| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Subjects with pathologically documented relapsed/ refractory multiple myeloma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Myeloma - A type of blood cancer |
|
| 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 – dose-exploration as monotherapy
-Evaluate the safety and tolerability of AMG 701 in subjects with
relapsed/refractory multiple myeloma (RRMM) to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose [RP2D]).
Phase 1b – AMG 701 dose-confirmation as monotherapy
-Establish the safety and tolerability of AMG 701 at the RP2D
Phase 1/1b -– AMG 701 in combination with Pomalidomide, with and
without Dexamethasone (AMG 701-P ± d)
-Evaluate the safety and tolerability of AMG 701 and determine the AMG 701 RP3D in combination with pomalidomide (P), with and without dexamethasone (± d) in subjects with RRMM
Phase 2 - AMG 701 monotherapy dose - expansion
-Estimate ORR per IMWG response criteria (sCR, CR, VGPR, PR) |
|
| E.2.2 | Secondary objectives of the trial |
Phase 1 –dose-exploration as monotherapy
-Characterize the pharmacokinetics (PK) of AMG 701 when administered
by intravenous infusion
-Estimate anti-myeloma activity of AMG 701
-Estimate duration of response (DOR) of AMG 701
-Estimate other measures of anti myeloma activity of AMG 701
Phase 1b –AMG701 dose-confirmation as monotherapy
- Estimate anti-myeloma activity of AMG 701:
- Evaluate the rate of minimum residual disease negative CR (MRD[-]CR)
- Characterize the PK of AMG 701 by IV infusion
- Evaluate other measures of anti-myeloma activity of AMG 701
Phase 1/1b -– AMG701 in combination with Pomalidomide, with and without Dexamethasone (AMG 701-P ± d)
- Characterize the PK of AMG701 when administered by intravenous (IV) infusion
-Estimate anti-myeloma activity of:
•AMG 701-P±d in each treatment group
•AMG 701-P±d in each treatment group at the RP3D
- Estimate the rate of MRD[-]CR
For all secondary objectives please check protocol |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Subject has provided informed consent/assent prior to initiation of any study specific activities/procedures.
- Age ≥ 18 years at the time of signing the 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 all approved and available therapies deemed eligible by the investigator, including at a minimum of a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and a CD38-directed antibody in combination in the same line or separate lines of treatment OR refractory to PI, IMiD and CD38-directed antibody
- Note: Subjects enrolled in the phase 1b AMG 701 monotherapy dose confirmation part group 2 must be relapsed or intolerant to BCMA targeting agent
- Measurable disease, defined by 1 or more of the following at time of screening
- a 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 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 as follows:
- absolute neutrophil count (ANC) ≥ 1.0 x 109/L (without growth factor support)
- platelet count ≥ 50 x 109/L (without transfusions within 7 days from screening assessment)
- hemoglobin ≥ 8.0 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
Hepatic function as follows:
- aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x upper limit of normal (ULN)
- total bilirubin < 1.5 x the ULN, unless subject has Gilbert’s syndrome (see below)
- In patients with Gilberts syndrome, enrollment will be allowed if the level of total bilirubin (TBIL) falls within the CTCAE grade 2 (ie, < 3 x ULN, which is < 3.6 mg/dL if the upper limit of normal is 1.2 mg)
Serum phosphate as follows:
- Serum phosphorus >= 2.5 mg/dL (>= 0.8 mmol/L) within 7 days of day 1
- A subject who does not meet this inclusion criteria may be treated with phosphate replacement therapy and re-screened up to 2 times at the discretion of the investigator
- Echocardiogram or multiple-gated acquisition (MUGA) scan with LVEF > 50%
- Subjects with a history of COVID-19 infection must be discussed with the medical monitor prior to enrollment. Subjects with a history of COVID-19 infection must have a negative qPCR test prior to enrollment.
- Subjects with a history of coronary artery disease, heart failure, cardiac arrythmia, or prior COVID-19 infection must have a cardiology consultation during screening, to include advice on appropriate management of subjects during episodes of CRS.
- Serum sodium, potassium, calcium, and magnesium must be normal. If abnormal, must be have resolved to CTCAE Grade <= 1 within 7 days of day 1. Subjects not meeting these inclusion criteria may be treated with replacement therapy and re-screened up to 2 times at the discretion of the investigator. |
|
| E.4 | Principal exclusion criteria |
•Known extramedullary relapse in the absence of any measurable
medullary involvement (exception: this exclusion criteria only applies to phase 1a (dose escalation) study.
•Known central nervous system involvement by multiple myeloma
•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) requiring systemic therapy within the last 4 weeks prior to start of study treatment
- any systemic therapy against GvHD within 4 weeks prior to start of investigational product treatment
•Autologous stem cell transplantation less than 90 days prior to study day 1
•Recent history of primary plasma cell leukemia (within last 6 months prior to enrollment) or evidence of primary or secondary plasma cell leukemia at the time of screening
•Waldenstrom's macroglobulinemia
•Prior amyloidosis (patients with multiple myeloma with asymptomatic deposition of amyloid plaques found on biopsy would be eligible if all other criteria are met)
•Treatment with systemic immune modulators including, but not limited to, non-topical systemic corticosteroids
•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
•Radiation therapy to multiple anatomic sites 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 or construct that targets BCMA on tumor cells (eg, other bispecific antibody constructs, antibody drug conjugates, or CAR-T cells), other than group 2 where prior treatment with BCMA targeting agent is required.
•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. Other investigational procedures while participating in this study are excluded.
•Treatment with medications known to cause QTc interval prolongation within the washout periods described in Section 12.9 of the protocol unless approved by the Amgen medical monitor
•Unresolved toxicities from prior anticancer therapy, defined as not having resolved to CTCAE version 4.0 grade 1 or to levels dictated in the eligibility criteria with the exception of grade 2 peripheral neuropathy, alopecia or toxicities from prior anticancer therapy that are considered irreversible
•Clinically-not controlled chronic or ongoing bacterial, fungal, viral or other infectious disease requiring treatment at the time of study day 1 or within the 14 days before study day 1
•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: Negative hepatitis B virus DNA by polymerase chain reaction (PCR) result is necessary.
- Positive Hepatitis C virus antibody (HepCAb): Negative hepatitis C virus RNA by PCR result is necessary.
•Positive results for human immunodeficiency virus (HIV)
•Baseline ECG QTc > 470 msec (applying Fridericia correction), defined as the average of individual baseline ECGs
•History of malignancy other than multiple myeloma within the past 3 years
•Known hypersensitivity to immunoglobulins or to any components of the study drug
•Current or known history of autoimmune diseases requiring systemic treatment in past 5 years, excluding autoimmune thyroid disease, for which treatment should be completed 6 months prior to enrollment.
•Males and females of reproductive potential who are unwilling to practice highly effective method(s) of birth control while on study through 75 days (females) and 135 days (males) after receiving the last dose of study drug.
•Females who are lactating/breastfeeding or who plan to breastfeed while on study through 75 days after receiving the last dose of study drug
•Females with a positive pregnancy test
•Females planning to become pregnant while on study through 75 days after receiving the last dose of study drug
•Males who are unwilling to abstain from sperm donation while on study through 135 days after receiving the last dose of study drug
•Subjects likely to not be available to complete all protocol-required study visits or procedures
- Administration of bone preserving therapies within 14 days of cycle 1 day 1 (including bisphosphonates)
please see protocol amendment 14 for complete list of exclusion criteria |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1 – dose-exploration as monotherapy:
-Dose limiting toxicities (DLTs), treatment-emergent adverse events, treatment-related adverse events
-Clinically-significant changes in vital signs, physical examinations, electrocardiogram (ECG)s, and clinical laboratory tests Phase 1b –AMG701 dose-confirmation as monotherapy 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 1/1b -– AMG701 in combination with Pomalidomide, with and without Dexamethasone (AMG 701-P ± d)
-DLTs, treatment-emergent adverse events, treatment-related adverse events, disease related events
-Clinically-significant changes in vital signs, physical examinations, ECGs, and clinical laboratory tests
Phase 2 - AMG701 monotherapy dose - expansion:
- OR according to IMWG response criteria |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
-The analysis of all endpoints, unless noted otherwise, will be conducted on the Safety Analysis Set defined as all subjects that are enrolled and receive at least 1 dose of AMG 701.
-The analysis of all endpoints from phase 2, unless noted otherwise, will be conducted on the phase 2 Dose Analysis Set defined as all subjects in phase 2 or phase 1 dose-confirmation part who receive at least 1 dose of AMG 701 at the same dose level and schedule as that in phase 2.
AMG701-P ± d:
The analysis of all endpoints, unless noted otherwise, will be conducted on the AMG 701-P±d Safety Analysis Set defined as all subjects that are enrolled and receive at least 1 dose of any study treatment (i.e. AMG 701, pomalidomide, or dexamethasone) in the AMG 701-P±d combination. |
|
| E.5.2 | Secondary end point(s) |
Phase 1 – AMG 701 dose exploration as monotherapy:
- AMG 701 PK parameters including, but not limited to, maximum concentration (Cmax), time of maximum concentration (Tmax) area under the concentration-time curve (AUC), and steady state concentration (Css) for extended IV
o Efficacy parameters:
- overall response (OR) according to International Myeloma Working Group (IMWG) response criteria (BOR of stringent CR [sCR],complete response [CR],very good partial response [VGPR], or Partial [PR]) - BOR by category (sCR, CR, VGPR, PR), MR, stable disease [SD], progressive disease [PD]
-DOR (defined as time from the first PR or better to disease progression or death)
-Time to response
- Progression free survival (PFS), defined as time from start of treatment until disease progression or death
- Overall survival (OS), defined as time from start of treatment until death due to any cause.
Phase 1b – AMG 701 dose confirmation as monotherapy:
o Efficacy parameters:
- OR according to IMWG response criteria (best overall response of stringent CR, CR, VGPR, or PR)
- Duration of response (DOR)
- BOR by category (sCR, CR, VGPR, PR, MR, SD, PD)
o MRD[-]negativity at the time of CR rate at level of <10^5
- AMG 701 PK parameters including, but not limited to, Cmax, Tmax, AUC, and Css for extended IV
- Efficacy parameters according to IMWG response criteria:
- time to response
- progression-free survival (PFS)
- overall survival (OS)
Phase 1/1b -– AMG701 in combination with Pomalidomide, with and without Dexamethasone (AMG 701-P ± d):
o AMG 701 PK parameters including, but not limited to: Cmax, Tmax, AUC, and Css for extended IV
o ORR per IMWG response criteria (sCR, CR, VGPR, PR)
-BOR by category (sCR, CR, VGPR, PR, MR, SD, PD)
-DOR
-Time to response
-PFS
-OS
o MRD[-]CR rate at level of 10-5
o Pomalidomide PK parameters including, but not limited to: Cmax and trough concentration (Ctrough)
Phase 2 – AMG 701 monotherapy dose-expansion:
o DOR
o MRD[-]negativity at level of 10^5 in the bone marrow by next generation sequencing (NGS)
o Efficacy parameters according to IMWG response criteria:
- BOR by category (sCR, CR, VGPR, PR, MR, MD, SD, PD)
- time to response
-PFS
-OS
- Treatment emergent adverse events, treatment related adverse events and changes in vital signs, ECGs, and clinical laboratory tests |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
-The analysis of all endpoints, will be conducted on the Safety Analysis Set
-The analysis of all endpoints from phase 2,will be conducted on the phase 2 Dose Analysis Set
-The PK Analysis Set will contain all subjects who have received at least 1 dose of AMG 701 and have at least 1 PK sample collected.
-The analysis of DOR will be restricted to subjects with a partial response or better.
-The interim analysis of efficacy futility will be conducted on the Efficacy Futility Analysis Set |
|
| 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 | Yes |
| 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 | Yes |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Phase 1 dose escalation and dose expansion study |
|
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| 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 |
| Canada |
| Japan |
| United States |
| France |
| Netherlands |
| Spain |
| Germany |
| Belgium |
|
| 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
|
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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