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

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

Study Description

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

Study Design

• 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

Arms and Interventions

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

Outcome Measures

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. ]

Eligibility Criteria

• 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

    • 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.

Contacts and Locations

Contacts

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

Locations

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

• Principal Investigator: Christopher MT Pleyer, M.D.; National Heart, Lung, and Blood Institute (NHLBI)

More Information

Additional Information:

NIH Clinical Center Detailed Web Page 

Publications:

Roberts AW, Davids MS, Pagel JM, Kahl BS, Puvvada SD, Gerecitano JF, Kipps TJ, Anderson MA, Brown JR, Gressick L, Wong S, Dunbar M, Zhu M, Desai MB, Cerri E, Heitner Enschede S, Humerickhouse RA, Wierda WG, Seymour JF. Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med. 2016 Jan 28;374(4):311-22. doi: 10.1056/NEJMoa1513257. Epub 2015 Dec 6.

Herling CD, Abedpour N, Weiss J, Schmitt A, Jachimowicz RD, Merkel O, Cartolano M, Oberbeck S, Mayer P, Berg V, Thomalla D, Kutsch N, Stiefelhagen M, Cramer P, Wendtner CM, Persigehl T, Saleh A, Altmüller J, Nürnberg P, Pallasch C, Achter V, Lang U, Eichhorst B, Castiglione R, Schäfer SC, Büttner R, Kreuzer KA, Reinhardt HC, Hallek M, Frenzel LP, Peifer M. Clonal dynamics towards the development of venetoclax resistance in chronic lymphocytic leukemia. Nat Commun. 2018 Feb 20;9(1):727. doi: 10.1038/s41467-018-03170-7.

• 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
• Last Update Posted: August 26, 2019
• Last Verified: August 20, 2019

• 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:

Venetoclax; 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; Antineoplastic Agents