Ensayos clínicos

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 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 doseconfirmation part, Group 2 must be relapsed/refractory 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) x 1.0 x 10^9 /L (without growth factor support);
    • platelet count ≥ 50 x 10^9 /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);
    • In patients with Gilberts syndrome, enrollment will be allowed if the level of total bilirubin (TBIL) falls within the CTCAE grade 2 (i.e., < 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 ≥ 2.0 mg/dL (≥ 0.6 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.

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, 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.
• 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 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 (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 both the investigator and Amgen medical monitor.
• 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 with the following exceptions:
  • Malignancy treated with curative intent and with no known active disease present for ≥ 3 years 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 (i.e., negative margins) and without evidence of disease;
  • Prostate cancer with a Gleason score < 7 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.
• 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 including BM aspirates/biopsies, and/or to comply with all required study procedures to the best of the subject and investigator’s knowledge
• History or evidence of any of the following clinically significant disorders:
  • Active congestive heart failure (New York Heart Association Class III to IV);
  • Symptomatic ischemia;
  • Uncontrolled arrythmia;
  • Screening ECG with corrected QT interval (QTc) of > 470.
• Myocardial infarction within 12 months prior to enrollment 
• Any other medical condition that, in the opinion of the investigator or Amgen medical monitor, if consulted, would pose a risk to subject safety or interfere with study evaluations or procedures.