Dose intensity of VAY736 was calculated as: Actual Cumulative dose (mg/kg) / (Duration of exposure in weeks/2)

Dose intensity of ibrutinib was calculated as: Actual Cumulative dose (mg) / (Duration of exposure in 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.

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](streamdown:incomplete-link)

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).

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).

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.

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.

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)).

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.

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.

PK parameters were calculated based on VAY7736 serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUClast calculation.

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.

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.

PK parameters were calculated based on ibrutinib plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUClast calculation.

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

Chronic lymphocytic leukemia (CLL) patients on ibrutinib for one or more than one year with residual disease but without clinical relapse

Chronic lymphocytic leukemia (CLL) patients on ibrutinib with acquired resistance mutations but without clinical relapse

VAY736 3 mg/kg i.v. once every 2 weeks in combination with ibrutinib 280 mg oral once daily

VAY736 3 mg/kg i.v. once every 2 weeks in combination with ibrutinib 420 mg oral once daily

VAY736 9 mg/kg i.v. once every 2 weeks in combination with ibrutinib 420 mg oral once daily

Total of all reporting groups

VAY736 1 mg/kg i.v. once every 2 weeks in combination with ibrutinib 420 mg oral once daily

VAY736 3 mg/kg i.v. once every 2 weeks in combination with ibrutinib 420 mg oral once daily

VAY736 9 mg/kg i.v. once every 2 weeks in combination with ibrutinib 420 mg oral once daily

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.

All patients who received at least one dose of study treatment in the dose escalation or dose expansion part of the study. Patients were analyzed according to the study treatment received.

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.

All patients who received at least one dose of study treatment in the dose escalation or dose expansion part of the study. Patients were analyzed according to the study treatment received.

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.

All patients who received at least one dose of study treatment in the dose escalation or dose expansion part of the study. Patients were analyzed according to the study treatment received.

Dose intensity of VAY736 was calculated as: Actual Cumulative dose (mg/kg) / (Duration of exposure in weeks/2)

All patients who received at least one dose of study treatment in the dose escalation or dose expansion part of the study. Patients were analyzed according to the study treatment received.

Dose intensity of ibrutinib was calculated as: Actual Cumulative dose (mg) / (Duration of exposure in days)

All patients who received at least one dose of study treatment in the dose escalation or dose expansion part of the study. Patients were analyzed according to the study treatment received.

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.

All patients who received at least one dose of study treatment in the dose expansion part of the study.

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.

All patients who received at least one dose of study treatment in the dose expansion part of the study.

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](streamdown:incomplete-link)

All patients who received at least one dose of study treatment in the dose expansion part of the study.

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).

All patients who received at least one dose of study treatment in the dose escalation part of the study.

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).

All patients who received at least one dose of study treatment in the dose expansion part of the study.

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.

All patients who received at least one dose of study treatment in the dose escalation part of the study.

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.

All patients who received at least one dose of study treatment in the dose expansion part of the study.

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)).

All patients in the dose expansion arm B who received at least one dose of study treatment.

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.

Patients in the pharmacokinetic analysis set (PAS) who had an available value for the outcome measure at each timepoint. PAS consists of all patients who received one of the planned treatments, provided at least one primary PK parameter and did not vomit within 8 hours after the dosing of ibrutinib. Patients were analyzed according to the study treatment received.

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.

Patients in the pharmacokinetic analysis set (PAS) who had an available value for the outcome measure at each timepoint. PAS consists of all patients who received one of the planned treatments, provided at least one primary PK parameter and did not vomit within 8 hours after the dosing of ibrutinib. Patients were analyzed according to the study treatment received.

PK parameters were calculated based on VAY7736 serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUClast calculation.

Patients in the pharmacokinetic analysis set (PAS) who had an available value for the outcome measure at each timepoint. PAS consists of all patients who received one of the planned treatments, provided at least one primary PK parameter and did not vomit within 8 hours after the dosing of ibrutinib. Patients were analyzed according to the study treatment received.

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.

Patients in the pharmacokinetic analysis set (PAS) who had an available value for the outcome measure at each timepoint. PAS consists of all patients who received one of the planned treatments, provided at least one primary PK parameter and did not vomit within 8 hours after the dosing of ibrutinib. Patients were analyzed according to the study treatment received.

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.

Patients in the pharmacokinetic analysis set (PAS) who had an available value for the outcome measure at each timepoint. PAS consists of all patients who received one of the planned treatments, provided at least one primary PK parameter and did not vomit within 8 hours after the dosing of ibrutinib. Patients were analyzed according to the study treatment received.

PK parameters were calculated based on ibrutinib plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUClast calculation.

Patients in the pharmacokinetic analysis set (PAS) who had an available value for the outcome measure at each timepoint. PAS consists of all patients who received one of the planned treatments, provided at least one primary PK parameter and did not vomit within 8 hours after the dosing of ibrutinib. Patients were analyzed according to the study treatment received.

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

Patients who received at least 1 dose of VAY736 and had a determinant baseline immunogenicity (IG) sample and at least 1 determinant post-baseline IG sample for assessing anti-VAY736 antibodies. Patients were analyzed according to the study treatment received.

On-treatment deaths were collected from first dose of study treatment to 30 days after the last dose of VAY736. Post-treatment deaths were collected from 31 days after last dose of VAY736 until end of study. All deaths refer to the sum of on-treatment and post-treatment deaths.

All patients who received at least one dose of study treatment in the dose escalation or dose expansion part of the study. Patients were analyzed according to the study treatment received.

Safety data up to 30 days after the last dose of VAY736

Safety data up to 30 days after the last dose of VAY736

Safety data up to 30 days after the last dose of VAY736

Safety data up to 30 days after the last dose of VAY736

Safety data up to 30 days after the last dose of VAY736

Deaths collected in the post-treatment period (starting from Day 31 after last dose of VAY736). No AEs were collected during this period.

Deaths collected in the post-treatment period (starting from Day 31 after last dose of VAY736). No AEs were collected during this period.

Deaths collected in the post-treatment period (starting from Day 31 after last dose of VAY736). No AEs were collected during this period.

Deaths collected in the post-treatment period (starting from Day 31 after last dose of VAY736). No AEs were collected during this period.

Deaths collected in the post-treatment period (starting from Day 31 after last dose of VAY736). No AEs were collected during this period.