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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) With GDC-0449 (GDC-0449)

Conditions
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Chronic Graft Versus Host Disease

Intervention / Treatment
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* Other: Laboratory Biomarker Analysis
* Drug: Vismodegib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) Life expectancy of greater than 12 months Leukocytes >= 3,000/microliter (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 milli-international unit (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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Supportive care (vismodegib)<br>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<br>* Correlative studies<br>Drug: Vismodegib<br>* Given PO<br>* Other names: Hedgehog Antagonist GDC-0449;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Failure Free Survival (FFS) | Defined as the count of participants at six months with an 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) at six months after start of treatment. | At 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Events | The count of participants who experience adverse events (AE) and serious adverse events (SAE) while on treatment or within one month after discontinuing treatment. | Up to 1 month post last date of treatment (max time of approximately one year) | 
| Chronic Graft-versus-host Disease Response | Chronic graft-versus-host disease (GVHD) severity was assessed at baseline with the National Institutes of Health (NIH) global score of chronic GVHD, which was defined using the 2014 NIH consensus criteria for diagnosis and staging of chronic GVHD (see Baseline Characteristics). Following initiation of treatment, the response to therapy was assessed as complete response (CR) (complete resolution of GVHD in one or more organ system) , partial response (PR) (improvement of GVHD in one or more organ system), stable disease (SD) (no change in GVHD), or progressive disease (PD) (worsened GVHD in one or more organ system), based on 2014 NIH consensus criteria for response assessment. GVHD was assessed monthly, with defined study endpoints at 6 and 12 months. Additionally, best overall response on the study is being reported to include response for patients who did not remain on study long enough to be included in the 6 month assessment. | Baseline to up to 12 months after initiation of protocol therapy | 
| One-year Non Relapse Mortality (NRM) | 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. Non relapse mortality is the number of participant deaths due to any cause other than relapse. | At 1 year | 
| One Year Relapse | 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. This measure is reported as the count of participants who experienced a relapse of their primary malignancy within one year of starting study therapy. | Up to one year | 
| One-year Failure Free Survival (FFS) | Defined as the count of participants at one year with an 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) at one year after start of treatment. | At 1 year | 
| One-year Overall Survival | A count of participants who are not deceased at one year after initiation of study therapy. | At 1 year | 
| Clinical Characteristics Associated With Failure Free Survival (FFS) | The study proposed to evaluate clinical characteristics that could be associated with FFS. Each patient was categorized as either having FFS greater than 6 months or less than 6 months. Factors evaluated were whether or not the patient had high intensity conditional with total-body irradiation (TBI) before bone marrow transplant, whether or not the patient had > 3 involved sites with chronic graft versus host disease (GVHD), whether or not the patient had lower gastrointestinal (GI) involvement by GVHD, and whether or not the patient had a Severe NIH global score at initiation of protocol treatment. | Up to 1 year |