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About
This phase I trial studies the side effects and best dose of ubiquitin-activating enzyme (UAE) inhibitor TAK-243 (TAK-243) in treating patients with a solid tumor that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced) or that has spread from where it first started (primary site) to other places in the body (metastatic) and in patients with lymphoma. TAK-243 is a drug that binds to and inhibits the ubiquitin-activating enzyme, an enzyme that is more active on cancer cells than healthy cells, inhibiting tumor cell proliferation and survival.
Full description
PRIMARY OBJECTIVE:
I. To establish the safety, tolerability, and the recommended phase II dose of UAE inhibitor TAK-243 (TAK-243) administered twice-weekly or once-weekly in patients with advanced solid tumors and lymphomas.
SECONDARY OBJECTIVES:
I. To evaluate the pharmacokinetic (PK) profiles of TAK-243 administered on twice-weekly and once-weekly schedules in patients with advanced solid tumors and lymphomas.
II. To determine the effects of TAK-243 on levels of K48-linked ubiquitination in pre- and post-treatment tumor biopsies.
III. To observe and record anti-tumor activity.
EXPLORATORY OBJECTIVES:
I. To determine the effects of TAK-243 on the endoplasmic reticulum (ER) stress marker CHOP, Mcl-1-Noxa heterodimer formation, and the apoptosis marker cleaved caspase-3 in pre- and post-treatment tumor biopsies II. To evaluate potential associations between TAK-243 activity and tumor genomic alterations or ribonucleic acid (RNA) expression profiles.
III. To preliminarily assess progression-free survival (PFS) and overall survival (OS) for TAK-243 monotherapy in patients with advanced solid tumors and lymphomas.
OUTLINE: This is a dose-escalation study of TAK-243 followed by a dose-expansion study. Patients are assigned to 1 of 2 arms.
ARM A: Patients receive UAE inhibitor TAK-243 intravenously (IV) on days 1, 4, 8, and 11 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo biopsy on study, and undergo computed tomography (CT), magnetic resonance imaging (MRI), and collection of blood throughout the study, and may undergo echocardiograms (ECHO) as clinically indicated on study.
ARM B: Patients receive UAE inhibitor TAK-243 IV once weekly (QW) on days 1, 8, and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo biopsy on study, and undergo CT, MRI, and collection of blood throughout the study, and may undergo ECHO as clinically indicated on study.
After completion of study treatment, patients are followed up for 30 days.
Enrollment
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Inclusion criteria
Patients with histologically documented advanced or metastatic solid tumors with relapsed or refractory disease who have received standard-of-care or approved therapies known to confer clinical benefit, or patients with aggressive lymphomas who have received ≥ 2 prior lines of lymphoma-directed therapy and who do not have remaining effective treatment options (including transplant). Additionally, patients with 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; 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; prior palliative radiation should have been completed >= 2 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:
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.)
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.)
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:
Clinically significant arrhythmia:
Prolonged rate corrected QT (QTc) interval >= 470 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
Patients undergoing vaccination with live vaccines and live attenuated vaccines in the 30 days prior to receiving TAK-243, during the study, and for 100 days after the last dose of study drug. Inactivated vaccines are permitted
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:
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
Primary purpose
Allocation
Interventional model
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95 participants in 2 patient groups
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Data sourced from clinicaltrials.gov
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