Refractory Diffuse Large B-Cell Lymphoma, Relapsed Diffuse Large B-Cell Lymphoma
Conditions
Brief summary
A Study of Venetoclax Plus Ibrutinib and Rituximab in Patients with Relapsed/Refractory Diffuse Large B-cell Lymphoma (DLBCL). Our hypothesis is that the combination therapy of BTK (Bruton's tyrosine kinase) Inhibitor Ibrutinib plus Venetoclax and Rituximab in relapsed or refractory DLBCL will have an increased activity with acceptable toxicity. Furthermore, this new novel therapeutic combination will be safe and well tolerated among this patient population.
Detailed description
This is a Phase 1b, single-arm, open-label, single-center study of venetoclax (ABT-199) in combination with ibrutinib and rituximab in Subjects with Relapsed/Refractory DLBCL. The trial consists of a dose-escalation of venetoclax in combination with standard doses of ibrutinib and rituximab. For the dose escalation part of the study, a standard 3+3 design will be utilized. Once the MTD has been established, the dose escalation part will be followed by a dose expansion part in a cohort with a maximum of 24 subjects with DLBCL. The purpose of the dose expansion part is to investigate the efficacy of the combination. Between the dose-escalation and dose-expansion, the maximum number of subjects will be 30. Cycle length will be 28 days. Venetoclax will be administered orally QD (Once Daily), continuously for 24 cycles. Ibrutinib will be administered orally QD, continuously for 24 cycles. Rituximab will be administered IV per institutional standards. weekly X 4 (Cycle 1); once on Day 1 of cycles 2-6 only, then every other cycle until Cycle 24 (total 18 doses of Rituxan from C1D1), Commercially available rituximab IV will be used.
Interventions
DRUG400mg ABT-199
Oral dose daily until disease progression
DRUGIbrutinib
Oral dose daily until disease progression
DRUGRituximab
Rituximab will be administered IV per institutional standards. weekly X 4 (Cycle 1); once on Day 1 of cycles 2-6 only, then every other cycle until Cycle 24 (total 18 doses of Rituxan from C1D1
DRUG800mg ABT-199
Oral dose daily until disease progression
Sponsors
Janssen Scientific Affairs, LLC
Genentech, Inc.
Hackensack Meridian Health
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* ECOG (Eastern Cooperative Oncology Group) Performance Status \</= 2. * Histologically or cytologically confirmed diagnosis of advanced DLBCL. * Ability and willingness to comply with the requirements of the study protocol * Prior therapy: relapsed or refractory patients who have received one prior therapy are eligible. If treated with small molecule, washout therapy with a period of greater than 5 times the half-life of the molecule. Patients who have previously received high-dose chemotherapy with peripheral stem cell support are eligible. Washout period of 21 days. * Presence of at least one lymph node evaluable or mass measurable for response. * Age greater than or equal to 18 years. * Recovery from any previous treatment therapy. * Laboratory parameters: * Absolute neutrophil count (ANC) 1000/mm3 independent of growth factor support (unless the treating physician deems the neutropenia is related to bone marrow involvement, then an ANC of \> 750/mm3 is allowed) * Platelets 100,000/mm3 or 50,000/mm3 if bone marrow involvement independent of transfusion support in either situation * Total bilirubin ≤ 1.5 x ULN unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin * Aspartate Aminotransferase (AST, SGOT) and Alanine Aminotransferase (ALT, SGPT) ≤ 3 x upper limit of normal (ULN) * Creatinine: Creatinine Clearance (CrCl) 50 ml/min (calculated using Cockcroft-Gault Formula-Appendix 2) -Prothrombin time (PT)or international normalized ratio and partial thromboplastin time (PTT) not to exceed 1.2 times the institution's normal range * Women of childbearing potential and men who are sexually active must be practicing a highly effective method of birth control during and after the study consistent with local regulations regarding the use of birth control methods for subjects participating in clinical trials. Men must agree to not donate sperm during and after the study. For females, these restrictions apply for 3 months after Venetoclax and 12 months after Rituximab For males, these restrictions apply for 3 months after the last dose of study drug. * Women of childbearing potential must have a negative serum (beta-human chorionic gonadotropin \[-hCG\]) or urine pregnancy test at Screening. Women who are pregnant or breastfeeding are ineligible for this study. * Sign (or their legally-acceptable representatives must sign) an informed consent document indicating that they understand the purpose of and procedures required for the study, including biomarkers, and are willing to participate in the study
Exclusion criteria
* Known central nervous system lymphoma. * History of stroke or intracranial hemorrhage within 6 months prior to enrollment. * Requires anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon). * Received the following agents within 7 days prior to the first dose of venetoclax or requires chronic treatment with strong Cytochrome P450 3A4 (CYP3A) inhibitors (e.g., ketoconazole, ritonavir, clarithromycin, itraconazole, voriconazole), moderate CYP3A inhibitors (e.g., erythromycin, ciprofloxacin, diltiazem, fluconazole, verapamil), strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, St. John's wort) or moderate CYP3A inducers (e.g., bosentan, efavirenz, etravirine). (See Appendix 4) * Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of Screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification. * Vaccinated with live, attenuated vaccines within 4 weeks of randomization. * Use of any other standard chemotherapy, radiation therapy, or experimental drug therapy for the treatment of DLBCL within 21 days of starting treatment * Known history of human immunodeficiency virus (HIV) or active Hepatitis C Virus or active Hepatitis B Virus infection or any uncontrolled active systemic infection or human T-cell leukemia virus 1 (HTLV-1) seropositive status * Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of ibrutinib capsules, venetoclax or rituximab or put the study outcomes at undue risk. * History of uncontrolled or symptomatic angina * Ejection fraction below the institutional normal limit * History of other malignancy that could affect compliance with the protocol or interpretation of results * Patients with a history of curatively treated basal or squamous cell carcinoma of the skin or in situ carcinoma of the cervix are generally eligible. Patients with a malignancy that has been treated, but not with curative intent, will also be excluded, unless the malignancy has been in remission without treatment for 2 years prior to enrollment. * Evidence of other clinically significant uncontrolled condition(s) including, but not limited to, uncontrolled systemic infection (viral, bacterial, or fungal) * Major surgery (within 4 weeks prior to the start of the first dose of study treatment), other than for diagnosis * Women who are pregnant or lactating * Female patients who are not surgically sterile or postmenopausal (for at least 1 year) must practice at least one of the following methods of birth control throughout the duration of study participation and for at least 12 months after study treatment: * Total abstinence from sexual intercourse * A vasectomized partner * Hormonal contraceptives (oral, parenteral, vaginal ring, or transdermal) that started at least 3 months prior to study drug administration * Double-barrier method (condom diaphragm or cervical cup with spermicidal contraceptive sponge, jellies, or cream) * Non-vasectomized male patients must comply with at least one of the following methods of birth control throughout the duration of study participation and for at least 12 months after study treatment: * A partner who is surgically sterile or postmenopausal (for at least 1 year) or who is taking hormonal contraceptives (oral, parenteral, vaginal ring, or transdermal) for at least 3 months prior to study drug administration * Total abstinence from sexual intercourse * Double-barrier method (condom diaphragm or cervical cup with spermicidal, contraceptive sponge, jellies, or cream) * Malabsorption syndrome or other condition that precludes enteral route of administration * Known allergy to both xanthine oxidase inhibitors and rasburicase
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) | 29 days | Define maximum tolerated dose and /or recommended phase II dose for the combinations of venetoclax (ABT-199, GDC-0199) plus Ibrutinib (PCI-32765) and rituximab in Relapsed or Refractory DLBCL by assessing the incidence of dose limiting toxicities (DLTs). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Treatment-emergent Adverse Events. | 36 Months | Adverse events will be assessed using the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE), version 4.03. |
| Efficacy as Assessed by Progression Free Survival (PFS) | 36 Months | The duration of PFS is defined as the time from the beginning of the first cycle of treatment to the date of progressive disease or death from any cause. PFS will be estimated using Kaplan-Meier method. |
| Efficacy as Assessed by Overall Survival (OS) | 36 Months | The duration of OS is defined as the time from the beginning of the first cycle of treatment to the date of death from any cause. OS will be estimated using Kaplan-Meier method. |
Countries
United States
Participant flow
Recruitment details
10 Patients Consented (9 started, 1 screen failure)
Participants by arm
| Arm | Count |
|---|---|
| 400mg ABT-199 400mg ABT-199 Dose Level | 5 |
| 800mg ABT-199 800mg ABT-199 Dose Level | 3 |
| Dose-Expansion 800mg ABT-199 800mg ABT-199 Dose Level Expansion Arm | 2 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Screen Failure | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Dose-Expansion 800mg ABT-199 | Total | 400mg ABT-199 | 800mg ABT-199 |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 7 Participants | 4 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 3 Participants | 1 Participants | 2 Participants |
| Age, Continuous | 84 Years | 71.5 Years | 70 Years | 53 Years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 10 Participants | 5 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 7 Participants | 4 Participants | 2 Participants |
| Region of Enrollment United States | 2 participants | 10 participants | 5 participants | 3 participants |
| Sex: Female, Male Female | 2 Participants | 6 Participants | 2 Participants | 2 Participants |
| Sex: Female, Male Male | 0 Participants | 4 Participants | 3 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 4 | 2 / 3 | 1 / 2 |
| other Total, other adverse events | 3 / 4 | 3 / 3 | 2 / 2 |
| serious Total, serious adverse events | 3 / 4 | 1 / 3 | 1 / 2 |
Outcome results
Primary
Maximum Tolerated Dose (MTD)
Define maximum tolerated dose and /or recommended phase II dose for the combinations of venetoclax (ABT-199, GDC-0199) plus Ibrutinib (PCI-32765) and rituximab in Relapsed or Refractory DLBCL by assessing the incidence of dose limiting toxicities (DLTs).
Time frame: 29 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ABT-199 Plus Ibrutinib and Rituximab | Maximum Tolerated Dose (MTD) | 800 mg |
Secondary
Efficacy as Assessed by Overall Survival (OS)
The duration of OS is defined as the time from the beginning of the first cycle of treatment to the date of death from any cause. OS will be estimated using Kaplan-Meier method.
Time frame: 36 Months
Population: Median Overall Survival
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ABT-199 Plus Ibrutinib and Rituximab | Efficacy as Assessed by Overall Survival (OS) | 8.6 Months |
| 800mg ABT-199 | Efficacy as Assessed by Overall Survival (OS) | 3.5 Months |
| Dose-Expansion 800mg ABT-199 | Efficacy as Assessed by Overall Survival (OS) | 9.4 Months |
Secondary
Efficacy as Assessed by Progression Free Survival (PFS)
The duration of PFS is defined as the time from the beginning of the first cycle of treatment to the date of progressive disease or death from any cause. PFS will be estimated using Kaplan-Meier method.
Time frame: 36 Months
Population: Median Progression Free Survival
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ABT-199 Plus Ibrutinib and Rituximab | Efficacy as Assessed by Progression Free Survival (PFS) | 2 Months |
| 800mg ABT-199 | Efficacy as Assessed by Progression Free Survival (PFS) | 2 Months |
| Dose-Expansion 800mg ABT-199 | Efficacy as Assessed by Progression Free Survival (PFS) | 2 Months |
Secondary
Incidence of Treatment-emergent Adverse Events.
Adverse events will be assessed using the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE), version 4.03.
Time frame: 36 Months
Population: Number of participants with treatment-emergency adverse events
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ABT-199 Plus Ibrutinib and Rituximab | Incidence of Treatment-emergent Adverse Events. | 3 Participants |
| 800mg ABT-199 | Incidence of Treatment-emergent Adverse Events. | 2 Participants |
| Dose-Expansion 800mg ABT-199 | Incidence of Treatment-emergent Adverse Events. | 1 Participants |