IRB Study Number 25-744
Status Recruiting
Phase Phase 2
Location Cleveland Clinic Main Campus
Institute Taussig Cancer Institute
Description
Phase 1B:
To evaluate the safety and tolerability of AZD0120, and determine the RP2D of AZD0120 in participants with AL amyloidosis;
To evaluate the efficacy of AZD0120 in participants with AL amyloidosis;
To characterize the CK of AZD0120 in peripheral blood following a single-dose of AZD0120 in participants with AL amyloidosis; To assess immunogenicity of AZD0120 in participants with AL amyloidosis
Phase 2: To evaluate the efficacy of AZD0120 in participants with AL amyloidosis;
To further evaluate the efficacy of AZD0120 in participants with AL amyloidosis;
To characterize the safety of AZD0120 in participants with AL amyloidosis;
To characterize the CK of AZD0120 in peripheral blood following a single-dose of AZD0120 in participants with AL amyloidosis;
To assess immunogenicity of AZD0120 in participants with AL amyloidosis;
To assess the effect of AZD0120 on overall health status in participants with AL amyloidosis
Inclusion Criteria
- Must be 18 years of age, at the time of signing the informed consent.
- Confirmed histopathological diagnosis of AL amyloidosis based on polarizing light microscopy of green bi-refringent material in Congo red stained tissue specimens and confirmation of AL derived amyloid deposits by at least one of the following: immunohistochemistry, immunofluorescence, mass spectrometry, characteristic electron microscopy appearance/immunoelectron microscopy. Confirmed diagnosis on historic biopsy is acceptable, with no requirement for repetition.
- One or more organs currently or historically impacted by AL amyloidosis according to consensus guidelines
- Measurable hematologic disease: dFLC > 20 mg/L or serum M-protein > 5g/L
- Relapsed disease or refractory disease defined as a need for additional therapy after at least 1 line of anti-plasma cell-directed therapy. Prior therapies must include at least one CD38 monoclonal antibody and at least one proteasome inhibitor. Participants should not be in a CR at the time of inclusion. Participants who did not reach VGPR after at least 2 cycles of initial therapy can be included, as well as participants who initially attained a CR or VGPR with initial therapy with evidence of rising dFLC, that the Investigator deems as requiring further anti-plasma cell directed treatment.
- ECOG performance status of 0 to 1
Exclusion Criteria
Main Exclusion Criteria:
Have any other form of amyloidosis other than AL amyloidosis
Cardiac exclusion criteria:
a. Mayo Stage IIIb AL amyloidosis (Wechalekar, 2013)
b. NT-proBNP levels as follows:
NT-proBNP 2000 ng/L (Phase 1b dose escalation portion and Phase 2 lower NT-proBNP group)
NT-proBNP < 2000 and > 5000 ng/L (Phase 1b dose extension portion and Phase 2 higher NT-proBNP group).
c. High-sensitivity cardiac troponin T > 75 ng/L
d. NYHA Class III – IV
e. LVEF < 45% by echocardiogram
f. Medically refractory atrial or ventricular arrhythmias as determined by Investigator
g. Symptomatic or medically refractory pleural effusions as determined by Investigator
h. Decompensated heart failure
i. Unexplained syncope, not believed to be vasovagal
j. Standing systolic BP < 100 mm Hg or symptomatic orthostatic hypotension, defined as a decrease in systolic BP upon standing of > 30 mmHg despite medical management (eg, midodrine, fludrocortisones) in the absence of volume depletion
k. Myocardial infarction, coronary revascularization or CABG 6 months prior to screening
l. Pacemaker/ICD/CRT-D implantation within 6 months prior to screeningSevere Factor X deficiency (Factor X < 10%) or Factor X deficiency with significant risk of bleeding as determined by Investigator
Extensive GI involvement with evidence of active GI bleeding/risk of bleeding as determined by Investigator
Oxygen saturation < 95% on room air
Prior therapies:
a. CAR T cell therapy directed at any target
c. Prior treatment with any FDA approved or investigational T cell engaging therapies (including T cell-directed bispecific or trispecific therapies) at any target within the last 6 months.
d. An allogenic stem cell transplant within 6 months before apheresis. Participants who received an allogeneic transplant must be off all immunosuppressive medications for 6 weeks before apheresis without signs of GVHD.
e. An autologous stem cell transplant 12 weeks before apheresis
f. Prior therapy as follows, prior to apheresis:
Investigational product within 5 half-lives or 21 days (whichever is the shorter).
Monoclonal antibody treatment for AL within 21 days.
Cytotoxic/alkylating therapy within 21 days
Proteasome inhibitor therapy within 14 days.
Immunomodulatory agent therapy within 14 days.
Received a cumulative dose of systemic corticosteroids, equivalent to 70 mg of prednisone, within 7 days prior to apheresis.Toxicity from previous anti-cancer or anti-PC-directed therapy did not resolve to baseline levels or to Grade 1 or less except for alopecia or peripheral neuropathy.
Active plasma cell leukemia at the time of screening, Waldenstrom’s macroglobulinemia or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes). IgM associated AL amyloidosis is permitted, as long as participant meets other eligibility criteria including requisite prior therapies.
Multiple myeloma defined as clonal bone marrow plasma cells 10% and any one or more of the following myeloma defining events (deemed as attributable to multiple myeloma by Investigator) (Rajkumar, 2014).
a. Hypercalcemia: serum calcium > 0.25 mmol/L (> 1 mg/dL) higher than the ULN or > 2.75 mmol/L (> 11 mg/dL) OR
b. Renal insufficiency: creatinine clearance < 40 mL per minute or serum creatinine > 177 mol/L (> 2 mg/dL) OR
c. Anemia: hemoglobin value of > 20 g/L below the lowest limit of normal, or a hemoglobin value < 100 g/L OR
d. Bone lesions: one or more lesions on imaging tests (performed 3 months prior to signing the ICF or during Screening): skeletal radiography, CT, or PET/CT, or MRI.
e. 60% or greater clonal plasma cells on bone marrow biopsy in screening
