Efficacy and Safety Evaluation of Epcoritamab, Venetoclax, and Lenalidomide in Relapsed/Refractory Chronic Lymphocytic Leukemia and Richter's Syndrome
- Trial ID
- 2023-504828-25-00
- Protocol
- GCT3013-03
- Sponsor
- Genmab A/S
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the safety and efficacy of **epcoritamab** in patients with relapsed or refractory Chronic Lymphocytic Leukemia (CLL) and Richter's Syndrome (RS). This includes identifying the recommended Phase 2 dose (RP2D) and the maximum tolerated dose (MTD) of epcoritamab, both as a monotherapy and in combination with venetoclax, lenalidomide, or R-CHOP. The clinical relevance of this objective lies in determining the optimal dosing and safety profile of epcoritamab, which is crucial for its potential therapeutic application in these patient populations.
Secondary objectives include:
- Characterizing the pharmacokinetic properties of epcoritamab.
- Evaluating the immunogenicity of epcoritamab.
- Assessing the safety and tolerability of epcoritamab.
- Assessing the preliminary anti-tumor activity of epcoritamab.
- Assessing minimal residual disease (MRD) in blood and marrow.
Participants
The clinical trial involves a total of **78 participants** diagnosed with **Chronic Lymphocytic Leukemia** (CLL) or Richter's Syndrome (RS). The study population includes both male and female subjects, aged 18 years and older, with an **ECOG performance status** score of 0, 1, or 2, indicating a range from fully active to ambulatory and capable of all self-care. Participants were selected based on their diagnosis of relapsed or refractory CLL or RS, requiring treatment as per iwCLL guidelines, and must have received at least two prior lines of therapy. The trial includes individuals with evidence of CD20 positivity and acceptable laboratory parameters. Lifestyle considerations such as diet and physical activity are not specified, but participants must adhere to specific contraceptive measures if of reproductive potential. The trial population includes vulnerable groups, ensuring comprehensive representation of the disease's impact across different demographics.
Plans and Procedures
The clinical trial is designed to evaluate the safety and efficacy of **epcoritamab** in patients with **relapsed/refractory chronic lymphocytic leukemia** (R/R CLL) and Richter's Syndrome (RS). This is a Phase 1b/2, open-label study, which involves multiple cohorts to assess both monotherapy and combination therapy regimens. The trial is structured to include dose escalation and expansion phases, with the primary objective of identifying the recommended Phase 2 dose (RP2D) and maximum tolerated dose (MTD) of epcoritamab, both as a monotherapy and in combination with other agents such as **venetoclax** and **lenalidomide**. The study also aims to evaluate the preliminary antitumor effects and safety profiles of these regimens.
The trial is expected to run from November 25, 2020, to March 29, 2026. Participants will be involved in the study for varying durations depending on the cohort and treatment arm they are assigned to. The study includes an initial screening visit to confirm eligibility based on criteria such as age, performance status, and disease characteristics. Following the screening, participants will undergo a series of study visits corresponding to their treatment schedule, which may include regular assessments for safety, efficacy, and pharmacokinetics. The end-of-study visit will occur after the completion of the treatment regimen or upon early termination.
Participants may be withdrawn from the study early due to reasons such as adverse events, disease progression, or withdrawal of consent. The trial employs rigorous inclusion criteria, including evidence of CD20 positivity and acceptable laboratory parameters, to ensure the safety and appropriateness of the study population. The primary endpoints focus on the incidence of dose-limiting toxicities (DLTs), adverse events (AEs), and overall response rates (ORR) as assessed by an independent review committee (IRC). Secondary endpoints include duration of response (DOR), progression-free survival (PFS), and overall survival (OS), among others.
Treatment
The clinical trial involves the administration of **Epcoritamab**, a **biological/biotechnological** agent, which is a **solution for injection**. Epcoritamab is administered via the **subcutaneous** route. The active substance, **epcoritamab**, is a **protein** of the type "Anti-CD3E x Anti-MS4A1 IgG1 monoclonal antibody," also known by the synonyms "Anti-(CD3 epsilon) and anti-(membrane-spanning 4-domains subfamily A member 1) IgG1 monoclonal antibody" and "GEN3013." The pharmaceutical form is a solution for injection, and it is not a pediatric formulation. Epcoritamab is designated as an orphan drug under the number EU/3/22/2581.
**Venetoclax** is used in combination therapy within the trial. It is a **chemical** agent administered **orally**. The pharmaceutical form is denoted as PHF00082MIG. Venetoclax is known by the synonyms "ABT-199" and "GDC-0199." It is classified under the ATC code L01XX52. The trial aims to identify the recommended phase 2 dose (RP2D) and the maximum tolerated dose (MTD) of Epcoritamab when coadministered with Venetoclax 400 mg, as well as to evaluate the safety and tolerability of this combination.
**Lenalidomide** is another **chemical** agent used in the trial, specifically in combination therapy for Richter's Syndrome. It is also administered **orally**, with the pharmaceutical form indicated as PHF00006MIG. Lenalidomide is classified under the ATC code L04AX04. The trial assesses the preliminary antitumor effect of Epcoritamab in combination with Lenalidomide.
Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment regimen. The trial is designed to evaluate the safety, tolerability, and preliminary efficacy of Epcoritamab both as a monotherapy and in combination with Venetoclax or Lenalidomide in patients with relapsed/refractory chronic lymphocytic leukemia and Richter's Syndrome.
Efficacy
The clinical trial aims to assess the efficacy of **Epcoritamab** in patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (R/R CLL) and Richter's Syndrome (RS). The primary efficacy endpoints include the Overall Response Rate (ORR) as assessed by the Independent Review Committee (IRC) for various treatment arms, including monotherapy and combination therapies with Venetoclax and Lenalidomide. Secondary efficacy endpoints encompass Duration of Response (DOR), Complete Response (CR) rate, Partial Response (PR) rate, Time to Response (TTR), Progression-Free Survival (PFS), Overall Survival (OS), Time to Next Treatment (TTNT), and incidence of Minimal Residual Disease (MRD) negativity.
Data collection will involve the use of validated scales and laboratory tests to measure these endpoints. The incidence and severity of adverse events (AEs) and serious adverse events (SAEs) will also be monitored. The trial will evaluate the pharmacokinetic (PK) parameters and the incidence of anti-drug antibodies (ADAs) to Epcoritamab. The schedule for measuring these parameters will be aligned with the trial's protocol, ensuring systematic data collection at specified timepoints throughout the study duration.
Inclusion and Exclusion Criteria
Inclusion Criteria
- All Subjects • Subject must sign an ICF, prior to any Screening procedures • Must be at least 18 years of age • ECOG performance status score of 0,1 or 2 • Evidence of CD20 positivity in a sample representative of the disease (eg, tumor biopsy/peripheral blood/bone arrow) at Screening • Has acceptable laboratory parameters • A woman with reproductive potential must agree to use adequate contraception during the trial, and for 12 months after the last administration of epcoritamab. • A woman of childbearing potential must have a negative serum (betahCG) pregnancy test at Screening and a negative serum or urine pregnancy test before treatment administration on Day 1 of every cycle. • A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the entire trial, until 12 months after last treatment. • A man who is sexually active with a woman of childbearing potential and has not had a vasectomy must agree to use a barrier method of birth control.
- Inclusion Criteria Specific to Subjects With R/R CLL– Dose Escalation Monotherapy (All Cohorts) and Expansion Monotherapy (Arm 1) • Must have active CLL/SLL disease that needs treatment per iwCLL • R/R CLL after receiving at least 2 prior lines of therapy. • Diagnosis of CLL/SLL that meets published diagnostic criteria (Hallek et al., 2018a) • Must take prophylaxis for TLS
- Inclusion Criteria Specific to Subjects With Richter's Syndrome – Expansion Monotherapy Arm 2A • Must have measurable disease as determined by FDG- PET CT and a CT scan (or MRI) • Must provide a mandatory FFPE tumor tissue sample;
- Inclusion Criteria Specific to Subjects With Richter's Syndrome – Lenalidomide Combination Therapy Expansion Arm 2B • Have tumor biopsy-proven CD20+ DLBCL and a clinical history of CLL/SLL. • Deemed as ineligible for chemoimmunotherapy • Eligible for treatment with lenalidomide. • Must have measurable disease as determined by FDG- PET CT and a CT scan (or MRI) • Must provide a mandatory FFPE tumor tissue sample; • Females of childbearing potential must use 2 forms of contraception • A woman of childbearing potential must have a negative serum (betahCG) pregnancy test • Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking lenalidomide
- Inclusion Criteria Specific to Subjects With Richter's Syndrome – R-CHOP Combination Therapy Expansion Arm 2C • Have tumor biopsy-proven CD20+ DLBCL and have a clinical history of CLL/SLL. • Eligible to receive R-CHOP per investigator determination. • Must have measurable disease as determined by FDG- PET CT and a CT scan (or MRI) • Must provide a mandatory FFPE tumor tissue sample;
- Inclusion Criteria Specific to Subjects with R/R CLL – Venetoclax Combination Therapy Dose Escalation Cohorts and Expansion Arm 3 • Must have active CLL/SLL disease that needs treatment per iwCLL
- Inclusion Criteria Specific to Subjects with R/R CLL – Pirtobrutinib Combination Therapy Safety Run-in CP cohorts and Expansion Arm 4: • Must have active CLL/SLL disease that needs treatment with at least 1 of the criteria being met. • Presence of measurable disease. • Previous treatment with at least one and a maximum 3 prior lines of therapy and must include a covalent BTKi. • Diagnosis of CLL/SLL that meets published iwCLL criteria at the time of diagnosis. • Females of childbearing potential must use highly effective contraceptive measures while taking pirtobrutinib and for 28 days after the last dose. • A woman must agree not to breastfeed a child during treatment and until one week after last dose. • A man who is sexually active with a woman of childbearing potential must use an effective method of contraception during treatment and for 3 months after last dose
Exclusion Criteria
- Subject received prior treatment with a CD3×CD20 bsAb.
- Subject received any prior allogeneic HSCT or solid organ transplantation
- Subject received treatment with an anticancer agent, as follows: - Subject received treatment with an investigational drug, within 4 weeks or 5 half lives, whichever is shorter, prior to the first dose of epcoritamab.
- Subject has autoimmune disease or other diseases that require permanent or high-dose immunosuppressive therapy
- Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia (requiring >20 mg of prednisolone daily) or other concurrent uncontrolled medical conditions.
- 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 v5.0 grade 2 or higher), or clinically significant ECG abnormalities
- Myocardial infarction, intracranial bleed, or stroke within the past 6 months
- Subject age ≥75 and 2 or more active grade ≥2 cardiovascular conditions.
- Subject has toxicities from previous anticancer therapies that have not resolved to baseline levels or to grade 1 or less except for alopecia and peripheral neuropathy
- Subject has history or presence of clinically relevant disorder affecting the CNS
- ICE score of less than 8 at study entry
- Subject has known past or current malignancy other than inclusion diagnosis, except for: a. Cervical carcinoma of Stage 1B or less b. Non-invasive basal cell or squamous cell skin carcinoma c. Non-invasive, superficial bladder cancer d. Prostate cancer with a current PSA level <0.1 ng/mL e. Any curable cancer with a CR of >2 years duration
- Subject has suspected allergies, hypersensitivity, or intolerance to epcoritamab or another anti-CD20 mAb or its excipients (refer to the IB for more information).
- Active HBV (DNA PCR-positive). Subjects with evidence of prior HBV but who are PCR-negative are permitted in the trial but should receive prophylactic antiviral therapy.
- Any of the following active infections: - Hepatitis C (RNA PCR-positive infection). Subjects who received treatment for HCV that was intended to eradicate the virus may participate if hepatitis C RNA levels are undetectable. Known Human T cell leukemia virus infection -Active CMV infection
- Subject is a woman who is pregnant or breastfeeding, or who is planning to become pregnant while enrolled in this trial or within 12 months after the last dose of epcoritamab.
- Subject is a man who plans to father a child while enrolled in this trial or within 12 months after the last dose of epcoritamab
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 25 Nov 2020 | 21 |
 Czechia | Not Recruiting | 25 Nov 2020 | 6 |
 Denmark | Not Recruiting | 25 Nov 2020 | 32 |
 France | Not Recruiting | 25 Nov 2020 | 12 |
 Germany | Not Recruiting | 25 Nov 2020 | 8 |
 Italy | Not Recruiting | 25 Nov 2020 | 11 |
 The Netherlands | Not Recruiting | 25 Nov 2020 | — |
 Poland | Not Recruiting | 25 Nov 2020 | 6 |
 Spain | Not Recruiting | 25 Nov 2020 | 12 |
| Netherlands | — | — | 17 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
VENETOCLAX | Test | PHF00082MIG | ORAL | — | — | SCP16272936 |
Epcoritamab | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS | — | — | PRD5599809 |
PREDNISOLONE | Test | PHF00059MIG | ORAL USE | — | — | SCP107974752 |
Jaypirca 50 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | — | — | PRD10918439 |
CYCLOPHOSPHAMIDE | Test | PHF00231MIG | SOLUTION FOR INFUSION | — | — | SCP106382672 |
Jaypirca 100 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | — | — | PRD10921625 |
RITUXIMAB | Test | PHF00230MIG | SOLUTION FOR INFUSION | — | — | SCP872361 |
Epcoritamab | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS | — | — | PRD10899078 |
VINCRISTINE | Test | PHF00007MIG | SOLUTION FOR INFUSION | — | — | SCP1137788 |
DOXORUBICIN | Test | PHF00231MIG | SOLUTION FOR INFUSION | — | — | SCP119562649 |