Clinical Trials /

GSK3174998 Alone or With Pembrolizumab in Subjects With Advanced Solid Tumors (ENGAGE-1)

NCT02528357

Description:

This is a first time in human (FTIH), open-label, non-randomized, multicenter study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and preliminary clinical activity of GSK3174998 administered intravenously to subjects with selected advanced or recurrent solid tumors. This dose-escalation study will assess the safety, activity of GSK3174998 as monotherapy (Part 1), in combination with pembrolizumab (Part 2), and potentially in combination with additional therapies. The study will be conducted in 2 parts, each part consisting of a dose-escalation phase followed by a cohort expansion phase. Part 1 will evaluate GSK3174998 monotherapy, while Part 2 will evaluate GSK3174998 in combination with pembrolizumab. GSK3174998 will first be evaluated as monotherapy in escalating doses. Once a dose of GSK3174998 has been identified that is both tolerable and demonstrates pharmacodynamic activity, enrollment of Part 2 may begin. In Part 2, escalating doses of GSK3174998 will be evaluated with fixed doses of pembrolizumab. The study will enroll up to approximately 264 subjects with different tumor types (approximately 144 subjects in Parts 1A and 2A [dose escalation]; approximately 120 subjects in Parts 1B and 2B [cohort expansion]). The maximum duration of treatment with GSK3174998 plus or minus pembrolizumab will be 2 years or 35 cycles, whichever comes first. The follow-up period for safety assessments will be a minimum of 3 months from the date of the last dose. The post-treatment follow-up period includes disease assessments every 12 weeks.

Related Conditions:
  • Bladder Carcinoma
  • Breast Carcinoma
  • Colorectal Carcinoma
  • Head and Neck Squamous Cell Carcinoma
  • Melanoma
  • Non-Small Cell Lung Carcinoma
  • Renal Cell Carcinoma
  • Soft Tissue Sarcoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

<span class="go-doc-concept go-doc-intervention">GSK3174998</span> Alone or With <span class="go-doc-concept go-doc-intervention">Pembrolizumab</span> in Subjects With Advanced Solid Tumors (ENGAGE-1)

Title

  • Brief Title: GSK3174998 Alone or With Pembrolizumab in Subjects With Advanced Solid Tumors (ENGAGE-1)
  • Official Title: A Phase I, Open-Label Study of GSK3174998 Administered Alone and in Combination With Anticancer Agents Including Pembrolizumab in Subjects With Selected Advanced Solid Tumors
  • Clinical Trial IDs

    NCT ID: NCT02528357

    ORG ID: 201212

    Trial Conditions

    Cancer

    Trial Interventions

    Drug Synonyms Arms
    GSK3174998 Part 2A: GSK3174998+ pembrolizumab - Dose escalation, Part 2B: GSK3174998+ pembrolizumab - Cohort expansion, Part 1A: GSK3174998 Monotherapy- Dose escalation, Part 1B: GSK3174998 Monotherapy- Cohort expansion
    Pembrolizumab Part 2A: GSK3174998+ pembrolizumab - Dose escalation, Part 2B: GSK3174998+ pembrolizumab - Cohort expansion

    Trial Purpose

    This is a first time in human (FTIH), open-label, non-randomized, multicenter study designed
    to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and
    preliminary clinical activity of GSK3174998 administered intravenously to subjects with
    selected advanced or recurrent solid tumors.

    This dose-escalation study will assess the safety, activity of GSK3174998 as monotherapy
    (Part 1), in combination with pembrolizumab (Part 2), and potentially in combination with
    additional therapies.

    The study will be conducted in 2 parts, each part consisting of a dose-escalation phase
    followed by a cohort expansion phase. Part 1 will evaluate GSK3174998 monotherapy, while
    Part 2 will evaluate GSK3174998 in combination with pembrolizumab.

    GSK3174998 will first be evaluated as monotherapy in escalating doses. Once a dose of
    GSK3174998 has been identified that is both tolerable and demonstrates pharmacodynamic
    activity, enrollment of Part 2 may begin. In Part 2, escalating doses of GSK3174998 will be
    evaluated with fixed doses of pembrolizumab.

    The study will enroll up to approximately 180 subjects with different tumor types
    (approximately 60 subjects in Parts 1A and 2A [dose escalation]; approximately 120 subjects
    in Parts 1B and 2B [cohort expansion]). The maximum duration of treatment with GSK3174998
    will be 48 weeks; the maximum duration of treatment with pembrolizumab will be 2 years. The
    follow-up period for safety assessments will be a minimum of 3 months from the date of the
    last dose. The post-treatment follow-up period includes disease assessments every 12 weeks.

    Detailed Description

    Trial Arms

    Name Type Description Interventions
    Part 1A: GSK3174998 Monotherapy- Dose escalation Experimental Subjects will receive GSK3174998 intravenously (IV) (dose range 0.003 to 10.0 milligram per kilogram [mg/kg]) every 3 weeks (Q3W) for up to 48 weeks GSK3174998
    Part 1B: GSK3174998 Monotherapy- Cohort expansion Experimental Subjects will receive GSK3174998 IV (at one dose level shown to be tolerable in dose escalation part 1A) Q3W for up to 48 weeks, in expansion cohorts. GSK3174998
    Part 2A: GSK3174998+ pembrolizumab - Dose escalation Experimental Subjects will receive GSK3174998 IV (dose range 0.003 to 10.0 mg/kg) Q3W for up to 48 weeks + Pembrolizumab 200 mg IV Q3W for up to 2 years. GSK3174998, Pembrolizumab
    Part 2B: GSK3174998+ pembrolizumab - Cohort expansion Experimental Subjects will receive GSK3174998 IV (at one dose level shown to be tolerable in dose escalation of part 2A) Q3W for up to 48 weeks + Pembrolizumab 200 mg IV Q3W for up to 2 years, in expansion cohorts. GSK3174998, Pembrolizumab

    Eligibility Criteria

    Inclusion Criteria:

    - Provide signed, written informed consent.

    - Male and female subjects, age >=18 years (at the time consent is obtained).

    - Histological documentation of locally advanced, recurrent or metastatic solid
    malignancy that has progressed after standard therapy appropriate for the specific
    tumor type, or for which standard therapy has proven to be ineffective, intolerable,
    or is considered inappropriate. Subjects should not have received more than 5 prior
    lines of therapy for advanced disease including both standards of care and
    investigational therapies. Subjects whose cancers harbor molecular alterations for
    which targeted therapy is standard of care should have received health authority
    approved appropriate targeted therapy for their tumor types before enrollment.

    - Subjects with the following solid tumors are eligible for screening: Non-small cell
    lung cancer (NSCLC), Squamous cell carcinoma of the head and neck (SCCHN), Renal cell
    carcinoma (RCC), melanoma, bladder, Soft tissue sarcoma (STS), Triple-negative breast
    cancer (TNBC), and Colorectal carcinoma displaying microsatellite instability (MSI
    CRC).

    - A biopsy of the tumor tissue obtained at anytime 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. For Part 1B
    and Part 2B, any archival tumor specimen must have been obtained within 3 months of
    starting study drug.

    - Measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST)
    version 1.1. Palpable lesions that are not measurable by radiologic or photographic
    evaluations may not be utilized as the only measurable lesion.

    - Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1.

    - Life expectancy of at least 12 weeks.

    - Adequate organ function as defined by System Laboratory Values; Hematologic (Absolute
    neutrophil count [ANC] >=1.5x10^9/ liter [L], Lymphocyte count >1,000/cubic
    millimeter [mm^3], Hemoglobin >=9 grams/deciliter [g/dL], Platelets >=100x10^9/L),
    Hepatic (Total bilirubin <=1.5x upper limit of normal [ULN] [For subjects with
    Gilbert's Syndrome, only if direct bilirubin <=35%, <=3.0xULN], alanine
    aminotransferase [ALT] <=1.5xULN); Renal (Serum Creatinine <=1.5xULN OR Calculated
    creatinine clearance [CrCl >50 mL/min) and Endocrine (Thyroid stimulating hormone
    [TSH] within normal limits. If TSH is not within normal limits at baseline, the
    subject may still be eligible if total T3 or free T3 and free T4 are within the
    normal limits.

    - QT duration corrected for heart rate by Fridericia's formula (QTcF) <450 msec or <480
    milliseconds (msec) for subjects with bundle branch block.

    Female subjects and male subjects with female partners of child bearing potential must
    comply with adequate contraception requirements from the time of first dose of study
    medication until 120 days after the last dose of study medication.

    Exclusion Criteria:

    - Prior treatment with the following agents (from last dose of prior treatment to first
    dose of GSK3174998): Tumor necrosis factor receptor (TNFR) agonists, including OX40,
    CD27, CD137 (4-1BB), CD357 (GITR): at any time; Checkpoint inhibitors, including
    PD-1, PD-L1, and anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitors: within 8
    weeks.

    - Prior allogeneic or autologous bone marrow transplantation or other solid organ
    transplantation.

    - Active residual toxicity from prior therapies.

    - Secondary malignancy.

    - Brain metastases.

    - Active autoimmune disease that has required systemic treatment within the last 2
    years.

    - Active infection, known human immunodeficiency virus infection, or positive test for
    hepatitis B surface antigen or hepatitis C.

    - Current active liver or biliary disease.

    - Acute diverticulitis, inflammatory bowel disease, intra-abdominal abscess, or
    gastrointestinal obstruction within the past 6 months.

    - Severe hypersensitivity to other monoclonal antibodies (mAbs).

    - Recent (within 6 months) history of second degree (Type II) or third degree
    atrioventricular (AV) block cardiomyopathy, myocardial infarction, acute coronary
    syndromes (including unstable angina), coronary angioplasty, stenting, or bypass
    grafting; Class II, III, or IV heart failure, or symptomatic pericarditis.

    - History of idiopathic pulmonary fibrosis, pneumonitis, interstitial lung disease, or
    organizing pneumonia, or evidence of active, non-infectious pneumonitis.

    - Uncontrolled symptomatic ascites or pleural effusions within 6 months.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Part 1 and 2: Number of subjects with adverse events (AEs) and serious adverse events (SAEs)

    Part 1A and 2A: Dose limiting toxicities (DLT)

    Part 1 and 2: Number of withdrawals due to AEs

    Part 1 and 2: Number of dose reductions or delays

    Part 1 and 2: Change in composite of clinical laboratory assessments as a measure of safety, including hematology, clinical chemistry, thyroid functions and urinalysis parameters

    Part 1 and 2: Change in composite of vital signs as a measure of safety, including temperature, systolic and diastolic blood pressure, and pulse rate

    Part 1 and 2: Changes in electrocardiogram (ECG) as a measure of safety

    Secondary Outcome Measures

    Part 1 and 2: Objective response rate (ORR)

    Part 1 and 2: Disease Control Rate (DCR)

    Part 1 and 2: Time to response

    Part 1 and 2: Overall survival (OS)

    Part 1 and 2: Duration of Response (DoR)

    Part 1 and 2: Progression Free Survival (PFS)

    Part 1: Pharmacodynamic activity of GSK3174998 in tissue and periphery

    Part 2: Pharmacodynamic activity of GSK3174998 in combination with pembrolizumab in tissue and periphery

    Part 1 and 2: Number and percentage of subjects who develop detectable antidrug antibodies (ADA) against GSK3174998

    Part 2 only: Number and percentage of subjects who develop detectable ADA against Pembrolizumab

    Part 1 and 2: GSK3174998 and Part 2: Pembrolizumab PK parameters - tmax, terminal phase half life

    Part 1 and 2: GSK3174998 and Part 2: Pembrolizumab PK parameter - AUC

    Part 1 and 2: GSK3174998 and Part 2: Pembrolizumab PK parameter - terminal phase rate constant

    Part 1 and 2: GSK3174998 and Part 2: Pembrolizumab PK parameter - clearance

    Part 1 and 2: GSK3174998 and Part 2: Pembrolizumab PK parameters - Cmax and Cmin

    Trial Keywords

    mAb

    GSK3174998

    anticancer agent

    checkpoint

    Pembrolizumab

    MK-3475-167

    solid tumor

    immunotherapy

    KEYNOTE-167

    monoclonal antibody

    antitumor