Combination Chemotherapy in Treating Patients With Neurofibromatosis and Progressive Plexiform Neurofibromas

• Sponsor: Children's Hospital of Philadelphia (Other)
• Overall Status: Completed
• CT.gov ID: NCT00030264
• Collaborator: (none)
• Enrollment: 23
• Location: 1
• Arm: 1
• Duration (Months): 180.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining methotrexate with vinblastine may be effective treatment for neurofibromatosis type 1 associated with progressive plexiform neurofibromas.

PURPOSE: Phase II trial to study the effectiveness of combination chemotherapy in treating patients who have neurofibromatosis type 1 associated with progressive plexiform neurofibromas.

Condition or Disease	Intervention/Treatment	Phase
Neurofibromatosis Type 1; Precancerous Condition	Drug: Methotrexate; Drug: Vinblastine	Phase 2

Detailed Description

OBJECTIVES:

• Determine the effect of chronic vinblastine and methotrexate on time to disease progression in children or young adults with progressive plexiform neurofibroma associated with neurofibromatosis type 1.

• Determine the objective response rate in patients treated with this regimen.

• Determine the toxic effects of this regimen in these patients.

• Determine the quality of life of patients treated with this regimen.

OUTLINE: Patients are stratified according to tumor status (severely debilitating and/or life-threatening vs cosmetically disfiguring).

Patients receive methotrexate and vinblastine IV weekly for 26 weeks and then every 2 weeks for 26 weeks in the absence of disease progression or unacceptable toxicity.

Quality of life is assessed at baseline and then every 3 months during study participation.

Patients are followed every 3 months until disease progression.

PROJECTED ACCRUAL: A total of 35 patients will be accrued for this study within approximately 3 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 23 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Vinblastine/Methotrexate For Severe Progressive Plexiform Neurofibromas: A Phase II Study
• Study Start Date: Feb 1, 2001
• Actual Primary Completion Date: Dec 1, 2013
• Actual Study Completion Date: Mar 1, 2016

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Methotrexate & Vinblastine Methotrexate and Vinblastine will be given once a week for the first 26 weeks and then every two weeks for the next 26 weeks or until disease progression (whichever occurs first).

Drug: Methotrexate; Methotrexate will be given at a dose of 30mg/m2/week intramuscular (IM) or intravenous (IV) for the first 26 weeks, then every 2 weeks for the next 26 weeks or until disease progression (whichever occurs first); Drug: Vinblastine; Vinblastine will be given at a dose of 6mg/m2/week intravenous (IV) for for the first 26 weeks, then every 2 weeks for the next 26 weeks or until disease progression (whichever occurs first). Maximum actual dose may not exceed 10mg.

Outcome Measures

Primary Outcome Measures

1. Time to Disease Progression [6 months]

   Disease progression was assessed both radiographically and clinically. Tumor assessments to assess for radiographic disease progression were assessed by magnetic resonance imaging (MRI) measurement whenever possible or computed tomography (CT) scan and/or tumor measurement during physical examination of palpable lesions. Clinical assessments for clinical progression of disease were assessed by treating physician or designee. Progressive disease as measured by the appearance of new lesions; an increased size of index tumor(s) by >/= 25% of the sum of the products of baseline measurements; and/or by increase in symptoms.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 25 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Progressive, debilitating, severely disfiguring or life-threatening plexiform neurofibroma (PN) which is not surgically resectable and for which there is no other standard medical management. Histologic confirmation of tumor is not required in the presence of consistent clinical and radiographic findings. However, if any clinical observation or scan suggests possible malignant transformation, the tumor must be biopsied prior to therapy. In addition to PN, all study subjects must have at least one other diagnostic criteria for Neurofibromatosis type 1 (NF1) listed below:

• 6 or more café-au-lait spots > 0.5 cm in prepubertal subjects or > 1.5 cm in postpubertal subjects

• freckling in the axilla or groin

• optic glioma

• 2 or more lisch nodules

• a distinctive bony lesion (dysplasia of the sphenoid bone or dysplasia or thinning of long bone cortex)

• a first degree relative with NF1

1. Adequate bone marrow, renal, hepatic function:

• Absolute Neutrophil Count (ANC)> 1000 and platelet count >100,000 prior to initiation of therapy

• must have normal renal function: Blood Urea Nitrogen (BUN)/Creatinine <1.5x normal for age), alkaline phosphatase (ALP), albumin, total protein and bilirubin

• must have normal liver function: Bilirubin, alanine transaminase (ALT), aspartate aminotransferase (AST) < 1.5x normal for age

1. Patients must have measurable PN by direct physical examination (documented by clinical measurement of tumor and serial photography) or by imaging studies. Most patients will have tumors that can be measured by magnetic resonance imaging (MRI), however, some patients may have cosmetically disfiguring PN which would be best measured clinically and with serial photography throughout treatment and follow-up. A measurable lesion is one whose size can be quantified in at least 2 dimensions. There must be evidence of recurrent or progressive disease as documented by an increase in size or the presence of new lesions on MRI. Progression is defined as the appearance of new tumors or a measurable increase in the sum of the product of the two longest perpendicular diameters of the index lesion(s) over a time period < 12 months prior to evaluation for this study. For purposes of this study, index PN lesions will be those PNs evaluated as the most life-threatening, debilitating, cosmetically disfiguring, and/or most easily measured.

2. Prior therapy: Patients with NF1 are eligible at the time of recurrence or progression of inoperable PN. A surgical consultation should be obtained prior to enrollment on the study to evaluate if tumor resection is a feasible option. Patients will only be eligible if complete tumor resection is not feasible or if a patient with a surgical option refuses surgery. Since there is no standard effective chemotherapy for patients with NF1 and progressive PN, patients may be treated on this trial without having received prior therapy. Patients must have recovered from the toxic effects of all prior therapy before entering this study. The Cancer Therapy Evaluation Program Common Toxicity Criteria (CTC) Version 2.0 will be used for toxicity assessment. Recovery is defined as a toxicity grade < 2, unless otherwise specified in the Inclusion and Exclusion Criteria. Patients must have had their last dose of radiation therapy at least 6 weeks prior to study entry, and their last dose of chemotherapy at least four weeks prior to study entry. Patients who received granulocyte-colony stimulating factor (G-CSF) after the prior cycle of chemotherapy must be off G-CSF for at least one week prior to entering this study.

3. Performance status: Patients should have a life expectancy of at least 12 months and a Lansky or Karnofsky performance score of > 60. Patients who are wheelchair bound because of paralysis should be considered "ambulatory" when they are mobile and active in their wheelchairs rather than actually ambulatory.

4. A Pregnancy test must be negative for females of childbearing age.

5. Informed consent: All patients or their legal guardians (if the patient is less than 18 years old) must sign an approved document of informed consent indicating their understanding of the investigational nature and the risks of this study before beginning therapy. When appropriate pediatric patients will be included in all discussion in order to obtain verbal assent.

Exclusion Criteria:

1. Pregnant females are excluded

2. Patient has had treatment with an investigational agent within the past 30 days.

3. Ongoing radiation therapy, chemotherapy, hormonal therapy directed at the tumor or immunotherapy.

4. Inability to return for follow-up visits or obtain follow-up studies required to assess toxicity and response to therapy.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104

Sponsors and Collaborators

• Children's Hospital of Philadelphia

Investigators

• Principal Investigator: Jean B. Belasco, MD, Children's Hospital of Philadelphia

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Children's Hospital of Philadelphia
• ClinicalTrials.gov Identifier: NCT00030264
• Other Study ID Numbers: 07-2339; CHP-686
• First Posted: Jan 27, 2003
• Last Update Posted: Aug 8, 2018
• Last Verified: Jul 1, 2018

• Keywords provided by Children's Hospital of Philadelphia: plexiform neurofibroma; neurofibromatosis type 1
• Additional relevant MeSH terms: Neurofibromatoses; Neurofibromatosis 1; Neurofibroma; Precancerous Conditions; Neurofibroma, Plexiform; Methotrexate; Vinblastine

Study Results

Participant Flow

Recruitment Details	23 eligible subjects were enrolled at the Children's Hospital of Philadelphia and Texas Children's Hospital between March 2001 and June 2011

Arm/Group Title	Methotrexate & Vinblastine
Arm/Group Description	Methotrexate and Vinblastine will be given once a week for the first 26 weeks and then every two weeks for the next 26 weeks or until disease progression (whichever occurs first). Methotrexate: Methotrexate will be given at a dose of 30mg/m2/week intramuscular (IM) or intravenous (IV) for the first 26 weeks, then every 2 weeks for the next 26 weeks or until disease progression (whichever occurs first) Vinblastine: Vinblastine will be given at a dose of 6mg/m2/week intravenous (IV) for for the first 26 weeks, then every 2 weeks for the next 26 weeks or until disease progression (whichever occurs first). Maximum actual dose may not exceed 10mg.
Period Title: Overall Study
STARTED	23
COMPLETED	23
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Methotrexate & Vinblastine
Arm/Group Description	Methotrexate and Vinblastine will be given once a week for the first 26 weeks and then every two weeks for the next 26 weeks or until disease progression (whichever occurs first). Methotrexate: Methotrexate will be given at a dose of 30mg/m2/week intramuscular (IM) or intravenous (IV) for the first 26 weeks, then every 2 weeks for the next 26 weeks or until disease progression (whichever occurs first) Vinblastine: Vinblastine will be given at a dose of 6mg/m2/week intravenous (IV) for for the first 26 weeks, then every 2 weeks for the next 26 weeks or until disease progression (whichever occurs first). Maximum actual dose may not exceed 10mg.
Overall Participants	23
Age (Count of Participants)
<=18 years	19 82.6%
Between 18 and 65 years	4 17.4%
>=65 years	0 0%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	5.56
Sex: Female, Male (Count of Participants)
Female	13 56.5%
Male	10 43.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 4.3%
Not Hispanic or Latino	13 56.5%
Unknown or Not Reported	9 39.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	2 8.7%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	2 8.7%
White	17 73.9%
More than one race	0 0%
Unknown or Not Reported	2 8.7%
Region of Enrollment (Count of Participants)
United States	23 100%

Outcome Measures

1. Primary Outcome

Title	Time to Disease Progression
Description	Disease progression was assessed both radiographically and clinically. Tumor assessments to assess for radiographic disease progression were assessed by magnetic resonance imaging (MRI) measurement whenever possible or computed tomography (CT) scan and/or tumor measurement during physical examination of palpable lesions. Clinical assessments for clinical progression of disease were assessed by treating physician or designee. Progressive disease as measured by the appearance of new lesions; an increased size of index tumor(s) by >/= 25% of the sum of the products of baseline measurements; and/or by increase in symptoms.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

20 subjects were analyzed for time to progression. 3 subjects were not included in the response analysis due to lost to follow up (N=2) or progression of comorbid condition which required early termination (N=1)

Arm/Group Title	Methotrexate & Vinblastine
Arm/Group Description	Methotrexate and Vinblastine will be given once a week for the first 26 weeks and then every two weeks for the next 26 weeks or until disease progression (whichever occurs first). Methotrexate: Methotrexate will be given at a dose of 30mg/m2/week intramuscular (IM) or intravenous (IV) for the first 26 weeks, then every 2 weeks for the next 26 weeks or until disease progression (whichever occurs first) Vinblastine: Vinblastine will be given at a dose of 6mg/m2/week intravenous (IV) for for the first 26 weeks, then every 2 weeks for the next 26 weeks or until disease progression (whichever occurs first). Maximum actual dose may not exceed 10mg.
Measure Participants	20
Total	25.8
Radiographic Progression	29.2
Clinical Progression	25.8

Adverse Events

Adverse Event Reporting Description	For non-serious events, CTCAE Grade 3 and 4 were collected.
Arm/Group Title	Methotrexate & Vinblastine
Arm/Group Description	Methotrexate and Vinblastine will be given once a week for the first 26 weeks and then every two weeks for the next 26 weeks or until disease progression (whichever occurs first). Methotrexate: Methotrexate will be given at a dose of 30mg/m2/week intramuscular (IM) or intravenous (IV) for the first 26 weeks, then every 2 weeks for the next 26 weeks or until disease progression (whichever occurs first) Vinblastine: Vinblastine will be given at a dose of 6mg/m2/week intravenous (IV) for for the first 26 weeks, then every 2 weeks for the next 26 weeks or until disease progression (whichever occurs first). Maximum actual dose may not exceed 10mg.
All Cause Mortality
	Methotrexate & Vinblastine
	Affected / at Risk (%)	# Events
Total	3/23 (13%)
Serious Adverse Events
	Methotrexate & Vinblastine
	Affected / at Risk (%)	# Events
Total	6/23 (26.1%)
Gastrointestinal disorders
Anorexia	1/23 (4.3%)	1
Hepatobiliary disorders
Hepatic - Other - Cholecytitis	1/23 (4.3%)	1
Infections and infestations
Infection - Bacterial	1/23 (4.3%)	1
Infection - Viral	1/23 (4.3%)	1
Infection	1/23 (4.3%)	1
Investigations
Febrile neutropenia	1/23 (4.3%)	1
Fever	1/23 (4.3%)	1
Fever	1/23 (4.3%)	1
Respiratory, thoracic and mediastinal disorders
Pulmonary - Other - Respiratory Distress	1/23 (4.3%)	1
Other (Not Including Serious) Adverse Events
	Methotrexate & Vinblastine
	Affected / at Risk (%)	# Events
Total	8/23 (34.8%)
Blood and lymphatic system disorders
Neutrophils/granulocytes (ANC/AGC)	8/23 (34.8%)	15
Leukocytes (total WBC)	2/23 (8.7%)	3
Lymphopenia	1/23 (4.3%)	1
Infections and infestations
Infection - Viral	1/23 (4.3%)	1
Investigations
SGPT (ALT) (serum glutamic pyruvic transaminase)	1/23 (4.3%)	1

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.