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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 : July 10, 2019
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )

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.


Condition or disease Intervention/treatment Phase
Chronic Lymphocytic Leukemia Drug: Venetoclax Phase 2

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 55 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Early Clonal Dynamics During Venetoclax Treatment for Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)
Actual Study Start Date : June 6, 2019
Estimated Primary Completion Date : January 15, 2020
Estimated Study Completion Date : December 31, 2020


Arm Intervention/treatment
Experimental: Relapsed/Refractory CLL pts
Ages 18 and older
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




Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. 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. ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 90 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

-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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03986034


Contacts
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Contact: Pia Nierman, R.N. (301) 827-1094 pia.nierman@nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)    800-411-1222 ext TTY8664111010    prpl@cc.nih.gov   
Sponsors and Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
Investigators
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Principal Investigator: Christopher MT Pleyer, M.D. National Heart, Lung, and Blood Institute (NHLBI)

Additional Information:
Publications:
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Responsible Party: National Heart, Lung, and Blood Institute (NHLBI)
ClinicalTrials.gov Identifier: NCT03986034     History of Changes
Other Study ID Numbers: 190111
19-H-0111
First Posted: June 14, 2019    Key Record Dates
Last Update Posted: July 10, 2019
Last Verified: June 21, 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) ):
ramp up
Rituximab
Tumor
Treatment
Cancer

Additional relevant MeSH terms:
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Leukemia
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Venetoclax
Antineoplastic Agents