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

Primary Purpose

Glioma, Glioblastoma

Status
Unknown status
Phase
Phase 1
Locations
Netherlands
Study Type
Interventional
Intervention
Hydroxyurea
Temozolomide
Sponsored by
M.E. van Linde
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Glioma focused on measuring Glioma, Recurrent glioma, Glioblastoma multiforme, Recurrent Glioblastoma multiforme, Hydroxyurea, Temozolomide

Eligibility Criteria

undefined - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Participants must have histologically or cytologically confirmed glioblastoma multiforme
  2. 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.
  3. 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.
  4. Karnofsky Performance Status (KPS) ≥60%
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. Because cytotoxic agents such as temozolomide and hydroxyurea 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 temozolomide and hydroxyurea administration.
  10. Patients must have archival tumor tissue available for molecular analysis and must be willing to consent for this tissue to be analyzed as part of this study. However, if no archival tumor tissue is available, the patient will not be excluded from the study.
  11. Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

  1. Participants who are receiving any other investigational agents or devices in investigation for glioblastoma.
  2. Patients must not have been previously treated with an anti-vascular endothelial growth factor (VEGF) inhibitor.
  3. History of allergic reactions attributed to compounds of similar chemical composition to temozolomide and/or hydroxyurea.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. Presence of extra-cranial metastatic disease.

Sites / Locations

  • VU University Medical CenterRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Daily hydroxyurea and temozolomide

Arm Description

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.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Full Information

First Posted
March 1, 2018
Last Updated
October 6, 2020
Sponsor
M.E. van Linde
Collaborators
Massachusetts General Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT03463733
Brief Title
Hydroxy-urea and Temozolomide in Patients With a Recurrent Malignant Brain Tumor (Glioblastoma)
Acronym
HUTMZ
Official Title
International Multicenter Phase I Trial of Hydroxyurea in Combination With Dose-Intense Temozolomide in Recurrent Glioblastoma
Study Type
Interventional

2. Study Status

Record Verification Date
October 2020
Overall Recruitment Status
Unknown status
Study Start Date
March 2, 2018 (Actual)
Primary Completion Date
June 1, 2021 (Anticipated)
Study Completion Date
June 1, 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
M.E. van Linde
Collaborators
Massachusetts General Hospital

4. Oversight

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.
Yes
Data Monitoring Committee
Yes

5. Study Description

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: Obtaining MTD and safety profile of daily HU+TMZ in patients with rGBM; 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Glioma, Glioblastoma
Keywords
Glioma, Recurrent glioma, Glioblastoma multiforme, Recurrent Glioblastoma multiforme, Hydroxyurea, Temozolomide

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
54 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Daily hydroxyurea and temozolomide
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Hydroxyurea
Other Intervention Name(s)
Hydroxycarbamide
Intervention Description
147-94-4/HYDROXYCARBAMIDE/HYDROXYCARBAMIDE/based on myeloproliferative disorders (MPD) record: SUB08076MIG
Intervention Type
Drug
Intervention Name(s)
Temozolomide
Other Intervention Name(s)
Temodar
Intervention Description
85622-93-1 /TEMOZOLOMIDE/TEMOZOLOMIDE/based on myeloproliferative disorders (MPD) record: SUB10889MIG
Primary Outcome Measure Information:
Title
Maximal tolerated dose (MTD) hydroxyurea in combination with dose intense temozolomide
Description
MTD
Time Frame
12 months

10. Eligibility

Sex
All
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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. Because cytotoxic agents such as temozolomide and hydroxyurea 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 temozolomide and hydroxyurea administration. Patients must have archival tumor tissue available for molecular analysis and must be willing to consent for this tissue to be analyzed as part of this study. However, if no archival tumor tissue is available, the patient will not be excluded from the study. Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: 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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Jelle Arts
Phone
+31 (0)20 4444254
Email
trialoffice-onc@vumc.nl
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
ME van Linde, MD
Organizational Affiliation
Amsterdam UMC, location VUmc
Official's Role
Principal Investigator
Facility Information:
Facility Name
VU University Medical Center
City
Amsterdam
State/Province
Noord-Holland
ZIP/Postal Code
1081 HV
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
M.E. van Linde, MD
Phone
+31 (0)20 4444321
Email
m.vanlinde@amsterdamumc.nl

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
In anonymized form

Learn more about this trial

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

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