Addition of Loncastuximab Tesirine to Acalbrutinib , Chronic Lymphocytic Leukemia

Addition of loNcasTuxImab teSirine to AcalabruTinib in Chronic Lymphocytic Leukemia(Anti-Static Study)

Study is a phase I study to determine the maximum tolerated dose of adding Loncastuximab Tesirine to Aclabrutinib in the treatment of chronic lymphocytic leukemia.

Study Overview

• Status: Recruiting
• Conditions: Chronic Lymphocytic Leukemia
• Intervention / Treatment: Drug: Loncastuximab Tesirine and Acalabrutinib

Detailed Description

The study is a phase I study which will employ the Bayesian optimal interval (BOIN) design to find the maximum tolerated dose (MTD).

Approximately 24 Dose-Limiting Toxicity (DLT) evaluable participants will be treated to find MTD with a target DLT rate of 25%, and 4 pre-specified doses. The total number of participants enrolled will depend on the frequency of DLTs and when the MTD is determined. The maximum number of patients at a given dose level is 12.

The dose of acalabrutinib will be fixed and loncastuximab tesirine will be titrated as in dose level table 1 below.

Table 1. Dose levels Dose Level Schedule

1. 45 µg/kg Loncastuximab Tesirine + Acalabrutinib 100 mg BID
2. 60 µg/kg Loncastuximab Tesirine + Acalabrutinib 100 mg BID
3. 75 µg/kg Loncastuximab Tesirine + Acalabrutinib 100 mg BID
4. 90 µg /kg Loncastuximab Tesirine (for first 2 cycles followed by 75µg/kg for subsequent cycles) + Acalabrutinib 100 mg BID

The DLT evaluation period is two cycles (42 days).

Loncastuximab Tesirine will be given as an IV infusion, each cycle is a 21 day cycle, with Loncastuximab Tesirine given day 1 of each cycle.

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Pamela M Hardwick; Phone Number: 2059755387; Email: pamdixon@uab.edu

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • Recruiting
      • University of Alabama at Birmingham
      • Contact: Mayur Narkhede; Phone Number: 205-934-4228; Email: msnarkhede@uabmc.edu
      • Contact: Pam Dixon; Phone Number: (205) 975-5387; Email: pamdixon@uab.edu
      • Principal Investigator: Mayur S Narkhede, M.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

- Inclusion Criteria For all patients

1. Diagnosis of CLL according to the IwCLL criteria or SLL according to the World Health Organization (WHO) criteria. This includes previous documentation of:

   • Biopsy-proven small lymphocytic lymphoma OR
   • Diagnosis of CLL according to the IWCLL criteria as evidenced by Peripheral blood lymphocyte count of greater than 5 x109/L .
   • Immunophenotype consistent with CLL defined as the predominant population of lymphocytes share both B cell antigens (CD19, CD20 (typically dim expression), or CD23) as well as CD5 in the absence of other pan-T-cell markers (CD3, CD2, etc).
2. On therapy with acalabrutinib for a minimum of 3 months without evidence of progression as per IWCLL 2018 criteria.
3. Relapsed or Refractory CLL who have received at least one prior therapy before initiation of acalabrutinib
4. Presence of measurable residual disease in the peripheral blood or bone marrow aspirate by NGS based clonoseq test.

5. Adequate organ function as defined below unless attributed to disease involvement:

   • Liver function (bilirubin ≤ 1.5 × ULN, AST and/or ALT <3 x ULN). Patients with Gilbert Disease are permitted irrespective of bilirubin values.
   • Kidney function (crcl > 30ml/min using Cockroft-Gault, based on actual weight).
   • ANC ≥ 1,000/µL, Hgb > 8, Platelet Count ≥ 50,000/ µL. Use of G-CSF is not permitted for up to 7 days prior to enrollment.

Exclusion Criteria:

• Exclusion Criteria For all patients

  1. Current evidence of central nervous system involvement.
  2. Unable to generate clonoseq ID specimen for measurable residual disease tracking.
  3. Completion of an autologous hematopoietic stem cell transplantation within 3 months prior to first dose of study drug.
  4. Prior allogeneic stem cell transplant within 6 months. The patient should not have any active Graft vs. Host disease (GVH) or should be on immune suppressive agents.
  5. Completion of treatment with any radiotherapy, chemotherapy, antibody, immunoconjugates and/or another investigational drug ≤4 weeks (or 5 half-lives of the drug, whichever is shorter) prior to the first dose of study drug. Patients may be enrolled after a minimum of 2 weeks of radiation if radiation was for palliative intent.
  6. Progression of disease on BTK inhibitor.
  7. Unable to tolerate full dose of acalabrutinib at 100 mg twice a day.
  8. Inability to swallow and retain oral medications.
  9. Pregnant women are excluded from this study.

  10. Any active, concurrent, significant illness or disease (other underlying lymphoma) or clinically significant findings including psychiatric and behavioral problems, medical history and/or physical examination findings that would preclude the patient from participation in the study such as:

      • active infection requiring systemic therapy ≤10 days before the first dose of study drug
      • unstable angina pectoris, symptomatic congestive heart failure (New York Heart Association [NYHA] II, III, IV;), myocardial infarction ≤6 months prior to first study drug, uncontrolled cardiac arrhythmia e.g., atrial fibrillation/flutter, cerebrovascular accidents ≤6 months before first dose of study drug
      • Significant (as defined by study doctor) pulmonary disease or disorder
      • any severe or uncontrolled other disease or condition which might increase the risk associated with study participation
  11. Vaccination with live, attenuated vaccines within 28 days prior to the first dose of study medication.
  12. Receiving systemic immunosuppressive medications (including, but not limited to, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents). The use of inhaled corticosteroids is permitted.
  13. Corticosteroids ≥ 10 mg of prednisone within the last 7 days.
  14. Has had a solid organ transplant within the last 3 years. Note: Patients who have had a Solid organ transplant >3 years ago are eligible if there are no signs/symptoms of graft versus host disease (GvHD) and off immunosuppressive medications as per above.
  15. Known history of hypersensitivity to loncastuximab tesirine
  16. Clinically significant third space fluid accumulation (i.e., ascites requiring drainage or pleural effusion that is either requiring drainage or associated with shortness of breath)
  17. Breastfeeding or pregnant

  18. Any other malignancy known to be active, with the exception of

      • Cervical carcinoma of Stage 1A (1A1,1A2) and 1B (1B1,1B2,1B3)
      • Non-invasive basal cell or squamous cell skin carcinoma
      • Non-invasive, superficial bladder cancer
      • Prostate cancer with a current PSA level < 0.1 ng/mL
      • Any curable or localized cancer with a CR of > 2 years' duration.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose Level 1: 45 µg/kg Loncastuximab Tesirine every 21 days + Acalabrutinib 100 mg BID for 12 cycles	Drug: Loncastuximab Tesirine and Acalabrutinib; Will be given on Day 1 of each cycle with each cycle being 21 days, and is being added to BID Acalabrutinib
Experimental: Dose Level 2; 60 µg/kg Loncastuximab Tesirine every 21 days + Acalabrutinib 100 mg BID for 12 cycles	Drug: Loncastuximab Tesirine and Acalabrutinib; Will be given on Day 1 of each cycle with each cycle being 21 days, and is being added to BID Acalabrutinib
Experimental: Dose Level 3; 75 µg/kg Loncastuximab Tesirine every 21 days + Acalabrutinib 100 mg BID for 12 cycles	Drug: Loncastuximab Tesirine and Acalabrutinib; Will be given on Day 1 of each cycle with each cycle being 21 days, and is being added to BID Acalabrutinib
Experimental: Dose level 4: 90 µg /kg Loncastuximab Tesirine (for first 2 cycles followed by 75µg/kg for subsequent 10 cycles) + Acalabrutinib 100 mg BID for a total of 12 cycles.	Drug: Loncastuximab Tesirine and Acalabrutinib; Will be given on Day 1 of each cycle with each cycle being 21 days, and is being added to BID Acalabrutinib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Primary Objective	Recommended phase 2 dose of loncastuximab tesirine in combination with acalabrutinib	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Secondary Objective 1	undetectable measurable residual disease rate (uMRD) at 6 months of combination therapy in peripheral blood by NGS based clonoseq test	6 months
Secondary Objective 2	Undetectable measurable residual disease rate (uMRD) at 12 months of combination therapy by NGS based clonoseq test.	12 months
Secondary Objective 3	Best Overall response rate (ORR = CR+CRi+PR) of loncastuximab tesirine in combination with acalabrutinib	12 months
Secondary Objective 4	Complete response rate (CRR= CR + CRi) of loncastuximab tesirine in combination with acalabrutinib in achieving a complete response.	12 months
Secondary Objective 5	Progression free survival (PFS) at 12 months after completion of all treatment.	12 months
Secondary Objective 6	Incidence of adverse events (AE) of loncastuximab tesirine in combination with acalabrutinib.	12 months
Secondary Objective 7	Duration of response (DOR) of loncastuximab tesirine in combination with acalabrutinib	12 months

Collaborators and Investigators

• Sponsor: Mayur Narkhede
• Collaborators: ADC Therapeutics S.A.
• Investigators: Principal Investigator: Mayur Narkhede, M.D., University of Alabama at Birmingham

Study record dates

Study Major Dates

• Study Start (Actual): December 18, 2023
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2028

Study Registration Dates

• First Submitted: July 14, 2023
• First Submitted That Met QC Criteria: July 24, 2023
• First Posted (Actual): August 2, 2023

Study Record Updates

• Last Update Posted (Actual): December 29, 2023
• Last Update Submitted That Met QC Criteria: December 21, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Leukemia, B-Cell; Chronic Disease; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Antineoplastic Agents; Antineoplastic Agents, Immunological; Acalabrutinib; Loncastuximab tesirine
• Other Study ID Numbers: IRB-300009213

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No