<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02998567</url>
  </required_header>
  <id_info>
    <org_study_id>CCR4420</org_study_id>
    <nct_id>NCT02998567</nct_id>
  </id_info>
  <brief_title>Combination Study of Guadecitabine and Pembrolizumab.</brief_title>
  <acronym>HyPeR</acronym>
  <official_title>HyPeR: A Phase 1 Dose Escalation Study of Guadecitabine (SGI-110) a Second Generation Hypo-Methylating Agent in Combination With Pembrolizumab (MK3475) in Patients With Refractory Solid Tumours</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Royal Marsden NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Astex Pharmaceuticals, Inc.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Merck Sharp &amp; Dohme LLC</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Institute of Cancer Research, United Kingdom</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Royal Marsden NHS Foundation Trust</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      HyPeR is a multi-centre Phase 1 Dose Escalation Study of Guadecitabine (SGI-110) a Second&#xD;
      Generation Hypo-Methylating Agent in Combination with Pembrolizumab (MK3475) in Patients with&#xD;
      Refractory Solid Tumours. The investigators will be investigating the safety and toxicity of&#xD;
      the combination.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a phase I trial of the combination of the hypo-methylating agent guadecitabine and an&#xD;
      anti-PD1 antibody (anti- programmed cell death protein 1) pembrolizumab. Patients will&#xD;
      receive subcutaneous guadecitabine daily on Days 1-4 of each 21-day cycle. Patients will&#xD;
      receive pembrolizumab intravenously once per 21-day cycle: on Day 8 of Cycle 2 and on Day 1&#xD;
      of each cycle from Cycle 3 onwards.&#xD;
&#xD;
      The rational for this design is that this pre-loading with Guadecitabine will sensitise the&#xD;
      tumour to Pembrolizumab through the re-expression of genes that enhance tumour recognition,&#xD;
      the increase in density of tumour infiltrating T-cells and stimulation of the adaptive immune&#xD;
      response.&#xD;
&#xD;
      In Part A (Dose Escalation) the investigators will investigate escalating doses of&#xD;
      Guadecitabine in combination with Pembrolizumab. Patients with advanced solid tumours will be&#xD;
      recruited in cohorts of 3 to 6 patients to investigate the combination of 200 mg of&#xD;
      pembrolizumab, administered as an intravenous injection, with escalating doses of&#xD;
      guadecitabine, administered via a subcutaneous injection, once a day for 4 days (Days 1-4).&#xD;
      Guadecitabine dosing will start at 45mg/m2 but can be decreased to 30mg/m2 in the event of&#xD;
      toxicities or increased to 60mg/m2 in the absence of toxicities. Once the maximum tolerated&#xD;
      dose is reached (or under the advice from the Safety Review Committee) patients will be&#xD;
      enrolled to the dose expansion phase (Part B).&#xD;
&#xD;
      Part B (Dose Expansion): 20 patients will be recruited to Part B to further explore the&#xD;
      safety and activity of the combination of guadecitabine and pembrolizumab. This cohort will&#xD;
      include, but not be limited to patients with: castration resistant prostate cancer (CRPC),&#xD;
      non-small cell lung cancer (NSCLC) and possibly other solid tumours based on emerging&#xD;
      anti-tumour activity data from Part A and any other relevant preclinical or clinical&#xD;
      published data.&#xD;
&#xD;
      Approximately 30 to 35 patients will be entered into this trial, 6 to 12 patients in Part A&#xD;
      and 20 patients in Part B.&#xD;
&#xD;
      The anticipated accrual rate of the dose escalation phase will involve approximately 3&#xD;
      patients per month across 2 centres. Accrual rates could be higher or lower but this estimate&#xD;
      takes into consideration that the first patient on an escalation cohort should complete Cycle&#xD;
      2 Day 15 prior to accrual of further patients in the cohort. Accrual in the expansion phase&#xD;
      is estimated at 2-4 patients per month across 2 centres. It is expected that the duration of&#xD;
      recruitment will be 12-24 months.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">January 26, 2017</start_date>
  <completion_date type="Anticipated">September 2024</completion_date>
  <primary_completion_date type="Anticipated">September 2024</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Health Services Research</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Establish maximum tolerated dose (MTD)</measure>
    <time_frame>12 months</time_frame>
    <description>To establish a maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of the combination of guadecitabine and pembrolizumab in patients with advanced solid tumours.&#xD;
To determine the maximum dose at which no more than 1 of 6 patients at the same dose level experience a drug related toxicity (DLT), as defined in section 3.1.4 of the protocol.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Measure Adverse Events according to CTCAE v4.0</measure>
    <time_frame>24 months</time_frame>
    <description>To assess the safety and toxicity profile of the combination of guadecitabine and pembrolizumab.&#xD;
To determine causality and grading severity of each adverse event by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Pharmacodynamic profile of guadecitabine in combination with pembrolizumab.</measure>
    <time_frame>24 months</time_frame>
    <description>Transcriptome analysis in whole bloods using the PAXgene assay.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacodynamic profile of guadecitabine in combination with pembrolizumab.</measure>
    <time_frame>24 months</time_frame>
    <description>Targeted sequencing in plasma circulating free DNA.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacodynamic profile of guadecitabine in combination with pembrolizumab.</measure>
    <time_frame>24 months</time_frame>
    <description>White blood cell analysis by flow cytometry.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacodynamic profile of guadecitabine in combination with pembrolizumab.</measure>
    <time_frame>24 months</time_frame>
    <description>DNA methylation analysis in blood peripheral blood mononuclear cells (PBMC).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacodynamic studies in guadecitabine in combination with pembrolizumab.</measure>
    <time_frame>24 months</time_frame>
    <description>Immunohistochemistry of immune cell in serial biopsies.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacodynamic studies in guadecitabine in combination with pembrolizumab.</measure>
    <time_frame>24 months</time_frame>
    <description>DNA methylation analysis in serial biopsies.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacodynamic studies in guadecitabine in combination with pembrolizumab.</measure>
    <time_frame>24 months</time_frame>
    <description>Transcriptome analysis in serial biopsies.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Preliminary assessment of the anti-tumour activity</measure>
    <time_frame>24 months</time_frame>
    <description>Target lesions will be measured according to RECIST v1.1 criteria.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">34</enrollment>
  <condition>Castration-Resistant Prostatic Cancer</condition>
  <condition>Non Small Cell Lung Cancer</condition>
  <arm_group>
    <arm_group_label>Escalation</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Fixed dose of Pembrolizumab with escalating dose of Guadecitabine to establish the phase 2 recommended dose.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Expansion</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Continuation of the Guadecitabine and Pembrolizumab dose established in arm 1: expansion in the recommended patient population.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Guadecitabine</intervention_name>
    <description>In arm 1 (escalation) and 2 (expansion).</description>
    <arm_group_label>Escalation</arm_group_label>
    <arm_group_label>Expansion</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pembrolizumab</intervention_name>
    <description>In arm 1 (escalation) and 2 (expansion).</description>
    <arm_group_label>Escalation</arm_group_label>
    <arm_group_label>Expansion</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Histologically or cytologically confirmed advanced solid tumours, refractory to&#xD;
             conventional treatment, or for which no conventional therapy exists or is declined by&#xD;
             the patient.&#xD;
&#xD;
          2. Life expectancy of at least 12 weeks.&#xD;
&#xD;
          3. Eastern Co-operative Oncology Group (ECOG) performance status of 0-1 with no&#xD;
             significant deterioration over the previous 2 weeks (Appendix 1).&#xD;
&#xD;
          4. Evaluable or measurable disease as assessed by RECIST 1.1.&#xD;
&#xD;
          5. Haematological and biochemical indices within the ranges shown below. These&#xD;
             measurements must be performed within one week (Day -7 to Day 1) prior to&#xD;
             administration of any investigational medicinal product.&#xD;
&#xD;
               -  Haemoglobin (Hb) ≥ 9.0 g/dL&#xD;
&#xD;
               -  Absolute neutrophil count ≥ 1.5 x 109/L&#xD;
&#xD;
               -  Platelet count ≥ 100 x 109/L&#xD;
&#xD;
               -  International normalised ratio (INR) ≤ 1.5x upper limit of normal (ULN)&#xD;
&#xD;
        Or:&#xD;
&#xD;
        Prothrombin time ≤ 1.5x upper limit of normal (ULN)&#xD;
&#xD;
        - Serum bilirubin ≤1.5x ULN&#xD;
&#xD;
        Or:&#xD;
&#xD;
        Direct bilirubin (for patients with total bilirubin &gt;1.5x ULN) ≤ 1.5x ULN&#xD;
&#xD;
          -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5x ULN (for&#xD;
             patients with liver metastases ≤ 5x ULN is permissible)&#xD;
&#xD;
          -  Calculated creatinine clearance (per institutional standard) ≥ 50 mL/min 6.18 years or&#xD;
             over. 7. Written (signed and dated) informed consent and be capable of co-operating&#xD;
             with treatment and follow-up.&#xD;
&#xD;
             8. Agree to the use of archival paraffin embedded tissue (if available) for PD-L1&#xD;
             (programmed death-ligand 1) analysis 9. Agree to provide a fresh tumour biopsy at&#xD;
             baseline and on Cycle 2 Day 8 of a tumour lesion not previously irradiated (tumours&#xD;
             progressing in a prior site of radiation are allowed for PD-L1 characterization, other&#xD;
             exceptions may be considered after consultation with the Chief Investigator).&#xD;
&#xD;
             10. Female subjects of childbearing potential should have a negative urine or serum&#xD;
             pregnancy test within 14 days prior to receiving the first dose of study medication.&#xD;
             If the urine test is positive or cannot be confirmed as negative, a serum pregnancy&#xD;
             test will be required.&#xD;
&#xD;
             11. Female subjects of childbearing potential should be willing to use 2 methods of&#xD;
             birth control or be surgically sterile, or abstain from heterosexual activity for the&#xD;
             course of the study through 6 months after the last dose of study medication. Subjects&#xD;
             of childbearing potential are those who have not been surgically sterilized or have&#xD;
             not been free from menses for &gt;1 year. Decitabine, a metabolite of Guadecitabine, can&#xD;
             affect fertility and so oocyte cryopreservation should be discussed with female&#xD;
             patients.&#xD;
&#xD;
             12. Male subjects should agree to use an adequate method of contraception starting&#xD;
             with the first dose of study therapy through 6 months after the last dose of study&#xD;
             therapy. Decitabine, a metabolite of Guadecitabine, can affect fertility and so&#xD;
             cryopreservation of sperm should be discussed with male patients.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Radiotherapy (except brief course for palliative reasons), endocrine therapy,&#xD;
             immunotherapy or chemotherapy during the previous four weeks (six weeks for&#xD;
             nitrosoureas, Mitomycin-C and 4 weeks for investigational medicinal products) before&#xD;
             treatment, except for hormonal therapy with luteinizing hormone-releasing hormone&#xD;
             (LHRH) analogues for medical castration in patients with CRPC, which are permitted.&#xD;
&#xD;
          2. Patient has a known additional malignancy that is progressing or requires active&#xD;
             treatment. Exceptions include basal cell carcinoma of the skin, squamous cell&#xD;
             carcinoma of the skin, or in situ bladder or cervical cancer that has undergone&#xD;
             potentially curative therapy.&#xD;
&#xD;
          3. Spinal cord compression or brain metastases unless asymptomatic, treated and stable&#xD;
             and not requiring steroids for at least 4 weeks prior to start of study treatment.&#xD;
&#xD;
          4. Ongoing toxic manifestations of previous treatments. Exceptions to this are:&#xD;
&#xD;
               -  Grade 1 toxicities, which in the opinion of the investigator should not exclude&#xD;
                  the patient&#xD;
&#xD;
               -  Alopecia of any grade&#xD;
&#xD;
          5. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any&#xD;
             other form of immunosuppressive therapy within 14 days prior to the first dose of&#xD;
             trial treatment. The use of physiologic doses of corticosteroids may be approved after&#xD;
             consultation with the chief Investigator.&#xD;
&#xD;
          6. Has an active autoimmune disease that has required systemic treatment in past 3 months&#xD;
             (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive&#xD;
             drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid&#xD;
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a&#xD;
             form of systemic treatment. Patients with Sjogren's syndrome will not be excluded from&#xD;
             the study. In addition patients that experienced a Grade 2 or higher immune-related&#xD;
             AE's on treatment with immunotherapy will be excluded from the study.&#xD;
&#xD;
          7. Has evidence of interstitial lung disease.&#xD;
&#xD;
          8. Has a history of (non-infectious) pneumonitis that required steroid treatment or has&#xD;
             active pneumonitis. Pneumonitis includes acute interstitial pneumonitis, pneumonitis&#xD;
             and idiopathic pneumonia syndrome.&#xD;
&#xD;
          9. Active infection, requiring systemic therapy.&#xD;
&#xD;
         10. Has received a live vaccine within 30 days of planned start of study therapy. Note:&#xD;
             The killed virus vaccines used for seasonal influenza vaccines for injection are&#xD;
             allowed; however intranasal influenza vaccines (e.g. FluMist®) are live attenuated&#xD;
             vaccines and are not allowed.&#xD;
&#xD;
         11. Major surgery (excluding minor procedures, e.g. placement of vascular access) from&#xD;
             which the patient has not yet recovered.&#xD;
&#xD;
         12. At high medical risk because of severe or uncontrolled non-malignant systemic disease&#xD;
             including active uncontrolled infection, active bleeding diathesis.&#xD;
&#xD;
         13. Known to be serologically positive for hepatitis B, hepatitis C or human&#xD;
             immunodeficiency virus (HIV). Screening for chronic conditions is not required.&#xD;
&#xD;
         14. Any of the following cardiac criteria:&#xD;
&#xD;
               -  Mean resting corrected QT interval (QTc) &gt; 470 msec obtained from 3 consecutive&#xD;
                  electrocardiograms (ECGs) within 5 minutes of each other.&#xD;
&#xD;
               -  Any clinically significant abnormalities in rhythm, conduction or morphology of&#xD;
                  resting ECG, e.g. complete left bundle branch block, third degree heart block.&#xD;
&#xD;
               -  Any factors that increase the risk of QTc prolongation or risk of arrhythmic&#xD;
                  events, such as heart failure, hypokalaemia, congenital long QT syndrome, family&#xD;
                  history of long QT syndrome or unexplained sudden death under 40 years of age or&#xD;
                  any concomitant medication known to prolong the QT interval&#xD;
&#xD;
               -  Experience of any of the following procedures or conditions in the preceding 6&#xD;
                  months: coronary artery bypass graft, angioplasty, vascular stent, myocardial&#xD;
                  infarction, angina pectoris, congestive heart failure New York Heart Association&#xD;
                  [NYHA Grade 2 (refer to Appendix 4)]&#xD;
&#xD;
               -  Uncontrolled hypertension - Systolic BP &gt;160mmHg and/or diastolic BP &gt;100mmHg&#xD;
&#xD;
               -  Left ventricular ejection fraction (LVEF) below institutional lower limit of&#xD;
                  normal.&#xD;
&#xD;
         15. History of hypersensitivity to active or inactive excipients of guadecitabine or&#xD;
             pembrolizumab or drugs with a similar chemical structure or class to either agent.&#xD;
&#xD;
         16. Is a participant or plans to participate in another interventional clinical trial,&#xD;
             whilst taking part in this Phase I study of guadecitabine and pembrolizumab.&#xD;
             Participation in an observational trial would be acceptable.&#xD;
&#xD;
         17. Any other condition which in the Investigator's opinion would not make the patient a&#xD;
             good candidate for the clinical trial.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Rpyal Marsden Hospital</name>
      <address>
        <city>Sutton</city>
        <state>Surrey</state>
        <zip>SM2 5PT</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UCLH</name>
      <address>
        <city>London</city>
        <zip>W1T 7HA</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>May 2022</verification_date>
  <study_first_submitted>November 2, 2016</study_first_submitted>
  <study_first_submitted_qc>December 16, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 20, 2016</study_first_posted>
  <last_update_submitted>May 25, 2022</last_update_submitted>
  <last_update_submitted_qc>May 25, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">May 26, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Prostatic Neoplasms</mesh_term>
    <mesh_term>Prostatic Neoplasms, Castration-Resistant</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pembrolizumab</mesh_term>
    <mesh_term>Guadecitabine</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02998567
org study id: CCR4420
nct id: NCT02998567
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
HyPeR is a multi-centre Phase 1 Dose Escalation Study of Guadecitabine (SGI-110) a Second
      Generation Hypo-Methylating Agent in Combination with Pembrolizumab (MK3475) in Patients with
      Refractory Solid Tumours. The investigators will be investigating the safety and toxicity of
      the combination.
This is a phase I trial of the combination of the hypo-methylating agent guadecitabine and an
      anti-PD1 antibody (anti- programmed cell death protein 1) pembrolizumab. Patients will
      receive subcutaneous guadecitabine daily on Days 1-4 of each 21-day cycle. Patients will
      receive pembrolizumab intravenously once per 21-day cycle: on Day 8 of Cycle 2 and on Day 1
      of each cycle from Cycle 3 onwards.

      The rational for this design is that this pre-loading with Guadecitabine will sensitise the
      tumour to Pembrolizumab through the re-expression of genes that enhance tumour recognition,
      the increase in density of tumour infiltrating T-cells and stimulation of the adaptive immune
      response.

      In Part A (Dose Escalation) the investigators will investigate escalating doses of
      Guadecitabine in combination with Pembrolizumab. Patients with advanced solid tumours will be
      recruited in cohorts of 3 to 6 patients to investigate the combination of 200 mg of
      pembrolizumab, administered as an intravenous injection, with escalating doses of
      guadecitabine, administered via a subcutaneous injection, once a day for 4 days (Days 1-4).
      Guadecitabine dosing will start at 45mg/m2 but can be decreased to 30mg/m2 in the event of
      toxicities or increased to 60mg/m2 in the absence of toxicities. Once the maximum tolerated
      dose is reached (or under the advice from the Safety Review Committee) patients will be
      enrolled to the dose expansion phase (Part B).

      Part B (Dose Expansion): 20 patients will be recruited to Part B to further explore the
      safety and activity of the combination of guadecitabine and pembrolizumab. This cohort will
      include, but not be limited to patients with: castration resistant prostate cancer (CRPC),
      non-small cell lung cancer (NSCLC) and possibly other solid tumours based on emerging
      anti-tumour activity data from Part A and any other relevant preclinical or clinical
      published data.

      Approximately 30 to 35 patients will be entered into this trial, 6 to 12 patients in Part A
      and 20 patients in Part B.

      The anticipated accrual rate of the dose escalation phase will involve approximately 3
      patients per month across 2 centres. Accrual rates could be higher or lower but this estimate
      takes into consideration that the first patient on an escalation cohort should complete Cycle
      2 Day 15 prior to accrual of further patients in the cohort. Accrual in the expansion phase
      is estimated at 2-4 patients per month across 2 centres. It is expected that the duration of
      recruitment will be 12-24 months.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Health Services Research
masking: None (Open Label)
measure: Establish maximum tolerated dose (MTD)
time frame: 12 months
description: To establish a maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of the combination of guadecitabine and pembrolizumab in patients with advanced solid tumours.
To determine the maximum dose at which no more than 1 of 6 patients at the same dose level experience a drug related toxicity (DLT), as defined in section 3.1.4 of the protocol.
measure: Measure Adverse Events according to CTCAE v4.0
time frame: 24 months
description: To assess the safety and toxicity profile of the combination of guadecitabine and pembrolizumab.
To determine causality and grading severity of each adverse event by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
measure: Pharmacodynamic profile of guadecitabine in combination with pembrolizumab.
time frame: 24 months
description: Transcriptome analysis in whole bloods using the PAXgene assay.
measure: Pharmacodynamic profile of guadecitabine in combination with pembrolizumab.
time frame: 24 months
description: Targeted sequencing in plasma circulating free DNA.
measure: Pharmacodynamic profile of guadecitabine in combination with pembrolizumab.
time frame: 24 months
description: White blood cell analysis by flow cytometry.
measure: Pharmacodynamic profile of guadecitabine in combination with pembrolizumab.
time frame: 24 months
description: DNA methylation analysis in blood peripheral blood mononuclear cells (PBMC).
measure: Pharmacodynamic studies in guadecitabine in combination with pembrolizumab.
time frame: 24 months
description: Immunohistochemistry of immune cell in serial biopsies.
measure: Pharmacodynamic studies in guadecitabine in combination with pembrolizumab.
time frame: 24 months
description: DNA methylation analysis in serial biopsies.
measure: Pharmacodynamic studies in guadecitabine in combination with pembrolizumab.
time frame: 24 months
description: Transcriptome analysis in serial biopsies.
measure: Preliminary assessment of the anti-tumour activity
time frame: 24 months
description: Target lesions will be measured according to RECIST v1.1 criteria.
arm group label: Escalation
arm group type: Experimental
description: Fixed dose of Pembrolizumab with escalating dose of Guadecitabine to establish the phase 2 recommended dose.
arm group label: Expansion
arm group type: Experimental
description: Continuation of the Guadecitabine and Pembrolizumab dose established in arm 1: expansion in the recommended patient population.
intervention type: Drug
intervention name: Guadecitabine
description: In arm 1 (escalation) and 2 (expansion).
arm group label: Escalation
arm group label: Expansion
intervention type: Drug
intervention name: Pembrolizumab
description: In arm 1 (escalation) and 2 (expansion).
arm group label: Escalation
arm group label: Expansion
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
facility: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Prostatic Neoplasms
mesh term: Prostatic Neoplasms, Castration-Resistant
mesh term: Pembrolizumab
mesh term: Guadecitabine