FAK PD1 Phase 1
A Phase I/IIA Study to Assess Safety, Tolerability and Preliminary Activity of the Combination of FAK (Defactinib) and PD-1 (Pembrolizumab) Inhibition in Patients With Advanced Solid Malignancies (FAK-PD1)
This study will explore whether defactinib (a FAK inhibitor) can be safely and tolerably combined with pembrolizumab (a PD-1 inhibitor) and will look for early indications of improved anticancer immunotherapy. It will focus on three key cancers, all in clear need of improved therapies – NSCLC, pancreatic cancer and mesothelioma.
Brief Summary
Programmed cell death receptor 1 (PD-1) blockade is a well-tolerated novel cancer immunotherapy with monotherapy response rates of 20-50% in tumour types such as bladder, melanoma, renal and non-small cell lung cancer (NSCLC), along with durable benefit. However, other tumour types (such as pancreatic cancer) have been poorly responsive and it is likely that the activity of PD-1 blockade is limited in many patients by the presence of additional immunosuppressive tumour microenvironment interactions. The investigators have recently shown in preclinical studies that Focal Adhesion Kinase (FAK) inhibition can re-model multiple aspects of the tumour immune microenvironment, shifting the balance from inhibitory Tregs, TAMs, CAFs & MDSCs, to one which supports an active CD8+ T cell adaptive immune response, suitable for synergistic anti-PD-1 therapy.
The current clinical study will explore whether FAK inhibition (defactinib/VS-6063) can be safely and tolerably combined with PD-1 blockade (pembrolizumab), with early indications of improved anticancer immunotherapy from this novel combination. The investigators will focus on three key tumour types, all cancers in clear need of improved therapies. NSCLC, aiming to augment the moderate monotherapy activity of PD-1 blockade; pancreatic cancer, aiming to release immunological activity in this otherwise resistant cancer; and, finally, mesothelioma, where emerging data suggests both agents may have monotherapy activity, including a potential additional mode of action via synthetic lethality of FAK inhibition in the ~50% of mesothelioma with NF2 mutation.
Phase I/IIa clinical study of defactinib (VS-6063, FAK inhibitor) in combination with pembrolizumab (anti-PD-1) therapy, initially in an “all-comers” dose escalation phase, and subsequently in expansion cohorts at the optimal doses in patients with: (a) pancreatic cancer; (b) NSCLC; and (c) mesothelioma. Safety, tolerability and clinical activity will be explored, as well as extensive translational work to characterise the biological effects and explore potential predictive and pharmacodynamic biomarkers.
PHASE I
Dose-escalation in an “all-comers” phase I population, with treatment-refractory advanced solid malignancies, unselected by tumour type as follows:
Cohorts 200 mg (IV) pembrolizumab every 3 weeks: plus 200 mg (oral) defactinib twice daily 200 mg (IV) pembrolizumab every 3 weeks: plus 400 mg (oral) defactinib twice daily
PHASE II
Expansions in pancreatic ductal adenocarcinoma, non-small cell lung cancer & mesothelioma (each 15-16 evaluable patients).
Pancreatic
Pancreatic expansion for response assessment (single arm). Optional paired biopsies prior to treatment and after 14 days of treatment. Concurrent therapy with pembrolizumab + defactinib (VS-6063) from the start (c.f. NSCLC & mesothelioma expansions below). 15 evaluable patients with an interim futility assessment for clinical response and tolerability when data available from 6.
Classic “stromal” cancer, where the tumour microenvironment is believed to limit the activity of multiple agents. However broad preclinical data for various approaches to re-modelling the tumour microenvironment to permit immunotherapy.
Minimal single-agent anti-PD-1/PD-L1 activity, explores hypothesis of conversion to sensitivity and predictive biomarkers for this.
NSCLC
NSCLC paired-biopsy expansion for tissue biomarkers. Mandatory biopsies prior to treatment and after around 14 days of treatment. 1:1 randomised split of patients having their on-treatment biopsy after concurrent therapy, or after a defactinib (VS-6063) monotherapy run-in. 16 evaluable patients with an interim futility assessment for clinical response and tolerability when data available from 11.
Moderate single-agent anti-PD-1/PD-L1 activity explores hypothesis of amplification of sensitivity and predictive biomarkers for this.
Paired-biopsy assessment of proof of mechanism biomarkers (FAK signalling, tumour immune microenvironment).
Mesothelioma
Mesothelioma paired-biopsy expansion for tissue biomarkers. Mandatory biopsies prior to treatment and after around 14 days of treatment. 1:1 randomised split of patients having their on-treatment biopsy after concurrent therapy, or after a defactinib (VS-6063) monotherapy run-in). 16 evaluable patients with an interim futility assessment for clinical response and tolerability when data available from 11.
Emerging single-agent immune checkpoint, as well as potential FAK-inhibitor activity, explores hypothesis of multi-modal combination activity (microenvironment, checkpoint and synthetic lethality), as well as predictive biomarkers for this.
Paired-biopsy assessment of proof of mechanism biomarkers (FAK signalling, tumour immune microenvironment).
Study Type
Interventional
Study Phase
Phase 1
Phase 2
Study Design
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Intervention
• Drug: Defactinib
cross reference with arm/group descriptions
Other Name: VS-6063
• Drug: Pembrolizumab
cross reference with arm/group descriptions
Other Name: Keytruda and MK-3475
Study Arms
• Experimental: Dose – escalation
Does-escalation in an “all-comers” phase I population, with treatment-refractory advanced solid malignancies, unselected by tumour type. Two cohorts of up to evaluable 6 patients in each:
• Cohort 1: 200mg (IV) pembrolizumab every 3 weeks; plus 200mg (oral) defactinib twice daily
• Cohort 2: 200mg (IV) pembrolizumab every 3 weeks; plus 400mg (oral) defactinib twice daily
Interventions:
• Drug: Defactinib
• Drug: Pembrolizumab
Interventions:
• Drug: Defactinib
• Drug: Pembrolizumab
• Experimental: Pancreatic
Pancreatic expansion for response assessment (single arm). Optional paired biopsies prior to treatment and after 14 days of treatment. All would have concurrent therapy with pembrolizumab + defactinib (VS-6063) from the start (c.f. NSCLC & mesothelioma expansions below). A total of 15 evaluable patients will be enrolled into this disease area, with an interim futility assessment for clinical response and tolerability being conducted when data from 6 patients becomes available.
Interventions:
• Drug: Defactinib
• Drug: Pembrolizumab
• Experimental: NSCLC
NSCLC paired-biopsy expansion for tissue biomarkers. Mandatory biopsies prior to treatment and after around 14 days of treatment. 1:1 randomised split of patients having their mandatory on-treatment biopsy after concurrent therapy, or after a defactinib (VS-6063) monotherapy run-in. A total of 16 evaluable patients will be enrolled into this disease area, with an interim futility assessment for clinical response and tolerability being conducted when data from 11patients becomes available.
Interventions:
• Drug: Defactinib
• Drug: Pembrolizumab
• Experimental: Mesothelioma
Mesothelioma paired-biopsy expansion for tissue biomarkers. Mandatory biopsies prior to treatment and around 14 days of treatment. 1:1 randomised split of patients having thier on-treatment biopsy after concurrent therapy, or after defactinib (VS-6063) monotherapy run-in. A total of 16 evaluable patients will be enrolled into this disease area, with an interim futility assessment for clinical response and tolerability being conducted when data from 11patients becomes available.
Interventions:
• Drug: Defactinib
• Drug: Pembrolizumab
Sponsors
NHS Greater Glasgow and Clyde
Collaborators
• University of Glasgow
• Cancer Research UK
• Merck Sharp & Dohme Corp.
• Verastem, Inc.
• University of Edinburgh
• University of Southampton
• University of Leicester
• Queen’s University, Belfast
Principal Investigators
Principal investigator: Stefan Symeonides Edinburgh Cancer Research Centre, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XR
Principal investigator: Jeff Evans Beatson West of Scotland Cancer Centre, 1053 Great Western Road, Glasgow G12 0YN
Principal investigator: Christian Ottensmeier Cancer Research UK Centre, Southampton University Hospitals and University of Southampton, Southampton SO16 6YD
Principal investigator: Dean Fennell Department of Cancer Studies, University of Leicester, Leicester Royal Infirmary, Leicester LE2 7LX
Principal investigator: Vicky Coyle Belfast Health and Social Care Trust, Cancer Centre, Lisburn Road, Belfast BT9 7BL
Recruitment start: 04/07/2017
Recruitment end: 01/12/2021
Contact:
Dawn Currie 00 44 141 301 7194 dawn.currie@glasgow.ac.uk