Clinical Trials List
Protocol NumberPCYC-1141-CA
NCT Number(ClinicalTrials.gov Identfier)NCT02947347
2017-10-01 - 2025-01-31
Phase III
Recruiting6
ICD-10C82.98
Follicular lymphoma, unspecified, lymph nodes of multiple sites
A Multicenter, Randomized, Double-blind, Placebo-controlled Phase 3 Study of the Bruton’s Tyrosine Kinase (BTK) Inhibitor, Ibrutinib, in Combination with Rituximab versus Placebo in Combination with Rituximab in Treatment Naïve Subjects with Follicular Lymphoma
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Trial Applicant
PPD DEVELOPMENT (HK) LIMITED
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Sponsor
Pharmacyclics LLC
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Trial scale
Multi-Regional Multi-Center
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Update
2025/08/20
Investigators and Locations
Co-Principal Investigator
The Actual Total Number of Participants Enrolled
0 Recruiting
The Actual Total Number of Participants Enrolled
0 Recruiting
The Actual Total Number of Participants Enrolled
0 Recruiting
Co-Principal Investigator
- Tzeon-jye Chiou Division of Hematology & Oncology
- 林可瀚 Division of Nuclear Medicine
- 陳蓉宣 Division of Hematology & Oncology
- Po-Shen Ko Division of Hematology & Oncology
- Sheng-Hsuan Chien Division of Hematology & Oncology
- 李函叡 Division of Radiology
- 吳嘉紘 Division of Hematology & Oncology
- Liang-Tsai Hsiao Division of Hematology & Oncology
- Rheun-Chuan Lee Division of Radiology
- Yao-Chung Liu Division of Hematology & Oncology
- Jyh-Pyng Gau Division of Hematology & Oncology
- Chun-Yu Liu Division of Radiation Therapy
- Chia-Jen Liu Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Recruiting
Co-Principal Investigator
- Chien-Yuan Chen Division of General Internal Medicine
- CHENG-HONG TSAI Division of General Internal Medicine
- 林耘曲 Division of General Internal Medicine
- HSIN-AN HOU Division of General Internal Medicine
- Jih-Luh Tang Division of General Internal Medicine
- Huai-Hsuan Huang Division of General Internal Medicine
- SHAN-CHI YU Division of General Internal Medicine
- Chien-Chin Lin Division of General Internal Medicine
- MING YAO Division of General Internal Medicine
- Tai-Chung Huang Division of General Internal Medicine
- CHIH-WEI YU Division of General Internal Medicine
- 林耘曲醫師 Division of General Internal Medicine
- Shang-Ju Wu Division of General Internal Medicine
- 柯紀綸 Division of Nuclear Medicine
- 柯紀綸醫師 Division of General Internal Medicine
The Actual Total Number of Participants Enrolled
0 Recruiting
Co-Principal Investigator
- Hui-Ching Wang Division of Hematology & Oncology
- 卓士醫師 Division of Hematology & Oncology
- 唐世豪 Division of Hematology & Oncology
- Hui-Hua Hsiao Division of Hematology & Oncology
- Jeng-Shiun Du Division of Hematology & Oncology
- 許瑞峰 Division of Hematology & Oncology
- Shih-Feng Cho Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Recruiting
Condition/Disease
Follicular lymphoma tumors (grades 1-3A) that have never received treatment meet the Groupe d'Etude des Lymphomes Folliculaire (GELF) treatment standards: elderly people over 70 years old, or 60-69 years old with complications
Objectives
Analysis Study 1To evaluate whether the addition of ibrutinib to rituximab will result in prolongation of progression-free survival (PFS) when compared with rituximab alone in treatment naïve subjects with follicular lymphomaDiscontinuation Analysis StudyFor subjects who are re-randomized in Part 2, to evaluate whether continuous treatment with ibrutinib will result in prolongation of progression-free survival (PFS) when compared with finite treatment with ibrutinib
Test Drug
Ibrutinib (PCI-32765)
Active Ingredient
Ibrutinib
Dosage Form
capsule
Dosage
140mg
Endpoints
Analysis Study 1
Primary Endpoint
●Progression-free survival (PFS) in Part 1
Secondary Endpoints
●Complete response (CR) rate in Part 1 as defined by the International Working Group (IWG) Revised Response Criteria for Malignant Lymphoma
●Overall response rate (ORR) in Part 1
●Overall Survival (OS) (Arm A vs. Arm B) through Part 2
●Frequency, severity, seriousness, and relatedness of adverse events (AEs) in Part 1
Exploratory Endpoints
●Health-related quality of life (QOL) as measured by the Functional Assessment of Cancer Therapy- Lymphoma (FACT- Lym)
●Pharmacokinetic parameters or metrics of systemic exposure of ibrutinib and rituximab
●Evaluation and/or identification of relevant patient populations defined by biomarker(s)
●Minimal residual disease (MRD)-negative rate defined as the proportion of follicular lymphoma subjects who achieve a CR and who reach MRD-negative disease status
●Complete response rate at 30 months (CR30) as defined by the International Working Group (IWG) Revised Response Criteria for Malignant Lymphoma
●Two, 3, 4 and 5-year landmark OS rate
Discontinuation Analysis Study
Primary Endpoint
●Progression-free survival in Part 2 (Arm A1 vs. Arm A2)
Secondary Endpoint
●Frequency, severity, seriousness, and relatedness of AEs in Part 2
Exploratory Endpoints
●To evaluate and/or identify patient populations defined by relevant biomarker(s)
●Minimal residual disease-negative rate defined as the proportion of FL subjects who achieve a CR and who reach MRD-negative disease status in Part 2
●The OS treatment effect HR and 3-year landmark survival rate for Arms A1 and A2
Primary Endpoint
●Progression-free survival (PFS) in Part 1
Secondary Endpoints
●Complete response (CR) rate in Part 1 as defined by the International Working Group (IWG) Revised Response Criteria for Malignant Lymphoma
●Overall response rate (ORR) in Part 1
●Overall Survival (OS) (Arm A vs. Arm B) through Part 2
●Frequency, severity, seriousness, and relatedness of adverse events (AEs) in Part 1
Exploratory Endpoints
●Health-related quality of life (QOL) as measured by the Functional Assessment of Cancer Therapy- Lymphoma (FACT- Lym)
●Pharmacokinetic parameters or metrics of systemic exposure of ibrutinib and rituximab
●Evaluation and/or identification of relevant patient populations defined by biomarker(s)
●Minimal residual disease (MRD)-negative rate defined as the proportion of follicular lymphoma subjects who achieve a CR and who reach MRD-negative disease status
●Complete response rate at 30 months (CR30) as defined by the International Working Group (IWG) Revised Response Criteria for Malignant Lymphoma
●Two, 3, 4 and 5-year landmark OS rate
Discontinuation Analysis Study
Primary Endpoint
●Progression-free survival in Part 2 (Arm A1 vs. Arm A2)
Secondary Endpoint
●Frequency, severity, seriousness, and relatedness of AEs in Part 2
Exploratory Endpoints
●To evaluate and/or identify patient populations defined by relevant biomarker(s)
●Minimal residual disease-negative rate defined as the proportion of FL subjects who achieve a CR and who reach MRD-negative disease status in Part 2
●The OS treatment effect HR and 3-year landmark survival rate for Arms A1 and A2
Inclution Criteria
1. Subjects with histologically documented follicular lymphoma (Grade 1, 2 or 3a) according to World Health Organization (WHO) criteria and Ann Arbor Stage II, III or IV disease.
2. At least one two-dimensionally measurable lesion ≥2.0 cm in the longest diameter (LDi) by contrast-enhanced CT scan. Lesions in anatomical locations (such as extremities or soft tissue lesions) that are not well visualized by CT may be measured by MRI instead.
3. Subjects 70 years of age or older; OR subjects 60-69 years of age who have one or more comorbidities that make them a candidate to receive single-agent rituximab therapy:
●Creatinine clearance 30-59 mL/min (by Cockcroft-Gault or creatinine clearance calculated based on 24-hour urine collection).
●ECOG performance status score of 2
4. In need of systemic therapy as evidenced by meeting one or more of the following Groupe d’Etude des Lymphomes Folliculaire (GELF) criteria:
●Involvement of ≥3 nodal sites, each with a diameter of >3 cm
●Any nodal or extranodal tumor mass with a diameter of >7 cm
●B symptoms (ie, fever, night sweats or weight loss)
●Splenomegaly
●Pleural effusions or peritoneal ascites
●Thrombocytopenia (platelet count <100 x 109/L)
●Peripheral blood involvement (>5.0 x 109/L malignant cells)
Laboratory
5. Adequate hematologic function defined as:
●Hemoglobin ≥8.0 g/dL
●Platelet count ≥50 x 109/L (50,000 cells/mm3)
●Absolute neutrophil count ≥1.0 x 109/L (1,000 cells/mm3)
6. Adequate renal and hepatic function defined as:
●Estimated creatinine clearance ≥ 30 mL/min (Cockcroft-Gault)
●Serum aspartate transaminase (AST) and alanine transaminase (ALT)≤3.0 x upper limit of normal (ULN).
●Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert’s syndrome such that bilirubin ≤3 x ULN or is of non-hepatic origin)
7. PT/ INR <1.5 x ULN (unless treated with warfarin or other vitamin K antagonists such that INR ≤3.0) and PTT (aPTT) <1.5 x ULN
Demographic
8. Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2.
Ethical/Other
9. Female subjects of reproductive potential must have a negative urine/serum pregnancy test upon study entry. Female subjects who are of non-reproductive potential (ie, post-menopausal by history - no menses for ≥1 year; OR history of hysterectomy; OR history of bilateral tubal ligation; OR history of bilateral oophorectomy) are exempt from pregnancy testing.
10. Male and female subjects of reproductive potential who agree to use both a highly effective method of birth control (eg, implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], complete abstinence1, or sterilized partner) and a barrier method (eg, condoms, cervical ring, sponge, etc) during the period of therapy. For female subjects, these birth control requirements must be adhered to for 30 days after the last dose of ibrutinib/placebo and 12 months after the last dose of rituximab, whichever is later. For male subjects, these birth control requirements must be adhered to for 90 days after the last dose of ibrutinib/placebo.
2. At least one two-dimensionally measurable lesion ≥2.0 cm in the longest diameter (LDi) by contrast-enhanced CT scan. Lesions in anatomical locations (such as extremities or soft tissue lesions) that are not well visualized by CT may be measured by MRI instead.
3. Subjects 70 years of age or older; OR subjects 60-69 years of age who have one or more comorbidities that make them a candidate to receive single-agent rituximab therapy:
●Creatinine clearance 30-59 mL/min (by Cockcroft-Gault or creatinine clearance calculated based on 24-hour urine collection).
●ECOG performance status score of 2
4. In need of systemic therapy as evidenced by meeting one or more of the following Groupe d’Etude des Lymphomes Folliculaire (GELF) criteria:
●Involvement of ≥3 nodal sites, each with a diameter of >3 cm
●Any nodal or extranodal tumor mass with a diameter of >7 cm
●B symptoms (ie, fever, night sweats or weight loss)
●Splenomegaly
●Pleural effusions or peritoneal ascites
●Thrombocytopenia (platelet count <100 x 109/L)
●Peripheral blood involvement (>5.0 x 109/L malignant cells)
Laboratory
5. Adequate hematologic function defined as:
●Hemoglobin ≥8.0 g/dL
●Platelet count ≥50 x 109/L (50,000 cells/mm3)
●Absolute neutrophil count ≥1.0 x 109/L (1,000 cells/mm3)
6. Adequate renal and hepatic function defined as:
●Estimated creatinine clearance ≥ 30 mL/min (Cockcroft-Gault)
●Serum aspartate transaminase (AST) and alanine transaminase (ALT)≤3.0 x upper limit of normal (ULN).
●Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert’s syndrome such that bilirubin ≤3 x ULN or is of non-hepatic origin)
7. PT/ INR <1.5 x ULN (unless treated with warfarin or other vitamin K antagonists such that INR ≤3.0) and PTT (aPTT) <1.5 x ULN
Demographic
8. Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2.
Ethical/Other
9. Female subjects of reproductive potential must have a negative urine/serum pregnancy test upon study entry. Female subjects who are of non-reproductive potential (ie, post-menopausal by history - no menses for ≥1 year; OR history of hysterectomy; OR history of bilateral tubal ligation; OR history of bilateral oophorectomy) are exempt from pregnancy testing.
10. Male and female subjects of reproductive potential who agree to use both a highly effective method of birth control (eg, implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], complete abstinence1, or sterilized partner) and a barrier method (eg, condoms, cervical ring, sponge, etc) during the period of therapy. For female subjects, these birth control requirements must be adhered to for 30 days after the last dose of ibrutinib/placebo and 12 months after the last dose of rituximab, whichever is later. For male subjects, these birth control requirements must be adhered to for 90 days after the last dose of ibrutinib/placebo.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating in the study.
Disease-Related
1. Transformed lymphoma; if clinical evidence of transformed lymphoma is present(high lactate dehydrogenase [LDH] and/or high maximum standard uptake value [SUVmax] of a lymph node/lesion on positron emission tomography [PET] scanning), transformation should be ruled out by biopsy of the suspicious lymph node/lesion.
2. Prior treatment for follicular lymphoma (eg, systemic anti-cancer therapy or involved site radiotherapy).
3. Medically apparent central nervous system lymphoma or leptomeningeal disease.
Concurrent conditions
4. 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.
5. Concurrent systemic immunosuppressant therapy (eg, cyclosporine A, tacrolimus, etc., or chronic administration of >20 mg/day of prednisone or equivalent) within 28 days of the first dose of study drug. For indications other than lymphoma or management of lymphoma-related symptoms, the following are exceptions to this criterion:
Intranasal, inhaled, topical corticosteroids or local corticosteroid injections (eg, intra-articular injection)
Systemic corticosteroids at doses not to exceed 20 mg/day of prednisone or its equivalent
Corticosteroids as pre-medication for hypersensitivity reactions (eg, computed tomography [CT] scan pre-medication)
6. Vaccinated with live, attenuated vaccines within 4 weeks of the first dose of study drug.
7. Known bleeding disorders (eg, von Willebrand’s disease or hemophilia).
8. History of stroke or intracranial hemorrhage within 6 months prior to enrollment.
9. Known history of human immunodeficiency virus (HIV) or active infection with hepatitis C virus (HCV) or hepatitis B virus (HBV). Subjects who are positive for hepatitis B core antibody, hepatitis B surface antigen, or hepatitis C antibody must have a negative polymerase chain reaction (PCR) result before enrollment. Those who are PCR positive will be excluded. In equivocal cases, hepatitis B or C PCR may be performed and must be negative for enrollment.
10. Any uncontrolled active systemic infection or recent infection requiring intravenous antibiotic treatment that was completed ≤14 days before the first dose of study drug.
11. Major surgery within 4 weeks of first dose of study drug.
12. Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator’s opinion, could compromise the subject’s safety or put the study outcomes at undue risk.
13. Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomization.
14. Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction.
15. Known anaphylaxis or IgE-mediated hypersensitivity to murine proteins or to any component of rituximab.
16. Prior use of an anti-CD20 agent or an inhibitor of Bruton’s tyrosine kinase (BTK) (eg, rituximab, ibrutinib). (NOTE: use of any prior treatment for follicular lymphoma is not permitted per protocol)
17. Any investigational drug within 4 weeks prior to randomization or concurrent enrollment in another therapeutic investigational clinical treatment study for a non-lymphoma indication.
18. Subject who received systemic administration of a strong cytochrome P (CYP) 450 3A inhibitor within 7 days prior to the first dose of ibrutinib or subject who requires continuous treatment with a strong CYP 450 3A inhibitor.
19. Currently active, clinically significant hepatic impairment Child-Pugh class B or C according to the Child Pugh classification.
20. Lactating or pregnant.
21. Unwilling or unable to participate in all required study evaluations and procedures.
22. Unable to understand the purpose and risks of the study and to provide a signed and dated informed consent form (ICF) and authorization to use protected health information (in accordance with national and local subject privacy regulations).
Disease-Related
1. Transformed lymphoma; if clinical evidence of transformed lymphoma is present(high lactate dehydrogenase [LDH] and/or high maximum standard uptake value [SUVmax] of a lymph node/lesion on positron emission tomography [PET] scanning), transformation should be ruled out by biopsy of the suspicious lymph node/lesion.
2. Prior treatment for follicular lymphoma (eg, systemic anti-cancer therapy or involved site radiotherapy).
3. Medically apparent central nervous system lymphoma or leptomeningeal disease.
Concurrent conditions
4. 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.
5. Concurrent systemic immunosuppressant therapy (eg, cyclosporine A, tacrolimus, etc., or chronic administration of >20 mg/day of prednisone or equivalent) within 28 days of the first dose of study drug. For indications other than lymphoma or management of lymphoma-related symptoms, the following are exceptions to this criterion:
Intranasal, inhaled, topical corticosteroids or local corticosteroid injections (eg, intra-articular injection)
Systemic corticosteroids at doses not to exceed 20 mg/day of prednisone or its equivalent
Corticosteroids as pre-medication for hypersensitivity reactions (eg, computed tomography [CT] scan pre-medication)
6. Vaccinated with live, attenuated vaccines within 4 weeks of the first dose of study drug.
7. Known bleeding disorders (eg, von Willebrand’s disease or hemophilia).
8. History of stroke or intracranial hemorrhage within 6 months prior to enrollment.
9. Known history of human immunodeficiency virus (HIV) or active infection with hepatitis C virus (HCV) or hepatitis B virus (HBV). Subjects who are positive for hepatitis B core antibody, hepatitis B surface antigen, or hepatitis C antibody must have a negative polymerase chain reaction (PCR) result before enrollment. Those who are PCR positive will be excluded. In equivocal cases, hepatitis B or C PCR may be performed and must be negative for enrollment.
10. Any uncontrolled active systemic infection or recent infection requiring intravenous antibiotic treatment that was completed ≤14 days before the first dose of study drug.
11. Major surgery within 4 weeks of first dose of study drug.
12. Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator’s opinion, could compromise the subject’s safety or put the study outcomes at undue risk.
13. Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomization.
14. Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction.
15. Known anaphylaxis or IgE-mediated hypersensitivity to murine proteins or to any component of rituximab.
16. Prior use of an anti-CD20 agent or an inhibitor of Bruton’s tyrosine kinase (BTK) (eg, rituximab, ibrutinib). (NOTE: use of any prior treatment for follicular lymphoma is not permitted per protocol)
17. Any investigational drug within 4 weeks prior to randomization or concurrent enrollment in another therapeutic investigational clinical treatment study for a non-lymphoma indication.
18. Subject who received systemic administration of a strong cytochrome P (CYP) 450 3A inhibitor within 7 days prior to the first dose of ibrutinib or subject who requires continuous treatment with a strong CYP 450 3A inhibitor.
19. Currently active, clinically significant hepatic impairment Child-Pugh class B or C according to the Child Pugh classification.
20. Lactating or pregnant.
21. Unwilling or unable to participate in all required study evaluations and procedures.
22. Unable to understand the purpose and risks of the study and to provide a signed and dated informed consent form (ICF) and authorization to use protected health information (in accordance with national and local subject privacy regulations).
The Estimated Number of Participants
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Taiwan
40 participants
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Global
440 participants
