A Study of Venetoclax and ABBV-838 Combination Therapy With Dexamethasone in Participants With Multiple Myeloma Whose Cancer Has Come Back or Had No Response to Recent Cancer Treatment

A Phase 1b, Open Label, Multicenter, Dose Escalation Study of Venetoclax and ABBV-838 Combination Therapy With Dexamethasone in Subjects With Relapsed or Refractory Multiple Myeloma

This is an open-label, multicenter clinical trial designed to evaluate the safety and potential efficacy of venetoclax and ABBV-838 combination therapy with dexamethasone in participants with relapsed or refractory multiple myeloma (MM) who have received 2 or more prior lines of therapy for multiple myeloma (MM). The study will consist of 2 arms: Arm A and Arm B (if applicable). Each arm will have a dose escalation and dose expansion portion.

Study Overview

• Status: Withdrawn
• Conditions: Multiple Myeloma
• Intervention / Treatment: Drug: Venetoclax; Drug: ABBV-838; Drug: Dexamethasone

Detailed Description

The study will consist of 2 arms: Arm A and Arm B (if applicable). Arm A dose escalation will investigate up to 3 doses of ABBV-838 at 3-week dosing intervals (Q3W) in combination with venetoclax and dexamethasone. Arm A dose expansion portion will investigate the ABBV-838 Q3W dosing interval with venetoclax and dexamethasone at the recommended phase two dose (RPTD) combination defined from the Dose Escalation portion.

Based on data from the ongoing ABBV-838 monotherapy study (Study M14-467) Arm B dose escalation may be conducted, if deemed necessary. If conducted, Arm B dose excalation will investigate up to 3 doses of ABBV-838 at either weekly (Q1W) or bi-weekly (Q2W) dosing intervals in combination with venetoclax and dexamethasone. Arm B dose expansion portion will investigate either the ABBV-838 Q1W or Q2W dosing interval in combination with venetoclax and dexamethasone at the RPTD combination defined from the Dose Escalation portion.

• Study Type: Interventional
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • Darlinghurst, Australia, 2010
    • St Vincent´s Hospital /ID# 153022
  • Fitzroy, Australia, 3065
    • St. Vincents Hospital Melbourne /ID# 157925
  • Prahran, Australia, 3181
    • The Alfred Hospital /ID# 150202

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 1 for participants in the dose escalation portion of the study and ECOG less than or equal to 2 in the dose expansion portion.
• Received at least 2 prior therapies including an Immunomodulatory Thalidomide Derivative Compounds (IMiD) and a proteasome inhibitor.
• Documented relapsed or progressive multiple myeloma on or after any regimen or is refractory to the most recent line of therapy.
• Received at least 2 prior therapies including an IMiD and a proteasome inhibitor.
• Documented relapsed or progressive multiple myeloma on or after any regimen or is refractory to the most recent line of therapy.
• Eligible for and agree to bone marrow (BM) aspirate prior to treatment start and at designated times per protocol.
• Measurable disease at Screening, defined as at least one of the following M component in serum (greater than or equal to 0.5 g/dL) and/or urine (greater than or equal to 0.2 g excreted in a 24 hour collection sample) or serum free light chain greater than or equal to 100 mg/dL with an abnormal κ/λ ratio of less than 0.26 or greater than 1.65.

Exclusion Criteria:

• Received any anti-myeloma therapy (other than monoclonal antibodies), including chemotherapy, radiotherapy, biological, immunotherapy or an investigational therapy, including targeted small molecule agents within 5 half-lives (or 14 days if half-live unknown) prior to first dose of first dose of venetoclax, ABBV-838, and dexamethasone.
• Received anti-myeloma monoclonal antibodies within 6 weeks prior to first dose of venetoclax, ABBV-838, and dexamethasone.
• Has a significant history of renal, neurologic (peripheral neuropathy), psychiatric, endocrinologic (diabetes mellitus), metabolic, immunologic, cardiovascular, pulmonary or hepatic disease within the last 6 months.
• Received corticosteroid therapy at a dose equivalent to greater than or equal to 4 mg/day of dexamethasone within 3 weeks prior to first dose.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A Venetoclax QD + ABBV-838 Q3W + Dexamethasone; ABBV-838 administered at cohort-defined doses every 3 weeks (Q3W; starting dose 4.0 mg/kg) in combination with venetoclax (400 mg or 800 mg once daily [QD]) and dexamethasone (40 mg once weekly [Q1W]); once the maximum-tolerated-dose (MTD) and recommended phase two dose (RPTD) are determined, ABBV-838 in combination with venetoclax and dexamethasone at RPTD will be administered in a dose expansion phase of the study.	Drug: Venetoclax; Tablet; Other Names: ABT-199; Drug: ABBV-838; Intravenous infusion; Drug: Dexamethasone; Tablet or intravenous infusion
Experimental: Arm B Venetoclax QD + ABBV-838 Q1W or Q2W + Dexamethasone Q1W; Dose escalation portion will investigate either the ABBV-838 weekly (Q1W) or bi-weekly (Q2W) dosing interval in combination with venetoclax (400 or 800 mg QD) and dexamethasone (40 mg Q1W). The dose expansion portion will investigate either the ABBV-838 weekly (Q1W) or bi-weekly (Q2W) dosing interval in combination with venetoclax and dexamethasone at the RPTD combination defined from the Dose Escalation portion.	Drug: Venetoclax; Tablet; Other Names: ABT-199; Drug: ABBV-838; Intravenous infusion; Drug: Dexamethasone; Tablet or intravenous infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum tolerated dose (MTD), and recommended phase two dose (RPTD) of venetoclax and ABBV-838 combination therapy when administered with dexamethasone	The MTD and the RPTD of venetoclax and ABBV-838 combination therapy with dexamethasone will be determined during the dose escalation phase of the study. Once the RPTD combination has been determined, the dose expansion portion will begin.	Minimum first cycle of dosing (21 or 28 days, depending on arm)
Number of participants with adverse events		Up to approximately 2 years following the first dose of the last subject enrolled

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum observed plasma concentration (Cmax) of venetoclax		Approximately 43 or 57 days (Treatment Arm A and Treatment Arm B, respectively)
Time to Cmax (Tmax) of venetoclax		Approximately 43 or 57 days (Treatment Arm A and Treatment Arm B, respectively)
Area under the plasma concentration-time curve over the 24-hour dose interval (AUC0-24) of venetoclax		Approximately 43 or 57 days (Treatment Arm A and Treatment Arm B, respectively)
Objective Response Rate (ORR)	The Objective Response Rate (ORR) is defined as the proportion of subjects with a response (Stringent Complete Response [sCR], Complete Response [CR], Very Good Partial Response [VGPR] or Partial Response [PR]) based on the International Myeloma Working Group (IMWG) criteria.	Cycle 2 Day 1 and Day 1 of every cycle thereafter for up to 2 years following the first dose of the last subject enrolled
Cmax of ABBV-838		Approximately 43 or 57 days (Treatment Arm A and Treatment Arm B, respectively)
Tmax of ABBV-838		Approximately 43 or 57 days (Treatment Arm A and Treatment Arm B, respectively)
AUC over the dose interval (AUC0-τ) of ABBV-838		Approximately 43 or 57 days (Treatment Arm A and Treatment Arm B, respectively)
Total monoclonal anti-CS1 antibody (total mAb)		Approximately 43 or 57 days (Treatment Arm A and Treatment Arm B, respectively)
Monomethyl auristatin E (MMAE) toxin levels		Approximately 43 or 57 days (Treatment Arm A and Treatment Arm B, respectively)
Minimal Residual Disease (MRD)	MRD will be assessed in the bone marrow by next generation sequencing (NGS). MRD negativity in bone marrow aspirates will be defined at 10-5 threshold as assessed by NGS.	Cycle 4 Day 1 and treatment completion (up to 2 years following the first dose of the last subject enrolled)
Terminal phase elimination rate constant (β) for ABBV-838		Cycle 1 Day 1
Terminal elimination half-life (t1/2) for ABBV-838		Cycle 1 Day 1

Collaborators and Investigators

• Sponsor: AbbVie
• Investigators: Study Director: Orlando Bueno, MD, AbbVie

Study record dates

Study Major Dates

• Study Start (Anticipated): August 31, 2017
• Primary Completion (Anticipated): July 28, 2020
• Study Completion (Anticipated): April 28, 2021

Study Registration Dates

• First Submitted: October 28, 2016
• First Submitted That Met QC Criteria: October 28, 2016
• First Posted (Estimate): November 1, 2016

Study Record Updates

• Last Update Posted (Actual): June 5, 2017
• Last Update Submitted That Met QC Criteria: June 1, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Keywords: Refractory Multiple Myeloma; Relapsed Multiple Myeloma; lymphoid malignancies; Next generation sequencing
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Dexamethasone; Venetoclax
• Other Study ID Numbers: M15-655; 2016-001300-28 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No