A Prospective, Multicenter, Phase-II Trial of Ibrutinib Plus Venetoclax in Patients With Creatinine Clearance >= 30 ml/Min Who Have Relapsed or Refractory Chronic Lymphocytic Leukemia (RR-CLL) With or Without TP53 Aberrations

Stichting Hemato-Oncologie voor Volwassenen Nederland

Status and phase: Active, not recruiting; Phase 2

Conditions: Chronic Lymphocytic Leukemia in Remission; Chronic Lymphocytic Leukemia in Relapse

Treatments: Drug: Ibrutinib + Venetoclax 15 cycles; Drug: Possible reinitiation treatment: Ibrutinib + Venetoclax 12 cycles; Drug: Ibrutinib until progression/relapse

Study type: Interventional

Funder types: Other

Identifiers

NCT03226301

HO141 CLL / VIsion trial

Details and patient eligibility

About

The aim of the current trial is to evaluate if combination treatment with venetoclax + ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia (RR CLL) can lead to MRD negativity, which may induce long lasting remissions for MRD-negative patients randomized to stopping treatment after 15 induction cycles.

Enrollment: 230 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Documented CLL or SLL requiring treatment according to IWCLL criteria after either being refractory to first line therapy or relapse after initial therapy.

  • Age at least 18 years.

  • Adequate bone marrow function defined as:

    • Absolute neutrophil count (ANC) >0.75 x 109/L
    • Platelet count >30,000 /μL 30 x 109/L.
    • Hemoglobin >8.0 g/dL (5 mmol/L) Unless directly attributable to CLL infiltration of the bone marrow, proven by bone marrow biopsy

  • Creatinine clearance (CrCL) ≥ 30ml/min calculated according to the modified formula of Cockcroft and Gault or directly measured with 24hr urine collection.

  • Adequate liver function as indicated

    • Serum aspartate transaminase (AST) or alanine transaminase (ALT) ≤ 3.0 x upper limit of normal (ULN)
    • Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of nonhepatic origin)
    • Prothrombin time (PT)/International normal ratio (INR) <1.5 x ULN and PTT (activated partial thromboplastin time [aPTT]) <1.5 x ULN (unless abnormalities are related to coagulopathy or bleeding disorder).

  • Negative serological testing for hepatitis B (HBsAg negative and anti-HBc negative; patients positive for anti-HBc may be included if PCR for HBV DNA is negative and HBV-DNA PCR is performed every month until 12 months after last dose), negative testing for hepatitis C RNA within 42 days prior to registration.

  • WHO/ECOG performance status 0-3 (appendix C), stage 3 only if attributable to CLL.

  • Negative pregnancy test at study entry (for women of childbearing potential).

  • Male and female subjects of reproductive potential must agree to use both a highly effective method of birth control (e.g. implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], complete abstinence , or sterilized partner) and a barrier method (e.g., condoms, cervical ring, sponge, etc.) during the period of therapy and for 90 days after the last dose of study drug.

  • Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements.

  • Written informed consent.

Exclusion criteria

• Any prior therapy with ibrutinib and/or venetoclax.
• Transformation of CLL (Richter's transformation).
• Patients with a history of confirmed progressive multifocal leukoencephalopathy (PML).
• Malignancies other than CLL currently requiring systemic therapies or not being treated in curative intention before or showing signs of progression after curative treatment.
• Known allergy to xanthine oxidase inhibitors and/or rasburicase.
• Known bleeding disorders (e.g., von Willebrand's disease or hemophilia).
• Uncontrolled or active infection.
• Patients requiring treatment with a strong cytochrome P450 (CYP) 3A inhibitor (see appendix K). or anticoagulant therapy with warfarin or phenoprocoumon or other vitamin K antagonists. Please note: Patients being treated with NOACs can be included, but must be properly informed about the potential risk of bleeding under treatment with ibrutinib.
• History of stroke or intracranial hemorrhage within 6 months prior to registration.
• Major surgery within 28 days prior to registration.
• Use of investigational agents which might interfere with the study drug within 28 days prior to registration.
• Vaccination with live vaccines within 28 days prior to registration
• Steroid therapy within 7 days prior to registration, with the exception of inhaled steroids for asthma, topical steroids, steroids up to 25 mg of prednisolone daily to control autoimmune phenomenon's, or replacement/stress corticosteroids.
• Pregnant women and nursing mothers.
• Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: None (Open label)

---

230 participants in 3 patient groups

Ibrutinib until progression/relapse

Experimental group

Description:

All patients receive ibrutinib + venetoclax (with delayed start and ramp up of venetoclax from cycle 3) for the 15 cycles. MRDpositive patients (PB and BM) will continue on Ibrutinib maintenance (non-randomized group) until progression/relapse

Treatment:

Drug: Ibrutinib until progression/relapse

Drug: Ibrutinib + Venetoclax 15 cycles

Arm A

Experimental group

Description:

All patients receive ibrutinib + venetoclax (with delayed start and ramp up of venetoclax from cycle 3) for the 15 cycles. MRD negative patients (PB and BM) will be randomized to Arm A or Arm B. Arm A: Ibrutinib until progression/relapse (Continuous ibrutinib treatment until toxicity or progression)

Treatment:

Drug: Ibrutinib until progression/relapse

Drug: Ibrutinib + Venetoclax 15 cycles

Arm B

Experimental group

Description:

All patients receive ibrutinib + venetoclax (with delayed start and ramp up of venetoclax from cycle 3) for the 15 cycles. MRD negative patients (PB and BM) will be randomized to Arm A or Arm B. Arm B: Observation until event. Patients randomized to Arm B will get reinitiation of therapy during the observation period in case of: * progression according to IWCLL criteria or * MRD≥10-3 (PB) and at least one month later MRD ≥10-2 (PB). Treatment reinitiation will consist of ibrutinib and venetoclax (with ramp up of venetoclax from cycle 1) for 12 cycles

Treatment:

Drug: Possible reinitiation treatment: Ibrutinib + Venetoclax 12 cycles

Drug: Ibrutinib + Venetoclax 15 cycles