Refractory Follicular Lymphoma, Relapsed Follicular Lymphoma
Conditions
Keywords
Ibrutinib, Venetoclax, Follicular, Refractory, Relapsed, Lymphoma
Brief summary
This is a phase I/II study in which patients will be enrolled in a standard 3+3 design. Once the maximum tolerated dose (MTD) is determined amongst patients with relapsed or refractory grade 1-3a follicular lymphoma, there will be a 17-patient phase II study.
Detailed description
In vitro studies of ibrutinib and venetoclax have noted significant cytotoxicity and synergy in mantle cell lymphoma and chronic lymphocytic leukemia cell lines.Data have demonstrated synergy between the two agents in various other B-cell Non-Hodgkin Lymphoma (NHL) cell lines. The investigators theorize that the combination of ibrutinib and venetoclax will provide dual, yet unique, targeted inhibition for patients with follicular lymphoma, resulting in both significant efficacy and less nonspecific toxicity.
Interventions
DRUGIbrutinib
Ibrutinib is dispensed as a capsule.
DRUGVenetoclax
Venetoclax is dispensed as a tablet.
Sponsors
AbbVie
Pharmacyclics LLC.
Hackensack Meridian Health
Georgetown University
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Relapsed or refractory, histologically confirmed follicular lymphoma, grade I, II, or IIIa which requires therapy defined by at least one of the following: * Constitutional symptoms * Cytopenias 2. High tumor burden (single mass \> 7 cm, three masses \> 3 cm, symptomatic splenomegaly, organ compression or compromise, ascites, pleural effusion)Must have received at least two prior systemic therapies 3. All risk by FLIPI 0-5 factors (Appendix I) 4. Measurable disease Measurable disease must be present either on physical examination or imaging studies; non-measurable disease alone is not acceptable. Any tumor mass \> 1.5 cm is acceptable. Lesions that are considered non-measurable include the following: * Bone lesions (lesions if present should be noted) * Ascites * Pleural/pericardial effusion * Lymphangitis cutis/pulmonis * Bone marrow (involvement by lymphoma should be noted) 5. Adequate hematologic function independent of transfusion and growth factor support for at least 3 weeks prior to screening unless attributable to disease. Defined as: * Absolute neutrophil count (ANC) \>1000 cells/mm3 (1.0 x 109/L). ANC \> 500 cells/mm3 is permissible if due to disease. * Platelet count \>50,000 cells/mm3 (50 x 109/L) unless attributable to disease. Platelet count \> 20,000 cells/mm3 is permissible if due to disease. * Hemoglobin \>8.0 g/dL. 6. Adequate hepatic and renal function defined as: * Serum aspartate transaminase (AST) or alanine transaminase (ALT) ≤ 2.5 x upper limit of normal (ULN) Serum aspartate transaminase (AST) or alanine transaminase (ALT) ≤ 5 is permissible if due to disease. * Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin) Bilirubin ≤3 x ULN is permissible if due to disease. * Estimated Creatinine Clearance ≥50 ml/min (Cockcroft-Gault based on actual weight) 7. Prothrombin time (PT)/International normalized ratio (INR) \<1.5 x ULN and PTT (aPTT) \<1.5 x ULN. 8. Men and women ≥ 18 years of age. 9. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2. (Appendix II) 10. Female subjects who are of non-reproductive potential (i.e., post-menopausal by history - no menses for ≥1 year; OR history of hysterectomy; OR history of bilateral tubal ligation; OR history of bilateral oophorectomy). Female subjects of childbearing potential must have a negative serum pregnancy test upon study entry. 11. Male and female subjects who agree to use highly effective methods of birth control (e.g., condoms, implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), sexual abstinence, or sterilized partner) during the period of therapy and for 30 days after the last dose of study drug
Exclusion criteria
1. Chemotherapy, monoclonal antibody, or small molecule kinase inhibitor less than or equal 21 days prior to first administration of study treatment 2. Prior exposure to a Bruton's tyrosine kinase (BTK) or B-cell lymphoma 2 (BCL-2) inhibitor. 3. History of allergic reactions attributed to compounds of similar chemical or biologic composition to ibrutinib or venetoclax. 4. Known allergy to xanthine oxidase inhibitors and/or rasburicase for subjects at risk for tumor lysis syndrome. 5. History of other malignancies, except: * Malignancy treated with curative intent and with no known active disease present for ≥ 3 years before the first dose of study drug and felt to be at low risk for recurrence by treating physician. * Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease. * Adequately treated carcinoma in situ without evidence of disease. 6. Concurrent systemic immunosuppressant therapy (e.g., cyclosporine A, tacrolimus, etc., or chronic administration \[\>14 days\] of \> 20 mg/day of prednisone) within 28 days of the first dose of study drug. 7. Undergone an allogeneic stem cell transplant within the past 1 year. 8. Current or history of graft versus host disease 9. Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug. 10. Recent infection requiring systemic treatment that was completed ≤14 days before the first dose of study drug. 11. Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved to Common Terminology Criteria for Adverse Event (CTCAE, version 4.03), grade ≤1, or to the levels dictated in the inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recommended Phase 2 Dose (RP2D) | Cycle 1 (28 days) | The maximum tolerated dose of Ibrutinib and Venetoclax as determined by number of DLTs observed. • If 0/3 DLT is observed, dose escalation will continue to the next upper dose level. • If ≥ 2/3 DLTs are observed, then the dose finding procedure will be terminated. • If 1/3 DLT is observed, then 3 additional patients will be enrolled in the same dose level. If no DLT is observed from the additional 3 patients, then dose escalation will continue to the next upper dose level. If any DLT is observed from the 3 additional patients, then the previously lower dose will be chosen as the MTD and the dose finding procedure will be terminated. |
| Dose Level 2 Overall Response Rate | 36 months | Number of participants on the recommended phase II dose level 2, with a partial or complete response, as determined by the revised Lugano Response Criteria for Non-Hodgkin Lymphoma, |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics of Ibrutinib (Cmax) Phase 1 | Cycle 1 (28 days) | Cmax- Maximiumum concentration of Ibrutinib of subjects in Phase 1. |
| Pharmacokinetics of Ibrutinib (Tmax) Phase 1 | Cycle 1 (28 days) | Tmax (time to maximum) plasma concentrations of ibrutinib for subjects in phase 1 |
| Pharmacokinetics of Ibrutinib (AUC) Phase 1 | Cycle 1 (28 days) | Area Under the Curve (AUC) 0 to 24 hours for subjects in phase 1 |
| Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.03 | 36 months | Toxicity (attribute and grade) will be summarized for each dose level (0, 1, 2, 3) for all patients who receive at least one dose of study treatment. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase I - Dose Level 0 Ibrutinib (capsule) - 420mg Venetoclax (tablet) - 400mg
Each medication is taken daily. Treatment cycles are 28 days long.
Ibrutinib: Ibrutinib is dispensed as a capsule.
Venetoclax: Venetoclax is dispensed as a tablet. | 3 |
| Phase I - Dose Level 1 Ibrutinib (capsule) - 560mg Venetoclax (tablet) - 400mg
Each medication is taken daily. Treatment cycles are 28 days long.
Ibrutinib: Ibrutinib is dispensed as a capsule.
Venetoclax: Venetoclax is dispensed as a tablet. | 6 |
| Phase I - Dose Level 2 Ibrutinib (capsule) - 560mg Venetoclax (tablet) - 600mg
Each medication is taken daily. Treatment cycles are 28 days long.
Ibrutinib: Ibrutinib is dispensed as a capsule.
Venetoclax: Venetoclax is dispensed as a tablet. | 6 |
| Phase I - Dose Level 3 Ibrutinib (capsule) - 560mg Venetoclax (tablet) - 800mg
Each medication is taken daily. Treatment cycles are 28 days long.
Ibrutinib: Ibrutinib is dispensed as a capsule.
Venetoclax: Venetoclax is dispensed as a tablet. | 1 |
| Phase II Dose The Phase II dose will be the maximum tolerated dose as determined in the Phase I portion.
Ibrutinib: Ibrutinib is dispensed as a capsule.
Venetoclax: Venetoclax is dispensed as a tablet. | 8 |
| Total | 24 |
Baseline characteristics
| Characteristic | Phase I - Dose Level 0 | Phase I - Dose Level 1 | Phase I - Dose Level 2 | Phase I - Dose Level 3 | Phase II Dose | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 1 Participants | 4 Participants | 1 Participants | 3 Participants | 11 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 5 Participants | 2 Participants | 0 Participants | 5 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 4 Participants | 5 Participants | 1 Participants | 7 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 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 | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) White | 1 Participants | 3 Participants | 5 Participants | 1 Participants | 7 Participants | 17 Participants |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 3 Participants | 0 Participants | 3 Participants | 7 Participants |
| Sex: Female, Male Male | 3 Participants | 5 Participants | 3 Participants | 1 Participants | 5 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 3 | 1 / 6 | 2 / 6 | 0 / 1 | 0 / 8 |
| other Total, other adverse events | 3 / 3 | 6 / 6 | 6 / 6 | 1 / 1 | 8 / 8 |
| serious Total, serious adverse events | 1 / 3 | 2 / 6 | 0 / 6 | 0 / 1 | 1 / 8 |
Outcome results
Primary
Dose Level 2 Overall Response Rate
Number of participants on the recommended phase II dose level 2, with a partial or complete response, as determined by the revised Lugano Response Criteria for Non-Hodgkin Lymphoma,
Time frame: 36 months
Population: Combined Phase I and Phase II participant on RP2D, Dose Level 2
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I - Dose Level 0 | Dose Level 2 Overall Response Rate | 9 Participants |
Primary
Recommended Phase 2 Dose (RP2D)
The maximum tolerated dose of Ibrutinib and Venetoclax as determined by number of DLTs observed. • If 0/3 DLT is observed, dose escalation will continue to the next upper dose level. • If ≥ 2/3 DLTs are observed, then the dose finding procedure will be terminated. • If 1/3 DLT is observed, then 3 additional patients will be enrolled in the same dose level. If no DLT is observed from the additional 3 patients, then dose escalation will continue to the next upper dose level. If any DLT is observed from the 3 additional patients, then the previously lower dose will be chosen as the MTD and the dose finding procedure will be terminated.
Time frame: Cycle 1 (28 days)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I - Dose Level 0 | Recommended Phase 2 Dose (RP2D) | 0 Dose Limiting toxicities |
| Phase I - Dose Level 1 | Recommended Phase 2 Dose (RP2D) | 1 Dose Limiting toxicities |
| Phase I - Dose Level 2 | Recommended Phase 2 Dose (RP2D) | 0 Dose Limiting toxicities |
| Phase I - Dose Level 3 | Recommended Phase 2 Dose (RP2D) | 0 Dose Limiting toxicities |
Secondary
Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.03
Toxicity (attribute and grade) will be summarized for each dose level (0, 1, 2, 3) for all patients who receive at least one dose of study treatment.
Time frame: 36 months
Population: All subjects who received dose level 2, regardless of the phase of the trial, phase 1 or phase 2, were combined since the adverse events are by dose level received not phase of the trial.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I - Dose Level 0 | Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.03 | 3 Participants |
| Phase I - Dose Level 1 | Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.03 | 6 Participants |
| Phase I - Dose Level 2 | Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.03 | 14 Participants |
| Phase I - Dose Level 3 | Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.03 | 1 Participants |
Secondary
Pharmacokinetics of Ibrutinib (AUC) Phase 1
Area Under the Curve (AUC) 0 to 24 hours for subjects in phase 1
Time frame: Cycle 1 (28 days)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase I - Dose Level 0 | Pharmacokinetics of Ibrutinib (AUC) Phase 1 | Cycle 1 Day 1 | 1340 ng*h/mL | Standard Deviation 570 |
| Phase I - Dose Level 0 | Pharmacokinetics of Ibrutinib (AUC) Phase 1 | Cycle 1 Day 15 | 1180 ng*h/mL | Standard Deviation 244 |
| Phase I - Dose Level 1 | Pharmacokinetics of Ibrutinib (AUC) Phase 1 | Cycle 1 Day 15 | 1170 ng*h/mL | Standard Deviation 304 |
| Phase I - Dose Level 1 | Pharmacokinetics of Ibrutinib (AUC) Phase 1 | Cycle 1 Day 1 | 1420 ng*h/mL | Standard Deviation 1020 |
| Phase I - Dose Level 2 | Pharmacokinetics of Ibrutinib (AUC) Phase 1 | Cycle 1 Day 15 | 1250 ng*h/mL | Standard Deviation 912 |
| Phase I - Dose Level 2 | Pharmacokinetics of Ibrutinib (AUC) Phase 1 | Cycle 1 Day 1 | 793 ng*h/mL | Standard Deviation 533 |
| Phase I - Dose Level 3 | Pharmacokinetics of Ibrutinib (AUC) Phase 1 | Cycle 1 Day 1 | 1980 ng*h/mL | Standard Deviation 1980 |
| Phase I - Dose Level 3 | Pharmacokinetics of Ibrutinib (AUC) Phase 1 | Cycle 1 Day 15 | 2440 ng*h/mL | Standard Deviation 2440 |
Secondary
Pharmacokinetics of Ibrutinib (Cmax) Phase 1
Cmax- Maximiumum concentration of Ibrutinib of subjects in Phase 1.
Time frame: Cycle 1 (28 days)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase I - Dose Level 0 | Pharmacokinetics of Ibrutinib (Cmax) Phase 1 | Cycle 1 Day 15 | 155 ng/mL | Standard Deviation 4 |
| Phase I - Dose Level 0 | Pharmacokinetics of Ibrutinib (Cmax) Phase 1 | Cycle 1 Day 1 | 185 ng/mL | Standard Deviation 84.8 |
| Phase I - Dose Level 1 | Pharmacokinetics of Ibrutinib (Cmax) Phase 1 | Cycle 1 Day 1 | 253 ng/mL | Standard Deviation 222 |
| Phase I - Dose Level 1 | Pharmacokinetics of Ibrutinib (Cmax) Phase 1 | Cycle 1 Day 15 | 195 ng/mL | Standard Deviation 109 |
| Phase I - Dose Level 2 | Pharmacokinetics of Ibrutinib (Cmax) Phase 1 | Cycle 1 Day 1 | 161 ng/mL | Standard Deviation 124 |
| Phase I - Dose Level 2 | Pharmacokinetics of Ibrutinib (Cmax) Phase 1 | Cycle 1 Day 15 | 181 ng/mL | Standard Deviation 105 |
| Phase I - Dose Level 3 | Pharmacokinetics of Ibrutinib (Cmax) Phase 1 | Cycle 1 Day 15 | 199 ng/mL | Standard Deviation 199 |
| Phase I - Dose Level 3 | Pharmacokinetics of Ibrutinib (Cmax) Phase 1 | Cycle 1 Day 1 | 227 ng/mL | Standard Deviation 227 |
Secondary
Pharmacokinetics of Ibrutinib (Tmax) Phase 1
Tmax (time to maximum) plasma concentrations of ibrutinib for subjects in phase 1
Time frame: Cycle 1 (28 days)
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Phase I - Dose Level 0 | Pharmacokinetics of Ibrutinib (Tmax) Phase 1 | Cycle 1 Day 1 | 4 hours |
| Phase I - Dose Level 0 | Pharmacokinetics of Ibrutinib (Tmax) Phase 1 | Cycle 1 Day 15 | 2 hours |
| Phase I - Dose Level 1 | Pharmacokinetics of Ibrutinib (Tmax) Phase 1 | Cycle 1 Day 15 | 2 hours |
| Phase I - Dose Level 1 | Pharmacokinetics of Ibrutinib (Tmax) Phase 1 | Cycle 1 Day 1 | 2 hours |
| Phase I - Dose Level 2 | Pharmacokinetics of Ibrutinib (Tmax) Phase 1 | Cycle 1 Day 1 | 2 hours |
| Phase I - Dose Level 2 | Pharmacokinetics of Ibrutinib (Tmax) Phase 1 | Cycle 1 Day 15 | 2 hours |
| Phase I - Dose Level 3 | Pharmacokinetics of Ibrutinib (Tmax) Phase 1 | Cycle 1 Day 1 | 2 hours |
| Phase I - Dose Level 3 | Pharmacokinetics of Ibrutinib (Tmax) Phase 1 | Cycle 1 Day 15 | 2 hours |