Dose Escalation and Expansion Study of GSK3359609 in Subjects With Selected Advanced Solid Tumors (INDUCE-1)

Inclusion Criteria

- Capable of giving signed, written informed consent.

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

- 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: bladder/urothelial cancer of the upper and lower urinary tract; cervical;
colorectal (includes appendix); esophagus, squamous cell; head and neck; melanoma;
malignant pleural mesothelioma (MPM); non-small-cell lung cancer (NSCLC), prostate;
Microsatellite Instability-High/deficient mismatch repair (MSI-H/dMMR) tumor (Part 1B
and Part 2B) and Human Papilloma Virus (HPV)-positive or Epstein-Barr (EBV)-positive
tumor (Part 1B and Part 2B).

- 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; exceptions are in these tumor
types in which pembrolizumab single agent may be a standard: NSCLC, head and neck
squamous cell cancer (HNSCC), bladder/urothelial cancer, MSI-H/dMMR cancers and
melanoma and cervical cancer. In Part 2B pembrolizumab combination expansion cohorts,
prior treatment with anti-Programmed cell death protein 1(PD-1)/ Ligand-1 (L1) may not
be required. 1) Subjects must not have received more than 5 prior lines of therapy for
advanced disease including both standards of care and investigational therapies. 2)
Subjects who received prior PD-1/L1 therapy must have fulfill the following
requirements (Part 1B [except PK/PD cohort]/ Part 2B):.a) Have achieved a CR, PR or SD
and subsequently had disease progression while still on PD-1/L1 therapy; b) Have
received at least 2 doses of an approved PD-1/L1 inhibitor (by any regulatory
authority), c) Have demonstrated disease progression as defined by RECIST v1.1 within
18 weeks from the last dose of the PD-1/L1 inhibitor. 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 (the confirmatory scan could be the Baseline
eligibility scan for this study).

- Archival tumor tissue obtained at any time from the initial diagnosis to study entry;
a fresh tumor biopsy using a procedure that is safe for the subject on a lesion not
previously irradiated unless lesion progressed will be required if archival tissue is
unavailable.

- Agree to undergo a pre-treatment and on treatment biopsy and have disease amenable to
biopsy required in pharmacokinetic (PK) / pharmacodynamics (PD) dose expansion
cohorts.

- Measurable disease per RECIST version 1.1. 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) 0-1.

- Life expectancy of at least 12 weeks.

- Adequate organ function.

- 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.

- A female subject is eligible to participate if she is not pregnant (as confirmed by a
negative serum beta-human chorionic gonadotrophin [beta-hCG] test in females of
reproductive potential), not lactating or if of reproductive potential agrees to
follow one of the options listed in protocol from 30 days prior to the first dose of
study medication and until 120 days after the last dose of study treatment.

- Male subjects with female partners of child bearing potential must agree to use one of
the methods of contraception specified in protocol from time of first dose of study
treatment until 120 days after the last dose of study treatment.

- Documented HPV/ EBV-positive tumor as determined by a local laboratory for Part 1B and
Part 2B pembrolizumab combination viral-positive expansion cohorts only.

- Documented MSI-H or dMMR-positive tumor as determined by local laboratory for Part 1B
and Part 2B pembrolizumab combination MSI-H/dMMR expansion cohorts only.

Exclusion Criteria

- Prior treatment with the following therapies: • Anticancer therapy within 30 days or 5
half-lives of the drug, whichever is shorter. At least 14 days must have elapsed
between the last dose of prior anticancer agent and the first dose of study drug is
administered. • Part 2B (GSK3359609/pembrolizumab combination): prior pembrolizumab
washout is not required. • Prior radiation therapy: permissible if at least one
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 two weeks before start of study drug for
radiation of any intended use to the extremities for bone metastases and 4 weeks for
radiation to the chest, brain, or visceral organs is required. • Investigational
therapy within 30 days or 5 half-lives of the investigational product (whichever is
shorter). At least 14 days must have elapsed between the last dose of investigational
agent and the first dose of study drug is administered.

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

- Toxicity from previous anticancer treatment.

- Invasive malignancy or history of invasive malignancy other than disease under study
within the last two years except: Any other invasive malignancy for which the subject
was definitively treated, has been disease-free for <=2 years and in the opinion of
the principal investigator and GSK Medical Monitor will not affect the evaluation of
the effects of the study treatment on the currently targeted malignancy, may be
included in this clinical trial; and curatively treated non-melanoma skin cancer.

- Central nervous system (CNS) metastases, with the following exception: • Subjects who
have previously-treated CNS metastases, are asymptomatic, and have no requirement for
steroids at least 14 days prior to first dose of study drug. Subjects with
carcinomatous meningitis or leptomeningeal spread are excluded regardless of clinical
stability.

- 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, recombinant
erythropoietin) within 14 days prior to the first dose of GSK3359609.

- 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.

- Active autoimmune disease that has required systemic treatment within the last two
years (i.e., with use of disease modifying agents, corticosteroids or
immunosuppressive drugs). • Note: Replacement therapy (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 7 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 subject is on a stable dose.

- Condition requiring treatment with strong inhibitors/inducers of cytochrome (CYP) p450
3A4 within 7 days prior to first dose of chemotherapy (requirement applies to subjects
enrolled to Part 2 chemotherapy combination with docetaxel).

- Active infection requiring systemic therapy, known human immunodeficiency virus
infection, or positive test for hepatitis B active infection or hepatitis C active
infection.

- 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).

- 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 prior to first dose of study treatment.

- Recent history of allergen desensitization therapy within 4 weeks of starting study
treatment.

- History of severe hypersensitivity to monoclonal antibodies or to the chemotherapies
under investigation including any ingredient used in the formulation.

- History or evidence of cardiac abnormalities.

- History of (current and past) idiopathic pulmonary fibrosis, pneumonitis (for past
pneumonitis exclusion only if steroids were required for treatment), interstitial lung
disease, or organizing pneumonia. 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 Medical Monitor.

- 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.