| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Lymphocytic Leukemia |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic Lymphocytic Leukemia |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10008976 |
| E.1.2 | Term | Chronic lymphocytic leukemia |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Monotherapy Cohorts (R/R CLL)
• Identify the RP2D and the MTD of epcoritamab
• Evaluate the safety and tolerability of epcoritamab
Expansion Monotherapy (R/R CLL [Arm 1] and RS [Arm 2A]):
• Assess the preliminary efficacy of epcoritamab
Dose Escalation Venetoclax Combination Therapy (R/R CLL)
• Identify the RP2D and the MTD of epcoritamab when coadministered with venetoclax 400 mg
• Evaluate safety and tolerability of the combination of epcoritamab and venetoclax
Expansion Venetoclax Combination Therapy in R/R CLL (Arm 3)
• Assess the preliminary antitumor effect of epcoritamab in combination with venetoclax
Expansion Lenalidomide Combination Therapy in RS (Arm 2B) and R CHOP Combination Therapy in RS (Arm 2C)
• Assess the preliminary anti tumor effect of epcoritamab in combination with lenalidomide or R-CHOP |
|
| E.2.2 | Secondary objectives of the trial |
• Characterize the pharmacokinetic properties of epcoritamab
• Evaluate immunogenicity of epcoritamab
• Evaluate safety and tolerability of epcoritamab
• Assess the preliminary anti-tumor activity of epcoritamab
• Assess MRD in blood and marrow |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 (beta-hCG) 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.
• 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 (beta-hCG) 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
• At least 1 of the following disease-related (constitutional) symptoms:
• Unintentional weight loss ≥ 10% within the previous 6 months
• Significant fatigue
|
|
| E.4 | Principal exclusion criteria |
All Subjects
• 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 (see Appendix 3), 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.
• Active 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
• 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 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Monotherapy Cohorts (R/R CLL)
• Incidence of DLTs
• Incidence and severity of AEs and SAEs.
• Incidence and severity of CRS, ICANS and TLS
Monotherapy (R/R CLL [Arm 1] and RS [Arm 2A]):
• ORR as assessed by the IRC
Dose Escalation Venetoclax Combination Therapy (R/R CLL)
• Incidence of DLTs
• Incidence and severity of AEs
Expansion Venetoclax Combination Therapy in R/R CLL (Arm 3)
• ORR as assessed by the IRC
Expansion Lenalidomide Combination Therapy in RS (Arm 2B) and R CHOP Combination Therapy in RS (Arm 2C)
• ORR as assessed by the IRC |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
DLT evaluation period is defined as the first 4 weeks, ie, 28 days after the first administration ofepcoritamab.
For the other end points, please refer to protocol
• DOR
• CR/CRi rate
• PR/nPR rate
• TTR
• PFS
• OS
• TTNT
• Incidence and severity of AEs and SAEs
• Incidence and severity of CRS, ICANS, and CTLS
• PK parameters (eg, clearance, volume of distribution and AUC0-last and AUC0-∞, Cmax, Tmax, predose values, and t1/2)
• Incidence of overall MRD negativity
• Duration of MRD negativity
• Incidence of ADAs to epcoritamab
|
|
| E.5.2 | Secondary end point(s) |
Monotherapy (R/R CLL [Arm 1] and RS [Arm 2A]), Expansion Lenalidomide Combination Therapy in RS (Arm 2B) and R CHOP Combination Therapy in RS (Arm 2C):
• DOR
• CR rate (both cohorts)/CRi rate (CLL cohort only)
• PR/nPR rate
• TTR
• PFS
• OS
• TTNT
• Incidence and severity of AEs and SAEs.
• Incidence and severity of CRS, ICANS, and CTLS
• PK parameters (eg, clearance, volume of distribution and AUC0-last and AUC0-∞, Cmax, Tmax, predose values, and t1/2)
• Incidence of overall MRD negativity
• Duration of MRD negativity
• Incidence of ADAs to epcoritamab
Dose Escalation Venetoclax Combination Therapy (R/R CLL)
• ORR
• DOR
• CR/CRi rate
• TTR
• PFS
• OS
• TTNT
• PK parameters (eg, clearance, volume of distribution and AUC0-last and AUC0-∞, Cmax, Tmax, predose values, and t1/2)
• Incidence of overall MRD negativity
• Duration of MRD negativity
• Incidence of ADAs to epcoritamab |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 70 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Israel |
| United Kingdom |
| United States |
| Belgium |
| Czechia |
| Denmark |
| France |
| Germany |
| Italy |
| Netherlands |
| Poland |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
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