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A Study of Durvalumab in Combination With Doxorubicin and Olaratumab for Advanced Soft Tissue Sarcoma

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ClinicalTrials.gov Identifier: NCT03802071
Recruitment Status : Not yet recruiting
First Posted : January 14, 2019
Last Update Posted : March 18, 2019
Sponsor:
Information provided by (Responsible Party):
Yonsei University

Brief Summary:

The yearly incidence of soft-tissue sarcomas (STS) in the USA is roughly 11,280 cases, and metastatic STS have a median overall survival of about 12 months. Sarcomas of the soft tissue are a heterogeneous group of malignant tumors of mesenchymal origin that originate in connective tissue. Local control with wide surgical resection with or without adjuvant radiation has a success rate of close to 90%. However, approximately 40% to 50% of patients with a large (>5 cm), deep, high-grade soft-tissue sarcoma eventually develop distant metastases, primarily in the lung. Therefore, overall survival of metastatic STS remained still poor, less than 1 year. Olaratumab, an inhibitor of platelet-derived growth factor receptor alpha, was approved for the treatment of patients with metastatic sarcoma when combined with the standard chemotherapy, doxorubicin. Beside the improved overall survival, outstanding safety of olaratumab in combined with cytotoxic chemotherapy is also worth further investigation. Therefore, current clinical trials with various targeted agents are ongoing add on the doxorubicin monotherapy.

Investigator planned to conduct the phase I/II trial of durvalumab in combination with standard chemotherapy, doxorubicin and olaratumab for metastatic/recurred sofe tissue sarcoma.


Condition or disease Intervention/treatment Phase
Sarcoma Drug: Durvalumab+olaratumab+doxorubicin cobination Phase 1 Phase 2

Detailed Description:

The yearly incidence of soft-tissue sarcomas (STS) in the USA is roughly 11,280 cases, and metastatic STS have a median overall survival of about 12 months. Sarcomas of the soft tissue are a heterogeneous group of malignant tumors of mesenchymal origin that originate in connective tissue. Local control with wide surgical resection with or without adjuvant radiation has a success rate of close to 90%. However, approximately 40% to 50% of patients with a large (>5 cm), deep, high-grade soft-tissue sarcoma (STS) eventually develop distant metastases, primarily in the lung. Therefore, overall survival (OS) of metastatic STS remained still poor, less than 1 year. Olaratumab, an inhibitor of platelet-derived growth factor receptor alpha, was approved for the treatment of patients with metastatic sarcoma when combined with the standard chemotherapy, doxorubicin. Beside the improved OS, outstanding safety of olaratumab in combined with cytotoxic chemotherapy is also worth further investigation. Therefore, current clinical trials with various targeted agents are ongoing add on the doxorubicin monotherapy.

Recently, Platelet-derived growth factor (PDGF) and PDGF receptor (PDGFR) signalling plays a significant part in mesenchymal biology, including mesenchymal stem cell differentiation, growth, and angiogenesis. Based on the background, PDGFR inhibitor, olaratumab with doxorubicin demonstrated significantly improved overall survival compared to doxorubicin monotherapy and approved as standard treatment in STS.

Durvalumab (MEDI4736) is a human monoclonal antibody that inhibits binding of PD-L1. For this orphan tumor, STS, PD-L1 may be a promising strategy and favorable toxicity may warrant further combination. For this orphan tumor, STS, PD-L1 targeting may be a promising strategy and favorable toxicity may warrant further combination. Regarding anti-PD-L1 treatment in STS, in phase I trial with human monoclonal antibody to PD-L1, MPDL3280A, one heavily treated synovial sarcoma patients demonstrated partial responses. In recent phase II study of pembrolizumab, PD-1 inhibitor in advanced STS among the 40 STS cases (17.5%) had responses (1 complete response and 6 partial response). Based on the study, pembrolizumab monotherapy was approved for previously treated STS in Korea.

Furthermore, targeting PDGFRα by olaratumab is hypothesized to alter the tumor microenvironment and may lead to a more pronounced activity of PD-1 targeting in STS. Therefore, various clinical trials are ongoing immune checkpoint inhibitor with PDGFR inhibitors [axitinib for renal cell carcinoma (RCC), pazopanib for RCC and STS, Sorafenib for RCC, and liver cancer, sunitinib for RCC, gastrointestinal stromal tumor, and pancreatic cancer]. Among them, pembrolizumab and olaratumab combination is ongoing for soft tissue sarcoma.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 44 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Study of Durvalumab in Combination With Standard Chemotherapy Doxorubicin and Olaratumab for Advanced Soft Tissue Sarcoma
Estimated Study Start Date : April 2019
Estimated Primary Completion Date : August 10, 2022
Estimated Study Completion Date : August 10, 2022


Arm Intervention/treatment
Experimental: Durvalumab+olaratumab+doxorubicin combination Drug: Durvalumab+olaratumab+doxorubicin cobination
Dervalumab 1500mg IV Olaratumab 15mg/kg IV D1, D8 Q3weeks Doxorubicin 75mg/m2 IV D1 Q3weeks (up to 8cycles)




Primary Outcome Measures :
  1. adverse event [ Time Frame: 3 weeks ]
    to evaluate the safety and tolerability of durvalumab in combination with doxorubicin/olaratumab



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Ages Eligible for Study:   19 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Histologically confirmed STS(soft tissue sarcoma)
  2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  3. Measurable disease by Response Evaluation Criteria in Solid Tumors Version 1.1
  4. Body weight >30kg
  5. Adequate normal organ and marrow function as defined below:
  6. Left ventricular ejection fraction (LVEF) ≥ 45%
  7. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause.
  8. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
  9. Must have a life expectancy of at least 12 weeks
  10. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent and any locally required authorization obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations

Exclusion Criteria:

  1. Histologically- or cytologically-confirmed Kaposi's sarcoma or GIST
  2. Previous treatment with anthracyclines
  3. Participation in another clinical study with an investigational product during the last 2 weeks
  4. Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies, other investigational agent) 14 days prior to the first dose of study drug
  5. Any previous treatment with a PD1 or PD-L1 inhibitor (including durvalumab) and/or PDGFR inhibitor
  6. Mean QT interval corrected for heart rate (QTc) > 480 ms calculated from 3 electrocardiograms (ECGs) using Fridericia's Correction
  7. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria
  8. Any concurrent chemotherapy, biologic, or hormonal therapy for cancer treatment within 14 days prior to entering the study. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable
  9. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 14 days of the first dose of study drug
  10. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP(investigational product).
  11. History of allogenic organ transplantation.
  12. Active or prior documented autoimmune or inflammatory disorders
  13. Uncontrolled intercurrent illness
  14. Known active infection
  15. History of another primary malignancy
  16. History of leptomeningeal carcinomatosis who are neurologically unstable or have required active treatment
  17. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP.
  18. Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose.
  19. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.

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): NCT03802071


Contacts
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Contact: Hyo Song Kim, Ph.D 82-2-2228-8124 hyosong77@yuhs.ac

Sponsors and Collaborators
Yonsei University

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Responsible Party: Yonsei University
ClinicalTrials.gov Identifier: NCT03802071     History of Changes
Other Study ID Numbers: 4-2018-0746
First Posted: January 14, 2019    Key Record Dates
Last Update Posted: March 18, 2019
Last Verified: March 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Sarcoma
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Doxorubicin
Liposomal doxorubicin
Durvalumab
Olaratumab
Antibodies, Monoclonal
Antibiotics, Antineoplastic
Antineoplastic Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Immunological
Immunologic Factors
Physiological Effects of Drugs