APR-246 in Combination With Acalabrutinib or Venetoclax Based Therapy in Subjects With R/R Non Hodgkin Lymphomas (NHL)

NCT04419389 | Terminated Phase 1 Results DMC FDA Drug

• 1 other identifier: A20-11197
• Study Type: interventional
• Target: 1
• Locations: 1 country
• Sites: 4

Brief Summary

Study to determine the preliminary safety, tolerability, and pharmacokinetic (PK) profile of APR-246 in combination with either acalabrutinib or venetoclax + rituximab therapy in subjects with NHL, including relapsed and/or refractory (R/R) CLL and R/R MCL.

Conditions

Non Hodgkin Lymphoma; Chronic Lymphocytic Leukemia; Mantle Cell Lymphoma

Keywords

APR-246; eprenetapopt

Outcome Measures

Primary Outcomes (3)

• To Determine the DLT of APR-246 in Combination With Acalabrutinib or in Combination With Venetoclax + Rituximab Therapy in Subjects With NHL, Including Subjects With R/R CLL, RT and R/R MCL.

  The occurrence of DLTs, classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events .

  Through study completion, approximately 1 year

• To Assess the Frequency of Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) Related to APR-246 in Combination With Acalabrutinib and With Venetoclax + Rituximab Therapy.

  The frequency of TEAEs and SAEs related to APR-246 in combination with acalabrutinib and with venetoclax + rituximab therapy

  Through study completion, approximately 6 months

• To Determine the Maximum Tolerated Dose (MTD) and the Recommended Phase 2 Dose (RP2D) in Subjects With TP53 Mutant NHL, Including Subjects With R/R CLL, RT and R/R MCL.

  The highest dose of APR-246 with acceptable toxicity (RP2D of APR-246) (the dose producing ≤ 20% of DLT).

  Through study completion, approximately 1 year

Study Arms (4)

Safety Lead-In Cohort 1

EXPERIMENTAL

APR-246 4.5 g/d + Acalabrutinib in Subjects with R/R CLL (APR 246 Monotherapy Lead-in; 4.5 g/d x 2)

Drug: APR-246 (eprenetapopt) + Acalabrutinib in CLL

Safety Lead-In Cohort 2

EXPERIMENTAL

APR-246 4.5 g/d + Venetoclax + Rituximab in Subjects with R/R CLL (APR 246 Monotherapy Lead-in; 4.5 g/d x 2).

Drug: APR-246 (eprenetapopt) 4.5 g/d + Venetoclax + Rituximab in CLL

Expansion Cohorts

EXPERIMENTAL

APR-246 4.5 g/d + (Acalabrutinib, OR, (Ven+R)) in Subjects with R/R TP53-mutant CLL, and/or MCL, and/or RT

Drug: APR-246 (eprenetapopt) 4.5 g/d + (Acalabrutinib, OR, (Venetoclax +Rituximab)), in CLL and/or MCL and/or RT

Safety Lead-In Cohort 3

EXPERIMENTAL

APR-246 4.5 g/d + Venetoclax + Rituximab in Subjects with RT

Drug: APR-246 (eprenetapopt) 4.5 g/d + Venetoclax + Rituximab in RT

Interventions

APR-246 (eprenetapopt) + Acalabrutinib in CLL DRUG

APR-246 D1, 8 and 15 of each cycle Acalabrutinib will be given at a standard dose and schedule (APR 246 Monotherapy Lead-in; 4.5 g/d x 2)

Safety Lead-In Cohort 1

APR-246 (eprenetapopt) 4.5 g/d + Venetoclax + Rituximab in CLL DRUG

APR-246 D1, 8 and 15 of each cycle Venetoclax + Rituximab will be given at a standard dose and schedule (APR 246 Monotherapy Lead-in; 4.5 g/d x 2)

Safety Lead-In Cohort 2

APR-246 (eprenetapopt) 4.5 g/d + (Acalabrutinib, OR, (Venetoclax +Rituximab)), in CLL and/or MCL and/or RT DRUG

APR-246 D1, 8 and 15 of each cycle Acalabrutinib will be given at a standard dose and schedule Venetoclax and Rituxiab will be given at a standard dose and schedule

Expansion Cohorts

APR-246 (eprenetapopt) 4.5 g/d + Venetoclax + Rituximab in RT DRUG

APR-246 4.5 g/d D1, 8 and 15 of each cycle Venetoclax + Rituximab will be given at a standard dose and schedule

Safety Lead-In Cohort 3

Eligibility Criteria

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

You may qualify if:

• Is able to understand and is willing and able to comply with the study requirements and to provide written informed consent.
• Documented histologic diagnosis of R/R CLL, RT, or R/R MCL
• Safety Lead-In Cohort 1: Patients whose most recent regimen did not include BTK inhibitor therapy.
• Safety Lead-In Cohort 2: Patients whose most recent regimen did not include Bcl-2 inhibitor therapy.
• Safety Lead-In Cohort 3: APR-246 + venetoclax + rituximab in patients with RT
• Prothrombin time (or international normalized ratio) and partial thromboplastin time not to exceed 1.2 × the institution's normal range.
• Adequate BM function independent of growth factor or transfusion support, per local laboratory reference range at screening as follows:
• platelet count ≥ 75 000/mm3;
• absolute neutrophil count (ANC) ≥ 1000/mm3 unless cytopenia is clearly due to marrow involvement from CLL or MCL
• total hemoglobin ≥ 9 g/dL (without transfusion support within 2 weeks of screening);
• Adequate organ function as defined by the following laboratory values:
• Creatinine clearance ≥ 30 mL/min.
• Total serum bilirubin ≤ 1.5 × upper limit of normal (ULN) unless due to Gilbert's syndrome, NHL organ involvement, controlled immune hemolysis or considered an effect of regular blood transfusions.
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN, unless due to NHL organ involvement.
• Age ≥18 years at the time of signing the informed consent form.

You may not qualify if:

• Patient with known allergies to xanthine oxidase inhibitors and/or rasburicase.
• For patients to receive rituximab on this protocol, prior allergy to rituximab is prohibited.
• No concomitant anticancer therapies, immunotherapies, cellular, or radiotherapy. No major surgery within 3 weeks prior to first dose of study treatment.
• Uncontrolled autoimmune hemolytic anemia (AIHA) or immune thrombocytopenia.
• Consumption of grapefruit, grapefruit products, Seville oranges, or star fruit within 7 days of starting study treatment.
• Concomitant steroids for disease related pain control are allowed at any dose but must be discontinued prior to any study treatment initiation. Chronic use of corticosteroids is allowed up to ≤ 20 mg prednisone daily for non-cancer related conditions at the time of study start.
• History of allogeneic or autologous stem cell transplant (SCT) or CAR-T therapy within the last 30 days or with any of the following:
• Active graft versus host disease (GVHD)
• Cytopenias from incomplete blood cell count recovery post-transplant;
• Need for anti-cytokine therapy for residual symptoms of neurotoxicity \> grade 1 from CAR-T therapy;
• Ongoing immunosuppressive therapy.
• Known history of human immunodeficiency virus (HIV) serum positivity.
• Active hepatitis B/C.
• Known central nervous system (CNS) involvement by lymphoma. Patients with previous treatment for CNS involvement who are neurologically stable and without evidence of disease may be eligible if a compelling clinical rationale is provided to sponsor.
• Known neurologic disorder or residual neurologic toxicities that may put patients at increased risk of neurologic toxicity in the opinion of the investigator.

Sponsors & Collaborators

• Aprea Therapeutics: lead

Study Sites (4)

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

MeSH Terms

Conditions

Lymphoma, Non-Hodgkin; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell

Interventions

eprenetapopt; acalabrutinib; venetoclax; Rituximab

Condition Hierarchy (Ancestors)

Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Hematologic Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Senior Medical Advisor
• Organization: Aprea Therapeutics

info@aprea.com

215-948-4119

Study Officials

• Joachim Gullbo, MD

  Theradex Oncology

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 1, 2020
• First Posted: June 5, 2020
• Study Start: March 2, 2021
• Primary Completion: August 23, 2021
• Study Completion: August 24, 2021
• Last Updated: March 17, 2025
• Results First Posted: November 15, 2024

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (4)