Study of the ITK Inhibitor Soquelitinib to Reduce Lymphoproliferation and Improve Cytopenias in Autoimmune Lymphoproliferative Syndrome (ALPS)-FAS Patients

A Phase 2a Study of the ITK Inhibitor Soquelitinib to Reduce Lymphoproliferation and Improve Cytopenias in Autoimmune Lymphoproliferative Syndrome (ALPS)-FAS Patients

Background:

Autoimmune lymphoproliferative syndrome (ALPS) is a rare disorder of the immune system caused by a mutation in the FAS gene. In ALPS, the body stores too many germ-fighting cells called lymphocytes. This can lead to an enlarged spleen and lymph nodes. Current treatments for ALPS can have many adverse effects. Better treatments for ALPS are needed.

Objective:

To test a study drug (soquelitinib) in people with ALPS.

Eligibility:

People aged 16 years and older with ALPS.

Design:

Participants will have 8 clinic visits and 6 remote visits within 1 year.

Participants will be screened. They will have a physical exam with blood and urine tests. Some may have tests of their lung function.

Soquelitinib is a tablet taken by mouth twice a day. Participants will record their doses and any symptoms on a paper or online form.

Blood tests and other procedures will be repeated during study visits. Three visits will include imaging scans. Participants will lie on a table that slides through a doughnut-shaped machine while X-rays capture pictures of the inside of their body.

Some participants may be able to remain in the study for a second year.

Study Description:

This is a multisite open-label phase 2a study to evaluate the safety, tolerability, and preliminary efficacy of the interleukin (IL)-2 inducible T-cell kinase (ITK) inhibitor soquelitinib for treating ALPS-FAS. This study will be conducted in two stages. In the first stage, following a background drug washout of up to 90 days, 8 participants will receive 200 mg of soquelitinib twice daily for up to 360 days, with approximately monthly study visits (in person or remote). A safety and futility interim analysis will be conducted after all 8 participants have had a computed tomography (CT) or positron emission tomography (PET)/CT scan at day 90 and have completed at least 80% of their study drug regimen. If at least one participant has a positive response to the study drug and there are no safety concerns among the 8 participants, then the study will proceed to stage 2, in which 6 new participants will be enrolled and, following a background drug washout of up to 90 days, receive the same dosage as stage 1 (200 mg twice daily for 360 days). Individual participation concludes at the end of the 360-day regimen.

Participants may re-enroll once in the study. They will repeat the whole study schedule except for the screening visit, but they will have a study drug washout period of up to 90 days with monthly visits during that time. Upon reaching pre-specified criteria, they will begin a second 360-day regimen of soquelitinib at 200 mg twice daily.

The primary endpoints will be assessed after all 6 participants of stage 2 have had a CT or PET/CT scan at day 90 and have completed at least 80% of their study drug regimen. The trial will automatically be determined a failure if safety concerns or lack of positive response prevent progression to stage 2.

Primary Objectives:

To determine the efficacy of soquelitinib in reducing spleen volume or target lymph node volume in people with ALPS-FAS.

Secondary Objective:

1. To determine the efficacy of soquelitinib in improvement of lymphoproliferation and autoimmune disease, including cytopenias, in

   people with ALPS-FAS.

2. To determine the safety and tolerability of soquelitinib in people with ALPS-FAS.

Primary Endpoints:

Reduction of spleen volume or target lymph node volume by 25% from baseline to day 90, assessed by CT or PET/CT scan.

Secondary Endpoints:

1. Shrinkage in spleen volume from baseline to day 90.
2. Shrinkage in target lymph node volume from baseline to day 90.
3. Reduction of cytopenias by one severity level from baseline to day 90.
4. Reduction in prednisone dosage.
5. Grade 3 or 4 systemic infections within 360 days (first or second regimen).
6. Clinically significant worsening of viral, mycobacterial, or fungal infection requiring new treatment or change of treatment by day 360 (first or second regimen).
7. Any drug-related grade 3 or 4 adverse event (AE) that triggers a pause.

• INCLUSION CRITERIA:

To be eligible to participate in this study and to re-enroll, an individual must meet all the following criteria:

1. Aged >= 16 years.
2. Able to provide informed consent (for ages >= 18 years) or has a parent(s) or guardian(s) who can provide permission to participate on their behalf (for ages <18 years).
3. Has a documented diagnosis of ALPS-FAS.
4. Has clinical evidence of active disease, defined as at least one enlarged lymph node and/or enlarged spleen.
5. If currently on corticosteroid therapy, then dose is less than 20 mg/day (prednisone equivalent) and has been stable for at least 4 weeks.
6. For participants to be seen at the NIH CC, co-enrolled on NIH protocol 93-I-0063.
7. Participants who can become pregnant or who can impregnate their partner must agree to either remain sexually abstinent or use two highly effective methods of contraception when engaging in sexual activities that can result in pregnancy, beginning 28 days before baseline until 3 months after the last dose. One method must be a barrier (eg, internal or external condom, cervical cap, or diaphragm). The second method may be any of the following:

7a. Oral contraceptive pill or hormonal patch or ring.

7b. Parenteral hormonal contraceptive implant.

7c. Intrauterine device.

EXCLUSION CRITERIA:

An individual who meets any of the following criteria will be excluded from participation or re-enrollment in this study:

1. Profound grade 3 or 4 cytopenias that cannot be improved with immunomodulatory treatments prior to enrolling in the clinical trial and starting the study drug. Per investigator discretion, individuals on a single agent may be included if the dose is stable for 12 weeks at screening and is not expected to confer additive toxicity.
2. Renal impairment, defined as serum creatinine >1.5 mg/dL (or 133 micromol/L) or estimated glomerular filtration rate <60 mL/min/1.73 m^2.
3. Liver impairment, defined as bilirubin, alanine aminotransferase, or aspartate aminotransferase greater than 2.5 times the upper limit of normal.
4. History of EBV-associated lymphoma.
5. Active EBV infection with EBV load >300 copies/mL.
6. Tuberculosis infection (active or latent) or undergoing tuberculosis treatment.
7. Infection with HIV or hepatitis B or C.
8. Current other invasive or systemic fungal, bacterial, or viral infection requiring therapy.
9. History of opportunistic infection within the previous 180 days.
10. History of invasive malignancy that required systemic therapy within the last 3 years.
11. Current use of moderate or strong cytochrome P450 isozyme (CYP)3A inhibitors or inducers that cannot be stopped before day 0.
12. Current use of P-glycoprotein (P-gp) inhibitors that cannot be stopped before day 0.
13. Known hypersensitivity or contraindication to CT contrast agent.
14. Pregnant or breastfeeding.
15. Any condition that, in the opinion of the study team contraindicates participation in this study.