PI3K and P110delta Hyperactivation Syndrome
Conditions
Keywords
PI3K, P110delta, hyperactivation
Brief summary
This study was designed to evaluate the efficacy and safety of CVL237 tablets in patients with APDS/PASLI (activated phosphoinositol 3-kinase δ syndrome /p110 delta-activated mutation leading to senescent T cells, lymphadenopathy, and immune deficiency).
Detailed description
The study was divided into two parts. Part I is an open, dose-escalation study planned to enroll five patients with APDS/PASLI to determine the safety, tolerability, pharmacokinetics (PK), and in vivo pharmacodynamics (PD pAkt) of CVL237 tablets at two different dose levels. Patients were given CVL237 tablets, 100 mg/ day, QD, for 4 weeks (28 days), and safety assessment was performed on day 28 of the first cycle. If there was no safety risk, patients could take CVL237 tablets, 200 mg/ day, QD, for 4 weeks (28 days). Part II is a randomized, double-blind, placebo-controlled study of approximately 30 patients with APDS/PASLI. On day 1, patients were randomly assigned to the trial and placebo groups in a 2:1 ratio to take an oral CVL237 tablet or a placebo CVL237 simulant once daily. Efficacy and safety were evaluated on days 29, 57, and 85. The efficacy of CVL237 tablets in reducing lymphadyopathy will be investigated as measured by changes in the sum of diameter products (SPD) of target lesions selected from MRI or CT imaging according to the Lugano 2014 method, as well as changes in the percentage of naive B cells to total B cells, relative to baseline. The CVL237 tablets will also be evaluated for safety, PK.
Interventions
DRUGCVL237 tablets
CVL237 tablets, tablets, specification: 0.1g, Storage condition: not more than 30 ℃ storage.Validity: 72 months tentatively.
DRUGCVL237 placebo tablets
CVL237 tablets, tablets, specification: 0g, Storage condition: not more than 30 ℃ storage.Validity: 72 months tentatively.
Sponsors
Convalife (Shanghai) Co., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
Part II is a randomized, double-blind, placebo-controlled study of approximately 30 patients with APDS/PASLI. On day 1, patients were randomly assigned to the trial and placebo groups in a 2:1 ratio to take an oral CVL237 tablet or a placebo CVL237 simulant once daily. Efficacy and safety were evaluated on days 29, 57, and 85. The efficacy of CVL237 tablets in reducing lymphadyopathy will be investigated as measured by changes in the sum of diameter products (SPD) of target lesions selected from MRI or CT imaging according to the Lugano 2014 method, as well as changes in the percentage of naive B cells to total B cells, relative to baseline. The CVL237 tablets will also be evaluated for safety, PK
Intervention model description
CVL237 tablets for APDS/PASLI (Activated phosphoinositol 3-kinase delta syndrome /p110 delta-activated Mutation leading to senescent T cells, lymphadenopathy, and immune deficiency)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Male and female patients aged 18-75 years (including boundary values); * Patients with a clinical phenotype consistent with APDS, including a history of recurrent ear, sinus, or lung infections (more frequently than expected in immunoactive individuals), and patients known to have type 1 APDS-related gene PI3K mutations (e.g., E1021K, N334K, E525K, and C416R) or type 2 APDS-related mutations; * In Parts I and II, the patient must have lymph node and/or extranodal lymphocyte proliferation, as well as clinical findings and manifestations consistent with APDS/PASLI, such as a history of recurrent ear - sinus - lung infections and/or organ dysfunction (e.g., lung, liver). In addition, in Part II, patients must have at least one measurable lymph node lesion on a CT or MRI scan. * During screening, vital signs (systolic blood pressure, diastolic blood pressure, and pulse rate) were assessed by sitting position after at least 3 minutes of rest. Seated vital signs should be within the following range: * Systolic blood pressure, 90-139 mm Hg * Diastolic blood pressure, 50-89 mm Hg * pulse rate, 50-100 bpm; Up to 110 bpm in teenagers * Expected survival ≥3 months; * Pregnant or lactating women or fertile women with a negative pregnancy test at baseline; Men and women with 6) fertility must consent to the use of medically approved contraceptive methods during the study period and within 6 months after the last dosing; * Did not participate in any clinical trials within 1 month before joining the study; * Able to comply with the test protocol (as determined by the investigator); * Volunteer to participate in this clinical trial, understand the study procedure and be able to sign the informed consent in person.
Exclusion criteria
* Previous or concurrent use of immunosuppressive drugs, such as: 1. Use of mTOR inhibitors (e.g., sirolimus, rapamycin, Everolimus) or PI3kδ inhibitors (selective or non-selective PI3K inhibitors) within 5 half-lives prior to initial medication, but allow short-term use, for a total of no more than 5 days, but only within 1 month prior to enrollment in the study. 2. Use B cell depleting agents (e.g. Rituximab) within 5 half-lives prior to initial administration; If the patient has previously been treated with B cell depleting agents, the absolute B lymphocyte count in the blood must return to normal. 3. had taken Belimumab or cyclophosphamide within 5 half-lives before first taking the study drug. 4. Use of cyclosporin A, nystatin, 6-mercaptopurine, azathioprine, or methotrexate within 5 half-lives prior to first administration of the study drug. 5. Use more than 25 mg of prednisone or an equivalent dose of glucocorticoids daily for 2 weeks prior to the first dose. 6. Other immunosuppressive drugs whose effects are expected to remain at the start of the study. * Being treated with known OATP1B1 and OATP1B3 substrate drugs, CYP3A4/5 substrate drugs, intermediate-acting and potent CYP3A4/5 inhibitors, CYP3A4/5 potent inducers, if treatment cannot be terminated or switched to another drug before initiating investigational therapy; * Drugs currently used that are metabolized by the isoenzyme CYP1A2 and have a narrow therapeutic index (exposure responses indicate that drugs that accompany increasing their exposure levels with the use of powerful inhibitors may cause serious safety concerns (e.g., tip torsion ventricular tachycardia)) * Current history of liver disease or chronic disease, unless liver enlargement is determined by their clinicianto be secondary to APDS, or known liver or biliary tract abnormalities (other than Gilbert syndrome or asymptomatic gallstones) * The investigator determined that the patient had clinically significant abnormalities in laboratory results (blood routine, blood biochemical, or urine routine) * Patients with liver disease or liver injury, clinically significant abnormal liver function tests (alanine aminotransferase and aspartate aminotransferase \> 2.5 times the upper limit of normal), a history of kidney injury/kidney disease (e.g., kidney trauma, glomerulonephritis, or having only one kidney), or impaired kidney function, The serum creatinine level was \>1.5 mg/dL (133 μmol/L). LVEF \< 50%, Fridericia corrected QT Interval (QTcF) ≥450 ms for men and 470 ms for women; * If a subject's clinical abnormality or laboratory parameters are not specifically listed in the inclusion or
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| part 1 : Incidence of Treatment-Emergent Adverse Events | Throughout the study for approximately 84 days | Abnormal changes in physical examination, vital signs, electrocardiograph laboratory tests, etc. compared to baseline were reported as AE |
| part 2:After 84 days of treatment, changes in the sum of diameter product (SPD) of log10 conversion in target lesions and changes in the percentage of naive B cells to total B cells from baseline were observed | At baseline (day 0) and at the end of treatment (day 84) | SPD:The maximum diameter of the tumor is multiplied by the longest diameter perpendicular to it |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| t1/2 | part 1： Up to day 56；part 2： Up to day 85 | Terminal elimination half-life: The time required for the terminal phase blood concentration to decrease by half |
| AUC | part 1： Up to day 56；part 2： Up to day 85 | Area under the drug time curve: The area surrounded by the blood concentration curve to the time axis. |
| Cmax | part 1： Up to day 56；part 2： Up to day 85 | Peak concentration: The highest blood concentration after administration |
| Tmax | part 1： Up to day 56；part 2： Up to day 85 | Peak time: The time required to reach peak concentration after administration |
Countries
China
Contacts
Primary ContactYun Ling, ph.D
Backup ContactYing Lv
Outcome results
None listed