AL Amyloidosis, Light Chain (AL) Amyloidosis, Systemic Light Chain Disease
Conditions
Keywords
Translocation
Brief summary
This phase I/II trial tests the safety, side effects, and best dose of venetoclax, daratumumab, and dexamethasone for the treatment of systemic light-chain amyloidosis in patients with a deoxyribonucleic acid (DNA) abnormality called a translocation involving chromosomes 11 and 14, or t(11;14). Venetoclax works by attaching to a protein called Bcl-2, in order to kill cancer cells. Daratumumab works by binding to a target on the surface of cancer cells called Cluster of differentiation 38 (CD38). When daratumumab binds to CD38, it enables the immune system to find the cancer cell and kill it. Dexamethasone is a type of drug called a corticosteroid. A corticosteroid is a drug made of artificial steroid hormones, that are used to treat symptoms such as inflammation (swelling and irritation to a part of the body). The combination of these medications may more effectively treat patients with systemic light-chain amyloidosis and t(11;14).
Detailed description
PRIMARY OBJECTIVES: I. To determine the maximum-tolerated dose (MTD)/ the recommended phase 2 dose (RP2D) of venetoclax (VEN) with or without daratumumab subcutaneous (DARA SC) and dexamethasone (DEX), in previously treated light chain (AL) amyloidosis (PTAL) participants with t(11;14). (Phase I). II. To evaluate the efficacy of the combination VEN/DARA SC and DEX as measured by Complete Hematologic Response (CHR rate) in PTAL participants with t(11;14). (Phase II) SECONDARY OBJECTIVES: I. To evaluate the safety and tolerability of VEN/DARA SC, and DEX in the treatment of PTAL participants with t(11;14). (Phase I) II. To evaluate the efficacy of VEN/DARA SC and DEX in the treatment of PTAL participants with t(11;14) as measured by overall hematologic response rate (ORR), progression free survival (PFS), overall survival (OS), organ response rate (orRR), major organ deterioration PFS (MOD-PFS), time to complete response (TTCR), duration of response (DOR), and time to new treatment (TTNT). To evaluate safety of VEN/DARA SC and DEX in the treatment of PTAL participants with t(11;14). (Phase II) IV. To evaluate the death rate, therapy-related death rate, infection rate, and cardiac event rate, in the VEN/DARA SC and DEX arm and the DARA SC and DEX arm. (Phase II). EXPLORATORY OBJECTIVES: I. To evaluate the feasibility of performing M protein detection by MALDI TOF mass spectrometry on the EXENT® system on serum and urine participant-samples collected by each site during the first 6 months of the study. II. To evaluate the agreement between MALDI TOF mass spectrometry results by the EXENT® system and standard serologic and urine measures of disease after the enrollment for both phase 1 and 2 has been complete. III. To evaluate the complete response (CR) rate, ORR, PFS, MOD-PFS, OS, OrRR, TTCR, TTNT and DOR separated by participants who are minimal residual disease (MRD) negative versus positive by EXENT®. IV. To evaluate the CR rate, overall hematologic response rate (ORR), progression-free survival (PFS), major organ deterioration PFS (MOD-PFS), overall survival (OS), organ response rate (OrRR), time to complete response (TTCR), time to next treatment (TTNT) and duration of response (DOR) and relationship to light-chain glycosylation patterns over time by EXENT®. OUTLINE: This is a phase I, dose-escalation study of venetoclax followed by a phase II study. If dose level 3 (VEN/DARA SC and DEX) is not the recommended phase 2 doses/maximum tolerated dose in phase 1, the study will not open to phase 2. PHASE I: All participants receive venetoclax orally (PO) once daily (QD) on days 1-28 of each cycle. Depending on dose-level assignment, participants may also receive dexamethasone PO on days 1, 8, 15, and 22 of each cycle with or without daratumumab SC on days 1, 8, 15, and 22 of cycles 1-2, days 1 and 15 of cycles 3-6, then on day 1 of cycles thereafter. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. PHASE II: Participants receive venetoclax PO QD on days 1-28 of each cycle, dexamethasone PO on days 1, 8, 15, and 22 of each cycle, and daratumumab SC on days 1, 8, 15, and 22 of cycles 1-2, days 1 and 15 of cycles 3-6, then on day 1 of cycles thereafter. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. After completion of study treatment, participants are followed up at 30 days and then every 3 months until the last participant on the study completes 2 years of treatment.
Interventions
DRUGVenetoclax
Given orally (PO)
DRUGDexamethasone
Given PO
DRUGDaratumumab
Given Subcutaneously (SC)
DEVICECyclin D1 gene (CCDN1) /immunoglobulin heavy chain (IGH) fluorescence in situ hybridization (FISH) assay
Lab test
Sponsors
Janssen Pharmaceuticals
AbbVie
Alfred Chung, MD
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age \>= 18 years 2. Histopathological diagnosis of amyloidosis based on detection by immunohistochemistry (IHC) and polarizing light microscopy of green bi-refringent material in Congo red-stained tissue specimens (in an organ other than bone marrow) or characteristic electron microscopy appearance. \*Considerations for specific populations where other types of amyloidosis may be encountered: \*\*For male subjects 70 years of age or older who have cardiac involvement only, and patients of African descent (black subjects), mass spectrometry typing of AL amyloid in a tissue biopsy is recommended to rule out other types of amyloidosis such as age-related amyloidosis or hereditary amyloidosis (ATTR mutation) 3. Presence of t(11;14) on bone marrow plasma cells (BMPC) by fluorescence in-situ hybridization (FISH), performed at the University of California San Francisco (UCSF) cytogenetics laboratory 4. \>= 1 prior line of therapy for the treatment of systemic AL amyloidosis. \*Note: Induction with only autologous stem cell transplant is considered 1 line of therapy. Steroid monotherapy treatment will not be counted as 1 prior line of therapy per National Comprehensive Cancer Network (NCCN) guidelines. Patients are not required to having progressed from the prior line of therapy 5. No prior CD38-directed antibody treatment OR If the patient previously received CD38-directed antibody treatment, the patient achieved \>= partial response (PR) and did not progress while on CD38-directed antibody therapy. Progression on CD38-directed antibody treatment will be defined as progressive disease while on therapy or within 60 days of last dose. \* Note: If the patient's last prior treatment included daratumumab and the patient relapsed (and does not meet the
Exclusion criteria
as outlined in exclusion criterion #1) after cessation of treatment, a 3-month wash-out from CD38 antibody treatment is required. No washout period for DARA is deemed necessary when patients are already on DARA-based treatment and the treatment regimen needs to be stopped due to hematologic very good partial response (VGPR) or PR (suboptimal response) or non-DARA-related toxicity. 6. Measurable disease of light chain amyloidosis as defined by at least ONE of the following: 1. Serum M-protein \>= 0.5 g/dL by protein electrophoresis (routine serum protein electrophoresis and immunofixation (IFE) performed at a local laboratory), 2. Serum free light chain \>= 40mg/L with an abnormal kappa:lambda ratio or 3. The difference between involved and uninvolved free light chains (dFLC) \>= 20 mg/L. 7. One or more organs impacted by AL amyloidosis according to consensus guidelines. 8. Eastern Cooperative Oncology Group (ECOG) performance status =\< 2. 9. Pretreatment clinical laboratory values meeting the following criteria during the Screening Phase (within 1 day of C1D1): 1. Absolute neutrophil count \>= 1.0 × 10\^9/L without growth factor support for 7 days (14 days if pegfilgrastim). 2. Hemoglobin level \>= 8.0 g/dL (\>= 5 mmol/L). 3. Platelet count \>= 100 × 10\^9/L without transfusion for 14 days. 4. Alanine aminotransferase level (ALT) =\< 2.5 times the upper limit of normal (ULN). 5. Aspartate aminotransferase (AST) =\< 2.5 times the ULN. 6. Total bilirubin level =\< 3 × ULN except for subjects with Gilbert syndrome, in which case direct bilirubin =\< 2 × ULN. 7. Creatinine clearance of ≥ 30 mL/min based upon Cockcroft-Gault formula calculation or a 24-hour urine collection. 10. Patients must have completed other systemic therapy \>= 14 days or investigational drug/vaccine \>= 28 days prior to treatment, focal radiation therapy \>= 14 days, surgery (other than biopsies) \>= 21 days prior to treatment, and any autologous stem cell transplant (ASCT) \>= 100 days prior to start of treatment. 11. Patients must not have received any medications or supplements which have been known to have some anti-amyloidogenic effect (such as: doxycycline; curcumin; prednisone; dexamethasone; epigallocatechin gallate) within 14 days prior to start of treatment. 12. Women of childbearing potential 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 treatment and continue for 30 days after discontinuation of venetoclax or 3 months after discontinuation of DARA SC, whichever is longer. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy or bilateral oophorectomy. 13. During the study and for 30 days after stopping VEN or 3 months after receiving the last dose of DARA SC, whichever is longer, a woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction. 14. 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 30 days after discontinuation of VEN or 3 months after discontinuation DARA SC, whichever is longer. All men must also not donate sperm during the study and for 30 days after discontinuation of VEN or 3 months after discontinuation of DARA SC, whichever is longer. 15. Patients must have documentation of yearly flu vaccination and a pneumococcus vaccination. Note: If the patient is due for 2 doses of pneumococcus vaccination, patients must have documentation of having received one dose of vaccine. Live attenuated vaccines are not allowed 16. Ability to understand a written informed consent document, and the willingness to sign it.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of participants with reported dose limiting toxicities (Phase 1) | Up to 1 cycle (1 cycle is equal to 28 days) | A dose limiting toxicity (DLT) will be defined as an adverse event that are considered by the investigator to be at least possibly related to the study drugs and are observed within the DLT assessment window (Cycle 1, Days 1 to 28) except those that are clearly and incontrovertibly due to extraneous causes. |
| Maximum tolerated dose (MTD) (Phase 1) | Up to 1 cycle (1 cycle is equal to 28 days) | The MTD is the last dose cohort at which no more than one instance of dose limiting toxicities (DLT) is observed among 6 participants treated. If the MTD cannot be determined due to lack of DLTs during the DLT window, the maximum dose level of venetoclax administered during the study will be declared the Recommended Phase 2 dose (RP2D). |
| Recommended phase 2 dose (RP2D) (Phase1) | Up to 1 cycle (1 cycle is equal to 28 days) | If the MTD cannot be determined due to lack of DLTs during the DLT window, the maximum dose level of venetoclax administered during the study will be declared the Recommended phase 2 dose (RP2D). |
| Proportion of participants who achieve a complete hematologic response (CHR) (Phase 2) | Up to 2 years | CHR is defined per updated 2021 International Society of Amyloidosis (ISA) consensus criteria as an absence of amyloidogenic light chains (either free and/or as part of a complete immunoglobulin) defined by negative immunofixation electrophoresis of both serum and urine, and also either a free-light chain (FLC) ratio within the reference range or the uninvolved FLC concentration is greater than involved FLC concentration with or without an abnormal FLC ratio. Participants with positive serum immunofixation (S-IFE) and confirmed daratumumab immunofixation (IFE) interference, that meet all other clinical criteria for CHR, will be considered CHR. CHR requires confirmation by 1 repeat assessment. Proportion and 95% binomial exact confidence interval will be reported |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Major Organ Deterioration Progression-Free Survival (MOD-PFS) (Phase 2) | Up to 2 years | MOD-PFS is defined as the time that elapses between initiation of trial therapy and the earlier of hematologic disease progression, cardiac deterioration that requires cardiac transplant, left ventricular assist device, or intra-aortic balloon pump, end-stage renal disease that requires hemodialysis or renal transplant, or death from any cause for participants enrolled in Phase 2. Median survival times will be reported in months along with 95% confidence intervals obtained using the Brookmeyer and Crowley (1982) method. |
| Time to complete response (TTCR) (Phase 2) | Up to 2 years | TTCR is defined as the time that elapses between the initiation of trial therapy (C1D1) and the first time that complete hematological response (CHR) is recorded for participants enrolled in Phase 2. |
| Median Time To Next Treatment (TTNT) (Phase 2) | Up to 2 years | For the RP2D combination, TTNT is defined as the time that elapses between the initiation of study treatment (C1D1) to the time the participant initiates subsequent anti-cancer therapy for participants enrolled in Phase 2. Median time will be reported in months along with 95% confidence intervals. |
| Median Duration of response (DOR) (Phase 2) | Up to 2 years | DOR is defined as the time that elapses between the day of first documented hematological response to trial therapy (PR or better whichever is first recorded) to the date of first documented evidence of hematological disease progression participants enrolled in Phase 2. Median duration will be reported in months along with 95% confidence intervals. |
| Median Progression-Free Survival (PFS) (Phase 2) | Up to 2 years | PFS is defined as the time that elapses between initiation of trial therapy and the earlier of the day of first documented disease progression (either hematologic or organ) or death from any cause for participants enrolled in Phase 2. Median survival times will be reported in months along with 95% confidence intervals obtained using the Brookmeyer and Crowley (1982) method. |
| Percentage of participants with treatment-emergent adverse events attributable to study treatment | Up to 2 years | Percentage of participants with reported treatment-emergent adverse events by type, severity, and attribution of probably, possible, or related to study drugs, according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be reported for both phases of the study. |
| Overall number of participant deaths (Phase 2) | Up to 2 years | The number of participants enrolled in Phase 2 whose death occurred while the participant was on study will be reported. |
| Number of treatment-related mortalities (Phase 2) | Up to 2 years | The number of participants enrolled in Phase 2 whose death was at least possibly attributable to treatment will be reported. |
| Proportion of participants with infection (Phase 2) | Up to 2 years | The proportion of participants enrolled in Phase 2 who develop a documented infection will be reported. |
| Percentage of participants with a cardiac event (Phase 2) | Up to 2 years | The percentage of participants enrolled in Phase 2 with a documented cardiac event will be reported. |
| Median Overall Survival (OS) (Phase 2) | Up to 2 years | The overall survival is defined as the time that elapses between the initiation of trial therapy (C1D1) and the date of death from any cause for all participants enrolled in Phase 2. Median survival times will be reported in months along with 95% confidence intervals obtained using the Brookmeyer and Crowley (1982) method. |
| Proportion of participants with complete hematologic response (CHR) (Phase 2) | Up to 2 years | CHR is defined per updated 2021 International Society of Amyloidosis (ISA) consensus criteria as an absence of amyloidogenic light chains (either free and/or as part of a complete immunoglobulin) defined by negative immunofixation electrophoresis of both serum and urine, and also either a free-light chain (FLC) ratio within the reference range or the uninvolved FLC concentration is greater than involved FLC concentration with or without an abnormal FLC ratio. Participants with positive serum immunofixation (S-IFE) and confirmed daratumumab immunofixation (IFE) interference, that meet all other clinical criteria for CHR, will be considered CHR. CHR requires confirmation by 1 repeat assessment. |
| Overall hematologic response rate (ORR) (Phase 2) | Up to 2 years | The proportion of participants enrolled in Phase 2 who experience a hematologic objective response defined as a partial response (PR), a very good partial response (VGPR), or a complete response (CR) per updated 2021 ISA consensus criteria. |
| Organ response rate (orRR) (Phase 2) | Up to 2 years | Organ disease considered to be quantifiable for response includes cardiac disease, renal disease, and hepatic disease. Liver organ response must be monitored by the ISA Consensus Criteria. Renal organ response must be monitored by Palladini criteria. Cardiac response must be monitored by the Boston University criteria. The proportion of participants enrolled in Phase 2 who experience an organ response (Heart, kidney, and/or liver). |
Outcome results
None listed