First or Second Recurrence of GlioblastomaPhase 1TKI258NCT01972750
Dovitinib (TKI258) in the Treatment of Patients With Relapsed Glioblastoma
A Phase 1 study testing Dovitinib in people with First or Second Recurrence of Glioblastoma, run by PD Dr. Martin Glas at 1 site in Germany.
Trial summary
In this study with a modified 3+3 dose finding design, a safe and tolerable dose of TKI258 in patients with relapsed glioblastoma should be established. Read more about this study
- Who is it for?
- Ages 18 to 100 years
- Conditions the study is for
- First or Second Recurrence of Glioblastoma
- What is being tested?
- Dovitinib
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 12 participants
- Where
- 1 siteGermany
- Study dates
- Oct 2013to Nov 2016
- 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 100 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Subjects, male or female, Age ≥ 18 years
- First or second recurrence of histologically confirmed glioblastoma
- A Performance Scale of Karnofsky > 60%, ECOG ≤ 2 or WHO < 2
- Patients must have been on no steroids or a stable dose of steroids for at least 5 days before the baseline MRI scan
- Prior treatment with radiotherapy and temozolomide and a maximum of two prior chemotherapies is permitted
- Chemotherapy must have been completed at least 4 weeks prior to study inclusion if prior temozolomide and 6 weeks if prior nitrosoureas or mitomycin c.
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- No radiotherapy within the 4 weeks prior to the diagnosis of progres-sion.
- Treatment with investigational drugs must have been completed at least 30 days prior to study inclusion if prior small molecules and at least 30 days if prior antibodies (e.g. bevacizumab)
- Patient may have been operated for recurrence. If operated residual and measurable disease after surgery is not required but surgery must have confirmed the recurrence a post-surgery. MRI should be available within 48 hours following surgery
- Surgery completed at least 2 weeks before study inclusion and pa-tients should have fully recovered
- Craniotomy or intracranial biopsy site must be adequately healed free of drainage or cellulitis, and the underlying cranioplasty must appear intact at the time of study inclusion.
- Adequate organ function as described below:
- Adequate bone marrow reserve: ANC ≥ 1.5 x 10^9/L, Platelets ≥ 100 x 10^9/L, Haemoglobin > 9 g/dL
- Adequate liver function: Total bilirubin ≤ 1.5 x ULN (excepted for patients with Gilbert's syndrome), ALT and AST ≤ 3.0 x ULN
- Adequate renal function: Creatinine ≤ 1.5 x ULN
- For non operated patients recurrent disease must be at least one bi-dimensionally measurable contrast-enhancing lesion with clearly de-fined margins by MRI scan, with minimal diameters of 10 mm, visible on 2 or more axial slices 5 mm apart, based on MRI scan done within two weeks prior to study inclusion.
- Patients who require anti-convulsant therapy must be taking non-enzyme inducing antiepileptic drugs (non-EIAED). Patients previously on EIAED must be switched to non-EIAED and stable at least 2 weeks prior to study inclusion and be stable on a constant dose.
- No non tumor related surgery or other invasive procedures (major sur-gical procedure, open biopsy or significant traumatic injury) within 4 weeks prior to study inclusion, or anticipation of the need for major surgery during the course of the study treatment.
- No core biopsy or other minor surgical procedure within 7 days prior to randomization. Placement of a central vascular access device (CVAD) if performed at least 5 days prior to study treatment administration is allowed.
- Before patient study inclusion and study related procedures (that would not have been performed as part as standard care), written in-formed consent must be given according to ICH/GCP, and nation-al/local regulations.
- Subjects with the ability to follow study instructions and likely to attend and complete all required visits
Who cannot join
- General Exclusion Criteria:
- Subjects not able to give consent
- Subject without legal capacity who is unable to understand the nature, scope, significance and consequences of this clinical trial
- Known history of hypersensitivity to the investigational drug or to drugs with a similar chemical structure
- Simultaneously participation in another clinical trial or participation in any clinical trial involving administration of an investigational medicinal product within 30 days prior to clinical trial beginning
- Subjects with a physical or psychiatric condition which at the investigator's discretion may put the subject at risk, may confound the trial results, or may interfere with the subject's participation in this clinical trial
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- Known or persistent abuse of medication, drugs or alcohol
- Indication specific exclusion criteria:
- Evidence of current/active intratumor hemorrhage by MRI
- More than two relapses
- Elongation of corrected QT-time (QTc) > 450 ms (male patients) and ≥ 460 ms (female patients), respectively
- Patients with any clinically significant medical or surgical condition which, according to investigators´ discretion, should preclude participation - i.e. severe renal disease, severe pancreatic disease, active or uncontrolled infection, uncontrolled diabetes, active or chronic liver disease (cirrhosis, chronic active hepatitis or chronic persistent hepatitis) - hepatitis B or C virus carriers with normal liver function tests, can be included.
- Patients with impaired cardiac function or clinically significant cardiac diseases, including any of the following:
- History or presence of serious uncontrolled ventricular arrhythmi-as
- Bradycardia (<60/min): i) Clinically significant resting bradycardia (=> 40/min) with syncopes or chronotropic incompetence or ii) asymptomatic bradycardia with a heart rate < 40/min and/or paus-es in ventricular rate > 3 s
- LVEF assessed by 2-D echocardiogram (ECHO) < 50% or lower limit of normal (which ever is higher)
- Any of the following within 6 months prior to starting TKI258:
- Myocardial infarction (MI),
- severe/unstable angina,
- Coronary Artery Bypass Graft (CABG),
- Congestive Heart Failure (CHF),
- Cerebrovascular Accident (CVA),
- Transient Ischemic Attack (TIA)
- Uncontrolled hypertension defined by a SBP ≥ 160 mm Hg and/or DBP ≥ 100 mm Hg, with or without anti-hypertensive medication. Initiation or adjustment of antihypertensive medication(s) is allowed prior to starting Dovitinib (TKI258)
- Patients with impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of TKI258 (e.g. severe ulcer-ative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or extensive (>1m) small bowel resection, inability to swal-low oral medications). Prior partial gastrectomy is not an exclusion cri-terion.
- Patients with prior complete gastrectomy
- Inadequate bone marrow reserve as demonstrated by an absolute neutrophil count ≤1.5 x 109 /L or platelet count ≤ 100 x 109 /L or re-quiring regular blood transfusions to maintain haemoglobin > 9g/dL
- Serum bilirubin ≥ 1.5 x ULRR (except for patients with known docu-mented cases of Gilbert's Syndrome)
- ALT or AST ≥ 2.5 x ULRR.
- Serum creatinine > 1.5 x ULRR or a creatinine clearance of ≤ 50 mL/min calculated by Cockcroft-Gault
- Unresolved toxicity > CTCAE grade 1 from previous anti-cancer thera-py (including radiotherapy) except alopecia (if applicable)
- Patients with another primary malignancy within 3 years prior to start-ing the study drug, with the exception of adequately treated in-situ car-cinoma of the uterine cervix, or completely excised (R0 resection) ba-sal or squamous cell carcinoma of the skin
- Known diagnosis of human immunodeficiency virus (HIV) infection. HIV testing is not mandatory
- Other concomitant anti-cancer therapy except steroids
- Patients who are currently receiving anticoagulation treatment with therapeutic doses of warfarin or equivalent anticoagulants (e.g., coumadin, rivaroxaban, apixaban, dabigatran) or receive antiplatelet agents (e.g., high dose aspirin or clopidogrel or other) or have an INR >1.5. Treatment with acetylsalicyclic acid 100 mg daily or prophylactic use of low molecular weight heparin (LMWH) is allowed.
- Patients who have undergone major surgery (e.g. intra-thoracic, intra-abdominal or intrapelvic) ≤ 4 weeks prior to starting TKI258 or who have not recovered from the adverse effects of such therapy
- Patients with a history of pulmonary embolism (PE), or untreated deep venous thrombosis (DVT) within the past 6 months
- Inability to undergo MRI
- Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up scheduled visits (at the discretion of the investigator)
- Exclusion criteria regarding special restrictions for females:
- Current or planned pregnancy or nursing women
- Positive pregnancy test (blood-test) prior to receiving IMP
- Females of childbearing potential, who are not using and not willing to use medically highly reliable methods of contraception for the entire study duration (such as injectable, or implantable contraceptives, or intrauterine contraceptive devices) unless they are surgically sterilized / hysterectomized or there are any other criteria considered sufficiently reliable by the investigator in individual cases
- Males, who are not using and/or not willing to use an effective form of barrier conception for the entire study duration (such as male con-doms) unless they are surgically vasectomised or there are any other criteria considered sufficiently reliable by the investigator in individual cases.
Trial locations and contacts
1 site in 1 country.
Germany1 site
Department of Neurology and Center of Integrated Oncology, University Hospital Bonn
Bonn, 53105
About this study
Official title: The Multi-targeted Tyrosine Kinase Inhibitor Dovitinib (TKI258) in the Treatment of Patients With Relapsed Glioblastoma
In this study with a modified 3+3 dose finding design, a safe and tolerable dose of TKI258 in patients with relapsed glioblastoma should be established.
Read the detailed description
Despite intensive treatment efforts combining surgery, radio- and chemotherapy, the prognosis of patients suffering from glioblastoma (GBM) remains poor. Virtually all GBMs progress despite therapy. Patients receiving the standard therapy at primary disease have a median overall survival of 12-15 months. There is currently no defined standard treatment regimen for recurrent GBM. Tyrosine kinase receptor-targeted therapy is widely used in preclinical and clinical experimental brain tumor research. Increased tyrosine kinase activity has been asssociated with GBM oncogenesis and several tyrosine kinase receptors, e.g. VEGFR, FGFR, PDGFR are upregulated in malignant glioma. In the past and in the present, targeting of VEGF- and PDGF-signaling (amongst others) has shown promising preclinical and clinical results in human glioblasto-ma.
In that context our own in vitro studies lead to the assumption that application of a multi-targeted tyrosine kinase inhibitor could be a most effective treatment approach for GBM patients. We were able to demonstrate that GBM cells from different tumor regions express different set of tyrosine kinase receptors that all could be targeted by the multi-targeted tyrosine kinase inhibitor TKI258, including PDGFRß, CSF 1R, KIT, FLT3, VEGFR, TrkA, RET and FGFRs. In combination with its ability to cross the blood-brain-barrier (BBB), the exploration of TKI258 for patients with recurrent GBM appears very promising.
Recently, safety and feasibility of TKI258 was demonstrated in adult patients with advanced solid malignan-cies. The maximum tolerated dose (MTD) was determined and a recommended dose for phase II trials was established. Meanwhile, TKI258 is in phase III development in renal cell carcinoma, and in phase II devel-opment in advanced breast cancer, relapsed multiple myeloma and urothelial cancer.
Since the toxicity profile for compounds that could cross the BBB might be different in patients with CNS diseases/disorders (e.g. brain tumors) compared to patients with malignancies outside the CNS, we here propose a phase I trial exploring TKI258 in patients with recurrent glioblastoma.
In this study with a modified 3+3 dose finding design, a safe and tolerable dose of TKI258 in patients with relapsed glioblastoma should be established.
- Being tested
- Dovitinib
- Keywords
- glioblastoma, recurrence
- Medical subject headings
- Glioblastoma, Recurrence
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DovitinibDrug
Also called TKI258
daily oral intake of capsule
| Study group | Role | What they receive |
|---|---|---|
| Dovitinib | Experimental | IMP: Dovitinib (TKI258) Manufacturer: Novartis Dose: 500 mg/day Mode of application: orally Duration of treatment: 5 days / week (5 days on / 2 days off) of a 28-days cycle until progression of disease Receives: Drug: Dovitinib |
What is being measured
The primary outcome is the main question the study is designed to answer.
safety and tolerance
The primary endpoint is safety and tolerance and will be based on the frequency of DLTs.
Measured: 2 cycles of Dovitinib application (2 months)
Secondary outcomes (5)
Tumor response (CR, PR)
Tumor response (CR, PR) according RANO criteria
Measured: 14 months
Overall safety
Overall safety
Measured: 14 months
Disease Control Rate (CR + PR + SD)
Disease Control Rate (CR + PR + SD)
Measured: 14 months
Progression free survival rate
Progression free survival rate at 6 months (PFS-6) and overall survival after initiation of therapy
Measured: 14 months
Quality of life
Quality of life (health questionnaires)
Measured: 14 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Oct 2013 (estimated)
- Study startOct 2013
- Primary completionNov 2016 (estimated)
- Study completionNov 2016 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for First or Second Recurrence of GlioblastomaStudies 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
- 12 participants (actual)
Sponsor and investigators
- Lead sponsor
- PD Dr. Martin Glas
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor-investigator, PD Dr. Martin Glas, University Hospital, Bonn
- Investigators
- Martin Glas, MD, Principal investigator, Neurooncology, University Hospital Bonn
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01972750
- Sponsor's protocol ID
- CTKI258ADE02T
- Acronym
- TKI258
- Status last verified
- Apr 2016
- First submitted
- 24 Oct 2013
- Last updated
- 19 Apr 2016
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 19 Apr 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Multi-targeted Tyrosine Kinase Inhibitor Dovitinib (TKI258) in the Treatment of Patients With Relapsed Glioblastoma
- ClinicalTrials.gov ID
- NCT01972750
- Acronym / sponsor ID
- TKI258 / CTKI258ADE02T
- Keywords
- glioblastoma, recurrence
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 12 participants (actual)
- Lead sponsor
- PD Dr. Martin GlasUniversity, hospital or other
- Study start
- Oct 2013
- Primary completion
- Nov 2016 (estimated)
- Study completion
- Nov 2016 (estimated)
- First posted
- 30 Oct 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.
In this study with a modified 3+3 dose finding design, a safe and tolerable dose of TKI258 in patients with relapsed glioblastoma should be established.
Detailed description
Despite intensive treatment efforts combining surgery, radio- and chemotherapy, the prognosis of patients suffering from glioblastoma (GBM) remains poor. Virtually all GBMs progress despite therapy. Patients receiving the standard therapy at primary disease have a median overall survival of 12-15 months. There is currently no defined standard treatment regimen for recurrent GBM. Tyrosine kinase receptor-targeted therapy is widely used in preclinical and clinical experimental brain tumor research. Increased tyrosine kinase activity has been asssociated with GBM oncogenesis and several tyrosine kinase receptors, e.g. VEGFR, FGFR, PDGFR are upregulated in malignant glioma. In the past and in the present, targeting of VEGF- and PDGF-signaling (amongst others) has shown promising preclinical and clinical results in human glioblasto-ma.
In that context our own in vitro studies lead to the assumption that application of a multi-targeted tyrosine kinase inhibitor could be a most effective treatment approach for GBM patients. We were able to demonstrate that GBM cells from different tumor regions express different set of tyrosine kinase receptors that all could be targeted by the multi-targeted tyrosine kinase inhibitor TKI258, including PDGFRß, CSF 1R, KIT, FLT3, VEGFR, TrkA, RET and FGFRs. In combination with its ability to cross the blood-brain-barrier (BBB), the exploration of TKI258 for patients with recurrent GBM appears very promising.
Recently, safety and feasibility of TKI258 was demonstrated in adult patients with advanced solid malignan-cies. The maximum tolerated dose (MTD) was determined and a recommended dose for phase II trials was established. Meanwhile, TKI258 is in phase III development in renal cell carcinoma, and in phase II devel-opment in advanced breast cancer, relapsed multiple myeloma and urothelial cancer.
Since the toxicity profile for compounds that could cross the BBB might be different in patients with CNS diseases/disorders (e.g. brain tumors) compared to patients with malignancies outside the CNS, we here propose a phase I trial exploring TKI258 in patients with recurrent glioblastoma.
In this study with a modified 3+3 dose finding design, a safe and tolerable dose of TKI258 in patients with relapsed glioblastoma should be established.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Dovitinib | Experimental | Drug: DovitinibIMP: Dovitinib (TKI258) Manufacturer: Novartis Dose: 500 mg/day Mode of application: orally Duration of treatment: 5 days / week (5 days on / 2 days off) of a 28-days cycle until progression of disease |
Who may qualify
- Ages
- 18 to 100 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (21 listed)
- Subjects, male or female, Age ≥ 18 years
- First or second recurrence of histologically confirmed glioblastoma
- A Performance Scale of Karnofsky > 60%, ECOG ≤ 2 or WHO < 2
- Patients must have been on no steroids or a stable dose of steroids for at least 5 days before the baseline MRI scan
- Prior treatment with radiotherapy and temozolomide and a maximum of two prior chemotherapies is permitted
Key exclusion criteria (44 listed)
- Subjects not able to give consent
- Subject without legal capacity who is unable to understand the nature, scope, significance and consequences of this clinical trial
- Known history of hypersensitivity to the investigational drug or to drugs with a similar chemical structure
- Simultaneously participation in another clinical trial or participation in any clinical trial involving administration of an investigational medicinal product within 30 days prior to clinical trial beginning
- Subjects with a physical or psychiatric condition which at the investigator's discretion may put the subject at risk, may confound the trial results, or may interfere with the subject's participation in this clinical trial
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 |
|---|---|---|
| DovitinibAlso: TKI258daily oral intake of capsule | Drug | Dovitinib |
Primary outcome
safety and tolerance
Time frame: 2 cycles of Dovitinib application (2 months)
The primary endpoint is safety and tolerance and will be based on the frequency of DLTs.
5 secondary outcomes
Tumor response (CR, PR)
Time frame: 14 months
Overall safety
Time frame: 14 months
Disease Control Rate (CR + PR + SD)
Time frame: 14 months
Progression free survival rate
Time frame: 14 months
Quality of life
Time frame: 14 months
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Apr 2016.
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.
Martin Glas, MD principal investigator
Neurooncology, University Hospital Bonn
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 Dovitinib in people with First or Second Recurrence of Glioblastoma, run by PD Dr. Martin Glas at 1 site in Germany.
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 21 inclusion and 44 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 19 Apr 2016. 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 Germany. 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?
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?
safety and tolerance (time frame: 2 cycles of Dovitinib application (2 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 19 Apr 2016; AzTrials last refreshed its copy on 8 Nov 2026.