Light Chain (AL) Amyloidosis, Stage 3B
Conditions
Brief summary
This is an open-label, multicenter, Phase 2 study in subjects with newly diagnosed stage 3B light chain (AL) amyloidosis.
Detailed description
The current study aims to investigate daratumumab as a monotherapy in patients with stage 3B AL amyloidosis who have not received prior therapy. Approximately 40 subjects will receive primary therapy with daratumumab. Subject participation will include a Screening Phase, a Treatment Phase, a Post-Treatment Observation Phase, and a Long-term Follow-up Phase. A safety run-in will be conducted in 6 subjects treated with daratumumab for at least 1 cycle to establish safety of daratumumab in patients with stage 3B AL amyloidosis. Dosing of these 6 subjects will be staggered so that no subject will receive their first dose sooner than 48 hours after the previously enrolled subject. Safety evaluation will be performed by a Data Safety Monitoring Board (DSMB) after at least 1 cycle is completed for all 6 subjects. If no safety signal is observed, the enrollment of the rest of the patients will begin. In Protocol Version 1.0, subjects receive daratumumab IV at a dose of 16 mg/kg. As of Protocol Amendment 1, all new subjects are dosed subcutaneously with daratumumab co-formulated with recombinant human hyaluronidase rHuPH20 (daratumumab SC). Subjects who already began treatment with daratumumab IV (i.e., prior to Amendment 1) switch to daratumumab SC on the next administration date according to the protocol schedule. Subjects receive daratumumab IV at a dose of 16 mg/kg and daratumumab SC at a fixed dose of 1800 mg for the first 8 weeks (Cycles 1 and 2) of treatment and then every 2 weeks for 4 cycles (Cycles 3 to 6) and then every 4 weeks until progression of disease (according to MOD-PFS), unacceptable toxicity or subsequent therapy, for a maximum of 2 years in total. All treatment cycles are 4 weeks (28 days) in length. Subjects who will not achieve either a hematologic VGPR or better, OR a hematologic PR with a major organ response by Cycle 4 Day 1 may receive at Investigator's discretion, in addition to daratumumab, bortezomib (1.3 mg/m2 weekly for a maximum of 6 cycles) and low dose dexamethasone (total maximum weekly dose of 20mg).
Interventions
DRUGDaratumumab
As of Protocol Amendment 1, all new subjects are dosed with daratumumab subcutaneous injection (SC) co-formulated with recombinant human hyaluronidase rHuPH20. Subjects who already began treatment with daratumumab intravenous (IV) infusion (i.e., prior to Am 1) switch to SC on the next administration date according to the protocol schedule. Subjects receive daratumumab IV at a dose of 16 mg/kg and daratumumab SC at a fixed dose of 1800 mg for the first 8 weeks (Cycles 1 and 2) of treatment and then every 2 weeks for 4 cycles (Cycles 3 to 6) and then every 4 weeks until progression of disease (according to MOD-PFS), unacceptable toxicity or subsequent therapy, for a maximum of 2 years in total. All treatment cycles are 4 weeks (28 days) in length.
Subjects who do not achieve either a hematologic VGPR or better, OR a hematologic PR with a major organ response by Cycle 4 Day 1 may receive at Investigator's discretion, in addition to daratumumab, bortezomib at a dose of 1.3 mg/m2 weekly for a maximum of 6 cycles as a subcutaneous injection
Subjects who do not achieve either a hematologic VGPR or better, OR a hematologic PR with a major organ response by Cycle 4 Day 1 may receive at Investigator's discretion, in addition to daratumumab low dose dexamethasone at a maximum total dose of 20 mg weekly.
Sponsors
Janssen Pharmaceutica
Stichting European Myeloma Network
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* KEY INCLUSION CRITERIA 1. Men or women 18 years of age or older. 2. Diagnosis of amyloidosis, AL type, based on: 1. Histopathological diagnosis of amyloidosis based on detection by immunohistochemistry and polarizing light microscopy of green bi-refringent material in Congo Red stained tissue specimens (excluding bone marrow) or characteristic electron microscopy appearance Considerations for specific populations where other types of amyloidosis may be encountered: • For male subjects over 70 years of age who have cardiac involvement only, and subjects of African descent (black subjects), mass spectrometry, immunoelectron microscopy, or other immunohistochemistry-based typing of AL amyloid in a tissue biopsy or a negative bone scintigraphy with Tc99m-PYP or -DPD is recommended to rule out other types of amyloidosis such as age related amyloidosis and/or hereditary amyloidosis (ATTR mutation) AND 2. Measurable disease of amyloid light chain amyloidosis as defined by at least ONE of the following: * serum monoclonal protein ≥0.5 g/dL by protein electrophoresis (routine serum protein electrophoresis and immunofixation performed at local lab), * serum free light chain (FLC) ≥2.0 mg/dL (20 mg/L) with an abnormal kappa:lambda ratio or the difference between involved and uninvolved free light chains (dFLC) ≥2mg/dL (20 mg/L). Serum free light chains (FLCs) will be measured using the Freelite assay at a central laboratory * Note: Measurable disease by Urine Bence-Jones Proteinuria is not sufficient for study enrolment. AND 3. Cardiac involvement by AL amyloidosis according to consensus guidelines 3. Mayo Stage 3B disease, defined as both A. increased cardiac troponin (hsTnT \> 54 pg/ml) AND B. increased NT-proBNP ≥ 8500 pg/ml 4. For subjects with congestive heart failure, symptoms should be optimally managed and clinically stable with no cardiovascular-related hospitalizations within 2 weeks prior to Cycle 1 Day 1, as assessed by the Principal Investigator. \[See also
Exclusion criteria
3\] 5. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0, 1, 2 or 3 6. Subject must have pre-treatment clinical laboratory values meeting the following criteria during the Screening Phase: 1. Absolute neutrophil count ≥1.0 × 109/L; 2. Hemoglobin level ≥8.0 g/dL (≥5 mmol/L) 3. Platelet count ≥75 × 109/L; platelet transfusions are NOT acceptable 4. Alanine aminotransferase level (ALT) ≤2.5 x the upper limit of normal (ULN); 5. Aspartate aminotransferase (AST) ≤2.5 x ULN 6. Total bilirubin level ≤1.5 × ULN, except for subjects with history of Gilbert Syndrome, in which case direct bilirubin ≤ 2 × ULN 7. Estimated Glomerular Filtration Rate (eGFR) ≥20 mL/min; Please note that the eGFR is measured using the CKD-EPI equation 7. 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 prior to dosing 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. 8. During the study and for 3 months after receiving the last dose of daratumumab, female subjects must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction. 9. 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 3 months after discontinuation of daratumumab. All men must not donate sperm during the study and for 3 months after discontinuation of daratumumab. 10. Female subjects of childbearing potential must have a negative serum or urine pregnancy test within 14 days prior to Cycle 1 Day 1. For requirements during the Treatment Phase, please see the Time and Events Schedule. 11. Each subject must sign an informed consent form (ICF) indicating that he or she understands the purpose of the 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| overall survival | 6 months | To evaluate the overall survival rate at 6 months following treatment with daratumumab in frontline AL patients with stage 3B disease. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Major Organ Deterioration Progression-Free Survival (MOD-PFS). | every 28 days from start of study treatment (cycle 1 Day1) to death or major organ deterioration 2 years with an average of 6 month | Major Organ Deterioration Progression-Free Survival (MOD-PFS) is a composite endpoint of clinically observable endpoints and will be defined from the start of study treatment (Cycle 1 Day 1) to any one of the following events (whichever occurs first) • Death or Major organ deterioration |
| Progression Free Survival | from registration to the date of disease progression or death with a maximum of 2 years | documentation of hematologic disease progression, or organ (cardiac, renal, or liver) progression/need for transplant, or need for additional therapy (excluding the addition of bortezomib under protocol) or death due to any cause, whichever occurs first according to central laboratory results and judged by international consensus guidelines |
| organ response rate (OrRR) | from registration to the date of disease progression or death with a maximum of 2 years | Heart, Kidney, Liver |
| overall Response Rate (ORR) | at 3 and 6 months | ORR, rate of very good partial (VGPR) and complete (CR) hematologic response |
| proportion of additional treatment | every 28 days, from start of study treatment (cycle 1 Day1) until end of treatment with a maximum of 2 years, average of 6 months | o describe the proportion of subjects who received additional treatment with bortezomib and low dose dexamethasone (at the investigator's discretion). |
| EORTC QLQ-C30 scores will be summarized at each time point. The relationship between response and change in domain scores will be explored. the results will also be presented in two groups (SC and IV daratumumab administration). | on day 1 of cycle 1-6 (each cycle is 28 days), every 8 weeks thereafter until end of treatment with a maximum of 2 years | The EORTC QLQ-C30 is a 30-item questionnaire containing both single and multi-item measures. These include five functional scales (Physical, Role, Cognitive, Emotional, and Social Functioning), three symptom scales (Fatigue, Pain, and Nausea/Vomiting), a Global Health Status/ Quality-of-Life (QoL) scale, and six single items (Constipation, Diarrhea, Insomnia, Dyspnea, Appetite Loss, and Financial Difficulties). The scores ranges from 0-100, a high score for functional scales and for Global Health Status/QoL represent better functioning ability or Health-Related Quality-of-Life (HRQoL), whereas a high score for symptom scales and single items represents significant symptomatology. |
| Time to hematologic response | 2 years | to evaluate the time to response |
Countries
France, Greece, Italy, Netherlands
Outcome results
None listed