E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsed or Refractory Multiple Myeloma and Other Hematologic Malignancies |
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E.1.1.1 | Medical condition in easily understood language |
Relapsed or Refractory Multiple Myeloma and Other Hematologic Malignancies |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10066481 |
E.1.2 | Term | Hematological malignancy |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10028228 |
E.1.2 | Term | Multiple myeloma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
- Determine the RP2D and if reached, the MTD of GEN3014
- Evaluate the safety and tolerability of GEN3014
Please refer to the protocol section 2 (Tables 2-2 and 2-3) for the full list of main objectives for the Expansion Part A (GEN3014 Single Cohorts) and Expansion Part B (Randomized H2H) of the study, respectively. |
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E.2.2 | Secondary objectives of the trial |
- Characterize the PK properties of GEN3014
- Evaluate immunogenicity
- Assess the preliminary anti-tumor activity of GEN3014
- Assess the clinical efficacy of GEN3014
Please refer to the protocol section 2 (Tables 2-2 and 2-3) for the full list of secondary objectives for the Expansion Part A (GEN3014 Single Cohorts) and Expansion Part B (Randomized H2H) of the study, respectively. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Must be at least 18 years of age.
2. Must sign an informed consent form (ICF) prior to any Screening procedures. Where required by local or country specific regulations, each subject must sign a separate ICF if he or she agrees to provide samples for genomic biomarker analysis (deoxyribonucleic acid [DNA] and ribonucleic acid [RNA]).
3. Must have fresh bone marrow samples collected at Screening.
4. Eastern Cooperative Oncology Group (ECOG) performance status (PS) score 0, 1, or 2.
5. Has acceptable laboratory test results during the Screening period
6. A woman of reproductive potential must agree to use adequate contraception during the trial and for 12 months after the last GEN3014 administration. Adequate contraception is defined as highly effective methods of contraception (refer to Appendix 10.4 for more information). In countries where 2 highly effective methods of contraception are required, both methods will be required for inclusion.
7. A woman of childbearing potential must have a negative serum beta-human chorionic gonadotropin (β-hCG) at Screening.
8. A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the trial and for 12 months after receiving the last dose of GEN3014.
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, eg, either condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository, and all men must also not donate sperm during the trial and for 12 months after receiving the last dose of GEN3014.
Specific Inclusion Criteria for RRMM:
10. 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:
- IgG, 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
11. For anti-CD38 mAb-naive RRMM subjects: Subject received at least 3 prior lines of therapy including a PI and an IMiD in any order, or is double refractory to a PI and an IMiD; or subject received ≥ 2 prior lines of therapy if 1 of those lines included a combination of PI and IMiD. Note: Subjects should not have received any anti-CD38 antibody. Anti-CD38 mAb-naive subjects with RRMM may be recruited from Sweden, France, Spain, Netherlands, and Australia, and from countries where anti-CD38 therapies are not available.
12. For anti-CD38 mAb-treated RRMM subjects: Subject 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: Subjects should not have received any other anti-CD38 antibody except daratumumab or isatuximab.
13. Potassium level ≥3.0 mEq/L (≥3.0 mmol/L); and corrected serum calcium ≤14.0 mg/dL (≤3.5 mmol/L) or free ionized calcium ≤6.5 mg/dL (≤1.6 mmol/L).
Specific Inclusion Criteria for R/R AML:
14. 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 patients who have been in complete remission (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.
15. Subject with relapsed AML who received at least 2 prior therapies for AML with the exception of hydroxyurea.
16. Subject with refractory AML who received at least 1 prior line of therapy for AML with the exception of hydroxyurea.
17. Subject's life expectancy at Screening is judged to be at least 3 months.
Please refer to Protocol sections 4.1.2 and 4.1.3 for the Inclusion Criteria for the Expansion Part A (GEN3014 Single Cohorts) and Expansion Part B (Randomized H2H), respectively |
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E.4 | Principal exclusion criteria |
Exclusion Criteria (Dose Escalation and Expansion Part A [GEN3014 Single Cohorts])
1. Prior treatment with any anti-CD38 directed therapies (eg. daratumumab, isatuximab, CD38 CAR-T, bispecific Ab) in anti-CD38 mAb- naive RRMM Cohort. Note: Prior daratumumab or isatuximab exposure is allowed for anti-CD38 mAb-treated RRMM subjects in the Dose Escalation and anti-CD38 mAb-refractory RRMM Cohort in the Expansion Part A.
2. Treatment with an anti-cancer agent (eg, small molecule, antibody, CAR-T cell therapy), chemotherapy, radiation therapy, or major surgery within 2 weeks prior to the first dose of GEN3014.
3. Treatment with an investigational drug within 4 weeks or 5 half-lives, whichever is shorter, prior to the first dose of GEN3014.
4. Cumulative dose of corticosteroids more than the equivalent of ≥140 mg of prednisone within 2-week period before the first dose of GEN3014.
5. Has clinically significant cardiac disease, including:
• Myocardial infarction within 1 year prior to the first dose of GEN3014, or unstable or uncontrolled disease/condition related to or affecting cardiac function (eg, unstable angina, congestive heart failure, New York Heart Association Class III-IV [see Appendix 10.6]) uncontrolled cardiac arrhythmia (CTCAE v5.0 grade 2 or higher) or clinically significant electrocardiogram (ECG) abnormalities.
• Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia’s formula (QTcF) >480 msec.
6. Toxicities from previous anti-cancer therapies have not resolved to baseline levels or to Grade 1 or less except for alopecia and peripheral neuropathy.
7. Primary central nervous system (CNS) tumor or known CNS involvement at Screening.
8. Has known history/positive serology for hepatitis B (unless immune due to vaccination or unless passive immunization due to Ig therapy):
• Positive test for antibodies to the hepatitis B core antigen (anti-HBc) and
• Negative test for antibodies to the hepatitis B surface antigen (anti-HBs).
9. Known medical history or ongoing hepatitis C infection that has not been cured.
10. Known history of seropositivity of human immunodeficiency virus (HIV).
11. Currently receiving any other investigational agents.
12. 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 GEN3014.
13. A man who plans to father a child while enrolled in this trial or within 12 months after the last dose of GEN3014.
Specific Exclusion Criteria for RRMM:
14. Prior allogeneic HSCT.
15. Autologous HSCT within 3 months of the first dose of GEN3014.
Specific Exclusion Criteria for R/R AML:
16. <5% blasts in blood or bone marrow at Screening.
17. Prior autologous HSCT.
18. Allogenic HSCT within 3 months of the first dose of GEN3014.
19. 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.
Please refer to the protocol section 4.2.2 for the full list of Exclusion criteria for the Expansion Part B (Randomized H2H). |
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E.5 End points |
E.5.1 | Primary end point(s) |
- Incidence of DLTs
- Safety: Incidence and severity of adverse events (AEs) and serious adverse events (SAEs), including changes in laboratory values, vital signs, electrocardiograms (ECGs)
- Tolerability: Dose interruptions, delay, and dose intensity.
Please refer to the protocol section 2 (Tables 2-2 and 2-3) for the full list of primary endpoints for the Expansion Part A (GEN3014 Single Cohorts) and Expansion Part B (Randomized H2H) of the study, respectively. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
• Noncompartmental PK parameters (if feasible):
o Maximum concentration (Cmax)
o Time to Cmax (Tmax)
o Predose concentration (Ctrough)
o Area under the concentration-time curve from time zero to last quantifiable sample (AUC0-last) and from time zero to 168 h (AUC0-168h)
o Accumulation ratios in Cmax (RA,Cmax) and AUC (RA,AUC]
• In addition, a population PK modeling approach may be employed
• Anti-GEN3014 antibodies
• Objective response rate (ORR)
• Clinical benefit rate (CBR)
• Duration of response (DOR)
• Time-to-response (TTR)
• Progression-free survival (PFS)
• Overall survival (OS)
Please refer to the protocol section 2 (Tables 2-2 and 2-3) for the full list of secondary endpoints for the Expansion Part A (GEN3014 Single Cohorts) and Expansion Part B (Randomized H2H) of the study, respectively. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Tolerability and Immunogenicity |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | Yes |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
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E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Randomized for Expansion Part B (Randomized H2H) |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 23 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Malaysia |
New Zealand |
Philippines |
Bosnia and Herzegovina |
North Macedonia |
Moldova, Republic of |
Ukraine |
Australia |
Georgia |
Korea, Republic of |
Serbia |
United States |
Czechia |
Denmark |
Greece |
Hungary |
Poland |
Spain |
Sweden |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 5 |