Clinical trial NCT04824794: GEN3014 Trial in Relapsed or Refractory Hematologic Malignancies
Official title: An Open-Label, Multicenter, Phase 1/2 Trial of GEN3014 (HexaBody®-CD38) in Relapsed or Refractory Multiple Myeloma and Other Hematologic Malignancies
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Relapsed or Refractory Multiple Myeloma (RRMM)
Diffuse Large B Cell Lymphoma (DLBCL)
Acute Myeloid Leukemia (AML)
Keywords: Hexabody®
Anti-CD38
monoclonal antibody
Lead sponsor: Genmab
Sponsor class: INDUSTRY
First posted: 2021-04-01
Enrollment: 130
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
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.
Primary purpose: TREATMENT

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.

Eligibility 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 Exclusion Criteria for RRMM:

* Prior allogeneic hematopoietic stem cell transplant (HSCT).
* Autologous HSCT within 3 months of the first dose of GEN3014.

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 GEN3014.
* Prior autologous HSCT.
* Allogenic HSCT within 3 months of the first dose of GEN3014.
* 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.

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Primary outcomes:
measure: Dose Escalation: Number of Participants with Dose Limiting Toxicities (DLTs)
timeFrame: Up to 28 days during the first cycle (cycle =28 days)
measure: Dose Escalation: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: From first dose until the end of the safety follow-up period (30 days after last dose; up to 8 years)
measure: Expansion Part A: Objective Response Rate (ORR) of GEN3014
timeFrame: Up to 8 years
measure: Expansion Part B: Objective Response Rate (ORR) of GEN3014 IV vs Daratumumab SC in Anti-CD38 mAb-naive RRMM Participants
timeFrame: Up to 8 years
Secondary outcomes:
measure: Dose Escalation: Maximum (peak) Plasma Concentration (Cmax) of GEN3014
timeFrame: 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)
measure: Dose Escalation: Time to Reach Cmax (Tmax) of GEN3014
timeFrame: 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)
measure: Dose Escalation: Pre-dose (trough) Concentrations (Ctrough) of GEN3014
timeFrame: Predose and postdose at multiple timepoints of each Cycle (Cycle length=28 days) (Up to 8 years)
measure: Dose Escalation: Area Under the Concentration Time Curve From Zero to Last Quantifiable Sample (AUC0-last)
timeFrame: 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)
measure: Dose Escalation: Area Under the Concentration Time Curve From Zero to 168 hours (AUC0-168 h)
timeFrame: 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)
measure: Dose Escalation: Accumulation Ratio in Cmax (RA, Cmax)
timeFrame: 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)
measure: Dose Escalation: Accumulation Ratio in AUC (RA, AUC)
timeFrame: 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)
measure: Dose Escalation: Number of Participants with Anti-Drug Antibody (ADA) of GEN3014
timeFrame: From first dose until treatment discontinuation (Up to 8 years)
measure: Dose Escalation: Objective Response Rate (ORR) of GEN3014
timeFrame: Up to 8 years
measure: Dose Escalation: Clinical Benefit Rate (CBR) of GEN3014
timeFrame: Up to 8 years
measure: Dose Escalation: Duration of Response (DOR) of GEN3014
timeFrame: Up to 8 years
measure: Dose Escalation: Time-to-response (TTR) of GEN3014
timeFrame: Up to 8 years
measure: Dose Escalation: Progression-free survival (PFS) of GEN3014
timeFrame: Up to 8 years
measure: Dose Escalation: Overall Survival (OS) of GEN3014
timeFrame: Up to 8 years
measure: Expansion Part A: Clinical Benefit Rate (CBR) of GEN3014
timeFrame: Up to 8 years
measure: Expansion Part A: Duration of Response (DOR) of GEN3014
timeFrame: Up to 8 years
measure: Expansion Part A: Time-to-response (TTR) of GEN3014
timeFrame: Up to 8 years
measure: Expansion Part A: Progression-free survival (PFS) of GEN3014
timeFrame: Up to 8 years
measure: Expansion Part A: Overall Survival (OS) of GEN3014
timeFrame: Up to 8 years
measure: Expansion Part A: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) per CTCAE Version 5.0
timeFrame: From first dose until the end of the safety follow-up period (30 days after last dose) (Up to 8 years)
measure: Expansion Part A: Number of Participants with Anti-Drug Antibody (ADA) of GEN3014
timeFrame: From first dose until treatment discontinuation (Up to 8 years)
measure: Expansion Part A: Maximum (peak) Plasma Concentration (Cmax) of GEN3014
timeFrame: 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)
measure: Expansion Part A: Time to Reach Cmax (Tmax) of GEN3014
timeFrame: 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)
measure: Expansion Part A: Pre-dose (trough) Concentrations (Ctrough) of GEN3014
timeFrame: Predose and postdose at multiple timepoints of each Cycle (Cycle length=28 days) (Up to 8 years)
measure: Expansion Part A: Area Under the Concentration Time Curve From Zero to Last Quantifiable Sample (AUC0-last)
timeFrame: 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)
measure: Expansion Part A: Area Under the Concentration Time Curve From Zero to 168 hours (AUC0-168 h)
timeFrame: 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)
measure: Expansion Part A: Accumulation Ratio in Cmax (RA, Cmax)
timeFrame: 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)
measure: Expansion Part A: Accumulation Ratio in AUC (RA, AUC)
timeFrame: 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)
measure: Expansion Part A: Accumulation Ratio in Ctrough (RA,Ctrough)
timeFrame: 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)
measure: Expansion Part B: Ctrough Levels of GEN3014 IV or Daratumumab SC on Cycle 3 Day 1
timeFrame: Cycle 3 Day 1 (cycle = 28 days)
measure: Expansion Part B: Very Good Partial Response (VGPR), or better of GEN3014 IV vs Daratumumab SC
timeFrame: Up to 8 years
measure: Expansion Part B: Complete Response (CR) or better of GEN3014 IV vs Daratumumab SC
timeFrame: Up to 8 years
measure: Expansion Part B: Duration of Response (DOR) of GEN3014 IV vs Daratumumab SC
timeFrame: Up to 8 years
measure: Expansion Part B: Time-to-response (TTR) of GEN3014 IV vs Daratumumab SC
timeFrame: Up to 8 years
measure: Expansion Part B: Progression-free Survival (PFS) of GEN3014 IV vs Daratumumab SC
timeFrame: Up to 8 years
measure: Expansion Part B: Overall Survival (OS) of GEN3014 IV vs Daratumumab SC
timeFrame: Up to 8 years
measure: Expansion Part B: Time to Next Therapy (TTNT)
timeFrame: Up to 8 years
measure: Expansion Part B: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) per CTCAE Version 5.0
timeFrame: From first dose until the end of the safety follow-up period (30 days after last dose) (Up to 8 years)
measure: Expansion Part B: Number of Participants with Anti-Drug Antibody (ADA) of GEN3014 and Anti-daratumumab Antibodies
timeFrame: From first dose until treatment discontinuation (Up to 8 years)
Other outcomes:
Locations:
city: Hackensack
country: United States
facility: John Theurer Cancer Center
state: New Jersey
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Center
state: Ohio
city: Milwaukee
country: United States
facility: Medical college of Wisconsin
state: Wisconsin
city: Epping
country: Australia
facility: Northern Health
city: Melbourne
country: Australia
facility: The Alfred Hospital
city: Sydney
country: Australia
facility: Royal Prince Alfred Hospital
city: Banja Luka
country: Bosnia and Herzegovina
facility: University Clinical Center of the Republic of the Srpska
city: Sarajevo
country: Bosnia and Herzegovina
facility: Klinika za hematologiju KCUS
city: Tuzla
country: Bosnia and Herzegovina
facility: UKC - University Clinical Center Tuzla
city: Brno
country: Czechia
facility: Fakultni Nemocnice Brno
city: Nové Město
country: Czechia
facility: Vseobecna fakultni nemocnice
city: Nový Hradec Králové
country: Czechia
facility: Fakultni Nemocnice Hradec Kralove FNHK
city: Olomouc
country: Czechia
facility: Fakultni Nemocnice Olomouc (FNOL)
city: Poruba
country: Czechia
facility: FNO - Fakultni nemocnice Ostrava
city: Aalborg
country: Denmark
facility: Aalborg Universitet
city: Vejle
country: Denmark
facility: Vejle Hospital
city: Lille
country: France
facility: CHRU de Lille
city: Nantes
country: France
facility: CHRU de Nantes
city: Tbilisi
country: Georgia
facility: ARENSIA Exploratory Medicine LLC
city: Athens
country: Greece
facility: Alexandra General Hospital
city: Athens
country: Greece
facility: Evangelismos Hospital NKUA
city: Río
country: Greece
facility: University General Hospital of Patras
city: Thessaloníki
country: Greece
facility: Ahepa University General hospital
city: Nyíregyháza
country: Hungary
facility: Szabolcs-Szatmar-Bereg County Hospitals and University Hospital, Josa Andras University Hospital
city: Gwangju
country: Korea, Republic of
facility: Chonnam National University Hwasun Hospital
city: Pusan
country: Korea, Republic of
facility: Pusan National University Hospital PNUH
city: Seongnam
country: Korea, Republic of
facility: Gachon University Gil Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Ampang
country: Malaysia
facility: Hospital Ampang
city: Johor Bahru
country: Malaysia
facility: Hospital Sultanah Aminah
city: Kuching
country: Malaysia
facility: Hospital Umum Sarawak
city: Petaling Jaya
country: Malaysia
facility: Beacon Hospital
city: Chisinau
country: Moldova, Republic of
facility: Institute of Oncology, ARENSIA Exploratory Medicine
city: Maastricht
country: Netherlands
facility: Maastricht UMC
city: Rotterdam
country: Netherlands
facility: Erasmus MC
city: Utrecht
country: Netherlands
facility: UMC Utrecht
city: Christchurch
country: New Zealand
facility: Christchurch Hospital
city: Grafton
country: New Zealand
facility: Auckland Cancer Trials Centre
city: Palmerston North
country: New Zealand
facility: Palmerston North Hospital
city: Takapuna
country: New Zealand
facility: North Shore Hospital
city: Skopje
country: North Macedonia
facility: University Clinic of Hematology
city: Makati City
country: Philippines
facility: Makati Medical Center
city: Gdańsk
country: Poland
facility: University Centrum Kliniczne
city: Katowice
country: Poland
facility: Pratia Onkologia Katowice
city: Kraków
country: Poland
facility: Pratia MCM
city: Wrocław
country: Poland
facility: Wroclaw Medical University
city: Pamplona
country: Spain
facility: University of Navarra
city: Salamanca
country: Spain
facility: University Hospital of Salamanca
city: Huddinge
country: Sweden
facility: Karolinska Institute
city: Lund
country: Sweden
facility: Universitetssjukhuset i Lund
city: Kyiv
country: Ukraine
facility: Arensia Exploratory Medicine
Study officials:
affiliation: Genmab
name: Study Official
role: STUDY_DIRECTOR
References: