Main info

Identifier:

HOVON 165 CLL

Sponsor:

HOVON

Working group party:

CLL

Age:

>= 18

Stage:

2nd Line

Echelon:

Level D

Included patients:

8

(of 90)

Active sites:

4

(of 1)

20 sites are pending

Title:

A prospective randomized phase I/II trial of venetoclax treatment (26 cycles) with 6 cycles or 12 cycles of epcoritamab in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma

Timeline

News

Flow

Details

Phase:

Prospective randomized Phase I/II study

Monitoring Type:

HOVON Monitoring Visit

Objectives:

Phase I
Primary Objective
To determine the RP2D for epcoritamab when used in combination with venetoclax for the phase II part of the study.

Phase II
Primary Objective
To evaluate efficacy of venetoclax treatment (26 cycles) in combination with 6 cycles or 12 cycles of epcoritamab in patients with relapsed or refractory CLL in terms of undetectable minimal residual disease <10-4 (uMRD4) in the bone marrow (BM) for the two treatment groups separately.

Secondary Objectives

• To evaluate the efficacy of epcoritamab in combination with venetoclax in terms of MRD depth in peripheral blood (PB),progression free survival (PFS), overall survival (OS), event free survival (EFS), overall response rate (ORR), time to next treatment (TTNT) for the two treatment groups separately.
• To evaluate the safety and tolerability of epcoritamab in combination with venetoclax.
• To evaluate quality of life (QoL) with epcoritamab in combination with venetoclax.
• To evaluate the incidence, severity, and type of infections.

Eligibility

Inclusion Criteria:

• Documented relapsed or refractory CLL or SLL (SLL in phase II part only) following at least one systemic 1st-line treatment
• Requiring treatment according to IWCLL criteria (appendix A);
• Age at least 18 years;
• ECOG/WHO performance status 0-2;
• In case of prior venetoclax treatment, enrollment can only occur at least 24 months after end of treatment and patients must not have progressed during venetoclax treatment;
• Adequate BM function defined as:
  • Hemoglobin >5.6 mmol/l or Hb > 9 g/dL, unless low Hb is directly attributable to CLL/SLL infiltration of the BM, proven by BM biopsy;
  • Absolute neutrophil count (ANC) >1.0 x 109/L (1,000/μL), unless low ANC is directly attributable to CLL/SLL infiltration of the BM, proven by BM biopsy;
  • 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) ≥ 50ml/min (Cockcroft-Gault appendix 0);
• 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);
• Prothrombin time (PT)/International normal ratio (INR) <1.5x ULN and activated partial thromboplastin time (aPTT) <1.5 x ULN; unless receiving anticoagulation;
• Negative serological testing for hepatitis B virus (HBV) (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 or hepatitis C antibody may be included if they have a negative PCR within 6 weeks before enrollment. Those who are PCR positive will be excluded; Please note: For patients positive for anti-HBc or antibodies for hepatitis C, HBV-DNA or HCV-DNA PCR, respectively, has to be repeated every month until 12 months after last dose of study treatment;
• Patient is able and willing to adhere to the study visit schedule and other protocol requirements;
• Patient is capable of giving informed consent;
• Written informed consent.

Exclusion Criteria:

• Active CLL/SLL directed therapy within the last 14 days;
• Prior treatment with a CD3 × CD20 bispecific antibody or CAR T-cell therapy
• Transformation of CLL (Richter’s transformation);
• Prior allogeneic stem cell transplantation and/or solid organ transplantation;
• Patient with a history of confirmed progressive multifocal leukoencephalopathy (PML);
• Malignancies other than CLL/SLL currently requiring systemic therapy or not treated in curative intention or showing signs of progression after curative treatment;
• Known allergy to xanthine oxidase inhibitors and/or rasburicase;
• History of drug-specific hypersensitivity or anaphylaxis to any study drug (including active product or excipient components);
• Active bleeding or uncontrolled severe bleeding diathesis (e.g., hemophilia or severe von Willebrand disease);
• Active fungal, bacterial, and/or viral infection CTCAE grade > 1; Please note: active controlled as well as chronic/recurrent infections are at risk of reactivation/infection during treatment;
• Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled: infection, auto-immune hemolysis, immune thrombocytopenia, diabetes, hypertension, hyperthyroidism or hypothyroidism etc.);
• Patient known to be HIV-positive;
• Patient requiring treatment with a strong cytochrome P450 (CYP) 3A inhibitor/inducer (see appendix I);
• CTCAE grade III-IV cardiovascular disease including but not limited to:
  • Unstable or uncontrolled disease/condition related to or affecting cardiac function, eg, unstable angina, congestive heart failure grade III or IV as classified by the New York Heart Association (see appendix A), uncontrolled clinically significant cardiac arrhythmia (CTCAE grade II or higher), or clinically significant electrocardiogram (ECG) abnormalities.
  • Myocardial infarction within 6 months prior to registration.
  • Subject age ≥75 and 2 or more active grade ≥2 cardiovascular conditions.
  • Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia’s formula (QTcF) >480 msec. NOTE: this criterion does not apply to subjects with a left bundle branch block.
  • Stroke or intracranial hemorrhage within 6 months prior to registration.
• Severe pulmonary dysfunction (CTCAE grade III-IV, see appendix D);
• Severe neurological or psychiatric disease (CTCAE grade III-IV, see appendix D);
• Neuropathy > CTCAE grade II
• Patient who has difficulty with or are unable to swallow oral medication, or have significant gastrointestinal disease that would limit absorption of oral medication;
• Vaccination with live vaccines within 28 days prior to registration;
• Use of any other experimental drug or therapy within 28 days of registration;
• Major surgery within 28 days prior to registration;
• 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 12 months after last dose of epcoritamab and 30 days after last dose of venetoclax;
• Previous participation in the HO139 CLL or HO140 CLL trial and eligible for and willing to participate in the HO159 CLL trial;
• Current participation in other clinical trial with medicinal products;
• 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