Safety and Efficacy Study of Epcoritamab in Subjects with Relapsed/Refractory Chronic Lymphocytic Leukemia and Richter's Syndrome

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Genmab A/S

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

16 Nov 2020 → ongoing

Decision date (initial)

2024-05-22

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Genmab A/S, Genmab US, Inc.

External identifiers

EU CT number

2023-504828-25-00

EudraCT number

2020-000848-57

ClinicalTrials.gov

NCT04623541

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacokinetic, Pharmacodynamic, Safety

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

Secondary objectives 5

1. Characterize the pharmacokinetic properties of epcoritamab
2. Evaluate immunogenicity of epcoritamab
3. Evaluate safety and tolerability of epcoritamab
4. Assess the preliminary anti-tumor activity of epcoritamab
5. Assess MRD in blood and marrow

Conditions and MedDRA coding

Chronic Lymphocytic Leukemia

Regulatory references

Scientific advice from competent authorities

Medicines And Healthcare Products Regulatory Agency, Federal Agency For Medicines And Health Products, Food And Drug Administration

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. 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.
2. 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
3. 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;
4. 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
5. 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;
6. 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
7. 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 17

1. Subject received prior treatment with a CD3×CD20 bsAb.
2. Subject received any prior allogeneic HSCT or solid organ transplantation
3. 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.
4. Subject has autoimmune disease or other diseases that require permanent or high-dose immunosuppressive therapy
5. Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia (requiring >20 mg of prednisolone daily) or other concurrent uncontrolled medical conditions.
6. 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
7. Myocardial infarction, intracranial bleed, or stroke within the past 6 months
8. Subject age ≥75 and 2 or more active grade ≥2 cardiovascular conditions.
9. 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
10. Subject has history or presence of clinically relevant disorder affecting the CNS
11. ICE score of less than 8 at study entry
12. 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
13. Subject has suspected allergies, hypersensitivity, or intolerance to epcoritamab or another anti-CD20 mAb or its excipients (refer to the IB for more information).
14. 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.
15. 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
16. 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.
17. 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 5

1. Monotherapy Cohorts (R/R CLL) • Incidence of DLTs • Incidence and severity of AEs and SAEs. • Incidence and severity of CRS, ICANS and TLS
2. Monotherapy (R/R CLL [Arm 1 and 1A] and RS [Arm 2A]): • ORR
3. Dose Escalation Venetoclax Combination Therapy (R/R CLL) • Incidence of DLTs • Incidence and severity of AEs
4. Expansion Venetoclax Combination Therapy in R/R CLL (Arm 3) • ORR as assessed by the IRC
5. Expansion Lenalidomide Combination Therapy in RS (Arm 2B) and R CHOP Combination Therapy in RS (Arm 2C) • ORR as assessed by the IRC

Secondary endpoints 4

1. 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 • Incidence of overall MRD negativity • Duration of MRD negativity • Incidence of ADAs to epcoritamab
2. Dose Escalation Venetoclax Combination Therapy (R/R CLL) • ORR • DOR • CR/CRi rate • TTR • PFS • OS • TTNT • PK parameters • Incidence of overall MRD negativity • Duration of MRD negativity • Incidence of ADAs to epcoritamab
3. Safety Run-in Pirtobrutinib Combination Therapy (R/R CLL – Cohort CP1) • ORR • DOR • CR/CRi rate • TTR • PFS • OS • TTNT • PK parameters • Incidence of overall MRD negativity • Incidence of MRD negativity 3 months after Day 1 of last cycle • Duration of MRD negativity • Incidence of ADAs to epcoritamab
4. Expansion Pirtobrutinib Combination Therapy in R/R CLL (Arm 4) • ORR • DOR • CR/CRi rate • TTR • PFS • OS • TTNT • Incidence and severity of AEs and SAEs • Incidence and severity of CRS, ICANS, and CTLS • PK parameters • Incidence of overall MRD negativity • Incidence of MRD negativity 3 months after Day 1 of last cycle • Duration of MRD negativity • Incidence of ADAs to epcoritamab

Investigational products

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

Test 11

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Genmab A/S

Sponsor organisation

Genmab A/S

Address

Kalvebod Brygge 43

City

Copenhagen V

Postcode

1560

Country

Denmark

Scientific contact point

Organisation

Genmab A/S

Contact name

Trial Information

Public contact point

Organisation

Genmab A/S

Contact name

Trial Information

Third parties 16

Locations

9 EU/EEA countries · 50 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

Serious breaches 1 · Art. 52 CTR

Results and documents

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

Documents 78 files

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

Application history

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