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Trial record 2 of 11 for:    dry mouth | Recruiting Studies | NIH

Vismodegib in Treating Patients With Steroid-Refractory Chronic Graft-Versus-Host Disease

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ClinicalTrials.gov Identifier: NCT02337517
Recruitment Status : Recruiting
First Posted : January 13, 2015
Last Update Posted : May 10, 2018
Sponsor:
Collaborator:
Genentech, Inc.
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This pilot clinical trial studies how well vismodegib works in treating patients with chronic graft-versus-host disease that did not respond to previous steroid treatment. Chronic graft-versus-host disease can cause a build-up of scar tissue under the skin and lead to symptoms such as sclerodermatous skin changes, dry mouth, dry eye, narrowing of the esophagus, or vaginal graft-versus-host disease. Vismodegib may work against the build-up of scar tissue and be a better treatment for chronic graft-versus-host disease caused by a hematopoietic stem cell transplant.

Condition or disease Intervention/treatment Phase
Chronic Graft Versus Host Disease Other: Laboratory Biomarker Analysis Drug: Vismodegib Not Applicable

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the clinical effects of GDC-0449 (vismodegib), in steroid-refractory chronic graft-versus-host disease (GVHD).

SECONDARY OBJECTIVES:

I. To determine the safety of GDC-0449 in patients with steroid-refractory GVHD.

II. To determine the change in National Institutes of Health (NIH) Consensus Criteria (CC) global score of chronic GVHD at 6 and 12 months from baseline.

III. To determine one-year non relapse mortality (NRM) and one-year relapse rate.

IV. To determine one-year failure free survival (FFS) and one-year overall survival (OS).

V. To determine baseline clinical characteristics that may be associated with decreased FFS.

OUTLINE:

Patients receive vismodegib orally (PO) daily, every other day, every three days, or twice weekly for 6-12 months in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 6 months.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 12 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) With GDC-0449 (GDC-0449)
Actual Study Start Date : September 8, 2015
Estimated Primary Completion Date : August 1, 2020


Arm Intervention/treatment
Experimental: Supportive care (vismodegib)
Patients receive vismodegib PO daily, every other day, every three days, or twice weekly for 6-12 months in the absence of disease progression or unacceptable toxicity.
Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Vismodegib
Given PO
Other Names:
  • Erivedge
  • GDC-0449
  • Hedgehog Antagonist GDC-0449




Primary Outcome Measures :
  1. Failure free survival (FFS) [ Time Frame: At 6 months ]
    Defined as absence of non relapse mortality (NRM), no recurrent malignancy, steroid dose at 6 months =< 0.2 mg/kg/day of prednisone dose equivalent (PDE), and no addition of new systemic treatment for chronic defined as absence of non relapse mortality (NRM), no recurrent malignancy, steroid dose at 6 months =< 0.2 mg/kg/day of prednisone dose equivalent (PDE), and no addition of new systemic treatment for chronic graft-versus-host disease (GVHD). Will be evaluated using the Kaplan-Meier method. The impact of different covariates on FFS will be analyzed using descriptive statistics, t-test, and Fisher's exact test where applicable.


Secondary Outcome Measures :
  1. Incidence of adverse events [ Time Frame: Up to 1 month post last date of treatment ]
    The proportion of subjects who experience adverse events and serious adverse events will be summarized descriptively; no inferential tests will be performed.

  2. Change in National Institutes of Health (NIH) global score of chronic graft-versus-host disease (GVHD) defined by using the National Institutes of Health (NIH) consensus criteria for assessment of chronic graft-versus-host disease (GVHD) severity [ Time Frame: Baseline to up to 12 months after initiation of protocol therapy ]
    NIH global score will be will be done from baseline, at 6 and 12 months. Differences in NIH scores will be analyzed using Wilcoxon signed-rank test.

  3. One-year non relapse mortality (NRM) [ Time Frame: At 1 year ]
    Relapse will be defined as malignancy relapse or as the initiation of any unintended intervention including an unplanned taper of immunosuppressant therapy to prevent malignancy progression due to any signs of recurrent, residual or new malignant disease after transplantation.

  4. One-year relapse rate [ Time Frame: At 1 year ]
    Relapse will be defined as malignancy relapse or as the initiation of any unintended intervention including an unplanned taper of immunosuppressant therapy to prevent malignancy progression due to any signs of recurrent, residual or new malignant disease after transplantation.

  5. One-year failure free survival (FFS) [ Time Frame: At 1 year ]
    Will be evaluated using the Kaplan-Meier method. The impact of different covariates on FFS will be analyzed using descriptive statistics, t-test, and Fisher's exact test where applicable.

  6. One-year overall survival [ Time Frame: At 1 year ]
    Will be measured.

  7. Clinical characteristics that may be associated with decreased failure free survival (FFS) [ Time Frame: Up to 1 year ]
    Clinical characteristics that may be associated with decreased FFS including the presence of high-risk disease at transplantation; high-intensity conditioning with total-body irradiation; > 3 involved sites with chronic GVHD, lower gastrointestinal involvement by GVHD and severe NIH global score at initiation of protocol treatment; and thrombocytopenia, hyperbilirubinemia, and steroid doses > 1 mg/kg per day immediately before treatment failure requiring treatment change will be evaluated.


Other Outcome Measures:
  1. Change in fibrocyte numbers, assessed using flow cytometry [ Time Frame: Baseline to up to 12 months ]
    Differences in biomarkers will be assessed using Wilcoxon rank-sum test.

  2. Change in leukocyte subsets, assessed using flow cytometry [ Time Frame: Baseline to up to 12 months ]
    Differences in biomarkers will be assessed using Wilcoxon rank-sum test.

  3. Change in T cell cytokine profiles, assessed using flow cytometry [ Time Frame: Baseline to up to 12 months ]
    Differences in biomarkers will be assessed using Wilcoxon rank-sum test.

  4. Change in cytokine profiles in plasma samples, assessed using enzyme-linked immunosorbent assay (ELISA) and the fibroplex assay [ Time Frame: Baseline to up to 12 months ]
    Differences in biomarkers will be assessed using Wilcoxon rank-sum test.

  5. Change in multimerin 1 biomarker in plasma samples, assessed by enzyme-linked immunosorbent assay (ELISA) and the fibroplex assay [ Time Frame: Baseline to up to 12 months ]
    Differences in biomarkers will be assessed using Wilcoxon rank-sum test.

  6. Change in mesenchymal cell phenotypes cultured from skin biopsies, assessed using immunohistochemistry and mesenchymal cell cultures [ Time Frame: Baseline to 6 months ]
    Differences in biomarkers will be assessed using Wilcoxon rank-sum test.

  7. Change in level of transforming growth factor beta on skin biopsies [ Time Frame: Baseline to 6 months ]
    Differences in biomarkers will be assessed using Wilcoxon rank-sum test.

  8. Change in hedgehog activation on skin biopsies [ Time Frame: Baseline to 6 months ]
    Differences in biomarkers will be assessed using Wilcoxon rank-sum test.



Information from the National Library of Medicine

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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:

  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
  • Life expectancy of greater than 12 months
  • Leukocytes >= 3,000/mcL
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 50,000/mcL
  • Total bilirubin within normal institutional limits
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal
  • Creatinine =< 1.5 mg/dl OR creatinine clearance >= 55 mL/min using the Cockcroft-Gault equation for patients with creatinine levels above 1.5 mg/dl
  • Patients with chronic GVHD diagnosed within 3 years after hematopoietic stem cell transplant (HSCT) for any disease, with any graft, and any conditioning regimen with at least one manifestation secondary to fibrosis, including: sclerodermatous skin changes, dry mouth, dry eye, esophageal strictures, or vaginal GVHD
  • Failure to respond to corticosteroids, defined as:

    • Progression of chronic GVHD despite optimal first line therapy (> 0.5 mg/kg/day of prednisone dose equivalent [PDE] for two weeks) or
    • No improvement after 4-8 weeks of sustained therapy; sustained therapy should include 2 weeks of > 0.5 mg/kg/day of PDE or
    • Inability to taper steroid dosage to less than 0.5 mg/kg/day of PDE without worsening of chronic GVHD or
    • Need for second or third line therapy beyond corticosteroids and calcineurin inhibitors or sirolimus, irrespective of other criteria
  • Women of child-bearing potential and men must use two forms of contraception (i.e., barrier contraception and one other method of contraception) at least 4 weeks prior to study entry, for the duration of study participation, and for at least 24 months post-treatment; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately

    • Women of childbearing potential are required to have a negative serum pregnancy test (with a sensitivity of at least 25 mIU/mL) within 7 days prior to the first dose of GDC-0449 (serum or urine); a pregnancy test (serum or urine) will be administered every 4 weeks if their menstrual cycles are regular or every 2 weeks if their cycles are irregular while on study within the 24-hour period prior to the administration of GDC-0449; a positive urine test must be confirmed by a serum pregnancy test; prior to dispensing GDC-0449, the investigator must confirm and document the patient's use of two contraceptive methods, dates of negative pregnancy test, and confirm the patient's understanding of GDC-0449 cause serious or life-threatening birth defects; patients must continue highly effective contraception during therapy and for 24 months after the last dose of GDC-0449
    • Women of childbearing potential are defined as follows:

      • Patients with regular menses
      • Patients with amenorrhea, irregular cycles, or using a contraceptive method that precludes withdrawal bleeding
      • Women who have had a tubal ligation
    • Women are considered not to be of childbearing potential for the following reasons:

      • The patient has undergone hysterectomy and/or bilateral oophorectomy
      • The patient is post-menopausal defined by amenorrhea for at least 12 months in a woman > 45 years old
    • Male patients should use condoms with spermicide, even after a vasectomy, during sexual intercourse with female partners while being treated with GDC-0449 and for 3 months after the last dose to avoid exposing an embryo or fetus to GDC-0449
  • Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are eligible provided that they meet the following criteria in addition to the other protocol criteria:

    • Cancer as the only acquired immunodeficiency syndrome (AIDS)-defining condition
    • Cluster of differentiation (CD)4 cell count >= 250
    • Treatment sensitive HIV and prospects for long term survival on the basis of HIV disease alone
    • Willing to take anti-HIV therapy that will have minimal potential for pharmacokinetic interactions with GDC-0449

Exclusion Criteria:

  • Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
  • Patients who are receiving any other investigational agents
  • Patients with known brain metastases should be excluded from this clinical trial
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to GDC-0449
  • Patients receiving any medications or substances that are strong inducers/inhibitors or substrates of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4)/5, cytochrome P450, family 2, subfamily C, polypeptide 9 (CYP2C9), CYP2C8, or CYP2C19 are ineligible; as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
  • Patients with malabsorption syndrome or other condition that would interfere with intestinal absorption; patients must be able to swallow capsules
  • Patients with clinically important history of liver disease, including viral or other hepatitis or cirrhosis are ineligible
  • Patients with uncontrolled hypocalcemia, hypomagnesemia, hyponatremia or hypokalemia defined as less than the lower limit of normal for the institution, despite adequate electrolyte supplementation are excluded from this study
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with GDC-0449
  • More than 2 lines of therapy beyond corticosteroids with or without calcineurin inhibitors or sirolimus
  • Relapsed malignancy after transplantation

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): NCT02337517


Locations
United States, Michigan
University of Michigan Comprehensive Cancer Center Suspended
Ann Arbor, Michigan, United States, 48109
United States, Utah
Huntsman Cancer Institute/University of Utah Recruiting
Salt Lake City, Utah, United States, 84112
Contact: Daniel R. Couriel    801-581-4477    clinical.trials@hci.utah.edu   
Principal Investigator: Daniel R. Couriel         
Sponsors and Collaborators
National Cancer Institute (NCI)
Genentech, Inc.
Investigators
Principal Investigator: Daniel Couriel Huntsman Cancer Institute/ University of Utah

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02337517     History of Changes
Other Study ID Numbers: NCI-2014-02672
NCI-2014-02672 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
IIT 9664
84584
9664 ( Other Identifier: Huntsman Cancer Institute/University of Utah )
9664 ( Other Identifier: CTEP )
P30CA042014 ( U.S. NIH Grant/Contract )
First Posted: January 13, 2015    Key Record Dates
Last Update Posted: May 10, 2018
Last Verified: May 2018

Additional relevant MeSH terms:
Graft vs Host Disease
Immune System Diseases