Clinical Trials /

Trabectedin and Venetoclax in Treating Patients With Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma Resistant or Intolerant to a BTK Inhibitor

NCT03884972

Description:

This phase I/Ib trial studies the best dose and side effects of trabectedin and venetoclax in treating patients with chronic lymphocytic leukemia or small lymphocytic lymphoma that is resistant or intolerant to a BTK inhibitor. Drugs used in chemotherapy, such as trabectedin and venetoclax, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

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

Withdrawn

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Trabectedin and Venetoclax in Treating Patients With Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma Resistant or Intolerant to a BTK Inhibitor
  • Official Title: A Phase I/Ib Pilot Study of Combined Trabectedin and Venetoclax in Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Resistant or Intolerant to a BTK Inhibitor

Clinical Trial IDs

  • ORG STUDY ID: 2018-0302
  • SECONDARY ID: NCI-2019-01555
  • SECONDARY ID: 2018-0302
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03884972

Conditions

  • Refractory Chronic Lymphocytic Leukemia
  • Refractory Small Lymphocytic Lymphoma

Interventions

DrugSynonymsArms
TrabectedinEcteinascidin, ecteinascidin 743, ET-743, YondelisCohort I (BTK-refractory)
VenetoclaxABT-0199, ABT-199, ABT199, GDC-0199, RG7601, VenclextaCohort I (BTK-refractory)

Purpose

This phase I/Ib trial studies the best dose and side effects of trabectedin and venetoclax in treating patients with chronic lymphocytic leukemia or small lymphocytic lymphoma that is resistant or intolerant to a BTK inhibitor. Drugs used in chemotherapy, such as trabectedin and venetoclax, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To evaluate safety and tolerability, and to determine dose and schedule of trabectedin in
      combination with venetoclax in patients with chronic lymphocytic leukemia (CLL)/small
      lymphocytic lymphoma (SLL) resistant or intolerant to a BTK inhibitor.

      SECONDARY OBJECTIVES:

      I. To determine the best response achieved by patients treated with combined trabectedin and
      venetoclax.

      II. To determine the progression-free (PFS) and overall survival (OS) of patients treated
      with combined trabectedin and venetoclax.

      III. To investigate the effects of trabectedin on CLL cells and on the components of the CLL
      microenvironment.

      IV. To investigate associations between baseline characteristics (including fluorescence in
      situ hybridization [FISH] status, IGHV mutation status and mutations responsible for
      resistance to BTK inhibitors) and response to the combination of trabectedin and venetoclax.

      OUTLINE: This is a dose-escalation study. Patients are assigned to 1 of 2 cohorts.

      COHORT I (BTK-REFRACTORY): Patients receive venetoclax orally (PO) once daily (QD) beginning
      on day 1 for 5 weeks (cycle 1). Beginning in cycle 2, patients receive venetoclax PO QD and
      trabectedin intravenously (IV) over 3 hours on day 1. Cycles 2+ repeat every 3 weeks in the
      absence of disease progression or unacceptable toxicity.

      COHORT II (BTK-INTOLERANT): Patients receive trabectedin IV over 3 hours on day 1 of a 3-week
      cycle (cycle 1), then receive venetoclax PO QD beginning on day 1 of a 5-week cycle (cycle
      2). Beginning in cycle 3, patients receive trabectedin IV over 3 hours on day 1 and
      venetoclax PO QD every 3 weeks in the absence of disease progression or unacceptable
      toxicity.

      After completion of study treatment, patients are followed up every 6 months.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort I (BTK-refractory)ExperimentalPatients receive venetoclax PO QD beginning on day 1 for 5 weeks (cycle 1). Beginning in cycle 2, patients receive venetoclax PO QD and trabectedin IV over 3 hours on day 1. Cycles 2+ repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.
  • Trabectedin
  • Venetoclax
Cohort II (BTK-intolerant)ExperimentalPatients receive trabectedin IV over 3 hours on day 1 of a 3-week cycle (cycle 1), then receive venetoclax PO QD beginning on day 1 of a 5-week cycle (cycle 2). Beginning in cycle 3, patients receive trabectedin IV over 3 hours on day 1 and venetoclax PO QD every 3 weeks in the absence of disease progression or unacceptable toxicity.
  • Trabectedin
  • Venetoclax

Eligibility Criteria

        Inclusion Criteria:

          -  Patients with a diagnosis of CLL/SLL who are progressing (based on 2018 International
             Workshop on Chronic Lymphocytic Leukemia [iwCLL] criteria) on or intolerant to a BTK
             inhibitor (BTK-inhibitor-intolerant is defined as unable to maintain on a stable and
             continuous dose of at least ibrutinib 140 mg/day [or acalabrutinib 100 mg/day] for at
             least 2 weeks due to recurrent treatment-related grade 2 or higher non-hematologic
             toxicity by Common Terminology Criteria for Adverse Events [CTCAE] grading)

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2

          -  Total bilirubin =< 1.0 x upper limit of normal (ULN) or =< 3 x ULN for patients with
             Gilbert's disease

          -  Creatinine clearance > 50 mL/min (calculated according to institutional standards or
             using Cockcroft-Gault formula)

          -  Alanine aminotransferase (ALT), aspartate aminotransferase (AST) =< 2.5 x ULN

          -  Alkaline phosphatase (ALP) =< 2.5 x ULN

          -  Platelet (PLT) count >= 50,000/l, with no platelet transfusion in 2 weeks prior to
             registration, unless cytopenia is due to bone marrow involvement with CLL, in which
             case PLT count > 30,000/l, with no PLT transfusion in 2 weeks prior to registration

          -  Absolute neutrophil count (ANC) >= 1000/l, unless cytopenia is due to bone marrow
             involvement with CLL, in which case ANC > 500/l

          -  Creatine phosphokinase (CPK) < 2.5 x ULN

          -  Left ventricular ejection fraction (LVEF) assessed by multi-gated acquisition scan
             (MUGA) or echocardiogram within limits of normal range

          -  Women of childbearing potential must agree to use an effective contraception method
             during the study and for 60 days following the last dose of study drug. Women of non-
             childbearing potential are those who are postmenopausal greater than 1 year or who
             have had a bilateral tubal ligation or hysterectomy. Men who have partners of
             childbearing potential must agree to use an effective contraceptive method during the
             study and for 60 days following the last dose of study drug

          -  Free of prior malignancies for 2 years with exception of patients diagnosed with basal
             cell or squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix or
             breast, who are eligible even if they are currently treated or have been treated
             and/or diagnosed in the past 2 years prior to study enrollment. If patients have
             another malignancy that was treated within the last 2 years, such patients may be
             enrolled, if the likelihood of requiring systemic therapy for this other malignancy
             within 2 years is less than 20%

          -  Patients or their legally authorized representative must provide written informed
             consent

        Exclusion Criteria:

          -  Radiotherapy or chemotherapy within 2 weeks prior to the first dose of the study
             drugs. Given the quick progression associated with resistance to BTK inhibitors, no
             limits will be placed to the use of BTK inhibitors for enrollment or initiation of
             treatment on this trial

          -  Uncontrolled active systemic infection (viral, bacterial, and fungal)

          -  Active, uncontrolled autoimmune phenomenon (autoimmune hemolytic anemia or immune
             thrombocytopenia) requiring steroid therapy with > 20 mg daily of prednisone or
             equivalent

          -  Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias,
             congestive heart failure, or myocardial infarction within 2 months of screening, or
             any class 3 or 4 cardiac disease as defined by the New York Heart Association
             Functional Classification

          -  Patient is pregnant or breast-feeding

          -  Venetoclax-refractory CLL or prior treatment with trabectedin

          -  Malabsorption syndrome or other condition that precludes oral/enteral route of
             administration

          -  Patients who received the following within 7 days prior to first dose of venetoclax:
             moderate and strong CYP3A inhibitors and inducers, P-glycoprotein inhibitors, or
             narrow therapeutic index P-glycoprotein substrates AND patients who received the
             following within 3 days prior to first dose of venetoclax: grapefruit or grapefruit
             products, Seville oranges and star fruit
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose and schedule of trabectedin in combination with venetoclax
Time Frame:Up to 6 months post-treatment
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Best response
Time Frame:Up to 6 months post-treatment
Safety Issue:
Description:Will be assessed using the 2018 International Workshop on Chronic Lymphocytic Leukemia response criteria. Minimal residual disease will be evaluated by 4-color flow cytometry.
Measure:Progression free survival
Time Frame:From treatment initiation to disease progression or death, assessed up to 6 months post-treatment
Safety Issue:
Description:
Measure:Overall survival
Time Frame:From treatment initiation to death due to any cause, assessed up to 6 months post-treatment
Safety Issue:
Description:
Measure:Frequency of myeloid cells and of other immune cells
Time Frame:Baseline up to 6 months post-treatment
Safety Issue:
Description:Will be analyzed in the peripheral blood and bone marrow (if available).

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated

June 20, 2019