| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed or refractory Multiple Myeloma (r/r MM) |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10028228 |
| E.1.2 | Term | Multiple myeloma |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
Phase 1:
Determine the maximum tolerable dose (MTD), select a recommended Phase 2 dose for HDP-101 as monotherapy in patients with relapsed or refractory multiple myeloma (r/r MM).
Phase 2a:
Assess efficacy of HDP-101 |
|
| E.2.2 | Secondary objectives of the trial |
Phase 1
- Assess the safety and tolerability of HDP-101 as monotherapy
- Assess the efficacy of HDP-101 monotherapy
- To assess the anticancer activity of HDP-101 in terms of time-to-event (TTE) in patients with r/r MM
- To evaluate the exposure of HDP-101 and its major metabolites following HDP-101 intravenous(IV) single and repeated dose administration in patients with r/r MM
- Evaluate clearance of HDP-101
- To assess immunogenicity of HDP-101 after single and repeated IV dosing
Phase 2a:
- Assess the safety and tolerability of HDP-101 as monotherapy
- To assess the efficacy of HDP-101 monotherapy
- To assess the anticancer activity of HDP-101 in TTE in patients with relapsed or refractory multiple myeloma (r/r MM)
- To evaluate the exposure of HDP-101 and its major metabolites following "HDP-101" (IV) single and repeated dose administration in patients with r/r MM
- Evaluate clearance of HDP-101
- To assess immunogenicity of HDP-101 after single and repeated IV dosing |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients are eligible to be included in the study only if all following criteria apply:
1.Patients who have signed an informed consent and are willing to comply with the requirements and restrictions listed in the study protocol.
2.Male or female aged ≥18 years at the time of informed consent.
3.Life expectancy >12 weeks, as determined by the Investigator.
4.Eastern Cooperative Oncology Group Performance Status (PS) of 0 to 2 (tumor related performance).
5.A confirmed diagnosis of active MM according to the diagnostic criteria established by the International Myeloma Working Group (IMWG).
6.Must have undergone SCT or is considered transplant ineligible.
7.Must have undergone prior treatments with antimyeloma therapy which must have included an immunomodulatory drug, proteasome inhibitor, and antiCD38 treatment, alone or in combination. Patients who are intolerant to these therapies or have contraindications are eligible if other eligibility criteria are fulfilled. Patient must have failed last line of treatment (refractory to or relapsed after last line of treatment) or had to permanently discontinue the last line of therapy due to toxicity (toxicity and reason for permanent discontinuation has to be documented in the electronic case report form [eCRF]). In addition, the patient should either refractory or intolerant to any established standard of care therapy providing a meaningful clinical benefit for the patient assessed by the Investigator.
8.a)Phase 1 part only: patients with non-secretory or oligo-secretory myeloma (NSMM) not meeting the measurability criteria described in
8.b)are eligible (all other eligibility criteria must apply).
Phase 2a part only - Measurable disease defined as:
•Serum M-protein ≥0.5 g/dL, or
•Urine M-protein ≥200 mg/24 hours, or
•Serum-free light chains (FLC) assay: involved FLC level ≥10 mg/dL (100 mg/L) provided serum FLC ratio is abnormal (<0.26 or >1.65).
9. Acute toxicities from any prior therapy, surgery, or radiotherapy must have resolved to Grade 0 or 1 as per the NCI-CTCAE, except for alopecia and Grade 2 neuropathy.
10.Adequate organ system function asdefined:
•Absolute neutrophil count: ≥1.0 × 10^9/L
•Platelet count: ≥50 × 10^9/L and absent platelet transfusion for ≥7 days
•Hemoglobin: >8.0 g/dL and absent RBC transfusion for ≥7 days
•Activated partial thromboplastin time/partial thromboplastin time: ≤1.5 × ULN
•Measured creatinine clearance (using 24-hour urine), if a measured Cr-Cl is not available, the calculated creatinine clearance using the Cockcroft-Gault-Formula can be used ≥60 mL/min
•Albuminuria: ≤500 mg/24hours
•Total serum bilirubin: ≤1.5 × ULN (isolated bilirubin >1.5 and ≤3.0 × ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)
•Aspartate and alanine transaminases: ≤1.5 × ULN
11.A female patient is eligible to participate if she is of
•Nonchildbearing potential defined as premenopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous follicle-stimulating hormone [FSH] >40 MIU/mL and estradiol <40 pg/mL [<147 pmol/L] is confirmatory). Women on hormone replacement therapy (HRT) and whose menopausal status is in doubt are treated like women of childbearing potential unless they discontinue their HRT to allow confirmation of postmenopausal status prior to study enrollment. For most forms of HRT, at least 2 to 4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their postmenopausal status, they can resume use of HRT during the study without use of a contraceptive method.
•Women of childbearing potential must have an negative urine pregnancy test 7 days before the first administration of the study treatment and on Day 1 before first dose of study treatment and commit to either abstain continuously from heterosexual intercourse or to use 2 methods of reliable birth control simultaneously, during the study and for 4 months following the last dose of the study treatment. This includes 1 highly effective form of contraception (tubal ligation, intrauterine device, hormonal [birth control pills, injections, hormonal patches, vaginal rings, or implants] or partner’s vasectomy) and 1 additional effective contraceptive method (male latex or synthetic condom, diaphragm, or cervical cap).
12.Male patients must have had a prior vasectomy or commit to use an effective contraception (complete abstinence from sexual intercourse, latex or synthetic condom and during sexual intercourse with a female a double-barrier method including a condom and occlusive cap [diaphragm or cervical/vault caps] plus spermicidal agent [foam/gel/film/cream/suppository]) from the time of first study treatment infusion until 3 months following the last study treatment infusion to allow for clearance of any altered sperm. |
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| E.4 | Principal exclusion criteria |
Patients are excluded from the study if any of the following criteria apply:
1. For patient entering the Phase 2a part only: Prior treatment with any approved or experimental BCMA-targeting modalities are not allowed including but not limited to chimeric antigen receptor T or NK cell treatment, mono or bispecific antibodies and other BCMA-ADCs. (Note that patients in the Phase 1 part could have had any type of prior BCMA directed treatment providing they fulfilled all other inclusion and exclusion criteria).
2. History of allergic reactions to any component of the study treatment.
3. Known central nervous system involvement.
4. Plasma cell leukemia (total plasma cell count of at least 2 × 10^9/L) at Screening.
5. History of congestive heart failure classified as Class ≥ III based on the New York Heart Association Classification or Grade 3/4 unstable angina pectoris within 6 months of enrollment, presence of unstable atrial fibrillation, ECG with QTc ≥480 ms, cardiac arrhythmia, or uncontrolled hypertension.
6. Treatment with systemic anticancer therapy within 4 weeks or 5 t½s of the agent if t½ is known (whichever is shorter) before first dose of the study treatment. Anticancer therapies include cytotoxic chemotherapy, targeted inhibitors, and immunotherapies, but do not include radiotherapy or corticosteroids.
7. Higher dose of systemic corticosteroids, defined as oral dexamethasone >40 mg/day (for patients aged >75 years reduced to >20 mg/day) or equivalent, within 3 days prior to the first study treatment infusion.
8. Currently participating in a study and receiving study therapy or participated in a study of an investigational agent and received study therapy or used an investigational device within 2 weeks of the first dose of study treatment.
9. Autologous or allogenic SCT within 12 weeks before the first infusion or is planning for autologous SCT.
10. Symptomatic graft versus host disease post allogenic hemopoietic cell transplant within 12 months prior to the first study treatment infusion.
11. Significant surgical intervention within 21 days prior to the first study treatment infusion or ongoing post-operative complications.
12.Patients who have a history of being nonresponsive to platelet and/or RBC transfusions and expected lack of adequate support with blood products on demand.
13. Radiotherapy within 21 days prior to the first study treatment infusion, or localized palliative radiotherapy within 7 days prior to the first study treatment infusion, therapy with radio immuno-conjugates performed less than 3 months prior to the first dose of study treatment.
14. Herbal remedies interfering or stimulating the metabolic pathways (eg, mistletoe extract) or known to potentially interfere with major organ function (eg, hypericin) within 21 days prior to the first study treatment infusion.
15. History of any other malignancy known to be active, with the exception of completely removed in situ cervical intraepithelial neoplasia, nonmelanoma skin cancer, ductal carcinoma in situ, early stage prostate cancer that has been adequately treated. Malignancies which are adequately treated and requiring hormonal therapies only to prevent the recurrence of the malignancy other than multiple myeloma may be permitted after discussion with and agreement of the Sponsor's Medical Monitor (eg, breast cancer treated with hormonal therapies).
16. Human immunodeficiency virus infection at the time of the screening.
17. Patients with active infection requiring systemic anti-infective (eg, antibiotic or antiviral) therapy. Patients who are successfully treated with systemic anti-infective treatment and have no clinical signs of infection for at least 2 days may be enrolled as per the discretion of the Investigator.
18. Patients with positive test results for hepatitis B surface antigen or Hepatitis B core antigen.
19. Patients with positive test results for hepatitis C virus (HCV) infection are excluded regardless of viral load. If the hepatitis C antibody test is positive, a confirmatory polymerase chain reaction or recombinant immunoblot assay (RIBA) test should be performed. If the RIBA test is negative, patient is eligible for study.
20. Current active liver or biliary disease (with the exception of Gilbert’s syndrome or asymptomatic gallstones), liver metastases, or other stable chronic liver disease per the Investigator’s assessment.
21. Pregnancy or breast feeding.
22. Refusal to use effective methods of contraception.
23. Legal incapacity/limited legal capacity for providing informed consent.
24. Any serious and/or unstable preexisting medical, psychiatric disorder, or other conditions (including lab abnormalities) that could interfere with patient’s safety, obtaining informed consent, or compliance to the study procedures.
25. Pneumonia or symptomatic pneumonitis (symptoms include but not limited to shortness of breath, wheezing, dyspnea, decrease oxygen
saturation).
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1:
Number of patients who experience a dose-limiting toxicity (DLT) during the first cycle of treatment.
Phase 2a:
Objective response rate (ORR). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase 1:
End of cycle 1.
Phase 2a:
Beginning of each cycle. |
|
| E.5.2 | Secondary end point(s) |
Phase 1:
• Number of patients with treatment emergent adverse events (TEAEs) grouped by system organ class and preferred terms based on Common Terminology Criteria for Adverse Events (CTCAE) classification.
• Number of patients with treatment emergent serious adverse events (SAEs) grouped by system organ class and preferred terms based on CTCAE classification.
• Number of patients with treatment emergent changes in selected safety laboratory parameters.
• Number of patients with treatment emergent, clinically significant changes in vital signs.
• Number of patients with clinically significant treatment-emergent, clinically significant changes in electrocardiogram evaluations.
• Number of patients with treatment emergent abnormal findings in physical examinations.
• Number of patients with dose interruptions and dose reductions.
• Objective response rate (ORR).
• Best overall response (BOR).
• Maximum percentage change of serum or urine M protein or free light chain compared with baseline concentrations.
• Clinical benefit rate (CBR) at months 3, 6, 9, and 12.
• Number of patients who achieve minimal residual disease (MRD) free status.
• Progression-free survival (PFS).
• Overall survival (OS).
• Overall survival rate.
• Duration of response (DOR).
• Duration of CBR or better.
• Time to objective response (TOR).
• Pharmakokinetic parameters as data permit of HDP 101 and its major metabolites in blood samples: maximum concentration (Cmax), minimum concentration (Cmin), time to Cmax (tmax), half life (t½), area under the curve (AUC) through infinity [AUC(0-inf)], AUC through last concentration [AUC(0-last)], AUC through Day 21 [AUC(0-21 d)], area under the curve (AUC) through the dosing interval [AUC(0-tau)], terminal rate constant (λz), accumulation, and time linearity, and for "HDP-101" only: total clearance (CL), volume of distribution (Vz), volume of distribution at steady state (Vss).
•Quantitate HDP-101 major metabolites in urine and if sufficient data are available, calculate renal clearance (CLr).
• Incidence and titer of antidrug antibodies (ADA).
• Incidence of ADAs with neutralizing capacity.
Phase 2a:
• Number of patients with treatment emergent adverse events (TEAEs) grouped by system organ class and preferred terms based on Common Terminology Criteria for Adverse Events (CTCAE) classification.
• Number of patients with treatment emergent serious adverse events (SAEs) grouped by system organ class and preferred terms based on CTCAE classification.
• Number of patients with treatment emergent changes in selected safety laboratory parameters.
• Number of patients with treatment emergent changes in vital signs.
• Number of patients with clinically significant treatment-emergent changes in electrocardiogram evaluations.
• Number of patients with treatment emergent abnormal findings in physical examinations.
• Number of patients with dose interruptions and dose reductions.
• Best overall response (BOR).
• Maximum percentage change of serum or urine M protein or free light chain compared with baseline concentrations.
• Clinical benefit rate (CBR).
• Number of patients who achieve minimal residual disease (MRD) free status.
• Progression-free survival (PFS).
• Overall survival (OS).
• Overall survival rate.
• Duration of response (DOR).
• Duration of CBR or better.
• Time to objective response (TOR)
• Pharmakokinetic parameters as data permit of HDP 101 and its major metabolites in blood samples: maximum concentration (Cmax), minimum concentration (Cmin), time to Cmax (tmax), half life (t½), AUC(0-inf),AUC(0-tau), AUC(0-last), AUC(0-21d), λz, accumulation, and time linearity, and for HDP 101 only: CL, Vz, Vss.
• Quantitate "HDP-101" major metabolites in urine and if sufficient data are available, calculate renal clearance (CLr).
• Incidence and titer of antidrug antibodies (ADA).
• Incidence of ADAs with neutralizing capacity.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Phase 1:
- Efficacy at every cycle.
- Safety, immunogenecity and pharmacokinetic at the end of patient treatment.
Phase 2a:
Time-to-event efficacy the end point will be assessed by the end of follow up. |
|
| 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 | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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 | No |
| E.7.1.3.1 | Other trial type description | |
| 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 | No |
| E.8.1.1 | Randomised | No |
| 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 | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 |
|
| 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
|
| The end of the study for each patient is defined as a follow-up of 12 months after the patient's end of treatment (EOT) visit. The end of study (EOS) is defined when the last patient of the Phase 2a part of the study completed the last follow-up visit. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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