Study of FAK (Defactinib) and PD-1 (Pembrolizumab) Inhibition in Advanced Solid Malignancies (FAK-PD1)

Inclusion Criteria:

All Patients:

* Informed, written consent
* Male or female, aged 18 years or older at the time consent is given
* ECOG performance status 0 or 1, with no deterioration over the previous 2 weeks
* Life expectancy of at least 3 months
* Measurable disease according to irRECIST criteria, with at least one measurable lesion that has objectively progressed since (or on) any previous therapy
* Adequate bone marrow, liver and renal function on blood investigations within 7 days prior to treatment initiation
* Patients must have been offered all appropriate standard-of-care treatments (or all those indicated before anti-PD-1/PD-L1 therapy, if licensed)
* Patients must agree to use adequate contraceptive measures for the course of the study through 120 days after the last dose of study medication
* Women of child-bearing potential must have a negative pregnancy test within 72 hours prior to start of dosing
* Consent to supply any available archival tissue

Dose escalation (Phase I):

* Pathological diagnosis of any advanced solid tumour type, with confirmation that a tissue sample (core biopsy or resected specimen) is available

Pancreatic expansion (Phase IIa):

* Pathological diagnosis of pancreatic ductal adenocarcinoma with confirmation that a tissue sample (core biopsy or resected specimen) is available

NSCLC expansion (Phase IIa):

* Pathological diagnosis of non-small cell lung cancer (NSCLC)
* Lesion suitable for repeat biopsy
* Baseline biopsy containing tumour material during eligibility
* Consent for paired biopsies on study

Mesothelioma expansion (Phase IIa):

* Pathological diagnosis of mesothelioma
* Lesion suitable for repeat biopsy
* Baseline biopsy containing tumour material during eligibility
* Consent for paired biopsies on study

Exclusion Criteria:

All patients:

* An additional invasive cancer in the last 5 years (other than treated and controlled localised non-melanoma skin cancer or cervical carcinoma-in-situ, or indolent prostate cancer that has been stable for \> 1 year)
* Any central nervous system metastases unless treated and asymptomatic, as well as stable on imaging and not requiring steroids in the preceding 4 weeks
* Any interventional studies, systemic cancer therapies or monoclonal antibodies in the preceding 4 weeks (6 weeks for mitomycin C and nitrosureas)
* Any live vaccines in the preceding 4 weeks
* Systemic immunosuppressive agents in the preceding 2 weeks. Immunosuppressive agents include steroids such as prednisolone (doses ≥ 15 mg daily) or dexamethasone (doses ≥ 2 mg daily).

Replacement therapy (e.g. physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency etc) is not considered a form of systemic treatment

* Diagnosis of immunodeficiency
* Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
* Known interstitial lung disease or active, non-infectious pneumonitis
* Known history of Tuberculosis (TB), Human Immunodeficiency Virus (HIV) or active Hepatitis B or C
* Other severe or uncontrolled systemic diseases (e.g. uncontrolled hypertension, recent myocardial infarction, organ failure or active infection)
* Residual (non-laboratory) toxicities greater than grade 1 (CTCAE v4.03) from previous therapies despite optimal supportive therapy, including fatigue, anorexia, nausea or diarrhoea, but with the exception of alopecia
* Pregnancy or lactation
* Limited ability to swallow or absorb oral medications
* Hypersensitivity to defactinib (VS-6063), pembrolizumab or excipients (including L-histidine, L-histidine hydrochloride monohydrate, sucrose or polysorbate 80)
* History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in is not in the best interest of the subject to participate, in the opinion of the treating investigator
* Previous treatment with an anti-PD-1 or anti-PDL1 agent
* Previous severe or life-threatening skin adverse reaction with other immune-stimulatory anticancer agents
* Current solid organ transplant recipient