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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04445701
Recruitment Status : Active, not recruiting
First Posted : June 24, 2020
Last Update Posted : August 5, 2022
Sponsor:
Information provided by (Responsible Party):
Arch Oncology

Study Description
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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).

Condition or disease Intervention/treatment Phase
Multiple Myeloma Drug: AO-176 Drug: AO-176 + Dex Drug: AO-176 + Dex + Bort Phase 1 Phase 2

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 Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 157 participants
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
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
Actual Study Start Date : November 30, 2020
Estimated Primary Completion Date : March 2024
Estimated Study Completion Date : March 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Multiple Myeloma

Arms and Interventions
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Arm Intervention/treatment
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.
 Drug: AO-176
Humanized monoclonal antibody (mAb) targeting CD47
Experimental: AO-176 + DEX Expansion Cohort
Once the monotherapy RP2D has been established, an expansion cohort of AO-176 + dexamethasone will be enrolled.
 Drug: AO-176 + Dex
Humanized mAb targeting CD47 plus dexamethasone
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.
 Drug: AO-176 + Dex + Bort
Humanized mAb targeting CD47 plus dexamethasone plus bortezomib


Outcome Measures
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Primary Outcome Measures :
  1. 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

  2. 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


Secondary Outcome Measures :
  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. Phase 2: OS of AO-176 + DEX + BORT [ Time Frame: 12 months ]
    Evaluate the clinical activity of AO-176 + dexamethasone + bortezomib based on OS


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04445701


Locations
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United States, Arizona
Mayo Clinic
Phoenix, Arizona, United States, 85054
United States, Florida
Mayo Clinic
Jacksonville, Florida, United States, 32224
United States, Georgia
Emory University
Atlanta, Georgia, United States, 30322
United States, Massachusetts
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02215
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
United States, Wisconsin
Medical College of Wisconsin and Froedtert Hospital
Milwaukee, Wisconsin, United States, 53226
Sponsors and Collaborators
Arch Oncology
Investigators
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Study Director: Ben Oshrine, MD Sr Medical Director, Arch Oncology
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Arch Oncology
ClinicalTrials.gov Identifier: NCT04445701    
Other Study ID Numbers: AO-176-102
First Posted: June 24, 2020    Key Record Dates
Last Update Posted: August 5, 2022
Last Verified: August 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Arch Oncology:
AO-176
CD47
Immunotherapy
Monoclonal antibody
Additional relevant MeSH terms:
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Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
 Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases