Hydroxy-urea and Temozolomide in Patients With a Recurrent Malignant Brain Tumor (Glioblastoma)

NCT03463733 | Unknown Phase 1 DMC FDA Drug

• 1 other identifier: Pro-16/11
• Study Type: interventional
• Target: 54
• Locations: 1 country
• Sites: 1

Brief Summary

Background Currently, no standard treatment exists for patients with recurrent glioblastoma multiforme (rGBM) and used 2nd line treatments have low (up to max. 20%) response rates and very modest response duration (months). The median overall survival for GBM patients is 12-14 months from the time of diagnosis; therefore the development of new therapeutic options is imperative. HU has been used to treat hematological diseases and solid tumors (such as melanoma, ovarian, squamous cell carcinoma, head and neck carcinoma and brain tumors) in combination with other anti-cancer agents, but never with TMZ. If found safe, HU+TMZ, is easily translated to the clinic. Purpose: Phase I trial to identify the maximum tolerated dose (MTD) for the combination of dose intense temozolomide (TMZ) and hydroxy-urea (HU) in (maximal) thirty patients with recurrent glioblastoma (rGBM). Plan of investigation: Month 0-24 (1st and 2nd year): Inclusion and follow-up of a maximum of 30 patients with rGBM Month 25-31 (3rd year): Follow-up of patients included in the trial, data analysis (determining MTD and explorative analysis) and manuscript preparation. Possible results:

1. 1.Obtaining MTD and safety profile of daily HU+TMZ in patients with rGBM;
2. 2.Preliminary data on the estimation of the median progression-free (PFS) and overall survival (OS), radiographic response proportion in patients with measurable disease, and exploratory correlation of treatment outcomes (PFS and OS) with o6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation status in archival tumor specimens and further elucidation of underlying mechanism of re-sensitization of TMZ by HU. Exploratory analysis of biomarkers profile of platelets in patients treated with HU+TMZ.

Conditions

Glioma; Glioblastoma

Keywords

Glioma; Recurrent glioma; Glioblastoma multiforme; Recurrent Glioblastoma multiforme; Hydroxyurea; Temozolomide

Outcome Measures

Primary Outcomes (1)

• Maximal tolerated dose (MTD) hydroxyurea in combination with dose intense temozolomide

  MTD

  12 months

Study Arms (1)

Daily hydroxyurea and temozolomide

EXPERIMENTAL

Hydroxyurea and temozolomide will be administered every 4 weeks, with 28 consecutive days defined as a treatment cycle. Treatment will be administered on an outpatient basis. Oral hydroxyurea (dose specified by the Dose Cohort below) and oral temozolomide (50 mg/m2/day) will be administered daily in 28-day cycles for 12 cycles or until unacceptable toxicity, intolerance, progressive disease, or withdrawal of consent. Patients will be treated in dose cohorts of 3 with each cohort receiving a specific daily dose assignment of hydroxyurea. All patients in the study will receive temozolomide at 50 mg/m2/day ("dose-intense" schedule). The starting dose level for hydroxyurea will be 200 mg daily (QD) up to a maximum of 2000mg hydroxyurea a day.

Drug: Hydroxyurea; Drug: Temozolomide

Interventions

Hydroxyurea DRUG

147-94-4/HYDROXYCARBAMIDE/HYDROXYCARBAMIDE/based on myeloproliferative disorders (MPD) record: SUB08076MIG

Also known as: Hydroxycarbamide

Daily hydroxyurea and temozolomide

Temozolomide DRUG

85622-93-1 /TEMOZOLOMIDE/TEMOZOLOMIDE/based on myeloproliferative disorders (MPD) record: SUB10889MIG

Also known as: Temodar

Daily hydroxyurea and temozolomide

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants must have histologically or cytologically confirmed glioblastoma multiforme
• Patients may have had any number of prior therapies for glioblastoma. Patients must be at least 28 days from any investigational agent, 28 days from prior cytotoxic therapy (except 23 days from prior temozolomide, 14 days from vincristine, 42 days from nitrosoureas, 21 days from procarbazine administration), and 7 days for patients who received metronomic chemotherapy or non-cytotoxic agents, e.g., interferon, tamoxifen, thalidomide, cis-retinoic acid, etc.
• Age ≥18 years. Because no dosing or adverse event data are currently available on the use of hydroxyurea in combination with temozolomide in participants \<18 years of age, children are excluded from this study, but will be eligible for future pediatric trials.
• Karnofsky Performance Status (KPS) ≥60%
• Participants must have normal organ and marrow function as defined below:
• leukocytes ≥3,000/microliter (mcL)
• absolute neutrophil count ≥1,500/mcL
• platelets ≥100,000/mcL
• total bilirubin within normal institutional limits
• Aspartate transaminase (AST; SGOT)/alanine transaminase (ALT; SGPT) ≤2.5 × institutional upper limit of normal
• creatinine below upper limit of normal institutional limits OR
• creatinine clearance ≥60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal.
• Progressive disease on contrast-enhanced brain CT or MRI as defined by Response Assessment in Neuro-Oncology (RANO) Criteria \[22\], or have documented recurrent glioblastoma on diagnostic biopsy. Patients who have been previously treated with bevacizumab therapy that have T2-weighted or FLAIR MRI sequences considered to be progressive disease by the study investigator but have no contrast-enhancing areas of recurrent disease are eligible.
• Interval of at least 2 weeks from any prior neurosurgical resection (1 week for intracranial biopsy) to start of study drug; and patient must have adequate wound healing.
• Interval of at least 12 weeks from prior radiotherapy unless there is either: a) histopathologic confirmation of recurrent tumor, or b) new enhancement on MRI outside of the radiation treatment (RT) field.

You may not qualify if:

• Participants who are receiving any other investigational agents or devices in investigation for glioblastoma.
• Patients must not have been previously treated with an anti-vascular endothelial growth factor (VEGF) inhibitor.
• History of allergic reactions attributed to compounds of similar chemical composition to temozolomide and/or hydroxyurea.
• 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.
• Pregnant women are excluded from this study because hydroxyurea and temozolomide have known teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with hydroxyurea and temozolomide, breastfeeding should be discontinued if the mother is treated with hydroxyurea and temozolomide.
• HIV-positive participants on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with hydroxyurea. In addition, these participants are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated.
• Patients with a history of a different malignancy are ineligible except for the following circumstances: if they have been disease-free for at least 3 years and are deemed by the investigator to be at low risk for recurrence of that malignancy; patients with treated cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin. Patients will not be eligible if they have evidence of other malignancy requiring therapy other than surgery within the last 3 years.
• Major surgery (not including minor diagnostic procedures such as lymph node biopsy) within 2 weeks of start of study drug; or not fully recovered from any side effects of previous procedures.
• Presence of extra-cranial metastatic disease.

Sponsors & Collaborators

• M.E. van Linde: lead
• Massachusetts General Hospital: collaborator

Study Sites (1)

VU University Medical Center

Amsterdam, North Holland, 1081 HV, Netherlands

RECRUITING

MeSH Terms

Conditions

Glioma; Glioblastoma

Interventions

Hydroxyurea; Temozolomide

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Astrocytoma

Intervention Hierarchy (Ancestors)

Urea; Amides; Organic Chemicals; Dacarbazine; Triazenes; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• ME van Linde, MD

  Amsterdam UMC, location VUmc

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Jelle Arts

CONTACT

+31 (0)20 4444254; trialoffice-onc@vumc.nl

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: MD, Principal Investigator

Study Record Dates

• First Submitted: March 1, 2018
• First Posted: March 13, 2018
• Study Start: March 2, 2018
• Primary Completion: June 1, 2021
• Study Completion: June 1, 2022
• Last Updated: October 8, 2020

Record last verified: 2020-10

Data Sharing

• IPD Sharing: Will share

Locations

NL (1)