VAY736 in Combination With Ibrutinib in Patients With CLL on Ibrutinib

Phase Ib Open-label Study of VAY736 and Ibrutinib in Patients With Chronic Lymphocytic Leukemia (CLL) on Ibrutinib Therapy

Patients enrolled to the study had chronic lymphocytic leukemia (CLL) and received ibrutinib. Patients have either received ibrutinib for one year without having had a complete response or patients developed a resistance mutation to ibrutinib. This study had two parts, a dose escalation part and a dose expansion part. Patients in the expansion part were enrolled into two arms depending on whether they had ibrutinib resistance mutations present at baseline.

Study Overview

• Status: Terminated
• Conditions: Chronic Lymphocytic Leukemia (CLL)
• Intervention / Treatment: Drug: VAY736; Drug: ibrutinib

• Study Type: Interventional
• Enrollment (Actual): 39
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • La Jolla, California, United States, 92093-0658
      • University of California San Diego - Moores Cancer Center
    • Los Angeles, California, United States, 90095
      • David Geffen School of Medicine at UCLA David Geffen School of Med
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State Comprehensive Cancer Center/James Cancer Hospital Ohio State University
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Tennessee Oncology Centennial Medical Center
  • Utah
    • Salt Lake City, Utah, United States, 84103
      • University of Utah / Huntsman Cancer Institute Oncology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosis of CLL per the WHO classification
• At least 18 years of age
• Lack of a complete response after receiving ibrutinib for > 1 year OR presence of known ibrutinib resistance mutation
• Actively receiving ibrutinib at either 420 mg (patients enrolled to the escalation arm) or at a stable dose for at least 2 months prior to starting study treatment (patients enrolled to the expansion arm)

Exclusion Criteria:

• Known history of HIV
• Active hepatitis B or C infection
• Receipt of attenuated vaccine within 2 weeks prior to starting study treatment.

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: Dose Escalation; Increasing doses of VAY736 in combination with a fixed dose of ibrutinib.	Drug: VAY736; Experimental; Drug: ibrutinib; Approved medication; Other Names: Imbruvica
Experimental: Dose expansion; Evaluation of the MTD/RD of the combination of VAY736 and ibrutinib that was identified in dose escalation.	Drug: VAY736; Experimental; Drug: ibrutinib; Approved medication; Other Names: Imbruvica

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1 (Dose escalation only)	A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value of Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3 assessed as unrelated to disease, disease progression, inter-current illness or concomitant medications that occurs within the first cycle of treatment during the dose escalation part of the study. Other clinically significant toxicities may be considered to be DLTs, even if not CTCAE grade 3 or higher. The duration of one treatment cycle is 28 days.	28 days
Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs)	Number of participants with AEs and SAEs, including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs.	2 years
Incidence of dose reductions and dose interruptions of the combination of VAY736 and ibrutinib	Dose reductions and interruptions to assess the tolerability of the combination of VAY736 and ibrutinib.	2 years
Dose intensity of the combination of VAY736 and ibrutinib	Dose intensity is calculated as actual cumulative dose divided by duration of exposure.	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of patients with complete response (CR) as assessed by investigators per IWCLL	Assessment of anti-tumor activity based on investigator assessment per International Working Group - Chronic Lymphocytic Leukemia (IWCLL)	Cycle 9 Day 1. The duration of one cycle is 28 days.
Overall response rate (ORR) assessed by investigators per IWCLL criteria	ORR is defined as best overall response (BOR) of complete response (CR) or partial response (PR), assessed by investigators per IWCLL criteria.	2 years
Time to progression (TTP)	TTP is the time from start of treatment to the date of event which is defined as the first documented progression or death due to underlying cancer.	2 years
Clearance of ibrutinib resistance mutations (BTKC481 and/or PLCγ2 hotspot)	Clearance of ibrutinib resistance mutation is defined as less than 1% mutation bearing alleles (BTKC481 and/or PLCγ2) during treatment. This endpoint is only applicable to the expansion arm involving chronic lymphocytic leukemia (CLL) patients on ibrutinib with acquired resistance mutations but without clinical relapse.	2 years
Peak plasma concentration (Cmax) of VAY736 and ibrutinib	Plasma pharmacokinetic (PK) parameters calculated using non-compartmental methods.	2 years
Area under the plasma concentration- time curve (AUC) of VAY736 and ibrutinib	Plasma pharmacokinetic (PK) parameters calculated using non-compartmental methods.	2 years
Presence of anti-VAY736 antibodies	Number of participants with anti-VAY736 antibodies at baseline and on treatment.	Baseline, up to 2 years

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Kipps TJ. Mining the Microenvironment for Therapeutic Targets in Chronic Lymphocytic Leukemia. Cancer J. 2021 Jul-Aug 01;27(4):306-313. doi: 10.1097/PPO.0000000000000536.

Study record dates

Study Major Dates

• Study Start (Actual): April 9, 2018
• Primary Completion (Actual): September 29, 2023
• Study Completion (Actual): September 29, 2023

Study Registration Dates

• First Submitted: January 9, 2018
• First Submitted That Met QC Criteria: January 9, 2018
• First Posted (Actual): January 17, 2018

Study Record Updates

• Last Update Posted (Estimated): November 14, 2023
• Last Update Submitted That Met QC Criteria: November 10, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Ibrutinib; VAY736; CLL; Chronic lymphocytic leukemia; Bruton's Tyrosine Kinase; BTK mutation
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Leukemia, B-Cell; Chronic Disease; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid
• Other Study ID Numbers: CVAY736Y2102

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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