A Study of Ixazomib and Ibrutinib in Relapsed/Refractory Mantle Cell Lymphoma

MCL is a rare subtype of non-Hodgkin lymphoma that is considered incurable with conventional
therapy. For relapsed patients, Ibrutinib, lenalidomide, and bortezomib are all approved by
the FDA but are not curative. Novel approaches are required to improve outcomes for patients
with relapsed/refractory MCL.

This is an open-label study that will be done in 2 phases. Phase I will test different doses
of ixazomib and ibrutinib to determine the maximum safe and tolerated dose. In Phase I,
patients who have already received ibrutinib, may participate if they meet certain criteria
(i.e., have not received ibrutinib for at least 3 months).

Phase II will find out the effects, good and/or bad, of ixazomib in combination with
ibrutinib. In Phase II, patients will be separated into 2 groups, patients who have never
received ibrutinib and patients who have received ibrutinib. This study is designed to
examine the effectiveness of this drug in treating patients with MCL.

Patients will be treated until progression or unacceptable toxicity.

Tumor assessments will be performed approximately every 3 months for the first year of
treatment, then every 6 months until progression.

Mandatory bone marrow and tumor tissue samples (i.e., obtained during a previous procedure or
biopsy) are required at baseline. Mandatory research blood samples will also be collected.

- Relapsed or refractory, pathologically proven mantle cell lymphoma. Must have a
current or prior tissue sample that is IHC positive for cyclin D 1 or that is positive
by FISH or cytogenetics for t(11;14).

- Must have been refractory to and/or relapsed/progressed after at least 1 prior
therapy.

- Prior autologous or allogeneic transplant are allowed. Patients may not have active
grade II-IV acute graft-versus-host disease (GVHD) or moderate/severe chronic GVHD by
NIH criteria and may not require immunosuppressive medications and/or corticosteroids
for the management of acute or chronic GVHD.

- Phase I: Prior proteasome inhibitor and/or Bruton's tyrosine kinase (BTK) inhibitors
are allowed but patients may not have been exposed to the combination of proteasome
inhibitor and BTK inhibitor. Patients who have progressed on ibrutinib that are felt
to be at high risk for rapid progression on this study shall not be eligible for the
phase I portion of the study. NOTE: Ibrutinib pre-treated patients must meet all
eligibility criteria AND must have discontinued prior ibrutinib at least 3 months
prior to starting study therapy.

- Phase II: Prior proteasome inhibitor and/or Bruton's tyrosine kinase inhibitors are
allowed but patients may not have been exposed to the combination of proteasome
inhibitor and BTK inhibitor. NOTE: Patients must have tolerated prior ibrutinib (i.e.,
not discontinued therapy due to toxicity).

- Age ≥ 18 years.

- Eastern Oncology Oncology Group (ECOG) performance status of 0-2.

- Ability to understand and willingness to sign Institutional Review Board
(IRB)-approved informed consent.

- Willing to provide archived tumor tissue and blood samples for research.

- Adequate organ function as measured by the following criteria

- Absolute Neutrophil Count (ANC) ≥ 750/mm³

- Platelets ˃50,000/mm³

- Serum Creatinine ≤ 2x Upper Limit Normal (ULN)

- ALT and AST ≤ 3x ULN

- Total Bilirubin ≤ 1.5x ULN

- Patients must not have received systemic treatment for MCL for at least 14 days prior
to enrollment, except for steroids which may be used to manage acute symptoms related
to disease up to 48 hours prior to starting study therapy. Radiation therapy must be
concluded at least 14 days prior to enrollment.

- Women must not be pregnant or breastfeeding since we do not know the effects of
ixazomib and ibrutinib on the fetus or breastfeeding child. All sexually active
females of childbearing potential must have a blood test to rule out pregnancy within
2 weeks prior to registration.

- Sexually active women of child-bearing potential with a non-sterilized male partner
and sexually active men must agree to use 2 methods of adequate contraception
(hormonal plus barrier or 2 barrier forms) OR abstinence prior to study entry, for the
duration of study participation, and for 3 months following last dose of study drugs.

- Patients must have resolved all prior non-hematologic toxicities assessed as related
to prior therapy to ≤ grade 1.

- Patients must have measurable disease (i.e., ≥ 1.5 cm in largest diameter) by
conventional imaging modalities. Patients with spleen or extranodal involvement as the
only measurable site of disease must have a discrete splenic lesion ≥ 1.5 cm in
largest diameter.

- Patients may not have current/active Central Nervous System (CNS) involvement with
mantle cell lymphoma (patients with prior CNS involvement are eligible as long as they
have had no evidence of active CNS disease for at least 6 months).

- Patients may not have another malignancy that could interfere with the evaluation of
safety or efficacy of this combination. Patients with a prior malignancy will be
allowed without study chair approval in the following circumstances:

- Not currently active and diagnosed at least 3 years prior to the date of
enrollment.

- Non-invasive diseases such as low risk cervical cancer or any cancer in situ

- Localized disease in which chemotherapy would not be indicated (such as Stage I
colon, lung, prostate or breast cancer). Patients with other malignancies not
meeting these criteria must be discussed with PrECOG prior to enrollment.

- Patients requiring long-term anticoagulation must be managed on an anticoagulant
besides warfarin. Patients who require warfarin are not eligible.

- Patients with a clinically significant bleeding episode as judged by the investigator
within 3 months of registration are not eligible, except patients who suffer bleeding
due to trauma.

- Patients may not have had major surgery within 14 days, or minor surgery within 3
days, before registration.

- Patients may not have any active infection requiring oral or intravenous antimicrobial
therapy at the time of therapy initiation. Patients with a recent self-limited
infection that has clinically resolved may complete a prescribed course of
antimicrobial therapy after study initiation as long as they are asymptomatic with no
clinical evidence of infection for at least 7 days prior to treatment. Patients with a
recent serious (grade ≥ 3) infection requiring hospitalization must have completed all
antimicrobial therapy within 14 days of therapy initiation.

- Patients may not have evidence of uncontrolled cardiovascular conditions, including
uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive
heart failure (New York Heart Association (NYHA) class III or higher, unstable angina,
or myocardial infarction within the past 6 months. Patients with a history of any
significant cardiovascular disease that has been controlled for at least 14 days
before registration are allowed (except for patients who have had a myocardial
infarction within 6 months).

- No systemic treatment, within 14 days before the first dose of ibrutinib with moderate
or strong inhibitors of CYP3A (Strong Inhibitors: ketoconazole, itraconazole,
voriconazole, posaconazole, clarithromycin, and telithromycin; Moderate Inhibitors:
fluconazole, darunavir, erythromycin, diltiazem, atazanavir, aprepitant, amprenavir,
fosamprenavir, crizotinib, imatinib, verapamil, ciprofloxacin, grapefruit juice
products, and Seville oranges) or strong CYP3A inducers for ibrutinib and ixazomib
(carbamazepine, rifampin, phenytoin, St. John's wort).

- Patients with ongoing or active systemic infection, active hepatitis B or C virus
infection, or known Human Immunodeficiency Virus (HIV) positive are not eligible.
Testing is not required in absence of clinical suspicion.

- Patients with a history of hepatitis B or C must have a negative peripheral blood
Polymerase Chain Reaction (PCR) and may not be positive for Hepatitis B surface
antigen. Patients with cirrhosis or other evidence of liver damage due to Hepatitis B
or C are not eligible.

- Patients with any serious medical or psychiatric illness that could, in the
investigator's opinion, potentially interfere with the completion of the treatment
according to the protocol are not eligible.

- Patients with a known allergy to any of the study medications, their analogues, or
excipients in the various formulations of any agent are not eligible.

- Patients with known gastrointestinal (GI) disease or prior GI procedure that could
interfere with the oral absorption or tolerance of ixazomib or ibrutinib including
difficulty swallowing are not eligible.

- Patients with ≥ Grade 2 peripheral neuropathy, or Grade 1 peripheral neuropathy with
pain on clinical examination during the screening period are not eligible.

- Patients may not participate in any other therapeutic clinical trials, including those
with other investigational agents not included in this trial throughout the duration
of this study.

- As ibrutinib will not be provided by the study, the patient must be able to obtain
ibrutinib through other means (i.e., commercially or through patient assistance
programs). This must be confirmed prior to registration.