GSK3174998 Alone and With Pembrolizumab in Participants With Advanced Solid Tumors (ENGAGE-1)
Condition: Neoplasms
Intervention: GSK3174998; Pembrolizumab
Intervention description: Lyophilized powder 40 mg reconstituted to get a dose range of 0.003 to <=10 mg/kg to be given as IV infusion for 30 minutes (min), Q3W; Pembrolizumab as 100 mg/4 milliliter (mL) solution (dose: 200 mg) to be given as IV infusion for 30 min, Q3W
Intervention MeSH terms: Pembrolizumab
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 141.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: GSK3174998; Non-small Cell Lung Cancer (NSCLC); OX40; Pembrolizumab; Monoclonal Antibody (mAb); Selected Advanced Solid Tumors

Summary:

      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 participants 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 starting with a
      dose-escalation phase followed by a cohort expansion phase. 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 maximum duration of treatment with GSK3174998 and pembrolizumab will be approximately 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
      will include disease assessments every 12 weeks until documented progressive disease (PD).
      Approximately 141 participants with selected advanced or recurrent solid tumors will be
      enrolled.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Provide signed, written informed consent.

          -  Male and female participants, 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. Participants should not have received more than 5
             prior lines of therapy for advanced disease including both standards of care and
             investigational therapies. Participants 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.

          -  Participants 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 high microsatellite
             instability (MSI CRC). In Part 2B (Cohort Expansion), specific subgroups of the above
             solid tumors will be studied. These subgroups may be defined by specific lines of
             treatment, types of prior treatment, histological subtypes, and may be enriched for
             selected biomarkers or participant characteristics. Populations to be studied in
             Amendment 3 include but are not limited to the following. Enrolment of additional
             populations will be communicated in writing: Participants with dedifferentiated
             liposarcoma who have not received prior treatment with a Programmed death ligand 1
             (PD-L1) inhibitor; Participants with melanoma who have received a prior PD-L1
             inhibitor, had a CR, PR or SD and subsequently progressed while on PD-L1 therapy.
             Participants who have received prior treatment with a PD-L1 inhibitor must have
             documented disease progression as defined by meeting all of the following criteria:
             Has received at least 2 doses of an approved PD-L1 inhibitor; has demonstrated disease
             progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST)
             version 1.1. The initial evidence of disease progression is to be confirmed by a
             second assessment no less than four weeks from the date of the first documented PD ,
             in the absence of rapid clinical progression; Progressive disease has been documented
             within 18 weeks from the last dose of the PD-L1 inhibitor.

          -  In Parts 1A and 2A, 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.

        Participants enrolled in Part 1A or Part 2A Pharmacodynamic Cohorts or in Part 2B of the
        study 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. In
        addition, an archived tumor tissue should be submitted for Participants in Part 2B, if
        available. The criterion for collection of fresh biopsies may be waived once
        GlaxoSmithKline (GSK)has determined an appropriate number of viable tissue samples have
        been analyzed 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 RECIST v1.1

          -  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 >=800/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 participants with Gilbert's
             Syndrome, only if direct bilirubin <=35 percent (%), <=3.0xULN], for Part 1A and 2A:
             alanine aminotransferase [ALT] <=1.5xULN), Part 2B: ALT <=2.5xULN; 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 participant may still be eligible if total
             triiodothyronine (T3) or free T3 and free thyroxine (T4) are within the normal limits.

          -  QT duration corrected for heart rate by Fridericia's formula (QTcF) <450 milliseconds
             (msec) or <480 msec for participants with bundle branch block.

          -  In France, a participant will be eligible for inclusion in this study only if either
             affiliated to or a beneficiary of a social security category.

          -  Female participant: is eligible to participate if she is not pregnant (as confirmed by
             a negative serum beta-human chorionic gonadotrophin [beta-hCG] test), not lactating,
             and at least one of the following conditions applies: Non-reproductive potential
             defined as: Pre-menopausal females with one of the following: Documented tubal
             ligation; Documented hysteroscopic tubal occlusion procedure with follow-up
             confirmation of bilateral tubal occlusion ; Hysterectomy; Documented Bilateral
             Oophorectomy.

        Postmenopausal defined as 12 months of spontaneous amenorrhea (in questionable cases a
        blood sample with simultaneous follicle stimulating hormone (FSH) and estradiol levels
        consistent with menopause). Females on hormone replacement therapy (HRT) and whose
        menopausal status is in doubt will be required to use one of the highly effective
        contraception methods if they wish to continue their HRT during the study. Otherwise, they
        must discontinue HRT to allow confirmation of post-menopausal status prior to study
        enrolment.

          -  Reproductive potential and agrees to follow one of the options listed below in the GSK
             Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of
             Reproductive Potential (FRP) requirements from 30 days prior to the first dose of
             study medication and until 120 days after the last dose of study medication and
             completion of the follow-up visit. GSK Modified List of Highly Effective Methods for
             Avoiding Pregnancy in Females of Reproductive Potential (FRP).

        This list does not apply to FRP with same sex partners, when this is their preferred and
        usual lifestyle or for participants who are and will continue to be abstinent from
        penile-vaginal intercourse on a long term and persistent basis: Contraceptive subdermal
        implant with a <1% rate of failure per year, as stated in the product label; Intrauterine
        device or intrauterine system with a <1% rate of failure per year, as stated in the product
        label; Oral Contraceptive, either combined or progestogen alone; Injectable progestogen;
        Contraceptive vaginal ring; Percutaneous contraceptive patches; Male partner sterilization
        with documentation of azoospermia prior to the female participant's entry into the study,
        and this male is the sole partner for that participant. These allowed methods of
        contraception are only effective when used consistently, correctly and in accordance with
        the product label. The investigator is responsible for ensuring that participants
        understand how to properly use these methods of contraception.

          -  Male Participants with female partners of child bearing potential must comply with the
             following contraception requirements from the time of first dose of study medication
             until 120 days after the last dose of study medication: Vasectomy with documentation
             of azoospermia; Male condom plus partner use of one of the contraceptive options
             below; Contraceptive subdermal implant with a <1% rate of failure per year, as stated
             in the product label; Intrauterine device or intrauterine system with a <1% rate of
             failure per year, as stated in the product label; Oral Contraceptive, either combined
             or progestogen alone Injectable progestogen; Contraceptive vaginal ring; Percutaneous
             contraceptive patches.

        These allowed methods of contraception are only effective when used consistently, correctly
        and in accordance with the product label. The investigator is responsible for ensuring that
        participants understand how to properly use these methods of contraception.

        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
             Programmed death receptor-1 (PD-1),

             1, and cytotoxic T-lymphocyte-associated antigen 4 (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 one unirradiated measurable lesion
             is available for assessment via RECIST version 1.1. A wash out of at least two weeks
             before start of study drug for palliative radiation to the extremities for osseous
             bone metastases and 4 weeks for radiation to the chest, brain, or visceral organs is
             required; Investigational therapy: if the participant has participated in a clinical
             trial and has received an investigational product: within 30 days or 5 half-lives of
             the investigational product (whichever is shorter). At least 14 days must have passed
             between the last dose of prior investigational agent and the first dose of study drug.

          -  Prior allogeneic or autologous bone marrow transplantation or other solid organ
             transplantation.

          -  Toxicity from previous treatment: Participants with >=Grade 3 toxicity related to
             prior immunotherapy leading to study treatment discontinuation are not eligible;
             participants whose toxicity related to prior treatment has not resolved to <=Grade 1
             (except alopecia, hearing loss, grade <=2 neuropathy or endocrinopathy managed with
             replacement therapy) are not eligible.

          -  Malignancy other than disease under study, except as noted below: any other malignancy
             from which the participant has been disease-free for more than 2 years and, in the
             opinion of the principal investigators and GSK Medical Monitor, will not affect the
             evaluation of the effects of this clinical trial treatment on currently targeted
             malignancy, can be included in this clinical trial.

          -  Central nervous system (CNS) metastases, with the following exception: Participants
             who have previously-treated CNS metastases, are asymptomatic, and have had no
             requirement for steroids for 2 weeks prior to first dose of study drug.

          -  Has 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 [GMCSF], recombinant
             erythropoietin) within 2 weeks before the first dose of study drug.

          -  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.

          -  Active autoimmune disease that has required systemic treatment within the last 2 years
             (that is with use of disease modifying agents, corticosteroids or immunosuppressive
             drugs). Replacement therapy (example [e.g.], thyroxine or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             form of systemic treatment.

          -  Concurrent medical condition requiring the use of systemic immunosuppressive
             medications within 28 days before the first dose of study treatment. 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.

          -  Active infection, known human immunodeficiency virus infection, or positive test for
             hepatitis B surface antigen or hepatitis C.

          -  Current active liver or biliary disease (with the exception of Gilbert's syndrome or
             asymptomatic gallstones, liver metastases, or otherwise stable chronic liver disease
             per investigator assessment).

          -  Known, current drug or alcohol abuse.

          -  Recent history (within the past 6 months) of acute diverticulitis, inflammatory bowel
             disease, intra-abdominal abscess, or gastrointestinal obstruction.

          -  Receipt of any live vaccine within 4 weeks.

          -  Recent history of allergen desensitization therapy within 4 weeks of starting study
             Treatment.

          -  History of severe hypersensitivity to other mAbs.

          -  History or evidence of cardiovascular 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; Documented cardiomyopathy, myocardial infarction, acute
             coronary syndromes (including unstable angina pectoris), coronary angioplasty,
             stenting, or bypass grafting within the past 6 months before enrollment; documented
             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 Current or history of idiopathic pulmonary
             fibrosis, interstitial lung disease, or organizing pneumonia.

          -  History of (non-infectious) pneumonitis that required steroids or current 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 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.

          -  History of severe hypersensitivity (>=Grade 3) to pembrolizumab and/or any of its
             excipients.