Clinical trial NCT04358458: First-in-Human (FIH) Trial of GEN3009 in Subjects With Relapsed or Refractory B-Cell Non-Hodgkin Lymphomas
Official title: Safety and Efficacy of GEN3009 (DuoHexaBody®-CD37) in Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma - A First-in-Human, Open-label, Phase 1/2a Dose Escalation Trial With Dose Expansion Cohorts
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Diffuse Large B-cell Lymphoma
Follicular Lymphoma
Marginal Zone Lymphoma
Small Lymphocytic Lymphoma
Mantle Cell Lymphoma
Chronic Lymphocytic Leukemia
High-grade B-cell Lymphoma
Primary Mediastinal Large B-cell Lymphoma
Keywords: Anti-CD37, monoclonal antibodies, DuoHexabody®
Lead sponsor: Genmab
Sponsor class: INDUSTRY
First posted: 2020-04-24
Enrollment: 46
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: The drug that will be investigated in the study is an antibody, GEN3009. Since this is the first study of GEN3009 in humans, the main purpose is to evaluate safety. Besides safety, the study will determine the recommended GEN3009 dose to be tested in a larger group of patients and assess preliminary clinical activity of GEN3009. GEN3009 will be studied in a broad group of cancer patients, having different kinds of lymphomas. All patients will get GEN3009 either as a single treatment (monotherapy) or in combination with another antibody-candidate for treatment of cancer in the blood. The study consists of two parts: Part 1 tests increasing doses of GEN3009 ("escalation"), followed by Part 2 which tests the recommended GEN3009 dose from Part 1 ("expansion").

Detailed description: This trial will be conducted in 2 parts: Part 1 (Dose Escalation) and Part 2 (Dose Expansion). All subjects in Part 1 will receive GEN3009, administered at various dose levels in 28-day cycles. Dose Limiting Toxicity (DLT) will be assessed during the first treatment cycle of Part 1 and the Maximum Tolerated Dose (MTD) and/or Recommended phase 2 dose (RP2D) will be identified.

Subjects in Part 2 will be treated with the Part 1-defined RP2D of GEN3009. Some subjects will receive GEN3009 in combination of a fixed dose of another antibody-candidate. Subjects in Part 2 are assigned either to one of 3 groups: Part 2 Monotherapy (hereafter referred to as 'Part 2A'), Part 2 Combination Safety Run-in ('Part2B') or Part 2 Combination ('Part2C').

Various types of B-cell NHLs are studied, including diffuse large B cell lymphoma (DLBCL), high-grade B cell lymphoma (HGBCL), mantle cell lymphoma (MCL), primary mediastinal large B-cell lymphoma (PMBCL), follicular lymphoma (FL), marginal zone lymphoma (MZL) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

Eligibility criteria: Key Inclusion Criteria:

1. Be at least 18 years of age.
2. Must sign an informed consent form prior to any screening procedures.
3. Dose Escalation: Has histologically or cytologically confirmed relapsed and/or refractory B-cell NHL with no available standard therapy or is not a candidate for available standard therapy, and for whom, in the opinion of the investigator, the experimental therapy may be beneficial. All subjects must have received at least two prior lines of systemic therapy.

   Dose Expansion: Has histologically or cytologically confirmed relapsed or refractory B-cell NHL. All subjects must have received at least 2 prior lines of systemic therapy, and,
   1. For FL and DLBCL, at least 1 of the 2 prior lines of treatment must have been a CD20 containing systemic regimen;
   2. For CLL, subjects must have received at least one prior line of BTK inhibitor or BCL 2 inhibitor.
4. Has one of the eligible subtypes of B-cell NHL :

   Dose Escalation: (DLBCL, HGBCL, PMBCL, FL, MCL, MZL, SLL, or CLL). Dose Expansion: (DLBCL, FL, CLL)
5. Has measurable disease for B-cell NHL or has active disease for Chronic Lymphocytic Leukemia (CLL).
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
7. Has adequate hepatic, renal, and bone marrow functions.
8. Before the first dose of GEN3009, during the trial, and for 12 months after the last dose of GEN3009 and/or the combination, a woman must be either not of childbearing potential or of childbearing potential and practicing a highly effective method of birth control, and must have a negative serum beta-human chorionic gonadotropin (beta-hCG) and urine pregnancy test at screening.
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.
10. Subjects must have a life expectancy of at least 3 months.

Key Exclusion Criteria:

1. Prior treatment with a CD37-targeting agent.
2. Prior allogeneic Hematopoietic Stem Cell Transplantation (HSCT).
3. Prior treatment with a CD3xCD20 bispecific antibody (Combination Expansion cohort only).
4. Autologous HSCT within 3 months before the first dose of GEN3009.
5. Lymphomas leukemic phase: high absolute lymphocyte count or the presence of abnormal cells in the peripheral blood indicating circulating lymphoma cells.
6. Treatment with an anti-cancer biologic including anti-CD20 therapy, radio-conjugated or toxin-conjugated antibody or chimeric antigen receptor (CAR) T-cell therapy within 4 weeks or 5 half-lives, whichever is shorter, before the first dose of GEN3009. Treatment with small molecules such as BTK inhibitors, BCL2 inhibitors, or PI3K inhibitors within 5 half-lives prior to the first dose of GEN3009.
7. Chemotherapy or radiation therapy within 2 weeks of the first dose of GEN3009.
8. Treatment with an investigational drug or an invasive investigational medical device within 4 weeks or 5 half-lives, whichever is shorter, prior to the first dose of GEN3009, and at any time during the study treatment period.
9. Autoimmune disease or other diseases that require permanent or high-dose immunosuppressive therapy.
10. Received a cumulative dose of corticosteroids more than the equivalent of 250 mg of prednisone within the 2-week period before the first dose of GEN3009.
11. Has uncontrolled intercurrent illness.
12. Seizure disorder requiring therapy (such as steroids or anti-epileptics) (Combination Expansion cohort only).
13. Toxicities from previous anti-cancer therapies have not resolved to baseline levels or to Grade 1 or less except for alopecia and peripheral neuropathy.
14. Primary central nervous system (CNS) lymphoma or known CNS involvement at screening.
15. Known past or current malignancy other than inclusion diagnosis.
16. Had allergic reactions to anti-CD20 or anti-CD37 monoclonal antibody treatment or intolerant to GEN3009 or to the combination therapy excipients.
17. Has had major surgery within 4 weeks before screening or will not have fully recovered from surgery, or has major surgery planned during the time the subject is expected to participate in the trial (or within 4 weeks after the last dose of GEN3009 and/or the combination therapy).
18. Known history/positive serology for hepatitis B.
19. Known medical history or ongoing hepatitis C infection that has not been cured.
20. Known history of seropositivity for HIV infection.
21. Is 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 GEN3009 and/or the combination therapy.
22. Is a man who plans to father a child while enrolled in this trial or within 12 months after the last dose of GEN3009 and/or the combination therapy.
23. Has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments. Additionally, vulnerable subjects or subjects under guardianship, curatorship, judicial protection or deprived of liberty), are excluded from participation in this trial.
24. Exposed to live/live attenuated vaccine within 4 weeks prior to initiation of GEN3009 treatment.

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

Primary outcomes:
measure: Number of Participants With Dose Limiting Toxicities (DLTs)
timeFrame: During the first treatment cycle (Cycle length=28 days)
measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs
timeFrame: From first dose until 30 days after the last dose (up to 15.5 months)
measure: Number of Participants With AEs of Special Interest (AESI)
timeFrame: From first dose until 30 days after the last dose (up to 15.5 months)
measure: Number of Participants With Clinically Significant Laboratory Abnormalities Reported as TEAEs
timeFrame: From first dose until 30 days after the last dose (up to 15.5 months)
measure: Number of Participants With Clinically Notable Vital Signs
timeFrame: From first dose up to end of treatment (up to 14.5 months)
measure: Number of Participants With Dose Delays and Dose Interruptions
timeFrame: From first dose until 30 days after the last dose (up to 15.5 months)
measure: Actual Dose Intensity
timeFrame: From first dose until 30 days after the last dose (up to 15.5 months)
Secondary outcomes:
measure: Apparent Total Plasma Clearance (CL) of GEN3009
timeFrame: Pre-dose and 5 minutes post-dose on days 1, 2, 4 (S2 only), 8, 15, 22 and 2 hours (h) and 4h post-dose on days 1 and 2, 24h post-dose on day 2 and 72h post-dose on day 4 of Cycles 1 and 2 (Each cycle length=28 days)
measure: Volume of Distribution of GEN3009
timeFrame: Pre-dose and 5 minutes post-dose on days 1, 2, 4 (S2 only), 8, 15, 22 and 2h and 4h post-dose on days 1 and 2, 24h post-dose on day 2 and 72h post-dose on day 4 of Cycles 1 and 2 (Each cycle length=28 days)
measure: Area Under the Plasma Concentration-Time Curve (AUC) From Time 0 to Day 7 of GEN3009
timeFrame: Pre-dose and 5 minutes post-dose on days 1, 2 and 4 (S2 only); 2h and 4h post-dose on days 1 and 2, 24h post-dose on day 2 and 72h post-dose on day 4 of Cycles 1 and 2 (Each cycle length=28 days)
measure: AUC From Time 0 to Infinity (AUCinf) of GEN3009
timeFrame: Pre-dose and 5 minutes post-dose on days 1, 2, 4 (S2 only), 8, 15, 22 and 2h and 4h post-dose on days 1 and 2, 24h post-dose on day 2 and 72h post-dose on day 4 of Cycles 1 and 2 (Each cycle length=28 days)
measure: AUC From Time 0 to Time of Last Dose (AUClast) of GEN3009
timeFrame: Pre-dose and 5 minutes post-dose on days 1, 2, 4 (S2 only), 8, 15, 22 and 2h and 4h post-dose on days 1 and 2, 24h post-dose on day 2 and 72h post-dose on day 4 of Cycles 1 and 2 (Each cycle length=28 days)
measure: Maximum Observed Plasma Concentration (Cmax) of GEN3009
timeFrame: Pre-dose and 5 minutes post-dose on days 1, 2, 4 (S2 only), 8, 15, 22 and 2h and 4h post-dose on days 1 and 2, 24h post-dose on day 2 and 72h post-dose on day 4 of Cycles 1 and 2 (Each cycle length=28 days)
measure: Time to Reach Cmax (Tmax) of GEN3009
timeFrame: Pre-dose and 5 minutes post-dose on days 1, 2, 4 (S2 only), 8, 15, 22 and 2h and 4h post-dose on days 1 and 2, 24h post-dose on day 2 and 72h post-dose on day 4 of Cycles 1 and 2 (Each cycle length=28 days)
measure: Trough Concentrations (Ctrough) of GEN3009
timeFrame: Pre-dose and 5 minutes post-dose on days 1, 2, 4 (S2 only), 8, 15, 22 and 2h and 4h post-dose on days 1 and 2, 24h post-dose on day 2 and 72h post-dose on day 4 of Cycles 1 and 2 (Each cycle length=28 days)
measure: Terminal Elimination Half-Life (t 1/2) of GEN3009
timeFrame: Pre-dose and 5 minutes post-dose on days 1, 2, 4 (S2 only), 8, 15, 22 and 2h and 4h post-dose on days 1 and 2, 24h post-dose on day 2 and 72h post-dose on day 4 of Cycles 1 and 2 (Each cycle length=28 days)
measure: Number of Participants With Positive Anti-drug Antibodies (ADAs)
timeFrame: From first dose until 30 days after the last dose (up to 15.5 months)
measure: Duration of Response (DoR)
timeFrame: From date of first documented CR or PR up to disease progression or death (up to approximately 3 years 4 months)
measure: Time to Response (TTR)
timeFrame: From date of first documented CR or PR up to disease progression or death (up to approximately 3 years 4 months)
measure: Progression-free Survival (PFS)
timeFrame: From day of first dose until disease progression or death due to any cause (up to approximately 3 years 4 months)
measure: Overall Survival (OS)
timeFrame: From day of first dose until disease progression or death due to any cause (up to approximately 3 years 4 months)
measure: Objective Response Rate (ORR)
timeFrame: From day of first dose until disease progression or death due to any cause (up to approximately 3 years 4 months)
measure: CR Rate
timeFrame: From day of first dose until disease progression or death due to any cause (up to approximately 3 years 4 months)
Other outcomes:
Locations:
city: Denver
country: United States
facility: Colorado Blood Cancer Institute
state: Colorado
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Center
state: Ohio
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Charleston
country: United States
facility: Medical University of South Carolina (MUSC)
state: South Carolina
city: Dallas
country: United States
facility: The University of Texas Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Seattle
country: United States
facility: University of Washington - Seattle Cancer Care Alliance
state: Washington
city: Leuven
country: Belgium
facility: UZ Leuven
city: Copenhagen
country: Denmark
facility: Rigshospitalet
city: Odense
country: Denmark
facility: Odense Universitetshospital
city: Vejle
country: Denmark
facility: Vejle Sygehus
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC, Locatie VUMC
city: Badalona
country: Spain
facility: ICO Badalona - Hospital Universitari Germans Trias i Pujol
state: Barcelona
city: Barcelona
country: Spain
facility: ICO l'Hospitalet - Hospital Duran i Reynals
state: L'Hospitalet De Llobregat
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Madrid
country: Spain
facility: Hospital Universitario Fundacion Jimenez Diaz
Study officials:
References: