Alsertib (MLN8237) and Brentuximab Vedotin for Relapsed/Refractory CD30-Positive Lymphomas and Solid Malignancies

This is an investigator-initiated, open label phase I trial designed to evaluate the maximum
tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics, and activity of
brentuximab vedotin in combination with MLN8237 in patients with relapsed/refractory
CD30-positive lymphomas and solid malignancies.

Brentuximab vedotin at a fixed dose of 1.8 mg/kg will be administered on Day 1 every three
weeks as a 30-minute outpatient intravenous infusion. MLN8237 will be orally administered in
two divided doses from Days 1-7. The starting dose (level 0) of MLN8237 will be 60 mg daily
given in two divided doses (30 mg qAM, 30 mg qPM).The dose of MLN8237 will be escalated in
20-mg increments up to 100 mg daily and de-escalated in 20-mg decrements to 40 mg daily. The
fixed dose of brentuximab vedotin on Day 1 and daily dose of MLN8237 on Day 1-7 will
constitute one treatment cycle. If no DLTs are observed in the last study cohort, the cohort
will be expanded to include a total of 12 patients. If a de-escalation dose is required
because 2 or more patients experience DLTs, the next lower cohort will be studied. If 2 or
more patients do not experience DLTs, this dose will be declared the MTD. This cohort will be
expanded to include 12 patients in order to study the biological endpoints and clinical
benefit of the combination. If at any point during the expansion cohort phase of the trial
33% or more of the patients treated at the MTD/maximum administered dose experience a DLT,
accrual of additional patients at this does level will cease and the next lowest dose may be
explored.

Inclusion Criteria:

- Voluntary written informed consent before performance of any study-related procedure
not part of normal medical care, with the understanding that consent may be withdrawn
by the patient at any time without prejudice to future medical care;

- Relapsed or refractory CD30-positive lymphoma such as Hodgkin's and anaplastic large
cell lymphoma or CD30-positive cancer such as testicular embryonal carcinoma,
cutaneous angiosarcoma, and nasopharyngeal non-keratinizing carcinoma or any
CD30-positive solid tumor. CD30 positivity is defined as ≥ 25% CD30 expression by
immunohistochemistry. (CD30 analysis will be performed by an in-house CLIA and
CAP-accredited laboratory);

- Male or female patients aged ≥ 18 years;

- Adequate cardiac function (cardiac ejection fraction of ≥ 45%);

- Patients must have received at least two prior therapies for CD30-positive lymphoma or
solid malignancy;

- Absolute neutrophil count > 1500/mm³, platelets > 100,000/mm³, and hemoglobin > 8
g/dL. Values must be obtained without the need for myeloid growth factor or platelet
transfusion support within 14 days of the first dose of the study treatment; however,
erythrocyte growth factor is allowed as per the American Society of Clinical Oncology
guidelines;

- Total bilirubin ≤ 1.5 x upper limit of normal (ULN) and aspartate transaminase (AST)
and alanine transaminase (ALT) < 2.5 x ULN. AST and/or ALT may be up to 5 x ULN if
liver metastases are present;

- Adequate renal function as defined by a serum creatinine of < 2.0 mg/dL and calculated
creatinine clearance of ≥ 30 mL/minute;

- Eastern Cooperative Oncology Group performance status of 0 to 2;

- Female patients must be either:

- post-menopausal for at least one year before the screening visit, or

- surgically sterilized, or

- willing to use an acceptable method of birth control (i.e., hormonal
contraceptive, intrauterine device, diaphragm with spermicide, condom with
spermicide, or abstinence) for the duration of the study;

- Male patients, even if surgically sterilized (i.e., post-vasectomy status), must agree
to use an acceptable contraceptive method during the course of the study and for 4
months after the last dose of alisertib.

Exclusion Criteria:

- Radiation therapy to more than 25% of the bone marrow. Whole pelvic radiation is
considered to be over 25%;

- Prior allogeneic bone marrow or organ transplantation;

- Expected survival of less than 4 weeks;

- Known gastrointestinal (GI) disease or GI procedures that could interfere with the
oral absorption of or tolerance to alisertib. Examples include but are not limited to
partial gastrectomy, history of small intestine surgery, and celiac disease;

- Known history of uncontrolled sleep apnea syndrome and other conditions that could
result in excessive daytime sleepiness, such as severe chronic obstructive pulmonary
disease;

- Known cerebral or meningeal disease (Hodgkin's lymphoma or any other etiology),
including signs or symptoms of progressive multifocal leukoencephalopathy;

- Symptomatic neurologic disease that compromises normal activities of daily living or
requires medication;

- Requirement for constant or intermittent administration of a proton pump inhibitor, a
H2 antagonist, or pancreatic enzymes. Intermittent use of antacids or H2 antagonists
is allowed;

- Systemic infection requiring intravenous antibiotic therapy within 14 days preceding
the first dose of the study treatment or other severe viral or bacterial infection;

- Absolute QT interval of > 460 msec in the presence of > 4.0 mEq/L potassium and > 1.8
mg/dL magnesium;

- Myocardial infarction within 6 months prior to enrollment or has New York Heart
Association Class III or IV heart failure, uncontrolled angina, severe uncontrolled
ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active
conduction system abnormalities. Prior to study entry, any electrocardiogram
abnormality at screening has to be documented by the investigator as not medically
relevant;

- Female patient who is pregnant or breastfeeding. Confirmation that the subject is not
pregnant must be established by a negative serum beta human chorionic gonadotropin
pregnancy test result obtained during screening. Pregnancy testing is not required for
post-menopausal or surgically sterilized women;

- Patient has received other investigational drugs within 14 days of enrollment;

- Serious medical or psychiatric illness likely to interfere with participation in this
clinical study;

- Other severe acute or chronic medical or psychiatric condition, including uncontrolled
diabetes, malabsorption, resection of the pancreas or upper small bowel, requirement
for pancreatic enzymes, any condition that would modify small bowel absorption of oral
medications, or laboratory abnormality that may increase the risk associated with
study participation or investigational product administration or may interfere with
the interpretation of study results and, in the judgment of the investigator, would
make the patient inappropriate for enrollment in this study;

- Diagnosed or treated for another malignancy within 3 years of enrollment, with the
exception of complete resection of basal cell carcinoma or squamous cell carcinoma of
the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy;

- Treatment with clinically significant enzyme inducers, such as phenytoin,
carbamazepine, phenobarbital, rifampin, rifabutin, rifapentine, and St. John's wort,
within 14 days prior to the first dose of alisertib;

- Known history of human immunodeficiency virus, hepatitis B, or hepatitis C infection.
Testing is not required in the absence of clinical findings or suspicion;

- Prior administration of an Aurora A kinase-targeted agent, including alisertib;

- Prior administration of brentuximab vedotin is allowed only if the patient did not
experience disease progression while on treatment;

- Known hypersensitivity to recombinant proteins, murine proteins, or any excipient
contained in the drug formulation of brentuximab vedotin;

- Concurrent or recent (within 2 weeks) use of strong cytochrome P450 (CYP) 3A4
inhibitors such as ketoconazole, itraconazole, clarithromycin, atanazir, inddinavir,
nefazodone, neflinavir, ritonavir, saquinavir, telithromycin, and voriconazole;

- Concurrent or recent (within 2 weeks) use of potent CYP3A4 inducers such as
dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin,
phenobarbital, and St. John's wort;

- Concurrent or recent (within 2 weeks) use of a P-glycoprotein inhibitor such as
cyclosporine, ketoconazole, ritonavir, saquinavir, tacrolimus, or verapamil;

- Receipt of corticosteroids within 7 days prior to the first dose of the study
treatment, unless the patient has been taking a continuous dose of no more than 15
mg/day of prednisone for at least 1 month prior to the first dose of the study
treatment. Low-dose steroid use for the control of nausea and vomiting will be
allowed. Topical steroid use is permitted. Inhaled steroids are permitted;

- Inability to swallow oral medication or inability or unwillingness to comply with the
administration requirements related to alisertib;

- Administration of myeloid growth factors or platelet transfusion within 14 days prior
to the first dose of the study treatment.