Phase II, Multicenter Study to Assess Safety and Efficacy of Combination of Sargramostim with D-VCd Therapy (Daratumumab, Cyclophosphamide, Bortezomib, Dexamethasone) in Untreated Patients with Light Chain Amyloidosis

Prior treatment

• Prior therapy for AL amyloidosis or multiple myeloma, except for 160 mg dexamethasone (or equivalent corticosteroid) maximum exposure.
• Concurrent medical condition or disease (e.g. active systemic infection) that is likely to interfere with study procedures or results, or that in the opinion of the investigator would constitute a hazard for participating in this study.
• Received an investigational drug (including investigational vaccines) or used an invasive investigational medical device within 4 weeks before Cycle 1 Day 1.
• Major surgery within 2 weeks before Cycle 1 Day 1, or will not have fully recovered from surgery, or has surgery planned during the time the subject is expected to participate in the study or within 2 weeks after the last dose of study treatment administration. Note: subjects with planned surgical procedures to be conducted under local anesthesia may participate.
• Subjects who are taking strong CYP3A4 inducers must discontinue their use at least 5 half-lives prior to the first dose of study treatment.
• Planned stem cell mobilization, collection, and stem cell transplant during the first 6 cycles of protocol therapy. Note: stem cell mobilization, collection and transplantation are allowed after study treatment completion.
• Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (i.e. subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR

Other illness

• Known to be seropositive for hepatitis C (except in the setting of a sustained virologic response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy).
• Known hypersensitivity or contraindication to any of the components of study drugs including sargramostim, daratumumab, bortezomib, boron, mannitol, or cyclophosphamide, dexamethasone, or any of its metabolites. Patients with known hypersensitivity to GM-CSF and yeast-derived products or any component of the product. Known allergies, hypersensitivity, or intolerance to monoclonal antibodies, hyaluronidase, human proteins, or their excipients, or known sensitivity to mammalian-derived products.
• Known or suspected of not being able to comply with the study protocol (e.g. because of alcoholism, drug dependency, or psychological disorder) or the subject has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (e.g. compromise their well-being) or that could prevent, limit, or confound the protocol-specified assessments.
• History of malignancy (other than AL amyloidosis) within 3 years before the date of enrollment (exceptions are squamous and basal cell carcinomas of the skin, carcinoma in situ of the cervix or breast, or other lesion that in the opinion of the investigator, with concurrence with the sponsor, is considered cured and/or with minimal risk of recurrence or progression within 3 years).
• Chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in 1 second (FEV1) < 50% of predicted normal. Note that FEV1 testing is required only for subjects suspected of having COPD and subjects must be excluded if FEV1 < 50% of predicted normal.
• Known to be seropositive for human immunodeficiency virus (HIV).

Lab values

• Previous or current diagnosis of symptomatic multiple myeloma, including the presence of lytic bone disease, plasmacytomas, infiltration with ≥60% clonal plasma cells in the bone marrow, or hypercalcemia (serum calcium >0.25 mmol/L (>1mg/dL) higher than the upper limit of normal or >2.75 mmol/L (>11mg/dL)
• Evidence of significant cardiovascular conditions as specified below:a. NT-ProBNP >8500 pg/ml (ng/L); b. New York Heart Association (NYHA) classification IIIB or IV heart failure; c. Heart failure that in the opinion of the investigator is on the basis of ischemic heart disease (e.g. prior myocardial infarction with documented history of cardiac enzyme elevation and ECG changes) or uncorrected valvular disease and not primarily due to AL amyloid cardiomyopathy; d. Inpatient admission to a hospital for unstable angina or myocardial infarction within the last 6 months prior to first dose or percutaneous cardiac intervention with recent stent within 6 months or coronary artery bypass grafting within 6 months; e. For subjects with congestive heart failure, cardiovascular-related hospitalizations within 4 weeks prior to enrollment;f. Subjects with a history of sustained ventricular tachycardia or aborted ventricular fibrillation or with a history of atrioventricular nodal or sinoatrial (SA) nodal dysfunction for which a pacemaker/ICD is indicated but not placed (subjects who do have a pacemaker/ICD are allowed in the study); g. Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia’s formula (QTcF) >500 msec. Subjects who have a pacemaker may be included regardless of calculated QTc interval; h. Supine systolic blood pressure < 90 mmHg or symptomatic orthostatic hypotension, defined as a decrease in systolic blood pressure upon standing of 20 mmHg despite medical management (e.g., midodrine, fludrocortisone) in the absence of volume depletion.

Other

• Grade 2 sensory or Grade 1 painful peripheral neuropathy.
• Any form of non-AL amyloidosis, including wild type or mutated ATTR amyloidosis.
• Woman who is pregnant or breastfeeding or planning to become pregnant while enrolled in this study or within 1 year after discontinuation of cyclophosphamide or 3 months following discontinuation of daratumumab, whichever is longer
• Moderate or severe persistent asthma within the past 2 years, or currently has uncontrolled asthma of any classification. (Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed in the study)

• 18 years of age or older.
• Each subject, or legally acceptable representative, must sign an informed consent form (ICF) indicating that he or she understands the purpose of procedures required for the study and are willing to participate in the study. Subjects must be willing and able to adhere to the prohibitions and restrictions specified in this protocol, as referenced in the ICF.
• Histopathological diagnosis of AL amyloidosis based on detection by polarizing light microscopy of green bi-refringent material in Congo red-stained tissue specimens (in an organ other than bone marrow) and typing of AL amyloid in a tissue specimen by IHC or immune electron microscopy or mass spectrometry.
• Measurable disease of amyloid light chain amyloidosis as defined by at least ONE of the following:a) serum M-protein ≥0.5 g/dL by routine protein serum protein electrophoresis and immunofixation (IFE), b) serum free light chain ≥50 mg/L with an abnormal kappa: lambda ratio or the difference between involved and uninvolved free light chains (dFLC) ≥50 mg/L. Note: Measurable disease by urine Bence-Jones proteinuria is not sufficient for study enrollment.
• One or more organs impacted by AL amyloidosis according to consensus guidelines.
• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0, 1 or 2.
• Pretreatment clinical laboratory values meeting the following criteria during the Screening Phase:a. Absolute neutrophil count (ANC) ≥1.0 × 109 /L b. Hemoglobin level ≥8.0 g/dL (≥5 mmol/L); red blood cell transfusion allowed until 7 days before enrollment c. Platelet count ≥50 × 109 /L; Platelet transfusions are acceptable without restriction during the Screening Period d. Alanine aminotransferase level (ALT) ≤2.5 times the upper limit of normal (ULN) e. Aspartate aminotransferase (AST) ≤2.5 times the ULN f. Total bilirubin level ≤1.5 × ULN except for subjects with Gilbert syndrome, in which case direct bilirubin ≤2 × ULN g. Estimated glomerular filtration rate (eGFR) ≥20 mL/min/1.73 m2. Please note the eGFR is measured by using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.
• A woman of childbearing potential must have a negative serum or urine pregnancy test (serum preferred) result at screening and must commit to either abstain continuously from heterosexual sexual intercourse (if this is the preferred and usual lifestyle of the subject) or to use 2 methods of reliable birth control simultaneously. This includes one highly effective form of contraception (tubal ligation, intrauterine device, hormonal [birth control pills, injections, hormonal patches, vaginal rings or implants] or partner’s vasectomy) and one additional effective contraceptive method (male latex or synthetic condom, diaphragm, or cervical cap). Contraception must begin 4 weeks prior to C1D1 and continue for 1 year after discontinuation of cyclophosphamide or 3 months after discontinuation of daratumumab, whichever is longer. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy or bilateral oophorectomy.
• During the study and for 1 year after stopping cyclophosphamide or 3 months after receiving the last dose of daratumumab, whichever is longer, a woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction.
• A man who is sexually active with a woman of childbearing potential and has not had a vasectomy must agree to use a barrier method of birth control, e.g., either condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository during and up to 6 months after discontinuation of cyclophosphamide or 3 months after discontinuation of daratumumab, whichever is longer. All men must also not donate sperm during the study and for 6 months after discontinuation of cyclophosphamide or 3 months after discontinuation of daratumumab, whichever is longer.