AL Amyloidosis
Conditions
Brief summary
This is a phase 1/2 open label study of melphalan flufenamide (melflufen) in combination with dexamethasone for participants with Al amyloidosis following at least one prior line of therapy. Melflufen will be administered on Day 1 of each 28-day cycle in combination with dexamethasone on days 1 and 2. In both phases, treatment of each individual participant will continue for up to 8 cycles or until any stopping events occur. Approximately 46 participants will be enrolled. The study was intended to be a Phase 1/2 trial but was early terminated and never moved forward to Phase 2.
Detailed description
This is a clinical trial of melphalan flufenamide (melflufen), a peptide-conjugated alkylator which belongs to an novel class of drugs called peptidase-enhanced compounds, and targets the transformation process of tumor cells with a unique mechanism of action, as potential treatment option of AL amyloidosis. AL amyloidosis is a rare progressive disease caused by proteotoxic light chain protein produced by small plasma cell clone. This plasma cell dyscrasia is characterized by monoclonal plasma cell's excessive production of monoclonal immunoglobulin light-chains that tends to misfold and subsequently deposit as amyloid fibrils in visceral organs. The plasma cell dyscrasia in AL amyloidosis is similar to that in multiple myeloma (MM) and therapies that are effective in MM are often used to treat AL amyloidosis. Melphalan flufenamide is currently been evaluated in several ongoing clinical trials in patients with multiple myeloma, with observed efficacy. There are currently no therapies approved for treatment of AL amyloidosis and based on the efficacy of melphalan flufenamide and the demonstrated efficacy of melphalan (and other alkylators), it is anticipated that patients with AL amyloidosis may receive benefit from treatment with melphalan flufenamide. This study consist of a screening period (up to 28 days), a treatment period (up to 8 cycles) and a follow-up period (up to 24 months). Phase 1: Approximately 8-30 participants will be screened to achieve 7-23 enrolled participants. Phase 2: Approximately 30 participants will be screened to achieve 23 enrolled participants. The study was intended to be a Phase 1/2 trial but was early terminated and study never moved forward to Phase 2.
Interventions
DRUGMelphalan-Flufenamide (Melflufen)
Treatment consist of i.v. melflufen on Day 1 of each 28-day cycle.
DRUGDexamethasone
Dexamethasone 40 mg (20 mg at investigator's discretion) administered on Days 1 and 2 of each 28-day cycle.
Sponsors
PRA Health Sciences
Oncopeptides AB
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Melflufen + Dexamethasone
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
(For full list of inclusion criteria, see study protocol) * Male or female, age 18 years or older at the time of signing the informed consent * Proven histochemical diagnosis of AL amyloidosis based on tissue specimens with Congo red staining * At least one prior line of therapy, defined as either one non-transplant regimen, one ASCT (autologous stem cell transplantation), or one regimen of induction therapy followed by a single ASCT. No more that 4 cycles of melphalan containing chemotherapy is allowed. * Measurable hematologic disease * Objectively measurable organ amyloid involvement * ECOG performance status ≤ 2 (ECOG = Eastern cooperative oncology group) * Women of child bearing potential must have a negative serum or urine pregnancy test * Less than 30% plasma cells in bone marrow aspirate or biopsy * Acceptable laboratory results met (absolute neutrophil count (ANC), platelet count, hemoglobin, total bilirubin,alkaline phosphatase, AST (aspartate aminotransferase) and ALT (alanine aminotransferase), renal function) * Male participant agrees to use contraception during treatment and 90 days after last dose of melflufen
Exclusion criteria
(For full list of
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The primary objective in Phase 1 is to explore safety and tolerability of melflufen | During phase 1 for up to 8 cycles of treatment of 28 days each (approx. up to 8 months) | Endpoints: * Frequency and grade of Adverse Events. The maximum grade for each type of AE will be recorded for each participant and frequency tables will be presented and reviewed to determine patterns * Laboratory values (laboratory abnormalities) for hematology, coagulation, blood chemistry, urinalysis |
| The primary objective in Phase 1 is to identify recommended Phase 2 dose (RP2D) | During phase 1 for up to 8 cycles of 28 days each (approx. up to 8 months) | Endpoint: Dose-Limiting Toxicity (DLT) during Cycle 1 up to maximum dose of melflufen of 40 mg. A DLT event is defined as thrombocytopenia, neutropenia, non-hematologic toxicity and/or inability to receive Cycle 2 Day 1 dose within 14 days from planned Cycle 2 Day 2 due to continued melflufen-related toxicity from Cycle 1. |
| The primary endpoint in Phase 2 is to evaluate the hematologic overall response rate (ORR) after 4 cycles at the RP2D determined in Phase 1 | During phase 2 after 4 cycles of treatment ( approx. 4 months) | The proportion of participants who achieve a hematologic Complete Response (CR), Very Good Partial Response (VGPR) or Partial Response (PR) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To assess the proportion of organ system responses | Throughout the study treatment period of up to 8 cycles of 28 days each (approx 8 months) per patient | Proportion of participants with kidney, cardiac or liver response, respectively |
| To assess duration of organ system responses | Throughout the study treatment period of up to 8 cycles (approx 8 months) per patient | Duration of organ responses separately for each organ |
| To assess pharmacokinetic profile of melflufen in this patient population | At Cycle 1 Day 1 and Cycle 2 Day 1 at time points 5-10 minutes, 1-2 hours and 3-8 hours after end of infusion. Each cycle length is 28 days. | Melphalan plasma concentration post melflufen administration at 3 time points |
| To assess time to next AL amyloidosis treatment | Throughout the study, covering up to 8 cycles (approx. 8 months) of treatment and 24 months of follow up | Time to next AL amyloidosis treatment |
| To assess Overall Survival (OS) | Throughout the study, covering up to 8 cycles (approx. 8 months) of treatment and up to 24 months of follow up | Overall survival |
| To assess hematologic ORR (overall response rate) | During phase 1 for up to 8 cycles of treatment of 28 days each (approx. up to 8 months) | Proportion of participants who achieve a hematologic CR, VGPR or PR |
| To assess best hematologic response | Throughout the study treatment of up to 8 cycles of 28 days each (approx. 8 months) per patient | Proportion of patients with each outcome (Complete Response (CR), Very Good Partial Response (VGPR), Partial Response (PR), No Response (NR) or Progressive Disease (PD)) |
| To assess the duration of hematologic response | Throughout the study treatment period of up to 8 cycles of 28 days each (approx 8 months) per patient | Median time (Complete Response (CR), Very Good Partial Response (VGPR), Partial Response (PR), No Response (NR) or Progressive Disease (PD)) |
Countries
Czechia, France, Germany, Greece, Israel, Norway, Spain, United Kingdom, United States
Outcome results
None listed