NF1Phase 2NF105-CABONCT02101736
Cabozantinib for Plexiform Neurofibromas (PN) in Subjects With NF1 in Children and Adults
A Phase 2 study testing Cabozantinib in people with NF1 and Neurofibromatosis, run by University of Alabama at Birmingham at 12 sites in United States.
Trial 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). Read more about this study
- Who is it for?
- Ages 3 years and older
- Conditions the study is for
- NF1, Neurofibromatosis, Plexiform Neurofibromas
- What is being tested?
- Cabozantinib
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 45 participants
- Where
- 12 sitesUnited States
- Study dates
- Jun 2014to 16 Feb 2022
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 3 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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.
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- 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.
Who cannot join
- 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.
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- 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.
Trial locations and contacts
12 sites in 1 country.
12 sites in 1 country
United States12 sites
National Cancer Institute (NCI)
Bethesda, Maryland, 20892
Children' Hospital Boston and Massachusetts General Hospital
Boston, Massachusetts, 02115
Lurie Children's Hospital of Chicago
Chicago, Illinois, 60611
University of Chicago
Chicago, Illinois, 60637
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, 45229
Indiana Unversity
Indianapolis, Indiana, 46202
Children's Hospital Los Angeles
Los Angeles, California, 90027
New York University Medical Center
New York, New York, 10016
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, 19096
University of Utah
Salt Lake City, Utah, 84132
Washington University - St. Louis
St Louis, Missouri, 63110
Children's National Medical Center
Washington D.C., District of Columbia, 20010
About this study
Official title: A Phase II Study of Cabozantinib (XL184) for Plexiform Neurofibromas in Subjects With Neurofibromatosis Type 1 in Children and Adults
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.
Read the 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).
- Conditions
- NF1, Neurofibromatosis, Plexiform Neurofibromas
- Being tested
- Cabozantinib
- Keywords
- Cohort A: 3-15 years, Cohort B: Ages >= 16 years, Cabozantinib, XL184, Plexiform Neurofibromas, Neurofibromatosis, Pathogenetic NF1 Mutations, Cometriq, NF1
- Medical subject headings
- Neurofibromatoses, Neurofibroma, Plexiform
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
CabozantinibDrug
Also called XL184, Cometriq
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.
| Study group | Role | What they receive |
|---|---|---|
| Experimental Agent XL184 (Cabozantinib) | Experimental | 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. Receives: Drug: Cabozantinib |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: baseline to 12 Months
Secondary outcomes (1)
Number of Participants With Adverse Events
This is the number of participants with one or more adverse events.
Measured: baseline to 24 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Apr 2014 (estimated)
- Study startJun 2014
- Primary completion16 Feb 2022
- Study completion16 Feb 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for NF1Studies of the same condition, open and under way.
- More trials run by University of Alabama at BirminghamThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- 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)
- Enrolment
- 45 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Alabama at Birmingham
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Bruce Korf, MD, University of Alabama at Birmingham
- Investigators
- Chie-Schin Shih, MD, Principal investigator, Indiana University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02101736
- Sponsor's protocol ID
- IRB-130423015
- Acronym
- NF105-CABO
- Status last verified
- May 2023
- First submitted
- 14 Mar 2014
- Last updated
- 24 May 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
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.
PubMed 33442015Armstrong 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.
PubMed 32562630
Study at a glance
From the registry record, last updated by the sponsor on 24 May 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase II Study of Cabozantinib (XL184) for Plexiform Neurofibromas in Subjects With Neurofibromatosis Type 1 in Children and Adults
- ClinicalTrials.gov ID
- NCT02101736
- Acronym / sponsor ID
- NF105-CABO / IRB-130423015
- Conditions
- 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
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 45 participants (actual)
- Lead sponsor
- University of Alabama at BirminghamUniversity, hospital or other
- Study start
- Jun 2014 (actual)
- Primary completion
- 16 Feb 2022 (actual)
- Study completion
- 16 Feb 2022 (actual)
- First posted
- 2 Apr 2014 (estimated)
- Results
- Posted 24 May 2023
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- Cohort A: Single-arm open label two-stage Simon optimal study design Cohort B: Single-arm open-label study design
| Arm | Type | Receives |
|---|---|---|
| Experimental Agent XL184 (Cabozantinib) | Experimental | Drug: CabozantinibCohort 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. |
Who may qualify
- Ages
- 3 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (19 listed)
- 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.
Key exclusion criteria (47 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| CabozantinibAlso: XL184, CometriqThis 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. | Drug | Experimental Agent XL184 (Cabozantinib) |
Primary outcome
The Change in Tumor Size Based on Radiographic Assessment
Time frame: baseline to 12 Months
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.
1 secondary outcome
Number of Participants With Adverse Events
Time frame: baseline to 24 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 May 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 33442015Fisher 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.
- Derived from this study: PubMed 32562630Armstrong 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Chie-Schin Shih, MD principal investigator
Indiana University
12 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Cabozantinib in people with NF1 and Neurofibromatosis, run by University of Alabama at Birmingham at 12 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 19 inclusion and 47 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 24 May 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 12 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 24 May 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The Change in Tumor Size Based on Radiographic Assessment (time frame: baseline to 12 Months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02101736, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 May 2023.