Clinical Trials /

Acalabrutinib and High Frequency Low Dose Subcutaneous Rituximab in Patients With Previously Untreated Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma

NCT03788291

Description:

The main purpose of this research study is to find out if the combination of acalabrutinib and high frequency low dose subcutaneous rituximab is safe and effective in patients who have previously untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

Related Conditions:
  • Chronic Lymphocytic Leukemia
  • Small Lymphocytic Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Acalabrutinib and High Frequency Low Dose Subcutaneous Rituximab in Patients With Previously Untreated Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma
  • Official Title: Phase II Study of Acalabrutinib and High Frequency Low Dose Subcutaneous Rituximab in Patients With Previously Untreated CLL/SLL

Clinical Trial IDs

  • ORG STUDY ID: ULYM18086
  • NCT ID: NCT03788291

Conditions

  • Chronic Lymphocytic Leukemia (CLL)
  • Small Lymphocytic Lymphoma (SLL)

Interventions

DrugSynonymsArms
AcalabrutinibAcalabrutinib and Rituximab treatment
RituximabAcalabrutinib and Rituximab treatment

Purpose

The main purpose of this research study is to find out if the combination of acalabrutinib and high frequency low dose subcutaneous rituximab is safe and effective in patients who have previously untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

Detailed Description

      Despite an array of available therapies, CLL remains an incurable disease. Furthermore, the
      presence of certain cytogenetic abnormalities and high-risk mutational features predicts for
      a reduced response to treatment, and as a result, a shorter period of progression-free
      survival. The development of a well-tolerated more effective, easily administered and limited
      duration therapy would be a major contribution to the management of CLL and other B cell
      malignancies.

      Acalabrutinib is an imidazopyrazine analogue and a potent inhibitor of BTK in vitro and in
      vivo. Acalabrutinib shows improved selectivity for BTK compared with ibrutinib. Functional
      inhibition of non-target cells (eg, T cells, NK cells, platelets) was not observed for
      acalabrutinib at clinically relevant concentrations. Rituximab is a chimeric monoclonal
      antibody targeting CD20 FDA approved for the treatment of CLL/SLL using intravenous or
      subcutaneous formulations.

      Antibody dependent cellular phagocytosis may be optimized using high frequency subcutaneous
      administration of anti-CD20 monoclonal antibodies. Unlike ibrutinib, acalabrutinib does not
      cause significant in vitro inhibition of rituximab induced antibody dependent cellular
      phagocytosis in vitro. The investigator thus proposes that acalabrutinib would be an ideal
      partner drug with high frequency low dose SQ rituximab in the treatment of CLL and that the
      combination will increase the efficacy of therapy for CLL patients by decreasing the time to
      achievement of complete response and allowing for shorter and less toxic therapy.
    

Trial Arms

NameTypeDescriptionInterventions
Acalabrutinib and Rituximab treatmentExperimentalRituximab: administered 2 times weekly for 6 cycles. Initial dose day 1: 50 mg IV, Then 50 mg SQ thereafter. Acalabrutinib: 100 mg po BID starting on day 8 of cycle 1. Patients who have attained a complete response who are also MRD negative at cycle 12 will undergo a BM biopsy to confirm CR and MRD negatively. If confirmed, the patient will stop therapy and be followed until disease progression. Patients not in a MRD negative CR, will continue acalabrutinib. Repeat response assessments (CTs, MRD testing in blood) will be performed at 24 cycles of therapy for those continuing on acalabrutinib. If both negative the patient will undergo a BM biopsy to confirm CR and MRD negativity. If confirmed, the patient will stop therapy and be followed until disease progression. In the absence of a CR or if MRD +, acalabrutinib may be continued until disease progression, unacceptable toxicity or physician/patient discretion.
  • Acalabrutinib
  • Rituximab

Eligibility Criteria

        Inclusion Criteria:

          1. Diagnosis of B-cell CLL or SLL, with diagnosis established according to IWCLL criteria
             and documented within medical records. Patients must not have received previous
             therapy for CLL/SLL

          2. CLL/SLL that warrants treatment consistent with accepted IWCLL criteria for initiation
             of therapy. Any one of the following conditions constitutes CLL/SLL that warrants
             treatment:

               1. Evidence of progressive marrow failure as manifested by the onset or worsening of
                  anemia and/or thrombocytopenia, or

               2. Massive (i.e., lower edge of spleen ≥6 cm below the left costal margin),
                  progressive, or symptomatic splenomegaly, or

               3. Massive (i.e., ≥10 cm in the longest diameter), progressive, or symptomatic
                  lymphadenopathy, or

               4. Progressive lymphocytosis in the absence of infection, with an increase in blood
                  absolute lymphocyte count (ALC) ≥50% over a 2-month period or lymphocyte doubling
                  time of <6 months (as long as initial ALC was ≥30,000/L), or

               5. Autoimmune anemia and/or thrombocytopenia that is poorly responsive to
                  corticosteroids or other standard therapy, or

               6. Constitutional symptoms, defined as any one or more of the following
                  disease-related symptoms or signs occurring in the absence of evidence of
                  infection:

             i. Unintentional weight loss of ≥10% within the previous 6 months, or

             ii. Significant fatigue (≥Grade 2), or

             iii. Fevers >100.5°F or 38.0°C for ≥2 weeks, or

             iv. Drenching night sweats for >1 month.

          3. Adequate organ system function, defined as follows:

               1. Absolute neutrophil count (ANC) ≥ 0.5x109/L and platelet count ≥ 30x109/L

               2. Total bilirubin ≤2.5 times the upper limit of normal (ULN) unless due to
                  Gilbert's disease

               3. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x ULN if
                  no liver involvement or ≤5 x the ULN if known liver involvement

               4. Calculated creatinine clearance >30 mL/min (as calculated by the Cockcroft-Gault
                  formula)

               5. Patients with PT/INR or aPTT ≤2xULN.

          4. ECOG performance status ≤ 2 unless related to CLL.

          5. Male or female ≥ 18 years of age.

          6. Ability to swallow and retain oral medication.

          7. Woman of childbearing potential (WOCBP) who are sexually active must use highly
             effective methods of contraception during treatment and for 2 days after the last dose
             of acalabrutinib and for 12 months following last dose of rituximab. (see Appendix 3
             for examples)

          8. Willingness and ability to comply with study and follow-up procedures, and give
             written informed consent.

        Exclusion Criteria:

          1. Patients receiving cancer therapy (i.e., chemotherapy, radiation therapy,
             immunotherapy, biologic therapy, hormonal therapy, surgery).

             a. Systemic corticosteroid therapy started prior to study entry is allowed as
             clinically warranted. Topical or inhaled corticosteroids are permitted.

          2. Serologic status reflecting active hepatitis B or C infection. Patients who are
             hepatitis B core antibody (anti-HBc) positive and who are surface antigen negative
             will need to have a negative polymerase chain reaction (PCR). Those who are hepatitis
             B surface antigen (HbsAg) positive or hepatitis B PCR positive will be excluded.
             Subjects who are hepatitis C antibody positive will need to have a negative PCR
             result. Those who are hepatitis C PCR positive will be excluded.

          3. Known history of HIV.

          4. Known histological transformation from CLL to an aggressive lymphoma.

          5. Evidence of ongoing systemic bacterial, fungal or viral infection, except localized
             fungal infections of skin or nails. NOTE: Patients may be receiving prophylactic
             antiviral or antibacterial therapies at investigator discretion.

          6. Live virus vaccines within 4 weeks prior to C1D1 or during rituximab therapy.

          7. History of anaphylaxis (excluding infusion related reactions) in association with
             previous anti-CD20 administration or acalabrutinib.

          8. Any severe and/or uncontrolled medical conditions or other conditions that could
             affect their participation in the study such as:

               1. Symptomatic, or history of documented congestive heart failure (NY Heart
                  Association functional classification III-IV)

               2. Uncontrolled cardiac arrhythmia (Patients with controlled atrial
                  fibrillation/flutter are eligible)

               3. Myocardial infarction within 3 months of enrollment

               4. Angina not well-controlled by medication

               5. Poorly controlled or clinically significant atherosclerotic vascular disease
                  including cerebrovascular accident (CVA), transient ischemic attack (TIA),
                  angioplasty, cardiac/vascular stenting within 3 months of enrollment.

               6. Active bleeding or history of bleeding diathesis (eg, hemophilia or von
                  Willebrand disease).

               7. Any history of intracranial bleed or stroke within 6 months of first dose of
                  study drug

               8. Patients with suspected or confirmed PML

               9. Patients with malabsorption syndrome or gastrointestinal disease that limits
                  absorption of oral medication

          9. Malignancy within 2 years of study enrollment except for adequately treated basal,
             squamous cell carcinoma or non-melanomatous skin cancer, carcinoma in situ of the
             cervix, superficial bladder cancer not treated with intravesical chemotherapy or BCG
             within 6 months, localized prostate cancer and PSA <1.0 mg/dL on 2 consecutive
             measurements at least 3 months apart with the most recent one being within 4 weeks of
             study entry.

         10. Patients with active uncontrolled autoimmune hemolytic anemia or ITP.

         11. Inability to discontinue use of strong CYP3A inhibitors. Patients taking moderate
             CYP3A inhibitors or strong CYP3A inducers are eligible.

         12. Requires or receiving anticoagulation with warfarin or equivalent vitamin K
             antagonists (eg, phenprocoumon) within 7 days of first dose of study drug.

         13. Requires treatment with proton pump inhibitors (eg, omeprazole, esomeprazole,
             lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole) at study entry. Subjects
             receiving proton pump inhibitors who switch to H2-receptor antagonists or antacids are
             eligible for enrollment to this study.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Proportion of subjects with a complete response rate (CR) at 1 year of therapy
Time Frame:1 year
Safety Issue:
Description:To satisfy criteria for a CR, all of the following criteria must be met: No evidence of new disease ALC in peripheral blood of <4 x 109/L Regression of all target nodal masses to normal size ≤1.5 cm in the LD Normal spleen and liver size Regression to normal of all nodal non-target disease and disappearance of all detectable non-nodal, non-target disease Morphologically negative bone marrow defined as <30% of nucleated cells being lymphoid cells and no lymphoid nodules in a bone marrow sample (the presence of benign reactive nodules is still compatible with a CR) Absence of constitutional symptoms Peripheral blood counts meeting all of the following criteria: ANC >1.5 x 109/L without need for exogenous growth factors (e.g., G-CSF) Platelet count ≥100 x 109/L without need for exogenous growth factors Hemoglobin ≥110 g/L (11.0 g/dL) without red blood cell transfusions or need for exogenous growth factors (e.g., erythropoietin)

Secondary Outcome Measures

Measure:Proportion of subjects with minimal residual disease in peripheral blood and bone
Time Frame:1 year
Safety Issue:
Description:6-color flow cytometry

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Rochester

Trial Keywords

  • Chronic Lymphocytic Leukemia (CLL)
  • Small Lymphocytic Lymphoma (SLL)
  • Phase II
  • Acalabrutinib
  • Rituximab

Last Updated

January 9, 2020