| Eligibility |
Inclusion Criteria:
- Patients with histologically documented advanced or metastatic solid tumors which have
progressed after at least one line of therapy (or, if no standard therapy exists,
patients with histologically documented metastatic solid tumors who have not undergone
prior treatment), or patients with lymphoma who have refused or do not have remaining
curative options (e.g., transplant). Patients with indolent lymphomas who have options
for effective therapy likely to induce remission lasting 1 year or longer are not
eligible for this study
- 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; elevated
indirect 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 patients with
liver metastases at baseline
- Creatinine =< 1.5 x institutional ULN OR creatinine clearance >= 60 mL/min/1.73 m^2 by
Cockcroft-Gault
- Any prior therapy must have been completed >= 4 weeks, or >= 5 half-lives of the prior
agent (whichever is shorter) prior to enrollment on protocol. Prior definitive
radiation should have been completed >= 4 weeks prior to enrollment. Patients must be
>= 2 weeks since any investigational agent administered as part of a Phase 0 study
(where a sub-therapeutic dose of drug is administered) and should have recovered to
grade 1 or baseline from any toxicities
- Female patients who:
- Are postmenopausal (age-related amenorrhea >= 12 consecutive months or
follicle-stimulating hormone > 40 mIU/mL), for at least 1 year before the
screening visit, OR
- Are surgically sterile (i.e., who had undergone hysterectomy or bilateral
oophorectomy), 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 informed
consent through 4 months after the last dose of study drug (female and male condoms
should not be used together), or
- Agree to practice true abstinence, when this is in line with the preferred and usual
lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation,
symptothermal, postovulation methods] withdrawal, spermicides only, and lactational
amenorrhea 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 treatment
period and through 4 months after the last dose of study drug (female and male condoms
should not be used together), or
- Agree to practice true abstinence, when this is in line with the preferred and usual
lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation,
symptothermal, postovulation methods for the female partner] withdrawal, spermicides
only, and lactational amenorrhea are not acceptable methods of contraception.)
- The effects of TAK-243 on the developing human fetus are unknown. For this reason
and because ubiquitin-activating enzyme inhibitors are known to 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. 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 TAK-243
administration
- Ability to understand and the willingness to sign a written informed consent
document
- Willingness to provide blood for research purpose
- For expansion phase patients, willingness to undergo 2 core needle biopsy
procedures for research purposes if there is a lesion or lesions amenable to
repeat biopsy
- Left ventricular ejection fraction >= 50% or >= institutional lower limit of
normal by echocardiogram (ECHO)
- Patients on anticoagulation therapy are eligible for this study in the absence of
anticipated drug-drug interactions (DDI) between the anticoagulation agent and
TAK-243. If DDI are anticipated and another anticoagulation agent that is
compatible with TAK-243 exists, the patient will be transitioned to this
alternative, 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 active
infection or psychiatric illness/social situations that would limit compliance with
study 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 who had
ischemic heart disease such as a [acute coronary syndrome (ACS)], MI, and/or
revascularization greater than 6 months before screening and who are without
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 >= 6
months,
- Persistent a fib, defined as sustained a fib lasting > 7 days and/or requiring
cardioversion in the 4 weeks before screening,
- Grade 3 a fib defined as symptomatic and incompletely controlled medically, or
controlled with device (e.g., pacemaker) or ablation, and
- Patients with paroxysmal a fib or < grade 3 a fib for period of at least 6 months
are permitted to enroll provided that their rate is controlled on a stable
regimen
- Prolonged rate corrected QT (QTc) interval >= 500 m/sec, calculated according to
institutional 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 lung
disease, 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 4
months after receiving their last dose of study drug(s)
- Male patients who intend to donate sperm during the course of this study or 4 months
after receiving their last dose of study drug(s)
- Patients with known brain metastases or carcinomatous meningitis are excluded from
this clinical trial, with the exception of patients whose brain metastatic disease
status has remained stable for >= 1 month after treatment of the brain metastases.
Patients on anti-seizure medications may be enrolled at the discretion of the
principal investigator
- TAK-243 is primarily metabolized by CYP3A4/5. Therefore, the concomitant use of strong
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 not permitted 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 not
permitted from 14 days prior to enrollment until the end of the study
- Other medications that are prohibited while on TAK-243 treatment include herbal
medications/preparations (except for vitamins). Because the lists of these agents
are constantly changing, it is important to regularly consult a
frequently-updated medical reference for a list of drugs to avoid or minimize use
of
- As part of the enrollment/informed consent procedures, the patient will be
counseled on the risk of interactions with other agents, and what to do if new
medications need to be prescribed or if the patient is considering a new
over-the-counter medicine or herbal product
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to TAK-243
- Patients with evidence of chronic hepatitis B virus (HBV) infection who are currently
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 treated
and cured. For patients with HCV infection who are currently on treatment, they are
eligible if they have an undetectable HCV viral load
- Known human immunodeficiency virus (HIV)-positive patients who meet the following
criteria 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 opportunistic
infections
- Pregnant and lactating/breast-feeding women are excluded from this study because
TAK-243 is a UAE-inhibiting agent with the potential for teratogenic or abortifacient
effects and there is an unknown but potential risk for adverse events in nursing
infants secondary to treatment of the mother with TAK-243
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