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Cabozantinib for Plexiform Neurofibromas (PN) in Subjects With NF1 in Children and Adults (NF105-CABO)

Primary Purpose

NF1, Neurofibromatosis, Plexiform Neurofibromas

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Cabozantinib
Sponsored by
University of Alabama at Birmingham
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for NF1 focused on measuring Cohort A: 3-15 years, Cohort B: Ages >= 16 years, Cabozantinib, XL184, Plexiform Neurofibromas, Neurofibromatosis, Pathogenetic NF1 Mutations, Cometriq, NF1

Eligibility Criteria

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

Inclusion Criteria:

  1. Clinical or molecular diagnosis of Neurofibromatosis Type 1
  2. Plexiform neurofibroma that is progressive OR causing significant morbidity.
  3. Measurable disease amenable to volumetric MRI imaging defined as lesion seen on at least 3 consecutive MRI slices and at least 3 mL in volume. Select tumors <3 cm may be eligible on review.
  4. Central review or MRI required prior to enrollment.
  5. Age ≥ 3 years of age at the time of study entry. Subjects ≥ 16 years will be enrolled in Cohort A. Subjects 3 - 15 years will be enrolled in Cohort B.
  6. Performance Level Karnofsky ≥ 50%. Subjects unable to walk because of paralysis, but up in a wheel chair will be considered ambulatory for purpose of assessing performance score.
  7. Complete resection of plexiform neurofibroma is not feasible or if subject refuses surgery.
  8. Fully recovered from acute toxic effects of all prior chemotherapy or radiotherapy.
  9. No myelosuppressive chemotherapy within 4 weeks of study entry.
  10. At least 7 days since completion of hematopoietic growth factors.
  11. At least 14 days since completion of biologic agent.
  12. At least 4 weeks since receiving any investigational drug.
  13. Physiologic or stress doses of steroids allowed in patients with endocrine deficiencies.
  14. At least 6 months from radiation therapy to index tumor and at least 6 weeks from radiation to areas outside of index plexiform neurofibroma.
  15. At least 3 months from major surgery or at least 1 month from minor surgery. No major surgery anticipated within 3 months of enrollment.
  16. Adequate bone marrow function.
  17. Adequate renal function.
  18. Adequate liver function.
  19. Blood pressure within upper limit of normal.

Exclusion Criteria:

  1. Active optic glioma or other low-grade glioma requiring treatment with chemotherapy or radiation therapy.
  2. Malignant glioma, malignant peripheral nerve sheath tumor, or other malignancy requiring treatment in the last 12 months.
  3. Dental braces or prosthesis that interferes with volumetric analysis of the neurofibroma(s).
  4. Unable to swallow tablets.
  5. Women who are pregnant or breast-feeding.
  6. Subjects of reproductive potential who have not agreed to use effective contraception.
  7. Subject has not recovered to baseline or CTCAE ≤ Grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant AEs.
  8. Subject requires anticoagulants. Low dose aspirin, low-dose warfarin, and prophylactic low molecular weight heparin are permitted.
  9. Concomitant treatment of strong CYP3A4 inducers or inhibitors.
  10. History of noncompliance to medical regimens
  11. A known history of HIV seropositivity or known immunodeficiency. HIV testing will not be required as part of this trial, unless HIV is clinically suspected.
  12. Impairment of gastrointestinal function or gastrointestinal disease that may affect the absorption of cabozantinib. (e.g. ulcerative disease, malabsorption syndrome, or small bowel resection). NG tube is allowed.

    • Any of the following within 28 days before the first dose of study treatment:

      1. intra-abdominal tumor/metastases invading GI mucosa
      2. active peptic ulcer disease
      3. inflammatory bowel disease (including ulcerative colitis and Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis
      4. malabsorption syndrome
    • Any of the following within 6 months before the first dose of study treatment:

      1. abdominal fistula
      2. gastrointestinal perforation
      3. bowel obstruction or gastric outlet obstruction
      4. intra-abdominal abscess. Complete resolution of an intra-abdominal abscess must be confirmed prior to initiating study treatment even if abscess occurred more than 6 months before the first dose of study treatment.
    • Other disorders associated with a high risk of fistula formation including PEG tube placement within 3 months before the first dose of study therapy
  13. Patients who have an uncontrolled infection.
  14. Clinically-significant gastrointestinal bleeding within 6 months before the first dose of study treatment
  15. Hemoptysis of ≥0.5 teaspoon (2.5 mL) of red blood within 3 months before the first dose of study treatment
  16. Any other signs indicative of pulmonary hemorrhage within 3 months before the first dose of study treatment
  17. Radiographic evidence of cavitating pulmonary lesion(s).
  18. Concurrent severe and/or uncontrolled medical disease which could compromise participation in the study (e.g. uncontrolled diabetes, uncontrolled hypertension, severe infection, severe malnutrition, chronic liver or renal disease, active upper GI tract ulceration)
  19. Cardiovascular disorders including:

    • Congestive heart failure (CHF): New York Heart Association (NYHA) Class III (moderate) or Class IV (severe) at the time of screening
    • Concurrent uncontrolled hypertension defined as sustained BP > 140 mm Hg systolic, or > 90 mm Hg diastolic despite optimal antihypertensive treatment within 7 days before the first dose of study treatment
    • Any history of congenital long QT syndrome
    • Baseline QTc interval >470 msec in women and >450 msec in men
    • Concomitant treatment with medications that prolong the QT interval and have a known risk of Torsades de Pointes is not contraindicated, but should be avoided if possible and will require more frequent EKG monitoring.
    • Any of the following within 6 months before the first dose of study treatment:

      1. unstable angina pectoris
      2. clinically-significant cardiac arrhythmias
      3. stroke (including TIA, or other ischemic event)
      4. myocardial infarction
      5. thromboembolic event requiring therapeutic anticoagulation (Note: subjects with a venous filter (e.g. vena cava filter) are not eligible for this study)
  20. Other clinically significant disorders such as:

    • Active infection requiring systematic treatment within 28 days before the first dose of study treatment
    • Serious non-healing wound/ulcer/bone fracture within 28 days before the first dose of study treatment
    • History of organ transplant
    • Concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days before the first dose of study treatment
  21. Complete wound healing from prior surgery must be confirmed at least 28 days before the first dose of study treatment irrespective of time from surgery.

Sites / Locations

  • Children's Hospital Los Angeles
  • Children's National Medical Center
  • Lurie Children's Hospital of Chicago
  • University of Chicago
  • Indiana Unversity
  • National Cancer Institute (NCI)
  • Children' Hospital Boston and Massachusetts General Hospital
  • Washington University - St. Louis
  • New York University Medical Center
  • Cincinnati Children's Hospital Medical Center
  • Children's Hospital of Philadelphia
  • University of Utah

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Experimental Agent XL184 (Cabozantinib)

Arm Description

Cohort A (≥ 16 years - closed to accrual): Starting cabozantinib of 40 mg daily by mouth per cycle. Duration of each cycle is 28 days. Subjects will dose escalate after 2 cycles to 60 mg based on dose tolerability. Subjects who do not tolerate 40 mg will dose reduce to 20 mg. Doses will be capped at 60 mg. Cohort B (3 - 15 years). The starting cabozantinib dose is 30 mg/m2/day by mouth per cycle. Duration of each cycle is 28 days. Subjects will dose escalate after 2 cycles to 40 mg/m2/day based on dose tolerability. Subjects who do not tolerate 30 mg/m2/day will dose reduce to 23 mg/m2/day. Doses will be capped at 60 mg/day max daily dose Each cohort will enroll up to 24 evaluable subjects with a target minimum of 17 evaluable subjects per cohort.

Outcomes

Primary Outcome Measures

The Change in Tumor Size Based on Radiographic Assessment
We will estimate the objective response rate (ORR) as defined by 20% volumetric MRI response of the target lesion to cabozantinib at 12 months in adolescents and adults with Neurofibromatosis type 1 (NF1) plexiform neurofibromas by volumetric MRI imaging.

Secondary Outcome Measures

Number of Participants With Adverse Events
This is the number of participants with one or more adverse events.

Full Information

First Posted
March 14, 2014
Last Updated
May 2, 2023
Sponsor
University of Alabama at Birmingham
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1. Study Identification

Unique Protocol Identification Number
NCT02101736
Brief Title
Cabozantinib for Plexiform Neurofibromas (PN) in Subjects With NF1 in Children and Adults
Acronym
NF105-CABO
Official Title
A Phase II Study of Cabozantinib (XL184) for Plexiform Neurofibromas in Subjects With Neurofibromatosis Type 1 in Children and Adults
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Completed
Study Start Date
June 2014 (Actual)
Primary Completion Date
February 16, 2022 (Actual)
Study Completion Date
February 16, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Alabama at Birmingham

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This study, "A Phase II Study of Cabozantinib (XL l84) for Plexiform Neurofibromas in Subjects with Neurofibromatosis Type I in Children and Adults diagnosed with Neurofibromatosis Type 1 (NF1) and have a type of tumor called a plexiform neurofibroma (PN). Neurofibromas are tumors that develop from the cells and tissues that cover the nerves. Plexiform neurofibromas can be disfiguring, painful, and life-threatening. These types of tumors typically do not respond well to most treatment approaches such as chemotherapy, radiation, and surgery because of their slow growth and location near vital structures of the body such as nerves, blood vessels, and the airway. The primary objective is to determine the response rate of NF1 patients with plexiform neurofibromas treated with Cabozantinib therapy using MRI scans. The objective response rate to cabozantinib is defined as ≥ 20% reduction in tumor volume at the end of 12 cycles.
Detailed Description
There are two cohorts: Cohort A is for patients ≥ 16 years of age and Cohort B is for patients 3 - 15 years of age. Cohort A is closed to enrollment but this study will open to Cohort B patients. This phase II open label study will evaluate adults and children with NF1 and plexiform neurofibromas treated with cabozantinib (XL184). This study will enroll subjects who either meet clinical diagnostic criteria or have an identified pathogenetic NF1 mutation. Subjects on study must have clinically significant plexiform neurofibroma defined as potentially life-threatening, impinging on vital structures or significantly impairing the quality of life from pain or other symptoms. Patients must not have lesions suspicious for malignant tumors such as MPNSTs (malignant peripheral nerve sheath tumors) and suspicious tumors must be proven negative by histopathology prior to enrollment on study. Since Cohort A is closed to accrual, this study will be open to Cohort B, patients 3 - 15 years of age that meet eligibility criteria. For Cohort A, the study will be a Simon two-stage study design. It will be a single-arm open-label study of cabozantinib and the primary endpoint is the objective response rate (ORR) to cabozantinib at 1 year. In the first stage, 9 evaluable subjects will be accrued. If there is at least 1 response, accrual will continue to the second stage and an additional 8 evaluable subjects will be enrolled. To allow for 25% unevaluable subjects, a maximum of 24 subjects will be enrolled. Radiographic response will be evaluated as the primary endpoint with 20% volumetric MRI response of the target lesion being the threshold criteria for tumor response. A target lesion will be selected at time of enrollment and tumor evaluations will occur serially while on study. For Cohort B, a minimum of 17 evaluable subjects will be enrolled. To allow for up to 25% unevaluable subjects, a minimum of 24 subjects will be enrolled. Based on preliminary response data and minimal toxicity in Cohort A, a 2-stage design is not felt to be necessary for Cohort B. In Cohort A, all subjects will start cabozantinib at 40 mg. The published maximum tolerated dose (MTD) for Cabozantinib is 140 mg and the current recommended dose in Phase 3 clinical trials for subjects with medullary thyroid cancer is 100 mg. Doses of 40 mg and 60 mg continue to show efficacy in on-going phase 2 and phase 3 trials with reduced toxicity. Subjects who tolerate 40 mg for 2 cycles will escalate to 60 mg. The rationale for this is that the majority of subjects who develop toxicity do so after >2 weeks on drug as cabozantinib has a long half-life. Subjects who experience dose-limiting toxicity at 40 mg will dose reduce to 20 mg when their toxicities resolve. Subjects without toxicity at 40mg will increase to 60mg. Subjects who experience toxicity at 60 mg will dose reduce to 40 mg. This dosing schema is designed to maximize safety and tolerability in this new population of patients. In Cohort B, subjects will start at 30 mg/m2/day dosing. Dose will be escalated at cycle 3 if tolerated to 40 mg/m2. Subjects who experience DLT at 40 mg/m2/day will dose reduce to 30 mg/m2/day. Subjects who experience DLT at 30 mg/m2/day will dose reduce to 23 mg/m2day. Actual dosing will be based on the dosing nomogram. Dosing will be continuous, with 28 days defined as a cycle and each cycle reporting period is day 1 to day 28. In the absence of progressive disease or dose limiting toxicity (DLT), subjects may continue on therapy for a total of 12 total cycles. Subjects who have a radiographic response (20% or greater reduction in tumor volume) on therapy at the end of 12 cycles can continue on therapy for up to an additional year. The maximum duration for treatment under this study design is 24 cycles. However, subjects who do not achieve at least 15% reduction in index tumor volume after 8 cycles (~8 months) will be considered treatment failures and taken off study. Subjects entered on the trial will be carefully monitored for the development of cabozantinib associated toxicities, and target modifications and interruptions will be performed. The investigational nature and objectives of this trial, the procedures and treatment involved, the risks, discomforts, and benefits, and potential alternatives therapies will be carefully explained to the subject and/or subject's parent(s) or guardian, if subject is a child,by the site Principal Investigator or designated associate investigator. When appropriate, pediatric patients will be included in all discussions. A signed informed consent document will be obtained prior to determining eligibility and entry criteria to this trial. Subjects entered on this trial will be treated with therapeutic intent and response to therapy will be closely monitored. This protocol involves greater than minimal risk but presents the potential for direct benefit to individual subjects Schedule of study evaluations are summarized below: Pre-Study: Medical history, physical exam with vital signs, blood pressure, and pulse oximetry Performance status to assess your ability to perform everyday tasks Laboratory tests including blood and urine tests for routine safety tests Urine pregnancy test for females of childbearing age Electrocardiogram (EKG) to monitor the electrical activity of the heart MRI of neurofibromas Completion of health-related questionnaires on quality of life, pain assessment, and PN symptom checklist (upon study entry) Research blood draws ( 2 tablespoons) to evaluate the tumor's response to treatment and the action of cabozantinib in the body over a period of time (Upon study entry on Cycle 1 Day 1, predose and 4-hours post dose) During Study Treatment: End of Cycles 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, 24 or Early Termination (additional visit that is not within the specified times mentioned.) Medical History Physical exam with vital signs, blood pressure and pulse oximetry Performance Status Review of Subject Diary Urine pregnancy test for females of childbearing age at end of cycles 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 Electrocardiogram (EKG) to monitor the electrical activity of the heart at end of cycles 1, 2, 4, 6, 9, 12, 16, 20, 24 End of Cycles 1 - 24, or Early Termination Laboratory tests including blood and urine tests for routine safety tests End of Cycles 4, 8, 12, 18, 24, or Early Termination MRI of neurofibromas Completion of health-related questionnaires on quality of life, pain assessment, and PN symptom checklist Cycles 1, 2, 3, 4 Research blood draws ( 2 tablespoons) to evaluate the tumor's response to treatment and the action of cabozantinib in the body over a period of time Phone Calls will be made at the end of cycles 13, 15, 17, 19, 21, and 23 to assess drug compliance and toxicity The protocol PI and clinical coordinator will review the subject eligibility, study progress, safety issues, protocol deviations and adverse events. A Data Safety Monitoring Board (DSMB) and a medical monitor has been established for the purpose of ensuring data compliance and regular monitoring of this trial. The medical monitor is a qualified physician and is not associated with this particular protocol. The medical monitor is specifically required to review all unanticipated problems involving risk to subjects or others, serious adverse events and deaths associated with the protocol and provide an unbiased written report of the event. An early stopping rule will be invoked for both cohorts to potentially prevent accrual of subjects onto the study in the event that Cabozantinib is associated with a higher than acceptable rate of dose-limiting toxicity (DLT) requiring removal from study (set at 10% or higher) during the first 2 cycles. Toxicity will be continuously monitored. If at any time >2 of the first 10 subjects or 4 or more of the first 15 total subjects are removed for DLT, then accrual will be stopped until the DSMB reviews safety and efficacy data for the study and recommends termination or despite the DLT (because of the benefit:risk assessment or other reasoning) recommends reopening recruitment. Boundaries for DSMB for consideration of terminating each cohort (both cohort A and B) would be the same. The sample size for this trial is based on the safety and feasibility factors. The data needed is based on risk versus benefit. For feasibility, we expect at least efficacy of a 25% response rate. For safety reasons, subjects who do not achieve at least a 15% reduction in tumor volume will not be continued beyond 8 courses, as the likelihood of achieving a response (20% reduction in tumor volume) by 12 months is minimal. These subjects will be discontinued from the trial and counted in an "Intent to Treat" analysis as evaluable and as failures. All analyses for outcome results will be based on evaluable subjects. Definitions of evaluable include: 1.) Evaluation for toxicity (subject who received at least one dose of study drug and removed from treatment for toxicity are evaluable. Any subject who completed one full cycle of therapy is evaluable for toxicity); 2.)Evaluation for response (subjects who have completed at least two cycles of therapy and have had their first follow-up MRI evaluation. Subjects who did not respond and are later found to have a target tumor other than a plexiform neurofibroma (e.g. malignant peripheral nerve sheath tumor) are not evaluable for response).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
NF1, Neurofibromatosis, Plexiform Neurofibromas
Keywords
Cohort A: 3-15 years, Cohort B: Ages >= 16 years, Cabozantinib, XL184, Plexiform Neurofibromas, Neurofibromatosis, Pathogenetic NF1 Mutations, Cometriq, NF1

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Model Description
Cohort A: Single-arm open label two-stage Simon optimal study design Cohort B: Single-arm open-label study design
Masking
None (Open Label)
Allocation
N/A
Enrollment
45 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Experimental Agent XL184 (Cabozantinib)
Arm Type
Experimental
Arm Description
Cohort A (≥ 16 years - closed to accrual): Starting cabozantinib of 40 mg daily by mouth per cycle. Duration of each cycle is 28 days. Subjects will dose escalate after 2 cycles to 60 mg based on dose tolerability. Subjects who do not tolerate 40 mg will dose reduce to 20 mg. Doses will be capped at 60 mg. Cohort B (3 - 15 years). The starting cabozantinib dose is 30 mg/m2/day by mouth per cycle. Duration of each cycle is 28 days. Subjects will dose escalate after 2 cycles to 40 mg/m2/day based on dose tolerability. Subjects who do not tolerate 30 mg/m2/day will dose reduce to 23 mg/m2/day. Doses will be capped at 60 mg/day max daily dose Each cohort will enroll up to 24 evaluable subjects with a target minimum of 17 evaluable subjects per cohort.
Intervention Type
Drug
Intervention Name(s)
Cabozantinib
Other Intervention Name(s)
XL184, Cometriq
Intervention Description
This is an open label Phase II clinical trial. For both cohorts, subjects will receive cabozantinib orally in continuous cycles. Each cycle is 28 days. In absence of progressive disease or dose limiting toxicity (DLT), subjects may continue therapy for a total of 24 cycles. Subjects with radiographic response (20% or greater reduction in tumor volume) at the end of 12 cycles can continue on therapy for up to an additional year. However, for Cohort A, subjects who do not achieve 15% reduction in tumor volume after 8 cycles will be considered treatment failure and taken off study. For Cohort B, the criteria that subjects who do not achieve 15% reduction by 8 cycles are considered treatment failure and taken off study was eliminated. Subjects will be carefully monitored for toxicities associated with cabozantinib.
Primary Outcome Measure Information:
Title
The Change in Tumor Size Based on Radiographic Assessment
Description
We will estimate the objective response rate (ORR) as defined by 20% volumetric MRI response of the target lesion to cabozantinib at 12 months in adolescents and adults with Neurofibromatosis type 1 (NF1) plexiform neurofibromas by volumetric MRI imaging.
Time Frame
baseline to 12 Months
Secondary Outcome Measure Information:
Title
Number of Participants With Adverse Events
Description
This is the number of participants with one or more adverse events.
Time Frame
baseline to 24 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
3 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Clinical or molecular diagnosis of Neurofibromatosis Type 1 Plexiform neurofibroma that is progressive OR causing significant morbidity. Measurable disease amenable to volumetric MRI imaging defined as lesion seen on at least 3 consecutive MRI slices and at least 3 mL in volume. Select tumors <3 cm may be eligible on review. Central review or MRI required prior to enrollment. Age ≥ 3 years of age at the time of study entry. Subjects ≥ 16 years will be enrolled in Cohort A. Subjects 3 - 15 years will be enrolled in Cohort B. Performance Level Karnofsky ≥ 50%. Subjects unable to walk because of paralysis, but up in a wheel chair will be considered ambulatory for purpose of assessing performance score. Complete resection of plexiform neurofibroma is not feasible or if subject refuses surgery. Fully recovered from acute toxic effects of all prior chemotherapy or radiotherapy. No myelosuppressive chemotherapy within 4 weeks of study entry. At least 7 days since completion of hematopoietic growth factors. At least 14 days since completion of biologic agent. At least 4 weeks since receiving any investigational drug. Physiologic or stress doses of steroids allowed in patients with endocrine deficiencies. At least 6 months from radiation therapy to index tumor and at least 6 weeks from radiation to areas outside of index plexiform neurofibroma. At least 3 months from major surgery or at least 1 month from minor surgery. No major surgery anticipated within 3 months of enrollment. Adequate bone marrow function. Adequate renal function. Adequate liver function. Blood pressure within upper limit of normal. Exclusion Criteria: Active optic glioma or other low-grade glioma requiring treatment with chemotherapy or radiation therapy. Malignant glioma, malignant peripheral nerve sheath tumor, or other malignancy requiring treatment in the last 12 months. Dental braces or prosthesis that interferes with volumetric analysis of the neurofibroma(s). Unable to swallow tablets. Women who are pregnant or breast-feeding. Subjects of reproductive potential who have not agreed to use effective contraception. Subject has not recovered to baseline or CTCAE ≤ Grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant adverse events (AEs). Subject requires anticoagulants. Low dose aspirin, low-dose warfarin, and prophylactic low molecular weight heparin are permitted. Concomitant treatment of strong CYP3A4 inducers or inhibitors. History of noncompliance to medical regimens A known history of HIV seropositivity or known immunodeficiency. HIV testing will not be required as part of this trial, unless HIV is clinically suspected. Impairment of gastrointestinal function or gastrointestinal disease that may affect the absorption of cabozantinib. (e.g. ulcerative disease, malabsorption syndrome, or small bowel resection). Nasogastric tube (NG) tube is allowed. Any of the following within 28 days before the first dose of study treatment: intra-abdominal tumor/metastases invading GI mucosa active peptic ulcer disease inflammatory bowel disease (including ulcerative colitis and Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis malabsorption syndrome Any of the following within 6 months before the first dose of study treatment: abdominal fistula gastrointestinal perforation bowel obstruction or gastric outlet obstruction intra-abdominal abscess. Complete resolution of an intra-abdominal abscess must be confirmed prior to initiating study treatment even if abscess occurred more than 6 months before the first dose of study treatment. Other disorders associated with a high risk of fistula formation including percutaneous endoscopic gastrostomy (PEG) tube placement within 3 months before the first dose of study therapy Patients who have an uncontrolled infection. Clinically-significant gastrointestinal bleeding within 6 months before the first dose of study treatment Hemoptysis of ≥0.5 teaspoon (2.5 mL) of red blood within 3 months before the first dose of study treatment Any other signs indicative of pulmonary hemorrhage within 3 months before the first dose of study treatment Radiographic evidence of cavitating pulmonary lesion(s). Concurrent severe and/or uncontrolled medical disease which could compromise participation in the study (e.g. uncontrolled diabetes, uncontrolled hypertension, severe infection, severe malnutrition, chronic liver or renal disease, active upper GI tract ulceration) Cardiovascular disorders including: Congestive heart failure (CHF): New York Heart Association (NYHA) Class III (moderate) or Class IV (severe) at the time of screening Concurrent uncontrolled hypertension defined as sustained BP > 140 mm Hg systolic, or > 90 mm Hg diastolic despite optimal antihypertensive treatment within 7 days before the first dose of study treatment Any history of congenital long QT syndrome Baseline heart-rate corrected QT (QTc) interval >470 msec in women and >450 msec in men Concomitant treatment with medications that prolong the QT interval and have a known risk of Torsades de Pointes is not contraindicated, but should be avoided if possible and will require more frequent EKG monitoring. Any of the following within 6 months before the first dose of study treatment: unstable angina pectoris clinically-significant cardiac arrhythmias stroke (including transient ischemic attack (TIA), or other ischemic event) myocardial infarction thromboembolic event requiring therapeutic anticoagulation (Note: subjects with a venous filter (e.g. vena cava filter) are not eligible for this study) Other clinically significant disorders such as: Active infection requiring systematic treatment within 28 days before the first dose of study treatment Serious non-healing wound/ulcer/bone fracture within 28 days before the first dose of study treatment History of organ transplant Concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days before the first dose of study treatment Complete wound healing from prior surgery must be confirmed at least 28 days before the first dose of study treatment irrespective of time from surgery.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Chie-Schin Shih, MD
Organizational Affiliation
Indiana University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Children's Hospital Los Angeles
City
Los Angeles
State/Province
California
ZIP/Postal Code
90027
Country
United States
Facility Name
Children's National Medical Center
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20010
Country
United States
Facility Name
Lurie Children's Hospital of Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
University of Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60637
Country
United States
Facility Name
Indiana Unversity
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202
Country
United States
Facility Name
National Cancer Institute (NCI)
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States
Facility Name
Children' Hospital Boston and Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Washington University - St. Louis
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
New York University Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10016
Country
United States
Facility Name
Cincinnati Children's Hospital Medical Center
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45229
Country
United States
Facility Name
Children's Hospital of Philadelphia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19096
Country
United States
Facility Name
University of Utah
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84132
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
33442015
Citation
Fisher MJ, Shih CS, Rhodes SD, Armstrong AE, Wolters PL, Dombi E, Zhang C, Angus SP, Johnson GL, Packer RJ, Allen JC, Ullrich NJ, Goldman S, Gutmann DH, Plotkin SR, Rosser T, Robertson KA, Widemann BC, Smith AE, Bessler WK, He Y, Park SJ, Mund JA, Jiang L, Bijangi-Vishehsaraei K, Robinson CT, Cutter GR, Korf BR; Neurofibromatosis Clinical Trials Consortium; Blakeley JO, Clapp DW. Cabozantinib for neurofibromatosis type 1-related plexiform neurofibromas: a phase 2 trial. Nat Med. 2021 Jan;27(1):165-173. doi: 10.1038/s41591-020-01193-6. Epub 2021 Jan 13.
Results Reference
derived
PubMed Identifier
32562630
Citation
Armstrong AE, Brossier NM, Hirbe AC. Neurofibromatosis type 1-related tumours in paediatrics: an evolving treatment landscape. Lancet Child Adolesc Health. 2020 Jul;4(7):488-490. doi: 10.1016/S2352-4642(20)30169-3. No abstract available.
Results Reference
derived

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Cabozantinib for Plexiform Neurofibromas (PN) in Subjects With NF1 in Children and Adults

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