A Study of Ixazomib and Ibrutinib in Relapsed/Refractory Mantle Cell Lymphoma
A Study of Ixazomib and Ibrutinib in Relapsed/Refractory Mantle Cell Lymphoma
Patients with mantle cell lymphoma (MCL) that has relapsed (come back) or refractory
 (progressed on treatment) will receive ixazomib and ibrutinib.

 Ibrutinib has been approved by the Food and Drug Administration (FDA) as treatment for
 patients with mantle cell lymphoma who have received at least one prior therapy.

 Ixazomib is in a class of medications called proteasome inhibitors. Cancer cells depend on
 proteasome to provide this protein metabolism (turnover) function to regulate their growth
 and survival. Ixazomib disrupts a cancer cells' ability to survive by blocking the proteasome
 and disrupting protein metabolism. This may help to slow down the growth of cancer or may
 cause cancer cells to die.

 The purpose of this study is to see whether the addition of ixazomib to ibrutinib
 chemotherapy is effective in treating people who have relapsed or refractory MCL and to
 examine the side effects associated with ixazomib in combination with ibrutinib.
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 I was completed November 25, 2019. Dose Level 2 (Ixazomib 4 mg and Ibrutinib 560 mg) is
 the recommended Phase II dose.

 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 a Bruton's Tyrosine Kinase (BTK) inhibitor and patients who have received a BTK
 inhibitor. 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.

 8/7/2020: Enrollment stopped to patients who have already received a BTK inhibitor. Total of
 two patients enrolled.
-  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 I COMPLETED NOVEMBER 25, 2019.

 -  Phase II: Prior proteasome inhibitors allowed. (Please note prior to Version 3.0 of
 the protocol prior proteasome inhibitor and/or Bruton's tyrosine kinase inhibitors
 were allowed but patients could not have been exposed to the combination of proteasome
 inhibitor and BTK inhibitor).

 -  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, bone marrow (if sufficient bone marrow and
 tumor tissue are available) 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 extranodal involvement as the only
 measurable site of disease must have a largest diameter ≥ 1.0 cm and must be
 attributable to active lymphoma in the opinion of the investigator.

 -  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.