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.

Objectives

PRIMARY OBJECTIVE:
I. To evaluate the safety and feasibility of inducing a hypothyroxinemic state in patients with recurrent glioblastoma.

SECONDARY OBJECTIVES:
I. 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.

Eligibility

1. Age >= 18 years
2. Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 70%) within a 14-day window prior to randomization
3. 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)
4. 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
5. 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
6. 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)
7. Absolute neutrophil count (ANC) >= 1,500/mcL (after at least 7 days without growth factor support or transfusion) (within 14 days of starting treatment)
8. 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)
9. International normalized ratio (INR) =< 1.5 (within 14 days of starting treatment)
10. Partial thromboplastin time (PTT) < 1.5 x upper limits of normal (ULN) (within 14 days of starting treatment)
11. Total bilirubin =< 1.5 times the institutional upper limit of normal (ULN) (within 14 days of starting treatment)
12. Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.0 times the ULN (within 14 days of starting treatment)
13. High amylase or lipase above UNL (within 14 days of starting treatment)
14. 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)
15. Electrocardiogram corrected QT interval by Fridericia's formula (QTcF) < 450 ms (within 14 days of starting treatment)
16. Clinically significant toxic effect(s) of the most recent prior anti-cancer therapy must be grade 1 or resolved (except alopecia)
17. A minimum time of 28 days elapsed from the administration of any prior cytotoxic agents
18. 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
19. Availability of tumor tissue representative of glioblastoma (GBM) from initial definitive surgery and/or, recurrent surgery, if performed
20. Female of child-bearing potential (FCBP) must have a negative serum or urine pregnancy test prior to starting therapy
21. 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)
22. 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

Treatment Sites in Georgia