Assessment of AMG 420 in Subjects With Relapsed and/or Refractory Multiple Myeloma
Condition: Relapsed and/or Refractory Multiple Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Intervention: AMG 420
Intervention description: 28 day continuous Intravenous infusion of either 400 mcg/d or 600 mcg/d followed by 2 treatment free weeks
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Intervention model description: Phase 1b Primary objective Establish the safety and tolerability of AMG 420 at dose levels of 400 mcg/day and 600 mcg/day in subjects with relapsed and/or refractory multiple myeloma (RRMM)
Phase 1b Key Secondary/Secondary objectives:
Estimate overall response rate (ORR) and duration of response (DOR) Evaluate the rate of minimal residual disease (MRD)-negativity at the time of CR Establish the safety and tolerability of AMG 420 in subjects with extramedullary relapsed MM Characterize the PK of AMG 420 when administered as 4-week continuous IV infusion Evaluate other measures of anti-myeloma activity of AMG 420: Time to response, PFS, OS, TFI, BOR
Masking: None (Open Label)
Enrollment: 23.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      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.
    

Eligibility 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.