VAY736 in Combination With Ibrutinib in Patients With CLL on Ibrutinib

May 14, 2025 updated by: Novartis Pharmaceuticals

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

Status

Indicates the current recruitment status or the expanded access status.
Terminated

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
39

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

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

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Number of Participants With Dose-Limiting Toxicities (DLTs) in Cycle 1 (Escalation Only)
Time Frame: 28 days
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)
Time Frame: 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 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
Time Frame: Up to 7.8 months
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
Time Frame: Up to 8.5 months
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
Time Frame: Up to 7.8 months
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
Time Frame: Up to 8.5 months
Dose intensity of ibrutinib was calculated as: Actual Cumulative dose (mg) / (Duration of exposure in days)
Up to 8.5 months

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
CR or CRi Rate at C9 for Expansion Arm A and Arm B by Investigator Per IWCLL
Time Frame: Cycle 9 Day 1 (C9). The duration of each cycle was 28 days.
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)
Time Frame: Cycle 9 Day 1 (C9). The duration of each cycle was 28 days.

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)
Time Frame: Cycle 9 Day 1 (C9). The duration of each cycle was 28 days.

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
Time Frame: Up to approximately 2.5 years

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
Time Frame: Up to approximately 2.7 years

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
Time Frame: Up to approximately 2.5 years

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
Time Frame: Up to approximately 2.7 years

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
Time Frame: Up to Cycle 9 Day 1. The duration of each cycle was 28 days.

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
Time Frame: 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
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
Time Frame: 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
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
Time Frame: 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
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
Time Frame: 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
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
Time Frame: 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
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
Time Frame: 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
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
Time Frame: Baseline (before first dose) and post-baseline (assessed throughout the VAY736 treatment, up to 7.8 months).

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

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Novartis Pharmaceuticals

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
April 9, 2018

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
September 29, 2023

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
September 29, 2023

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
January 9, 2018

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
January 9, 2018

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
January 17, 2018

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
May 16, 2025

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
May 14, 2025

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
May 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant 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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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