Clinical trial NCT01362803: AZD6244 Hydrogen Sulfate for Children With Nervous System Tumors
Official title: A Phase I/II Study of the Mitogen Activated Protein Kinase Kinase (MEK) 1 Inhibitor Selumetinib (AZD6244; Hydrogen Sulfate in Children With Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibromas (PN)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Neurofibromatosis 1
Neurofibromatosis Type 1
NF1
Neurofibroma, Plexiform
Keywords: Maximum Tolerated Dose
Pharmacokinetics
Pharmacodynamics
Response Rate
pain, quality of life and physical functioning
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2011-05-30
Enrollment: 99
Sex: ALL
Minimum age (years): 2
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Background:

- Plexiform neurofibromas are tumors that grow in and around nerves. The only way to treat them is with surgery. Some of these tumors cannot be completely removed. The tumors may be too large, too numerous, or in a bad location for surgery. An experimental drug called AZD6244 hydrogen sulfate may be able to prevent the tumors from growing, slow down their growth, or shrink them. This drug has been tested in adults with cancer and in children with some types of brain cancer. This study will test how well this drug works with these types of tumors.

Objectives:

- To study the safety and effectiveness of AZD6244 hydrogen sulfate in children and young adults with plexiform neurofibromas that cannot be completely removed by surgery.

Eligibility:

- Children and young adults between 12 and 18 years of age who have plexiform neurofibromas that cannot be completely removed by surgery.

Design:

* Patients will be screened with a physical exam, medical history, blood tests, and imaging studies.
* They will take the study drug twice a day with 8 ounces of water, every day for 28-day cycles of treatment. During study visits, participants will have blood and urine tests and physical exams. They will also have imaging studies to examine the tumor sizes and locations. They will answer questions about their health. They may have other tests as needed.
* Participants will continue to receive the study drug as long as they have no severe side effects and the disease is not getting worse.

Detailed description: Background

* Patients with Neurofibromatosis 1 (NF1) have an increased risk of developing tumors of the central and peripheral nervous system, including plexiform neurofibromas (PN), which are benign nerve sheath tumors that are among the most debilitating complications of NF1. PN may be congenital and appear to have the fastest growth rate in young children. Surgery is the only standard treatment option available for PN. However, this is often difficult due to the encasement of vital structures, and extensive and invasive PN growth.
* PN are composed of neoplastic Schwann cells that lack NF1 gene expression. This results in upregulation of Ras, which initiates several signaling cascades regulating cell proliferation.
* Selumetinib (AZD6244 hyd sulfate), a novel orally bioavailable mitogen activated protein kinase inhibitor, is a specific inhibitor of MEK 1, which may mediate anti-tumor effects in PN by inhibition of downstream signaling of Ras. Selumetinib is currently undergoing evaluation in adult cancers and children with brain tumors.
* In this phase I study of selumetinib directed at NF1 PN, we have observed a degree of activity which has not been observed previously; therefore a phase II evaluation will be conducted.

Objectives

Phase I:

* To determine the maximum tolerated dose (MTD) of oral selumetinib administered daily to pediatric patients with NF1 and inoperable PN. Based on the results of the dose escalation in this study, the current MTD has been determined as 20 mg/m2/dose. To be consistent in pediatric dosing, an additional dose level of 25 mg/m2/dose was added, which is the MTD recently determined in a study conducted by the Pediatric Brain Tumor Consortium (PBTC). Amendment H (November 2014): The MTD has been determined to be 25 mg/m(2)/dose.
* To define the acute and chronic toxicities and pharmacokinetics (PK) of selumetinib. Completed with amendment H.

Phase II:

-Primary objectives: To evaluate the confirmed partial and complete response rate of selumetinib using volumetric MRI analysis in children and young adults with NF1 and inoperable PN with PN related morbidity at the time of enrollment.

Eligibility

Pediatric Patients (greater than or equal to 2 and less than or equal to 18 years) who are able to swallow intact capsules, with NF1 and inoperable measurable PN that cause or have the potential to cause significant morbidity.

Design

* Selumetinib will be administered orally BID on a continuous dosing schedule (28 days = 1 treatment cycle). In the phase I portion, limited dose escalations will be performed to define the MTD based on tolerability of selumetinib during the first three treatment cycles. In the phase II portion, the recommended phase II dose level (RP2D) will be administered.
* Phase II: Patients will be enrolled on one of two strata:

  * Stratum 1: PN related morbidity present at enrollment

    ---PN related pain, disfigurement, or difficulty in physical functioning
  * Stratum 2: No significant PN related morbidity present at enrollment, but potential for development of PN morbidity
* Patient reported and functional outcomes will be evaluated at regular intervals.
* Disease status will be evaluated using volumetric MRI analysis at regular intervals.
* The day 1 and steady state plasma PK and PD of selumetinib will be evaluated.

Eligibility criteria: -INCLUSION CRITERIA:

1. Age Phase I: greater than or equal to 3 years and less than or equal to 18 years of age at the time of study enrollment, if able to swallow whole capsules. The age limits including young children were chosen because early childhood and puberty are considered to be the greatest risk for disease progression, and selumetinib may provide the most benefit to this young group of patients. In addition, an important objective of this study is to characterize the pharmacokinetics of selumetinib in the pediatric population since it has been well studied in adults.

   Age Phase II: geater than or equal to 2 and less than or equal to 18 years. BSA greater than or equal to 0.55 m(2), and able to swallow whole capsules.
2. Diagnosis: Patients with NF1 and inoperable PN, defined as PN that cannot be surgically completely removed without risk for substantial morbidity due to encasement of, or close proximity to, vital structures, invasiveness, or high vascularity of the PN. The PN has to cause (stratum 1) or have the potential to cause (stratum 2) significant morbidity, such as (but not limited to) head and neck lesions that could compromise the airway or great vessels, paraspinal lesions that can cause myelopathy brachial or lumbar plexus lesions that could cause nerve compression and loss of function, lesions that could result in major deformity (e.g., orbital lesions) or are significantly disfiguring, lesions of the extremity that cause limb hypertrophy or loss of function, and painful lesions. Patients will be enrolled into stratum 1 or 2 based on PN related morbidity.

   Histologic confirmation of tumor is not necessary in the presence of consistent clinical and radiographic findings, but should be considered if malignant degeneration of a PN is clinically suspected.

   A PN is defined as a neurofibroma that has grown along the length of a nerve and may involve multiple fascicles and branches. A spinal PN involves two or more levels with connection between the levels or extending laterally along the nerve. In addition to PN, all study subjects must have either positive genetic testing for NF1 or have at least one other diagnostic criterion for NF1 listed below: (NIH Consensus conference):
   * Six or more caf(SqrRoot)(Copyright)-au-lait macules (greater than or equal to 0.5cm in prepubertal subjects or greater than or equal to 1.5 cm in post pubertal subjects)
   * Freckling in axilla or groin
   * Optic glioma
   * Two or more Lisch nodules
   * A distinctive bony lesion (dysplasia of the sphenoid bone or dysplasia or thinning of long bone cortex)
   * A first-degree relative with NF1
3. Measurable disease: Patients must have at least one measurable PN, defined as a lesion of at least 3 cm measured in one dimension. Patients who underwent surgery for resection of a PN are eligible provided the PN was incompletely resected and is measurable.

   Phase II: Measurability and suitability for volumetric MRI analysis of the target PN must be confirmed with the NCI POB prior to enrolling a patient. The target PN will be defined as the clinically most relevant PN, which has to be amenable to volumetric MRI analysis. PN will be classified as typical PN versus nodular PN versus solitary nodular PN prior to enrollment
4. Prior Therapy: Patients with NF1 will only be eligible if complete tumor resection is not considered to be feasible without substantial risk or morbidity.

   * Since there is no standard effective chemotherapy for patients with NF1 and PN, patients may be treated on this trial without having received prior medical therapy directed at their PN.
   * Since selumetinib is not expected to cause substantial myelosuppression, there will be no limit to number of prior myelosuppressive regimen for PN or other tumor manifestations associated with NF1 such as optic glioma.
   * Patients who have received previous investigational agents or biologic therapy, such as tipifarnib, pirfenidone, Peg-Intron, sorafenib, imatinib or other targeted therapies are eligible for enrollment. At least 4 weeks must have elapsed since receiving medical therapy directed at the PN. Patients who received prior medical therapy for their PN must have recovered from the acute toxic effects of all prior therapy to less than or equal to grade 1 before entering this study.
   * Growth factors that support platelet or white cell number or function must not have been administered within the 7 days prior to enrollment.
   * At least 6 weeks must have elapsed prior to enrollment since the patient received any prior radiation therapy.
   * At least 4 weeks must have elapsed since any surgeries, with evidence of good wound healing.
5. Performance status: Patients greater than or equal to 16 years of age must have a Karnofsky performance level of greater than or equal to 70%, and children less than or equal to 16 years old must have a Lansky performance of greater than or equal to 70%. Patients who are wheelchair bound because of paralysis secondary to a plexiform neurofibroma should be considered ambulatory when they are up in their wheelchair. Similarly, patients with limited mobility secondary to need for mechanical support (such as an airway PN requiring tracheostomy or CPAP) will also be considered ambulatory for the purpose of the study.
6. Hematologic Function: Patients must have an absolute neutrophil count greater than or equal to 1500/(micro)l, hemoglobin greater than or equal to 9g/dl, and platelets greater than or equal to 100,000/(micro)l.
7. Hepatic Function: Patients must have bilirubin within 1.5 times the upper limit of normal for age, with the exception of those with Gilbert syndrome, and AST/ ALT within less than or equal to 3 times the upper limit of normal.
8. Renal Function: Patients must have a creatinine clearance or radioisotope GFR greater than or equal to 60ml/min/1.73 m(2) or a normal serum creatinine based on age described below.

   Age (years)/ Maximum Serum Creatinine(mg/dL):

   Age less than or equal to 5/ Maximum Serum Creatinine 0.8 mg/dL

   Age greater than 5 to less than or equal to 10/ Maximum Serum Creatinine 1.0 mg/dL

   Age greater than 10 to less than or equal to 15/ Maximum Serum Creatinine 1.2 mg/dL

   Age greater than 15/ Maximum Serum Creatinine 1.5 mg/dL
9. Cardiac Function: Normal ejection fraction (ECHO or cardiac MRI) greater than or equal to 53% (or the institutional normal; if a range is given then the upper value of the range will be used); QTC or QTcF less than or equal to 450 msec.
10. Adequate Blood Pressure defined as:

    A blood pressure (BP) less than or equal to the 95th percentile for age, height, and gender measured as described in (Appendix IB). Adequate blood pressure can be achieved using medication for treatment of hypertension.
11. Informed Consent: Diagnostic or laboratory studies performed exclusively to determine eligibility for this trial must only be done after obtaining written informed consent from all patients or their legal guardians (if the patient is \<18 years old). When appropriate, pediatric patients will be included in all discussions. This can be accomplished through one of the following mechanisms: a) the NCI POB screening protocol, b) an IRB-approved institutional screening protocol, or c) the study-specific protocol. Documentation of the informed consent for screening will be maintained in the patient s research chart. Studies or procedures that were performed for clinical indications (not exclusively to determine eligibility) may be used for baseline values even if the studies were done before informed consent was obtained.
12. Willingness to avoid excessive sun exposure and use adequate sunscreen protection if sun exposure is anticipated.
13. Willingness to avoid the ingestion of grapefruit and Seville oranges (as well as other products containing these fruits, e.g. grapefruit juice or marmalade) during the study, as these may affect selumetinib metabolism.

EXCLUSION CRITERIA:

1. Pregnant or breast-feeding females are excluded due to potential risks of fetal and teratogenic adverse events of an investigational agent. Pregnancy tests must be obtained prior to enrollment for all females of childbearing potential as per institutional standards (at NIH subjects 9 years and older or those showing pubertal development). Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method. Abstinence is an acceptable method of birth control.
2. Phase I: Patients who anticipate the need for surgical intervention within the first three cycles (3 months), as surgical intervention during the period of DLT evaluation may affect analysis of adherence and/or make the subject inevaluable.
3. Use of an investigational agent within the past 30 days.
4. Ongoing radiation therapy, chemotherapy, hormonal therapy directed at the tumor, immunotherapy, or biologic therapy.
5. Any evidence of severe or uncontrolled systemic disease, active infection, active bleeding diatheses, or renal transplant, including any patient known to have hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) will be excluded. Patients with HIV who have adequate CD4 count, not requiring antiretroviral medication, may be enrolled.
6. Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study.
7. Inability to swallow capsules, since capsules cannot be crushed or broken.
8. Inability to undergo MRI and/or contraindication for MRI examinations following the MRI protocol. Prosthesis or orthopedic or dental braces that would interfere with volumetric analysis of target PN on MRI.
9. Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g., inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption.
10. Prior treatment with selumetinib or another specific MEK1/2 inhibitor (unless the subject meets criteria for re-treatment).
11. Evidence of an optic glioma, malignant glioma, malignant peripheral nerve sheath tumor, or other cancer requiring treatment with chemotherapy or radiation therapy.
12. Supplementation with vitamin E greater than 100% of the daily recommended dose. Any multivitamin containing vitamin E must be stopped prior to initiation of therapy.
13. Patients not achieving adequate blood pressure in spite of antihypertensive therapy for control of blood pressure.
14. Cardiac Function:

    1. Known inherited coronary disease
    2. Symptomatic heart failure (NYHA Class II-IV prior or current cardiomyopathy, or severe valvular heart disease)
    3. Prior or current cardiomyopathy
    4. Severe valvular heart disease
    5. History of atrial fibrillation
15. Ophthalmologic conditions:

    1. Current or past history of central serous retinopathy
    2. Current or past history of retinal vein occlusion
    3. Known intraocular pressure (IOP) greater than or equal to 21 mmHg (or ULN adjusted by age) or uncontrolled glaucoma (irrespective of IOP). Patients with known glaucoma and increased IOP who do not have meaningful vision (light perception only or no light perception) and are not experiencing pain related to the glaucoma, may be eligible after discussion with the study chair.
    4. Subjects with any other significant abnormality on ophthalmic examination should be discussed with the Study Chair for potential eligibility
    5. Ophthalmological findings secondary to long-standing optic pathway glioma (such as visual loss, optic nerve pallor or strabismus) or long-standing orbito-temporal PN (such as visual loss, strabismus) will NOT be considered a significant abnormality for the purposes of the study
16. Known severe hypersensitivity to selumetinib or any excipient of selumetinib or history of allergic reactions attributed to compounds of similar chemical or biologic composition to selumetinib.
17. Recent major surgery within a minimum of 4 weeks prior to starting study treatment, with the exception of surgical placement for vascular access.
18. Any unresolved chronic toxicity with CTC AE grade greater than or equal to 2 from previous anti-NF1 therapy, except for alopecia.
19. Clinical judgement by the investigator that the patient should not participate in the study.
20. While not an exclusion criterion, unless considered clinically indicated, patients should avoid taking other additional non-study medications that may interfere with the study medications. In particular, patients should avoid medications that are known to either induce or inhibit the activity of hepatic microsomal isoenzymes CYP1A2, CYP2C19 and CYP3A4, as this may interfere with the metabolism of selumetinib.

Primary outcomes:
measure: Ph2: Evaluate the confirmed partial and complete response rate of selumetinib in children and young adults with NF1 and inoperable PN.
timeFrame: prior to cycles 5,6,13,17,21,25 and then every 6 cycles
measure: Ph1: Determine MTD and extended tolerability
timeFrame: 3 treatment cycles
Secondary outcomes:
measure: Study PK
timeFrame: first course
measure: Ph2: Evaluate effect of selumetinib on bone mineral density, pain, quality of life and physical functioning.
timeFrame: before cycles 3,5,9,13 and then every 12 cycles
measure: Ph2: Evaluate confirmed partial and complete response rate, and duration of response.
timeFrame: at each response evaluation
measure: Ph2: determine long term tolerability, and safety
timeFrame: at each response evaluation
measure: Measure adherence of chronic dosing
timeFrame: at each response evaluation
measure: determine effect on growth rate of PN
timeFrame: at time of PD
measure: Define toxicities
timeFrame: at each response evaluation
Other outcomes:
Locations:
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center
state: Maryland
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
Study officials:
affiliation: National Cancer Institute (NCI)
name: Brigitte C Widemann, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Gross AM, Glassberg B, Wolters PL, Dombi E, Baldwin A, Fisher MJ, Kim A, Bornhorst M, Weiss BD, Blakeley JO, Whitcomb P, Paul SM, Steinberg SM, Venzon DJ, Martin S, Carbonell A, Heisey K, Therrien J, Kapustina O, Dufek A, Derdak J, Smith MA, Widemann BC. Selumetinib in children with neurofibromatosis type 1 and asymptomatic inoperable plexiform neurofibroma at risk for developing tumor-related morbidity. Neuro Oncol. 2022 Nov 2;24(11):1978-1988. doi: 10.1093/neuonc/noac109.
citation: Gross AM, Wolters PL, Dombi E, Baldwin A, Whitcomb P, Fisher MJ, Weiss B, Kim A, Bornhorst M, Shah AC, Martin S, Roderick MC, Pichard DC, Carbonell A, Paul SM, Therrien J, Kapustina O, Heisey K, Clapp DW, Zhang C, Peer CJ, Figg WD, Smith M, Glod J, Blakeley JO, Steinberg SM, Venzon DJ, Doyle LA, Widemann BC. Selumetinib in Children with Inoperable Plexiform Neurofibromas. N Engl J Med. 2020 Apr 9;382(15):1430-1442. doi: 10.1056/NEJMoa1912735. Epub 2020 Mar 18.
citation: Dombi E, Baldwin A, Marcus LJ, Fisher MJ, Weiss B, Kim A, Whitcomb P, Martin S, Aschbacher-Smith LE, Rizvi TA, Wu J, Ershler R, Wolters P, Therrien J, Glod J, Belasco JB, Schorry E, Brofferio A, Starosta AJ, Gillespie A, Doyle AL, Ratner N, Widemann BC. Activity of Selumetinib in Neurofibromatosis Type 1-Related Plexiform Neurofibromas. N Engl J Med. 2016 Dec 29;375(26):2550-2560. doi: 10.1056/NEJMoa1605943.