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Early Clonal Dynamics During Venetoclax Treatment for Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)

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ClinicalTrials.gov Identifier: NCT03986034
Recruitment Status : Recruiting
First Posted : June 14, 2019
Last Update Posted : August 26, 2019
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )

Tracking Information
First Submitted Date  ICMJE June 13, 2019
First Posted Date  ICMJE June 14, 2019
Last Update Posted Date August 26, 2019
Actual Study Start Date  ICMJE June 6, 2019
Estimated Primary Completion Date January 15, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 13, 2019)
Determine the rate of clonal shift during the ramp-up phase of venetoclax [ Time Frame: 5 weeks ]
The planned analyses will include descriptive statistics on the proportions of clonal shift probability during the venetoclax ramp-up phase. The clonal shift probabilities will be estimated using the sample proportions and their inferences including confidence intervals and hypotheses testing will be evaluated
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03986034 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 13, 2019)
Determine response kinetics of venetoclax therapy in the peripheral blood, lymph nodes and bone marrow [ Time Frame: 5 weeks (Primary Endpoint). F/u every 6 months thereafter until disease progression. ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Early Clonal Dynamics During Venetoclax Treatment for Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)
Official Title  ICMJE Early Clonal Dynamics During Venetoclax Treatment for Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)
Brief Summary

Background:

The drug venetoclax treats chronic lymphocytic leukemia (CLL). Researchers want to find better treatments for CLL. To do that, they need to learn how the drug affects CLL cancer cells and the immune system.

Objective:

To learn about genetic changes that happen during treatment of CLL with venetoclax.

Eligibility:

Adults ages 18 and older with relapsed or refractory CLL after at least 1 prior therapy

Design:

Participants will be screened under a separate protocol.

In Phase 1, participants will get venetoclax free of charge through the NIH. Venetoclax is started at a low dose. The dose will be increased every week until participants reach their maximum tolerable dose. This usually take about 5 weeks. Participants will visit the NIH at least once per week. Visits will be about 4 hours. They may have to stay in the hospital to be observed.

In Phase 2, participants will continue to get the drug through their local cancer doctor and their health insurance. Patients will also visit the NIH every 6 months, or if their disease progresses.

At the NIH participants will have regular health assessments. These will include physical exams and a review of the medicines they are taking. They will talk about how they are feeling.

The study included the following tests:

Blood draws

CT scans: Participants will lie in a machine that takes pictures of the body (maximum 3 per year)

Bone marrow biopsies: A small amount of marrow will be taken out of the participant s hip bone with a needle.

Optional lymph node biopsies: A small piece of the participant s tissue will be taken out with a needle.

The study will last at least 2 years.

Detailed Description

This study aims to study the clonal dynamics and kinetics of response during the ramp-up phase of venetoclax in relapsed or refractory chronic lymphocytic leukemia (CLL).

Key Eligibility Criteria:

  1. Diagnosis of relapsed or refractory CLL after at least one prior therapy
  2. Must have designated hematologist/oncologist who has agreed to assume care and continue venetoclax after the ramp-up phase is complete
  3. Age greater than or equal to 18 years
  4. ECOG 0-2

Design:

Patients with relapsed or refractory CLL will enroll on the study. Subjects will be treated at the NIH Clinical Center for the duration of the ramp-up phase of venetoclax. After the ramp-up phase is complete, subjects will be transitioned to the care of their local hematologist/oncologist and receive venetoclax monotherapy or in combination with other agent(s) at the discretion of the treating oncologist. Subjects will have the option to follow-up at the NIH every 6 months (from initiation of venetoclax) and at (suspected) progression.

Study Objectives:

Primary Objective:

-Determine the proportion of subjects with clonal shift during the ramp-up phase of venetoclax

Secondary Objective:

-Determine response kinetics of venetoclax therapy in the peripheral blood, lymph nodes and bone marrow

Exploratory Objectives:

  • Assess relationship between clonal shifts and minimal residual disease (MRD) status, progression free survival (PFS) and overall survival (OS)
  • Assess immunologic changes in the peripheral blood and bone marrow during venetoclax treatment
  • Assess circulating-tumor DNA in response to treatment during venetoclax treatment
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Condition  ICMJE Chronic Lymphocytic Leukemia
Intervention  ICMJE Drug: Venetoclax
Patients with relapsed or refractory CLL who have progressed after at least one prior line of treatment will enroll on the study. Subjects will be treated for the duration of the ramp- up phase of venetoclax at the NIH Clinical Center and receive primary response assessment after reaching the maximum dose of venetoclax. After the ramp-up phase is complete, patients will continue to follow- up at the NIH every 6 months, however subjects' medical care will be transitioned to their local hematologist /oncologist
Study Arms  ICMJE Experimental: Relapsed/Refractory CLL pts
Ages 18 and older
Intervention: Drug: Venetoclax
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 13, 2019)
55
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 31, 2020
Estimated Primary Completion Date January 15, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

-INCLUSION CRITERIA:

  1. Diagnosis of relapsed/refractory CLL which is made according to the updated criteria of the NCI Working Group15, after treatment with at least one prior line of therapy
  2. Active disease as defined by at least one of the following (iwCLL consensus criteria):

    • Weight loss greater than or equal to 10% within the previous 6 months
    • Extreme fatigue
    • Fevers of greater than 100.5o F for greater than or equal to 2 weeks without evidence of infection
    • Night sweats for more than one month without evidence of infection
    • Evidence of progressive marrow failure as manifested by the development of, or worsening of

      • Anemia and/or thrombocytopenia
      • Massive or progressive splenomegaly
      • Massive nodes or clusters or progressive lymphadenopathy
      • Progressive lymphocytosis with an increase of >50% over a 2-month period, or an anticipated doubling time of less than 6 months
  3. Must have designated hematologist/oncologist will assume care and provide venetoclax after the ramp-up phase is complete
  4. Must have G6PD testing performed to determine whether rasburicase can be given
  5. Must have HLA-testing performed to determine whether allopurinol hypersensitivity exists
  6. Age greater than or equal to 18 years
  7. ECOG 0-2
  8. Agreement to use acceptable methods of contraception for the duration of venetoclax treatment if sexually active and able to bear or beget children
  9. Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty
  10. Able to comprehend the investigational nature of the protocol and provide informed consent

EXCLUSION CRITERIA:

  1. Female patients who are currently pregnant or nursing
  2. Any uncontrolled active systemic infection
  3. Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator s opinion, could compromise the subject s safety or put the study outcomes at undue risk
  4. Known additional malignancy that is progressing or requires active treatment.

    --Note: Exceptions include basal cell carcinoma of skin, squamous cell carcinoma of skin, and in situ cervical cancer that has undergone potentially curative therapy. Further exceptions include other cancers from which the subject has been diseasefree for > 2 years, cancers which will not limit survival to < 2 years or cancers in remission receiving endocrine therapy.

  5. Richter s Transformation
  6. Any prior therapy with BCL-2 inhibitors
  7. Concomitant use of strong CYP3A4 inhibitors
  8. Disease significantly affecting gastrointestinal function or absorption
  9. Active autoimmune hemolytic anemia or thrombocytopenia requiring steroid therapy
  10. Concomitant immunotherapy, chemotherapy, radiotherapy or corticosteroids
  11. Absolute neutrophil count (ANC) <1000/microL, platelets (Plt) <30,000/ microL
  12. Serum bilirubin >3 times upper limit of normal (ULN)
  13. Severe psychiatric illness/social situations or cognitive impairment that would limit the patient s ability to tolerate and/or comply with study requirements

    • If the PI assesses the decreased ANC and/or Plt to be related to CLL involvement, patients may still be enrolled in the study, as cytopenias as expected to improve with treatment of CLL. Patients may receive supportive measures (e.g. transfusions, IVIG, growth factor support, etc.) to avoid severe cytopenias prior to and during therapy with venetoclax.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 90 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Pia Nierman, R.N. (301) 827-1094 pia.nierman@nih.gov
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03986034
Other Study ID Numbers  ICMJE 190111
19-H-0111
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )
Study Sponsor  ICMJE National Heart, Lung, and Blood Institute (NHLBI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Christopher MT Pleyer, M.D. National Heart, Lung, and Blood Institute (NHLBI)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date August 20, 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP