Alrizomadlin (APG-115) in Subjects With BAP1 Cancer Syndrome and Early-Stage Mesothelioma

NCT06654050 | Withdrawn Phase 2 FDA Drug

• 2 other identifiers: 10001605001605-C
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

Background: Mesothelioma is a rare cancer typically caused by exposure to asbestos and related fibers. Most people with mesothelioma survive less than 5 years after diagnosis. About 3000 people in the United States die from this disease each year. People with inherited mutations in the BAP1 gene \[called BAP1 Cancer Syndrome (BCS)\] are more likely to develop mesothelioma and other cancers such as melanomas and renal cell carcinomas without asbestos exposure. Almost all people with BCS develop multiple cancers, of which mesothelioma is the most commonly observed. Objective: To test a study drug (APG-115) in participants with BAP1 Cancer Syndrome (BCS) and early-stage mesothelioma. Eligibility: People aged 18 years and older with germline BAP1 mutations and early-stage mesothelioma that does not yet need standard treatment are eligible for protocol enrollment. Participants will be required to also enroll in NIH protocols 20-C-0106 and 06-C-0014 which allow for pre- and post-treatment biopsies and bloodwork to be obtained for additional research studies. Design: Participants will be screened. They will have a physical exam with blood tests. Their medical records will be reviewed. They will have imaging scans and tests of their heart and lung functions. A procedure using a flexible tube with a camera and light will be inserted into the participant s chest and abdomen through a small cut to look at the tumors and to collect a tissue sample (biopsy). APG-115 capsules are taken by mouth. Participants will take the drug at home every other day for the first 13 days of the 21-day treatment cycles. On the first day of each cycle, researchers will call or email participants to check on their health. Participants will have blood tests 2 times a week during the first 2 cycles; after that, the blood tests will be weekly. These blood tests can be done at a local medical facility or at the NIH Clinical Center. Participants may continue treatment for up to 16 cycles. Imaging scans, biopsy, and other tests will be repeated after 8 and 16 cycles.

Conditions

Early-stage Mesothelioma; Subclinical Mesothelioma; BRCA1-Associated Protein-1 (BAP1) Mutations; Early-stage BAP1-associated Malignancies; Mesothelioma; Malignant Mesothelioma (MM)

Keywords

BRCA1-Associated Protein-1 (BAP1); BAP1 Cancer Syndrome (BCS); BAP1 Cancer Predisposition Syndrome (CPDS); ring finger domains 1 (UHRF1); mdm2 inhibitors (MDM2 inhibitors); p53; DNA methyltransferases 1 (DNMT1); peripheral immune subsets

Outcome Measures

Primary Outcomes (1)

• To determine stabilization or disease improvement rates in participants with early-stage mesotheliomas arising in the context of BAP1 Cancer Syndrome (BCS) following APG-115 treatment

  Fraction of evaluable participants who are able to have stabilization or improvement of disease will be reported along with a 95% confidence interval. Response rates will be calculated as the percent of participants whose best response is a stabilization or improvement of disease.

  baseline, and after every 8 treatment cycles (Course 1 and Course 2)

Secondary Outcomes (1)

• To evaluate the safety of APG-115

  starts at initiation of study drug, assessed Days 1 of every cycle, and through 30 days (safety visit) after the last study drug administration

Study Arms (1)

1/ Arm 1

EXPERIMENTAL

APG-115

Drug: alrizomadlin

Interventions

alrizomadlin DRUG

Alrizomadlin (APG-115) oral tablets (150 mg) taken every other day on Days 1, 3, 5, 7, 9, 11, and 13 of every cycle (1 cycle=21 days) for 8 cycles (i.e., Course 1). Individuals with stable or responding disease may receive an additional 8 cycles (i.e., Course 2). Maximum (total) of 2 treatment courses.

1/ Arm 1

Eligibility Criteria

• Age: 18 Years - 120 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• History of germline BRCA1-Associated Protein-1 (BAP1) mutations.
• Histologically confirmed by NCI Laboratory of Pathology (LP) subclinical/early-stage mesotheliomas.
• Participants with other early-stage BAP1-associated malignancies in addition to subclinical, early-stage mesotheliomas are eligible for the study.
• The extent of the disease (Tx by clinical staging criteria) must be insufficient to warrant approved front-line standard of care (SOC) therapies (surgery, chemotherapy, immunotherapy). Participants with clinical T1 tumors are eligible for protocol if they have been offered and have refused front-line SOC therapy.
• Age \>=18 years.
• Evaluable disease as confirmed by minimally invasive (videoscopic) assessment (thoracoscopy and/or laparoscopy with biopsy).
• Willingness to undergo pre- and post-treatment minimally invasive thoracoscopy and/orlaparoscopy to assess treatment response.
• Willingness to co-enroll on 20-C-0106 (Prospective Evaluation of High Resolution Dual Energy Computed Tomographic Imaging, Noninvasive (Liquid) Biopsies, and Minimally Invasive Surgical Surveillance for Early Detection of Mesotheliomas in Patients with BAP1 Tumor Predisposition Syndrome) and 06-C-0014 (Prospective Evaluation of Genetic and Epigenetic Alterations in Patients with Thoracic) to enable collection/processing of tumor, blood and normal pleura).
• ECOG performance status \<=1
• Adequate pulmonary reserve evidenced by forced expiratory volume (FEV)1 and diffusing capacity of the lungs for carbon monoxide (DLCO) \>=35% predicted on screening pulmonary function testing (PFTs).
• Oxygen saturation \>=92% on room air by pulse oximetry at screening.
• Adequate renal, hepatic, and hematopoietic function as defined below:
• leukocytes \>= 3,000/micro L
• absolute neutrophil count \>=1,500/micro L (without transfusion or cytokine support within 2 months prior to study treatment initiation)
• absolute lymphocyte count \> 800/micro L

You may not qualify if:

• Participants with any cancers requiring front-line standard of care treatment.
• Clinically significant cardiovascular/cerebrovascular disease as follows: cerebral vascular accident/stroke within 6 months prior to study treatment initiation, myocardial infarction within 6 months prior to study treatment initiation unless revascularized post infarction and cleared by cardiology consultants.
• Unstable angina, congestive heart failure (New York Heart Association Classification Class \>= II (https://manual.jointcommission.org/releases/TJC2016A/DataElem0439.html#:\~:text=Class%20II%20%2D%20Mild%20symptoms%20(mild,Class%20IV%20%2D%20Severe%20limitations.), serious cardiac arrhythmia, clinically significant bleeding or clinically significant pulmonary embolism at screening.
• QTcF interval \> than the 470 ms.
• Therapeutic anticoagulation within 2 weeks prior to study treatment initiation. Note: Oral agents and Lovenox, etc., are monitored by factor 10 levels, not PT or partial thromboplastin time (PTT).
• Participants receiving inhibitors or inducers of CYP3A4/3A5 as well as participants receiving P-glycoprotein inhibitors within 2 weeks prior to study treatment initiation treatment initiation
• (https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm#table2-2,table3-3,table5-2,
• Positive Hepatitis A (HAV) serological test, positive Hepatitis B (HBV) serological test, or positive Hepatitis C (HCV) serological test with detected quantitative HCV RNA at screening.
• Participants seropositive for human immunodeficiency virus (HIV) infection.
• Active infections requiring systemic therapy.
• Immunosuppressive medications within 4 weeks prior to study treatment initiation except non-systemic corticosteroids.
• Positive beta human chorionic gonadotropin (beta-HCG) serum or urine pregnancy test performed in individuals of childbearing potential at screening.
• Uncontrolled intercurrent illness evaluated by medical history and physical exam or situation that is not stable (e.g., recent hospitalization, Emergency Room visit or undergoing medication changes) that would potentially increase in risk of participant.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Mesothelioma; Mesothelioma, Malignant

Condition Hierarchy (Ancestors)

Adenoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Mesothelial; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Pleural Neoplasms; Lung Diseases; Respiratory Tract Diseases

Study Officials

• David S Schrump, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 22, 2024
• First Posted: October 23, 2024
• Study Start: March 16, 2026
• Primary Completion: March 16, 2026
• Study Completion: March 16, 2026
• Last Updated: March 17, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Data from this study may be requested from other researchers within 10 years after the completion of the primary endpoint by contacting the Principal Investigator.
• Access Criteria: Data from this study may be requested by contacting the PI.

Locations

US (1)