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A Study to Evaluate the Safety and Efficacy of Vactosertib and Imatinib in Patients With Advanced Desmoid Tumor

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ClinicalTrials.gov Identifier: NCT03802084
Recruitment Status : Not yet recruiting
First Posted : January 14, 2019
Last Update Posted : January 14, 2019
Sponsor:
Information provided by (Responsible Party):
Yonsei University

Brief Summary:
This is a phase I/II, open-label, non-randomized, multicentre study to evaluate the clinical activity of vactosertib plus imatinib in desmoid tumor. Based on the background, TGF-β inhibition as a potential therapeutic target for desmoid tumor and convey significant implications for the clinical development. Therefore, investigator will conduct the phase II trial of vactosertib in combined with imatinib in desmoid tumor.

Condition or disease Intervention/treatment Phase
Desmoid Tumor Drug: vactosertib/imatinib combination Phase 1 Phase 2

Detailed Description:

Desmoid tumor (aggressive fibromatosis) is a mesenchymal neoplasm associated with mutations, resulting in -catenin-mediated transcriptional activation. It is composed of a clonal proliferation of mesenchymal, fibroblast-like cells occurred sporadic or as a part of familial adenomatosis polyposis. This tumor has high local recurrence rate after complete excision (~40%). Therefore, although lacking metastatic capability, patients experience repeated recurrence with attendant severe morbidity. Various systemic therapy using NSAID, cytotoxic agent (doxorubicin and vinblastine), biologic agents (tamoxifen, low-dose interferon), and tyrosine kinase inhibitors (imatinib) are recommended with modest activity. Among them, imatinib has shown promising activity and approved as standard treatment for desmoid tumor. However, still there is modest response (10-15% responses) and further combination strategy is warranted to improve antitumor efficacy.

The transforming growth factor-β (TGF-β) family of cytokines has 33 members in humans, including TGF-β isoforms, activins, bone morphogenetic proteins (BMPs), and growth and differentiation factors (GDFs). These factors regulate growth, survival, differentiation and migration of cells, and have important roles during embryonal development and in the control of adult tissue homeostasis. During carcinogenesis, TGF-β has a dual role; initially it suppresses tumorigenesis by inducing growth arrest and promoting apoptosis, however, in advanced cancers, where TGF-β often is overexpressed. In addition, TCGA (the cancer genome atlas) pan-cancer also demonstrated high expression of TGF-β responsive signature in desmoid tumor. Regarding the combination, TEW-7197 (vactosertib), a TGF-β inhibitor and imatinib demonstrated synergistic effect in vitro and xenograft model. Compared to imatinib alone, administration of imatinib plus vactosertib to mice significantly delayed disease relapse and prolonged survival. Collectively, these results indicate that vactosertib may be a promising candidate for a new therapeutic strategy.

Based on the background, TGF-β inhibition as a potential therapeutic target for desmoid tumor and convey significant implications for the clinical development. Therefore, investigator will conduct the phase II trial of vactosertib in combined with imatinib in desmoid tumor.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1b/2a, Open-label, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics, and Antitumor Activity of Vactosertib in Combination With Imatinib in Patients With Advanced Desmoid Tumor (Aggressive Fibromatosis)
Estimated Study Start Date : February 15, 2019
Estimated Primary Completion Date : December 31, 2020
Estimated Study Completion Date : December 31, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: vactosertib/imatinib combination Drug: vactosertib/imatinib combination

Phase 1 : Imatinib 400mg QD P q28days Vactosertib 1 cohort 200mg bid (D1-5, 8-12, 15-19, 22-26)

  • 1 cohort 100mg bid Phase 2 : Imatinib 400mg QD PO q28days. Vactosertib RP2D, bid (D1-5, 8-12, 15-19, 22-26)




Primary Outcome Measures :
  1. adverse event [ Time Frame: 4 weeks ]
    to evaluate the safety and tolerability



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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 desmoid tumor (aggressive fibromatosis) not available for local treatment (surgical resection or radiation therapy)
  2. Eastern Cooperative Oncology Group performance status of 0-1
  3. Measurable lesion (RECIST 1.1.)
  4. Adequate laboratory findings
  5. All patients must be able to provide a newly acquired tumor biopsy during screening (preferred) or provide an available tumor sample taken ≤3 years prior to screening.
  6. Subjects must have ejection fraction ≥ 50% and no clinically significant valvular dysfunction

Exclusion Criteria:

  1. Previous TGF-β inhibitor and/or imatinib exposed patient
  2. Patient who has had chemotherapy, radiotherapy, or biological therapy within 2 weeks
  3. Any unresolved chronic toxicity greater than grade 2 from previous anticancer therapy.
  4. Has an active infection requiring systemic therapy
  5. Uncontrolled intercurrent illness, including symptomatic congestive heart failure (NYHA Class III/IV), uncontrolled hypertension (≥150/90mmHg), unstable angina pectoris or myocardial infarction (≤ 6 months prior to screening), uncontrolled cardiac arrhythmia, cardiac valulopathy
  6. Uncontrolled or active central nervous system metastasis and/or carcinomatous meningitis
  7. Child-Pugh B or C liver cirrhosis
  8. History of another primary malignancy.
  9. 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 of investigational product(IP).
  10. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of investigational product(IP).
  11. Current or prior use of immunosuppressive medication within 14 days before the first investigational product(IP).

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): NCT03802084


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

Sponsors and Collaborators
Yonsei University

Responsible Party: Yonsei University
ClinicalTrials.gov Identifier: NCT03802084     History of Changes
Other Study ID Numbers: 4-2018-0807
First Posted: January 14, 2019    Key Record Dates
Last Update Posted: January 14, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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

Additional relevant MeSH terms:
Neoplasms, Fibrous Tissue
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Fibromatosis, Aggressive
Fibroma
Imatinib Mesylate
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action