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Sequential Neoadjuvant Chemotherapy in Soft Tissue Sarcoma

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ClinicalTrials.gov Identifier: NCT04776525
Recruitment Status : Recruiting
First Posted : March 1, 2021
Last Update Posted : September 13, 2021
Sponsor:
Collaborator:
Haukeland University Hospital
Information provided by (Responsible Party):
Kjetil Boye, Oslo University Hospital

Brief Summary:
Nearly half of patients with high-grade, localized soft tissue sarcoma (STS) of extremities and trunk wall develop disease recurrence after local therapy. Adjuvant chemotherapy with ifosfamide and doxorubicin may improve long-term disease-free survival, but the benefit of adjuvant treatment is limited and predictive factors for treatment response are lacking. The aim of this study is to explore sequential treatment with ifosfamide and doxorubicin in a neoadjuvant setting and to investigate biomarkers predictive of treatment response.

Condition or disease Intervention/treatment Phase
Soft Tissue Sarcoma Drug: Ifosfamide Drug: Doxorubicin Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 49 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Sequential Neoadjuvant Ifosfamide and Doxorubicin in Localized High-grade Soft Tissue Sarcoma of Extremities and Trunk Wall
Actual Study Start Date : April 27, 2021
Estimated Primary Completion Date : September 2024
Estimated Study Completion Date : September 2034


Arm Intervention/treatment
Experimental: Sequential ifosfamide and doxorubicin
Four cycles ifosfamide 9 g/m2 and four cycles doxorubicin 80 mg/m2. Each cycle has a duration of 14 days.
Drug: Ifosfamide
3 g/m2 each day for three days
Other Name: Holoxan

Drug: Doxorubicin
80 mg/m2 over four hours day 1
Other Name: Adriamycin




Primary Outcome Measures :
  1. Overall response rate [ Time Frame: Up to 16 weeks ]
    Partial or complete response using RECIST v1.1


Secondary Outcome Measures :
  1. Incidence of treatment-related adverse events as assessed by CTCAE v5.0 and dose reductions (safety and tolerability) [ Time Frame: Until 30 days after last dose of study treatment ]
    Number and type of adverse events, serious adverse events, dose reductions and discontinuation due to toxicity

  2. Correlation between TP53 mutation assessed by sequencing of tumor DNA and overall response [ Time Frame: Up to 16 weeks ]
    To investigate if TP53 mutations assessed by sequencing of tumor DNA predict response to high-dose alkylating chemotherapy and/or sequential doxorubicin monotherapy in STS


Other Outcome Measures:
  1. Disease-free survival [ Time Frame: Up to 10 years after completion of study treatment ]
  2. Overall survival [ Time Frame: Up to 10 years after completion of study treatment ]
  3. Health-related quality of life [ Time Frame: Up to 10 years after completion of study treatment ]
    To assess change from baseline in the European Organization for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ-C30) scores during treatment

  4. Number of patients who experience a change in the extent of the planned surgical procedure due to study treatment [ Time Frame: From baseline and up to 6 months ]
    To investigate if the extent of the surgical procedure is changed due to neoadjuvant treatment



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. ≥ 18 years of age at the time of informed consent.
  2. Histological diagnosis of soft tissue sarcoma belonging to one of the following histotypes:

    1. Leiomyosarcoma
    2. Malignant peripheral nerve sheath tumor
    3. Undifferentiated pleomorphic sarcoma
    4. Myxofibrosarcoma
    5. Synovial sarcoma
    6. Pleomorphic liposarcoma
    7. Pleomorphic rhabdomyosarcoma
    8. Unclassified spindle cell sarcoma
  3. Malignancy grade ≥ 2 according to the Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grading system.
  4. Tumor localized in extremity, girdle and/or trunk wall.
  5. Primary tumor size ≥5.0 cm as measured in the longest diameter on diagnostic MRI or CT scan.
  6. Primary tumor location below the superficial fascia or involving the superficial fascia, i.e. deep-seated according to the World Health Organization (WHO) Classification of Tumors of Soft Tissue and Bone (4th edition, 2013).
  7. The primary tumor must be available for biopsy collection at protocol inclusion.
  8. Patients must have a measurable tumor according to RECIST v1.1.
  9. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
  10. Before patient registration, written informed consent must be given according to national and local regulations.
  11. Adequate organ function and bone marrow reserve as indicated by the following laboratory assessments:

    1. Hemoglobin ≥ 8.0 g/dL
    2. Neutrophil count ≥ 1.0 x 109/L
    3. Platelet count ≥ 75 x 109/L
    4. Total bilirubin ≤ 1.5 x the upper limit of normal (ULN)
    5. Creatinine clearance ≥ 60 ml/min based on Cockcroft Gault estimation or direct measurement
  12. Negative Hepatitis B and C and HIV serology.
  13. Adequate contraception in women of childbearing potential (WOCBP) and their fertile partners during the study and until 6 months after end of study treatment. WOCBP should have a negative highly sensitive serum or urine pregnancy test within 72 hours prior to receiving the first dose of study medication. A woman is considered fertile following menarche and until becoming post-menopausal unless permanently sterile. WOCBP should be willing to use one of the mentioned highly effective methods of birth control mentioned below or be surgically sterile, or abstain from heterosexual activity for the course of the study through 1 year after the last dose of study medication. Methods considered as highly effective birth control methods include combined (estrogen and progestogen containing) or progestogen-only hormonal contraception associated with inhibition of ovulation (oral, intravaginal, injectable, implantable or transdermal), intrauterine device (including hormone-releasing), male condom, bilateral tubal occlusion, vasectomised partner or sexual abstinence (see appendix 5 for definitions).

Exclusion Criteria:

  1. Any prior therapy for soft tissue sarcoma.
  2. Locoregional or distant metastasis as assessed by CT and/or MRI at time of diagnosis. Patients with lung nodules <10 mm of uncertain etiology may be included.
  3. Clinical evidence of serious coagulopathy. Prior arterial/venous thrombosis or embolism does not exclude patients from inclusion, unless patient is considered unfit by study oncologist.
  4. Urinary obstruction.
  5. Known hypersensitivity towards ifosfamide, doxorubicin or pegfilgrastim, their metabolites and other ingredients in the drug administration formulation.
  6. New York Heart Association class II-IV heart disease, myocardial infarction within 6 months of diagnosis of soft tissue sarcoma, active ischemia or any other uncontrolled cardiac condition such as angina pectoris, clinically significant cardiac arrhythmia requiring therapy, uncontrolled hypertension or congestive heart failure.
  7. Left ventricular ejection fraction (LVEF) < 50%.
  8. Patients with a prior or concurrent malignant disease whose natural history or treatment have the potential to interfere with the safety or efficacy assessment of this clinical trial are not eligible. Patients with a history of breast cancer, requiring continued hormonal treatment (e.g. anti-estrogen or an aromatase inhibitor) may be included. Patients with a history of prostate cancer, requiring continued support with luteinizing hormone releasing hormone (LHRH) agonists, with or without androgens, may be included.
  9. Patients not able to give an informed consent or comply with study regulations as deemed by study investigator.
  10. Any other significant comorbidities, such as active infection, uncontrolled pulmonary or liver disease, active cystitis, or any other condition, that based on the assessment of the treating physician could compromise compliance with the protocol or predispose the patient to safety risks.
  11. Pregnant or lactating patients.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04776525


Contacts
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Contact: Kjetil Boye, MD PhD +4722934000 kjetil.boye@ous-hf.no

Locations
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Norway
Haukeland University Hospital Not yet recruiting
Bergen, Norway
Contact: Åse Hjelle, MD       ase.hjelle@helse-bergen.no]   
Oslo University Hospital Recruiting
Oslo, Norway
Contact: Kjetil Boye, MD PhD       kjetil.boye@ous-hf.no   
Sponsors and Collaborators
Oslo University Hospital
Haukeland University Hospital
Investigators
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Principal Investigator: Kjetil Boye, MD PhD Oslo University Hospital
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Responsible Party: Kjetil Boye, Senior Consultant, Oslo University Hospital
ClinicalTrials.gov Identifier: NCT04776525    
Other Study ID Numbers: 44-2020
First Posted: March 1, 2021    Key Record Dates
Last Update Posted: September 13, 2021
Last Verified: September 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Kjetil Boye, Oslo University Hospital:
Doxorubicin
Ifosfamide
Sarcoma
Neoadjuvant
Sequential
Additional relevant MeSH terms:
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Sarcoma
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Doxorubicin
Ifosfamide
Antibiotics, Antineoplastic
Antineoplastic Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Alkylating
Alkylating Agents