Assessment of AMG 420 in Subjects With Relapsed and/or Refractory Multiple Myeloma
Assessment of AMG 420 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.
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.
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.