ClinTrial Refer

Trial Acronym
M14-728

Registration Number
NCT02966756

Scientific Title
A Phase 2 Open-Label Study of the Efficacy of Venetoclax in Subjects with Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

This is a Phase 2, open-label, single-arm, multicenter study, evaluating the efficacy of venetoclax in participants with relapsed or refractory Chronic Lymphocytic Leukemia (CLL) in the presence of 17p deletion.

A subject will be eligible for participation in the study if she or he meets the following criteria:

1. Subject must voluntarily sign and date an informed consent, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study specific procedures.

2. Subject must be ≥ 18 years of age.

3. Subject must have a diagnosis of relapsed or refractory CLL/SLL that meets 2008 Modified iwCLL NCI-WG Guidelines and the following:

- Subject must have an indication for treatment according to the 2008 Modified iwCLL NCI-WG Guidelines;

- CLL subject must have measurable disease (B-lymphocytosis > 5 × 109/L or an enlarged lymph node(s) (LDi > 1.5 cm at baseline) or hepatomegaly or splenomegaly due to CLL

- SLL subject must have presence of lymphadenopathy and the absence of cytopenias caused by a clonal marrow infiltrate; B-lymphocyte count should be < 5 × 109/L. Diagnosis should be confirmed by histopathological evaluation of a lymph node biopsy or biopsy from other tissues. Note: some subjects may present with enlarged lymph nodes that are not suspicious for solid tumors and with peripherical blood B lymphocytes < 5 × 109/L that carry a typical CLL immunophenotype; in these cases a tissue or lymph biopsy can be omitted.

·         Subject must have relapsed or refractory CLL/SLL after receiving at least one prior line of therapy; as defined by the 2018 revision to the 2008 iwCLL NCI-WG criteria

o   Relapsed – evidence of disease progression in a patient who has previously achieved the criteria for CR or PR, for ≥ 6 months;

o   Refractory disease – a patient who has a treatment failure (stable disease, non-response, progressive disease, or death from any cause) or disease progression within 6 months from the last dose of antileukemic therapy.

4. Subject (in Cohort 1) must have 17p deletion, assessed by a central laboratory (in peripheral blood)

5. Subject (in Cohort 2) must meet both of the following:

- relapsed/refractory disease to BCRI treatment;

- and either of the following: (a) relapsed/refractory disease to CIT, or (b) ineligible to receive CIT, defined as having 17p deletion, or Cumulative Illness Rating Scale (CIRS) >6 or calculated creatinine clearance <70 mL/min.

6. Subject must have an Eastern Cooperative Oncology Group (ECOG) performance score of ≤ 2.

7. Subject must have adequate bone marrow function at Screening as follows:

·         Absolute Neutrophil Count (ANC) ≥ 1000/μL, or

o   for subjects with an ANC < 1000/μL at Screening and bone marrow heavily infiltrated with underlying disease, growth factor support may be administered after Screening and prior to the first dose of venetoclax to achieve the ANC eligibility criteria (≥ 1000/μL);

·         Platelets ≥ 30,000/mm3

o   without transfusion support within 14 days of Screening,

o   without evidence of mucosal bleeding,

o   without history of bleeding episode within 3 months of Screening,

o   without a history of a bleeding disorder.

·         Hemoglobin ≥ 8.0 g/dL.

8. Subject must have adequate coagulation, hepatic, and renal function, per laboratory reference range at Screening as follows:

·         Activated partial thromboplastin time (aPTT) and prothrombin time (PT) must not exceed 1.5 × the upper limit of normal (ULN);

·         Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) must be ≤ 3.0 × ULN; bilirubin ≤ 1.5 × ULN. Subjects with documented Gilbert's Syndrome may have a bilirubin > 1.5 × ULN, per correspondence between the investigator and the AbbVie medical monitor;

·         Calculated creatinine clearance > 50 mL/min

9. If female, subject must be either postmenopausal defined as:

·         Age > 55 years with no menses for 12 or more months without an alternative medical cause.

·         Age ≤ 55 years with no menses for 12 or more months without an alternative medical cause AND an FSH level > 40 IU/L.

OR

·         Permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy orhysterectomy)

OR

·         Women of Childbearing Potential (WOCBP) practicing at least one protocol specified method of birth control, starting at Study Day 1 through at least 30 days after the last dose of study drug.

10. Females of childbearing potential must have a negative serum pregnancy test at the Screening Visit, and a negative urine pregnancy test at baseline prior to the first dose of study drug.

Females of non-childbearing potential (either postmenopausal or permanently surgically sterile as defined above) at Screening do not require pregnancy testing.

11. Male subjects must agree to refrain from sperm donation from initial venetoclax administration until 30 days after the last dose of venetoclax.

12. No known active SARS-CoV-2 infection. If a subject has signs/symptoms suggestive of SARS-CoV-2 infection, they should undergo molecular (e.g., PCR) testing to rule out SARS-CoV-2 infection. In addition, if based on internal site's assessment tool the site considers the subject currently at risk for developing SARS-CoV-2 infection, then the subject should either be tested or advised to come back for study screening after 14 days.

A subject will not be eligible for participation in the study if she or he meets any of the following criteria:

1. Subject has undergone an allogeneic stem cell transplant.

2. Subject has developed Richter's transformation confirmed by biopsy.

·         Subjects with clinically suspected Richter's transformation (due to any of the following, rapid enlargement of lymph nodes, B symptoms, increased LDH, hypercalcemia, extranodal involvement such as in the CNS, skin, testes, etc.) are required to undergo a PET-CT scan. Subjects who have an abnormal SUV (SUVmax > 7) must have an excisional biopsy, or a core biopsy if excisional biopsy is not feasible. Subjects who have biopsy confirmed RT are not eligible for this study. Subjects who have an abnormal SUV who cannot undergo biopsy are not eligible for this study.

3. Subject has prolymphocytic leukemia.

4. Subject has active and uncontrolled autoimmune cytopenias (for 2 weeks prior to Screening), including autoimmune hemolytic anemia (AIHA) and idiopathic thrombocytopenic purpura (ITP).

5. Subject has previously received venetoclax.

6. Subject is known to be positive for HIV (due to potential drug-drug interactions between anti-retroviral medications and venetoclax, as well as anticipated venetoclax mechanism-based lymphopenia that may potentially increase the risk of opportunistic infections).

7. Subject has received the following within 30 days prior to the first dose of venetoclax:

·         A biologic agent (i.e., monoclonal antibodies) for anti-neoplastic intent.

8. Subject has received any of the following within 14 days or 5 half-lives (whichever is shorter) prior to the first dose of venetoclax, or has not recovered to less than Common Terminology Criteria for Adverse Events (CTCAE) grade 2 clinically significant adverse effect(s)/toxicity(s) of the previous therapy:

·         Any anti-cancer therapy including chemotherapy, immunotherapy, radiotherapy or targeted small molecule agents

·         Investigational therapy, including targeted small molecule agents.

9. Subject has received the following within 7 days prior to the first dose of venetoclax:

·         Steroid therapy for anti-neoplastic intent;

·         Strong and moderate CYP3A inhibitors;

·         Strong and moderate CYP3A inducers.

10. Subject has consumed the following within 3 days prior to the first dose of venetoclax.

·         Grapefruit or grapefruit products;

·         Seville oranges (including marmalade containing Seville oranges);

·         Starfruit.

11. Subject has known allergy to both xanthine oxidase inhibitors and rasburicase.

12. Subject has a cardiovascular disability status of New York Heart Association Class ≥ 2. Class 2 is defined as cardiac disease in which subjects are comfortable at rest but ordinary physical activity, results in fatigue, palpitations, dyspnea or angina pain.

13. Subject exhibits evidence of other clinically significant uncontrolled condition(s)

including, but not limited to:

·         Uncontrolled and/or active systemic infection (viral, bacterial, or fungal);

·         Febrile neutropenia;

·         Hepatitis B surface antigen (HBsAg) – positive test;

·         Hepatitis B virus DNA > lower limit of quantitation;

·         Chronic hepatitis C requiring treatment.

14. Subject has a significant history of cardiovascular, endocrine, hepatic, immunologic, metabolic, neurologic, psychiatric, pulmonary, or renal disease that in the opinion of the investigator would adversely affect her or his participating in this study. For subjects who have required an intervention for any of the above diseases within the past 6 months, correspondence between the investigator and the AbbVie medical monitor must occur as part of the screening review process.

15. A female subject is pregnant or breastfeeding or is considering becoming pregnant during the study or for approximately 30 days after the last dose of venetoclax.

16. Male subject who is considering fathering a child or donating sperm during the study or for approximately 30 days after the last dose of venetoclax.

17. Subject has a history of active malignancies other than CLL within the past 2 years prior to study entry, with the exception of:

·         Adequately treated in situ carcinoma of the cervix uteri;

·         Adequately treated basal cell carcinoma or localized squamous cell carcinoma of the skin;

·         Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent.

18. Subject has malabsorption syndrome or other condition that precludes enteral route of administration.

Trial Location Name

Address

Status

Christchurch Hospital (Haematology)

2 Riccarton Ave, Christchurch Central, Christchurch 8011, New Zealand

Closed

Primary Contact : Haematology trials coordinator, HaemClinTrials@cdhb.health.nz , 03 364 0386

Concord Repatriation General Hospital (Haematology)

Hospital Rd, Concord NSW 2139, Australia

Recruiting

Primary Contact : Jennifer Harman, SLHD-ConcordHaematologyClinicalResearch@health.nsw.gov.au , 02 9767 6348

St George Hospital (Haematology)

Gray St, Kogarah NSW 2217, Australia

Recruiting

Primary Contact : Lorraine King, SESLHD-STGHaematologyClinicalTrials@health.nsw.gov.au , 02 9113 2977

AbbVie

Website URL

Link Name

Link URL

Clinicaltrials.gov

https://clinicaltrials.gov/ct2/show/NCT02966756

ANZCTR

http://www.anzctr.org.au/TrialSearch.aspx?searchTxt=NCT02966756

Secondary IDs
2017-002413-54M14-728

Study Type
Interventional

Intervention Code
Treatment - Drugs

Phase
Phase 2

Minimum Age
18

Maximum Age
100

Date Registered
02/08/2019

Date Closed
N/A

Status
Closed

Enrolment Type
By Specialist and/or Surgeon Referral

Mutation Status and Biomarker
N/A

Is it a Cohort Trial?
Yes

Is this a Tele-Trial?
No

Can healthy volunteer participate?
No

Cohort Details

Cohort Name

Description

Status

Cohort 1

Cohort 1 = the presence of 17p deletion

Closed

Cohort 2

Cohort 2 = those who have failed a B-Cell Receptor Signaling Pathway Inhibitor (BCRI) therapy and who have also failed, were intolerant to, or were unable to receive chemoimmunotherapy (CIT) irrespective of 17p status

Open

Discipline

Health Condition

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