A Phase 1/1b/2 Study of Cabozantinib in Combination With Selumetinib for Plexiform Neurofibroma in Adults and Adolescents With Neurofibromatosis Type 1
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.
• 1. All participants must have a diagnosis of NF1 based on the 2021 revised consensus criteria.
• 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.
• 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.
• 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.
• 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.
• 4. Age: Participants must be ≥16 years of age at the time of study entry.
• 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.
• 6. Body Surface Area (BSA): Participants must have a BSA of 1.0 m2 or greater.
• 7. Organ Function Requirements:
• 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)
• 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.
• 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
• 7.4. Adequate Thyroid Function Defined as: ≤ Grade 1 or adequately managed asymptomatic Grade 2 hypothyroidism.
• 7.5. CPK level within normal limits within 14 days from the start of treatment.
• 7.6. Normal pancreatic function: amylase and lipase levels ≤ 1.5 x ULN
• 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.
• 8. Major surgery: Only participants who are not anticipated to need major surgery within 3 months after enrollment are eligible.
• 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.
• 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.
• 11. Willingness to avoid excessive sun exposure and use adequate sunscreen protection if sun exposure is anticipated.
• 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.