PRIMARY OBJECTIVE:
I. Best overall response of complete response/partial response (CR/PR).
SECONDARY OBJECTIVES:
I. Toxicity defined as any adverse event (AE) grade 3 and higher. II. Progression free
survival.
EXPLORATORY/CORRELATIVE OBJECTIVES:
I. Gene expression profiling using Lymph5Cx test. II. Sequencing using the ion torrent
platform (76 gene panel for known mutations in lymphoma).
III. Sequencing of BTK and phospholipase-C gamma (PLC) to evaluate for mutations.
IV. Minimal residual disease testing (MRD by flow cytometry and targeted sequencing post
treatment).
OUTLINE:
Patients receive obinutuzumab intravenously (IV) over 30 minutes on days 1, 8, and 15 of
cycle 1, and day 1 of cycles 2-6. Patients also receive ibrutinib orally (PO) once daily (QD)
on days 1-28. Treatment repeats every 28 days for 6 cycles in the absence of disease
progression or unacceptable toxicity. Patients achieving partial response (PR) continue to
receive obinutuzumab IV every 2 months and ibrutinib PO QD for up to 2 years in the absence
of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 6 months for up to 3
years.
Inclusion Criteria:
- Subjects must have a diagnosis of relapsed or refractory mantle cell lymphoma as
follows:
- Diagnosis of mantle cell lymphoma (MCL) must include morphology and expression of
either cyclin D1 in association with other relevant markers (eg, CD19, CD20, CD5)
or evidence of t(11;14) as assessed by cytogenetics, fluorescent in situ
hybridization (FISH), or polymerase chain reaction (PCR)
- Relapsed or refractory disease is defined as no response or progressive disease
to prior treatment if the prior treatment comprised any of the following:
- 1 regimen containing an anti-CD20 antibody administered for >= 2 doses,
and/or
- >= 1 regimen containing 1 cytotoxic agent (e.g., bendamustine, chlorambucil,
cyclophosphamide, cytarabine, doxorubicin) administered for 2 cycles
- At least 1 measurable site of disease according to Revised Response Criteria for
Malignant Lymphoma (Cheson Criteria); the site of disease must be greater than 1.5 cm
in the long axis regardless of short axis measurement or greater than 1.0 cm in the
short axis regardless of long axis measurement, and clearly measurable in 2
perpendicular dimensions
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
- Absolute neutrophil count (ANC) >= 1.0 K/cu mm; for subjects with ANC < 1.0 K/cu mm
due to significant marrow involvement by MCL, ANC must be > .5 K/cu mm
- Platelets (plt) >= 50 K/cu mm; for subjects with plt < 50 K/cu mm due to significant
marrow involvement by MCL, plt must be > 25 K/cu mm
- Total bilirubin =< 2.5 X institutional limits
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 X institutional upper limit of normal
- Creatinine =< 2
- 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 18 months after last dose of
obinutuzumab, or 1 month after the last dose of ibrutinib, whichever is later; for
males, these restrictions apply for 180 days after the last dose of obinutuzumab or 3
months after the last dose of ibrutinib, whichever is later
- Women of childbearing potential must have a negative serum (beta-human chorionic
gonadotropin [beta-hCG]) or urine pregnancy test at screening; women who are pregnant
or breastfeeding are ineligible for this study
- Ability to understand and the willingness to sign a written informed consent document
Exclusion Criteria:
- Major surgery within 4 weeks of drug administration
- Diagnosed or treated for malignancy other than MCL, except:
- Malignancy treated with curative intent and with no known active disease present
for >= 2 years
- Adequately treated non-melanoma skin cancer or melanoma in situ without evidence
of disease
- Adequately treated cervical carcinoma in situ without evidence of disease
- Asymptomatic prostate cancer managed with "active surveillance"
- Localized prostate cancer treated with definitive treatment including radiation
or surgery. Patients on adjuvant hormone deprivation treatment such as lupron are
eligible. Patients with known metastatic disease are ineligible
- History of stroke or intracranial hemorrhage within 6 months prior to randomization
- Requires anticoagulation with warfarin or equivalent vitamin K antagonists (eg,
phenprocoumon)
- Vaccinated with live, attenuated vaccines within 4 weeks of randomization
- Requires treatment with strong cytochrome P450 3A (CYP3A) inhibitors
- Subjects who have had standard cytotoxic chemotherapy or radiotherapy within 3 weeks
prior to entering the study or those whose adverse events due to agents administered
more than 3 weeks earlier have not recovered to =< grade 1; this excludes alopecia and
hematologic adverse events
- Subjects who have had radiotherapy within 2 weeks prior to entering the study or those
whose adverse events due to radiotherapy more than 2 weeks earlier have not recovered
to =< grade 1
- Subjects who have received investigational or approved oral or "targeted" agents (such
as spleen tyrosine kinase [SYK], phosphatidylinositol 3 kinase [PI3K], B-cell chronic
lymphocytic leukemia [CLL]/lymphoma 2 [bcl-2], BTK inhibitors) or lenalidomide within
1 week prior to entering the study or those whose adverse events due to agents
administered more than 1 week earlier have not recovered to =< grade 1; this excludes
hematologic adverse events; the exception is subjects who are currently receiving
ibrutinib (for < 14 days). In this case, ibrutinib can be continued
- Subjects who have received monoclonal antibodies (such as Rituxan) within 1 week prior
to entering the study or those whose adverse events due to agents administered more
than 1 week earlier have not recovered to =< grade 1; this excludes hematologic
adverse events
- Subjects who are actively receiving any other investigational agents
- History of severe allergic reactions attributed to compounds of similar chemical or
biologic composition as obinutuzumab or ibrutinib or other agents used in the study
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements
- Pregnant or lactating women are excluded from this study
- Known history of human immunodeficiency virus (HIV) or active hepatitis C
- Virus or active hepatitis B virus infection; patients who are hepatitis B core
antibody (HBcAb) positive may be eligible as long as there is no evidence of active
infection with negative hepatitis B (Hep B) by polymerase chain reaction (PCR); in
this case, Hep B PCR must be monitored monthly
- Any uncontrolled active systemic infection requiring intravenous (IV) antibiotics
- 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, or put the study outcomes at undue
risk
- Patients previously treated with ibrutinib > 14 days are ineligible; no drug
intervention or cessation is required for patients already receiving ibrutinib prior
to initiation of on-study therapy
- Active graft versus (vs.) host disease (GVHD)
- Ongoing glucocorticoids (prednisone > 10 mg daily, or equivalent); higher doses (> 10
mg daily) are permitted for up to 5 days to help control disease related symptoms
