Clinical Trials /

Image-guided Targeted Doxorubicin Delivery With Hyperthermia to Optimize Loco-regional Control in Breast Cancer

NCT03749850

Description:

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.

Related Conditions:
  • Breast Adenocarcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Image-guided Targeted Doxorubicin Delivery With Hyperthermia to Optimize Loco-regional Control in Breast Cancer
  • 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

Clinical Trial IDs

  • ORG STUDY ID: NL67422.041.18
  • SECONDARY ID: 2015-005582-23
  • NCT ID: NCT03749850

Conditions

  • Metastatic Breast Cancer
  • Breast Cancer
  • Breast Neoplasms
  • Stage IV Breast Cancer
  • Metastatic Cancer
  • Invasive Ductal Carcinoma of Female Breast
  • Invasive Ductal Breast Cancer
  • Adenocarcinoma Breast

Interventions

DrugSynonymsArms
LTLDThermoDox, Lyso-Thermosensitive Liposomal DoxorubicinStudy treatment
CyclophosphamideEndoxanStudy treatment

Purpose

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.

Detailed Description

      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.

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Study treatmentExperimentalLTLD in combination with MR-HIFU induced hyperthermia and cyclophosphamide Single arm study
  • LTLD
  • Cyclophosphamide

Eligibility Criteria

        Inclusion Criteria:

        Patients must meet all of the following inclusion criteria:

          1. Histologically confirmed adenocarcinoma of the breast and planned for palliative
             chemotherapy with doxorubicine en cyclophosphamide

          2. Biopsy-proven stage tumor 1-2, any nodes, metastasis 1 (T1-2AnyNM1) at diagnosis of
             breast cancer.

          3. Non-pregnant, non-lactating female at least 18 years of age. If patient is of
             child-bearing age, she must have a negative serum pregnancy test prior to enrollment
             and must agree to practice an acceptable form of birth control while on study.

          4. The tumor is located within the reach of the HIFU beam (based on pre-treatment Dynamic
             Contrast Enhanced (DCE-) MRI findings).

          5. The distance of the tumor from the skin, nipple, and pectoral wall is at least 1.0 cm
             (based on pre-treatment DCE-MRI findings).

          6. The target breast is expected to fit in the cup of the dedicated MR-HIFU breast system
             (based on pre-treatment MRI findings).

          7. The patient weighs less than 90 kg (restrictment of the HIFU table top).

          8. Provide written informed consent and willing to comply with protocol requirements.

        Exclusion Criteria:

        Patients will be excluded if any of the following conditions are observed:

          1. Her2-positive disease or classic invasive lobular carcinoma (ILC).

          2. A treatment plan with curative intent is available.

          3. Any prior chemotherapy treatment for invasive breast cancer (previous anti-hormonal
             therapy is allowed)

          4. Any prior therapy with anthracyclines

          5. Radiologically confirmed brain metastases. Patients with clinically suspected brain
             metastases at screening should have a CT/MRI of the brain prior to study entry.

          6. Any concomitant malignancy or previous malignancy in the last 5 years, except basal
             cell or squamous cell cancer of the skin or in situ carcinoma of the cervix. Subjects
             with a prior contralateral breast malignancy more than 5 years ago can be included if
             they did not receive any chemotherapy.

          7. Any previous malignancy in the unilateral breast (even if more than 5 years ago)

          8. Prior sensitivity (including rash, dyspnea, wheezing, urticarial, or other symptoms)
             attributed to any liposomal-encapsulated drug.

          9. Baseline laboratory values:

             Absolute Neutrophil Count (ANC) < 1.5 x 10^9/L, Platelets < 75 x 10^9/L, Hemoglobin <
             5.6 mmol/L (9 g/dl), Total Bilirubin > 1.5 x upper limit of normal, Alanine
             Transaminase (ALAT) and Aspartate Transaminase (ASAT) > 2.5 x upper limit of normal >5
             x upper limit of normal in case of liver metastases, Estimated Glomerular Filtration
             Rate (eGFR) < 30 ml/min/1.73m2.

         10. World Health Organization Performance Status (WHO-PS) >2.

         11. Left Ventricular Ejection Fraction <50% (validated by baseline scan).

         12. History of:

               1. Acute coronary syndrome in the last year

               2. Cerebral vascular accident in the last year

               3. Abnormal cardiac stress testing within last 6 months

               4. Symptomatic coronary artery disease

               5. Uncontrolled hypertension or cardiomyopathy

               6. Cardiac valvular surgery or open heart surgery in the last year

               7. Known structural heart disease

         13. Any condition which may interfere with the hyperthermia portion of the trial such as:
             functioning cardiac pacemaker; metal plates, rods or prosthesis of the chest wall,
             breast prosthesis in the treated breast, severe numbness and/or tingling of the chest
             wall or breast, skin grafts and/or flaps on the breast or chest wall, scar tissue or
             surgical clips in the HIFU beam path.

         14. Active infection

         15. Body temperature > 38.0 degrees Celsius on the day of a MR-HIFU treatment.

         16. Concurrent use of any of the following prohibited medications within a reasonable
             wash-out time: protease inhibitors, cyclosporine, carbamazepine, phenytoin, valproic
             acid, paclitaxel, trastuzumab and other liposomal drugs (Abelect, Ambisome, Nyotran,
             etc.) or lipid-complexed drugs.

         17. Caution will be exercised with all the medications mentioned in appendix C, for
             interactions are theoretically possible.

         18. Contraindications to MR imaging (e.g., pacemaker in situ, severe claustrophobia, metal
             implants incompatible with the MRI-scan, body size incompatible with MR bore).

         19. Contraindications to gadolinium-based contrast agent, including prior allergic
             reaction to gadolinium-based contrast agent, and/or renal failure.

         20. Contraindications to sedation and analgesia with propofol and Remifentanil, including
             history of Chronic Obstructive Pulmonary Disease (COPD) that results in the inability
             to perform a physical activity corresponding with a Metabolic Equivalent (MET(57)) of
             4; dependence on artificial ventilation at home; sleep apnea or an American Society of
             Anesthesiologists (ASA) classification ≥4.

         21. Inability to lie in prone position.

         22. A medical or psychiatric condition or other circumstances which would significantly
             decrease the chances of understanding the informed consent process, obtaining reliable
             data, achieving study objectives, or completing the study treatment and/or
             examinations.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

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
Safety Issue:
Description:Safety and tolerability of the study treatment

Secondary Outcome Measures

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.
Safety Issue:
Description:Efficacy of the study treatment
Measure:Radiological objective response systemically on Computed Tomography, assessed by RECIST 1.1.
Time Frame:Assessed after 2 cycles and after 6 cycles of the study treatment. Each cycle is 21 days.
Safety Issue:
Description:Efficacy of the study treatment

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:UMC Utrecht

Trial Keywords

  • High Intensity Focused Ultrasound
  • lyso-thermosensitive liposomal doxorubicin
  • ThermoDox
  • MR-HIFU
  • mild local hyperthermia
  • local drug delivery
  • image-guided therapy
  • nanomedicine
  • liposome
  • doxorubicin
  • adriamycin
  • cyclophosphamide
  • HIFU
  • LTLD
  • hyperthermia
  • de novo stage IV
  • metastatic breast cancer

Last Updated