NF2-related schwannomatosis (formerly Neurofibromatosis Type II) (NF2) Nervous System Diseases
Conditions
Interventions
All participants recruited will commence both drugs, orally, Kaletra (AbbVie) at a strength of 100 mg Lopinavir + 25 mg Ritonavir and Norvir (AbbVie) Ritonavir dose at 200 mg, twice daily from Day 1,
Sponsors
University Hospitals Plymouth NHS Trust
Eligibility
Sex/Gender
All
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: 1. Written informed consent 2. Diagnosis of NF2-related schwannomatosis as defined using the 2022 criteria 3. Meningioma as identified by imaging 4. Over 18 years of age 5. Peripheral schwannomas under the skin (CS) biopsies amenable to biopsy 6. Karnofsky performance status >60% 7. Adequate bone marrow function within 28 days prior to the baseline visit: WBC >3.4 x 10e9/l, platelets >99 x 10e9/l 8. Adequate renal function within 28 days prior to the baseline visit: creatinine <2.5 x upper limit of normal 9. Adequate hepatic function within 28 days prior to the baseline visit: LFT <1.5 x upper limit of normal, serum amylase <1.5 x upper limit of normal 10. Prothrombin (PT) or INR (International Normalised Ratio) and Prothrombin Time (PTT) < 1.5 x upper limit of normal 11. Able to swallow tablets 12. Patients with the potential for pregnancy or impregnating their partner must agree to use acceptable methods of birth control to avoid conception. Female patients must agree to employ two barrier methods of contraception (e.g. condom, diaphragm with spermicidal jelly) during the trial and for 3 months following the end of their trial participation. Post-menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. 13. Women of childbearing potential with a negative serum pregnancy test at screening and a negative urine pregnancy test at the baseline visit.
Exclusion criteria
Exclusion criteria: 1. Hypersensitivity to ritonavir or lopinavir or any of its excipients 2. Current or expected use of any medications or substances that are highly dependent on Cytochrome P450 3A4 (CYP3A4) for clearance or are strong inducers of CYP3A4. See current SmPC for details of medications. Participants who have not had their contraindicated medication either discontinued or switched to a different medication at least 2 weeks prior to starting the trial drug. 3. Cardiac arrhythmias requiring anti-arrhythmics (beta-blockers and digoxin are allowed) 4. Symptomatic coronary artery disease or ischemia 5. Myocardial infarction (MI) within the last 6 months; congestive cardiac failure >NYHA Class II 6. Active clinically serious bacterial or fungal infections 7. Known diagnosis of human immunodeficiency virus (HIV) infection or chronic hepatitis B or C 8. Prior treatment with Norvir/Kaletra 9. Pregnant or breastfeeding 10. Patients with uncontrolled hypertension 11. Serious uncontrolled concomitant medical or psychiatric illness 12. Grade 3 or higher impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the trial drug (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhoea, malabsorption syndrome) 13. History of acute pancreatitis within one year of trial entry or medical history of chronic pancreatitis 14. History of another primary malignancy that is currently clinically significant or currently requires active intervention 15. Any other clinically significant medical or surgical condition which, according to the CI/PI’s discretion, should preclude participation 16. History of significant congenital or acquired bleeding disorder 17. Patients taking warfarin or cytotoxic drugs
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Target inhibition will be analysed in the tumour before and after drug treatment via Wes™, an automated capillary-based immunoassay quantitative system to determine the levels of: 1. Phosphorylated (active) and total (phosphorylated and non-phosphorylated) ERK1/2 (proliferation marker) 2. Cyclin D1 (cell cycle progression marker) 3. Cleaved (active) Caspase 3 (apoptosis marker) 4. Cleaved PARP1 (apoptosis) as main targets This will be complemented by an extended biomarker investigation looking for the effect of ritonavir and lopinavir on: 1. Phospho FAK/FAK, p53 2. Phospho S6 Ribosomal Protein/s6 3. cJun, phospho AKT/AKT 4. P-Glycoprotein (MDR-1) Measured at Day 0 and Day 30 | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. Steady-state plasma and Intra-tumoural (CS) concentration of ritonavir and lopinavir (Kaletra plus Norvir) after 30 days of oral dosing - drug concentration (µg/kg) from pharmacokinetic blood and tissue samples. 2. Assessment of biomarkers for treatment response in patients by testing target inhibition in PBMC after 30 days of dosing - Western blotting will be performed for detection of: 2.1. Phosphorylated (active) and total (phosphorylated and non-phosphorylated) ERK1/2 (proliferation marker), 2.2. Cyclin D1 (cell cycle progression marker), 2.3. Cleaved (active) caspase 3 (apoptosis marker). 3. Minimal biological effective dose - the dose level is declared effective if at least two of the initial five or second stage 8 (5+3) patients demonstrate a PD response which is significant at the 0.05 level. Measured at Day 0 and Day 30. 4. Toxicity of ritonavir and lopinavir (Kaletra plus Norvir) in patients treated at this dose schedule for 30 days for meningioma or schwannoma - assessment of adverse events (AEs), serious adverse events (SAEs), ARrs, serious adverse reactions (SARs) and suspected unexpected serious adverse reactions (SUSARs). Measured at Day 0 and Day 60. | — |
Countries
England, United Kingdom
Outcome results
None listed