VAY736 in Combination With Ibrutinib in Patients With CLL on Ibrutinib
- Conditions
- Chronic Lymphocytic Leukemia (CLL)
- Interventions
- Registration Number
- NCT03400176
- Lead Sponsor
- Novartis Pharmaceuticals
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 39
- 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)
- Known history of HIV
- Active hepatitis B or C infection
- Receipt of attenuated vaccine within 2 weeks prior to starting study treatment.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Dose expansion VAY736 Evaluation of the MTD/RD of the combination of VAY736 and ibrutinib that was identified in dose escalation. Dose expansion ibrutinib Evaluation of the MTD/RD of the combination of VAY736 and ibrutinib that was identified in dose escalation. Dose Escalation VAY736 Increasing doses of VAY736 in combination with a fixed dose of ibrutinib. Dose Escalation ibrutinib Increasing doses of VAY736 in combination with a fixed dose of ibrutinib.
- Primary Outcome Measures
Name Time Method Dose Intensity of Ibrutinib Up to 8.5 months Dose intensity of ibrutinib was calculated as: Actual Cumulative dose (mg) / (Duration of exposure in days)
Number of Participants With Dose-Limiting Toxicities (DLTs) in Cycle 1 (Escalation Only) 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.
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) 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.Number of Participants With Dose Reductions and Dose Interruptions of VAY736 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.
Number of Participants With Dose Reductions and Dose Interruptions of Ibrutinib 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.
Dose Intensity of VAY736 Up to 7.8 months Dose intensity of VAY736 was calculated as: Actual Cumulative dose (mg/kg) / (Duration of exposure in weeks/2)
- Secondary Outcome Measures
Name Time Method CR or CRi Rate at C9 for Expansion Arm A and Arm B by Investigator Per IWCLL 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.
Posterior Mean of CR or CRi Response Rate at C9 for Expansion Arm A and Arm B (Bayesian Analysis) 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.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) 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 benefitOverall Response Rate (ORR) Assessed by Investigator Per IWCLL in the Dose Escalation Part 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).Overall Response Rate (ORR) Assessed by Investigator Per IWCLL in the Dose Expansion Part 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).Time to Progression (TTP) in the Dose Escalation Part 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.Time to Progression (TTP) in the Dose Expansion Part 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.Percentage of Participants With Clearance of Ibrutinib Resistance Mutation During Treatment (up to C9) for Expansion Arm B 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)).Maximum Observed Serum Concentration (Cmax) of VAY736 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.
Time to Reach Maximum Serum Concentration (Tmax) of VAY736 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.
Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of VAY736 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.
Maximum Observed Plasma Concentration (Cmax) of Ibrutinib 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.
Time to Reach Maximum Plasma Concentration (Tmax) of Ibrutinib 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.
Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Ibrutinib 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.
Number of Participants With Anti-VAY736 Antibodies 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
Trial Locations
- Locations (5)
David Geffen School of Medicine at UCLA
🇺🇸Los Angeles, California, United States
Ohio ST Compr Cancer Ctr James Hosp
🇺🇸Columbus, Ohio, United States
SCRI Oncology Partners
🇺🇸Nashville, Tennessee, United States
Uni of Utah Huntsman Cancer Inst
🇺🇸Salt Lake City, Utah, United States
University of California San Diego - Moores Cancer Center
🇺🇸La Jolla, California, United States