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

Sponsor

Arch Oncology (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT04445701

Collaborator

(none)

157

Enrollment

Locations

Arms

Anticipated Duration (Months)

26.2

Patients Per Site

0.7

Patients Per Site Per Month

Study Details

Study Description

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

Study Type:

Interventional

Anticipated 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.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 :

Nov 30, 2020

Anticipated Primary Completion Date :

Mar 1, 2024

Anticipated Study Completion Date :

Mar 1, 2024

Arms and Interventions

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

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

Primary Outcome Measures

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 Outcome Measures

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 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
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 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 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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic	Phoenix	Arizona	United States	85054
2	Mayo Clinic	Jacksonville	Florida	United States	32224
3	Emory University	Atlanta	Georgia	United States	30322
4	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
5	Mayo Clinic	Rochester	Minnesota	United States	55905
6	Medical College of Wisconsin and Froedtert Hospital	Milwaukee	Wisconsin	United States	53226