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A Phase 1/2a, Open-Label, Dose Escalation Trial of GEN3017 With Expansion Cohorts in Relapsed or Refractory CD30+ Classical Hodgkin Lymphoma and CD30+ Non-Hodgkin Lymphoma

A First-in-human Trial of GEN3017 in Hodgkin Lymphoma and Non-Hodgkin Lymphoma

9

A total of 9 subjects signed the informed consent form (ie, were enrolled) and received at least one dose of GEN3017. This included 4 subjects with relapsed or refractory (R/R) CD30+ classical Hodgkin lymphoma (cHL) and 5 subjects with R/R CD30+ T-cell lymphoma (TCL). In the cHL cohort 1 subject received DL1 (medium priming dose + low full dose) and 3 subjects received DL2 (high priming dose + high full dose). In the TCL cohort 2 subjects received DL1 (medium priming dose + low full dose) and 3 subjects received DL2 (low priming dose + high full dose). In the cHL cohort, the median age was 57.0 years old (range: 41 to 72). Two (50.0%) subjects were male and 3 (75.0%) subjects were White. All subjects had an ECOG performance status of 0 or 1 at screening. All subjects had received 3 to 8 prior lines of anti-cancer therapy. In the TCL cohort, the median age was 54.0 years old (range: 24 to 75). Four (80.0%) subjects were male and 4 (80.0%) subjects were White. All subjects had an ECOG performance status of 0 or 1 at screening. All subjects had received 2 to 6 prior lines of anti-cancer therapy.

In the cHL cohort, the median number of cycles of GEN3017 received was 4.5 cycles (range: 2, 5) and the median duration of exposure was 3.10 months (range: 1.8, 3.9). In the TCL cohort, the median number of cycles of GEN3017 received was 3.0 cycles (range: 1, 8) and the median duration of exposure was 2.30 months (range: 0.6, 5.6). All subjects have discontinued treatment. Seven (77.8%) subjects discontinued treatment due to disease progression according to response criteria, 1 (11.1%) subject discontinued due to clinical progression, and 1 (11.1%) subject discontinued treatment due to sponsor decision. All subjects had also discontinued from the trial: 5 (55.6%) subjects due to sponsor decision and 4 (44.4%) due to death.

In the cHL cohort, all 4 (100%) subjects experienced at least 1 TEAE. The TEAEs that occurred in >1 subject were injection site reaction and rash maculo-papular (3 subjects each; 75.0%) and headache (2 subjects; 50.0%). Two (50.0%) subjects experienced at least 1 Grade >=3 TEAE, including rash maculo-papular and urticaria in 1 (25.0%) subject each. Both events were Grade 3. In the cHL cohort, all 4 (100%) subjects experienced at least 1 related TEAE. The related TEAEs that occurred in >1 subject were injection site reaction and rash maculo-papular (3 subjects each; 75.0%). One (25.0%) subject experienced at least 1 related Grade >=3 TEAE. This was an event of Grade 3 urticaria. In the cHL cohort, 1 (25.0%) subject experienced at least 1 serious TEAE. This event was tumor pain and it was reported as unrelated to GEN3017. Overall, no subject died due to a Grade 5 TEAE. In the cHL cohort, 1 (25.0%) subject died. This subject died due to disease progression more than 100 days after the last dose of GEN3017. In the cHL cohort, all 4 (100%) subjects experienced at least 1 TEAE considered to be a skin reaction, all of which were in the System Organ Class (SOC) of Skin and Subcutaneous Tissue Disorders. TEAEs included rash maculo-papular (3 subjects; 75.0%), and rash, skin exfoliation, and urticaria (1 subject each; 25.0%). These subjects experienced Grade 1 (1 subject; 25.0%), Grade 2 (1 subject; 25.0%), and Grade 3 (2 subjects; 50.0%) events. No subject experienced serious events but 1 (25.0%) subject had an event that led to dose delay. In the cHL cohort, 1 (25.0%) subject experienced at least 1 event of cytokine release syndrome (CRS). This was a Grade 1 CRS event that was not serious and considered related to GEN3017. The event did not lead to treatment discontinuation or dose interruption/delay. In the TCL cohort, all 5 (100%) subjects experienced at least 1 TEAE. The TEAEs that occurred in >1 subject were pyrexia, rash maculo-papular, and thrombocytopenia (3 subjects each; 60.0%) and anemia, cytokine release syndrome, decreased appetite, hypoalbuminemia, leukopenia, neutropenia, and sepsis (2 subjects each; 40.0%). Four (80.0%) subjects experienced at least 1 Grade >=3 TEAE, including anemia (Grade 3), leukopenia (Grade 3 and Grade 4), neutropenia (Grade 4), and sepsis (Grade 3) (2 subjects each; 40.0%) and blood alkaline phosphatase increased (Grade 3), febrile neutropenia (Grade 3), thrombocytopenia (Grade 4), and vascular access complication (Grade 3) in 1 (20.0%) subject each. In the TCL cohort, all 5 (100%) subjects experienced at least 1 related TEAE. The related TEAEs that occurred in >1 subject were thrombocytopenia and rash maculo-papular (3 subjects each; 60.0%) and cytokine release syndrome (CRS) (2 subjects; 40.0%). Three (60.0%) subjects experienced at least 1 related Grade >=3 TEAE. These TEAEs included anemia, febrile neutropenia, leukopenia, neutropenia, and thrombocytopenia in 1 (20.0%) subject each. In the TCL cohort, 4 (80.0%) subjects experienced at least 1 serious TEAE, including pyrexia in 3 (60.0%) subjects, CRS in 2 (40.0%) subjects, sepsis in 2 (40.0%) subjects, and febrile neutropenia in 1 (20.0%) subject. The events of febrile neutropenia and CRS were reported as related to GEN3017. Overall, no subject died due to a Grade 5 TEAE. In the TCL cohort, 3 (60.0%) subjects died. Of these, 2 (40.0%) subjects died due to disease progression and 1 (20.0%) subject died due to a reason of other. All 3 deaths occurred between 30 and 100 days after the last dose of GEN3017. In the TCL cohort, 4 (80.0%) subjects experienced at least 1 TEAE considered to be a skin reaction, all of which were in the SOCs of Skin and Subcutaneous Tissue Disorders and Infections and Infestations. TEAEs included rash maculo-papular (3 subjects; 60.0%) and rash and rash pustular in 1 (20.0%) subject each. These subjects experienced Grade 1 (2 subjects; 40.0%) and Grade 2 (2 subjects; 40.0%) events. No subject experienced events considered serious or events that led to dose delay. In the TCL cohort, 2 (40.0%) subjects experienced at least 1 event of CRS. Both subjects experienced Grade 1 serious events that were suspected by the investigator to be related to GEN3017. Neither event led to treatment discontinuation or dose interruption/delay.

In the cHL cohort, 2 subjects experienced dose-limited toxicities (DLTs). The first subject experienced Grade 3 urticaria on study day 4 after receiving their dose of GEN3017 and Grade 3 urticaria on study day 10 after their dose of GEN3017. The second subject experienced Grade 3 rash maculo-papular on study day 4 after receiving their dose of GEN3017. The event led to a delay in the next dose of GEN3017. In the TCL cohort, no DLTs were observed. In the cHL cohort, the 1 subject who received DL1 (medium priming dose + low full dose) had a best overall response of progressive disease. Of the 3 subjects who received DL2 (high priming dose + high full dose), 1 (33.3%) subject each had a best overall response of partial response, stable disease, and progressive disease. An overall response rate (ORR) of 33.3% was observed at this dose level. In the subject who had a response, the time to response (TTR) was 1.18 months and the duration of response (DOR) was 2.23 months. In the TCL cohort, of the 2 subjects who received DL1 (medium priming dose + low full dose), 1 (50.0%) subject each had a best overall response of complete response and not evaluable. An ORR of 50.0% was observed at this dose level. Of the 3 subjects who received DL2 (low priming dose + high full dose), 2 (66.7%) subjects had a best overall response of progressive disease and 1 (33.3%) subject had a best response of not evaluable. An ORR of 0% was observed at this dose level. In the subject who had a response, the TTR was 1.25 months and the DOR was 4.17 months. The pharmacokinetic (PK) parameters and PK profiles across cohorts and dose levels followed the typical characteristics of monoclonal antibodies administered with an absorption and elimination phase. The limited sample size did not allow for evaluation of the PK linearity. In the cHL cohort, 1 (25.0%) subject was anti-drug antibody (ADA) positive. In the TCL cohort, 1 (20.0%) subject was ADA positive.

Clinical activity of single-agent GEN3017 has been observed in a single subject in both cHL and TCL. Observed CRS events were of low grade and no immune effector cell-associated neurotoxicity syndrome was reported. The mechanism of cutaneous toxicities was unclear. No strong conclusions can be made, as this study was terminated by the sponsor for strategic reasons.

No

https://jrct.mhlw.go.jp/latest-detail/jRCT2031230576

Genmab Trial Information

Genmab

35F, Midtown Tower, 9-7-1 Akasaka, Minato-ku, Tokyo

clinicaltrial-jp@genmab.com

Contact for Clinical Trial Information

Genmab K.K.

35F, Midtown Tower, 9-7-1 Akasaka, Minato-ku, Tokyo

+81-3-4494-8615

clinicaltrial-jp@genmab.com

Complete

Oct. 01, 2024

Interventional

non-randomized controlled trial

open(masking not used)

dose comparison control

single assignment

treatment purpose

Dose Escalation Part:
1. Must be at least 18 years of age.
2. Histologically confirmed R/R cHL or R/R TCL.
3. Participants must have at least 1 measurable lesion by fluorodeoxyglucose-positron emission tomography (FDG-PET) scan demonstrating positive lesion compatible with computed tomography (CT)- or magnetic resonance imaging (MRI)-defined anatomical tumor sites and a CT scan (or MRI) with involvement of >=1 measurable nodal lesion and/or >=1 measurable extranodal lesion.
4. Eastern Cooperative Oncology Group (ECOG) performance status score 0 or 1 for participants.
5. Confirmed CD30-positivity in tumor biopsy prior to the first dose of GEN3017.
6. R/R cHL Cohort:
- Must have relapsed or progressive cHL after receiving at least 2 or 3 prior lines of therapy; OR
- Refractory to the second line of therapy.

1. Primary central nervous system (CNS) tumor or known CNS involvement.
2. Received prior investigational CD30-targeting therapy.
3. Autologous hematopoietic stem cell transplant (HSCT) within 60 days prior to the first dose of GEN3017 or any prior allogeneic HSCT.
4. Chemotherapy within 2 weeks or major surgery within 4 weeks prior to the first dose of GEN3017.
5. Curative radiotherapy within 4 weeks or palliative radiotherapy within 2 weeks prior to the first dose of GEN3017.
6. Treatment with an investigational drug within 4 weeks or 5 half-lives of the drug, whichever is shorter prior to the first dose of GEN3017 or currently receiving any other investigational agents.
7. Prior treatment with live, attenuated vaccines within 30 days prior to the first dose of GEN3017.
8 Receiving immunosuppressive drugs or systemic corticosteroids such as prednisone at doses >25 milligrams (mg) daily or its equivalent within 14 days prior to the first dose of GEN3017.

Both

Classical Hodgkin Lymphoma and Non-Hodgkin Lymphoma

Biological: GEN3017

- Incidence of dose-limiting toxicities (DLTs)
- Incidence and severity of adverse events (AEs)
- ORR based on the Lugano criteria as assessed by independent review committee (IRC)

+81-3-3542-2511

Jan. 26, 2024

USA/Australia/Denmark/France/Germany/Italy/Netherlands