Main info

Identificatie:

HOVON 182 CLL

Sponsor:

HOVON

Working group party:

CLL

Stadium:

2de lijn

Echelon:

Level D

Active sites:

0

(of 1)

40 sites are pending

Title:

Prospective randomized phase 3 study of treatment with rituximab (6 cycles) in combination with 6 or 26 cycles of venetoclax in patients with relapsed or refractory chronic lymphocytic leukemia

Timeline

Details

Phase:

Prospective randomized Phase III study

Monitoring Type:

HOVON Monitoring Visit

Objectives:

Primary study objective

• To compare progression free survival (PFS) from the time of randomization between continuation of treatment with venetoclax for 20 cycles (Arm A) versus discontinuation of treatment (Arm B), in patients treated with 6 cycles Ven-R.

Secondary study objectives

• To evaluate overall response rate (ORR).
• To evaluate overall survival (OS).
• To evaluate event free survival (EFS).
• To evaluate time to next treatment (TTNT).
• To evaluate overall response rate to next line treatment (ORR2).
• To evaluate second progression free survival after next line treatment (PFS2).
• To evaluate depth and kinetics of response by measuring minimal residual disease (MRD).
• To compare safety and tolerability between continuation of treatment with venetoclax for 20 cycles (arm A) versus discontinuation of treatment (arm B), in patients treated with 6 cycles Ven-R.
• To evaluate quality of life (QoL).
• To calculate the budget impact of cessation of venetoclax after 6 months versus continuation until 24 months.

Exploratory objectives

• To evaluate the dynamics of MRD at different time points and their association with outcome.
• To evaluate the impact on immunological function.
• To evaluate the correlation between outcomes (e.g. MRD and PFS) and baseline molecular factors.

Eligibility

Inclusion Criteria:

• Documented relapsed or refractory CLL or SLL following at least one systemic 1st-line treatment.
• Requiring treatment according to IWCLL 2018 criteria.
• Age at least 18 years.
• WHO performance status 0-3; stage 3 only if attributable to CLL/SLL.
• Adequate BM function defined as:
  • Hemoglobin (Hb) > 5.0 mmol/l, unless low Hb is directly attributable to CLL/SLL infiltration of the BM;
  • Absolute neutrophil count (ANC) > 0.75 x 109/L (1,000/μL), unless low ANC is directly attributable to CLL/SLL infiltration of the BM;
  • Platelet count > 30 x 109/L (30,000/μL), unless low platelets is directly attributable to CLL/SLL infiltration in the BM.
• Estimated Glomerular Filtration Rate (eGFR) (MDRD) or estimated creatinine clearance (CrCl) ≥ 30ml/min (Cockcroft-Gault)
• Adequate liver function as indicated:
  • serum aspartate transaminase (ASAT) and alanine transaminase (ALAT) ≤ 3.0 x

upper limit of normal (ULN);

• bilirubin ≤ 1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or controlled autoimmune hemolytic anemia).
• Negative serological testing for hepatitis B virus (Hepatitis B surface antigen (HBsAg) negative and hepatitis B core antibody (anti-HBc) negative) and hepatitis C virus (hepatitis C antibody). Patients who are positive for anti-HBc, HBsAg, or hepatitis C antibody must have a negative PCR result before enrollment. Those who are PCR positive will be excluded.
• IGHV mutation status assessed at least once.
• TP53 mutation status tested after last treatment.
• Del17p mutation status tested after last treatment.
• Patient is able and willing to adhere to the study visit schedule and other protocol requirements.
• Written informed consent.
• Patient is capable of giving informed consent.

Exclusion Criteria:

• Transformation of CLL (Richter’s transformation).
• Patient received prior venetoclax treatment within 24 months of registration OR patient had progressed during previous venetoclax treatment.
• Patient with central nervous system involvement.
• Malignancies other than CLL/SLL currently requiring systemic therapy, not treated with curative intent, or showing signs of progression after curative treatment.
• Patient with a history of confirmed progressive multifocal leukoencephalopathy (PML).
• Known allergy to xanthine oxidase inhibitors and/or rasburicase.
• History of drug-specific hypersensitivity or anaphylaxis to any study drug.
• Active fungal, bacterial, and/or viral infection that requires systemic therapy. Note: patients with active controlled as well as chronic/recurrent infections are at risk of reactivation/infection during treatment.
• Severe cardiovascular disease (arrhythmias requiring chronic treatment, congestive heart failure or symptomatic ischemic heart disease) (CTCAE grade III-IV).
• Severe pulmonary dysfunction (CTCAE grade III-IV).
• Severe neurological or psychiatric disease (CTCAE grade III-IV).
• Patient with Child Pugh C.
• Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, infection, hypertension, etc.).
• Patient known to be HIV-positive.
• Patient who has difficulty with or are unable to swallow oral medication, or have significant gastrointestinal disease that would limit absorption of oral medication.
• Pregnant women and nursing mothers.
• Fertile men or women of childbearing potential (WOCBP) unless: (1) surgically sterile or ≥ 2 years after the onset of menopause; (2) willing to use a highly effective contraceptive method such as oral contraceptives, intrauterine device or sexual abstinence during study treatment

and for 30 days after last dose of venetoclax and/or 12 months after the last dose of rituximab.

• Previous participation in the HO139 CLL or HO140 CLL trial, and eligible for and willingness to participate in the HO159 CLL trial.
• Active treatment with anti-neoplastic drugs in another clinical trial.
• Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule.

Registration Details

Participating Sites

= Active hospitals

= Inactive hospitals