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

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Brief Title

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

Official Title

A Phase II Study of Cabozantinib (XL184) for Plexiform Neurofibromas in Subjects With Neurofibromatosis Type 1 in Children and Adults

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 NFI 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
      NF1and 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 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 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 Phase

Phase 2

Study Type

Interventional


Primary Outcome

The change in tumor size based on radiographic assessment

Secondary Outcome

 The number of subjects experiencing an SAE after receiving cabozantinib

Condition

NF1

Intervention

Cabozantinib

Study Arms / Comparison Groups

 Experimental Agent XL184 (Cabozantinib)
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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

45

Start Date

June 2014

Completion Date

December 2023

Primary Completion Date

December 2023

Eligibility Criteria

        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.
      

Gender

All

Ages

3 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Chie-Schin Shih, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT02101736

Organization ID

IRB-130423015


Responsible Party

Principal Investigator

Study Sponsor

University of Alabama at Birmingham


Study Sponsor

Chie-Schin Shih, MD, Principal Investigator, Indiana University


Verification Date

September 2021