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Phase 1 Nilotinib in Steroid Dependent/Refractory Chronic Graft Versus Host Disease

Primary Purpose

Bone Marrow Transplant Failure, Lymphoma, Non-Hodgkin, Lymphoma, T-Cell, Peripheral

Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Nilotinib
Sponsored by
Stanford University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Bone Marrow Transplant Failure

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:5.1.1 Steroid dependent/refractory cGVHD defined as:

  1. Dependent disease - Persistent cGVHD manifestations requiring a glucocorticoid dose >= prednisone 0.25 mg/kg/day (0.5 mg/kg po qod) for at least 12 weeks.
  2. Refractory disease - Progressive cGVHD manifestations despite treatment with a glucocorticoid dose >= prednisone 0.5 mg/kg/day (1 mg/kg po qod) for at least 4 weeks.

5.1.2 Any previous treatments for cGVHD (except nilotinib). Participants may have received nilotinib for other reasons besides cGVHD such as leukemia or solid tumor.

5.1.3 Participants must be receiving baseline systemic glucocorticoid therapy for cGVHD at study entry. The dose of steroids must be stable for 14 days prior to starting nilotinib.

5.1.4 At the time of trial enrollment, participants may be receiving one or two other immunosuppressive therapies in addition to glucocorticoids. Immunosuppressant doses must be stable for 14 days prior to starting nilotinib. Monoclonal T or B cell antibodies must be discontinued at least 28 days before starting nilotinib.

5.1.5 Chronic GVHD manifestations that can be followed on physical or laboratory exam. A list of potential manifestations is presented in Appendix D.

  1. Skin changes
  2. Oral mucosa changes
  3. Hepatic dysfunction

5.1.6 >= 18 years old

5.1.7 Life expectancy >= 6 months.

5.1.8 Karnofsky performance status >= 60 (defined as being unable to work, able to live at home, and able to care for most personal needs but requiring occasional assistance from others).

5.1.9 Laboratory parameters:

  1. Creatinine < 1.5 x ULN
  2. ANC > 1.5 x 10^9/L
  3. Platelets > 100 x 10^9/L
  4. Total bilirubin < 1.5 x ULN
  5. AST (SGOT) and ALT (SGPT) < 2.5 x ULN
  6. Serum amylase and lipase <= 1.5 x ULN
  7. Alkaline phosphatase <= 2.5 x ULN
  8. Patients must have the following laboratory values within normal limits at the local institution lab or corrected to within normal limits with supplements prior to the first dose of study medication:

Potassium Magnesium Phosphorus Calcium

5.1.10 Oxygen saturation during exertion maintained at >= 88% on room air.

5.1.11 Ability to understand and willingness to sign a written informed consent form.

5.1.12 Females with reproductive potential must have a negative pregnancy test <= 7 days before starting nilotinib. Reproductive potential will be defined as having at least 1 menstrual period in the past 12 months. Male and female subjects with reproductive potential agree to the use of barrier contraception during their treatment and for up to 3 months after the last dose.

5.1.13 Careful rationalization of concomitant medications with the intent to discontinue or change to alternative medications when any concomitant medications are identified that have the potential to prolong the QTcB interval or are associated with an increased risk of torsades de pointes. (Appendix B)

5.1.14 . Careful rationalization of concomitant medications with the intent to discontinue or change to alternative medications if any concomitant medications are identified to be strong CYP3A4 inhibitors. (Appendix C)

5.1.15 Myeloablative or non-myeloablative allogeneic hematopoietic cell transplant.

Exclusion Criteria:5.2.1 Currently receiving or has received within 28 days of starting study drug nilotinib or any other tyrosine kinase inhibitor.

5.2.2 Received any anti-T or anti-B cell monoclonal antibody <= 28 days prior to the anticipated start of study drug.

5.2.3 Currently receiving > two immunosuppressants other than glucocorticoids.

5.2.4 Currently receiving a calcineurin inhibitor and sirolimus

5.2.5 Received any investigational agents <= 28 days before starting nilotinib.

5.2.6 Impaired cardiac function including any one of the following:

  1. Clinically significant resting brachycardia (<50 beats per minute).
  2. QTc > 450 msec on baseline ECG. If QTc >450 msec and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-screened for QTc.
  3. Myocardial infarction within 12 months prior to starting study.
  4. Other clinically significant uncontrolled heart disease (e.g. unstable angina, congestive heart failure or uncontrolled hypertension).
  5. History of or presence of clinically significant ventricular or atrial tachyarrhythmias. (including congenital long QT syndrome or a known family history of congenital long QT syndrome)

5.2.7 Allogeneic cell infusion within 100 days

5.2.8 Uncontrolled infections not responsive to antibiotics, antiviral medicines, or antifungal medicines.

5.2.9 Progressive malignant disease including post transplant lymphoproliferative disease.

5.2.10 Any secondary malignancy except basal and squamous cell carcinoma of the skin within the past five years.

5.2.11 Nilotinib intolerance or hypersensitivity. 5.2.12 Impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection or gastric bypass surgery).

5.2.13 Acute or chronic pancreatic disease 5.2.14 Major surgery within 4 weeks prior to Day 1 of the study or who have not recovered from prior surgery.

5.2.15 Subject is pregnant, breast-feeding, or of childbearing potential without a negative serum or urine pregnancy test within 7 days of enrollment. Male or female patients of childbearing potential unwilling to use effective contraceptive precautions throughout the trial.

5.2.16 Subject not willing to comply with treatment or response evaluation (including associated procedures such as skin biopsy).

5.2.17 Subject has a concurrent illness which in the opinion of the investigator may interfere with the treatment and evaluation of the patient.

Sites / Locations

  • Stanford University School of Medicine
  • Colorado Blood Cancer Institute
  • Roswell Park Cancer Institute
  • Fred Hutchinson Cancer Research Center
  • Gordon and Leslie Diamond Health Care Centre Hematology Administration

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Nilotinib

Arm Description

Outcomes

Primary Outcome Measures

Frequency and severity of adverse events graded according to CTCAE v4.0

Secondary Outcome Measures

Chronic GVHD response measured as change in physical exam and laboratory testing
Chronic GVHD response measured as change in daily corticosteroid requirement
Chronic GVHD response measured as frequency of treatment failure defined as discontinuation of study drug due to severe adverse effects or initiation of a new treatment for cGVHD
Chronic GVHD response measured as change in cGVHD symptom burden

Full Information

First Posted
June 15, 2010
Last Updated
April 13, 2020
Sponsor
Stanford University
Collaborators
Novartis
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1. Study Identification

Unique Protocol Identification Number
NCT01155817
Brief Title
Phase 1 Nilotinib in Steroid Dependent/Refractory Chronic Graft Versus Host Disease
Official Title
A Phase 1 Study of Nilotinib in Steroid Dependent/Refractory Chronic Graft Versus Host Disease
Study Type
Interventional

2. Study Status

Record Verification Date
April 2020
Overall Recruitment Status
Completed
Study Start Date
August 2010 (undefined)
Primary Completion Date
December 2013 (Actual)
Study Completion Date
December 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Stanford University
Collaborators
Novartis

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
PRIMARY OBJECTIVES: Determine the safety and tolerability of nilotinib in steroid dependent / refractory cGVHD. SECONDARY OBJECTIVES: Determine the clinical efficacy of nilotinib in steroid dependent / refractory cGVHD.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Bone Marrow Transplant Failure, Lymphoma, Non-Hodgkin, Lymphoma, T-Cell, Peripheral

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
33 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Nilotinib
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
Nilotinib
Other Intervention Name(s)
Tasigna, AMN107
Intervention Description
200, 400, 800, oral
Primary Outcome Measure Information:
Title
Frequency and severity of adverse events graded according to CTCAE v4.0
Time Frame
2 years
Secondary Outcome Measure Information:
Title
Chronic GVHD response measured as change in physical exam and laboratory testing
Time Frame
baseline and 2 years
Title
Chronic GVHD response measured as change in daily corticosteroid requirement
Time Frame
baseline and 2 years
Title
Chronic GVHD response measured as frequency of treatment failure defined as discontinuation of study drug due to severe adverse effects or initiation of a new treatment for cGVHD
Time Frame
2 years
Title
Chronic GVHD response measured as change in cGVHD symptom burden
Time Frame
baseline and 2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:5.1.1 Steroid dependent/refractory cGVHD defined as: Dependent disease - Persistent cGVHD manifestations requiring a glucocorticoid dose >= prednisone 0.25 mg/kg/day (0.5 mg/kg po qod) for at least 12 weeks. Refractory disease - Progressive cGVHD manifestations despite treatment with a glucocorticoid dose >= prednisone 0.5 mg/kg/day (1 mg/kg po qod) for at least 4 weeks. 5.1.2 Any previous treatments for cGVHD (except nilotinib). Participants may have received nilotinib for other reasons besides cGVHD such as leukemia or solid tumor. 5.1.3 Participants must be receiving baseline systemic glucocorticoid therapy for cGVHD at study entry. The dose of steroids must be stable for 14 days prior to starting nilotinib. 5.1.4 At the time of trial enrollment, participants may be receiving one or two other immunosuppressive therapies in addition to glucocorticoids. Immunosuppressant doses must be stable for 14 days prior to starting nilotinib. Monoclonal T or B cell antibodies must be discontinued at least 28 days before starting nilotinib. 5.1.5 Chronic GVHD manifestations that can be followed on physical or laboratory exam. A list of potential manifestations is presented in Appendix D. Skin changes Oral mucosa changes Hepatic dysfunction 5.1.6 >= 18 years old 5.1.7 Life expectancy >= 6 months. 5.1.8 Karnofsky performance status >= 60 (defined as being unable to work, able to live at home, and able to care for most personal needs but requiring occasional assistance from others). 5.1.9 Laboratory parameters: Creatinine < 1.5 x ULN ANC > 1.5 x 10^9/L Platelets > 100 x 10^9/L Total bilirubin < 1.5 x ULN AST (SGOT) and ALT (SGPT) < 2.5 x ULN Serum amylase and lipase <= 1.5 x ULN Alkaline phosphatase <= 2.5 x ULN Patients must have the following laboratory values within normal limits at the local institution lab or corrected to within normal limits with supplements prior to the first dose of study medication: Potassium Magnesium Phosphorus Calcium 5.1.10 Oxygen saturation during exertion maintained at >= 88% on room air. 5.1.11 Ability to understand and willingness to sign a written informed consent form. 5.1.12 Females with reproductive potential must have a negative pregnancy test <= 7 days before starting nilotinib. Reproductive potential will be defined as having at least 1 menstrual period in the past 12 months. Male and female subjects with reproductive potential agree to the use of barrier contraception during their treatment and for up to 3 months after the last dose. 5.1.13 Careful rationalization of concomitant medications with the intent to discontinue or change to alternative medications when any concomitant medications are identified that have the potential to prolong the QTcB interval or are associated with an increased risk of torsades de pointes. (Appendix B) 5.1.14 . Careful rationalization of concomitant medications with the intent to discontinue or change to alternative medications if any concomitant medications are identified to be strong CYP3A4 inhibitors. (Appendix C) 5.1.15 Myeloablative or non-myeloablative allogeneic hematopoietic cell transplant. Exclusion Criteria:5.2.1 Currently receiving or has received within 28 days of starting study drug nilotinib or any other tyrosine kinase inhibitor. 5.2.2 Received any anti-T or anti-B cell monoclonal antibody <= 28 days prior to the anticipated start of study drug. 5.2.3 Currently receiving > two immunosuppressants other than glucocorticoids. 5.2.4 Currently receiving a calcineurin inhibitor and sirolimus 5.2.5 Received any investigational agents <= 28 days before starting nilotinib. 5.2.6 Impaired cardiac function including any one of the following: Clinically significant resting brachycardia (<50 beats per minute). QTc > 450 msec on baseline ECG. If QTc >450 msec and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-screened for QTc. Myocardial infarction within 12 months prior to starting study. Other clinically significant uncontrolled heart disease (e.g. unstable angina, congestive heart failure or uncontrolled hypertension). History of or presence of clinically significant ventricular or atrial tachyarrhythmias. (including congenital long QT syndrome or a known family history of congenital long QT syndrome) 5.2.7 Allogeneic cell infusion within 100 days 5.2.8 Uncontrolled infections not responsive to antibiotics, antiviral medicines, or antifungal medicines. 5.2.9 Progressive malignant disease including post transplant lymphoproliferative disease. 5.2.10 Any secondary malignancy except basal and squamous cell carcinoma of the skin within the past five years. 5.2.11 Nilotinib intolerance or hypersensitivity. 5.2.12 Impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection or gastric bypass surgery). 5.2.13 Acute or chronic pancreatic disease 5.2.14 Major surgery within 4 weeks prior to Day 1 of the study or who have not recovered from prior surgery. 5.2.15 Subject is pregnant, breast-feeding, or of childbearing potential without a negative serum or urine pregnancy test within 7 days of enrollment. Male or female patients of childbearing potential unwilling to use effective contraceptive precautions throughout the trial. 5.2.16 Subject not willing to comply with treatment or response evaluation (including associated procedures such as skin biopsy). 5.2.17 Subject has a concurrent illness which in the opinion of the investigator may interfere with the treatment and evaluation of the patient.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
David Miklos
Organizational Affiliation
Stanford University
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
George Chen
Organizational Affiliation
Stanford University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Stanford University School of Medicine
City
Stanford
State/Province
California
ZIP/Postal Code
94305
Country
United States
Facility Name
Colorado Blood Cancer Institute
City
Denver
State/Province
Colorado
ZIP/Postal Code
80218
Country
United States
Facility Name
Roswell Park Cancer Institute
City
Buffalo
State/Province
New York
ZIP/Postal Code
14263
Country
United States
Facility Name
Fred Hutchinson Cancer Research Center
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109-1024
Country
United States
Facility Name
Gordon and Leslie Diamond Health Care Centre Hematology Administration
City
Vancouver
State/Province
British Columbia
ZIP/Postal Code
V5Z1M9
Country
Canada

12. IPD Sharing Statement

Citations:
PubMed Identifier
29051021
Citation
Chen GL, Carpenter PA, Broady R, Gregory TK, Johnston LJ, Storer BE, Beumer JH, Qiu J, Cerda K, Le R, Otani JM, Liu H, Ross MA, Arai S, Flowers MED, McCarthy PL, Miklos DB. Anti-Platelet-Derived Growth Factor Receptor Alpha Chain Antibodies Predict for Response to Nilotinib in Steroid-Refractory or -Dependent Chronic Graft-Versus-Host Disease. Biol Blood Marrow Transplant. 2018 Feb;24(2):373-380. doi: 10.1016/j.bbmt.2017.10.021. Epub 2017 Oct 16.
Results Reference
derived

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Phase 1 Nilotinib in Steroid Dependent/Refractory Chronic Graft Versus Host Disease

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