrolizumab.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:GlaxoSmithKline

Trial Keywords

  • pembrolizumab
  • GSK1795091
  • Dose-escalation
  • 204686
  • Immunotherapies
  • GSK3359609
  • Phase I
  • anticancer agent
  • OX40
  • 201212
  • 204691
  • ICOS
  • TLR4
  • GSK3174998
  • Advanced Solid Tumors

Last Updated