Clinical Trials /

Venetoclax and Chemotherapy as Frontline Therapy in Older Patients and Patients With Relapsed/Refractory ALL

NCT03319901

Description:

This research study is studying a medication called Venetoclax and a chemotherapy regimen as a possible treatment for Acute Lymphoblastic Leukemia. The drugs involved in this study are: - Venetoclax - Standard Chemotherapy (which includes cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, 6-mercaptopurine, etoposide, and cytarabine

Related Conditions:
  • Acute Lymphoblastic Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Venetoclax and Chemotherapy In ALL
  • Official Title: A Phase Ib Study of the Combination of Venetoclax With Chemotherapy as Frontline Therapy in Older Patients With Acute Lymphoblastic Leukemia

Clinical Trial IDs

  • ORG STUDY ID: 16-648
  • NCT ID: NCT03319901

Conditions

  • Leukemia

Interventions

DrugSynonymsArms
VenetoclaxABT199Venetoclax + Chemotherapy
Standard ChemotherapyVenetoclax + Chemotherapy

Purpose

This research study is studying a medication called Venetoclax and a chemotherapy regimen as a possible treatment for Acute Lymphoblastic Leukemia. The drugs involved in this study are: - Venetoclax - Standard Chemotherapy (which includes cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, 6-mercaptopurine, etoposide, and cytarabine

Detailed Description

      This research study is a Phase I clinical trial, which tests the safety of an investigational
      drug and drug combination and also tries to define the appropriate dose of the
      investigational drug and drug combination to use for further studies. "Investigational" means
      that the drug and drug combination is being studied.

      The FDA (the U.S. Food and Drug Administration) has not approved Venetoclax for this specific
      disease, but it has been approved for other uses.

      Venetoclax is an inhibitor of Bcl-2. Bcl-2 is critical for keeping cancer cells alive.

      By inhibiting Bcl-2, venetoclax promotes cancer cell death. This drug is currently being used
      in other clinical trials for people with certain types of leukemia, lymphoma, and multiple
      myeloma. There is some evidence from those and other laboratory trials that venetoclax may
      kill cancer cells and cause tumors to shrink.

      In this research study, the investigators are investigating how safe the combination of
      Venetoclax and standard chemotherapy is and how it affects this disease.. The participant
      will be given Venetoclax alone first and the standard chemotherapies will be given in
      combination. This study aims to provide information to help determine the dose of Venetoclax
      , in combination with standard chemotherapy, affects this disease the best and which dose is
      the safest.
    

Trial Arms

NameTypeDescriptionInterventions
Venetoclax + ChemotherapyExperimentalVenetoclax is administered orally once daily for 21 days in each cycle Standard Chemotherapy will be administered every 28 days
  • Venetoclax
  • Standard Chemotherapy

Eligibility Criteria

        Inclusion Criteria:

          -  Patients with previously untreated acute lymphoblastic leukemia (B-cell or T-cell)

          -  Bone marrow involvement with ≥5% lymphoblasts

          -  Age ≥ 60 Years

          -  Eastern Cooperative Oncology Group (ECOG) performance status ≤2 (Refer to Appendix D)

          -  Adequate organ function

               -  Serum total bilirubin ≤1.5 x upper limit of normal (ULN) or ≤3 x ULN for patients
                  with Gilbert's disease

               -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3.0 x ULN,
                  unless clearly due to disease involvement

               -  Creatinine clearance >50 mL/min (calculated according to institutional standards
                  or using Cockcroft-Gault or Modification of Diet in Renal Disease (MDRD) formula)

          -  Women of childbearing potential must have a negative serum or urine beta human
             chorionic gonadotropin (β-hCG) pregnancy test result within 14 days prior to the first
             dose of study drugs and must agree to use an effective contraception method during the
             study and for 30 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 30 days following the last dose of study drug

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

        Exclusion Criteria:

          -  Ph-positive ALL, Burkitt's leukemia/lymphoma, or lymphoblastic lymphoma

          -  Patient is pregnant or breastfeeding

          -  Patients with uncontrolled infection

          -  Hepatitis B or C infection, or known seropositivity for human immunodeficiency virus
             (HIV)

          -  Major surgery or radiation therapy within 4 weeks prior to the first study dose

          -  Systemic chemotherapy/radiotherapy/investigational therapy within 14 days (with the
             exception of hydroxyurea and/or dexamethasone, or one dose of cytarabine) prior to
             starting therapy

          -  Symptomatic or untreated leptomeningeal disease or spinal cord compression

          -  Patients with active heart disease (New York Heart Association (NYHA) class 3-4 as
             assessed by history and physical examination, unstable angina/stroke/myocardial
             infarction within the last 6 months)

          -  Patients with a cardiac ejection fraction (as measured by either Multi Gated
             Acquisition (MUGA) or echocardiogram (EKG)) <40%

          -  History of another primary invasive malignancy that has not been definitively treated
             or in remission for at least 2 years. Patients with non-melanoma skin cancers or with
             carcinomas in situ are eligible regardless of the time from diagnosis (including
             concomitant diagnoses)

          -  Concurrent use of warfarin

          -  Received Cytochrome P450 3A (CYP3A) inhibitors (such as fluconazole, ketoconazole,
             voriconazole, and clarithromycin) within 3 days of starting venetoclax; received
             strong CYP3A inducers (such as rifampin, rifabutin, phenytoin, carbamazepine, and St.
             John's Wort) within 3 days of starting venetoclax

          -  Consumed grapefruit, grapefruit products, Seville oranges, or star fruit within 3 days
             prior to starting venetoclax

          -  Prior treatment with venetoclax

          -  Malabsorption syndrome or other conditions that preclude enteral route of
             administration

          -  Other severe acute or chronic medical or psychiatric condition or laboratory
             abnormality that in the opinion of the investigator may increase the risk associated
             with study participation or investigational product administration or may interfere
             with the interpretation of study results and/or would make the patient inappropriate
             for enrollment into this study
      
Maximum Eligible Age:N/A
Minimum Eligible Age:60 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose
Time Frame:2 years
Safety Issue:
Description:To determine the maximum tolerated dose (MTD) of venetoclax in combination with chemotherapy in patients with newly diagnosed Acute Lymphoblastic Leukemia (ALL)

Secondary Outcome Measures

Measure:To Evaluate The Safety of the Combination
Time Frame:2 years
Safety Issue:
Description:To evaluate the safety of this combination in a dose expansion cohort. The proportion of patients having a grade 3 or higher adverse event will be estimated with a 95% confidence interval in the expansion cohort.
Measure:Complete Response
Time Frame:2 years
Safety Issue:
Description:To determine the efficacy: complete response (CR) with incomplete marrow recovery (CRi) of venetoclax in combination with chemotherapy in patients with newly diagnosed ALL
Measure:Progression Free Survival
Time Frame:2 years
Safety Issue:
Description:To determine the duration of response: progressive-free survival (PFS) and overall survival (OS) of venetoclax in combination with chemotherapy in patients with newly diagnosed ALL
Measure:Overall Survival
Time Frame:2 years
Safety Issue:
Description:To determine the duration of response: progressive-free survival (PFS) and overall survival (OS) of venetoclax in combination with chemotherapy in patients with newly diagnosed ALL
Measure:Minimal Residual Disease
Time Frame:2 years
Safety Issue:
Description:To determine the rate of minimal residual disease (MRD) negativity in patients achieving CR/CRi and its correlation with disease-free survival (DFS) and OS
Measure:Disease Free Survival
Time Frame:2 years
Safety Issue:
Description:To determine the rate of minimal residual disease (MRD) negativity in patients achieving CR/CRi and its correlation with disease-free survival (DFS) and OS
Measure:Change in expression of BCL-2 family proteins: BCL-2
Time Frame:2 years
Safety Issue:
Description:To measure expression and function of Bcl-2 family proteins and its modulation by venetoclax in ALL blasts. The change in expression of BCL-2 family proteins from baseline to the time of each response assessment will be measured including BCL-2 and summary statistics including the median and interquartile range of the change will be reported for all patients in the expansion cohort and also summarized for those achieving a CR/CRi and those patients who do not achieve a CR/CRi. This is based on section 9.1: We plan to collect bone marrow and peripheral blood samples at baseline, at the time of clinical response assessment and at the time of progression for correlative studies. These will be done in the laboratory of Dr. Marina Konopleva at MDACC and Dr. Tony Letai at DFCI.
Measure:Change in expression of BCL-2 family proteins: BCL-XL
Time Frame:2 years
Safety Issue:
Description:To measure expression and function of Bcl-2 family proteins and its modulation by venetoclax in ALL blasts. The change in expression of BCL-2 family proteins from baseline to the time of each response assessment will be measured including BCL-XL and summary statistics including the median and interquartile range of the change will be reported for all patients in the expansion cohort and also summarized for those achieving a CR/CRi and those patients who do not achieve a CR/CRi. This is based on section 9.1: We plan to collect bone marrow and peripheral blood samples at baseline, at the time of clinical response assessment and at the time of progression for correlative studies. These will be done in the laboratory of Dr. Marina Konopleva at MDACC and Dr. Tony Letai at DFCI.
Measure:Change in expression of BCL-2 family proteins: MCL-1 (anti-apoptotic)
Time Frame:2 years
Safety Issue:
Description:To measure expression and function of Bcl-2 family proteins and its modulation by venetoclax in ALL blasts. The change in expression of BCL-2 family proteins from baseline to the time of each response assessment will be measured including MCL-1 (anti-apoptotic) and summary statistics including the median and interquartile range of the change will be reported for all patients in the expansion cohort and also summarized for those achieving a CR/CRi and those patients who do not achieve a CR/CRi. This is based on section 9.1: We plan to collect bone marrow and peripheral blood samples at baseline, at the time of clinical response assessment and at the time of progression for correlative studies. These will be done in the laboratory of Dr. Marina Konopleva at MDACC and Dr. Tony Letai at DFCI.
Measure:Change in expression of BCL-2 family proteins: BCL-2 homology 3 (BH3)
Time Frame:2 years
Safety Issue:
Description:To measure expression and function of Bcl-2 family proteins and its modulation by venetoclax in ALL blasts. The change in expression of BCL-2 family proteins from baseline to the time of each response assessment will be measured including BCL-2 homology 3 (BH3) and summary statistics including the median and interquartile range of the change will be reported for all patients in the expansion cohort and also summarized for those achieving a CR/CRi and those patients who do not achieve a CR/CRi. This is based on section 9.1: We plan to collect bone marrow and peripheral blood samples at baseline, at the time of clinical response assessment and at the time of progression for correlative studies. These will be done in the laboratory of Dr. Marina Konopleva at MDACC and Dr. Tony Letai at DFCI.
Measure:Change in expression of BCL-2 family proteins: BIM
Time Frame:2 years
Safety Issue:
Description:To measure expression and function of Bcl-2 family proteins and its modulation by venetoclax in ALL blasts. The change in expression of BCL-2 family proteins from baseline to the time of each response assessment will be measured including BIM and summary statistics including the median and interquartile range of the change will be reported for all patients in the expansion cohort and also summarized for those achieving a CR/CRi and those patients who do not achieve a CR/CRi. This is based on section 9.1: We plan to collect bone marrow and peripheral blood samples at baseline, at the time of clinical response assessment and at the time of progression for correlative studies. These will be done in the laboratory of Dr. Marina Konopleva at MDACC and Dr. Tony Letai at DFCI.
Measure:Change in expression of BCL-2 family proteins: BID
Time Frame:2 years
Safety Issue:
Description:To measure expression and function of Bcl-2 family proteins and its modulation by venetoclax in ALL blasts. The change in expression of BCL-2 family proteins from baseline to the time of each response assessment will be measured including BID and summary statistics including the median and interquartile range of the change will be reported for all patients in the expansion cohort and also summarized for those achieving a CR/CRi and those patients who do not achieve a CR/CRi. This is based on section 9.1: We plan to collect bone marrow and peripheral blood samples at baseline, at the time of clinical response assessment and at the time of progression for correlative studies. These will be done in the laboratory of Dr. Marina Konopleva at MDACC and Dr. Tony Letai at DFCI.
Measure:Change in expression of BCL-2 family proteins: BAD
Time Frame:2 years
Safety Issue:
Description:To measure expression and function of Bcl-2 family proteins and its modulation by venetoclax in ALL blasts. The change in expression of BCL-2 family proteins from baseline to the time of each response assessment will be measured including BAD and summary statistics including the median and interquartile range of the change will be reported for all patients in the expansion cohort and also summarized for those achieving a CR/CRi and those patients who do not achieve a CR/CRi. This is based on section 9.1: We plan to collect bone marrow and peripheral blood samples at baseline, at the time of clinical response assessment and at the time of progression for correlative studies. These will be done in the laboratory of Dr. Marina Konopleva at MDACC and Dr. Tony Letai at DFCI.
Measure:Change in expression of BCL-2 family proteins: NOXA
Time Frame:2 years
Safety Issue:
Description:To measure expression and function of Bcl-2 family proteins and its modulation by venetoclax in ALL blasts. The change in expression of BCL-2 family proteins from baseline to the time of each response assessment will be measured including NOXA and summary statistics including the median and interquartile range of the change will be reported for all patients in the expansion cohort and also summarized for those achieving a CR/CRi and those patients who do not achieve a CR/CRi. This is based on section 9.1: We plan to collect bone marrow and peripheral blood samples at baseline, at the time of clinical response assessment and at the time of progression for correlative studies. These will be done in the laboratory of Dr. Marina Konopleva at MDACC and Dr. Tony Letai at DFCI.
Measure:Change in expression of BCL-2 family proteins: PUMA
Time Frame:2 years
Safety Issue:
Description:To measure expression and function of Bcl-2 family proteins and its modulation by venetoclax in ALL blasts. The change in expression of BCL-2 family proteins from baseline to the time of each response assessment will be measured including PUMA and summary statistics including the median and interquartile range of the change will be reported for all patients in the expansion cohort and also summarized for those achieving a CR/CRi and those patients who do not achieve a CR/CRi. This is based on section 9.1: We plan to collect bone marrow and peripheral blood samples at baseline, at the time of clinical response assessment and at the time of progression for correlative studies. These will be done in the laboratory of Dr. Marina Konopleva at MDACC and Dr. Tony Letai at DFCI.
Measure:Change in expression of BCL-2 family proteins: HRK (pro-apoptotic)
Time Frame:2 years
Safety Issue:
Description:To measure expression and function of Bcl-2 family proteins and its modulation by venetoclax in ALL blasts. The change in expression of BCL-2 family proteins from baseline to the time of each response assessment will be measured including HRK (pro-apoptotic) and summary statistics including the median and interquartile range of the change will be reported for all patients in the expansion cohort and also summarized for those achieving a CR/CRi and those patients who do not achieve a CR/CRi. This is based on section 9.1: We plan to collect bone marrow and peripheral blood samples at baseline, at the time of clinical response assessment and at the time of progression for correlative studies. These will be done in the laboratory of Dr. Marina Konopleva at MDACC and Dr. Tony Letai at DFCI.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Dana-Farber Cancer Institute

Trial Keywords

  • Leukemia

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