Studying TAK-243 in Patients With Advanced Cancer

A Phase I Study to Investigate the Safety of the Ubiquitin Activating Enzyme Inhibitor TAK-243 in Adult Solid Tumor and Lymphoma Patients

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Advanced Lymphoma; Advanced Malignant Solid Neoplasm; Metastatic Malignant Solid Neoplasm
• Intervention / Treatment: Procedure: Biospecimen Collection; Procedure: Magnetic Resonance Imaging; Procedure: Computed Tomography; Procedure: Biopsy; Drug: UAE Inhibitor TAK-243

Detailed 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.

EXPLORATORY OBJECTIVES:

I. To assess the preliminary antitumor activity of TAK-243 monotherapy in patients with advanced solid tumors and lymphomas.

II. To determine the effects of TAK-243 on monoubiquitinated histone H2B, 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.

III. To evaluate potential associations between TAK-243 activity and tumor genomic alterations or ribonucleic acid (RNA) expression profiles.

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) twice weekly (BIW) on study. Patients also undergo biopsy on study, and undergo computed tomography (CT), magnetic resonance imaging (MRI), and collection of blood throughout the study.

ARM B: Patients receive UAE inhibitor TAK-243 IV once weekly (QW) on study. Patients also undergo biopsy on study, and undergo CT, MRI, and collection of blood throughout the study.

• Study Type: Interventional
• Enrollment (Estimated): 95
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A (twice weekly UAE inhibitor TAK-243); Patients receive TAK-243 IV BIW on study. Patients also undergo biopsy on study, and undergo CT, MRI, and collection of blood throughout the study.	Procedure: Biospecimen Collection; Undergo collection of blood; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Procedure: Magnetic Resonance Imaging; Undergo MRI; Other Names: MRI; Magnetic Resonance; Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MR; MR Imaging; MRI Scan; NMR Imaging; NMRI; Nuclear Magnetic Resonance Imaging; Magnetic Resonance Imaging (MRI); sMRI; Magnetic resonance imaging (procedure); MRIs; Structural MRI; Procedure: Computed Tomography; Undergo CT; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Computerized Tomography (CT) scan; Procedure: Biopsy; Undergo biopsy; Other Names: Bx; BIOPSY_TYPE; Drug: UAE Inhibitor TAK-243; Given IV; Other Names: AOB87172; MLN7243; TAK-243
Experimental: Arm B (once weekly UAE inhibitor TAK-243); Patients receive TAK-243 IV QW on study. Patients also undergo biopsy on study, and undergo CT, MRI, and collection of blood throughout the study.	Procedure: Biospecimen Collection; Undergo collection of blood; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Procedure: Magnetic Resonance Imaging; Undergo MRI; Other Names: MRI; Magnetic Resonance; Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MR; MR Imaging; MRI Scan; NMR Imaging; NMRI; Nuclear Magnetic Resonance Imaging; Magnetic Resonance Imaging (MRI); sMRI; Magnetic resonance imaging (procedure); MRIs; Structural MRI; Procedure: Computed Tomography; Undergo CT; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Computerized Tomography (CT) scan; Procedure: Biopsy; Undergo biopsy; Other Names: Bx; BIOPSY_TYPE; Drug: UAE Inhibitor TAK-243; Given IV; Other Names: AOB87172; MLN7243; TAK-243

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum tolerated dose (MTD)	The MTD for each arm will be based on the assessment of dose-limiting toxicities (DLTs) and will be defined as the dose level at which less than one-third of patients (< 2/6 patients) treated at that dose experience a DLT, with the next higher dose level demonstrating a one-third or greater number of patients (>= 2/3 or >= 2/6 patients) having DLT.	Within the first cycle of treatment (Arm A: 21-day cycle; Arm B: 28-day cycle)
Recommended phase 2 dose		Within the first cycle of treatment (Arm A: 21-day cycle; Arm B: 28-day cycle)
Incidence of DLTs	A DLT is defined as an adverse event that is felt to be related (possibly, probably, or definitely) to administration of study drugs, and meets pre-specified criteria. All toxicities will be reported for all patients who receive any amount of study drug on this study.	Within the first cycle of treatment (Arm A: 21-day cycle; Arm B: 28-day cycle)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacodynamic (PD) variables	With 10 PD sample pairs, there is 90% power to detect a treatment effect equivalent to 1.8 standard deviations (associated with the inter-patient baseline variability of the PD marker) with the paired 2-sample t-test, at the 1-sided .01 significance level (to accommodate multiple endpoints while maintaining a reasonable over-all type 1 error bound), for a given PD variable of interest. PD variables may be log-transformed to achieve more nearly normal distributions.	Up to 30 days after the last dose of treatment

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Naoko Takebe, National Cancer Institute LAO

Study record dates

Study Major Dates

• Study Start (Estimated): April 30, 2024
• Primary Completion (Estimated): May 31, 2024
• Study Completion (Estimated): May 31, 2024

Study Registration Dates

• First Submitted: January 24, 2024
• First Submitted That Met QC Criteria: January 24, 2024
• First Posted (Actual): January 25, 2024

Study Record Updates

• Last Update Posted (Estimated): March 6, 2024
• Last Update Submitted That Met QC Criteria: March 5, 2024
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Neoplasms; Lymphoma
• Other Study ID Numbers: NCI-2022-11194 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); 10299 (Other Identifier: CTEP)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: "NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page."

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No