Study of AO-176 as Monotherapy and in Combination With Bortezomib/Dexamethasone in Relapsed/Refractory Multiple Myeloma

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase 1/2, Dose Escalation Safety and Tolerability Study of AO-176 as Monotherapy and in Combination With Bortezomib and Dexamethasone in Adults With Relapsed or Refractory Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: AO-176
* Drug: AO-176 + Dex
* Drug: AO-176 + Dex + Bort


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Confirmed diagnosis of symptomatic MM per IMWG criteria Measurable disease Relapsed or refractory to at least 3 prior systemic lines of therapy for MM Eastern Cooperative Oncology Group (ECOG) status 0-2 Resolution of prior therapy-related adverse events Minimum of 2 weeks since last dose of cancer therapy or radiotherapy Key Exclusion Criteria: Previous Grade 3-4 infusion or hypersensitivity reaction Severe asthma or chronic obstructive pulmonary disease exacerbations requiring hospital admission or steroids Prior treatment with a checkpoint inhibitor (anti-PD-1, PD-L1 or CTLA-4) within 4 weeks. Prior treatment with a therapeutic agent that targets the CD47 axis.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional 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.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AO-176 Dose Escalation Monotherapy<br>The dose escalation monotherapy cohorts will initially recruit 3 patients to receive AO-176 in a standard 3+3 design; cohorts will be expanded in the event of a DLT. | Drug: AO-176<br>* Humanized monoclonal antibody (mAb) targeting CD47<br>|
| Experimental: AO-176 + DEX Expansion Cohort<br>Once the monotherapy RP2D has been established, an expansion cohort of AO-176 + dexamethasone will be enrolled. | Drug: AO-176 + Dex<br>* Humanized mAb targeting CD47 plus dexamethasone<br>|
| Experimental: AO-176 + DEX + BORT Dose Escalation<br>Following evaluation of AO-176 + dexamethasone, dose escalation cohorts of AO-176 + dexamethasone + bortezomib will be enrolled. Each dose escalation cohort will initially recruit 3 patients in a standard 3+3 design; cohorts will be expanded in the event of a DLT. The Phase 2 portion of the study will further evaluate the RP2D of AO-176 + DEX + BORT. | Drug: AO-176 + Dex + Bort<br>* Humanized mAb targeting CD47 plus dexamethasone plus bortezomib<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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 | 12 months | 
| Phase 2: Objective response rate (ORR) of AO-176 + DEX + BORT | Evaluate the clinical activity of AO-176 + dexamethasone + bortezomib based on ORR using International Myeloma Working Group (IMWG) uniform response criteria | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: ORR of single agent AO-176 | Evaluate the clinical activity of single agent AO-176 based on ORR using IMWG uniform response criteria | 12 months | 
| Phase 1: Duration of response (DOR) of single agent AO-176 | Evaluate the clinical activity of single agent AO-176 based on DOR using IMWG uniform response criteria | 12 months | 
| Phase 1: Disease control rate (DCR) of single agent AO-176 | Evaluate the clinical activity of single agent AO-176 based on DCR using IMWG uniform response criteria | 12 months | 
| Phase 1: Progression-free survival (PFS) of single agent AO-176 | Evaluate the clinical activity of single agent AO-176 based on PFS using IMWG uniform response criteria | 12 months | 
| Phase 1: Overall survival (OS) of single agent AO-176 | Evaluate the clinical activity of single agent AO-176 based on OS | 12 months | 
| Phase 2: DOR of AO-176 + DEX + BORT | Evaluate the clinical activity of AO-176 + dexamethasone + bortezomib based on DOR using IMWG uniform response criteria | 12 months | 
| Phase 2: DCR of AO-176 + DEX + BORT | Evaluate the clinical activity of AO-176 + dexamethasone + bortezomib based on DCR using IMWG uniform response criteria | 12 months | 
| Phase 2: PFS of AO-176 + DEX + BORT | Evaluate the clinical activity of AO-176 + dexamethasone + bortezomib based on PFS using IMWG uniform response criteria | 12 months | 
| Phase 2: OS of AO-176 + DEX + BORT | Evaluate the clinical activity of AO-176 + dexamethasone + bortezomib based on OS | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AO-176, CD47, Immunotherapy, Monoclonal antibody