Ibrutinib in Treating Patients With Relapsed or Refractory Follicular Lymphoma

Phase 2

Active, not recruiting

Conditions: Recurrent Grade 3 Follicular Lymphoma
Refractory Follicular Lymphoma
Grade 3a Follicular Lymphoma
Recurrent Grade 1 Follicular Lymphoma
Recurrent Grade 2 Follicular Lymphoma

Interventions: Drug: Ibrutinib
Other: Laboratory Biomarker Analysis

Registration Number: NCT01849263

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: This phase II trial studies how well ibrutinib works in treating patients with follicular lymphoma that has come back after a period of improvement or does not respond to treatment. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed Description: PRIMARY OBJECTIVES:

I. Evaluate the overall response rate of ibrutinib in patients with relapsed or refractory follicular lymphoma.

SECONDARY OBJECTIVES:

I. Assess the safety and tolerability of ibrutinib in patients with follicular lymphoma.

II. Evaluate overall survival, time to response, duration of response, progression-free survival, time to treatment failure, and time to subsequent treatment.

TERTIARY OBJECTIVES:

I. Describe the relationship between interim positron emission tomography (PET)/computed tomography (CT) scan results, CT response, and response duration.

II. Biomarker studies including exploring associations between ibrutinib response and somatic mutations identified in follicular lymphoma, whole transcriptome shotgun sequencing (ribonucleic acid-sequencing \[RNA-seq\]), exploration of inhibition of Bruton's tyrosine kinase (BTK) and other kinases, expression of cytokines, chemokines, and other proteins with an aim to develop predictors of response and resistance.

III. Assess changes in various cancer-derived molecules in the blood over the course of treatment with ibrutinib.

IV. As part of ongoing research for Phase II Consortium (P2C) studies, we are banking paraffin-embedded tissue blocks/slides and blood products for future studies.

OUTLINE:

Patients receive ibrutinib orally (PO) once daily (QD) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients with progressive disease at the end of course 2 may continue on therapy until the end of course 5 at the discretion of the treating physician.

After completion of study treatment, patients are followed up every 3 months until progressive disease, and then every 6 months for 5 years.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 41

Inclusion Criteria

Histologically confirmed diagnosis of follicular lymphoma, grade 1, 2, or 3a
- Note: Fresh (frozen) tumor biopsy must be available or attempted; a frozen tumor biopsy equivalent to a minimum of four at least 16 gauge needle cores is an important component of this study; patients without adequate frozen material should have a biopsy performed to obtain material; if biopsy is performed and does not yield adequate material, the patient is still eligible for the study; if a biopsy cannot be done safely, the patient may still be eligible for the study if permission is granted in writing (email) by the study chair (Dr. Nancy Bartlett) or her designees; Dr. Bartlett may be consulted to discuss situations involving invasive biopsy procedures that may pose an increased risk to the patient
Measurable disease as defined by a lymph node or tumor mass that is >= 1.5 cm in at least one dimension by CT or the CT portion of the PET/CT
Relapsed or refractory follicular lymphoma which has progressed during or following 1 or more prior chemotherapy regimens for lymphoma
Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2
Absolute neutrophil count >= 750/mm^3 (0.75 x 10^9/L)
Hemoglobin >= 8.0 g/dL
Platelets >= 30,000/mm^3 (30 x 10^9/L)
Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) unless Gilbert's syndrome or disease infiltration of the liver is present
Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.0 x institutional ULN
Creatinine =< 2.0 x institutional ULN
Creatinine clearance (estimated [est.] glomerular filtration rate [GFR] Cockcroft-Gault) >= 30 mL/min
Negative serum pregnancy test done =< 7 days prior to registration for women of childbearing potential only
Ability to understand and the willingness to sign a written informed consent document
Willingness to provide biologic samples for correlative research purposes

Exclusion Criteria

Any of the following:
- Chemotherapy/systemic therapy =< 4 weeks prior to registration
- Radiotherapy =< 4 weeks prior to registration
- Nitrosoureas or mitomycin C =< 6 weeks prior to registration
- Those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
- Major surgery =< 10 days prior to registration or minor surgery =< 7 days prior to registration
- Prior therapy with ibrutinib or another Bruton's tyrosine kinase inhibitor
- Receiving any other investigational agents
Active central nervous system (CNS) involvement
Receiving any medications or substances that are strong inhibitors or inducers of cytochrome P450 family 3 subfamily A member 4/5 (CYP3A4/5)
Any of the following:
- Pregnant women
- Nursing women
- Men or women of childbearing potential who are unwilling to employ adequate contraception
  - Note: Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of ibrutinib administration
  - Note: Breastfeeding should be discontinued if the mother is treated with ibrutinib
Human immunodeficiency virus (HIV)-positive patients on antiretroviral therapy are ineligible; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated
- Note: HIV-positive patients who are not on anti-viral medications that are strong CYP3A4/5 inhibitors and who do not have cluster of differentiation (CD)4 counts less than the lower limit of normal by institutional criteria are eligible; no patients with CD4 counts below institutional normals are eligible
Known active infection with hepatitis C virus (HCV) or hepatitis B virus (HBV)
Known histological transformation from follicular lymphoma to diffuse large B-cell lymphoma
- Note: A prior history of adequately treated transformed lymphoma does not exclude a patient if the current active disease is biopsy-proven follicular lymphoma
History of stroke or intracranial hemorrhage =< 6 months prior to the first dose of study drug
Requires anticoagulation with warfarin or similar vitamin K antagonist
- Note: Warfarin or similar vitamin K antagonist must have been discontinued at least 28 days prior to study entry
Patient has the inability to swallow tablets
Uncontrolled intercurrent illness including, but not limited to:
- Ongoing or active infection,
- Uncontrolled diabetes mellitus
- Cardiac disease
- Psychiatric illness/social situations that would limit compliance with study requirements
"Currently active" second malignancy, other than non-melanoma skin cancers
- Note: Patients are not considered to have a "currently active" malignancy if they have completed anti-cancer therapy, and are considered by their physician to be at less than 30% risk of relapse
History of allergic reactions attributed to compounds of similar chemical or biologic composition to ibrutinib
Concurrent treatment with therapeutic doses (> 20 mg prednisone or equivalent) of systemic steroids within 14 days of start of protocol therapy
Prior history of allogeneic stem cell transplant

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (ibrutinib)	Laboratory Biomarker Analysis	Patients receive ibrutinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients with progressive disease at the end of course 2 may continue on therapy until the end of course 5 at the discretion of the treating physician.
Treatment (ibrutinib)	Ibrutinib	Patients receive ibrutinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients with progressive disease at the end of course 2 may continue on therapy until the end of course 5 at the discretion of the treating physician.

Primary Outcome Measures

Name	Time	Method
Overall Response Rate	Up to 5 years	Overall response rate defined as a partial response (PR) or complete response (CR) as the objective status at any time during treatment, evaluated using the Cheson et al. Revised Response Criteria for Malignant Lymphoma. Ninety-five percent binomial confidence intervals for the true success proportion will be calculated. A CR is defined as the disappearance of all evidence of disease. A PR is defined as ≥ 50% decrease in the sum of the products of dimensions (SPD) of up to 6 largest dominant masses; no increase in size of other nodes and regression on CT, and no increase in size of liver/spleen.

Secondary Outcome Measures

Name	Time	Method
Time to Response	Time from the date of registration to the date at which the patient's objective status is first noted to be a CR or PR, assessed up to 5 years	Time to response is defined for all evaluable patients who have achieved a confirmed response as the time from the date of registration to the date at which the patient's objective status is first noted to be a CR or PR.The median and 95% confidence interval will be calculated using the methods of Kaplan-Meier.
Time to Subsequent Treatment	Time from registration to the date of initiation of subsequent treatment for lymphoma, assessed up to 5 years	Time to subsequent treatment is defined as the time from registration to the date of initiation of subsequent treatment for lymphoma. The distribution of time to subsequent treatment will be estimated using the method of Kaplan-Meier.
Overall Survival	Assessed up to 5 years	Overall Survival is defined as the time from registration to death due to any cause. Estimated using the method of Kaplan-Meier.
Duration of Response	Time from the date at which the patient's objective status is first noted to be a CR or PR to the earliest date progression is documented, assessed up to 5 years	Duration of response is defined as the time from first evidence of a response to the first documented time of progressive disease (PD). Response and Progression were assessed using the Cheson et al. Revised Response Criteria for Malignant Lymphoma. \> \> A CR is defined as the disappearance of all evidence of disease. A PR is defined as ≥ 50% decrease in the sum of the products of dimensions (SPD) of up to 6 largest dominant masses; no increase in size of other nodes and regression on CT, and no increase in size of liver/spleen.Estimated using the method of Kaplan-Meier.\> \> Progressive Disease (PD) is defined as any new lesion or increase by ≥ 50% of previously involved sites from nadir.
Progression-free Survival	Time from registration to progression or death due to any cause, assessed up to 5 years	Progression-Free Survival is defined as the time from registration to documented progression or death due to any cause, whichever occurs first. Estimated using the method of Kaplan-Meier.
Time to Treatment Failure	Time from registration to the date of treatment discontinuation due to any reason, assessed up to 5 years	Time to treatment failure is defined as the time from registration to the date of treatment discontinuation due to any reason. The distribution of time to treatment failure will be estimated using the method of Kaplan-Meier.

Trial Locations

Locations (13): National University Hospital Singapore
🇸🇬
Singapore, Singapore
National Cancer Centre Singapore
🇸🇬
Singapore, Singapore
Metro Minnesota Community Oncology Research Consortium
🇺🇸
Saint Louis Park, Minnesota, United States
Fox Chase Cancer Center
🇺🇸
Philadelphia, Pennsylvania, United States
Mayo Clinic in Rochester
🇺🇸
Rochester, Minnesota, United States
Park Nicollet Clinic - Saint Louis Park
🇺🇸
Saint Louis Park, Minnesota, United States
University Health Network-Princess Margaret Hospital
🇨🇦
Toronto, Ontario, Canada
Kingston Health Sciences Centre
🇨🇦
Kingston, Ontario, Canada
Mayo Clinic in Arizona
🇺🇸
Scottsdale, Arizona, United States
Mayo Clinic in Florida
🇺🇸
Jacksonville, Florida, United States
Washington University School of Medicine
🇺🇸
Saint Louis, Missouri, United States
Juravinski Cancer Centre at Hamilton Health Sciences
🇨🇦
Hamilton, Ontario, Canada
University of Wisconsin Carbone Cancer Center - University Hospital
🇺🇸
Madison, Wisconsin, United States

Ibrutinib in Treating Patients With Relapsed or Refractory Follicular Lymphoma

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