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 had 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.

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
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio ST Compr Cancer Ctr James Hosp
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • SCRI Oncology Partners
  • Utah
    • Salt Lake City, Utah, United States, 84103
      • Uni of Utah Huntsman Cancer Inst

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
Number of Participants With Dose-Limiting Toxicities (DLTs) in Cycle 1 (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 28 days of treatment with the combination of VAY736 and ibrutinib and meets the criteria defined in the study protocol. Other clinically significant toxicities may be considered to be DLTs, even if not CTCAE grade 3 or higher.	28 days
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	Number of participants with AEs (any AE regardless of seriousness) and SAEs, including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs. AE grades to characterize the severity of the AEs were based on the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. For CTCAE v4.03, Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death related to AE. All patients were followed for a 30-day safety follow-up period subsequent to completion of VAY736 therapy. No new AEs or SAEs were collected beyond the 30-day safety follow-up or during the efficacy follow up period.	From first dose of study treatment up to 30 days after the last dose of VAY736, up to approximately 8.8 months
Number of Participants With Dose Reductions and Dose Interruptions of VAY736	For patients who did not tolerate the protocol-specified dosing schedule of the study drugs, dose adjustments could be permitted in order to allow the patient to continue study treatment.	Up to 7.8 months
Number of Participants With Dose Reductions and Dose Interruptions of Ibrutinib	For patients who did not tolerate the protocol-specified dosing schedule of the study drugs, dose adjustments could be permitted in order to allow the patient to continue study treatment.	Up to 8.5 months
Dose Intensity of VAY736	Dose intensity of VAY736 was calculated as: Actual Cumulative dose (mg/kg) / (Duration of exposure in weeks/2)	Up to 7.8 months
Dose Intensity of Ibrutinib	Dose intensity of ibrutinib was calculated as: Actual Cumulative dose (mg) / (Duration of exposure in days)	Up to 8.5 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CR or CRi Rate at C9 for Expansion Arm A and Arm B by Investigator Per IWCLL	Percentage of participants with Complete Response (CR) or Complete Response with Incomplete Marrow Recovery (CRi) by investigator assessment per International Working Group - Chronic Lymphocytic Leukemia (IWCLL) response criteria.	Cycle 9 Day 1 (C9). The duration of each cycle was 28 days.
Posterior Mean of CR or CRi Response Rate at C9 for Expansion Arm A and Arm B (Bayesian Analysis)	The rate of CR/CRi at C9 was analyzed for each expansion arm using a Bayesian modeling approach. A minimally informative beta distribution was used as prior distribution with parameters a=0.25 and b=1. This assumed, a priori, that the response rate was 20%. Values estimated from the model at Cycle 9 are presented in the table. Posterior geometric mean for CR/CRi rate and 90% credible intervals in each group are presented.	Cycle 9 Day 1 (C9). The duration of each cycle was 28 days.
Posterior Probability That the True CR or CRi Response Rate at C9 for Expansion Arm A and Arm B Falls in Pre-defined Activity Intervals (Bayesian Analysis)	The rate of CR/CRi at C9 was analyzed for each expansion arm using a Bayesian modeling approach. A minimally informative beta distribution was used as prior distribution with parameters a=0.25 and b=1. This assumed, a priori, that the response rate was 20%. Values estimated from the model at Cycle 9 are presented in the table. The posterior probability that the true CR/CRi rate falls in the activity intervals defined below is presented: [0, 20%) - clinically not meaningful; [20%, 40%) - moderate clinical benefit; [40%, 100%] - superior clinical benefit	Cycle 9 Day 1 (C9). The duration of each cycle was 28 days.
Overall Response Rate (ORR) Assessed by Investigator Per IWCLL in the Dose Escalation Part	Efficacy was based on local investigator assessment per International Working Group - Chronic Lymphocytic Leukemia (IWCLL) response criteria. ORR per IWCLL is defined as the percentage of participants with a best overall response of Complete Response (CR), Complete Response with Incomplete Marrow Recovery (CRi) or Partial Response (PR).	Up to approximately 2.5 years
Overall Response Rate (ORR) Assessed by Investigator Per IWCLL in the Dose Expansion Part	Efficacy was based on local investigator assessment per International Working Group - Chronic Lymphocytic Leukemia (IWCLL) response criteria. ORR per IWCLL is defined as the percentage of participants with a best overall response of Complete Response (CR), Complete Response with Incomplete Marrow Recovery (CRi) or Partial Response (PR).	Up to approximately 2.7 years
Time to Progression (TTP) in the Dose Escalation Part	Efficacy was based on local investigator assessment per International Working Group - Chronic Lymphocytic Leukemia (IWCLL) response criteria. TTP is defined as the time from start of treatment to date of event which is defined as the first documented progression or death due to underlying cancer. If a patient had not had an event, TTP was censored at the date of the last adequate disease assessment. TTP was analyzed using Kaplan-Meier estimates.	Up to approximately 2.5 years
Time to Progression (TTP) in the Dose Expansion Part	Efficacy was based on local investigator assessment per International Working Group - Chronic Lymphocytic Leukemia (IWCLL) response criteria. TTP is defined as the time from start of treatment to date of event which is defined as the first documented progression or death due to underlying cancer. If a patient had not had an event, TTP was censored at the date of the last adequate disease assessment. TTP was analyzed using Kaplan-Meier estimates.	Up to approximately 2.7 years
Percentage of Participants With Clearance of Ibrutinib Resistance Mutation During Treatment (up to C9) for Expansion Arm B	Clearance was defined as less than 1% mutation bearing alleles (BTKC481 and/or PLCγ2) during treatment. Negative mutation is defined as having clearance of the baseline ibrutinib resistance mutation during treatment (up to Cycle 9 (C9)).	Up to Cycle 9 Day 1. The duration of each cycle was 28 days.
Maximum Observed Serum Concentration (Cmax) of VAY736	Pharmacokinetic (PK) parameters were calculated based on VAY736 serum concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed concentration following a dose.	Pre-infusion and 2, 6, 24, 72, 168 and 336 hours after end of infusion on Cycle 1 Day 1 and Cycle 3 Day 1. The duration of the infusion was approximately 2 hours. 1 cycle=28 days
Time to Reach Maximum Serum Concentration (Tmax) of VAY736	PK parameters were calculated based on VAY736 serum concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) concentration following a dose. Actual recorded sampling times were considered for the calculations.	Pre-infusion and 2, 6, 24, 72, 168 and 336 hours after end of infusion on Cycle 1 Day 1 and Cycle 3 Day 1. The duration of the infusion was approximately 2 hours. 1 cycle=28 days
Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of VAY736	PK parameters were calculated based on VAY7736 serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUClast calculation.	Pre-infusion and 2, 6, 24, 72, 168 and 336 hours after end of infusion on Cycle 1 Day 1 and Cycle 3 Day 1. The duration of the infusion was approximately 2 hours. 1 cycle=28 days
Maximum Observed Plasma Concentration (Cmax) of Ibrutinib	PK parameters were calculated based on ibrutinib plasma concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed concentration following a dose.	Pre-dose and 0.5, 2, 6 and 24 hours post-dose on Cycle 1 Day 1 and Cycle 1 Day 8. 1 cycle=28 days
Time to Reach Maximum Plasma Concentration (Tmax) of Ibrutinib	PK parameters were calculated based on ibrutinib plasma concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) concentration following a dose. Actual recorded sampling times were considered for the calculations.	Pre-dose and 0.5, 2, 6 and 24 hours post-dose on Cycle 1 Day 1 and Cycle 1 Day 8. 1 cycle=28 days
Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Ibrutinib	PK parameters were calculated based on ibrutinib plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUClast calculation.	Pre-dose and 0.5, 2, 6 and 24 hours post-dose on Cycle 1 Day 1 and Cycle 1 Day 8. 1 cycle=28 days
Number of Participants With Anti-VAY736 Antibodies	VAY736 immunogenicity was evaluated in serum samples. Anti-drug antibodies (ADA) status was defined as follows: ADA-negative at baseline: baseline sample where assay is ADA negative; ADA-positive at baseline: baseline sample where assay is ADA positive; ADA-negative post-baseline: ADA-negative sample at baseline and at least 1 post-baseline sample, all of which are ADA-negative samples; Treatment-induced ADA-positive: ADA-negative sample at baseline and at least 1 treatment-induced ADA-positive sample; Treatment-boosted ADA-positive: ADA-positive sample at baseline and at least 1 treatment-boosted ADA-positive sample; ADA-inconclusive post-baseline: patient who does not qualify for any of the above definitions	Baseline (before first dose) and post-baseline (assessed throughout the VAY736 treatment, up to 7.8 months).

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.

Helpful Links

• A Plain Language Trial Summary is available on www.novctrd.com

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 (Actual): May 16, 2025
• Last Update Submitted That Met QC Criteria: May 14, 2025
• Last Verified: May 1, 2025

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; Neoplasms; Chronic Disease; Disease Attributes; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Leukemia, B-Cell; Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Tyrosine Kinase Inhibitors; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Ibrutinib
• Other Study ID Numbers: CVAY736Y2102; 5R01CA177292-09 (U.S. NIH Grant/Contract)

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