Multiple Myeloma
Conditions
Keywords
AO-176, CD47, Immunotherapy, Monoclonal antibody
Brief summary
Open-label, dose escalation study to evaluate the safety, tolerability, pharmacokinetics (PK)/pharmacodynamics and initial efficacy of AO-176 as monotherapy and in combination with dexamethasone and bortezomib in adults with relapsed/refractory multiple myeloma (MM).
Detailed description
An open-label, multicenter, dose escalation study to evaluate the safety, tolerability and PK/pharmacodynamics of AO-176 in adults with relapsed/refractory multiple myeloma whose disease has progressed following at least 3 prior systemic lines of treatment and must have progressed on the final line of therapy received before being considered for this study. The study will be conducted in 2 phases; Phase 1 is an ascending-dose study of AO-176 monotherapy utilizing the classic 3+3 design, with enrollment of 3 patients per cohort and expansion of the cohort in the event of a dose-limiting toxicity (DLT). Following the dose escalation portion and determination of the monotherapy recommended phase 2 dose (RP2D), an ascending dose escalation study of AO-176 and dexamethasone combined with bortezomib will be evaluated utilizing the same 3+3 dose escalation design. Phase 2 will evaluate the clinical activity of AO-176 plus dexamethasone and bortezomib at the RP2D as determined in Phase 1 Part 2.
Interventions
DRUGAO-176
Humanized monoclonal antibody (mAb) targeting CD47
DRUGAO-176 + Dex
Humanized mAb targeting CD47 plus dexamethasone
DRUGAO-176 + Dex + Bort
Humanized mAb targeting CD47 plus dexamethasone plus bortezomib
Sponsors
Arch Oncology
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Phase 1 Part 1: Up to 4 dose escalation cohorts will be enrolled; each cohort will initially recruit 3 patients to receive AO-176 monotherapy in a standard 3+3 design; the cohort will be expanded in the event of a DLT. Once the RP2D has been identified, an expansion cohort will be enrolled to evaluate AO-176 at the RP2D in combination with dexamethasone (DEX). Phase 1 Part 2: Dose escalation cohorts will evaluate AO-176 in combination with DEX and bortezomib (BORT) to determine the RP2D of AO-176 + DEX + BORT in a standard 3+3 design; the cohort will be expanded in the event of a DLT. Phase 2: Up to 48 patients will be enrolled to evaluate the preliminary efficacy of AO-176 + DEX + BORT using a Simon 2-stage design.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. Confirmed diagnosis of symptomatic MM per IMWG criteria 2. Measurable disease 3. Relapsed or refractory to at least 3 prior systemic lines of therapy for MM 4. Eastern Cooperative Oncology Group (ECOG) status 0-2 5. Resolution of prior therapy-related adverse events 6. Minimum of 2 weeks since last dose of cancer therapy or radiotherapy Key
Exclusion criteria
1. Previous Grade 3-4 infusion or hypersensitivity reaction 2. Severe asthma or chronic obstructive pulmonary disease exacerbations requiring hospital admission or steroids 3. Prior treatment with a checkpoint inhibitor (anti-PD-1, PD-L1 or CTLA-4) within 4 weeks. 4. Prior treatment with a therapeutic agent that targets the CD47 axis.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1: MTD / RP2D of AO-176 assessed by incidence of dose-limiting toxicities and incidence of treatment-related adverse events (TEAEs) as assessed by CTCAE v5.0 | 12 months | Safety and tolerability of AO-176 when administered as monotherapy and in combination with dexamethasone or with dexamethasone plus bortezomib in adult patients with R/R MM as assessed by incidence of DLTs and TEAEs as assessed by CTCAE v5.0 |
| Phase 2: Objective response rate (ORR) of AO-176 + DEX + BORT | 12 months | Evaluate the clinical activity of AO-176 + dexamethasone + bortezomib based on ORR using International Myeloma Working Group (IMWG) uniform response criteria |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1: Disease control rate (DCR) of single agent AO-176 | 12 months | Evaluate the clinical activity of single agent AO-176 based on DCR using IMWG uniform response criteria |
| Phase 1: Progression-free survival (PFS) of single agent AO-176 | 12 months | Evaluate the clinical activity of single agent AO-176 based on PFS using IMWG uniform response criteria |
| Phase 1: Overall survival (OS) of single agent AO-176 | 12 months | Evaluate the clinical activity of single agent AO-176 based on OS |
| Phase 1: ORR of single agent AO-176 | 12 months | Evaluate the clinical activity of single agent AO-176 based on ORR using IMWG uniform response criteria |
| Phase 2: DCR of AO-176 + DEX + BORT | 12 months | Evaluate the clinical activity of AO-176 + dexamethasone + bortezomib based on DCR using IMWG uniform response criteria |
| Phase 2: PFS of AO-176 + DEX + BORT | 12 months | Evaluate the clinical activity of AO-176 + dexamethasone + bortezomib based on PFS using IMWG uniform response criteria |
| Phase 2: OS of AO-176 + DEX + BORT | 12 months | Evaluate the clinical activity of AO-176 + dexamethasone + bortezomib based on OS |
| Phase 2: DOR of AO-176 + DEX + BORT | 12 months | Evaluate the clinical activity of AO-176 + dexamethasone + bortezomib based on DOR using IMWG uniform response criteria |
| Phase 1: Duration of response (DOR) of single agent AO-176 | 12 months | Evaluate the clinical activity of single agent AO-176 based on DOR using IMWG uniform response criteria |
Countries
United States
Outcome results
None listed