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A Phase I Study of Rituximab, Lenalidomide, and Ibrutinib in Previously Untreated Follicular Lymphoma


Phase 1
18 Years
N/A
Not Enrolling
Both
Contiguous Stage II Grade 1 Follicular Lymphoma, Contiguous Stage II Grade 2 Follicular Lymphoma, Contiguous Stage II Grade 3 Follicular Lymphoma, Noncontiguous Stage II Grade 1 Follicular Lymphoma, Noncontiguous Stage II Grade 2 Follicular Lymphoma, Noncontiguous Stage II Grade 3 Follicular Lymphoma, Stage III Grade 1 Follicular Lymphoma, Stage III Grade 2 Follicular Lymphoma, Stage III Grade 3 Follicular Lymphoma, Stage IV Grade 1 Follicular Lymphoma, Stage IV Grade 2 Follicular Lymphoma, Stage IV Grade 3 Follicular Lymphoma

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Trial Information

A Phase I Study of Rituximab, Lenalidomide, and Ibrutinib in Previously Untreated Follicular Lymphoma


PRIMARY OBJECTIVES:

I. To determine the recommended phase II doses of ibrutinib and lenalidomide for combination
with rituximab in previously untreated follicular lymphoma.

SECONDARY OBJECTIVES:

I. To determine pharmacokinetics of ibrutinib in combination with lenalidomide and
rituximab.

II. To determine Bruton tyrosine kinase (BTK) occupancy pharmacodynamics of ibrutinib in
combination with lenalidomide and rituximab.

OUTLINE: This is a dose-escalation study of lenalidomide and ibrutinib.

Patients receive lenalidomide orally (PO) once daily (QD) on days 1-21 and ibrutinib PO QD
on days 1-28. Treatment repeats every 28 days for 12 courses in the absence of disease
progression or unacceptable toxicity. Patients also receive rituximab intravenously (IV) on
days 1, 8, 15, and 22 of course 1 and once weekly at weeks 13, 21, 29, and 37.

After completion of study treatment, patients are followed up every 4 months for 2 years and
then every 6 months for 8 years.


Inclusion Criteria:



- Previously untreated, histologically confirmed follicular lymphoma, World Health
Organization (WHO) classification grade 1, 2, or 3a (> 15 centroblasts per high power
field with centrocytes present) that is stage III, IV, or bulky (i.e., single mass >=
7 cm in any unidimensional measurement) stage II and requires therapy at the
discretion of the primary physician

- Bone marrow biopsies as the sole means of diagnosis are not acceptable, but they
may be submitted in conjunction with nodal biopsies; fine needle aspirates are
not acceptable for diagnosis

- Failure to submit pathology specimens within 60 days of patient registration
will be considered a major protocol violation

- Institutional flow cytometry or immunohistochemistry must confirm cluster of
differentiation 20 (CD20) antigen expression

- All risk by follicular lymphoma international prognostic index (FLIPI): 0-5 risk
factors

- No prior systemic therapy for non-Hodgkin lymphoma (NHL) including chemotherapy or
immunotherapy (e.g., monoclonal antibody-based therapy), radiation therapy, or
radioimmunotherapy

- No corticosteroids within two weeks prior to study entry, except for maintenance
therapy for a non-malignant disease

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2

- Measurable disease must be present either on physical examination or imaging studies;
non-measurable disease alone is not acceptable; any tumor mass > 1 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 NHL should be noted)

- Patients with human immunodeficiency virus (HIV) infection are eligible, provided
they meet the following:

- No evidence of coinfection with hepatitis B or C

- Cluster of differentiation 4 (CD4)+ cell count >= 400/mm^3

- No evidence of resistant strains of HIV

- If not on anti-HIV therapy, HIV viral load < 10,000 copies HIV ribonucleic acid
(RNA)/mL

- If on anti-HIV therapy, HIV viral load < 50 copies HIV RNA/mL

- No history of acquired immunodeficiency syndrome (AIDS)-defining conditions

- No known central nervous system (CNS) involvement by lymphoma

- No patients who require strong inhibitors of cytochrome P450, family 3, subfamily A,
polypeptide 4 (CYP 3A4) and cytochrome P450, family 2, subfamily D, polypeptide 6
(CYP 2D6)

- No evidence of active hepatitis B or C infections (i.e., no positive serology for
anti-hepatitis B virus [HBV] or anti-hepatitis C virus [HCV] antibodies); HBV
seropositive patients (hepatitis B surface antigen [HBsAg] +) are eligible if they
are closely monitored for evidence of active HBV infection by HBV deoxyribonucleic
acid (DNA) testing and receive suppressive therapy with lamivudine or other HBV
suppressive therapy until 6 months after the last rituximab dose

- No history of erythema multiforme, toxic epidermal necrolysis or Stevens-Johnson
syndrome

- No history of uncontrolled seizures

- No autoimmune disorder that requires active immunosuppression

- Non-pregnant and non-nursing; females of childbearing potential (FCBP) must have a
negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL
within 10-14 days prior to registration; further, they must either commit to
continued abstinence from heterosexual intercourse or begin TWO acceptable methods of
birth control: one highly effective method and one additional effective method AT THE
SAME TIME, at least 28 days before starting lenalidomide; FCBP must also agree to
ongoing pregnancy testing; men must agree to use a latex condom during sexual contact
with a FCBP, even if they have had a successful vasectomy; a FCBP is a sexually
mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy, or
2) has not been naturally postmenopausal for at least 24 consecutive months (i.e.,
has had menses at any time preceding 24 consecutive months)

- No known human anti-chimeric antibody (HACA) positivity

- No anticoagulation with warfarin; alternative anticoagulant may be used

- No treatment with strong CYP3A4/cytochrome P450, family 3, subfamily A, polypeptide 5
(CYP3A5) and/or CYP2D inhibitors

- Absolute neutrophil count (ANC) >= 1,000/microliter

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper
limit of normal (ULN)

- Total bilirubin =< 1.5 x ULN unless attributable to NHL; unless attributable to
Gilbert's syndrome, or disease infiltration of the liver is present

- Creatinine clearance >= 40 mL/min (patients on dialysis are not eligible); to be
calculated by method of Cockcroft-Gault, using actual weight, maximum creatinine
clearance (CrCl) 125 mL/min

- Creatinine =< 2 x ULN

- Platelet count >= 75,000/microliter

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximally tolerated dose (MTD) of lenalidomide and ibrutinib for combination with rituximab, determined by dose-limiting toxicities (DLT) graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0

Outcome Time Frame:

28 days

Safety Issue:

Yes

Principal Investigator

Chaitra Ujjani

Investigator Role:

Principal Investigator

Investigator Affiliation:

Cancer and Leukemia Group B

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2013-00792

NCT ID:

NCT01829568

Start Date:

April 2013

Completion Date:

Related Keywords:

  • Contiguous Stage II Grade 1 Follicular Lymphoma
  • Contiguous Stage II Grade 2 Follicular Lymphoma
  • Contiguous Stage II Grade 3 Follicular Lymphoma
  • Noncontiguous Stage II Grade 1 Follicular Lymphoma
  • Noncontiguous Stage II Grade 2 Follicular Lymphoma
  • Noncontiguous Stage II Grade 3 Follicular Lymphoma
  • Stage III Grade 1 Follicular Lymphoma
  • Stage III Grade 2 Follicular Lymphoma
  • Stage III Grade 3 Follicular Lymphoma
  • Stage IV Grade 1 Follicular Lymphoma
  • Stage IV Grade 2 Follicular Lymphoma
  • Stage IV Grade 3 Follicular Lymphoma
  • Lymphoma
  • Lymphoma, Follicular

Name

Location

Cancer and Leukemia Group BChicago, Illinois  60606