Acute Myeloid Leukemia (AML), Diffuse Large B Cell Lymphoma (DLBCL), Relapsed or Refractory Multiple Myeloma (RRMM)
Conditions
Keywords
Hexabody®, Anti-CD38, monoclonal antibody
Brief summary
The drug that will be investigated in the study is an antibody, GEN3014. Since this is the first study of GEN3014 in humans, the main purpose is to evaluate safety. In addition to safety, the study will determine the recommended GEN3014 dose to be tested in a larger group of participants and assess preliminary clinical activity of GEN3014. GEN3014 will be studied in relapsed (disease has returned) or refractory (resistant to treatment) multiple myeloma (also known as RRMM) and other blood cancers. The study consists of 3 parts: 1. The Dose Escalation will test increasing doses of GEN3014 to identify a safe dose level to be tested in the other two parts. 2. Expansion Part A will further test the GEN3014 dose determined from the Dose Escalation. 3. Expansion Part B will compare intravenous (IV) GEN3014 with the subcutaneous (SC) daratumumab in ex-US countries. Participants will receive either GEN3014 into the vein or daratumumab under the skin; none will be given placebo. The study duration will be different for the individual participants. Overall, the study may be ongoing up to 5 years after the last participant's first treatment.
Detailed description
This trial will be conducted in 3 parts: Dose Escalation (phase 1), Expansion Parts, A and B (phase 2). In the dose escalation phase GEN3014 will be evaluated in RRMM and relapsed and refractory acute myeloid leukemia (R/R AML). The participants will receive GEN3014 administered at various dose levels in 28-day cycles. Dose Limiting Toxicities (DLTs) will be assessed during the first treatment cycle and the Maximum Tolerated Dose (MTD) and/or Recommended phase 2 dose (RP2D) will be determined. In Expansion Part A, GEN3014 will be further evaluated in 4 cohorts: anti-CD38 monoclonal antibody (mAb)-naive RRMM, anti-CD38 mAb-refractory RRMM, relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL), and R/R AML at the RP2D identified from the Dose Escalation. In Expansion Part B, GEN3014 IV will be compared to daratumumab SC, head-to-head (H2H) to evaluate whether GEN3014 may be more potent in anti-CD38 mAb-naïve RRMM participants.
Interventions
GEN3014 is administered by IV infusion.
Daratumumab is administered by SC injections.
Sponsors
Study design
Intervention model description
Dose escalation part is sequential while the expansion Part A cohorts are parallel. Expansion Part B is sequential to Expansion Part A RRMM cohort. In Expansion Part B, participants with RRMM are randomized (1:1) to treatment.
Eligibility
Inclusion criteria
Key Inclusion Criteria * Must have fresh bone marrow samples collected at Screening for RRMM, R/R AML, and R/R DLBCL with suspected bone marrow involvement. * Dose Escalation phase, Expansion Part A (for MM and AML) and Expansion Part B- Eastern Cooperative Oncology Group (ECOG) performance status (PS) score 0, 1, or 2. Expansion Part A (for DLBCL): ECOG PS 0 or 1. * Has acceptable laboratory test results during the Screening period. * 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. * 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. * 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. * 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 not donate sperm during the trial and for 12 months after receiving the last dose of GEN3014 or daratumumab SC. Specific for RRMM: * 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: * Immunoglobulin (Ig) G, 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. Note: Participants with RRMM must have exhausted standard therapies, at the investigator's discretion. * For anti-CD38 mAb-naive RRMM Cohort: Participant received at least 3 prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory imide drug (IMiD) in any order, or is double refractory to a PI and an IMiD; or participant received ≥ 2 prior lines of therapy if 1 of those lines included a combination of PI and IMiD. Note: Participants should not have received any anti-CD38 antibody. * Anti-CD38 mAb-naive RRMM participants will be enrolled from ex-US countries. * Dose Escalation phase - For anti-CD38 mAb-treated RRMM Cohort: 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. Specific for R/R AML: * 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 participants who have been in 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. * Participant with relapsed AML who received at least 2 prior therapies for AML with the exception of hydroxyurea. * Participant with refractory AML who received at least 1 prior line of therapy for AML with the exception of hydroxyurea. * Participant's life expectancy at Screening is judged to be at least 3 months. Specific for DLBCL: * Expansion phase: Relapsed or refractory DLBCL, both de novo or histologically transformed. Participants with R/R DLBCL must have exhausted standard therapies, at the investigator's discretion. * Expansion phase: Received at least 2 prior lines of systemic therapy, with 1 being a CD20-containing chemoimmunotherapy. * Expansion phase: Have at least 1 measurable site of disease as per Lugano criteria. * Expansion phase: Must have available archival or fresh tumor tissue or both to submit to a central laboratory for CD38 assay. Key
Exclusion criteria
* Prior treatment with any CD38-directed therapies (eg, daratumumab, isatuximab, CD38 chimeric antigen receptor T cell (CAR-T), bispecific antibody (Ab)) in anti-CD38 mAb-naive RRMM Cohort. Note: Prior daratumumab or isatuximab exposure is allowed for anti-CD38 mAb-treated RRMM participants in the Dose Escalation and anti-CD38 mAb-refractory RRMM Cohort in the Expansion Part A. * 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). * 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). * 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). * Has clinically significant cardiac disease. * Toxicities from previous anti-cancer therapies have not resolved to baseline levels or to Grade 1 or less except for alopecia and peripheral neuropathy. * Primary central nervous system (CNS) tumor or known CNS involvement at Screening. * Has known history/positive serology for hepatitis B. * Known medical history or ongoing hepatitis C infection that has not been cured. * 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). * Currently receiving any other investigational agents. * 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. * A man who plans to father a child while enrolled in this trial or within 12 months after the last dose of study treatment. Specific
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Escalation: Number of Participants With Dose Limiting Toxicities (DLTs) | 28 days during the first cycle (cycle =28 days) | DLTs were defined as: All Grade 5 toxicities, Grade 4 thrombocytopenia, neutropenia or anemia and Grade 3/4 febrile neutropenia and hemorrhage associated with thrombocytopenia, all non-hematological toxicities of grade ≥3 (with exceptions per protocol), Grade 4 tumor lysis syndrome (TLS), Grade 4 infusion-related reaction (IRR), and any liver toxicity of elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥3 times or greater above the upper limit of normal (ULN) with serum total bilirubin of ≥2 times the upper limit of normal, without findings of cholestasis and in the absence of alternative etiologies. DLTs were graded for severity according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0. |
| Dose Escalation: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Up to approximately 4 years 3 months | An AE was any untoward medical occurrence in a participant or clinical trial participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE was defined as an AE that met 1 of the following criteria: fatal or life-threatening, resulted in persistent or significant disability/incapacity, a congenital anomaly/birth defect, was medically significant (jeopardized the participant or may have required medical or surgical intervention to prevent one of the outcomes listed above), required inpatient hospitalization or prolongation of existing hospitalization. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section. |
| Expansion Part A: Objective Response Rate (ORR) | Up to approximately 4 years 3 months | ORR was defined as the percentage of participants with a partial response (PR) or better based on International Myeloma Working Group (IMWG) criteria for RRMM participants and based on Lugano criteria for DLBCL participants. Per IMWG criteria, PR was defined as ≥50% reduction of serum M-protein plus reduction in 24-h urinary M-protein by ≥90% or to \<200 mg per 24 h. In addition to these criteria, if present at baseline, a ≥50% reduction in the size (sum of the product of the diameters \[SPD\]) of soft tissue plasmacytomas was also required. Per Lugano criteria, PR was defined as ≥50% decrease in SPD of up to 6 target measurable nodes and extranodal sites, absent/normal, regressed, but no increase in non-measurable lesions, spleen regressed \>50% in length beyond normal (13 centimeters \[cm\]), and no new lesions. |
| Expansion Part B: ORR | Up to approximately 4 years 3 months | ORR was defined as the percentage of participants with a PR or better based on IMWG criteria. Per IMWG criteria, PR was defined as ≥50% reduction of serum M-protein plus reduction in 24-h urinary M-protein by ≥90% or to \<200 mg per 24 h. In addition to these criteria, if present at baseline, a ≥50% reduction in the size (SPD) of soft tissue plasmacytomas was also required. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Dose Escalation and Expansion Part A: Maximum (Peak) Plasma Concentration (Cmax) of GEN3014 | Dose Escalation: Cycle 1 Day 1, Cycle 1 Day 8 (RRMM Dose Escalation: GEN3014 0.2/0.6 mg/kg only), Cycle 2 Day 1, Expansion Part A: Cycle 1 Day 1, Cycle 2 Day 1 (cycle =28 days) | Venous blood samples were collected for analyzing concentrations of GEN3014. For the RRMM Dose Escalation 0.2/0.6 mg/kg arm, the participant underwent intraparticipant dose escalation in Cycle 1, where the participant received 0.2 mg/kg during the first week and 0.6 mg/kg from second week and beyond. Therefore, pharmacokinetic (PK) parameters were additionally calculated for Cycle 1 Day 8 dosing only in the RRMM Dose Escalation 0.2/0.6 mg/kg arm to account for the change in dosing over Cycle 1 in this arm. |
| Dose Escalation, Expansion Part A and Expansion Part B: Pre-dose (Trough) Concentrations (Ctrough) of GEN3014 | Dose Escalation: Cycle (C) 1 Day (D) 1, C1D8 (RRMM GEN3014 0.2/0.6 mg/kg, R/R AML Dose Escalation), C2D1, Expansion Part A: C1D1, C2D1 (R/R DLBCL Expansion Part A: C1D8 and C2D8) Expansion Part B: C1D1, C1D8, C2D1, C3D1, C7D1, C8D1 (cycle = 28 days) | Venous blood samples were collected for analyzing concentrations of GEN3014. For the RRMM Dose Escalation 0.2/0.6 mg/kg arm, the participant underwent intraparticipant dose escalation in Cycle 1, where the participant received 0.2 mg/kg during the first week and 0.6 mg/kg from second week and beyond. Therefore, PK parameters were additionally calculated for Cycle 1 Day 8 dosing in the RRMM Dose Escalation 0.2/0.6 mg/kg arm to account for the change in dosing over Cycle 1 in this arm. |
| Dose Escalation and Expansion Part A: Area Under the Concentration Time Curve From Zero to Last Quantifiable Sample (AUC0-last) of GEN3014 | Dose Escalation: Cycle 1 Day 1, Cycle 1 Day 8 (RRMM Dose Escalation: GEN3014 0.2/0.6 mg/kg only), Cycle 2 Day 1, Expansion Part A: Cycle 1 Day 1, Cycle 2 Day 1 (cycle =28 days) | Venous blood samples were collected for analyzing concentrations of GEN3014. For the RRMM Dose Escalation 0.2/0.6 mg/kg arm, the participant underwent intraparticipant dose escalation in Cycle 1, where the participant received 0.2 mg/kg during the first week and 0.6 mg/kg from second week and beyond. Therefore, PK parameters were additionally calculated for Cycle 1 Day 8 dosing only in the RRMM Dose Escalation 0.2/0.6 mg/kg arm to account for the change in dosing over Cycle 1 in this arm. |
| Dose Escalation and Expansion Part A: Area Under the Concentration Time Curve From Zero to 168 Hours (AUC0-168 h) of GEN3014 | Dose Escalation: Cycle 1 Day 1, Cycle 1 Day 8 (RRMM Dose Escalation: GEN3014 0.2/0.6 mg/kg only), Cycle 2 Day 1, Expansion Part A: Cycle 1 Day 1, Cycle 2 Day 1 (R/R DLBCL Expansion Part A: Cycle 1 Day 1 only) (cycle =28 days) | Venous blood samples were collected for analyzing concentrations of GEN3014. For the RRMM Dose Escalation 0.2/0.6 mg/kg arm, the participant underwent intraparticipant dose escalation in Cycle 1, where the participant received 0.2 mg/kg during the first week and 0.6 mg/kg from second week and beyond. Therefore, PK parameters were additionally calculated for Cycle 1 Day 8 dosing only in the RRMM Dose Escalation 0.2/0.6 mg/kg arm to account for the change in dosing over Cycle 1 in this arm. |
| Dose Escalation and Expansion Part A: Number of Participants With Anti-Drug Antibodies (ADAs) to GEN3014 | Dose Escalation: Baseline up to a max of approx. 34.5 months, Expansion Part A: Baseline up to a max of approx. 16.6 months | Venous blood samples were drawn for analysis of ADAs to GEN3014. |
| Dose Escalation: ORR | Up to approximately 4 years 3 months | ORR was defined as the percentage of participants with a PR or better. The response in RRMM Cohorts was assessed following IMWG criteria 2016. Per IMWG criteria, PR was defined as ≥50% reduction of serum M-protein plus reduction in 24-h urinary M-protein by ≥90% or to \<200 mg per 24 h. In addition to these criteria, if present at baseline, a ≥50% reduction in the size (SPD) of soft tissue plasmacytomas was also required. |
| Dose Escalation and Expansion Part A: Clinical Benefit Rate (CBR) | Up to approximately 4 years 3 months | CBR was defined as the percentage of participants with a best overall response of minimal response (MR), partial response (PR), very good partial response (VGPR), complete response (CR) or stringent complete response (sCR) as determined by the investigator per IMWG response criteria for RRMM participants. MR=≥25% but ≤49% reduction of serum M-protein, reduction of 24-h urine by 50%-89% and if present at baseline, ≥50% reduction in the size (SPD) of soft tissue plasmacytomas. PR=≥50% reduction of serum M-protein, reduction in 24-h urinary M-protein by ≥90% or to \<200mg/24h and if present at baseline,≥50% reduction in SPD of soft tissue plasmacytomas. VGPR=Serum+urine M-protein detectable by IFE but not electrophoresis or ≥90% reduction in serum M-protein+urine M-protein level \<100mg/24h. CR=Negative IFE on serum/urine + disappearance of soft tissue plasmacytomas and ≤5% plasma cells in bone marrow aspirates. sCR=CR+normal FLC ratio, absence of clonal cells in bone marrow biopsy by IHC. |
| Dose Escalation, Expansion Part A and Expansion Part B: Duration of Response (DOR) | Up to approximately 4 years 3 months | DOR was defined as time from first response (PR or better) to timing of disease progression or death (due to any cause), whichever came first. |
| Dose Escalation, Expansion Part A and Expansion Part B: Time-to-response (TTR) | Up to approximately 4 years 3 months | TTR was defined as the time from date of first dose, or date of randomization for participants in the Expansion Part B, to time of first response (PR or better). |
| Dose Escalation, Expansion Part A and Expansion Part B: Progression-free Survival (PFS) | Up to approximately 4 years 3 months | PFS was defined as the time from the date of first dose, or date of randomization for participants in the Expansion Part B, to the date of progression or death (due to any cause), whichever came first. |
| Dose Escalation, Expansion Part A and Expansion Part B: Overall Survival (OS) | Up to approximately 4 years 3 months | OS was defined as the time from the date of first dose, or date of randomization for participants in the Expansion Part B, to the date of death due to any cause. |
| Expansion Part A and Part B: Number of Participants With AEs and SAEs | Up to approximately 4 years 3 months | An AE was any untoward medical occurrence in a participant or clinical trial participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE was defined as an AE that met 1 of the following criteria: fatal or life-threatening, resulted in persistent or significant disability/incapacity, a congenital anomaly/birth defect, was medically significant (jeopardized the participant or may have required medical or surgical intervention to prevent one of the outcomes listed above), required inpatient hospitalization or prolongation of existing hospitalization. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section. |
| Expansion Part B: Percentage of Participants With Very Good Partial Response (VGPR) or Better | Up to approximately 4 years 3 months | Based on Investigator Assessment per IMWG 2016 Criteria, VGPR was defined as serum and urine M-protein detectable by immunofixation (IFE) but not on electrophoresis or ≥90% reduction in serum M-protein plus urine M-protein level \<100 mg per 24 h. Data are reported for the percentage of participants with a VGPR or better. |
| Expansion Part B: Percentage of Participants With Complete Response (CR) or Better | Up to approximately 4 years 3 months | CR was defined as negative IFE on the serum and urine and disappearance of any soft tissue plasmacytomas and ≤5% plasma cells in bone marrow aspirates based on Investigator assessment per IMWG response criteria. Data are reported for the percentage of participants with CR or better. |
| Expansion Part B: Time to Next Therapy (TTNT) | Up to approximately 4 years 3 months | TTNT for participants in the Expansion Part B was defined as the time from randomization to the start of subsequent anti-cancer therapy. Participants who withdrew consent or were lost to follow up or died due to causes other than disease progression were censored at their last disease assessment. |
| Expansion Part B: Number of Participants With Anti-GEN3014 Antibodies and Anti-Daratumumab Antibodies | Cycle 1 Day 22 up to a maximum of approximately 23.9 months (cycles = 28 days) | Venous blood samples were drawn for analysis of ADAs to GEN3014 and daratumumab. In the GEN3014 arm, participants were tested for anti-GEN3014-antibodies; in the daratumumab arm, participants were tested for anti-daratumumab-antibodies. |
Countries
Australia, Bosnia and Herzegovina, Czechia, Denmark, France, Georgia, Greece, Hungary, Malaysia, Moldova, Netherlands, New Zealand, North Macedonia, Philippines, Poland, South Korea, Spain, Sweden, Ukraine, United States
Contacts
Genmab
Participant flow
Pre-assignment details
This study had 3 parts (Dose Escalation, Expansion Part A & Part B) and was terminated early. Due to enrollment challenges, the acute myeloid leukemia (AML) Dose Escalation and diffuse large B-cell lymphoma (DLBCL) Expansion Part A cohorts were terminated early. The anti-CD38 monoclonal antibody (mAb)-refractory relapsed or refractory multiple myeloma (RRMM) Cohort and relapsed or refractory (R/R) AML Cohort in Expansion Part A were not opened.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 25 Participants |
| Age, Categorical Between 18 and 65 years | 59 Participants |
| Age, Continuous | 65.3 years STANDARD_DEVIATION 9.35 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian/Other Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 0 Participants |
| Race/Ethnicity, Customized Not Reported | 124 Participants |
| Race/Ethnicity, Customized Other | 7 Participants |
| Race/Ethnicity, Customized White | 101 Participants |
| Region of Enrollment Australia | 12 Participants |
| Region of Enrollment Czechia | 0 Participants |
| Region of Enrollment Denmark | 0 Participants |
| Region of Enrollment Georgia | 0 Participants |
| Region of Enrollment Greece | 1 Participants |
| Region of Enrollment Hungary | 0 Participants |
| Region of Enrollment Malaysia | 3 Participants |
| Region of Enrollment Moldova | 6 Participants |
| Region of Enrollment Netherlands | 1 Participants |
| Region of Enrollment New Zealand | 0 Participants |
| Region of Enrollment North Macedonia | 0 Participants |
| Region of Enrollment Poland | 22 Participants |
| Region of Enrollment South Korea | 2 Participants |
| Region of Enrollment Spain | 0 Participants |
| Region of Enrollment Sweden | 6 Participants |
| Region of Enrollment Ukraine | 26 Participants |
| Region of Enrollment United States | 0 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 1 | 1 / 1 | 1 / 3 | 1 / 3 | 4 / 11 | 2 / 5 | 3 / 5 | 5 / 11 | 2 / 2 | 9 / 43 | 4 / 45 |
| other Total, other adverse events | 1 / 1 | 1 / 1 | 3 / 3 | 3 / 3 | 11 / 11 | 5 / 5 | 5 / 5 | 9 / 11 | 2 / 2 | 34 / 43 | 45 / 45 |
| serious Total, serious adverse events | 1 / 1 | 1 / 1 | 1 / 3 | 2 / 3 | 6 / 11 | 4 / 5 | 4 / 5 | 6 / 11 | 1 / 2 | 11 / 43 | 19 / 45 |