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Recurrent GlioblastomaEarly Phase 1NCT05017610

Inducing a Hypothyroxinemic State in Patients With Recurrent Glioblastoma or Gliosarcoma

A Early Phase 1 study testing Liothyronine, Lomustine and Methimazole in people with Recurrent Glioblastoma and Recurrent Gliosarcoma, run by Emory University.

Withdrawn

Withdrawn. The study stopped before anyone enrolled.

Official record
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Trial summary

This early phase I trial studies the safety and feasibility of inducing a hypothyroxinemic state in patients with glioblastoma or gliosarcoma that has come back (recurrent). This trial aims to see if giving a specific thyroid hormone, such as methimazole and liothyronine, is safe and could benefit cancer treatment. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Recurrent Glioblastoma, Recurrent Gliosarcoma
What is being tested?
Liothyronine, Lomustine and Methimazole
Could I receive a placebo?
No, everyone receives an active treatment
How many people
0 participants
Where
No sites listed yet
Study dates
20 Oct 2021to 14 Oct 2022
Phase
Early Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Age >= 18 years
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 70%) within a 14-day window prior to randomization
  • Patients must have histologically confirmed glioblastoma (or gliosarcoma) at first or second recurrence after initial standard, control or experimental, therapy that includes at least radiation therapy (RT) and temozolomide (TMZ)
  • Evidence of progressive disease (PD) by modified response assessment in neuro-oncology criteria (using the post-chemoradiation time point as baseline), defined by any of the following:
  • >= 25% increase in sum of products of perpendicular diameters of measurable enhancing lesions, compared with the smallest tumor measurement obtained either at the post-chemoradiation baseline (if no decrease) or best response (on stable or increasing steroid dose).
  • Any new measurable (> 1 x 1 cm) enhancing lesions after the post-chemoradiation scan
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  • A total of at least 2 serial magnetic resonance imaging (MRI) scans documented at Screening including: 1) a scan at the time of suspected tumor progression; and 2) a scan prior to the time of progression. Patients must have progressed after standard of care treatment (it typically includes surgery, radiation and temozolomide). Pseudoprogression or radiation necrosis has been ruled out
  • Hemoglobin >= 9.0 g/dl (no transfusions allowed within 7 days of cycle 1 day 1 to meet entry criteria) (within 14 days of starting treatment)
  • Absolute neutrophil count (ANC) >= 1,500/mcL (after at least 7 days without growth factor support or transfusion) (within 14 days of starting treatment)
  • Platelets >= 100,000/mcL (no transfusions allowed within 7 days of cycle 1 day 1 to meet entry criteria) (within 14 days of starting treatment)
  • International normalized ratio (INR) =< 1.5 (within 14 days of starting treatment)
  • Partial thromboplastin time (PTT) < 1.5 x upper limits of normal (ULN) (within 14 days of starting treatment)
  • Total bilirubin =< 1.5 times the institutional upper limit of normal (ULN) (within 14 days of starting treatment)
  • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.0 times the ULN (within 14 days of starting treatment)
  • High amylase or lipase above upper normal limit (UNL) (within 14 days of starting treatment)
  • Serum creatinine =< 1.5 x ULN or creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels > 1.5 x ULN. Creatinine clearance should be calculated per institutional standard (within 14 days of starting treatment)
  • Electrocardiogram corrected QT interval by Fridericia's formula (QTcF) < 450 ms (within 14 days of starting treatment)
  • Clinically significant toxic effect(s) of the most recent prior anti-cancer therapy must be grade 1 or resolved (except alopecia)
  • A minimum time of 28 days elapsed from the administration of any prior cytotoxic agents
  • Have undergone recent surgery for recurrent or progressive brain tumor are eligible provided that:
  • Prior to surgery there was imaging evidence of measurable progressive disease (PD) as described above.
  • Craniotomy or intracranial biopsy site must be adequately healed and free of drainage or cellulitis, and the underlying cranioplasty must appear intact at the time of randomization.
  • Initiation of study treatment is at least 14 days from prior surgery/biopsy
  • Availability of tumor tissue representative of glioblastoma (GBM) from initial definitive surgery and/or, recurrent surgery, if performed
  • Female of child-bearing potential (FCBP) must have a negative serum or urine pregnancy test prior to starting therapy
  • FCBP 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 study administration. A female of childbearing potential (FCBP) is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
  • Willingness and ability of the subject to comply with scheduled visits, drug administration plan, protocol-specified laboratory tests, other study procedures, and study restrictions. Evidence of a personally signed informed consent indicating that the subject is aware of the neoplastic nature of the disease and has been informed of the procedures to be followed, the experimental nature of the therapy, alternatives, potential risks and discomforts, potential benefits, and other pertinent aspects of study participation

Who cannot join

  • Patients who received temozolomide within 28 days prior to starting first cycle under this study
  • Optune device is not allowed
  • Patients who received prior lomustine, carmustine wafers, bevacizumab or any other anti-angiogenic agent
  • Dexamethasone at time of study entry is not allowed. After a stable dose of methimazole and T3 is reached, dexamethasone can be used with a dose determined by treating physician
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Computed tomography (CT) scan with contrast within 6 weeks from enrollment as it may influence thyroid tests due to the iodine content
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  • History of cardiac arrhythmias (in particular, sinus bradycardia, atrial fibrillation or flutter, atrioventricular [AV] block, prolonged QTc, ventricular arrythmias, pacemaker, or implantable cardiac defibrillator).). Significant cardiovascular disease (eg, myocardial infarction, arterial thromboembolism, cerebrovascular thromboembolism) within 6 months prior to start of study therapy; angina requiring therapy; symptomatic peripheral vascular disease; left ventricular ejection fraction less than or equal to 35%;New York Heart Association class 3 or 4 congestive heart failure; or uncontrolled grade >= 3 hypertension (diastolic blood pressure >= 100 mmHg or systolic blood pressure >= 160 mmHg) despite antihypertensive therapy, or use of amiodarone within the last 6 months.
  • Uncontrolled type 2 diabetes mellitus (T2DM) (HbA1C greater than 8%) or a history of frequent hypoglycemia, or significantly uncontrolled hyperglycemia
  • Pregnant women are excluded from this study because of the potential for teratogenic or abortifacient effects of the study drugs. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with study drugs breastfeeding should be discontinued if the mother will be on treatment
  • Early disease progression prior to 3 months (12 weeks) from the completion of RT-TMZ, unless histologically proven to be recurrent GBM
  • Had more than 2 prior lines for chemotherapy administration. NOTE: In the 1st line adjuvant setting, combination of TMZ with an experimental agent, is considered one line of chemotherapy
  • Any prior treatment with an intracerebral agent
  • Receiving additional, concurrent, active therapy for GBM outside of the trial
  • Extensive leptomeningeal disease and defined by the principal investigator (PI)
  • History of allergy or hypersensitivity to any of the study treatments or any of their excipient
  • Unable or unwilling to undergo brain MRI scans with gadolinium
  • History of another malignancy in the previous 2 years, with a disease-free interval of < 2 years. Participant with prior history of in situ cancer or basal or squamous cell skin cancer are eligible
  • Serious, non-healing wound, ulcer, bone fracture, or abscess
  • Any cerebrovascular accident (including transient ischemic attacks) within the last 6 months prior to initiation of study treatment
  • Any hemorrhage or bleeding event that is >= grade 3 based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), grade 2 intracranial hemorrhage, or persistent thrombotic/embolic event within 4 weeks prior to the start of study medication
  • History of interstitial lung disease, history of slowly progressive dyspnea and unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, pulmonary hypersensitivity pneumonitis, or symptomatic pleural effusion
  • Active, known or systemic suspected autoimmune disease, including systemic lupus erythematosus, scleroderma, polyarteritis nodose, or auto-immune hepatitis
  • Known history of hepatitis B, human immunodeficiency virus (HIV), or active hepatitis C infection requiring treatment with antiviral therapy
  • History of bleeding diathesis (irrespective of severity)
  • History of agranulocytosis
  • History of pancreatitis
  • Uncontrolled psychiatric illness or any condition that could make the subject noncompliant with the study procedures and/or study requirements
  • Participant has not been on a stable dose of anticoagulants for at least 2 weeks before randomization

About this study

Official title: A Single Arm Pilot Study to Evaluate the Safety and Feasibility of Inducing a Hypothyroxinemic State in Patients With Recurrent Glioblastoma

This early phase I trial studies the safety and feasibility of inducing a hypothyroxinemic state in patients with glioblastoma or gliosarcoma that has come back (recurrent). This trial aims to see if giving a specific thyroid hormone, such as methimazole and liothyronine, is safe and could benefit cancer treatment.

Read the detailed description

PRIMARY OBJECTIVE:

  1. To evaluate the safety and feasibility of inducing a hypothyroxinemic state in patients with recurrent glioblastoma.

SECONDARY OBJECTIVES:

  1. To evaluate the anti-tumor activity of inducing hypothyroxinemic state by assessing progression-free survival (PFS) and overall survival (OS).

II. To evaluate the correlation of PFS and OS with thyroid hormone levels. III. To evaluate the correlation of overall response rate (ORR) with thyroid hormone levels.

IV. To evaluate the correlation of potential side effects with T3 levels or methimazole dose.

OUTLINE:

CATEGORY 1 (normal baseline thyroid function and no levothyroxine replacement): Patients receive methimazole orally (PO) daily and lomustine daily. Treatment with lomustine repeats every 6 weeks for up to 6 cycles or 12 months. Patients may receive liothyronine PO twice daily (BID) when thyroid-stimulating hormone (TSH) is above upper normal limit. Treatment continues in the absence of disease progression or unacceptable toxicity.

CATEGORY 2 (baseline primary hypothyroidism in patients taking levothyroxine): Patients receive liothyronine PO BID to maintain lower free T4 below lower limit of normal and TSH and free T3 in the normal range. At the time of cessation of exogenous T4, patients receive lomustine every 6 weeks for up to 6 cycles or 12 months. Treatment continues in the absence of disease progression or unacceptable toxicity.

CATEGORY 3 (secondary/tertiary hypothyroidism): Patients receive liothyronine PO BID to maintain lower free T4 below lower limit of normal and free T3 within normal range. At the time of cessation of exogenous T4, patients receive lomustine every 6 weeks for up to 6 cycles or 12 months. Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 6 and 8 weeks.

Being tested
Liothyronine, Lomustine, Methimazole
Medical subject headings
Glioblastoma, Gliosarcoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • LiothyronineDrug

    Also called L-Triiodothyronine, Therapeutic T3, Triiodothyronine

    Given PO

  • LomustineDrug

    Also called 1-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea, 1-Nitrosourea, 1-(2-chloroethyl)-3-cyclohexyl-, Belustin, Belustine

    Given PO

  • MethimazoleDrug

    Also called Tapazole

    Given PO

Study groups in NCT05017610
Study groupRoleWhat they receive
Treatment (methimazole, lomustine, liothyronine)ExperimentalSee Outline in Detailed Description.
Receives: Drug: Liothyronine; Drug: Lomustine; Drug: Methimazole

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Incidence of adverse events

    Descriptive statistics (e.g., frequency and percentage) for each adverse event/severe adverse event will be tabulated by association and grade.

    Measured: Up to study completion, an average of 2 years

Secondary outcomes (3)

  1. Overall response rate

    Will be assessed by Response Assessment in Neuro-Oncology Criteria. Will be summarized with the 2-sided 95% confidence interval using the Clopper-Pearson method.

    Measured: Up to study completion, an average of 2 years

  2. Progression free survival

    Kaplan-Meier methods will be used to estimate median survival time or time-specific survival rate with a 95% confidence interval.

    Measured: Up to study completion, an average of 2 years

  3. Overall survival

    Kaplan-Meier methods will be used to estimate median survival time or time-specific survival rate with a 95% confidence interval.

    Measured: Up to study completion, an average of 2 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted24 Aug 2021
  2. Study start20 Oct 2021
  3. Primary completion14 Oct 2022
  4. Study completion14 Oct 2022

Why it stopped: Per the PI-slow accrual

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Early Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
0 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05017610
Sponsor's protocol ID
STUDY00002497
Other IDs
NCI-2021-02249, STUDY00002497, WINSHIP5264-21, P30CA138292
Status last verified
Nov 2022
First submitted
28 Jul 2021
Last updated
2 Dec 2022
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Early Phase 1 study testing Liothyronine, Lomustine and Methimazole in people with Recurrent Glioblastoma and Recurrent Gliosarcoma, run by Emory University.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 27 inclusion and 28 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: withdrawn, as of the sponsor's last update on 2 Dec 2022. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was withdrawn before enrolling participants, so there are no results.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Incidence of adverse events (time frame: Up to study completion, an average of 2 years). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05017610.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Dec 2022.

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