Malignant GliomaPhase 1NCT01811992
Combined Cytotoxic and Immune-Stimulatory Therapy for Glioma
A Phase 1 study testing Dose Escalation of Ad-hCMV-TK and Ad-hCMV-Flt3L in people with Malignant Glioma and Glioblastoma Multiforme, run by University of Michigan Rogel Cancer Center at 1 site in United States.
Trial summary
Despite the marginal improvements in survival of patients suffering from malignant glioma treated with gene therapy vectors, the clinical trials conducted so far using viral vectors, in particular adenoviral vectors, have proven that the use of adenoviral vectors is a safe therapeutic approach, even in large… Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Malignant Glioma, Glioblastoma Multiforme
- What is being tested?
- Dose Escalation of Ad-hCMV-TK and Ad-hCMV-Flt3L
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 19 participants
- Where
- 1 siteUnited States
- Study dates
- Apr 2014to Jan 2021
- 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 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Newly diagnosed supratentorial brain lesion compatible with a high grade glioma by MR (magnetic resonance) with no prior treatment with either gene therapy, chemotherapy or radiation treatments that is amenable to attempted gross total resection (GTR).Intraoperative histological frozen section at the time of tumor resection should be compatible with high-grade glioma. If intraoperative diagnosis is not high grade glioma, the patient will not be enrolled. "High grade glioma" can include:Glioblastoma multiforme (WHO grade IV); Anaplastic astrocytoma (WHO grade III); Anaplastic oligodendroglioma (WHO grade III); and Anaplastic ependymoma (WHO grade III).
- Karnofsky score ≥70 (Karnofsky scoring system used to quantify general well-being and activities of daily life; scores range from 0 to 100 where 100 represents perfect health and 0 represents death)
- CBC (complete blood count)/differential obtained within 14 days prior, with adequate bone marrow function defined as follows:
- Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3;
- Platelets ≥ 100,000 cells/mm3;
- Hemoglobin ≥ 10.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb ≥10.0 g/dl is acceptable.);
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- Adequate renal function, as defined below:
- BUN (blood urea nitrogen) ≤ 30 mg/dl within 14 days prior.
- Creatinine ≤ 1.7 mg/dl within 14 days prior.
- Adequate hepatic function, as defined below:
- Bilirubin ≤ 2.0 mg/dl within 14 days prior.
- ALT (alanine aminotransferase)/AST (aspartate aminotransferase) ≤ 3x laboratory upper limit of normal within 14 days prior.
- Male and female; both genders must use contraception if of reproductive capacity
- Capable of informed consent
- 18-75 years of age
- For women of child bearing age, a negative pregnancy test performed within 14 days of surgery
Who cannot join
- Diffusely multifocal lesion that is not amenable to GTR (gross total resection)
- Tumors infiltrating the cerebellum, bilateral corpus callosum ("butterfly glioma"), ventricular system, or brain stem
- Infratentorial high grade glioma
- Primary central nervous system (CNS) disease that would interfere with subject evaluation
- Current diagnosis of other cancer except curative cervical cancer in situ, basal or squamous cell carcinoma of the skin.
- Evidence of other significant disease including hematologic, renal or liver disease that is not explained by the patient's current medical condition or concomitant disease, (i.e. levels of absolute neutrophil count (ANC), hemoglobin, platelets, clotting time, serum creatinine, etc). Final decision on inclusion will be made by physician, concerning suitability of patient for surgery.
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- HIV, Hepatitis B, Hepatitis
- Active systemic infection
- Immunosuppressive disorders (chronic steroid therapy, acquired or congenital immune deficiency syndromes, autoimmune disease)
- Serious medical conditions (CHF (congestive heart failure), angina, diabetes mellitus, Chronic obstructive pulmonary disease, abnormal bleeding diathesis)
- Any contraindication for undergoing MRI (magnetic resonance imaging)
- Pregnant or lactating females
- Unacceptable anesthesia risk
- Evidence of bleeding diathesis or use of anticoagulant medication or any medication that may increase the risk of bleeding that cannot be stopped prior to surgery.
- Prior gene therapy
- Allergy to valacyclovir or unable to take oral tablets
Trial locations and contacts
1 site in 1 country.
United States1 site
University of Michigan Health System Department of Neurosurgery
Ann Arbor, Michigan, 48109
About this study
Official title: A Non-randomized, Open-label Dose-finding Trial of Combined Cytotoxic and Immune-Stimulatory Strategy for the Treatment of Resectable Primary Malignant Glioma
Despite the marginal improvements in survival of patients suffering from malignant glioma treated with gene therapy vectors, the clinical trials conducted so far using viral vectors, in particular adenoviral vectors, have proven that the use of adenoviral vectors is a safe therapeutic approach, even in large, multicenter, phase 3 clinical trials. Treatment of malignant glioma using gene transfer modalities typically consists of surgical debulking of the tumor mass followed by the administration of the viral vectors into the brain tissue surrounding the tumor cavity. This study will combine direct tumor cell killing (TK) and immune-mediated stimulatory (Flt3L) gene transfer approaches delivered by first generation adenoviral vectors.
Read the detailed description
This is a Phase 1, multiple center open label, dose escalation safety study of Ad-hCMV-TK and Ad-hCMV-Flt3L delivered to the peritumoral region after tumor resection. This study will combine direct tumor cell killing (TK) and immune-mediated stimulatory (Flt3L) gene transfer approaches delivered by first generation adenoviral vectors. Treatment with HSV1-TK is expected to kill transduced brain cells, thus exposing tumor antigen. Treatment with Flt3L, a cytokine known to cause proliferation of dendritic cells, should cause the migration of dendritic cells to the peritumoral brain and remaining tumor. There, they will be exposed to tumor antigens released from dying glioma cells through TK + valacyclovir-induced glioma cell death, and thus mediate a specific anti-malignant glioma immune response against remaining malignant glioma cells.
- Conditions
- Malignant Glioma, Glioblastoma Multiforme
- Being tested
- Dose Escalation of Ad-hCMV-TK and Ad-hCMV-Flt3L
- Medical subject headings
- Glioma, Glioblastoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Dose Escalation of Ad-hCMV-TK and Ad-hCMV-Flt3LBiological
Two adenoviral vectors will be used, each to deliver one of the therapeutic genes. Both vectors are human serotype 5, replication-defective, first generation adenoviral vectors deleted in E1a and E3 viral encoding regions. Each vector will constitutively express their respective therapeutic transgene (i.e. HSV1-TK or Flt3L) under the control of the human cytomegalovirus promoter (hCMV). Valacyclovir treatment will begin 1-3 days after vector administration at a dose of 2 grams given orally 3X per day for 14 days. A second course of valacyclovir will be given beginning Week 10.
Radiation and chemotherapy will be administered as per standard of care.
| Study group | Role | What they receive |
|---|---|---|
| Dose escalation of Ad-hCMV-TK and Ad-hCMV-Flt3L | Experimental | This protocol is a dose escalation study of Ad-hCMV-TK and Ad-hCMV-Flt3L infused at the time of surgical resection followed by systemic oral administration of valacyclovir in addition to current standard of care with temozolomide and radiotherapy. Eligible subjects will be enrolled in six sequential dosing cohorts:
* A= Ad-hCMV-TK: 1x10^10 vp and Ad-hCMV-Flt3L: 1x10^9 vp
* B= Ad-hCMV-TK: 1x10^11 vp and Ad-hCMV-Flt3L: 1x10^9 vp
* C= Ad-hCMV-TK: 1x10^10 vp and Ad-hCMV-Flt3L: 1x10^10 vp
* D= Ad-hCMV-TK: 1x10^11 vp and Ad-hCMV-Flt3L: 1x10^10 vp
* E= Ad-hCMV-TK: 1x10^10 vp and Ad-hCMV-Flt3L: 1x10^11 vp
* F= Ad-hCMV-TK: 1x10^11 vp and Ad-hCMV-Flt3L: 1x10^11 vp
Subjects will be treated sequentially with a minimum of 21 days before treatment of new subjects within a cohort or before dose escalation. Receives: Biological: Dose Escalation of Ad-hCMV-TK and Ad-hCMV-Flt3L |
What is being measured
The primary outcome is the main question the study is designed to answer.
Maximum Tolerated Dose (MTD)
Vectors AdhCMV- TK and Ad-hCMV-Flt3L were administered at time of surgery and the MTD determined by dose-limiting toxicities. Toxicities assessed and graded by the NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0.
Measured: 21 days post administration of study vectors
Secondary outcomes (1)
Number of Patients Alive at 12 and 24 Months
To assess in a preliminary fashion the potential benefit of AdhCMV- TK and Ad-hCMV-Flt3L treatment of primary malignant gliomas by assessing overall survival (OS) at 12 and 24 months.
Measured: 24 Months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Mar 2013 (estimated)
- Study startApr 2014
- Primary completionFeb 2019
- Study completionJan 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Malignant GliomaStudies of the same condition, open and under way.
- More trials run by University of Michigan Rogel Cancer CenterThe sponsor's other registered studies.
- 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
- 19 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Michigan Rogel Cancer Center
- Sponsor type
- University, hospital or other
- Collaborators
- Phase One Foundation
- Responsible party
- Sponsor
- Investigators
- Pedro Lowenstein, MD, PhD, Principal investigator, University of Michigan
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01811992
- Sponsor's protocol ID
- UMCC 2015.024
- Other IDs
- HUM00057130
- Status last verified
- Sep 2024
- First submitted
- 13 Feb 2013
- Last updated
- 19 Sep 2024
- Results posted
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Publications
Umemura Y, Orringer D, Junck L, Varela ML, West MEJ, Faisal SM, Comba A, Heth J, Sagher O, Leung D, Mammoser A, Hervey-Jumper S, Zamler D, Yadav VN, Dunn P, Al-Holou W, Hollon T, Kim MM, Wahl DR, Camelo-Piragua S, Lieberman AP, Venneti S, McKeever P, Lawrence T, Kurokawa R, Sagher K, Altshuler D, Zhao L, Muraszko K, Castro MG, Lowenstein PR. Combined cytotoxic and immune-stimulatory gene therapy for primary adult high-grade glioma: a phase 1, first-in-human trial. Lancet Oncol. 2023 Sep;24(9):1042-1052. doi: 10.1016/S1470-2045(23)00347-9.
PubMed 37657463Lowenstein PR, Castro MG. Evolutionary basis of a new gene- and immune-therapeutic approach for the treatment of malignant brain tumors: from mice to clinical trials for glioma patients. Clin Immunol. 2018 Apr;189:43-51. doi: 10.1016/j.clim.2017.07.006. Epub 2017 Jul 15.
PubMed 28720549
Study at a glance
From the registry record, last updated by the sponsor on 19 Sep 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Non-randomized, Open-label Dose-finding Trial of Combined Cytotoxic and Immune-Stimulatory Strategy for the Treatment of Resectable Primary Malignant Glioma
- ClinicalTrials.gov ID
- NCT01811992
- Acronym / sponsor ID
- UMCC 2015.024
- Conditions
- Malignant Glioma, Glioblastoma Multiforme
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 19 participants (actual)
- Lead sponsor
- University of Michigan Rogel Cancer CenterUniversity, hospital or other
- Collaborators
- Phase One Foundation
- Study start
- Apr 2014 (actual)
- Primary completion
- Feb 2019 (actual)
- Study completion
- Jan 2021 (actual)
- First posted
- 15 Mar 2013 (estimated)
- 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.
Despite the marginal improvements in survival of patients suffering from malignant glioma treated with gene therapy vectors, the clinical trials conducted so far using viral vectors, in particular adenoviral vectors, have proven that the use of adenoviral vectors is a safe therapeutic approach, even in large, multicenter, phase 3 clinical trials. Treatment of malignant glioma using gene transfer modalities typically consists of surgical debulking of the tumor mass followed by the administration of the viral vectors into the brain tissue surrounding the tumor cavity. This study will combine direct tumor cell killing (TK) and immune-mediated stimulatory (Flt3L) gene transfer approaches delivered by first generation adenoviral vectors.
Detailed description
This is a Phase 1, multiple center open label, dose escalation safety study of Ad-hCMV-TK and Ad-hCMV-Flt3L delivered to the peritumoral region after tumor resection. This study will combine direct tumor cell killing (TK) and immune-mediated stimulatory (Flt3L) gene transfer approaches delivered by first generation adenoviral vectors. Treatment with HSV1-TK is expected to kill transduced brain cells, thus exposing tumor antigen. Treatment with Flt3L, a cytokine known to cause proliferation of dendritic cells, should cause the migration of dendritic cells to the peritumoral brain and remaining tumor. There, they will be exposed to tumor antigens released from dying glioma cells through TK + valacyclovir-induced glioma cell death, and thus mediate a specific anti-malignant glioma immune response against remaining malignant glioma cells.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Dose escalation of Ad-hCMV-TK and Ad-hCMV-Flt3L | Experimental | Biological: Dose Escalation of Ad-hCMV-TK and Ad-hCMV-Flt3LThis protocol is a dose escalation study of Ad-hCMV-TK and Ad-hCMV-Flt3L infused at the time of surgical resection followed by systemic oral administration of valacyclovir in addition to current standard of care with temozolomide and radiotherapy. Eligible subjects will be enrolled in six sequential dosing cohorts: * A= Ad-hCMV-TK: 1x10^10 vp and Ad-hCMV-Flt3L: 1x10^9 vp * B= Ad-hCMV-TK: 1x10^11 vp and Ad-hCMV-Flt3L: 1x10^9 vp * C= Ad-hCMV-TK: 1x10^10 vp and Ad-hCMV-Flt3L: 1x10^10 vp * D= Ad-hCMV-TK: 1x10^11 vp and Ad-hCMV-Flt3L: 1x10^10 vp * E= Ad-hCMV-TK: 1x10^10 vp and Ad-hCMV-Flt3L: 1x10^11 vp * F= Ad-hCMV-TK: 1x10^11 vp and Ad-hCMV-Flt3L: 1x10^11 vp Subjects will be treated sequentially with a minimum of 21 days before treatment of new subjects within a cohort or before dose escalation. |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (16 listed)
- Newly diagnosed supratentorial brain lesion compatible with a high grade glioma by MR (magnetic resonance) with no prior treatment with either gene therapy, chemotherapy or radiation treatments that is amenable to attempted gross total resection (GTR).Intraoperative histological frozen section at the time of tumor resection should be compatible with high-grade glioma. If intraoperative diagnosis is not high grade glioma, the patient will not be enrolled. "High grade glioma" can include:Glioblastoma multiforme (WHO grade IV); Anaplastic astrocytoma (WHO grade III); Anaplastic oligodendroglioma (WHO grade III); and Anaplastic ependymoma (WHO grade III).
- Karnofsky score ≥70 (Karnofsky scoring system used to quantify general well-being and activities of daily life; scores range from 0 to 100 where 100 represents perfect health and 0 represents death)
- CBC (complete blood count)/differential obtained within 14 days prior, with adequate bone marrow function defined as follows:
- Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3;
- Platelets ≥ 100,000 cells/mm3;
Key exclusion criteria (16 listed)
- Diffusely multifocal lesion that is not amenable to GTR (gross total resection)
- Tumors infiltrating the cerebellum, bilateral corpus callosum ("butterfly glioma"), ventricular system, or brain stem
- Infratentorial high grade glioma
- Primary central nervous system (CNS) disease that would interfere with subject evaluation
- Current diagnosis of other cancer except curative cervical cancer in situ, basal or squamous cell carcinoma of the skin.
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 |
|---|---|---|
| Dose Escalation of Ad-hCMV-TK and Ad-hCMV-Flt3LTwo adenoviral vectors will be used, each to deliver one of the therapeutic genes. Both vectors are human serotype 5, replication-defective, first generation adenoviral vectors deleted in E1a and E3 viral encoding regions. Each vector will constitutively express their respective therapeutic transgene (i.e. HSV1-TK or Flt3L) under the control of the human cytomegalovirus promoter (hCMV). Valacyclovir treatment will begin 1-3 days after vector administration at a dose of 2 grams given orally 3X per day for 14 days. A second course of valacyclovir will be given beginning Week 10. Radiation and chemotherapy will be administered as per standard of care. | Biological | Dose escalation of Ad-hCMV-TK and Ad-hCMV-Flt3L |
Primary outcome
Maximum Tolerated Dose (MTD)
Time frame: 21 days post administration of study vectors
Vectors AdhCMV- TK and Ad-hCMV-Flt3L were administered at time of surgery and the MTD determined by dose-limiting toxicities. Toxicities assessed and graded by the NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0.
1 secondary outcome
Number of Patients Alive at 12 and 24 Months
Time frame: 24 Months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Sep 2024.
- Results publication: PubMed 37657463Umemura Y, Orringer D, Junck L, Varela ML, West MEJ, Faisal SM, Comba A, Heth J, Sagher O, Leung D, Mammoser A, Hervey-Jumper S, Zamler D, Yadav VN, Dunn P, Al-Holou W, Hollon T, Kim MM, Wahl DR, Camelo-Piragua S, Lieberman AP, Venneti S, McKeever P, Lawrence T, Kurokawa R, Sagher K, Altshuler D, Zhao L, Muraszko K, Castro MG, Lowenstein PR. Combined cytotoxic and immune-stimulatory gene therapy for primary adult high-grade glioma: a phase 1, first-in-human trial. Lancet Oncol. 2023 Sep;24(9):1042-1052. doi: 10.1016/S1470-2045(23)00347-9.
- Derived from this study: PubMed 28720549Lowenstein PR, Castro MG. Evolutionary basis of a new gene- and immune-therapeutic approach for the treatment of malignant brain tumors: from mice to clinical trials for glioma patients. Clin Immunol. 2018 Apr;189:43-51. doi: 10.1016/j.clim.2017.07.006. Epub 2017 Jul 15.
- Pubmed LinkLink provided by the sponsor.
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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.
Pedro Lowenstein, MD, PhD principal investigator
University of Michigan
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 Dose Escalation of Ad-hCMV-TK and Ad-hCMV-Flt3L in people with Malignant Glioma and Glioblastoma Multiforme, run by University of Michigan Rogel Cancer Center at 1 site in United States.
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 16 inclusion and 16 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: finished, as of the sponsor's last update on 19 Sep 2024. 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 United States. 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?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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?
Maximum Tolerated Dose (MTD) (time frame: 21 days post administration of study vectors). 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 NCT01811992, which also lists 2 linked publications.
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 19 Sep 2024.