Assessment of AMG 420 in Subjects With Relapsed and/or Refractory Multiple Myeloma (AMG420)

A Phase 1b Multicenter, Open-label, Expansion Study to Assess the Safety and Efficacy of AMG 420 as Monotherapy in Subjects With Relapsed and/or Refractory Multiple Myeloma

To confirm the maximum tolerated dose (MTD) from the BI 836909 trial of 400 mcg/d, given as 28-day continuous intravenous infusion in patients with relapsed and/or refractory multiple myeloma, to test the 600 mcg/d dose, given as a 28-day continuous iV infusion.

Study Overview

• Status: Terminated
• Conditions: Relapsed and/or Refractory Multiple Myeloma
• Intervention / Treatment: Drug: AMG 420

Detailed Description

Cohort 1 will consist of 10 subjects dosed at 400 mcg/d. Cohort 2 will consist of 10 subjects dosed at 600 mcg/d. All doses will be given as a 28-day continuous IV infusion, followed by a 2 week treatment-free interval, until subject experiences disease progression as per International Myeloma Working Group (IMWG) criteria.

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Darlinghurst, New South Wales, Australia, 2010
      • St Vincents Hospital Sydney
  • Victoria
    • Fitzroy, VIC, Victoria, Australia, 3065
      • St Vincents Hospital Melbourne
• Belgium
  • Haine Saint Paul - La Louviere, Belgium, 7100
    • Centres Hospitaliers Jolimont - Hopital de Jolimont
  • Yvoir, Belgium, 5530
    • Centre Hospitalier Universitaire Dinant Godinne - Universite Catholique de Louvain Namur
• Japan
  • Okayama
    • Okayama-shi, Okayama, Japan, 701-1192
      • National Hospital Organization Okayama Medical Center
• Switzerland
  • St. Gallen, Switzerland, 9007
    • Kantonsspital St Gallen
• United States
  • Illinois
    • Park Ridge, Illinois, United States, 60068
      • Advocate Lutheran General Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • New York
    • New York, New York, United States, 10021
      • Memorial Sloan Kettering Cancer Center
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest Baptist Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

1. Subject has provided informed consent prior to initiation of any study specific activities/procedures
2. Multiple myeloma meeting the following criteria:

3. Pathologically-documented diagnosis of multiple myeloma that is relapsed or is refractory as defined by the following: Relapsed after 3 or more lines of prior therapy that must include a proteasome inhibitors (PI), an immunomodulators (IMiD), and a CD38-directed monoclonal antibody in any order during the course of treatment OR refractory to a PI, IMiD, and CD38-directed monoclonal antibody.

   -Measurable disease, defined by 1 or more of the following at time of screening: 1) serum M-protein > 0.5 g/dL measured by serum protein electrophoresis (SPEP); 2) urinary M-protein excretion > 200 mg/24 hours; 3) Involved serum free light chain (sFLC ) measurement > 10 mg/dL, provided that the sFLC ratio is abnormal (<0.26 or >1.65) as per IMWG response criteria

4. . ECOG performance status of less than or equal to 2
5. Life expectancy of at least 3 months per PI judgement at screening

6. Hematological function without transfusion support (within 7 days from screening assessment) as follows:

   • ANC ≥ 1.0 x 10^9/L (without growth factor support)
   • platelet count ≥ 25 x 10^9/L (without transfusions)
   • hemoglobin ≥ 7.0 g/dL (transfusions permitted no later than 48 hours before screening)
7. 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
8. Hepatic function as follows: AST and ALT < 3x upper limit of normal (ULN); TBIL <1.5 x ULN (unless considered due to Gilbert's syndrome)

Key Exclusion Criteria:

1. Known central nervous system involvement by multiple myeloma
2. Evidence of primary or secondary plasma cell leukemia at the time of screening
3. Waldenstrom's macroglobulinemia
4. Unresolved toxicities from prior anticancer therapy, defined as not having resolved to CTCAE version 5.0 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 (defined as having been present and stable for > 4 weeks) which may be allowed if they are not otherwise described in the exclusion criteria and there is agreement to allow by the PI and Amgen medical monitor
5. History of other malignancy within the past 3 years, with the following exceptions: 1. 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; 2. adequately-treated non-melanoma skin cancer or lentigo maligna without evidence of disease; 3. adequately-treated cervical carcinoma in situ without evidence of disease; 4. breast ductal carcinoma in situ with full surgical resection (ie, negative margins) and without evidence of disease; 5. prostate cancer with a Gleason score < 6 with undetectable PSA over 12 months; 6. treated medullary or papillary thyroid cancer; 7. adequately-treated urothelial papillary noninvasive carcinoma or carcinoma in situ; similar neoplastic conditions with an expectation of > 95% five-year disease-free survival; 8. see exclusion criterion # 2 for exclusion of subjects with evidence of primary or secondary plasma cell leukemia at the time of screening
6. Known history of amyloidosis
7. 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.
8. 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
9. Symptomatic peripheral sensory or motor neuropathy of grade ≥3
10. 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
11. Active hepatitis B and C based on the following results: a) Positive for HepBsAg; b) Negative HepBsAg and positive for hepatitis B core antibody; c) Positive Hepatitis C virus antibody (HepCAb)
12. Known or suspected HIV infection or subjects who are HIV seropositive
13. Baseline ECG QTc > 470 msec (applying Fridericia correction)
14. Previously received an allogeneic stem cell transplant and the occurrence of 1 or more of the following: a) received the transplant within 6 months prior to study day 1; b) received immunosuppressive therapy within the last 3 months prior to study day 1; c) any active acute graft versus host disease (GvHD), grade 2 to 4, according to the Glucksberg criteria or active chronic GvHD requiring systemic treatment; d) any systemic therapy against GvHD within 2 weeks prior to start of investigational product treatment
15. Autologous stem cell transplantation < 90 days prior to study day 1
16. 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
17. Last anticancer treatment < 2 weeks prior to study day 1
18. Last treatment with a therapeutic antibody less than 4 weeks prior to study day 1
19. Systemic radiation therapy within 28 days prior to study day 1. Focal radiotherapy within 14 days prior to study day 1.
20. 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
21. 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
22. Treatment with medications known to cause QTc interval prolongation within the washout periods described in Section 12.10 unless approved by the Amgen medical monitor
23. 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). Other investigational procedures while participating in this study are excluded.
24. History or evidence of any other clinically-significant disorder, condition, or disease (eg, symptomatic congestive heart failure, unstable angina pectoris,cardiac arrhythmia requiring therapy at time of screening) with the exception of those outlined above that, in the opinion of the investigator or Amgen medical monitor, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures, or completion.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AMG 420; Single Arm Design	Drug: AMG 420; 28 day continuous Intravenous infusion of either 400 mcg/d or 600 mcg/d followed by 2 treatment free weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Dose-limiting Toxicities (DLTs)	DLTs were graded using Common Terminology Criteria for Adverse Events (CTCAE) v5.0, with the exception of cytokine release syndrome (CRS) and tumor lysis syndrome (TLS), which graded using the criteria referenced in the publication by Lee et al, 2014 and the Cairo Bishop criteria referenced in the publication by Coiffier et al, 2008 respectively. A participant was non-DLT evaluable if they dropped out before completion of the DLT-evaluable period for reasons other than a DLT.	Day 1 to Week 4
Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE)	The severity of TEAEs were graded using the CTCAE version 5.0 with the exception of CRS and TLS, which graded using the criteria referenced in the publication by Lee et al, 2014 and the Cairo Bishop criteria referenced in the publication by Coiffier et al, 2008. Any clinically significant changes in vital signs, electrocardiograms (ECGs) and clinical laboratory tests were recorded as TEAEs.	Up to approximately 3 years
Number of Participants Who Experienced a Treatment-related TEAE	The severity of treatment-related TEAEs were graded using the CTCAE version 5.0 with the exception of CRS and TLS, which graded using the criteria referenced in the publication by Lee et al, 2014 and the Cairo Bishop criteria referenced in the publication by Coiffier et al, 2008. Treatment-related TEAEs were those that were considered related to the study treatment by the investigator.	Up to approximately 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR)	ORR was defined as the percentage of participants for whom the best overall response was a stringent complete response (CR), CR, very good partial response (PR), or partial response as determined by the IMWG Uniform Response Criteria. The ORR along with the associated 95% exact binomial confidence interval (Clopper Pearson Method) was determined.	Up to approximately 3 years
Duration of Response (DOR)	DOR was defined as number of months between first objective response to progressive disease or death (due to any cause), whichever occurred first. Kaplan-Meier methods were used to estimate the distribution of DOR. The median and corresponding two-sided 95% confidence intervals were calculated.	Up to approximately 3 years
Percentage of Participants With Minimal Residual Disease (MRD) Negativity Response at CR	MRD negativity at CR or better assessed by using the IMWG criteria. Percentage of MRD negative responders at CR along with exact 2- sided 95% were provided by using the Clopper Pearson method.	Up to approximately 3 years
Number of Participants With Minimal Residual Disease (MRD) Negativity Response at CR	Number of participants with MRD negativity at CR or better assessed by using the IMWG criteria.	Up to approximately 3 years

Collaborators and Investigators

• Sponsor: Amgen
• Investigators: Study Director: MD, Amgen

Publications and helpful links

Helpful Links

• AmgenTrials clinical trials website

Study record dates

Study Major Dates

• Study Start (Actual): March 4, 2019
• Primary Completion (Actual): April 21, 2022
• Study Completion (Actual): April 21, 2022

Study Registration Dates

• First Submitted: February 5, 2019
• First Submitted That Met QC Criteria: February 8, 2019
• First Posted (Actual): February 11, 2019

Study Record Updates

• Last Update Posted (Actual): January 5, 2024
• Last Update Submitted That Met QC Criteria: March 28, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell
• Other Study ID Numbers: 20160370; 2018-002879-17 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request
• IPD Sharing Time Frame: Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication (or other new use) have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.
• IPD Sharing Access Criteria: Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors, and if not approved, may be further arbitrated by a Data Sharing Independent Review Panel. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the link below.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No