An Open-Label, Multicenter, Phase 1/2 Trial of GEN3014 (HexaBody®-CD38) in Relapsed or Refractory Multiple Myeloma and Other Hematologic Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- Genmab
- 入组人数
- 130
- 试验地点
- 72
- 主要终点
- Dose Escalation: Number of Participants With Dose Limiting Toxicities (DLTs)
研究概览
简要总结
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:
- The Dose Escalation will test increasing doses of GEN3014 to identify a safe dose level to be tested in the other two parts.
- Expansion Part A will further test the GEN3014 dose determined from the Dose Escalation.
- 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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
- •Expansion Part A (for DLBCL): ECOG PS 0 or
- •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 GEN
- •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.
排除标准
- •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 Exclusion Criteria for RRMM:
- •Prior allogeneic hematopoietic stem cell transplant (HSCT).
- •Autologous HSCT within 3 months of the first dose of GEN
- •Specific Exclusion Criteria for R/R AML:
- •<5% blasts in blood or bone marrow at Screening.
- •White blood cell (WBC) counts ≥50,000/microliter (μL) in peripheral blood that cannot be controlled by hydroxyurea prior to the first dose of GEN
- •Prior autologous HSCT.
- •Allogenic HSCT within 3 months of the first dose of GEN
- •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 GEN
- •NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.
研究组 & 干预措施
Daratumumab
Participants in Expansion Part B with
- RRMM (anti-CD38 mAb-naïve)
干预措施: Daratumumab (Drug)
GEN3014
Experimental: GEN3014 Participants in Dose Escalation phase with
- RRMM
- R/R AML
Participants in Expansion Part A with
- RRMM (anti-CD38 mAb-naïve)
- RRMM (anti-CD38 mAb-refractory)
- R/R DLBCL
- R/R AML
Participants in Expansion Part B with
• RRMM (anti-CD38 mAb-naïve)
干预措施: GEN3014 (Biological)
结局指标
主要结局
Dose Escalation: Number of Participants With Dose Limiting Toxicities (DLTs)
时间窗: 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)
时间窗: 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)
时间窗: 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
时间窗: 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.
次要结局
- Dose Escalation: Time-to-response (TTR) of GEN3014(Up to 8 years)
- 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))
- 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))
- Dose Escalation: Maximum (peak) Plasma Concentration (Cmax) of GEN3014(Predose and postdose at multiple timepoints up to Cycle 6 (Cycle length=28 days); Pre-dose and 5 minutes post end of infusion from Cycle 7 and beyond (Up to 8 years))
- Dose Escalation: Pre-dose (trough) Concentrations (Ctrough) of GEN3014(Predose and postdose at multiple timepoints of each Cycle (Cycle length=28 days) (Up to 8 years))
- Dose Escalation: Area Under the Concentration Time Curve From Zero to Last Quantifiable Sample (AUC0-last)(Predose and postdose at multiple timepoints up to Cycle 6 (Cycle length=28 days); Pre-dose and 5 minutes post end of infusion from Cycle 7 and beyond (Up to 8 years))
- Dose Escalation: Area Under the Concentration Time Curve From Zero to 168 hours (AUC0-168 h)(Predose and postdose at multiple timepoints up to Cycle 6 (Cycle length=28 days); Pre-dose and 5 minutes post end of infusion from Cycle 7 and beyond (Up to 8 years))
- Dose Escalation: Number of Participants with Anti-Drug Antibody (ADA) of GEN3014(From first dose until treatment discontinuation (Up to 8 years))
- Dose Escalation: Objective Response Rate (ORR) of GEN3014(Up to 8 years)
- Dose Escalation: Clinical Benefit Rate (CBR) of GEN3014(Up to 8 years)
- Dose Escalation: Duration of Response (DOR) of GEN3014(Up to 8 years)
- Dose Escalation: Progression-free survival (PFS) of GEN3014(Up to 8 years)
- Dose Escalation: Overall Survival (OS) of GEN3014(Up to 8 years)
- Expansion Part A: Clinical Benefit Rate (CBR) of GEN3014(Up to 8 years)
- Expansion Part A: Duration of Response (DOR) of GEN3014(Up to 8 years)
- Expansion Part A: Time-to-response (TTR) of GEN3014(Up to 8 years)
- Expansion Part A: Progression-free survival (PFS) of GEN3014(Up to 8 years)
- Expansion Part A: Overall Survival (OS) of GEN3014(Up to 8 years)
- Expansion Part A: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) per CTCAE Version 5.0(From first dose until the end of the safety follow-up period (30 days after last dose) (Up to 8 years))
- Expansion Part A: Number of Participants with Anti-Drug Antibody (ADA) of GEN3014(From first dose until treatment discontinuation (Up to 8 years))
- Expansion Part A: Maximum (peak) Plasma Concentration (Cmax) of GEN3014(Predose and postdose at multiple timepoints up to Cycle 6 (Cycle length=28 days); Pre-dose and 5 minutes post end of infusion from Cycle 7 and beyond (Up to 8 years))
- Expansion Part A: Pre-dose (trough) Concentrations (Ctrough) of GEN3014(Predose and postdose at multiple timepoints of each Cycle (Cycle length=28 days) (Up to 8 years))
- Expansion Part B: Ctrough Levels of GEN3014 IV or Daratumumab SC on Cycle 3 Day 1(Cycle 3 Day 1 (cycle = 28 days))
- Expansion Part B: Very Good Partial Response (VGPR), or better of GEN3014 IV vs Daratumumab SC(Up to 8 years)
- Expansion Part B: Complete Response (CR) or better of GEN3014 IV vs Daratumumab SC(Up to 8 years)
- Expansion Part B: Duration of Response (DOR) of GEN3014 IV vs Daratumumab SC(Up to 8 years)
- Expansion Part B: Time-to-response (TTR) of GEN3014 IV vs Daratumumab SC(Up to 8 years)
- Expansion Part B: Progression-free Survival (PFS) of GEN3014 IV vs Daratumumab SC(Up to 8 years)
- Expansion Part B: Overall Survival (OS) of GEN3014 IV vs Daratumumab SC(Up to 8 years)
- Expansion Part B: Time to Next Therapy (TTNT)(Up to 8 years)
- Expansion Part B: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) per CTCAE Version 5.0(From first dose until the end of the safety follow-up period (30 days after last dose) (Up to 8 years))
- Expansion Part B: Number of Participants with Anti-Drug Antibody (ADA) of GEN3014 and Anti-daratumumab Antibodies(From first dose until treatment discontinuation (Up to 8 years))
- 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))
- 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))
- 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)
- Dose Escalation: ORR(Up to approximately 4 years 3 months)
- Dose Escalation and Expansion Part A: Clinical Benefit Rate (CBR)(Up to approximately 4 years 3 months)
- Dose Escalation, Expansion Part A and Expansion Part B: Duration of Response (DOR)(Up to approximately 4 years 3 months)
- Dose Escalation, Expansion Part A and Expansion Part B: Time-to-response (TTR)(Up to approximately 4 years 3 months)
- Dose Escalation, Expansion Part A and Expansion Part B: Progression-free Survival (PFS)(Up to approximately 4 years 3 months)
- Dose Escalation, Expansion Part A and Expansion Part B: Overall Survival (OS)(Up to approximately 4 years 3 months)
- Expansion Part A and Part B: Number of Participants With AEs and SAEs(Up to approximately 4 years 3 months)
- Expansion Part B: Percentage of Participants With Very Good Partial Response (VGPR) or Better(Up to approximately 4 years 3 months)
- Expansion Part B: Percentage of Participants With Complete Response (CR) or Better(Up to approximately 4 years 3 months)
- Expansion Part B: Time to Next Therapy (TTNT)(Up to approximately 4 years 3 months)
- 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))