<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/NCT03749850</url>
  </required_header>
  <id_info>
    <org_study_id>NL67422.041.18</org_study_id>
    <secondary_id>2015-005582-23</secondary_id>
    <nct_id>NCT03749850</nct_id>
  </id_info>
  <brief_title>Image-guided Targeted Doxorubicin Delivery With Hyperthermia to Optimize Loco-regional Control in Breast Cancer</brief_title>
  <acronym>i-GO</acronym>
  <official_title>Image-guided Targeted Doxorubicin Delivery With Hyperthermia to Optimize Loco-regional Control in Breast Cancer. Phase I Feasibility Study of Hifu-Induced Hyperthermia, LTLD and Cyclophosphamide for Metastatic Breast Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>UMC Utrecht</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Dutch Cancer Society</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Center for Translational Molecular Medicine</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Vrienden UMC Utrecht</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>UMC Utrecht</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      In this phase I feasibility study, the investigators evaluate the combination of&#xD;
      lyso-thermosensitive liposomal doxorubicin (LTLD, ThermoDox) with local hyperthermia and&#xD;
      cyclophosphamide (C), for the local treatment of the primary breast tumour in patients with&#xD;
      metastatic breast cancer.&#xD;
&#xD;
      When heated to 40-43 degrees Celsius (ºC), LTLD releases a very high concentration of&#xD;
      doxorubicin locally within seconds. Hyperthermia of the primary tumour will be induced by&#xD;
      Magnetic Resonance guided High Intensity Focused Ultrasound (MR-HIFU) on a dedicated&#xD;
      Sonalleve MR-HIFU breast system.&#xD;
&#xD;
      The investigators hypothesize that by substituting doxorubicin (A) in the AC-chemotherapy&#xD;
      regimen for the combination of LTLD and MR-HIFU induced hyperthermia, optimal local tumour&#xD;
      control can be achieved without compromising systemic toxicity or efficacy.&#xD;
&#xD;
      This will be the first study to evaluate LTLD with MR-HIFU hyperthermia in breast cancer&#xD;
      patients.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Advances in systemic treatment led to improved overall survival in patients with metastatic&#xD;
      breast cancer. Various studies suggest that by obtaining loco-regional control, overall&#xD;
      survival in advanced disease can further be improved.&#xD;
&#xD;
      Pre-operative chemotherapy can be used in metastatic breast cancer to make radical removal of&#xD;
      the primary tumor feasible, while simultaneously maintaining control of already present&#xD;
      metastatic sites. The doxorubicin and cyclophosphamide regimen (AC) is well-known both in&#xD;
      (neo-)adjuvant setting as in treatment of metastatic breast cancer. At present, optimal local&#xD;
      control in advanced breast cancer using adequate dosing of doxorubicin is hampered by its&#xD;
      toxic systemic effects. Therefore the investigators aim to increase doxorubicin deposition in&#xD;
      the primary tumor without interfering with systemic efficacy and toxicity, by combining&#xD;
      lyso-thermosensitive liposomal doxorubicin (LTLD, ThermoDox) with local mild hyperthermia,&#xD;
      induced by Magnetic Resonance guided High Intensity Focused Ultrasound (MR-HIFU). When heated&#xD;
      to 40-43 ºC, ThermoDox releases a very high concentration of doxorubicin locally within&#xD;
      seconds. In the absence of hyperthermia, ThermoDox leads to a similar biodistribution and&#xD;
      antitumor efficacy to free doxorubicin. MR-HIFU allows for controlled heating of deep-seated&#xD;
      tumors.&#xD;
&#xD;
      This is a single-arm phase I feasibility study in 12 patients with de novo stage IV (distant&#xD;
      metastasis at the time of diagnosis) her2-negative breast cancer, who have not received&#xD;
      previous chemotherapy. The study treatment consists of up to 6 cycles at 21-day intervals of&#xD;
      ThermoDox (50mg/m2) administered during MR-HIFU induced hyperthermia (60 minutes at 40-42 ᵒC)&#xD;
      and cyclophosphamide (600 mg/m2) administered afterwards. A dedicated MR-HIFU breast system&#xD;
      integrated with a clinical 1.5 Tesla Magnetic Resonance Imaging (MRI) scanner will be used&#xD;
      for safe and controlled heating of the tumour. Primary endpoints are safety, tolerability and&#xD;
      feasibility. Secondary endpoint is efficacy, assessed by radiological response of the local&#xD;
      tumor and the distant metastases.&#xD;
&#xD;
      In the Biobank side study, extra blood samples will be collected. These samples will be used&#xD;
      for further research on not yet determined topics related to breast cancer.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Anticipated">March 2021</start_date>
  <completion_date type="Anticipated">November 2022</completion_date>
  <primary_completion_date type="Anticipated">November 2022</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Incidence of adverse events assessed by CTCAE v 5.0</measure>
    <time_frame>From first study treatment (day 1) until the end of study visit between day 161 and 175</time_frame>
    <description>Safety and tolerability of the study treatment</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of dose limiting toxicities</measure>
    <time_frame>From first study treatment (day 1) until the end of study visit between day 161 and 175</time_frame>
    <description>Safety and tolerability of the study treatment</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of necessity for dose adjustments, delay or early cessation</measure>
    <time_frame>From first study treatment (day 1) until the end of study visit between day 161 and 175</time_frame>
    <description>Safety and tolerability of the study treatment</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence and severity of post-procedural pain</measure>
    <time_frame>From first study treatment (day 1) until the end of study visit between day 161 and 175</time_frame>
    <description>Safety and tolerability of the study treatment</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Patient reported tolerability via an adapted version of the Cancer Therapy Satisfaction Questionnaire (CTSQ)</measure>
    <time_frame>Baseline, day 49 and day 112</time_frame>
    <description>Tolerability of the study treatment. Scores will be described.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Patient reported tolerability via the Functional Assessment of Cancer Therapy - Breast (FACT-B) questionnaire</measure>
    <time_frame>Baseline, and on day 14 of each cycle (with a maximum of six 21-day cycles in 18 weeks)</time_frame>
    <description>Tolerability of the study treatment. Scores will be described.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of cardiotoxity</measure>
    <time_frame>From first study treatment (day 1) until the end of study visit between day 161 and 175</time_frame>
    <description>Safety and tolerability of the study treatment</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Description of MR thermometry data (describing the temperatures achieved)</measure>
    <time_frame>On day 1 (study treatment day) of each cycle (with a maximum of six 21-day cycles in 18 weeks)</time_frame>
    <description>Feasibility of the study treatment</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Duration of procedures on a treatment day</measure>
    <time_frame>On day 1 (study treatment day) of each cycle (with a maximum of six 21-day cycles in 18 weeks)</time_frame>
    <description>Feasibility of the study treatment</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of completed cycles with MR-HIFU induced hyperthermia, ThermoDox and cyclophosphamide</measure>
    <time_frame>From first study treatment (day 1) until the end of study visit between day 161 and 175</time_frame>
    <description>Feasibility of the study treatment</description>
  </primary_outcome>
  <primary_outcome>
    <measure>The number of cycles in which hyperthermia was sufficient: at least 30 minutes at the target temperature of 40-42°C</measure>
    <time_frame>From first study treatment (day 1) until the end of study visit between day 161 and 175</time_frame>
    <description>Feasibility of the study treatment</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Radiological objective response locally on breast Magnetic Resonance Imaging, assessed by RECIST 1.1.</measure>
    <time_frame>Assessed after 2 cycles and after 6 cycles of the study treatment. Each cycle is 21 days.</time_frame>
    <description>Efficacy of the study treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Radiological objective response systemically on Computed Tomography, assessed by RECIST 1.1 or (for patients without RECIST-measurable disease) Positron Emission Tomography Computed Tomography, assessed by PERCIST 1.0</measure>
    <time_frame>Assessed after 2 cycles and after 6 cycles of the study treatment. Each cycle is 21 days.</time_frame>
    <description>Efficacy of the study treatment</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">12</enrollment>
  <condition>Metastatic Breast Cancer</condition>
  <condition>Breast Cancer</condition>
  <condition>Breast Neoplasms</condition>
  <condition>Stage IV Breast Cancer</condition>
  <condition>Metastatic Cancer</condition>
  <condition>Invasive Ductal Carcinoma of Female Breast</condition>
  <condition>Invasive Ductal Breast Cancer</condition>
  <condition>Adenocarcinoma Breast</condition>
  <arm_group>
    <arm_group_label>Study treatment</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>LTLD in combination with MR-HIFU induced hyperthermia and cyclophosphamide&#xD;
Single arm study</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>LTLD</intervention_name>
    <description>Patients will receive up to six cycles at three-weeks intervals of:&#xD;
Intravenous LTLD dosed at 50mg/m2 administered during the MR-HIFU treatment&#xD;
60 minutes of MR-HIFU mild local hyperthermia at 40 °C - 42 °C to the primary breast tumour&#xD;
Intravenous Cyclophosphamide 600 mg/m2 after MR-HIFU treatment&#xD;
In case of toxicity, LTLD, cyclophosphamide and/or hyperthermia dosages will be adjusted as specified in the study protocol.</description>
    <arm_group_label>Study treatment</arm_group_label>
    <other_name>ThermoDox</other_name>
    <other_name>Lyso-Thermosensitive Liposomal Doxorubicin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>MR-HIFU induced hyperthermia</intervention_name>
    <description>Patients will receive up to six cycles at three-weeks intervals of:&#xD;
- 60 minutes of MR-HIFU mild local hyperthermia at 40 °C - 42 °C to the primary breast tumour.&#xD;
In case of toxicity, hyperthermia dosages will be adjusted as specified in the study protocol.</description>
    <arm_group_label>Study treatment</arm_group_label>
    <other_name>MR-HIFU</other_name>
    <other_name>Magnetic Resonance guided High Intensity Focused Ultrasound</other_name>
    <other_name>MLHT</other_name>
    <other_name>Mild local hyperthermia</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cyclophosphamide</intervention_name>
    <description>Patients will receive up to six cycles at three-weeks intervals of:&#xD;
- Intravenous Cyclophosphamide 600 mg/m2 after MR-HIFU treatment&#xD;
In case of toxicity, cyclophosphamide dosages will be adjusted as specified in the study protocol.</description>
    <arm_group_label>Study treatment</arm_group_label>
    <other_name>Endoxan</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Patients must meet all of the following inclusion criteria:&#xD;
&#xD;
          1. Histologically confirmed adenocarcinoma of the breast and planned for palliative&#xD;
             chemotherapy with doxorubicine en cyclophosphamide&#xD;
&#xD;
          2. Biopsy-proven stage tumor 1-2, any nodes, metastasis 1 (T1-2AnyNM1) at diagnosis of&#xD;
             breast cancer.&#xD;
&#xD;
          3. Non-pregnant, non-lactating female at least 18 years of age. If patient is of&#xD;
             child-bearing age, she must have a negative serum pregnancy test prior to enrollment&#xD;
             and must agree to practice an acceptable form of birth control while on study.&#xD;
&#xD;
          4. The tumor is located within the reach of the HIFU beam (based on pre-treatment Dynamic&#xD;
             Contrast Enhanced (DCE-) MRI findings).&#xD;
&#xD;
          5. The distance of the tumor from the skin, nipple, and pectoral wall is at least 1.0 cm&#xD;
             (based on pre-treatment DCE-MRI findings).&#xD;
&#xD;
          6. The target breast is expected to fit in the cup of the dedicated MR-HIFU breast system&#xD;
             (based on pre-treatment MRI findings).&#xD;
&#xD;
          7. The patient weighs less than 90 kg (restrictment of the HIFU table top).&#xD;
&#xD;
          8. Provide written informed consent and willing to comply with protocol requirements.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Patients will be excluded if any of the following conditions are observed:&#xD;
&#xD;
          1. Her2-positive disease or classic invasive lobular carcinoma (ILC).&#xD;
&#xD;
          2. A treatment plan with curative intent is available.&#xD;
&#xD;
          3. Any prior chemotherapy treatment for invasive breast cancer (previous anti-hormonal&#xD;
             therapy is allowed)&#xD;
&#xD;
          4. Any prior therapy with anthracyclines&#xD;
&#xD;
          5. No measurable disease at baseline (according to RECIST 1.1 or PERCIST 1.0)&#xD;
&#xD;
          6. Any concomitant malignancy or previous malignancy in the last 5 years, except basal&#xD;
             cell or squamous cell cancer of the skin or in situ carcinoma of the cervix.&#xD;
&#xD;
             Subjects with a prior contralateral breast malignancy more than 5 years ago can be&#xD;
             included if they did not receive any chemotherapy.&#xD;
&#xD;
          7. Any previous malignancy in the unilateral breast (even if more than 5 years ago)&#xD;
&#xD;
          8. Prior sensitivity (including rash, dyspnea, wheezing, urticarial, or other symptoms)&#xD;
             attributed to any liposomal-encapsulated drug.&#xD;
&#xD;
          9. Baseline laboratory values:&#xD;
&#xD;
             Absolute Neutrophil Count (ANC) &lt; 1.5 x 10^9/L, Platelets &lt; 75 x 10^9/L, Hemoglobin &lt;&#xD;
             5.6 mmol/L (9 g/dl), Total Bilirubin &gt; 1.5 x upper limit of normal, Alanine&#xD;
             Transaminase (ALAT) and Aspartate Transaminase (ASAT) &gt; 2.5 x upper limit of normal &gt;5&#xD;
             x upper limit of normal in case of liver metastases, Estimated Glomerular Filtration&#xD;
             Rate (eGFR) &lt; 30 ml/min/1.73m2.&#xD;
&#xD;
         10. World Health Organization Performance Status (WHO-PS) &gt;2.&#xD;
&#xD;
         11. Left Ventricular Ejection Fraction &lt;50% (validated by baseline scan).&#xD;
&#xD;
         12. History of:&#xD;
&#xD;
               1. Acute coronary syndrome in the last year&#xD;
&#xD;
               2. Cerebral vascular accident in the last year&#xD;
&#xD;
               3. Abnormal cardiac stress testing within last 6 months&#xD;
&#xD;
               4. Symptomatic coronary artery disease&#xD;
&#xD;
               5. Uncontrolled hypertension or cardiomyopathy&#xD;
&#xD;
               6. Cardiac valvular surgery or open heart surgery in the last year&#xD;
&#xD;
               7. Known structural heart disease&#xD;
&#xD;
         13. Any condition which may interfere with the hyperthermia portion of the trial such as:&#xD;
             functioning cardiac pacemaker; metal plates, rods or prosthesis of the chest wall,&#xD;
             breast prosthesis in the treated breast, severe numbness and/or tingling of the chest&#xD;
             wall or breast, skin grafts and/or flaps on the breast or chest wall, scar tissue or&#xD;
             surgical clips in the HIFU beam path.&#xD;
&#xD;
         14. Active infection&#xD;
&#xD;
         15. Body temperature &gt; 38.0 degrees Celsius on the day of a MR-HIFU treatment.&#xD;
&#xD;
         16. Concurrent use of any of the following prohibited medications within a reasonable&#xD;
             wash-out time: protease inhibitors, cyclosporine, carbamazepine, phenytoin, valproic&#xD;
             acid, paclitaxel, trastuzumab and other liposomal drugs (Abelect, Ambisome, Nyotran,&#xD;
             etc.) or lipid-complexed drugs.&#xD;
&#xD;
         17. Caution will be exercised with all the medications mentioned in appendix C, for&#xD;
             interactions are theoretically possible.&#xD;
&#xD;
         18. Contraindications to MR imaging (e.g., pacemaker in situ, severe claustrophobia, metal&#xD;
             implants incompatible with the MRI-scan, body size incompatible with MR bore).&#xD;
&#xD;
         19. Contraindications to gadolinium-based contrast agent, including prior allergic&#xD;
             reaction to gadolinium-based contrast agent, and/or renal failure.&#xD;
&#xD;
         20. Contraindications to sedation and analgesia with propofol and Remifentanil, including&#xD;
             history of Chronic Obstructive Pulmonary Disease (COPD) that results in the inability&#xD;
             to perform a physical activity corresponding with a Metabolic Equivalent (MET(57)) of&#xD;
             4; dependence on artificial ventilation at home; sleep apnea or an American Society of&#xD;
             Anesthesiologists (ASA) classification ≥4.&#xD;
&#xD;
         21. Inability to lie in prone position.&#xD;
&#xD;
         22. A medical or psychiatric condition or other circumstances which would significantly&#xD;
             decrease the chances of understanding the informed consent process, obtaining reliable&#xD;
             data, achieving study objectives, or completing the study treatment and/or&#xD;
             examinations.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Britt BM Suelmann, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>UMC Utrecht</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Mirjam A de Visser, MD</last_name>
    <phone>+31(0)887563142</phone>
    <email>M.A.deVisser-30@umcutrecht.nl</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Britt BM Suelmann, MD</last_name>
    <phone>+31(0)887556308</phone>
    <email>B.B.M.Suelmann@umcutrecht.nl</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>University Medical Center Utrecht</name>
      <address>
        <city>Utrecht</city>
        <zip>3584 CX</zip>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location_countries>
    <country>Netherlands</country>
  </location_countries>
  <verification_date>February 2021</verification_date>
  <study_first_submitted>November 9, 2018</study_first_submitted>
  <study_first_submitted_qc>November 20, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">November 21, 2018</study_first_posted>
  <last_update_submitted>February 16, 2021</last_update_submitted>
  <last_update_submitted_qc>February 16, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">February 17, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>UMC Utrecht</investigator_affiliation>
    <investigator_full_name>BBM Suelmann</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>High Intensity Focused Ultrasound</keyword>
  <keyword>lyso-thermosensitive liposomal doxorubicin</keyword>
  <keyword>ThermoDox</keyword>
  <keyword>MR-HIFU</keyword>
  <keyword>mild local hyperthermia</keyword>
  <keyword>local drug delivery</keyword>
  <keyword>image-guided therapy</keyword>
  <keyword>nanomedicine</keyword>
  <keyword>liposome</keyword>
  <keyword>doxorubicin</keyword>
  <keyword>adriamycin</keyword>
  <keyword>cyclophosphamide</keyword>
  <keyword>HIFU</keyword>
  <keyword>LTLD</keyword>
  <keyword>hyperthermia</keyword>
  <keyword>de novo stage IV</keyword>
  <keyword>metastatic breast cancer</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast Neoplasms</mesh_term>
    <mesh_term>Carcinoma, Ductal</mesh_term>
    <mesh_term>Carcinoma, Ductal, Breast</mesh_term>
    <mesh_term>Hyperthermia</mesh_term>
    <mesh_term>Fever</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cyclophosphamide</mesh_term>
    <mesh_term>Doxorubicin</mesh_term>
    <mesh_term>Liposomal doxorubicin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- 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/NCT03749850
org study id: NL67422.041.18
secondary id: 2015-005582-23
nct id: NCT03749850
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
In this phase I feasibility study, the investigators evaluate the combination of
      lyso-thermosensitive liposomal doxorubicin (LTLD, ThermoDox) with local hyperthermia and
      cyclophosphamide (C), for the local treatment of the primary breast tumour in patients with
      metastatic breast cancer.

      When heated to 40-43 degrees Celsius (ºC), LTLD releases a very high concentration of
      doxorubicin locally within seconds. Hyperthermia of the primary tumour will be induced by
      Magnetic Resonance guided High Intensity Focused Ultrasound (MR-HIFU) on a dedicated
      Sonalleve MR-HIFU breast system.

      The investigators hypothesize that by substituting doxorubicin (A) in the AC-chemotherapy
      regimen for the combination of LTLD and MR-HIFU induced hyperthermia, optimal local tumour
      control can be achieved without compromising systemic toxicity or efficacy.

      This will be the first study to evaluate LTLD with MR-HIFU hyperthermia in breast cancer
      patients.
Advances in systemic treatment led to improved overall survival in patients with metastatic
      breast cancer. Various studies suggest that by obtaining loco-regional control, overall
      survival in advanced disease can further be improved.

      Pre-operative chemotherapy can be used in metastatic breast cancer to make radical removal of
      the primary tumor feasible, while simultaneously maintaining control of already present
      metastatic sites. The doxorubicin and cyclophosphamide regimen (AC) is well-known both in
      (neo-)adjuvant setting as in treatment of metastatic breast cancer. At present, optimal local
      control in advanced breast cancer using adequate dosing of doxorubicin is hampered by its
      toxic systemic effects. Therefore the investigators aim to increase doxorubicin deposition in
      the primary tumor without interfering with systemic efficacy and toxicity, by combining
      lyso-thermosensitive liposomal doxorubicin (LTLD, ThermoDox) with local mild hyperthermia,
      induced by Magnetic Resonance guided High Intensity Focused Ultrasound (MR-HIFU). When heated
      to 40-43 ºC, ThermoDox releases a very high concentration of doxorubicin locally within
      seconds. In the absence of hyperthermia, ThermoDox leads to a similar biodistribution and
      antitumor efficacy to free doxorubicin. MR-HIFU allows for controlled heating of deep-seated
      tumors.

      This is a single-arm phase I feasibility study in 12 patients with de novo stage IV (distant
      metastasis at the time of diagnosis) her2-negative breast cancer, who have not received
      previous chemotherapy. The study treatment consists of up to 6 cycles at 21-day intervals of
      ThermoDox (50mg/m2) administered during MR-HIFU induced hyperthermia (60 minutes at 40-42 ᵒC)
      and cyclophosphamide (600 mg/m2) administered afterwards. A dedicated MR-HIFU breast system
      integrated with a clinical 1.5 Tesla Magnetic Resonance Imaging (MRI) scanner will be used
      for safe and controlled heating of the tumour. Primary endpoints are safety, tolerability and
      feasibility. Secondary endpoint is efficacy, assessed by radiological response of the local
      tumor and the distant metastases.

      In the Biobank side study, extra blood samples will be collected. These samples will be used
      for further research on not yet determined topics related to breast cancer.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Incidence of adverse events assessed by CTCAE v 5.0
time frame: From first study treatment (day 1) until the end of study visit between day 161 and 175
description: Safety and tolerability of the study treatment
measure: Incidence of dose limiting toxicities
time frame: From first study treatment (day 1) until the end of study visit between day 161 and 175
description: Safety and tolerability of the study treatment
measure: Incidence of necessity for dose adjustments, delay or early cessation
time frame: From first study treatment (day 1) until the end of study visit between day 161 and 175
description: Safety and tolerability of the study treatment
measure: Incidence and severity of post-procedural pain
time frame: From first study treatment (day 1) until the end of study visit between day 161 and 175
description: Safety and tolerability of the study treatment
measure: Patient reported tolerability via an adapted version of the Cancer Therapy Satisfaction Questionnaire (CTSQ)
time frame: Baseline, day 49 and day 112
description: Tolerability of the study treatment. Scores will be described.
measure: Patient reported tolerability via the Functional Assessment of Cancer Therapy - Breast (FACT-B) questionnaire
time frame: Baseline, and on day 14 of each cycle (with a maximum of six 21-day cycles in 18 weeks)
description: Tolerability of the study treatment. Scores will be described.
measure: Incidence of cardiotoxity
time frame: From first study treatment (day 1) until the end of study visit between day 161 and 175
description: Safety and tolerability of the study treatment
measure: Description of MR thermometry data (describing the temperatures achieved)
time frame: On day 1 (study treatment day) of each cycle (with a maximum of six 21-day cycles in 18 weeks)
description: Feasibility of the study treatment
measure: Duration of procedures on a treatment day
time frame: On day 1 (study treatment day) of each cycle (with a maximum of six 21-day cycles in 18 weeks)
description: Feasibility of the study treatment
measure: Number of completed cycles with MR-HIFU induced hyperthermia, ThermoDox and cyclophosphamide
time frame: From first study treatment (day 1) until the end of study visit between day 161 and 175
description: Feasibility of the study treatment
measure: The number of cycles in which hyperthermia was sufficient: at least 30 minutes at the target temperature of 40-42°C
time frame: From first study treatment (day 1) until the end of study visit between day 161 and 175
description: Feasibility of the study treatment
measure: Radiological objective response locally on breast Magnetic Resonance Imaging, assessed by RECIST 1.1.
time frame: Assessed after 2 cycles and after 6 cycles of the study treatment. Each cycle is 21 days.
description: Efficacy of the study treatment
measure: Radiological objective response systemically on Computed Tomography, assessed by RECIST 1.1 or (for patients without RECIST-measurable disease) Positron Emission Tomography Computed Tomography, assessed by PERCIST 1.0
time frame: Assessed after 2 cycles and after 6 cycles of the study treatment. Each cycle is 21 days.
description: Efficacy of the study treatment
arm group label: Study treatment
arm group type: Experimental
description: LTLD in combination with MR-HIFU induced hyperthermia and cyclophosphamide
Single arm study
intervention type: Drug
intervention name: LTLD
description: Patients will receive up to six cycles at three-weeks intervals of:
Intravenous LTLD dosed at 50mg/m2 administered during the MR-HIFU treatment
60 minutes of MR-HIFU mild local hyperthermia at 40 °C - 42 °C to the primary breast tumour
Intravenous Cyclophosphamide 600 mg/m2 after MR-HIFU treatment
In case of toxicity, LTLD, cyclophosphamide and/or hyperthermia dosages will be adjusted as specified in the study protocol.
arm group label: Study treatment
other name: ThermoDox
other name: Lyso-Thermosensitive Liposomal Doxorubicin
intervention type: Procedure
intervention name: MR-HIFU induced hyperthermia
description: Patients will receive up to six cycles at three-weeks intervals of:
- 60 minutes of MR-HIFU mild local hyperthermia at 40 °C - 42 °C to the primary breast tumour.
In case of toxicity, hyperthermia dosages will be adjusted as specified in the study protocol.
arm group label: Study treatment
other name: MR-HIFU
other name: Magnetic Resonance guided High Intensity Focused Ultrasound
other name: MLHT
other name: Mild local hyperthermia
intervention type: Drug
intervention name: Cyclophosphamide
description: Patients will receive up to six cycles at three-weeks intervals of:
- Intravenous Cyclophosphamide 600 mg/m2 after MR-HIFU treatment
In case of toxicity, cyclophosphamide dosages will be adjusted as specified in the study protocol.
arm group label: Study treatment
other name: Endoxan
criteria: 
gender: Female
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Britt BM Suelmann, MD
role: Principal Investigator
affiliation: UMC Utrecht
last name: Mirjam A de Visser, MD
phone: +31(0)887563142
email: M.A.deVisser-30@umcutrecht.nl
last name: Britt BM Suelmann, MD
phone: +31(0)887556308
email: B.B.M.Suelmann@umcutrecht.nl
facility: 
status: Recruiting
country: Netherlands
responsible party type: Principal Investigator
investigator affiliation: UMC Utrecht
investigator full name: BBM Suelmann
investigator title: Principal Investigator
mesh term: Breast Neoplasms
mesh term: Carcinoma, Ductal
mesh term: Carcinoma, Ductal, Breast
mesh term: Hyperthermia
mesh term: Fever
mesh term: Cyclophosphamide
mesh term: Doxorubicin
mesh term: Liposomal doxorubicin
sharing ipd: No