Trial Title:
Study of Cabozantinib with Selumetinib for Plexiform Neurofibromas
NCT ID:
NCT06502171
Condition:
Neurofibromatosis 1
Plexiform Neurofibroma
Conditions: Official terms:
Neurofibromatoses
Neurofibromatosis 1
Neurofibroma
Neurofibroma, Plexiform
Conditions: Keywords:
adolescents
adults
Study type:
Interventional
Study phase:
Phase 1
Overall status:
Not yet recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Intervention model description:
This will be an open label, single arm, prospective, multicenter study to assess the
tolerability and efficacy of selumetinib and cabozantinib in combination in patients with
NF1 ≥16 years old with progressive or symptomatic PN.
The primary goal of the phase 1 is to determine the feasibility of combination therapy
with cabozantinib and selumetinib to treat plexiform neurofibromas in people with NF1
based on toxicity and tolerability.
If the results of Phase 1 show it is feasible to combine the study drugs, the plan is to
submit amendments for phases 1b and 2 to evaluate the efficacy of these agents at a
reduced dose compared with the prior monotherapy clinical trials and determine if these
biologically active agents are effective at lower doses in combination; specifically, if
that they have improved rates of response, improved depth of response and tolerability
profiles that could translate into long term use to support durability of response.
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Cabozantinib Oral Tablet
Description:
Cabozantinib will be taken once a day. It must be swallowed whole and not crushed and
taken on an empty stomach. The dose will depend on when a participant enrolls on the
study. First group will take 20 mg.
If participants are enrolled early in this study, they may receive doses that are lower
than those who are enrolled later. Participants will be told what dose they will take
when they start the study. Once a dose is started, the dose will not be increased.
However, a dose can be reduced up to 2 times if a participant experience adverse events.
Cabozantinib may be taken simultaneously with selumetinib.
Arm group label:
Phase 1 cabozantinib and selumetinib combination
Intervention type:
Drug
Intervention name:
Selumetinib Oral Capsule
Description:
Selumetinib will be taken twice a day, at least 6 hours apart. It must be swallowed whole
and not crushed and taken on an empty stomach. The dose will depend on when a participant
enrolls on the study. First group will take 15 mg twice a day.
If participants are enrolled early in this study, they may receive doses that are lower
than those who are enrolled later. Participants will be told what dose they will take
when they start the study. Once a dose is started, the dose will not be increased.
However, a dose can be reduced up to 2 times if a participant experience adverse events.
Arm group label:
Phase 1 cabozantinib and selumetinib combination
Other name:
Koselugo
Summary:
Based on the clinical activity of both selumetinib and cabozantinib as monotherapies in
clinical trials, the demonstrated activity of these agents in reduced doses in
preclinical studies, and the non-overlapping toxicity profiles, the study will assess the
tolerability and efficacy of selumetinib and cabozantinib in combination in participants
with NF1 ≥16 years old with progressive and/or symptomatic PN in a phase 1/1b/2 clinical
trial.
Trial Design Phase 1 This will be an open label, dose escalation phase. Dose level
escalation will be determined by a rolling six design. In this design, up to 6
participants can be enrolled at a given dose level and then evaluated for dose limiting
toxicity (DLT) within the DLT window. The DLT window is defined as 16 weeks in this study
based on the long half-life of cabozantinib and the desire to have maximum confidence
about long-term tolerability of the combination prior to proceeding to the next dose
level.
Phase 1b Once the recommended phase 2 dose has been determined in phase 1, an expanded
cohort of 12 participants will be enrolled in phase 1b portion of the study.
Phase 2 This will be an open label, single-arm phase using the recommended phase 2 dose.
Detailed description:
Neurofibromatosis type 1 (NF1) is one of the most common inherited tumor predisposition
syndromes, affecting approximately 1 in 3000 people worldwide. NF1 is an autosomal
dominant condition caused by pathogenic variants in the NF1 tumor suppressor gene
resulting in a deficiency in the protein neurofibromin resulting in constitutive
activation of the Ras oncoprotein and subsequent tumors. Plexiform neurofibromas (PN) are
a complex of Schwann cells, fibroblasts, endothelial cells, and mast cells, which can
cause disfigurement, pain, life threatening complications and can undergo malignant
transformation. These tumors are refractory to most therapeutic approaches including
chemotherapy, radiation, and surgery; thus, novel treatment interventions are urgently
needed. Two agents have shown substantial activity in shrinking PN in adults with
symptomatic or progressive PN in clinical trials through the NCI and the Congressionally
Directed Medical Research Programs (CDMRP) Neurofibromatosis Clinical Trials Consortium
(NFCTC): the MEK inhibitor selumetinib and the multi-tyrosine kinase inhibitor
cabozantinib. Unfortunately, confirmed objective responses are not uniformly achieved and
the degree of volumetric tumor reduction might be improved in patients with partial
response as only a small percentage of patients have deep responses. In an open-label,
phase 2 study evaluating selumetinib for children with inoperable PN, 68% of participants
treated with selumetinib achieved a partial response (defined as a reduction in tumor
volume by ≥20%). In a phase 2 trial (NCT02101736) of cabozantinib in participants >16
years old with symptomatic or progressive PN, 42% of patients had a partial response. Of
note, dose reductions and/or discontinuation of treatment was common in both studies,
with 28% of patients in the selumetinib study requiring dose reductions and 10%
eventually requiring permanent discontinuation of treatment. In the cabozantinib study
42% of the participants required dose reductions or discontinuation of therapy due to
either dose-limiting toxicity or low-grade adverse events (AEs) perceived to be
intolerable.
Based on the demonstrated significant clinical activity of both selumetinib and
cabozantinib as monotherapies in clinical trials and the demonstrated activity of these
agents in reduced doses in the preclinical studies, as well as the non-overlapping
toxicity profiles, the study will assess the tolerability and efficacy of selumetinib and
cabozantinib in combination in patients with NF1 ≥16 years old with progressive or
symptomatic PN in a phase 1/1b/2 clinical trial.
Criteria for eligibility:
Criteria:
1.0 INCLUSION CRITERIA
1.1. All participants must have a diagnosis of NF1 based on the 2021 revised consensus
criteria.
1.2. Participants must have PN(s) that are progressive OR are causing significant
morbidity, such as (but not limited to) head and neck lesions that are compromising the
airway or great vessels, brachial or lumbar plexus lesions that are causing nerve
compression and loss of function, lesions causing significant disfigurement (e.g.,
orbital lesions), lesions of the extremity that cause limb hypertrophy or loss of
function, and painful lesions. Participants with paraspinal PN will be eligible for this
trial. Histologic confirmation of tumor is not necessary but should be considered if
there are clinical or radiographic findings concerning for malignant transformation of a
PN.
1.2.1. For participants enrolled for tumor progression, progression is defined as:
Presence of new PN on MRI or CT (documented by comparison with prior MRI or CT), OR A
measurable increase in PN size (≥ 20% increase in the volume, or a ≥ 13% increase in the
product of the two longest perpendicular diameters, or a ≥ 6% increase in the longest
diameter) documented by comparison of two scans (MRI or CT) in the time period of 18
months or less prior to evaluation for this study.
1.2.2. For participants enrolled for tumors causing "significant disfigurement" without
meeting another criterion (i.e., not progressive or causing other significant morbidity),
eligible tumors will be limited to tumors of the head & neck or those on other areas of
the body that are unable to be concealed by standard garments. In order to enroll a
participant with PN for these indications, photographs must be reviewed by a Study Chair
and/or Co-Chair for decision regarding participant eligibility prior to enrollment.
1.3. Disease status: Measurable disease: Participants must have measurable PN(s) amenable
to volumetric MRI analysis. For the purpose of this study, the target lesion must be seen
on at least 3 consecutive MRI slices and the field of view must contain the entire tumor
of interest. Tumors must be at least 3 mL in volume (most PN 3 cm in longest diameter
will meet this criteria). If the tumor is <3 cm in longest diameter, the participant may
still be eligible. Central review of the MRI of the target PN is required prior to
enrollment to ensure that the tumor is measurable and amenable to volumetric analysis.
1.4. Age: Participants must be ≥16 years of age at the time of study entry.
1.5. Performance Level: Participants must have Karnofsky ³ 50%. Note: Participants who
are unable to walk because of paralysis, but who are up in a wheelchair, will be
considered ambulatory for assessing the performance score.
1.6. Body Surface Area (BSA): Participants must have a BSA of 1.0 m2 or greater.
1.7. Organ Function Requirements:
1.7.1. Adequate Bone Marrow Function Defined as: Absolute neutrophil count (ANC) ≥
1500/µL without granulocyte colony-stimulating factor support.
White blood cell count ≥ 2500/µL Platelet count ³ 100,000/mL without transfusion
Hemoglobin ³10.0 gm/dL (>5 days between enrollment and last RBC transfusion)
1.7.2. Adequate Renal Function Defined as: Maximum serum creatinine based on age/gender
as per institutional standards OR a creatinine clearance, radioisotope GFR, or calculated
creatinine clearance using the Cockcroft-Gault equation ³70ml/min/1.73 m2.
Cockcroft-Gault equation:
- Males: (140 - age) x weight (kg)/(serum creatinine [mg/dL] × 72)
- Females: [(140 - age) x weight (kg)/(serum creatinine [mg/dL] × 72)] × 0.85 Urine
protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol), or 24-h urine protein ≤
1 g.
1.7.3. Adequate Liver Function Defined as: Total bilirubin (sum of conjugated +
unconjugated) £ 1.5x upper limit of normal (ULN) for age (for participants with Gilbert's
disease ≤3x ULN), and Alanine aminotransferase (ALT), aspartate aminotransferase (AST),
and alkaline phosphatase (ALP) < 2.5x the upper limit of normal (ULN).
Serum albumin ³ 2.8 g/dL. PT/INR and partial thromboplastin time (PTT) test < 1.3x the
laboratory ULN
1.7.4. Adequate Thyroid Function Defined as: ≤ Grade 1 or adequately managed asymptomatic
Grade 2 hypothyroidism.
1.7.5. CPK level within normal limits within 14 days from the start of treatment.
1.7.6. Normal pancreatic function: amylase and lipase levels ≤ 1.5 x ULN
1.7.7. Blood pressure within upper limit of normal as defined below. Antihypertensives
are permissible to achieve blood pressure within ULN, however must be on stable
antihypertensive regimen with no adjustments within 30 days of enrollment.
In adolescents, a blood pressure (BP) ≤ 90th percentile for age, height, and sex.
In adults (³18 years of age), a systolic blood pressure ≤130 mmHg and a diastolic
pressure of ≤80 mmHg.
1.8. Major surgery: Only participants who are not anticipated to need major surgery
within 3 months after enrollment are eligible.
1.9. Sexually active fertile participants and their partners must agree to use effective
methods of contraception e.g., hormonal oral contraception, injectables, intrauterine
device, surgical sterilization including vasectomy, or hormonal implant with barrier
methods (male condom, female condom, or diaphragm with spermicidal gel) during the course
of the study and for 4 months after the last dose of study treatment. Barrier methods
alone are insufficient. True sexual abstinence is an acceptable method of birth control
for both men and women. Persons of childbearing potential will be given a pregnancy test
within 7 days prior to first dose of study treatment and must have a negative urine or
serum pregnancy test.
1.10. Written informed consent must be obtained from all participants (>18 years of age)
or their legal guardians (if the participant is <18 years of age). Participants or legal
guardians must be capable of understanding and complying with the protocol requirements
and must have signed the informed consent document. Participants unable to provide
informed consent/assent will NOT be enrolled on this study.
1.11. Willingness to avoid excessive sun exposure and use adequate sunscreen protection
if sun exposure is anticipated.
1.12. 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.
2.0 EXCLUSION CRITERIA
2.1. Evidence of an optic pathway or other low-grade glioma, high-grade glioma, malignant
peripheral nerve sheath tumor, or other cancer/tumor requiring treatment with
chemotherapy, biologic therapy or radiation therapy.
2.2. Patients with high-grade glioma, atypical or malignant peripheral nerve sheath
tumor, or other malignancy who received treatment in the last 12 months. Exceptions
include basal cell carcinoma of the skin and squamous cell carcinoma of the skin that
have undergone potentially curative therapy.
2.3. Dental braces or prosthesis that interfere with volumetric analysis of the
neurofibroma(s).
2.4. Prior Therapy: Participants may have received treatment for a PN or other
tumor/malignancy but must have fully recovered to baseline or CTCAE ≤ Grade 1 from acute
toxicities from prior therapies except alopecia.
Myelosuppressive chemotherapy: Must not have received within 28 days of entry onto this
study.
2.5. Hematopoietic growth factors: Must not have received a growth factor that supports
platelet, red or white cell number or function within 14 days of initiation of therapy.
2.6. Biologic (anti-neoplastic agent): At least 28 days (or 5 half-lives whichever is
longer) since the completion of therapy with a biologic agent. For agents that have known
adverse events occurring beyond 28 days after administration (or 5 half-lives whichever
is longer), this period must be extended beyond the time during which adverse events are
known to occur. These participants must be discussed with the Study Chair on a
case-by-case basis.
2.7. Investigational Drugs: At least 28 days (or 5 half-lives whichever is longer) since
the completion of therapy with an investigational drug or systemic anticancer treatment.
For agents that have known adverse events occurring beyond 28 days after administration
(or 5 half-lives whichever is longer), this period must be extended beyond the time
during which adverse events are known to occur. These participants must be discussed with
the Study Chair on a case-by-case basis.
- Prior treatment with cabozantinib or selumetinib is permitted for participants on
Phase 1 of this study only (not Phase 1b/2). Participants may have previously
received cabozantinib and/or a MEK inhibitor but not simultaneously. If participants
have received either cabozantinib or selumetinib previously, they must have
tolerated either medication at the recommended entry doses for this study or greater
and must not have discontinued therapy due to toxicity. Participants who have
received the combination of cabozantinib with any MEK inhibitor previously will not
be eligible. Prior treatment with cabozantinib and/or selumetinib will not be
permitted for participants on Phase 1b or Phase 2.
2.8. Radiation therapy: 6 months from involved field radiation to index PN(s) must have
elapsed prior to study entry; ³ 6 weeks must have elapsed if participant has received
radiation to areas outside index PN(s) Participants who received radiation to the orbit
at any time previously are not eligible.
>12 weeks must have elapsed between systemic treatment with radionuclides and first dose
of study treatment.
Participants with clinically relevant ongoing complications from prior radiation therapy
are not eligible.
2.9. Surgery:
2.9.1. Participants are not eligible if complete resection of a PN with acceptable
morbidity is feasible, or if a participant with a feasible surgical option with minimal
risk for surgical morbidity refuses surgery. Participants who underwent surgery for a
progressive PN will be eligible to enter the study after the surgery, provided the PN was
incompletely resected and is measurable.
2.9.2. Any major surgery within 3 months before first dose of study treatment.
2.9.3. Any minor surgeries (e.g., the placement of an implanted vascular device, tooth
extractions, biopsy, or an invasive operative procedure for procurement of tissue samples
or body fluids using a needle or trocar, other than routine peripheral venous access)
within 1 month before first dose of study treatment.
2.9.4. Participants must have complete wound healing from major surgery or minor surgery
before first dose of study treatment. Participants with clinically relevant ongoing
complications from prior surgery are not eligible.
2.10. Concomitant anticoagulation with coumarin agents (e.g., warfarin), low molecular
weight heparins, direct thrombin inhibitors (e.g., dabigatran), direct factor Xa
inhibitor betrixaban, or platelet inhibitors (e.g., clopidogrel). Allowed anticoagulants
are the following: Prophylactic use of low-dose aspirin for cardio-protection (per local
applicable guidelines)
2.11. Clinically significant hematuria, hematemesis, or hemoptysis of >0.5 teaspoon
(2.5ml) of red blood, or other history of significant bleeding (e.g., pulmonary
hemorrhage) within 12 weeks before first dose of study treatment.
2.12. Known cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease
manifestation.
2.13. Cardiovascular disorders: 2.13.1. Congestive heart failure New York Heart
Association Class 2-4, unstable angina pectoris (Canadian Cardiovascular Society grade
II-IV despite medical therapy), prior or current cardiomyopathy, or severe valvular heart
disease, baseline left ventricular ejection fraction (LVEF) below the LLN or <55%
measured by echocardiography or institution's LLN for MUGA, serious cardiac arrhythmias
including atrial fibrillation.
2.13.2. Stroke (including transient ischemic attack [TIA]), acute coronary syndrome or
myocardial infarction (MI), or other ischemic event, or thromboembolic event (e.g., deep
venous thrombosis, pulmonary embolism) within 6 months before first dose of study
treatment.
2.13.3. Participants with a diagnosis of incidental, subsegmental PE or DVT within 6
months are allowed if stable, asymptomatic, and treated with a stable dose of permitted
anticoagulation (aspirin) for at least 1 week before first dose of study treatment.
2.13.4. Baseline QTc interval >450 msec
2.14. Gastrointestinal (GI) disorders including those associated with a high risk of
perforation or fistula formation:
2.14.1. The participant has evidence of tumor invading the GI tract, active peptic ulcer
disease, inflammatory bowel disease (e.g., Crohn's disease), diverticulitis,
cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis, acute
obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction.
2.14.2. Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess
within 6 months before first dose of study treatment.
Note: Complete healing of an intra-abdominal abscess must be confirmed before first dose
of study treatment.
2.15. Ophthalmologic conditions:
2.15.1. Current or history of central serous retinopathy
2.15.2. Current or history of retinal vein occlusion
2.15.3. Known intraocular pressure (IOP) >21 mmHg (or ULN adjusted by age) or
uncontrolled glaucoma (irrespective of IOP). Participants 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. Participants with orbital plexiform neurofibromas should
have IOP measured prior to enrollment.
2.15.4. Participants with any other significant abnormality on ophthalmic examination
should be discussed with the Study Chair for potential eligibility.
2.15.5. 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.
2.16. Other clinically significant disorders that would preclude safe study
participation, including:
2.16.1. Serious non-healing wound, ulcer, or bone fracture.
2.16.2. Uncompensated/symptomatic hypothyroidism.
2.16.3. Moderate to severe hepatic impairment (Child-Pugh B or C).
2.16.4. Active infection
2.16.5. 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.
2.16.6. Uncontrolled diabetes, severe malnutrition, chronic liver or renal disease
2.16.7. History of organ transplant
2.17. Pregnant or lactating women.
2.18. Inability to swallow tablets.
2.19. Previously identified allergy or hypersensitivity to components of the study
treatment formulations.
2.20. Impairment of gastrointestinal function or gastrointestinal disease that may
significantly alter the absorption of cabozantinib or selumetinib (e.g., ulcerative
disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel
resection).
2.21. Participants who require chronic concomitant treatment of moderate/strong CYP3A4
inducers or inhibitors (Appendix XIII). While not an exclusion criterion, unless
clinically indicated, participants should avoid taking other additional non-study
medications that may interfere with the study medications. Participants should avoid
medications that are known to either induce or inhibit the activity of hepatic microsomal
isoenzymes CYP1A2, and CYP2C19, as this may interfere with the metabolism of selumetinib
(Appendix XIII).
2.22. Participants with a history of significant noncompliance to medical regimens, are
unwilling to or unable to comply with the protocol, or who in the opinion of the
investigator may not be able to comply with the safety monitoring requirements of the
study.
Gender:
All
Minimum age:
16 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
University of Alabama at Birmingham
Address:
City:
Birmingham
Zip:
34294
Country:
United States
Contact:
Last name:
Karen Cole-Plourde, BA
Phone:
2055141317
Email:
kplourde@uab.edu
Contact backup:
Last name:
Juliette Southworth, BS
Phone:
2055298967
Email:
jsouthworth@uab.edu
Contact backup:
Last name:
Girish Dhall, MD
Start date:
January 1, 2025
Completion date:
January 1, 2033
Lead sponsor:
Agency:
Girish Dhall, MD
Agency class:
Other
Collaborator:
Agency:
Children's Hospital of Philadelphia
Agency class:
Other
Collaborator:
Agency:
Indiana University
Agency class:
Other
Collaborator:
Agency:
United States Department of Defense
Agency class:
U.S. Fed
Source:
University of Alabama at Birmingham
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06502171
