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

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Brief Title

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

Official Title

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)

Brief Summary

      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.
    

Detailed Description

      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 Phase

Phase 1/Phase 2

Study Type

Interventional


Primary Outcome

Adverse events (AEs) using CTCAE v4.03 (to determine dose limiting toxicities (DLTs) and maximum tolerated dose (MTD))

Secondary Outcome

 Objective response rate (ORR), using best objective response by irRECIST

Condition

Carcinoma, Non-small-cell Lung

Intervention

Defactinib

Study Arms / Comparison Groups

 Dose - escalation
Description:  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

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

59

Start Date

July 4, 2017

Completion Date

December 2021

Primary Completion Date

May 2019

Eligibility Criteria

        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
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Stefan Symeonides, 00 44 141 301 7194, [email protected]

Location Countries

United Kingdom

Location Countries

United Kingdom

Administrative Informations


NCT ID

NCT02758587

Organization ID

GN15ON133

Secondary IDs

2015-003928-31

Responsible Party

Sponsor

Study Sponsor

NHS Greater Glasgow and Clyde

Collaborators

 University of Glasgow

Study Sponsor

Stefan Symeonides, Principal Investigator, Edinburgh Cancer Research Centre, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XR


Verification Date

March 2018