Venetoclax and Dexamethasone in the Treatment of Relapsed or Refractory AL Amyloidosis

Inclusion Criteria

• Signed informed consent form. LARs (legally authorized representatives) are permitted
• Age >= 18 years at time of informed consent
• Ability to comply with the study protocol, in the investigator's judgment
• Confirmed diagnosis of systemic AL amyloidosis by mass spectrometry or immunohistochemistry (IHC) or immunofluorescence (IF) on a tissue biopsy
• Has received >= 1 prior lines of therapy, including an anti-cluster of differentiation 38 (CD 38) monoclonal antibody (Patients must have prior exposure to an anti-CD 38 monoclonal antibody to be eligible for this study)
• FOR PHASE 2: Patients must have one of the following criteria regarding lines of therapy * ≥ 2 prior lines of therapy * If 1 prior line of therapy, it must be Dara-VCd (daratumumab-bortezomib-cyclophosphamide-dexamethasone)
• Participants with a history of autologous hematopoietic cell transplantation must have recovered from any transplant-related toxicities
• Measurable hematologic disease defined as: * Positive serum and/or urine immunofixation eletcrophoresis with a serum monoclonal (M)-protein ≥ 0.5 g/dl and/or * Serum differential free light chain (dFLC) concentration ≥ 20 mg/L or 2 mg/dL (dFLC is the difference between amyloid forming [involved] and non-amyloid forming [uninvolved] FLC)
• Presence of t(11;14) on fluorescence in situ hybridization (FISH). Eligibility must be confirmed by FISH testing at Columbia University Irving Medical Center (CUIMC), which will serve as a central laboratory for this trial. The cut-off for positive t(11;14) test is 5% on CD-138 enriched cells
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
• Prothrombin time (or international normalized ratio) and partial thromboplastin time not to exceed 1.2 times the institution’s normal range, unless on a stable dose of anticoagulant
• Calculated creatinine clearance >= 20 ml/min using Cockcroft-Gault equation
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN)
• Total bilirubin =< 1.5 x ULN * Patients with known Gilbert disease who have serum bilirubin =< 3 x ULN may be enrolled
• Platelet >= 50,000 cells/mm^3
• Hemoglobin >= 8 g/dL
• Absolute neutrophil count >= 1.0 x 10^9 cells/mm^3
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception and agreement to refrain from donating eggs, as defined below: * Women must remain abstinent or use contraceptive methods with a failure rate of =< 1% per year during the treatment period and for 30 days after the final dose of venetoclax. Women must refrain from donating eggs during this same period * A woman is considered to be of childbearing potential if she is post-menarchal, has not reached a postmenopausal state (> 12 continuous months of amenorrhea with no identified cause other than menopause), and is not permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined by the investigator (e.g., Müllerian agenesis). The definition of childbearing potential may be adapted for alignment with local guidelines or regulations * Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices * Hormonal contraceptive methods must be supplemented by a barrier method * The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are not acceptable methods of contraception. If required per local guidelines or regulations, locally recognized acceptable methods of contraception and information about the reliability of abstinence will be described in the local informed consent form
• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm, as defined below: * With a female partner of childbearing potential or pregnant female partner, men must remain abstinent or use a condom during the treatment period and for 30 days after the final dose of venetoclax to avoid exposing the embryo. Men must refrain from donating sperm during this same period * The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are not acceptable methods of preventing drug exposure. If required per local guidelines or regulations, information about the reliability of abstinence will be described in the local informed consent form

Exclusion Criteria

• Known hypersensitivity to any of the study drugs
• History of other malignancy that could affect compliance with the protocol or interpretation of results * Patients with a history of curatively treated basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix, breast cancer, or Hodgkin’s lymphoma are generally eligible. Patients with a malignancy that has been treated, but not with curative intent, will be excluded, unless the malignancy has been in remission without treatment for >= 2 years prior to enrollment
• Evidence of other clinically significant uncontrolled condition(s) including, but not limited to, uncontrolled systemic infection (viral, bacterial, or fungal)
• Patients on renal replacement therapy
• Known gastrointestinal (GI) disease or GI procedure that could interfere with oral absorption (including difficulty swallowing)
• Administration of live attenuated vaccine within 28 days prior to study entry
• New York Heart Association (NYHA) class IIIB and IV heart failure
• Mayo stage IIIB with N-terminal-pro hormone B-type natriuretic peptide (NT-Pro BNP) > 8500 pg/mL
• Prior exposure to BCL-2 inhibitors
• In Phase I part of the trial, treatment with moderate or strong CYP3A inhibitors, CYP3A inducers, or P-glycoprotein (P-gp) inhibitors within 7 days of starting study drug and during DLT period (1st cycle)
• In phase II part of the trial, treatment with moderate or strong CYP3A inhibitors or P-gp inhibitors would be permissible if the venetoclax dose is modified
• Consumption of grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or starfruit within 3 days prior to the initiation of study treatment
• Patients with human immunodeficiency virus (HIV) who are not on highly active antiretroviral therapy (HAART) or those with active hepatitis A, B, or C infection
• Treatment with investigational drug 14 days prior to cycle 1 day 1 (C1D1)
• Patients meeting criteria for symptomatic multiple myeloma by one of the following: (a) Lytic lesions on imaging (b) Plasmacytoma, (c) Hypercalcemia without any alternate etiology, or (c) Bone marrow plasma cell infiltrate of greater than 60%