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

• ClinicalTrials.gov Identifier: NCT04445701
• Recruitment Status: Completed
• First Posted: June 24, 2020
• Last Update Posted: August 22, 2023
• Sponsor: Arch Oncology
• Information provided by (Responsible Party): Arch Oncology

Tracking Information

• First Submitted Date: June 17, 2020
• First Posted Date: June 24, 2020
• Last Update Posted Date: August 22, 2023
• Actual Study Start Date: November 30, 2020
• Actual Primary Completion Date: August 5, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 22, 2020)

• 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 [ Time Frame: 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 [ Time Frame: 12 months ]
  Evaluate the clinical activity of AO-176 + dexamethasone + bortezomib based on ORR using International Myeloma Working Group (IMWG) uniform response criteria

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: June 22, 2020)

• Phase 1: ORR of single agent AO-176 [ Time Frame: 12 months ]
  Evaluate the clinical activity of single agent AO-176 based on ORR using IMWG uniform response criteria
• Phase 1: Duration of response (DOR) of single agent AO-176 [ Time Frame: 12 months ]
  Evaluate the clinical activity of single agent AO-176 based on DOR using IMWG uniform response criteria
• Phase 1: Disease control rate (DCR) of single agent AO-176 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 12 months ]
  Evaluate the clinical activity of single agent AO-176 based on OS
• Phase 2: DOR of AO-176 + DEX + BORT [ Time Frame: 12 months ]
  Evaluate the clinical activity of AO-176 + dexamethasone + bortezomib based on DOR using IMWG uniform response criteria
• Phase 2: DCR of AO-176 + DEX + BORT [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 12 months ]
  Evaluate the clinical activity of AO-176 + dexamethasone + bortezomib based on OS

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of AO-176 as Monotherapy and in Combination With Bortezomib/Dexamethasone in Relapsed/Refractory Multiple Myeloma
• Official Title: 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
• 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.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2

Study Design

Allocation: Non-Randomized
Intervention Model: Sequential Assignment
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.

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: Multiple Myeloma

Intervention

• Drug: AO-176
  Humanized monoclonal antibody (mAb) targeting CD47
• Drug: AO-176 + Dex
  Humanized mAb targeting CD47 plus dexamethasone
• Drug: AO-176 + Dex + Bort
  Humanized mAb targeting CD47 plus dexamethasone plus bortezomib

Study Arms

• Experimental: AO-176 Dose Escalation Monotherapy
  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.
  Intervention: Drug: AO-176
• Experimental: AO-176 + DEX Expansion Cohort
  Once the monotherapy RP2D has been established, an expansion cohort of AO-176 + dexamethasone will be enrolled.
  Intervention: Drug: AO-176 + Dex
• Experimental: AO-176 + DEX + BORT Dose Escalation
  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.
  Intervention: Drug: AO-176 + Dex + Bort

• Publications *: Andrejeva G, Capoccia BJ, Hiebsch RR, Donio MJ, Darwech IM, Puro RJ, Pereira DS. Novel SIRPalpha Antibodies That Induce Single-Agent Phagocytosis of Tumor Cells while Preserving T Cells. J Immunol. 2021 Feb 15;206(4):712-721. doi: 10.4049/jimmunol.2001019. Epub 2021 Jan 11.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 21, 2023): 10
• Original Estimated Enrollment (submitted: June 22, 2020): 102
• Actual Study Completion Date: November 14, 2022
• Actual Primary Completion Date: August 5, 2022 (Final data collection date for primary outcome measure)

Eligibility 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04445701
• Other Study ID Numbers: AO-176-102
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Arch Oncology
• Original Responsible Party: Same as current
• Current Study Sponsor: Arch Oncology
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Ben Oshrine, MD; Sr Medical Director, Arch Oncology

• PRS Account: Arch Oncology
• Verification Date: August 2023