Ibrutinib and Palbociclib in Treating Patients With Previously Treated Mantle Cell Lymphoma
Ibrutinib and Palbociclib in Treating Patients With Previously Treated Mantle Cell Lymphoma
This phase I trial studies the side effects and best dose of ibrutinib and palbociclib in
 treating patients with previously treated mantle cell lymphoma. Ibrutinib and palbociclib may
 stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.
 Palbociclib may also help ibrutinib work better by making cancer cells more sensitive to the
 drug.
PRIMARY OBJECTIVE:

 I. To evaluate the safety of ibrutinib plus PD 0332991 (palbociclib) in patients with
 previously treated mantle cell lymphoma (MCL) and select the recommended phase 2 dose
 schedule.

 SECONDARY OBJECTIVES:

 I. To estimate the toxicity profile of ibrutinib plus PD 0332991 (palbociclib). II. To
 estimate the overall response rate (ORR) and complete response (CR) rates.

 III. To estimate the progression-free survival (PFS). IV. To estimate the response duration
 (RD).

 LABORATORY OBJECTIVES:

 I. To evaluate the genomic profile of MCL cells pre-treatment and at relapse. II. To estimate
 the pharmacokinetic profile of ibrutinib when given concurrently with PD 0332991
 (palbociclib).

 III. To evaluate the level of cell-free tumor deoxyribonucleic acid (DNA) over time in
 conjunction with response to therapy.

 IV. To evaluate the presence of circulating MCL cells over time.

 OUTLINE: This is a dose-escalation study.

 Patients receive ibrutinib orally (PO) once daily (QD) on days 1-28 and palbociclib PO QD on
 days 1-21. Cycles repeat every 28 days in the absence of disease progression or unacceptable
 toxicity.

 After completion of study treatment, patients are followed up for 2 years.
Inclusion Criteria:

 -  Patients must have histologically or cytologically confirmed mantle cell lymphoma as
 defined by the World Health Organization; all patients must have either t(11;14) by
 karyotype or fluorescent in-situ hybridization (FISH) or positive immunohistochemistry
 for cyclin D1

 -  Subjects must have measurable disease defined as at least one tumor lesion of at least
 1.5 cm or a peripheral blood cluster of differentiation (CD)5+, CD19+ lymphocyte count
 of at least 5,000 cells/uL

 -  Subjects must have received at least one prior treatment regimen

 -  Subjects that have received a prior Bruton's agammaglobulinemia tyrosine kinase
 (BTK) inhibitor or cyclin-dependent kinases 4 and 6 (CDK4/6) inhibition are
 ineligible

 -  Subjects that have undergone prior allogeneic stem cell transplantation will only
 be eligible if the transplant occurred at least 1 year prior to study entry, the
 patient is no longer taking any immunosuppressive therapy, and there are no
 significant ongoing transplant-related adverse effects

 -  Subjects must not have received chemotherapy =< 21 days prior to first
 administration of study treatment, monoclonal antibody =< 6 weeks prior to first
 administration of study treatment, and/or radiotherapy or other investigational
 agents =< 4 weeks prior to first administration study treatment unless the
 subjects' tumor has progressed on the previous therapy and the investigator
 believes that the patient should not postpone further therapy and, all
 treatment-related toxicities have resolved to Common Terminology Criteria for
 Adverse Events (CTCAE) version (v) 5 =< grade 1; subjects may be receiving
 equivalent to prednisone at a maximum dose of 20 mg/day orally

 -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

 -  Patients must have normal organ and marrow function, independent of transfusion or
 growth factor support within 14 days before enrollment; patients should not receive
 growth factors or transfusions for at least 7 days prior to the first dose of study
 drug, with the exception of pegylated GCSF (pegfilgrastim) and darbepoetin, which
 require at least 14 days prior to screening and enrollment

 -  Absolute neutrophil count (ANC) >= 750 cells/uL (within 14 days before enrollment)

 -  Platelets >= 50,000 cells/uL (within 14 days before enrollment)

 -  Total bilirubin =< 1.5 times upper limit of normal unless due to Gilbert's disease
 (within 14 days before enrollment)

 -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
 [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
 =< 2.5 times upper limit of normal (within 14 days before enrollment)

 -  Calculated creatinine clearance >= 30 mL/min by Cockcroft-Gault (within 14 days before
 enrollment)

 -  Corrected QT interval (QTc) =< 480 ms (within 14 days before enrollment)

 -  Prothrombin time (PT)/international normalized ratio (INR) < 1.5 times upper limit of
 normal (within 14 days before enrollment)

 -  Partial thromboplastin time (PTT) < 1.5 times upper limit of normal (within 14 days
 before enrollment)

 -  The effects of ibrutinib and PD 0332991 (palbociclib) on the developing human fetus
 are unknown; for this reason and because tyrosine kinase inhibitors as well as other
 therapeutic agents used in this trial may be teratogenic, women of child-bearing
 potential and men must agree to use adequate contraception (hormonal or barrier method
 of birth control; abstinence) prior to study entry and for the duration of study
 participation; female patients who are of non-reproductive potential include the
 following: post-menopausal by history - no menses for >= 1 year; OR history of
 hysterectomy; OR history of bilateral tubal ligation; OR history of bilateral
 oophorectomy); female patients of childbearing potential must have a negative serum
 pregnancy test upon study entry; male and female patients who agree to use highly
 effective methods of birth control (e.g., condoms, implants, injectables, combined
 oral contraceptives, some intrauterine devices [IUDs], complete sexual abstinence, or
 sterilized partner) during the period of therapy and for 90 days after the last dose
 of study drug

 -  Should a woman become pregnant or suspect she is pregnant while she or her partner is
 participating in this study, she should inform her treating physician immediately; men
 treated or enrolled on this protocol must also agree to use adequate contraception
 prior to the study, for the duration of study participation, and 4 months after
 completion of ibrutinib administration; subjects should be offered the opportunity to
 bank sperm or eggs prior to initiation of study drug

 -  Subjects that have undergone major surgery within 4 weeks prior to the first dose of
 study drug are not eligible

 -  Subjects with currently active, clinically significant hepatic impairment (> moderate
 hepatic impairment according to the National Cancer Institute (NCI)/Child Pugh
 classification)

 -  Subjects requiring daily corticosteroids at a prednisone equivalent of > 20 mg daily
 should not be enrolled; if corticosteroids can be discontinued (or reduced to < 20 mg
 per day or prednisone equivalent), the discontinuation or dose reduction should be
 done at least 7 days prior to the first dose

 -  Subjects should be willing to undergo a research related biopsy prior to treatment and
 at the time of progression

 -  Subjects must give informed consent and must be willing and able to comply with the
 scheduled visits, treatment plans, laboratory tests, and other procedures

 Exclusion Criteria:

 -  Subjects with known or suspected central nervous system (CNS) involvement are not
 eligible

 -  Subjects with serologic status reflecting active viral hepatitis B or C infection are
 not eligible; subjects that are positive for hepatitis B core antibody positive
 hepatitis B surface antigen (HBsAg), or hepatitis C antibody must have a negative
 polymerase chain reaction (PCR) prior to enrollment. (PCR-positive patients will be
 excluded.)

 -  Subjects with uncontrolled human immunodeficiency virus (HIV) are not eligible;
 controlled HIV is defined as a CD4 count > institutional lower limit of normal and no
 current co-infection; uncontrolled HIV is all other HIV infection; note that patients
 with controlled infection should be allowed to participate only if they are not
 receiving prohibited cytochrome P450 (CYP) interactive medications

 -  Subjects unable to swallow capsules or with disease significantly affecting
 gastrointestinal function and/or inhibiting small intestine absorption, such as
 malabsorption syndrome, resection of the stomach or small bowel, partial or complete
 bowel obstruction, or symptomatic inflammatory bowel disease are not eligible

 -  Subjects with uncontrolled 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 are not eligible; recent infections requiring systemic treatment
 need to have completed therapy > 14 days before the first dose of the study drugs

 -  Subjects with uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic
 purpura (ITP) resulting in declining platelet or hemoglobin levels within the 4 weeks
 prior to first dose of study drug are not eligible

 -  Patients with transfusion-dependent thrombocytopenia are not eligible

 -  Subjects with acute coronary syndrome within 6 months prior to enrollment or has New
 York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina,
 severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute
 ischemia or active conduction system abnormalities are not eligible; prior to study
 entry, any electrocardiogram (ECG) abnormality at screening has to be documented by
 the investigator as not medically relevant

 -  Subjects with a history of stroke or intracranial hemorrhage within 6 months prior to
 enrollment are not eligible

 -  Subjects with a history of malignancy are not eligible with the exception of the
 following:

 -  Malignancy treated within curative intent and with no evidence of active disease
 present for more than 3 years prior to screening and felt to be at low risk for
 recurrence by treating physician

 -  Adequately treated non-melanomatous skin cancer or lentigo maligna melanoma
 without current evidence of disease

 -  Adequately treated cervical carcinoma in situ without current evidence of disease

 -  Female subjects that are pregnant or breastfeeding are not eligible

 -  Subjects that have received anticoagulation therapy with warfarin or equivalent
 vitamin K antagonists within the last 28 days are not eligible

 -  Subjects with a bleeding diathesis (e.g., von Willebrand's disease or hemophilia) are
 not eligible

 -  Subjects receiving other investigational agents are not eligible

 -  Subjects who received a strong cytochrome P450 family 3 subfamily A (CYP3A) inhibitor
 within 7 days prior to the first dose of study drug, or patients who require
 continuous treatment with a strong CYP3A inhibitor are not eligible

 -  Subjects receiving systemic immunosuppressant therapy (e.g., cyclosporine, tacrolimus,
 etc.) within 28 days of the first dose of study drug are not eligible

 -  Subjects that have been vaccinated with live, attenuated vaccines within 4 weeks of
 the first dose of study drug are not eligible