GSK3359609 Plus Tremelimumab for the Treatment of Advanced Solid Tumors

A Phase I/II, Open-label, Two Part Study of GSK3359609 in Combination With Tremelimumab in Participants With Selected, Advanced Solid Tumors

The purpose of this study is to evaluate if the combination of GSK3359609 and tremelimumab is safe and tolerable (Part 1) and provides significant survival benefit to subjects with relapsed/refractory (R/R) Head and Neck Squamous Cell Carcinomas (HNSCC) to warrant further clinical investigation (Part 2). Part 1 (dose escalation) will enroll subjects with advanced, selected solid tumors. Subjects will receive escalating doses of GSK3359609 and tremelimumab in combination in Part 1. Part 2 is randomized expansion and will enroll subjects with R/R HNSCC who have disease progression after receiving at least 1 platinum-based chemotherapy and at least 1 anti-programmed death receptor protein-1 (PD-1)/anti-programmed death-ligand 1 (PD-L1) therapy, whether in combination or separately. In Part 2, subjects will be randomized in a ratio of 2:1 to receive either GSK3359609 in combination with tremelimumab at the recommended Phase 2 dose or investigators choice of a single-agent standard of care (SOC) therapy including paclitaxel, docetaxel or cetuximab. The total duration of subjects in the study will be approximately 4 years.

Inclusion Criteria:

• Capable of giving signed informed consent/assent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and protocol.
• Male or female, aged 18 years or older.
• Body weight >=30 kilograms (kg).
• Histological or cytological documentation of an invasive malignancy that was diagnosed as locally advanced/metastatic or relapsed/refractory and is of one of the following tumor types: a) Part 1: cutaneous melanoma; HNSCC (oral cavity, larynx, oropharynx, hypopharynx, nasal cavity/paranasal sinuses); non-small cell lung cancer (squamous and non-squamous); urothelial carcinoma of the upper and lower urinary tract; clear cell renal carcinoma; castrate resistant prostate adenocarcinoma. b) Part 2: HNSCC (oral cavity, larynx, pharynx, paranasal sinuses).
• Part 1 only: 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, or where standard therapy is refused. May be anti-PD-1/anti-PD-L1 experienced or naïve.
• Part 2 only: Disease that has progressed after receiving platinum-based chemotherapy (unless medically contraindicated or discontinued due to toxicity) and anti-PD-1/anti-PD-L1 therapy (in combination or as separate lines of therapy in either sequence).
• Measurable disease per RECIST version 1.1 guidelines. Palpable lesions that are not measurable by radiographic or photographic evaluations may not be utilized as the only measurable lesion. Any measurable lesion biopsied at Screening cannot be followed as a target/index lesion unless agreed upon by GlaxoSmithKline (GSK).
• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0 or 1.
• Adequate organ function.
• A female subject is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions apply: a) Not a woman of childbearing potential (WOCBP); or, b) A WOCBP who agrees to follow the contraceptive while receiving study intervention and for at least 180 days after the last dose of study intervention.
• A male subject must agree to use a highly effective contraception while receiving study intervention and for at least 180 days after the last dose of study intervention and refrain from donating sperm during this period.
• Agree to collection of tumor tissue: a) Part 1 and Part 2: Archival tumor tissue collected any time from the initial diagnosis of invasive malignancy; a fresh tumor biopsy will be required if archival specimen is unavailable prior to first dose. b) Part 1 pharmacokinetic/pharmacodynamic cohort(s): Archival tissue as noted in point (a) above. Paired tumor biopsies: tumor tissue collected any time after completion of dosing of the last therapy and prior to first dose and an on-treatment biopsy. c) Part 2: A minimum of 15 subjects from each arm will be required to provide paired tumor biopsies (in addition to the archival tissues as noted in point (a) above): tumor tissue collected any time after completion of dosing of the last therapy and prior to first dose and an on-treatment biopsy.

Exclusion Criteria:

• Received prior treatment with the following therapies; calculation is based on date of last therapy to date of first dose of study intervention or SOC: a) Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA-4 [including tremelimumab] or Inducible T Cell Co-Stimulator (ICOS)-directed therapies at any time; b) >=4 lines of prior anticancer treatment: In subjects that relapse or progress within 1 year from the beginning of adjuvant or concurrent therapy, the adjuvant/concurrent therapy is considered first line therapy; c) Systemic anticancer therapy or investigational therapy within 30 days, or 5 half-lives, whichever is shorter; at least 14 days must have elapsed between the date of the last prior therapy to the date of first dose of study intervention or SOC.
• Prior radiation therapy: permissible if at least one non-irradiated measurable lesion is available for assessment per RECIST v1.1 or if a solitary measurable lesion was irradiated, objective progression is documented. At least 14 days must have elapsed between the date of the last dosage of radiation and the first dose of study intervention/SOC.
• Invasive malignancy or history of invasive malignancy other than disease under study within the last two years, except: a) Any other invasive malignancy for which the subject was definitively treated, has been disease-free for <=2 years and in the opinion of the Investigator and Medical Monitor will not affect the evaluation of the effects of the study intervention or SOC on the currently targeted malignancy, may be included in this clinical study; Curatively treated non-melanoma skin cancer or successfully treated in-situ carcinoma.
• Toxicity from previous anticancer treatment that includes: a) >=Grade 3 toxicity considered related to prior immunotherapy and that led to treatment discontinuation; b) Toxicity related to prior treatment that has not resolved to <=Grade 1 (except alopecia, vitiligo, hearing loss, endocrinopathy managed with replacement therapy, and peripheral neuropathy which must be <=Grade 2).
• Central nervous system (CNS) metastases, with the following exception: Subjects with previously treated CNS metastases who are clinically stable and had no requirement for steroids during at least 14 days prior to first dose of study intervention or SOC.
• Major surgery <=28 days of first dose of study intervention or SOC.
• Autoimmune disease (current or history) or syndrome that required systemic treatment within the past 2 years. Replacement therapies which include physiological doses of corticosteroids for treatment of endocrinopathies (i.e., adrenal insufficiency) are not considered systemic treatments.
• Recent history (within 24 weeks) of gastrointestinal obstruction that required surgery, acute diverticulitis, inflammatory bowel disease, or intra-abdominal abscess.
• Receiving systemic steroids (>=10 milligrams [mg] oral prednisone or equivalent) or other immunosuppressive agents within 7 days prior to first dose of study intervention or SOC.
• Prior allogeneic/autologous bone marrow or solid organ transplantation.
• Received live-virus vaccine within 30 days from start of study intervention or SOC.
• Current or history of idiopathic pulmonary fibrosis, pneumonitis (for past, subject is excluded if steroids were required), interstitial lung disease or organizing pneumonia.
• Recent history (within 24 weeks) of uncontrolled, symptomatic ascites, pleural or pericardial effusions.
• History or evidence of cardiac abnormalities within the 24 weeks prior to enrollment which include: a) Serious uncontrolled cardiac arrhythmia or clinically significant electrocardiogram 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. c) Symptomatic pericarditis.
• 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.
• Active infection requiring systemic therapy.
• Known human immunodeficiency virus infection; positive test for hepatitis B active infection (presence of hepatitis B surface antigen) or hepatitis C active infection.
• History of severe hypersensitivity to monoclonal antibodies, the Standard of Care agents, including any ingredient used in the formulation, based on which treatment the subject is to receive.
• Any serious and/or unstable pre-existing medical (aside from malignancy), psychiatric disorder, or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures, in the opinion of the Investigator.
• For subjects receiving SOC: Requires therapy with a medication that may alter the PK of the SOC agent (e.g., strong inducers or inhibitors of cytochrome P (CYP)3A4 for subjects receiving docetaxel or paclitaxel) during the study treatment period. Please refer to the package insert for the agent the subject is to receive.
• For subjects receiving SOC: Any contraindication, per the package insert and/or Institutional guidelines, to the treatment the subject is to receive.