Sunitinib Malate and Hydroxychloroquine in Treating Patients With Advanced Solid Tumors That Have Not Responded to Chemotherapy
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|ClinicalTrials.gov Identifier: NCT00813423|
Recruitment Status : Active, not recruiting
First Posted : December 23, 2008
Last Update Posted : May 24, 2018
|Condition or disease||Intervention/treatment||Phase|
|Adult Solid Neoplasm||Drug: Hydroxychloroquine Other: Laboratory Biomarker Analysis Other: Pharmacological Study Drug: Sunitinib Malate||Phase 1|
I. To determine the maximum tolerated dose (MTD) of the combination of sunitinib (sunitinib malate) (Sutent), an oral tyrosine kinase inhibitor with antiangiogenic activity that inhibits vascular endothelial growth factor receptor 2 (VEGFR2), stem cell factor receptor (c-kit) and platelet derived growth factor receptor (PDGFR), in combination with hydroxychloroquine (HCQ), an inhibitor of autophagy, in patients with advanced solid tumors that are refractory to standard chemotherapy.
I. Evaluating blocks of tissue from pre-treatment diagnostic biopsies and tissue from biopsies taken during therapy, when available from enrolled patients, for expression of markers beclin1, light chain 3 (LC3), sequestosome 1 (p62) and hypoxia up-regulated 1 (GRp170) as indicators of autophagy potential.
II. Evaluating pre- and post- treatment peripheral blood mononuclear cells (PBMC) and tumor tissue, when available, for the presence of autophagosomes by electron microscopy (EM) as indication of flux through the autophagy pathway.
III. Evaluating pre- and post- treatment PBMC for changes in the expression of LC3, p62 and GRp170 with the use of single agent sunitinib and the use of the combination of sunitinib with hydroxychloroquine.
IV. Evaluating circulating tumor cells (CTCs) pre- and post- treatment with single agent sunitinib and sunitinib + HCQ, and characterize these for markers of autophagy. (exploratory) V. To determine whether the steady-state plasma concentration of HCQ correlates with inhibition of autophagy and whether a pharmacokinetic interaction exists between sunitinib and HCQ.
VI. To examine, when available, post treatment tumor biopsies for vascular markers to detect decreased vascular proliferation by staining cluster of differentiation 31 (CD31), vascular endothelial growth factor (VEGF), thrombospondin-1, and cluster of differentiation 105 (CD105) staining to monitor micro vessel density.
OUTLINE: This is a dose-escalation study of hydroxychloroquine.
Patients receive sunitinib malate orally (PO) once daily (QD) on days 1-28 and hydroxychloroquine PO once daily (QD) or twice daily (BID) on days 1-42 (beginning day 4 of course 1). Treatment repeats every 42 days for 6 courses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 6 months.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||40 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Autophagic Modulation With Anti-angiogenic Therapy in Patients With Advanced Malignancies: A Phase I Trial of Sunitinib and Hydroxychloroquine|
|Actual Study Start Date :||January 27, 2010|
|Actual Primary Completion Date :||July 30, 2013|
Experimental: Treatment (sunitinib malate, hydroxychloroquine)
Patients receive sunitinib malate PO QD on days 1-28 and hydroxychloroquine PO QD or BID on days 1-42 (beginning day 4 of course 1). Treatment repeats every 42 days for 6 courses in the absence of disease progression or unacceptable toxicity.
Other: Laboratory Biomarker Analysis
Other: Pharmacological Study
Drug: Sunitinib Malate
- MTD of sunitinib malate, as assessed by the NCI CTCAE version 4.0 (v4.0) [ Time Frame: 28 days ]
- Response rate using the international criteria RECIST [ Time Frame: Up to 2 years ]Reported with 95% confidence interval.
- Survival [ Time Frame: Up to 2 years ]Analyzed using Kaplan-Meier product limit method.
- Percent changes of the marker expressions, beclin1, LC3, p62 and GRp170, as indicators of autophagy potential in tissue [ Time Frame: Up to 96 hours post-dose (course 2) ]Mean or median changes estimated by t-test or Wilcoxon signed rank test. Multiple test adjustment will be considered to control the overall type-I error rate.
- Mean number of autophagic vesicles per cell (mAV/cell) by electron microscopy (EM) as indication of flux through the autophagy pathway for non-apoptotic cells [ Time Frame: Up to 96 hours post-dose (course 2) ]Perform using a (pre-post samples) paired t-test.
- Steady-state plasma concentration of hydroxychloroquine (HCQ) [ Time Frame: Up to 96 hours post-dose (course 2) ]The correlation between the steady-state plasma concentration of HCQ and of autophagy inhibition and pharmacokinetic (PK) interaction will be assessed by regression analyses with treatment (sunitinib malate and +HCQ) as a stratification covariate in the model.
- Autophagy inhibition and PK interaction [ Time Frame: Up to 96 hours post-dose (course 2) ]The correlation between the steady-state plasma concentration of HCQ and of autophagy inhibition and PK interaction will be assessed by regression analyses with treatment (sunitinib malate and +HCQ) as a stratification covariate in the model.
- Percent changes of the vascular marker levels of CD31, VEGF, thrombospondin-1, and CD105 for detection of decreased vascular proliferation [ Time Frame: Up to 96 hours post-dose (course 2) ]Mean or median changes examined by t-test or Wilcoxon signed rank test. Multiple test adjustment will be considered to control the overall type-I error rate.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00813423
|United States, Massachusetts|
|Dana-Farber Cancer Institute|
|Boston, Massachusetts, United States, 02215|
|United States, New Jersey|
|Rutgers Cancer Institute of New Jersey|
|New Brunswick, New Jersey, United States, 08903|
|Principal Investigator:||Janice Mehnert||Rutgers Cancer Institute of New Jersey|