A Study Evaluating AMG 424 in Subjects With Multiple Myeloma

Overview

About this study

Prior clinical experience with CD38-targeting antibodies, including daratumumab, establish this molecule as an important therapeutic target in multiple myeloma. CD38 is a type II transmembrane glycoprotein with both ectoenzymatic and signal transductionfunctions. CD38 dimerization is required for its catalytic activity (Desphande et al, 2017).Dimeric CD38 possesses both ADP ribosyl cyclase and cADPR hydrolyase activities; the former generates cyclic ADP ribose (cADPR) from NAD+ and the latter generates ADPR. CD38-mediated cADPR generation enables calcium release from intracellular stores, leading to a variety of cell type-specific physiological outcomes (Schuber and und, 2004; Lee and Aarhus, 1991). A distinct mode of CD38-dependent signal transduction involved in the regulation of proliferation and survival requires interactions with other cell surface molecules (Deshpande et al, 2017; Deaglio et al, 2007; Konopleva et al, 1998). In B- lymphocytes for example, CD38-dependent signal transduction activity utilizes interactions with CD19 and CD31/PECAM-1, the latter of which is the sole identified ligand for CD38 (Deaglio et al, 2007). Importantly, AMG 424 binding to CD38 on target cells results in redirection of T cell mediated cytotoxicity but should not modulate CD38 enzymatic activity or CD38-dependent signal transduction, based on expected serum concentrations in our proposed dosing scheme and significanty reduced binding affinity compared to a monoclonal antibody that does inhibit CD38 activity (Deckert et al., 2014).For this first-in-human study, relapsed/refractory multiple myeloma has been chosen as the indication for clinical investigation of AMG 424 because of the nearly uniform high expression of CD38 on plasma cells observed at the protein level, using flow cytometry (Lin et al, 2004). Although low level CD38 expression is widespread in different tissue types, including hematopoietic cells, plasma cells express CD38 protein at signficantly higher levels than other cell types (Malavasi et al, 2008 and Section 3 of AMG 424 IB).

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.

Inclusion Criteria:

  • Subject has provided informed consent prior to initiation of any study-specific activities/procedures.
  • Male or female age ≥ 18 years at the time of signing the informed consent.
  • Subject has Multiple Myeloma meeting the following criteria:
    • Pathologically-documented diagnosis of multiple myeloma that has relapsed after at least two prior lines of therapy that must include a proteasome inhibitor (PI), immunomodulatory drug (IMiD), and, where approved and available, anti-CD38 therapy in any order OR that is refractory to PI, IMiD, and anti-CD38 therapy;
      • Subjects who could not tolerate a PI, IMiDs, or a CD38-directed therapeutic antibody due to unacceptable toxicities are eligible to enroll in the study.
    • Measurable disease, defined by one or more of the following at time of screening:
      • Sserum M protein > 0.5 g/dl measured by serum protein electrophoresis;
      • Urinary M protein excretion > 200 mg/24 hours;
      • For subjects without measurable M protein by serum protein electrophoresis (SPEP) and urine protein electrophoresis (UPEP): serum free light chain (FLC) measurement > 10 mg/dl, provided that the serum FLC ratio is abnormal (< 0.26 or > 1.65) as per IMWG unified response criteria;
      • Dose expansion Group A only:
        • In addition to the above, have received a CD38-targeting antibody > 6 months prior to enrollment.
      • Dose expansion Group B only:
        • Relapsed or refractory with prior treatment with a CD38 targeting antibody; and
        • Evidence of standard/low risk cytogenetics defined as not meeting high risk cytogenetic criteria as defined below.
      • Dose expansion Group C only:
        • Relapsed or refractory with prior treatment with a CD38 targeting antibody and evidence of high risk cytogenetics defined by fluorescent in situ hybridization (FISH) as ≥ 1 of the following: t(4;14), t(14;16), t(14;20), del(17/17p), gain(1q).
  • Eastern Cooperative Oncology Group (ECOG) performance of ≤ 2.
  • Hematological function without transfusion or growth factor support as follows:
    • Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L. Subjects should not have received granulocyte- and granulocyte/macrophage colony stimulating factor (G-CSF and GM-CSF) support for ≥ 1 week and of pegylated G-CSF for ≥ 2 weeks prior to screening;
    • Platelet count ≥ 75 x 10^9/L (if < 50% of bone marrow nucleated cells are plasma cells) or ≥ 50 X 10^9/L (if ≥ 50% of bone marrow nucleated cells are plasma cells). Subjects should not have received platelet transfusions for ≥ 1 week prior to screening;
    • Hemoglobin > 8.0 g/dL (> 80 g/L). Use of erythropoietic stimulating factors and red blood cell (RBC) transfusions per institutional guidelines is allowed; however, most recent RBC transfusion must be ≥ 1 week prior to screening.
  • Renal function as follows:
    • Calculated or measured creatinine clearance ≥ 30 mL/min using the Cockcroft-Gault equation or 24-hour urine collection with plasma and urine creatinine concentrations, respectively.
  • Hepatic function as follows:
    • aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3x upper limit of normal (ULN);
    • total bilirubin < 1.5 x ULN (unless considered due to Gilbert’s syndrome).
  • Coagulation function as follows: Prothrombin time (PT)/ international normalized ratio (INR) and partial thromboplastin time (PTT) < 1.5 x institutional upper limit of normal.
  • Cardiac function, as follows; left ventricular ejection fraction (LVEF) > 50%.  2-D transthoracic echocardiogram (ECHO) is the preferred method of evaluation.  Multi-gated Acquisition Scan (MUGA) is acceptable if ECHO is not available.

Exclusion Criteria:

  • Known central nervous system involvement by multiple myeloma.
  • Previously received an allogeneic stem cell transplant and one or more of the following:
    • Received the transplant < 6 months prior to study Day 1;
    • Received immunosuppressive therapy < 3 months prior to study Day 1;
    • Any active acute graft versus host disease (GvHD), grade 2- 4, according to the Glucksberg criteria or active chronic GvHD requiring systemic treatment;
    • Any systemic therapy against GvHD < 2 weeks prior to study Day 1.
  • Autologous stem cell transplantation < 90 days prior to study Day 1.
  • Multiple myeloma with IgM subtype.
  • POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes).
  • Evidence of primary or secondary plasma cell leukemia at the time of screening.
  • Waldenstrom’s macroglobulinemia.
  • Amyloidosis.
  • Dexamethasone at cumulative doses of greater than 160 mg or equivalent < 3 weeks prior to study Day 1 is not allowed. Use of topical or inhaled steroids is acceptable.
  • Anticancer treatment (chemotherapy, IMiD, PI, molecular targeted therapy) < 2 weeks prior to study Day 1.
  • Treatment with a therapeutic antibody targeting CD38 < 12 weeks prior to study Day 1.
  • Systemic radiation therapy < 28 days prior to study Day 1. Focal radiotherapy < 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.
  • Currently receiving treatment in another investigational device or drug study or < 28 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 7 days of study day 1 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 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: hepatitis B virus DNA by polymerase chain reaction (PCR) is necessary. Detectable hepatitis B virus DNA suggests occult hepatitis B;
    • Positive Hepatitis C virus antibody (HepCAb): hepatitis C virus RNA by PCR is necessary. Detectable hepatitis C virus RNA suggests chronic hepatitis C.
  • Known positivity for Human Immunodeficiency Virus (HIV).
  • Baseline ECG QTc > 470 msec.
  • History of malignancy other than multiple myeloma within the past 5 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 < 6 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.
  • Males and females of reproductive potential who are unwilling to practice highly effective method(s) of birth control while on study through 120 days (females) and 180 days (males) after receiving the last dose of study drug.
  • Highly Effective Contraceptive Methods include:
    • NOTE: Failure rate of < 1% per year when used consistently and correctly;
    • Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, or transdermal);
    • Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable);
    • Intrauterine device (IUD);
    • Intrauterine hormonal-releasing system (IUS);
    • Bilateral tubal ligation/occlusion;
    • Vasectomized partner (provided that partner is the sole sexual partner of the female subject of childbearing potential and that the vasectomized partner has received medical assessment of the surgical success);
    • Sexual abstinence, which is defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments; the reliability of sexual abstinence must be evaluated in relation to the duration of the trial and the preferred and usual lifestyle of the subject.
  • Females who are lactating/breastfeeding or who plan to breastfeed while on study through 120 days after receiving the last dose of study drug.
  • Females with a positive pregnancy test.
  • Females planning to become pregnant while on study through 120 days after receiving the last dose of study drug.
  • Males who are unwilling to abstain from sperm donation while on study through 180 days after receiving the last dose of study drug.
  • Subject likely to not be available to complete all protocol-required study visits or procedures including bone marrow 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 other clinically-significant disorder, condition or disease (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.
  • Clinically-relevant concurrent or history of any other medical disease or condition, which according to the investigator’s judgment would either compromise subject safety or interfere with the study evaluation, procedures of completion; e.g., symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia requiring therapy at time of screening.

Participating Mayo Clinic locations

Study statuses change often. Please contact the study team for the most up-to-date information regarding possible participation.

Mayo Clinic Location Status Contact

Jacksonville, Fla.

Mayo Clinic principal investigator

Sikander Ailawadhi, M.D.

Closed for enrollment

Contact information:

Cancer Center Clinical Trials Referral Office

(855) 776-0015

Rochester, Minn.

Mayo Clinic principal investigator

Prashant Kapoor, M.D.

Closed for enrollment

Contact information:

Cancer Center Clinical Trials Referral Office

(855) 776-0015

Scottsdale/Phoenix, Ariz.

Mayo Clinic principal investigator

Jeremy Larsen, M.D.

Closed for enrollment

Contact information:

Cancer Center Clinical Trials Referral Office

(855) 776-0015

More information

Publications

Publications are currently not available
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