0908-09: Pilot Study of Gleevec/Imatinib Mesylate (STI-571, NSC 716051) in Neurofibromatosis (NF1) Patient With Plexiform Neurofibromas

• Sponsor: Kent Robertson (Other)
• Overall Status: Completed
• CT.gov ID: NCT01140360
• Collaborator: (none)
• Enrollment: 21
• Location: 1
• Arm: 1
• Duration (Months): 58
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

This is a second Pilot Study to determine the efficacy of Gleevec® in neurofibromatosis (NF1) patients with plexiform neurofibromas using new response assessment modalities with the secondary goals of assessing Gleevec toxicity, and characterizing markers of response. The rationale for this study arises from the response of human and murine NF1 cells to Gleevec® in vitro, the response of a NF1 patient treated with Gleevec® for airway compression by a plexiform neurofibroma with a dramatic response not previously seen in NF1 therapy, and the experience in 37 NF1 patients treated with Gleevec® in the initial pilot study. Gleevec will be dosed orally with a starting dose of 100 mg twice daily for patients with a BSA > 1.8 m2 or 55 mg/m2 twice daily for patients with BSA < 1.8 m2. For patients with a BSA > 1.8 m2 the dose will increase by increments of 100 mg bid every two weeks as tolerated up to a maximum dose of 400 mg bid. For patients with a BSA < 1.8 m2 the dose will increase by increments of 55 mg/m2 bid every two weeks as tolerated up to a maximum dose of 220 mg/m2 bid. Treatment will continue for 6 months with an option to continue for 24 months if the patient is deriving a clinical benefit.

Condition or Disease	Intervention/Treatment	Phase
Neurofibromatosis; Neurofibromas	Drug: Gleevec	Phase 1/Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 21 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Pilot Study of Gleevec/Imatinib Mesylate (STI-571, NSC 716051) in Neurofibromatosis (NF1) Patient With Plexiform Neurofibromas
• Study Start Date: Feb 1, 2012
• Actual Primary Completion Date: Aug 1, 2016
• Actual Study Completion Date: Dec 1, 2016

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Gleevec Gleevec will be dosed orally with a starting dose of 100 mg twice daily for patients with a BSA > 1.8 m2 or 55 mg/m2 twice daily for patients with BSA < 1.8 m2. For patients with a BSA > 1.8 m2 the dose will increase by increments of 100 mg bid every two weeks as tolerated up to a maximum dose of 400 mg bid. For patients with a BSA < 1.8 m2 the dose will increase by increments of 55 mg/m2 bid every two weeks as tolerated up to a maximum dose of 220 mg/m2 bid.Treatment will continue for 6 months with an option to continue for 24 months if the patient is deriving a clinical benefit.

Drug: Gleevec; Gleevec will be dosed orally with a starting dose of 100 mg twice daily for patients with a BSA > 1.8 m2 or 55 mg/m2 twice daily for patients with BSA < 1.8 m2. For patients with a BSA > 1.8 m2 the dose will increase by increments of 100 mg bid every two weeks as tolerated up to a maximum dose of 400 mg bid. For patients with a BSA < 1.8 m2 the dose will increase by increments of 55 mg/m2 bid every two weeks as tolerated up to a maximum dose of 220 mg/m2 bid.Treatment will continue for 6 months with an option to continue for 24 months if the patient is deriving a clinical benefit.; Other Names: Imatinib Mesylate

Outcome Measures

Primary Outcome Measures

1. Disease Response [1 year]

   To estimate the disease control rate (SD, PR, CR) with Gleevec/Imatinib Mesylate in patients with neurofibromas (NF1). The sum of the longest diameter (LD) for all target lesions will be calculated and reported as the disease measurement. Complete Response (CR) disappearance of target lesions. Partial Response (PR) at least a 30% decrease in the disease measurement, taking as reference the disease measurement done to confirm measurable disease at study entry. Progressive Disease (PD) at least a 20% increase in the disease measurement, taking as reference the smallest disease measurement recorded since the start of treatment. Stable Disease (SD) neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest disease measurement since the treatment started.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 3 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria

1. Patients > 3 years of age.

2. Diagnosis of neurofibromatosis type 1 (NF1).

3. Presence of clinically significant plexiform neurofibromas (biopsy proven if possible with tissue blocks available); defined as tumors that are potentially life threatening or are impinging on vital structures or significantly impair the quality of life from pain or other symptoms.

4. Patients must have measurable disease by magnetic resonance imaging (MRI).

5. Patients must have a Karnofsky of > 70% or Lansky of > 50% and a life expectancy of > 2 months.

6. Adequate end organ function, defined as the following:

total bilirubin < 1.5 x ULN, SGOT and SGPT < 2.5 x UNL, creatinine < 1.5 x ULN, ANC > 1.5 x 109/L, platelets > 100 x 109/L.

1. Patients must be able to swallow whole pills.

2. Female patients of childbearing potential must have negative pregnancy test within 7 days before initiation of study drug dosing. Postmenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. Male and female patients of reproductive potential must agree to employ an effective barrier method of birth control throughout the study and for up to 3 months following discontinuation of study drug.

3. Written, voluntary informed consent.

Exclusion criteria

1. Patient has received any other investigational agents within 28 days of first day of study drug dosing, unless the disease is rapidly progressing.

2. Patient is < 5 years free of another primary malignancy except: if the other primary malignancy is not currently clinically significant nor requiring active intervention, or if other primary malignancy is a basal cell skin cancer or a cervical carcinoma in situ. Existence of any other malignant disease is not allowed.

3. Patient with Grade III/IV cardiac problems as defined by the New York Heart Association Criteria. (i.e., congestive heart failure, myocardial infarction within 6 months of study)

4. Female patients who are pregnant or breast-feeding.

5. Patient has a severe and/or uncontrolled medical disease (i.e., uncontrolled diabetes, chronic renal disease, or active uncontrolled infection).

6. Patient has a known brain metastasis. Non-specific CNS changes on MRI/CT characteristic of NF1 are allowed, but not known CNS malignancies.

7. Patient has known chronic liver disease (i.e., chronic active hepatitis, and cirrhosis).

8. Patient has a known diagnosis of human immunodeficiency virus (HIV) infection.

9. Patient received chemotherapy within 4 weeks (6 weeks for nitrosourea or mitomycin-C) prior to study entry, unless the disease is rapidly progressing.

10. Patient previously received radiotherapy to greater than or equal to 25 % of the bone marrow

11. Patient had a major surgery within 2 weeks prior to study entry.

12. Patient with any significant history of non-compliance to medical regimens or with inability to grant reliable informed consent.

13. Patients who have or anticipate receiving permanent (or semi-permanent) metallic structures attached to their body. (e.g., braces on teeth, body piercings), which their physicians believe will interfere with the MRI.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Riley Hospital for Children	Indianapolis	Indiana	United States	46202

Sponsors and Collaborators

• Kent Robertson

Investigators

• Principal Investigator: Kent Robertson, MD PhD, Indiana University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Kent Robertson, Associate Professor of Pediatrics, Indiana University School of Medicine
• ClinicalTrials.gov Identifier: NCT01140360
• Other Study ID Numbers: NF/Gleevec DOD Trial; 0908-09
• First Posted: Jun 9, 2010
• Last Update Posted: Jul 2, 2017
• Last Verified: Jun 1, 2017

• Keywords provided by Kent Robertson, Associate Professor of Pediatrics, Indiana University School of Medicine: Neurofibromas
• Additional relevant MeSH terms: Neurofibromatoses; Neurofibromatosis 1; Neurofibroma; Neurofibroma, Plexiform; Imatinib Mesylate

Study Results

Participant Flow

Arm/Group Title	Gleevec
Arm/Group Description	Gleevec will be dosed orally with a starting dose of 100 mg twice daily for patients with a BSA > 1.8 m2 or 55 mg/m2 twice daily for patients with BSA < 1.8 m2. For patients with a BSA > 1.8 m2 the dose will increase by increments of 100 mg bid every two weeks as tolerated up to a maximum dose of 400 mg bid. For patients with a BSA < 1.8 m2 the dose will increase by increments of 55 mg/m2 bid every two weeks as tolerated up to a maximum dose of 220 mg/m2 bid.Treatment will continue for 6 months with an option to continue for 24 months if the patient is deriving a clinical benefit.
Period Title: Overall Study
STARTED	21
COMPLETED	15
NOT COMPLETED	6

Baseline Characteristics

Arm/Group Title	Gleevec
Arm/Group Description	Gleevec will be dosed orally with a starting dose of 100 mg twice daily for patients with a BSA > 1.8 m2 or 55 mg/m2 twice daily for patients with BSA < 1.8 m2. For patients with a BSA > 1.8 m2 the dose will increase by increments of 100 mg bid every two weeks as tolerated up to a maximum dose of 400 mg bid. For patients with a BSA < 1.8 m2 the dose will increase by increments of 55 mg/m2 bid every two weeks as tolerated up to a maximum dose of 220 mg/m2 bid.Treatment will continue for 6 months with an option to continue for 24 months if the patient is deriving a clinical benefit.
Overall Participants	21
Age (Count of Participants)
<=18 years	10 47.6%
Between 18 and 65 years	11 52.4%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	14 66.7%
Male	7 33.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 4.8%
Not Hispanic or Latino	20 95.2%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 4.8%
White	19 90.5%
More than one race	1 4.8%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	21 100%

Outcome Measures

1. Primary Outcome

Title	Disease Response
Description	To estimate the disease control rate (SD, PR, CR) with Gleevec/Imatinib Mesylate in patients with neurofibromas (NF1). The sum of the longest diameter (LD) for all target lesions will be calculated and reported as the disease measurement. Complete Response (CR) disappearance of target lesions. Partial Response (PR) at least a 30% decrease in the disease measurement, taking as reference the disease measurement done to confirm measurable disease at study entry. Progressive Disease (PD) at least a 20% increase in the disease measurement, taking as reference the smallest disease measurement recorded since the start of treatment. Stable Disease (SD) neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest disease measurement since the treatment started.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

13 participants reached the 1 year evaluation time-point. 6 participants withdrew prior to the 1 year evaluation time-point.

Arm/Group Title	Gleevec
Arm/Group Description	Gleevec will be dosed orally with a starting dose of 100 mg twice daily for patients with a BSA > 1.8 m2 or 55 mg/m2 twice daily for patients with BSA < 1.8 m2. For patients with a BSA > 1.8 m2 the dose will increase by increments of 100 mg bid every two weeks as tolerated up to a maximum dose of 400 mg bid. For patients with a BSA < 1.8 m2 the dose will increase by increments of 55 mg/m2 bid every two weeks as tolerated up to a maximum dose of 220 mg/m2 bid.Treatment will continue for 6 months with an option to continue for 24 months if the patient is deriving a clinical benefit.
Measure Participants	13
Stable Disease (SD)	13 61.9%
Partial Response (PR)	0 0%
Complete Response (CR)	0 0%
Progressive Disease (PD)	0 0%

Adverse Events

Time Frame	1 year
Arm/Group Title	Gleevec
Arm/Group Description	Gleevec will be dosed orally with a starting dose of 100 mg twice daily for patients with a BSA > 1.8 m2 or 55 mg/m2 twice daily for patients with BSA < 1.8 m2. For patients with a BSA > 1.8 m2 the dose will increase by increments of 100 mg bid every two weeks as tolerated up to a maximum dose of 400 mg bid. For patients with a BSA < 1.8 m2 the dose will increase by increments of 55 mg/m2 bid every two weeks as tolerated up to a maximum dose of 220 mg/m2 bid.Treatment will continue for 6 months with an option to continue for 24 months if the patient is deriving a clinical benefit.
All Cause Mortality
	Gleevec
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Gleevec
	Affected / at Risk (%)	# Events
Total	3/21 (14.3%)
Hepatobiliary disorders
Hepatic Failure	1/21 (4.8%)	1
Metabolism and nutrition disorders
Dehydration	1/21 (4.8%)	1
Vascular disorders
Pseudoaneurysm of carotid artery	1/21 (4.8%)	1
Other (Not Including Serious) Adverse Events
	Gleevec
	Affected / at Risk (%)	# Events
Total	21/21 (100%)
Blood and lymphatic system disorders
anemia	9/21 (42.9%)	11
Lymphopenia	2/21 (9.5%)	4
Gastrointestinal disorders
Constipation	3/21 (14.3%)	3
Diarrhea	3/21 (14.3%)	5
dysphagia	2/21 (9.5%)	3
Nausea	10/21 (47.6%)	16
vomitting	4/21 (19%)	4
General disorders
Back Pain	3/21 (14.3%)	4
edema limbs	5/21 (23.8%)	6
fatigue	7/21 (33.3%)	9
Investigations
Alanine aminotransferase increased	3/21 (14.3%)	4
Neutrophil count decreased	7/21 (33.3%)	10
Aspartate aminotransferase increased	3/21 (14.3%)	6
blood bilirubin increased	3/21 (14.3%)	4
white blood cell decreased	11/21 (52.4%)	16
weight loss	3/21 (14.3%)	3
Metabolism and nutrition disorders
anorexia	3/21 (14.3%)	3
hypocalcemia	2/21 (9.5%)	3
hypokalemia	5/21 (23.8%)	9
Musculoskeletal and connective tissue disorders
Neck pain	3/21 (14.3%)	4
Nervous system disorders
dizziness	2/21 (9.5%)	2
Headache	6/21 (28.6%)	6
Renal and urinary disorders
Urinary frequency	3/21 (14.3%)	3
Respiratory, thoracic and mediastinal disorders
dyspnea	2/21 (9.5%)	2
Skin and subcutaneous tissue disorders
alopecia	2/21 (9.5%)	2
puritits	2/21 (9.5%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.