PRIMARY OBJECTIVES:
I. To evaluate the complete remission rate of Bruton's tyrosine kinase (BTK) inhibitor
refractory mantle cell lymphoma (MCL) patients with ixazomib citrate (ixazomib) and rituximab
at 16 weeks of therapy.
SECONDARY OBJECTIVES:
I. To evaluate overall response rate (ORR) assessed by Lugano criteria. II. To evaluate
progression free survival (PFS) and overall survival (OS). III. To evaluate the safety and
tolerability.
TERTIARY/EXPLORATORY OBJECTIVES:
I. To evaluate biomarkers of response to treatment and mechanisms of resistance with
pretreatment and post-treatment bone marrow and blood samples with deoxyribonucleic acid
(DNA) and ribonucleic acid (RNA) sequencing and immune profiling by flow cytometry.
OUTLINE:
Patients receive ixazomib orally (PO) on days 1, 8, and 15. Treatment repeats every 28 days
for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients
also receive rituximab intravenously (IV) over 4-8 hours on days 1, 8, 15, and 22 of cycle 1.
Beginning in cycle 3, patients receive rituximab IV over 4-8 hours on day 1. Treatment
repeats every 28 days up to cycle 12 in the absence of disease progression or unacceptable
toxicity. Patients benefiting from treatment may continue to receive ixazomib indefinitely in
the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up periodically.
Inclusion Criteria:
- Patients must have histologically confirmed diagnosis of mantle cell lymphoma
- Patients must have measurable disease, as defined by at least one of the following:
- Lymph node or mass 2 cm or greater, splenomegaly > 13 cm
- Bone marrow only disease as per morphology or flow cytometry
- Patients must have relapsed and/or refractory disease to at least 2 lines of therapy
including either an anthracycline- or bendamustine- based regimen and a BTK inhibitor
- Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status
and/or other performance status 0, 1, or 2
- Absolute neutrophil count (ANC) >= 1,000/mm^3
- Platelets >= 50,000/mm^3
- Total bilirubin < 1.5 x institutional upper limit of normal (ULN). In patients with
documented Gilbert's syndrome, total bilirubin =< 2.5 x ULN
- Aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) and
alanine aminotransferase (ALT)/serum glutamic-pyruvic transaminase (SGPT) =< 3 x ULN
- Creatinine clearance >= 30 mL/min
- Patients must be willing to give written consent before performance of any study
related procedures not part of standard medical care, with the understanding that
consent may be withdrawn by the patient at any time without prejudice to future
medical care
- Female patients who:
- Are postmenopausal for at least 1 year before the screening visit, OR
- Are surgically sterile, OR
- If they are of childbearing potential, agree to practice 2 effective methods of
contraception, at the same time, from the time of signing the informed consent
form through 90 days after the last dose of study drug
- Male patients, even if surgically sterilized (i.e., status post-vasectomy), must agree
to one of the following:
- Agree to practice effective barrier contraception during the entire study
treatment period and through 90 days after the last dose of study drug
Exclusion Criteria:
- Female patients who are lactating or have a positive serum pregnancy test during the
screening period
- Failure to have fully recovered (i.e., =< grade 1 toxicity) from the reversible
effects of prior chemotherapy
- Major surgery within 14 days before enrollment
- Radiotherapy within 14 days before enrollment. If the involved field is small, 7 days
will be considered a sufficient interval between treatment and administration of the
ixazomib
- Central nervous system involvement
- Infection requiring systemic antibiotic therapy or other serious infection within 14
days before study enrollment. Patient may be eligible, if infectious disease
specialist approves start of therapy AND subject has completed course of antibiotic
therapy
- Evidence of current uncontrolled cardiovascular conditions, including uncontrolled
hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure,
unstable angina, or myocardial infarction within the past 6 months
- Systemic treatment, within 14 days before the first dose of ixazomib, with strong
CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin,
phenobarbital), or use of St. John's wort
- Ongoing or active systemic infection, active (deoxyribonucleic acid [DNA] polymerase
chain reaction [PCR] positivity) hepatitis B or C virus infection, or known human
immunodeficiency virus (HIV) positive
- Any serious medical or psychiatric illness that could, in the investigator's opinion,
potentially interfere with the completion of treatment according to this protocol
- Known allergy to any of the study medications, their analogues, or excipients in the
various formulations of any agent
- Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral
absorption or tolerance of ixazomib including difficulty swallowing
- Diagnosed or treated for another malignancy within 2 years before study enrollment or
previously diagnosed with another malignancy and have any evidence of residual
disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are
not excluded if they have undergone complete resection
- Patient has >= grade 3 peripheral neuropathy, or grade 2 with pain on clinical
examination during the screening period
- Participation in other clinical trials, including those with other investigational
agents not included in this trial, within 30 days of the start of this trial and
throughout the duration of this trial
- Patients that have previously been treated with proteasome inhibitors, or participated
in a study with proteasome inhibitors whether treated with proteasome inhibitors or
not
