GEN3014 Trial in Relapsed or Refractory Hematologic Malignancies

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

9 Mar 2021 → 1 Aug 2025

Decision date (initial)

2024-10-02

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2023-507086-26-00

EudraCT number

2020-003781-40

ClinicalTrials.gov

NCT04824794

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Safety, Others, Pharmacodynamic, Efficacy

Determine the RP2D and if reached, the MTD of GEN3014
Evaluate the safety and tolerability of GEN3014
Please refer to the protocol section 3 (Tables 3-2 and 3-3) for the full list
of main objectives for the Expansion Part A (GEN3014 Single Cohorts)
and Expansion Part B (Randomized H2H) of the study, respectively.

Secondary objectives 1

1. Characterize the PK properties of GEN3014 Evaluate immunogenicity Assess the preliminary anti-tumor activity of GEN3014Assess the clinical efficacy of GEN3014 Please refer to the protocol section 3 (Tables 3-2 and 3-3) for the full list of secondary objectives for the Expansion Part A (GEN3014 Single Cohorts) and Expansion Part B (Randomized H2H) of the study, respectively.

Conditions and MedDRA coding

Relapsed or Refractory Multiple Myeloma (RRMM) Diffuse Large B Cell Lymphoma (DLBCL) Acute Myeloid Leukemia (AML)

Study design 1 period

Regulatory references

Scientific advice from competent authorities

Medicines Evaluation Board, Danish Medicines Agency, Swedish Medical Products Agency, Food And Drug Administration

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 17

1. 1. Must be at least 18 years of age.
2. 2. Must sign an informed consent form (ICF) prior to any Screening
3. 3. Must have fresh bone marrow samples collected at Screening.
4. 4. Eastern Cooperative Oncology Group (ECOG) performance status (PS) score 0,1 or 2
5. 5. Has acceptable laboratory test results during the Screening period
6. 6. A woman of reproductive potential must agree to use adequate contraception during the trial and for 12 months after the last GEN3014 or daratumumab SC administration.
7. 7. A woman of childbearing potential must have a negative serum beta-human chorionic gonadotropin (β-hCG) at Screening and additionally, for Expansion Part B, within 72 hours of the first dose of study treatment prior to dosing.
8. 8. A woman must agree not to donate eggs (ova, oocytes) for assisted reproduction during the trial and for 12 months after receiving the last dose of GEN3014 or daratumumab SC.
9. 9. 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, and all men must also not donate sperm during the trial and for 12 months after receiving the last dose of GEN3014 or daratumumab SC.
10. Specific Inclusion Criteria for RRMM: 10. Must have documented multiple myeloma as defined by the criteria below and have evidence of disease progression on the most recent prior treatment regimen based on IMWG criteria: • Prior documentation of monoclonal plasma cells in the bone marrow ≥ 10% or presence of a biopsy-proven plasmacytoma and • Measurable disease at baseline as defined by any of the following: - IgG, IgA, IgD, or IgM myeloma: Serum M-protein level ≥0.5 g/dL (≥ 5 g/L) or urine M-protein level ≥200 mg/24 hours; or - Light chain myeloma: Serum Ig free light chain (FLC) ≥10 mg/dL and abnormal serum Ig kappa lambda FLC ratio. Participants with RRMM must have exhausted standard therapies, at the investigator’s discretion.
11. 11. For anti-CD38 mAb-naive RRMM subjects: Subject received at least 3 prior lines of therapy including a PI and an IMiD in any order, or is double refractory to a PI and an IMiD; or subject received ≥ 2 prior lines of therapy if 1 of those lines included a combination of PI and IMiD. Note: Subjects should not have received any anti-CD38 antibody.
12. 12. For anti-CD38 mAb-treated RRMM participants: Participant has received at least 2 prior lines of therapy and must have discontinued daratumumab or isatuximab for at least 4 weeks prior to the first dose of GEN3014. Note: Participants should not have received any other anti-CD38 antibody except daratumumab or isatuximab.
13. 13. Potassium level ≥3.0 mEq/L (≥3.0 mmol/L); and corrected serum calcium ≤14.0 mg/dL (≤3.5 mmol/L) or free ionized calcium ≤6.5 mg/dL (≤1.6 mmol/L).
14. Specific Inclusion Criteria for R/R AML: 14. Relapsed or refractory AML, both de novo or secondary; must have failed all conventional therapy. Acute promyelocytic leukemia (APL) is excluded from this trial. Note: Relapse is defined by BM blasts ≥5% in patients who have been in complete remission (CR) previously, or reappearance of blasts in the blood, or development of extramedullary AML. Refractory is defined as not being able to achieve a CR after the initial therapy.
15. Specific Inclusion Criteria for R/R AML: 15. Subject with relapsed AML who received at least 2 prior therapies for AML with the exception of hydroxyurea.
16. Specific Inclusion Criteria for R/R AML: 16. Subject with refractory AML who received at least 1 prior line of therapy for AML with the exception of hydroxyurea.
17. Specific Inclusion Criteria for R/R AML: 17. Subject's life expectancy at Screening is judged to be at least 3 months. Please refer to Protocol sections 5.1.2 and 5.1.3 for the Inclusion Criteria for the Expansion Part A (GEN3014 Single Cohorts) and Expansion Part B (Randomized H2H), respectively

Exclusion criteria 19

1. 1. Prior treatment with any anti-CD38 directed therapies (eg. daratumumab, isatuximab, CD38 CAR-T, bispecific Ab) in anti-CD38 mAb- naive RRMM Cohort. Note: Prior daratumumab or isatuximab exposure is allowed for anti-CD38 mAb-treated RRMM subjects in the Dose Escalation and anti-CD38 mAb-refractory RRMM Cohort in the Expansion Part A.
2. 2. Treatment with an anti-cancer agent, chemotherapy, radiation therapy, or major surgery within 2 weeks prior to the first dose of study treatment (Dose Escalation and Expansion Part A) or randomization (Expansion Part B).
3. 3. Treatment with an investigational drug within 4 weeks or 5 half-lives, whichever is shorter, prior to the first dose of study treatment (Dose Escalation and Expansion Part A) or randomization (Expansion Part B).
4. 4. Cumulative dose of corticosteroids more than the equivalent of ≥140 mg of prednisone within 2-week period before the first dose of study treatment (Dose Escalation and Expansion Part A) or maximum cumulative dose of dexamethasone 160 mg within 28 days of randomization (Expansion Part B).
5. 5. Has clinically significant cardiac disease
6. 6. Toxicities from previous anti-cancer therapies have not resolved to baseline levels or to Grade 1 or less except for alopecia and peripheral neuropathy.
7. 7. Primary central nervous system (CNS) tumor or known CNS involvement at Screening.
8. 8. Has known history/positive serology for hepatitis B
9. 9. Known medical history or ongoing hepatitis C infection that has not been cured.
10. 10. Known history of seropositivity of human immunodeficiency virus (HIV) (Dose Escalation and Expansion Part A) or to be positive for HIV with details in the protocol (Expansion Part B).
11. 11. Currently receiving any other investigational agents.
12. 12. A woman who is pregnant or breast-feeding, or who is planning to become pregnant while enrolled in this trial or within 12 months after the last dose of study treatment.
13. 13. A man who plans to father a child while enrolled in this trial or within 12 months after the last dose of study treatment.
14. Specific Exclusion Criteria for RRMM: 14. Prior allogeneic HSCT.
15. 15. Specific Exclusion Criteria for RRMM: Autologous HSCT within 3 months of the first dose of GEN3014.
16. 16. Specific Exclusion Criteria for R/R AML: <5% blasts in blood or bone marrow at Screening.
17. 17. Specific Exclusion Criteria for R/R AML: Prior autologous HSCT.
18. 18. Specific Exclusion Criteria for R/R AML: Allogenic HSCT within 3 months of the first dose of GEN3014
19. 19. Specific Exclusion Criteria for R/R AML: Active graft-versus-host-disease requiring immunosuppressive treatment. Any immunosuppressive medication (eg, calcineurin inhibitors) must be stopped ≥4 weeks prior to the first dose of GEN3014. Please refer to the protocol section 5.2.2 for the full list of Exclusion criteria for the Expansion Part B (Randomized H2H).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. - Incidence of DLTs
2. - Safety: Incidence and severity of adverse events (AEs) and serious adverse events (SAEs), including changes in laboratory values, vital signs, electrocardiograms (ECGs)
3. - Tolerability: Dose interruptions, delay, and dose intensity. Please refer to the protocol section 3 (Tables 3-2 and 3-3) for the full list of primary endpoints for the Expansion Part A (GEN3014 Single Cohorts) and Expansion Part B (Randomized H2H) of the study, respectively.

Secondary endpoints 3

1. • Noncompartmental PK parameters (if feasible): o Maximum concentration (Cmax) o Time to Cmax (Tmax) o Predose concentration (Ctrough) o Area under the concentration-time curve from time zero to last quantifiable sample (AUC0-last) and from time zero to 168 h (AUC0- 168h) o Accumulation ratios in Cmax (RA,Cmax) and AUC (RA,AUC]. In addition, a population PK modeling approach may be employed.
2. • Anti-GEN3014 antibodies • Objective response rate (ORR) • Clinical benefit rate (CBR) • Duration of response (DOR) • Time-to-response (TTR)
3. • Progression-free survival (PFS) • Overall survival (OS).Please refer to the protocol section 3 (Tables 3-2 and 3-3) for the full list of secondary endpoints for the Expansion Part A (GEN3014 Single Cohorts) and Expansion Part B (Randomized H2H) of the study, respectively.

Investigational products

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

Test 1

Comparator 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Genmab A/S

Sponsor organisation

Genmab A/S

Address

Carl Jacobsens Vej 30

City

Valby

Postcode

2500

Country

Denmark

Scientific contact point

Organisation

Genmab A/S

Contact name

Information

Public contact point

Organisation

Genmab A/S

Contact name

Information

Third parties 15

Locations

7 EU/EEA countries · 17 investigational sites

By country

Investigational sites

Country notifications

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

Results and documents

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

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 48 files

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

Application history

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