Addition of Loncastuximab Tesirine to Acalbrutinib , Chronic Lymphocytic Leukemia

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

• 45 µg/kg Loncastuximab Tesirine + Acalabrutinib 100 mg BID
• 60 µg/kg Loncastuximab Tesirine + Acalabrutinib 100 mg BID
• 75 µg/kg Loncastuximab Tesirine + Acalabrutinib 100 mg BID
• 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.

Inclusion criteria

• Inclusion Criteria For all patients

• 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).
• On therapy with acalabrutinib for a minimum of 3 months without evidence of progression as per IWCLL 2018 criteria.
• Relapsed or Refractory CLL who have received at least one prior therapy before initiation of acalabrutinib
• Presence of measurable residual disease in the peripheral blood or bone marrow aspirate by NGS based clonoseq test.
• 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

• Current evidence of central nervous system involvement.
• Unable to generate clonoseq ID specimen for measurable residual disease tracking.
• Completion of an autologous hematopoietic stem cell transplantation within 3 months prior to first dose of study drug.
• 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.
• 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.
• Progression of disease on BTK inhibitor.
• Unable to tolerate full dose of acalabrutinib at 100 mg twice a day.
• Inability to swallow and retain oral medications.
• Pregnant women are excluded from this study.
• 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
• Vaccination with live, attenuated vaccines within 28 days prior to the first dose of study medication.
• 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.
• Corticosteroids ≥ 10 mg of prednisone within the last 7 days.
• 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.
• Known history of hypersensitivity to loncastuximab tesirine
• 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)
• Breastfeeding or pregnant
• 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.