HOVON 165 CLL: 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. AETHER study (ABT199 + Epcoritamab THErapy for Relapsed/refractory CLL/SLL)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Stichting Hemato-Oncologie voor Volwassenen Nederland (Hovon)

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

10 Apr 2024 → ongoing

Decision date (initial)

2024-01-16

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Genmab A/S · AbbVie

External identifiers

EU CT number

2022-500305-40-00

ClinicalTrials.gov

NCT05791409

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

Phase I: To determine the recommended phase II dose level (RP2D) of epcoritamab when used in combination with venetoclax for the phase II part of the trial.
Phase II: 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) after treatment for the two treatment groups separately.

Secondary objectives 8

1. 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.
2. To evaluate the safety and tolerability of epcoritamab in combination with venetoclax.
3. To evaluate quality of life (QoL) with epcoritamab in combination with venetoclax.
4. To evaluate the incidence, severity, and type of infections.
5. Association between MRD (after cycle 9 and 12 weeks after day 28 of cycle 26) in PB and BM, and PFS/OS.
6. To evaluate value of different techniques for MRD testing.
7. To evaluate the impact on immunological function of epcoritamab in combination with venetoclax.
8. To evaluate circulating tumor DNA (ctDNA) at several time points.

Conditions and MedDRA coding

Small Lymphocytic Lymphoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Documented relapsed or refractory CLL or SLL (SLL in phase II part only) following at least one systemic 1st-line treatment
2. 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;
3. Patient is able and willing to adhere to the study visit schedule and other protocol requirements;
4. Patient is capable of giving informed consent;
5. Written informed consent
6. Requiring treatment according to IWCLL criteria
7. Age at least 18 years
8. ECOG/WHO performance status 0-2
9. 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;
10. Estimated Glomerular Filtration Rate (eGFR) (MDRD) or estimated creatinine clearance (CrCl) ≥ 50ml/min (Cockcroft-Gault)
11. 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);
12. Prothrombin time (PT)/International normal ratio (INR) <1.5x ULN and activated partial thromboplastin time (aPTT) <1.5 x ULN; unless receiving anticoagulation;

Exclusion criteria 26

1. Patient received treatment with anti-cancer agent as follows: a. Standard agents within 2 weeks or 5 half-lives, whichever is shorter, prior to the planned first dose of epcoritamab (excluding anti-CD20 mAbs and BTKi, which can be administered until first full dose of epcoritamab); OR b. Patient received treatment with an investigational drug, within 4 weeks or 5 half-lives, whichever is shorter, prior to the planned first dose of Venetoclax;
2. a. Ongoing active bacterial, viral, fungal, mycobacterial, parasitic or other infection requiring systemic treatment (excluding prophylactic treatment) at the time of enrollment or within the previous 2 weeks prior to the planned first dose of trial drug, including COVID-19 infection. Note that a past COVID-19 infection may be a risk factor, but if resolved and the subject is vaccinated, it may be allowable to enroll the subject. b. Has suspected active or inadequately treated latent tuberculosis;
3. Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled: infection, auto-immune hemolysis, immune thrombocytopenia, diabetes, hypertension, hyperthyroidism or hypothyroidism etc.)
4. Patient known to be HIV-positive
5. Patient requiring treatment with a strong cytochrome P450 (CYP) 3A inhibitor/inducer
6. 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, 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.
7. Severe pulmonary dysfunction (CTCAE grade III-IV)
8. Severe neurological or psychiatric disease (CTCAE grade III-IV)
9. Neuropathy > CTCAE grade II
10. Patient who has difficulty with or are unable to swallow oral medication, or have significant gastrointestinal disease that would limit absorption of oral medication
11. Vaccination with live vaccines within 28 days prior to registration
12. Prior treatment with a CD3 × CD20 bispecific antibody or CAR T-cell therapy
13. Major surgery within 28 days prior to registration
14. Pregnant women and nursing mothers
15. 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 4 months after last dose of epcoritamab and 30 days after last dose of venetoclax
16. Previous participation in the HO139 CLL or HO140 CLL trial and eligible for and willing to participate in the HO159 CLL trial
17. Current participation in other clinical trial and using study medication
18. Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule
19. Transformation of CLL (Richter’s transformation)
20. Prior allogeneic stem cell transplantation and/or solid organ transplantation
21. Patient with a history of confirmed progressive multifocal leukoencephalopathy (PML)
22. Malignancies other than CLL/SLL currently requiring systemic therapy or not treated in curative intention or showing signs of progression after curative treatment
23. Known allergy to xanthine oxidase inhibitors and/or rasburicase
24. History of drug-specific hypersensitivity or anaphylaxis to any study drug (including active product or excipient components)
25. Active bleeding or uncontrolled severe bleeding diathesis (e.g., hemophilia or severe von Willebrand disease)
26. Patient received prior venetoclax treatment within 24 months of registration OR patient had progressed during previous venetoclax treatment

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Phase I: recommended Phase 2 Dose (RP2D) for the combination of venetoclax and epcoritamab based on dose limiting toxicity (DLT).
2. Phase II: undetectable minimal residual disease <10-4 (uMRD4) in the bone marrow (BM), i.e., less than 1 CLL cell per 10 000 leukocytes (equivalently: <0.01%, or <10-4), in absence of progression according to the IWCLL criteria, at 12 weeks after the last day, i.e., day 28, of cycle 26.

Secondary endpoints 19

1. MRD status in PB at cycle 4, 6, 9, 12, 15, 18, 21, 24 and 12 weeks after day 28 of cycle 26; following treatment: every 3 months for the first year, then every 6 months until relapse or until 6 years after randomization.
2. Progression free survival (PFS), defined as time from randomization to the first occurrence of disease progression or death from any cause, whichever occurs first.
3. Overall survival (OS), defined as the time from randomization to death from any cause.
4. Best overall response rate (ORR) defined as the proportion of patients with a complete response (CR), complete response with incomplete marrow recovery (CRi), or partial response (PR) according to IWCLL 2018 criteria.
5. Event free survival (EFS), defined as time from randomization to date of start of next CLL treatment, progression or death, whichever comes first.
6. Time to next CLL treatment (TTNT), defined as time from randomization to next new line of treatment.
7. Treatment free survival (TFS), defined as time from date of last protocol treatment to date start of next (new) line of treatment, or death from any cause, whichever comes first.
8. Duration of response (DOR), defined as time from first response (i.e., ≥PR and CR) to progressive disease (PD) or death from any cause..
9. Depth (level) of MRD measured in BM after cycle 9 and 12 weeks after day 28 of cycle 26.
10. Depth (level) of MRD measured in PB at cycle 4, 6, 9, 12, 15, 18, 21, 24, 12 weeks after day 28 of cycle 26 and thereafter every 3 months for the first year, then every 6 months until relapse or until 6 years after registration.
11. Safety parameters: Type, frequency, and severity of- adverse events (AEs) and- adverse events of special interest (AESI) and their relationship to study treatment (determined according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0).
12. Health-related quality of life (QoL) by EORTC QLQ-C30, QLQ-CLL17 and PRO-CTCAE questionnaires.
13. Evaluation of relationship between various baseline markers and clinical outcome parameters (response, MRD, EFS, etc)
14. Immunophenotyping and functional T cell studies.
15. Circulating tumor DNA study on several time points.
16. Baseline molecular characteristics (IGHV mutation status, TP53 mutations, genomic complexity).
17. Retrospective exploratory analysis to investigate the effect of epcoritamab in combination with venetoclax on immune composition, genomic and transcriptomic profiles and clonal repertoire.
18. Association between MRD (after cycle 9 and 12 weeks after cycle 26) in PB and BM, and PFS/OS.
19. Immune markers in relation to CRS and infections.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Stichting Hemato-Oncologie voor Volwassenen Nederland (Hovon)

Sponsor organisation

Stichting Hemato-Oncologie voor Volwassenen Nederland (Hovon)

Address

Dr. Molewaterplein 40

City

Rotterdam

Postcode

3015 GD

Country

Netherlands

Scientific contact point

Organisation

Haemato Oncology Foundation For Adults Netherlands (Hovon)

Contact name

dr. Kater

Public contact point

Organisation

Haemato Oncology Foundation For Adults Netherlands (Hovon)

Contact name

HOVON

Third parties 9

Locations

4 EU/EEA countries · 24 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Urgent safety measures 1 · Art. 54 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 38 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications