Addition of Loncastuximab Tesirine to Acalbrutinib , Chronic Lymphocytic Leukemia
Study Details
Study Description
Brief Summary
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.
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
|
Phase 1 |
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
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45 µg/kg Loncastuximab Tesirine + Acalabrutinib 100 mg BID
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60 µg/kg Loncastuximab Tesirine + Acalabrutinib 100 mg BID
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75 µg/kg Loncastuximab Tesirine + Acalabrutinib 100 mg BID
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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 Design
Arms and Interventions
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
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
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
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
Will be given on Day 1 of each cycle with each cycle being 21 days, and is being added to BID Acalabrutinib
|
Outcome Measures
Primary Outcome Measures
- Primary Objective [12 months]
Recommended phase 2 dose of loncastuximab tesirine in combination with acalabrutinib
Secondary Outcome Measures
- Secondary Objective 1 [6 months]
undetectable measurable residual disease rate (uMRD) at 6 months of combination therapy in peripheral blood by NGS based clonoseq test
- Secondary Objective 2 [12 months]
Undetectable measurable residual disease rate (uMRD) at 12 months of combination therapy by NGS based clonoseq test.
- Secondary Objective 3 [12 months]
Best Overall response rate (ORR = CR+CRi+PR) of loncastuximab tesirine in combination with acalabrutinib
- Secondary Objective 4 [12 months]
Complete response rate (CRR= CR + CRi) of loncastuximab tesirine in combination with acalabrutinib in achieving a complete response.
- Secondary Objective 5 [12 months]
Progression free survival (PFS) at 12 months after completion of all treatment.
- Secondary Objective 6 [12 months]
Incidence of adverse events (AE) of loncastuximab tesirine in combination with acalabrutinib.
- Secondary Objective 7 [12 months]
Duration of response (DOR) of loncastuximab tesirine in combination with acalabrutinib
Eligibility Criteria
Criteria
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:
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Biopsy-proven small lymphocytic lymphoma OR
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Diagnosis of CLL according to the IWCLL criteria as evidenced by Peripheral blood lymphocyte count of greater than 5 x109/L .
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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).
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On therapy with acalabrutinib for a minimum of 3 months without evidence of progression as per IWCLL 2018 criteria.
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Relapsed or Refractory CLL who have received at least one prior therapy before initiation of acalabrutinib
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Presence of measurable residual disease in the peripheral blood or bone marrow aspirate by NGS based clonoseq test.
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Adequate organ function as defined below unless attributed to disease involvement:
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Liver function (bilirubin ≤ 1.5 × ULN, AST and/or ALT <3 x ULN). Patients with Gilbert Disease are permitted irrespective of bilirubin values.
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Kidney function (crcl > 30ml/min using Cockroft-Gault, based on actual weight).
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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
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Current evidence of central nervous system involvement.
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Unable to generate clonoseq ID specimen for measurable residual disease tracking.
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Completion of an autologous hematopoietic stem cell transplantation within 3 months prior to first dose of study drug.
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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.
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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.
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Progression of disease on BTK inhibitor.
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Unable to tolerate full dose of acalabrutinib at 100 mg twice a day.
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Inability to swallow and retain oral medications.
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Pregnant women are excluded from this study.
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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:
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active infection requiring systemic therapy ≤10 days before the first dose of study drug
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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
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Significant (as defined by study doctor) pulmonary disease or disorder
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any severe or uncontrolled other disease or condition which might increase the risk associated with study participation
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Vaccination with live, attenuated vaccines within 28 days prior to the first dose of study medication.
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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.
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Corticosteroids ≥ 10 mg of prednisone within the last 7 days.
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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.
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Known history of hypersensitivity to loncastuximab tesirine
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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)
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Breastfeeding or pregnant
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Any other malignancy known to be active, with the exception of
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Cervical carcinoma of Stage 1A (1A1,1A2) and 1B (1B1,1B2,1B3)
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Non-invasive basal cell or squamous cell skin carcinoma
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Non-invasive, superficial bladder cancer
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Prostate cancer with a current PSA level < 0.1 ng/mL
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Any curable or localized cancer with a CR of > 2 years' duration.
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- Mayur Narkhede
- ADC Therapeutics S.A.
Investigators
- Principal Investigator: Mayur Narkhede, M.D., University of Alabama at Birmingham
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- IRB-300009213