GliomaPhase 1HUTMZNCT03463733
Hydroxy-urea and Temozolomide in Patients With a Recurrent Malignant Brain Tumor (Glioblastoma)
A Phase 1 study testing Hydroxyurea and Temozolomide in people with Glioma and Glioblastoma, run by M.E. van Linde at 1 site in Netherlands.
Trial 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). Read more about this study
- Who is it for?
- Any age
- Conditions the study is for
- Glioma, Glioblastoma
- What is being tested?
- Hydroxyurea and Temozolomide
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 54 participants
- Where
- 1 siteNetherlands
- Study dates
- 2 Mar 2018to 1 Jun 2022
- Phase
- 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 Any age
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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)
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- 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.
Who cannot join
- 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.
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- 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.
Trial locations and contacts
1 site in 1 country.
Netherlands1 site, 1 recruiting
- Recruiting
VU University Medical Center
Amsterdam, North Holland, 1081 HV
M.E. van Linde, MD, +31 (0)20 4444321, m.vanlinde@amsterdamumc.nl
About this study
Official title: International Multicenter Phase I Trial of Hydroxyurea in Combination With Dose-Intense Temozolomide in Recurrent Glioblastoma
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.
Read more
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.
- Conditions
- Glioma, Glioblastoma
- Being tested
- Hydroxyurea, Temozolomide
- Keywords
- Glioma, Recurrent glioma, Glioblastoma multiforme, Recurrent Glioblastoma multiforme, Hydroxyurea, Temozolomide
- Medical subject headings
- Glioma, Glioblastoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
HydroxyureaDrug
Also called Hydroxycarbamide
147-94-4/HYDROXYCARBAMIDE/HYDROXYCARBAMIDE/based on myeloproliferative disorders (MPD) record: SUB08076MIG
TemozolomideDrug
Also called Temodar
85622-93-1 /TEMOZOLOMIDE/TEMOZOLOMIDE/based on myeloproliferative disorders (MPD) record: SUB10889MIG
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Drug: Hydroxyurea; Drug: Temozolomide |
What is being measured
The primary outcome is the main question the study is designed to answer.
Maximal tolerated dose (MTD) hydroxyurea in combination with dose intense temozolomide
MTD
Measured: 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Mar 2018
- Study start2 Mar 2018
- Primary completion1 Jun 2021 (estimated)
- Study completion1 Jun 2022 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for GliomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 54 participants (estimated)
Sponsor and investigators
- Lead sponsor
- M.E. van Linde
- Sponsor type
- University, hospital or other
- Collaborators
- Massachusetts General Hospital
- Responsible party
- Sponsor-investigator, M.E. van Linde, Amsterdam UMC, location VUmc
- Investigators
- ME van Linde, MD, Principal investigator, Amsterdam UMC, location VUmc
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03463733
- Sponsor's protocol ID
- Pro-16/11
- Acronym
- HUTMZ
- Status last verified
- Oct 2020
- First submitted
- 1 Mar 2018
- Last updated
- 8 Oct 2020
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: In anonymized form
Study at a glance
From the registry record, last updated by the sponsor on 8 Oct 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- International Multicenter Phase I Trial of Hydroxyurea in Combination With Dose-Intense Temozolomide in Recurrent Glioblastoma
- ClinicalTrials.gov ID
- NCT03463733
- Acronym / sponsor ID
- HUTMZ / Pro-16/11
- Conditions
- Glioma, Glioblastoma
- Keywords
- Glioma, Recurrent glioma, Glioblastoma multiforme, Recurrent Glioblastoma multiforme, Hydroxyurea, Temozolomide
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 54 participants (estimated)
- Lead sponsor
- M.E. van LindeUniversity, hospital or other
- Collaborators
- Massachusetts General Hospital
- Study start
- 2 Mar 2018 (actual)
- Primary completion
- 1 Jun 2021 (estimated)
- Study completion
- 1 Jun 2022 (estimated)
- First posted
- 13 Mar 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Daily hydroxyurea and temozolomide | Experimental | Drug: Hydroxyurea, Drug: TemozolomideHydroxyurea 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. |
Who may qualify
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (18 listed)
- 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:
Key exclusion criteria (9 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| HydroxyureaAlso: Hydroxycarbamide147-94-4/HYDROXYCARBAMIDE/HYDROXYCARBAMIDE/based on myeloproliferative disorders (MPD) record: SUB08076MIG | Drug | Daily hydroxyurea and temozolomide |
| TemozolomideAlso: Temodar85622-93-1 /TEMOZOLOMIDE/TEMOZOLOMIDE/based on myeloproliferative disorders (MPD) record: SUB10889MIG | Drug | Daily hydroxyurea and temozolomide |
Primary outcome
Maximal tolerated dose (MTD) hydroxyurea in combination with dose intense temozolomide
Time frame: 12 months
MTD
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 8 Oct 2020.
- Individual participant dataSharing planned: Yes. In anonymized form
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
ME van Linde, MD principal investigator
Amsterdam UMC, location VUmc
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Hydroxyurea and Temozolomide in people with Glioma and Glioblastoma, run by M.E. van Linde at 1 site in Netherlands.
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 18 inclusion and 9 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: status not confirmed, as of the sponsor's last update on 8 Oct 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
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?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Jelle Arts (+31 (0)20 4444254, trialoffice-onc@vumc.nl), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Maximal tolerated dose (MTD) hydroxyurea in combination with dose intense temozolomide (time frame: 12 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 8 Oct 2020.