Study of Cabozantinib With Selumetinib for Plexiform Neurofibromas

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.
• •\>12 weeks must have elapsed between systemic treatment with radionuclides and first dose of study treatment.
• •2.9. Surgery:
• •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.