APR-246 in Combination With Ibrutinib or Venetoclax-R in Subjects With TP53-Mutant R/R Non Hodgkin Lymphomas (NHL) (R/R)

• ClinicalTrials.gov Identifier: NCT04419389
• Recruitment Status: Recruiting
• First Posted: June 5, 2020
• Last Update Posted: January 19, 2021
• Sponsor: Aprea Therapeutics
• Information provided by (Responsible Party): Aprea Therapeutics

Tracking Information

• First Submitted Date: June 1, 2020
• First Posted Date: June 5, 2020
• Last Update Posted Date: January 19, 2021
• Estimated Study Start Date: January 2021
• Estimated Primary Completion Date: December 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 3, 2020)

• To determine the DLT of APR-246 in combination with ibrutinib or in combination with venetoclax + rituximab therapy in subjects with TP53 mutant NHL, including subjects with R/R CLL and R/R MCL. [ Time Frame: Through study completion, approximately 1 year ]
  The occurrence of DLTs, classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events .
• To assess the frequency of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) related to APR-246 in combination with ibrutinib and with venetoclax + rituximab therapy. [ Time Frame: Through study completion, approximately 1 year ]
  The frequency of TEAEs and SAEs related to APR-246 in combination with ibrutinib and with venetoclax + rituximab therapy
• 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 and R/R MCL. [ Time Frame: Through study completion, approximately 1 year ]
  The highest dose of APR-246 with acceptable toxicity (RP2D of APR-246) (the dose producing ≤ 20% of DLT).

• Original Primary Outcome Measures: Same as current
• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: APR-246 in Combination With Ibrutinib or Venetoclax-R in Subjects With TP53-Mutant R/R Non Hodgkin Lymphomas (NHL)
• Official Title: Phase 1 and Dose Expansion Study of APR-246 in Combination With Ibrutinib or Venetoclax-based Therapy in Subjects With TP53-Mutant R/R NHL Including Chronic Lymphocytic Leukemia (CLL) and Mantle Cell Lymphoma (MCL)
• Brief Summary: Study to determine the preliminary safety, tolerability, and pharmacokinetic (PK) profile of APR-246 in combination with either ibrutinib or venetoclax + rituximab therapy in subjects with TP53-mutant NHL, including relapsed and/or refractory (R/R) CLL and R/R MCL.

Detailed Description

Phase 1, open-label, dose-finding and cohort expansion study to determine the preliminary safety, tolerability, and pharmacokinetic (PK) profile of APR-246 (eprenetapopt) in combination with either ibrutinib or venetoclax + rituximab therapy in subjects with TP53-mutant NHL, including relapsed and/or refractory (R/R) CLL and R/R MCL.

The study includes a safety lead-in portion followed by an expansion portion in subjects with R/R CLL and R/R MCL.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: Single (Participant); Primary Purpose: Treatment

Condition

• Non Hodgkin Lymphoma
• Chronic Lymphocytic Leukemia
• Mantle Cell Lymphoma

Intervention

• Drug: APR-246 (eprenetapopt)
  APR-246 D1-4 of each cycle
• Drug: Ibrutinib
  Ibrutinib will be given at a standard dose and schedule.
• Drug: venetoclax-R
  Venetoclax and Rituximab will be given at a standard dose and schedule.

Study Arms

• Experimental: Safety Lead-In Cohort 1
  Subjects with R/R TP53-mutant CLL.
  Interventions:

  • Drug: APR-246 (eprenetapopt)
  • Drug: Ibrutinib
• Experimental: Safety Lead-In Cohort 2
  Subjects with R/R TP53-mutant CLL.
  Interventions:

  • Drug: APR-246 (eprenetapopt)
  • Drug: venetoclax-R
• Experimental: Expansion Cohorts
  Subjects with R/R TP53-mutant CLL and/or MCL
  Interventions:

  • Drug: APR-246 (eprenetapopt)
  • Drug: Ibrutinib
  • Drug: venetoclax-R

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: June 3, 2020): 116
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: June 2023
• Estimated Primary Completion Date: December 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Is able to understand and is willing and able to comply with the study requirements and to provide written informed consent.
2. Documented histologic diagnosis of R/R CLL or R/R MCL
3. Safety Lead-In Cohort 1: Patients whose most recent regimen did not include BTK inhibitor therapy.
4. Safety Lead-In Cohort 2: Patients whose most recent regimen did not include Bcl-2 inhibitor therapy.
5. Prothrombin time (or international normalized ratio) and partial thromboplastin time not to exceed 1.2 × the institution's normal range.

6. Adequate BM function independent of growth factor or transfusion support, per local laboratory reference range at screening as follows:

   1. platelet count ≥ 75 000/mm3;
   2. absolute neutrophil count (ANC) ≥ 1000/mm3 unless cytopenia is clearly due to marrow involvement from CLL or MCL
   3. total hemoglobin ≥ 9 g/dL (without transfusion support within 2 weeks of screening);

7. Adequate organ function as defined by the following laboratory values:

   1. Creatinine clearance ≥ 30 mL/min.
   2. 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.
   3. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN, unless due to NHL organ involvement.
8. Age ≥18 years at the time of signing the informed consent form.
9. At least one TP53 mutation which is not benign or likely benign.
10. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
11. Projected life expectancy of ≥ 12 weeks.

12. Women of childbearing potential and men with female partners of childbearing potential must be willing to use an effective form of contraception.

    Exclusion Criteria:

13. Patient with known allergies to xanthine oxidase inhibitors and/or rasburicase.
14. For patients to receive rituximab on this protocol, prior allergy to rituximab is prohibited.
15. No concomitant anticancer therapies, immunotherapies, cellular, or radiotherapy. No major surgery within 3 weeks prior to first dose of study treatment.
16. Uncontrolled autoimmune hemolytic anemia (AIHA) or immune thrombocytopenia.
17. Consumption of grapefruit, grapefruit products, Seville oranges, or star fruit within 7 days of starting study treatment.
18. 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.
19. History of allogeneic or autologous stem cell transplant (SCT) or CAR-T therapy within the last 30 days or with any of the following:
20. Active graft versus host disease (GVHD)
21. Cytopenias from incomplete blood cell count recovery post-transplant;
22. Need for anti-cytokine therapy for residual symptoms of neurotoxicity > grade 1 from CAR-T therapy;
23. Ongoing immunosuppressive therapy.
24. Known history of human immunodeficiency virus (HIV) serum positivity.
25. Active hepatitis B/C.
26. 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.
27. Known neurologic disorder or residual neurologic toxicities that may put patients at increased risk of neurologic toxicity in the opinion of the investigator.
28. Cardiac abnormalities.
29. Concomitant malignancies or previous malignancies with less than a 1 year disease- free interval at the time of signing consent.
30. A female patient who is pregnant or breast-feeding.
31. Active uncontrolled systemic infection.
32. Received an investigational agent within 30 days or within 5 T1/2, whichever is shorter prior to the first dose of study treatment.
33. Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal (GI) absorption of ibrutinib or venetoclax.
34. Current treatment with certain strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers and/or strong P-gp inhibitors..

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Eyal Attar, MD; +1 617 804 6947; info@aprea.com

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04419389
• Other Study ID Numbers: A20-11197
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Aprea Therapeutics
• Study Sponsor: Aprea Therapeutics
• Collaborators: Not Provided

Investigators

• Study Director: Joachim Gullbo, MD; Theradex Oncology

• PRS Account: Aprea Therapeutics
• Verification Date: September 2020