A Study of Intraventricular Liposomal Encapsulated Ara-C (DepoCyt) in Patients With Recurrent Glioblastoma
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|ClinicalTrials.gov Identifier: NCT01044966|
Recruitment Status : Terminated (The study was terminated due to lack of adequate patient enrollment into trial.)
First Posted : January 8, 2010
Results First Posted : February 12, 2019
Last Update Posted : February 12, 2019
|Condition or disease||Intervention/treatment||Phase|
|Glioblastoma Multiforme Glioma Astrocytoma Brain Tumor||Drug: ITV DepoCyt + Temozolomide||Phase 1 Phase 2|
Despite significant improvements in diagnostic imaging and neurosurgical techniques, the current treatment modalities for high-grade gliomas are inadequate. As such, the median survival for most patients with GBM is on the order of months, even after cytoreductive surgery, radiation and chemotherapy. Fewer than 3% of GBM patients are still alive at 5 years after diagnosis. A rising incidence has been reported for GBM, and the survival rate for patients with GBM has not shown improvement in the last two decades. For this reason exploring novel therapies for the treatment of GBM is warranted.
Neuro-oncology is currently in the midst of a paradigm shift in terms of our accepted understanding of the pathophysiology of gliomagenesis. Classic "dedifferentiation" hypotheses, modeling the cellular origin of gliomas after neoplastic transformation of differentiated glia, are currently being challenged by hypotheses suggesting dysregulated glial progenitor cells are responsible for gliomagenesis. Growing evidence exists that glial progenitor cells persisting in the adult mammalian brain, lining the lateral ventricles in the subventricular zone (SVZ) and dentate gyrus, play a role in gliomagenesis. Gliomas frequently occur in close proximity to the ventricular system and SVZ with high-grade lesions like GBM "spreading" to midline structures and crossing the corpus callosum to the contralateral hemisphere. Glial progenitor cells lining the lateral ventricles in the SVZ and dentate gyrus may be the source of "tumor" cells "spreading" to midline structures such as the corpus callosum as well as continuously replenishing the tumor bed resulting in local recurrences.
The lack of significant clinical advances in treating GBM may be due to oversight of the SVZ component of this disease. It is our hypothesis that successful treatment of GBM will require suppression of the SVZ component in addition to the currently accepted modalities of hemispheric tumor resection followed by radiation and chemotherapy. This understanding of gliomagenesis has not yet been used clinically for the treatment of GBM. We hypothesize that the SVZ is the incubator for future recurrences of GBM and propose targeting SVZ progenitor cells with intraventricular liposomal encapsulated Ara-C (DepoCyt) in combination with systemic metronomic dose temozolomide. Ara-C has been previously demonstrated to inhibit the proliferation and migration of SVZ precursor cells in adult animals. Two patients treated using this novel regimen have demonstrated significant responses warranting further study of this treatment in the Phase I/II clinical trial proposed here. This has also been the basis for successful application and granting of Orphan-Drug designation for cytarabine (Ara-C) liposome injection (trade name: DepoCyt) for the treatment of gliomas (Designation # 06-2348) on January 30, 2007.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||12 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase I/II Intraventricular DepoCyt (OD # 06-2348) in Glioblastoma (76,730, 11/06)|
|Study Start Date :||September 2009|
|Actual Primary Completion Date :||August 2013|
|Actual Study Completion Date :||September 2014|
Experimental: ITV DepoCyt + Temozolomide
Patients will undergo an induction phase of intraventricular (ITV) DepoCyt, using the dosage determined from the Phase I portionPatients with stable disease (clinically and radiographically), not exhibiting systemic toxicity, will undergo a three month consolidation phase of ITV DepoCyt, for one month (Cycles 3-6). Patients without progression or toxicity will undergo maintenance therapy using ITV DepoCyt every four weeks (+/- 3 days) for a maximum of 8 months (cycles 7-14) or until recurrence or toxicity ensues. Oral metronomic Temozolomide dosing of 75 mg/m2 daily for 21 days followed by 7 days off will be given throughout the Induction, Consolidation, and Maintenance Phases of the ITV DepoCyt described above.
Drug: ITV DepoCyt + Temozolomide
Intrathecal liposomal Ara-C dosing will begin at 50 mg ITV every 2-4 weeks, and de-escalated based on toxicity obtained from the Phase I portion of the trial. Metronomic dosing of temozolomide will be given at 75 mg/m2 for 21 days (continuous oral dosing), followed by 7 days off in a 28 day cycle as a once daily dosing regimen.
- Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0 [ Time Frame: 52 weeks ]The type and number of adverse events will be recorded and reported by the number of participants with treatment-related adverse events as assessed by CTCAE v4.0
- Proportion of Patients With Recurrent GBM Treated With ITV DepoCyt in Combination With Oral Temozolomide Who Are Progression-free at 16 Weeks. [ Time Frame: 16 weeks ]Eligibility of patients with GBM that are able to receive study drug to estimate the proportion of patients with recurrent GBM treated with ITV DepoCyt in combination with oral temozolomide who are progression-free at 16 weeks. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
- Progression Free Survival [ Time Frame: At 6 months ]The progression free survival of patients receiving study drug will be recorded. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
- Response Rate of Drug Treatment [ Time Frame: 52 weeks ]Those responding to study drug will be recorded. Response will be defined as stable neurological examination in conjunction with the absence of progression as defined above.
- Quality of Life Outcomes Measurement [ Time Frame: 52 weeks ]
Participants recorded are those who had an improvement in QOL score, QOL outcomes will be assessed and recorded using the EORTC QLQ C30 version 3.
This 30 question questionnaire will be used to asses our patient overall feeling of well-being during the trial. Questions to assess quality of life are measured from 1-4 with the following graded values:
- Not at all
- A little
- Quite a bit
- Very much Lower total scores are consistent with better quality of life and changes of greater or equal to 10 points are considered a significant change in quality of life.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01044966
|United States, South Carolina|
|Medical University of South Carolina|
|Charleston, South Carolina, United States, 29425|
|Principal Investigator:||Bruce M Frankel, MD||Medical University of South Carolina, Dept. of Neurosciences, Division of Neurosurgery|
|Study Chair:||Gustavo Leone||Medical University of South Carolina, Hollings Cancer Center|