Studying TAK-243 in Patients With Advanced Cancer

Inclusion Criteria:

• Patients with histologically documented advanced or metastatic solid tumors withrelapsed or refractory disease who have received standard-of-care or approvedtherapies known to confer clinical benefit, or patients with aggressive lymphomaswho have received ≥ 2 prior lines of lymphoma-directed therapy and who do not haveremaining effective treatment options (including transplant). Additionally, patientswith indolent lymphomas must meet criteria for treatment.

• Patients must have measurable or evaluable disease

• Age >= 18 years

• Eastern Cooperative Oncology Group (ECOG) performance status =< 2

• Hemoglobin >= 9 g/dL (patients may be transfused to achieve this value; elevatedindirect bilirubin due to post-transfusion hemolysis is allowed)

• Absolute neutrophil count >= 1,000/mcL

• Platelets >= 75,000/mcL

• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 3 x institutional ULN OR =< 5 x institutional upper limit of normal for patientswith liver metastases at baseline

• Creatinine =< 1.5 x institutional ULN OR creatinine clearance >= 60 mL/min/1.73 m^2by Cockcroft-Gault

• Any prior therapy must have been completed >= 4 weeks, or >= 5 half-lives of theprior agent (whichever is shorter) prior to enrollment on protocol. Prior definitiveradiation should have been completed >= 4 weeks prior to enrollment; priorpalliative radiation should have been completed >= 2 weeks prior to enrollment.Patients must be >= 2 weeks since any investigational agent administered as part ofa Phase 0 study (where a sub-therapeutic dose of drug is administered) and shouldhave recovered to grade 1 or baseline from any toxicities

• Female patients who:

• Are postmenopausal (age-related amenorrhea >= 12 consecutive months orfollicle-stimulating hormone > 40 mIU/mL), for at least 1 year before thescreening visit, OR

• Are surgically sterile (i.e., who had undergone hysterectomy or bilateraloophorectomy), OR

If they are of childbearing potential:

• Agree to practice 1 highly effective method and 1 additional effective (barrier)method of contraception, at the same time, from the time of signing the informedconsent through 4 months after the last dose of study drug (female and male condomsshould not be used together), or

• Agree to practice true abstinence, when this is in line with the preferred and usuallifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation,symptothermal, postovulation methods] withdrawal, spermicides only, and lactationalamenorrhea are not acceptable methods of contraception.)

• Male patients, even if surgically sterilized (i.e., status postvasectomy), who:

• Agree to practice effective barrier contraception during the entire study treatmentperiod and through 4 months after the last dose of study drug (female and malecondoms should not be used together), or

• Agree to practice true abstinence, when this is in line with the preferred and usuallifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation,symptothermal, postovulation methods for the female partner] withdrawal, spermicidesonly, and lactational amenorrhea are not acceptable methods of contraception.)

• The effects of TAK-243 on the developing human fetus are unknown. For thisreason and because ubiquitin-activating enzyme inhibitors are known to beteratogenic, women of child-bearing potential and men must agree to useadequate contraception (hormonal or barrier method of birth control;abstinence) prior to study entry and for the duration of study participation.Should a woman become pregnant or suspect she is pregnant while she or herpartner is participating in this study, she should inform her treatingphysician immediately. Men treated or enrolled on this protocol must also agreeto use adequate contraception prior to the study, for the duration of studyparticipation, and 4 months after completion of TAK-243 administration

• Ability to understand and the willingness to sign a written informed consentdocument

• Willingness to provide blood for research purposes

• For expansion phase patients, willingness to undergo 2 core needle biopsyprocedures for research purposes if there is a lesion or lesions amenable torepeat biopsy

• Patients on anticoagulation therapy are eligible for this study in the absenceof anticipated drug-drug interactions (DDI) between the anticoagulation agentand TAK-243. If DDI are anticipated and another anticoagulation agent that iscompatible with TAK-243 exists, the patient will be transitioned to thisalternative, TAK-243-compatible anticoagulation agent

Exclusion Criteria:

• Patients who are receiving any other investigational agents

• Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection or psychiatric illness/social situations that would limit compliance withstudy requirements

• Life-threatening illness unrelated to cancer

• Patients with uncontrolled coagulopathy or bleeding disorder

• Known hepatic cirrhosis or severe pre-existing hepatic impairment

• Known cardiopulmonary disease defined as:

• Unstable angina pectoris;

• Congestive heart failure (New York Heart Association [NYHA] class III or IV);

• Myocardial infarction (MI) within 6 months prior to first dose (patients whohad ischemic heart disease such as a [acute coronary syndrome (ACS)], MI,and/or revascularization greater than 6 months before screening and who arewithout cardiac symptoms may enroll);

• Cardiomyopathy

• Clinically significant arrhythmia:

• History of polymorphic ventricular fibrillation or torsade de pointes,

• Permanent atrial fibrillation (a fib), defined as continuous a fib for >= 6months,

• Persistent a fib, defined as sustained a fib lasting > 7 days and/or requiringcardioversion in the 4 weeks before screening,

• Grade 3 a fib defined as symptomatic and incompletely controlled medically, orcontrolled with device (e.g., pacemaker) or ablation, and

• Patients with paroxysmal a fib or < grade 3 a fib for period of at least 6months are permitted to enroll provided that their rate is controlled on astable regimen

• Prolonged rate corrected QT (QTc) interval >= 470 m/sec, calculated according toinstitutional guidelines

• Uncontrolled high blood pressure (i.e., systolic blood pressure > 180 mm Hg,diastolic blood pressure > 95 mm Hg)

• Known moderate to severe chronic obstructive pulmonary disease, interstitial lungdisease, and pulmonary fibrosis

• Major surgery within 14 days before the first dose of any study drug

• Female patients who intend to donate eggs (ova) during the course of this study or 4months after receiving their last dose of study drug(s)

• Male patients who intend to donate sperm during the course of this study or 4 monthsafter receiving their last dose of study drug(s)

• Patients with known brain metastases or carcinomatous meningitis are excluded fromthis clinical trial, with the exception of patients whose brain metastatic diseasestatus has remained stable for >= 1 month after treatment of the brain metastases.Patients on anti-seizure medications may be enrolled at the discretion of theprincipal investigator

• TAK-243 is primarily metabolized by CYP3A4/5. Therefore, the concomitant use ofstrong inhibitors of CYP3A4/5 (e.g., ketoconazole, itraconazole, clarithromycin,ritonavir, indinavir, nelfinavir and saquinavir) and strong inducers of CYP3A4/5 (e.g. rifampin, phenytoin, carbamazepine, phenobarbital, St. John's Wort) is notpermitted from 14 days prior to enrollment until the end of the study

• TAK-243 is a substrate for both organic anion transporting polypeptides (OATP)in human hepatocytes and the drug efflux transporter BCRP (ABCG2). Therefore,concomitant use of drugs that are strong inhibitors of BCRP or OATP is notpermitted from 14 days prior to enrollment until the end of the study

• Other medications that are prohibited while on TAK-243 treatment include herbalmedications/preparations (except for vitamins). Because the lists of theseagents are constantly changing, it is important to regularly consult afrequently-updated medical reference for a list of drugs to avoid or minimizeuse of

• As part of the enrollment/informed consent procedures, the patient will becounseled on the risk of interactions with other agents, and what to do if newmedications need to be prescribed or if the patient is considering a newover-the-counter medicine or herbal product

• Patients undergoing vaccination with live vaccines and live attenuated vaccines inthe 30 days prior to receiving TAK-243, during the study, and for 100 days after thelast dose of study drug. Inactivated vaccines are permitted

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to TAK-243

• Patients with evidence of chronic hepatitis B virus (HBV) infection who arecurrently on treatment are eligible if they have an undetectable HBV viral load

• Patients with a history of hepatitis C virus (HCV) infection must have been treatedand cured. For patients with HCV infection who are currently on treatment, they areeligible if they have an undetectable HCV viral load

• Known human immunodeficiency virus (HIV)-positive patients who meet the followingcriteria will be considered eligible:

• CD4 count > 350 cells/mm^3

• Undetectable viral load for 6 months prior to enrollment

• Maintained on modern therapeutic regimens utilizing non-CYP-interactive agents

• No history of acquired immunodeficiency syndrome (AIDS)-defining opportunisticinfections

• Pregnant and lactating/breast-feeding women are excluded from this study becauseTAK-243 is a UAE-inhibiting agent with the potential for teratogenic orabortifacient effects and there is an unknown but potential risk for adverse eventsin nursing infants secondary to treatment of the mother with TAK-243