E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsed or Refractory Multiple Myeloma |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10028228 |
E.1.2 | Term | Multiple myeloma |
E.1.2 | System Organ Class | 100000004864 |
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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 |
Phase 1b
• Establish the safety and tolerability of AMG 420 at dose levels of 400 µg/day and 600 µg/day in subjects with relapsed and/or refractory multiple myeloma (RRMM).
Phase 2
• Estimate overall response rate (ORR) per IMWG response criteria (stringent complete response [sCR], complete response [CR], very good partial response [VGPR], partial response [PR]) in subjects with RRMM.
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E.2.2 | Secondary objectives of the trial |
Phase 1b
Key Secondary
• Estimate ORR and duration of response (DOR) of AMG 420 in subjects with RRMM
• Evaluate the rate of minimal residual disease (MRD)-negativity at the time of CR
Secondary
• Establish the safety and tolerability of AMG 420 in subjects with extramedullary relapsed multiple myeloma
•Characterize the pharmacokinetics of AMG 420 when administered as 4- week continuous intravenous (cIV) infusion
•Evaluate other measures of anti-myeloma activity of AMG 420 in subjects with RRMM:
?Time to response
?Progression-free survival (PFS)
?Overall survival (OS)
?Treatment-free interval (TFI)
?Best overall response (BOR)
Phase 2
Key Secondary
• Estimate DOR of AMG 420 in subjects with RRMM
• Evaluate the rate of MRD-negative disease at the time of CR
Secondary
• Evaluate other measures of anti-myeloma activity of AMG 420 in subjects with RRMM:
?Time to response
?PFS
?OS
?TFI
?BOR
• Establish the safety and tolerability of AMG 420 in subjects with RRMM
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subject has provided informed consent prior to initiation of any study specific activities/procedures.
Age ? 18 years at the time of the signing of informed consent.
Multiple myeloma meeting the following criteria:
•Pathologically-documented diagnosis of multiple myeloma that is relapsed or is refractory as defined by the following:
?Relapsed after ? 3 lines of prior therapy that must include a PI, an IMiD, and a CD38-directed monoclonal antibody in any order during the course of treatment OR refractory to PI, IMiD, and CD38-directed monoclonal antibody.
•Measurable disease, defined by 1 or more of the following at time of screening:
?serum M-protein > 0.5 g/dL measured by serum protein electrophoresis (SPEP)
?urinary M-protein excretion > 200 mg/24 hours
?Involved sFLC measurement > 10 mg/dL, provided that the sFLC ratio is abnormal (< 0.26 or > 1.65) as per IMWG response criteria.
Eastern Cooperative Oncology Group (ECOG) performance status of ? 2.
Life expectancy of at least 3 months as per investigator`s judgment at time of screening.
Hematological function without transfusion support (within 7 days from screening assessment) as follows:
•ANC ? 1.0 x 109/L (without growth factor support)
•platelet count ? 25 x 109/L (without transfusions)
•hemoglobin ? 7.0 g/dL (transfusions permitted no later than 48 hours before screening).
Renal function as follows:
• calculated or measured creatinine clearance ? 30 mL/min using the Cockcroft-Gault equation or via 24-hour urine collection with plasma and urine creatinine concentrations, respectively.
Hepatic function as follows:
•aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x upper limit of normal (ULN)
• total bilirubin (TBIL) < 1.5 x ULN (unless considered due to Gilbert’s syndrome).
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E.4 | Principal exclusion criteria |
Disease Related:
Known central nervous system involvement by multiple myeloma.
Evidence of primary or secondary plasma cell leukemia at the time of screening.
Waldenstrom’s macroglobulinemia.
Unresolved toxicities from prior anticancer therapy.
Other Medical Conditions
History of other malignancy within the past 3 years, with the following exceptions:
•malignancy treated with curative intent and with no known active disease present for ? 1 year before enrollment and felt to be at low risk for recurrence by the treating physician
•adequately-treated non-melanoma skin cancer or lentigo maligna without evidence of disease
•adequately-treated cervical carcinoma in situ without evidence of disease
•breast ductal carcinoma in situ with full surgical resection (ie, negative margins) and without evidence of disease
•prostate cancer with a Gleason score < 6 with undetectable prostate specific antigen (PSA) over 12 months
•treated medullary or papillary thyroid cancer
•adequately-treated urothelial papillary noninvasive carcinoma or carcinoma in situ
•similar neoplastic conditions with an expectation of > 95% five-year disease-free survival
• see exclusion criterion 202 (Evidence of primary or secondary plasma cell leukemia at the time of screening) for exclusion of subjects with evidence of primary or secondary plasma cell leukemia at the time of screening.
Known history of amyloidosis.
Current or known history of autoimmune diseases requiring systemic treatment in past 5 years except vitiligo, resolved childhood asthma/atopy, or subjects with history of hypothyroidism after completing treatment for autoimmune thyroid disease, stable on hormone replacement therapy.
Clinically not-controlled chronic or ongoing infectious disease requiring treatment at the time of study day 1 or within the 14 days before study day 1
Symptomatic peripheral sensory or motor neuropathy of grade ? 3.
History or presence of clinically relevant central nervous system (CNS) pathology as uncontrolled epilepsy or seizure disorder, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson’s disease, cerebellar disease, organic brain syndrome, and psychosis.
Active hepatitis B and C based on the following results:
•Positive for hepatitis B surface antigen (HepBsAg) (indicative of chronic hepatitis B or recent acute hepatitis B).
•Negative HepBsAg and positive for hepatitis B core antibody: hepatitis B virus DNA by polymerase chain reaction (PCR) is necessary. Detectable hepatitis B virus DNA suggests occult hepatitis B.
•Positive Hepatitis C virus antibody (HepCAb): hepatitis C virus RNA by PCR is necessary. Detectable hepatitis C virus RNA suggests chronic hepatitis C.
Known or suspected HIV infection or subjects who are HIV seropositive.
Baseline ECG QTc > 470 msec (applying Fridericia correction), defined as the average of individual baseline ECGs.
Prior/Concomitant Therapy
Previously received an allogeneic stem cell transplant and the occurrence of 1 or more of the following:
•received the transplant within 6 months prior to study day 1
•received immunosuppressive therapy within the last 3 months prior to study day 1
•any active acute graft versus host disease (GvHD), grade 2 to 4, according to the Glucksberg criteria or active chronic GvHD requiring systemic treatment
•any systemic therapy against GvHD within 2 weeks prior to start of investigational product treatment.
Autologous stem cell transplantation < 90 days prior to study day 1.
Treatment with systemic immune modulators including, but not limited to, nontopical systemic corticosteroids (unless the dose is ? 10 mg/day prednisone or equivalent), cyclosporine, and tacrolimus within 2 weeks before study day 1.
Last anticancer treatment (chemotherapy, IMiD, PI, molecular targeted therapy) < 2 weeks prior to study day 1.
Last treatment with a therapeutic antibody less than 4 weeks prior to study day 1.
Systemic radiation therapy within 28 days prior to study day 1. Focal radiotherapy within 14 days prior to study day 1.
Major surgery defined as surgery requiring general anesthesia with endotracheal intubation within 28 days prior to study day 1, unless discussed with and eligibility approved by Amgen medical monitor.
Prior treatment with any drug that specifically targets BCMA on tumor cells (eg, other bi-specific antibody constructs, antibody drug conjugates, or CAR T-cells, except for subjects who were previously treated with AMG 420 in this study and who are candidates for second-course treatment.
Treatment with medications known to cause QTc interval prolongation within the washout periods unless approved by the Amgen medical monitor.
Prior/Concurrent Clinical Study Experience
Currently receiving treatment in another investigational device or drug study, or less than 30 days since ending treatment on another investigational device or drug study(ies).
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E.5 End points |
E.5.1 | Primary end point(s) |
Phase 1b
• Dose-limiting toxicities (DLTs), treatment-emergent adverse events, treatment-related adverse events, disease-related events, and changes in vital signs, electrocardiograms (ECGs), and clinical laboratory tests
Phase 2
• ORR according to IMWG response criteria, per IRC assessment
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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) |
Phase 1b
Key secondary
•ORR
•DOR
•MRD negativity at the time of CR
Secondary
•DLTs, treatment-emergent adverse events, treatment-related adverse events, disease-related events, and changes in vital signs, ECGs, and clinical laboratory tests
•AMG 420 PK parameters including, but not limited to, half-life (t1/2), clearance, and apparent Css
• Efficacy parameters according to International Myeloma Working Group (IMWG) response criteria, per independent review committee (IRC) assessment:
?Time to response
?PFS
?BOR
•OS
•TFI
Phase 2
Key secondary
• DOR
• MRD negativity at the time of CR
Secondary
•Efficacy parameters according to IMWG
response criteria, per IRC assessment:
?Time to response
?PFS
?BOR
•OS
•TFI
• Treatment-emergent adverse events, treatment-related adverse events, disease-related events, and changes in vital signs, ECGs, and clinical laboratory tests
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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 | 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 | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
Phase 1b: dose confirmation |
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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 | 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.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 32 |
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 |
Australia |
Austria |
Belgium |
Canada |
France |
Germany |
Italy |
Japan |
Romania |
Spain |
Switzerland |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
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 | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |