Navitoclax and Sorafenib Tosylate in Treating Patients With Relapsed or Refractory Solid Tumors
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|ClinicalTrials.gov Identifier: NCT02143401|
Recruitment Status : Active, not recruiting
First Posted : May 21, 2014
Last Update Posted : August 6, 2019
|Condition or disease||Intervention/treatment||Phase|
|Cirrhosis Hepatitis B Infection Hepatitis C Infection Metastatic Malignant Solid Neoplasm Recurrent Hepatocellular Carcinoma Recurrent Malignant Solid Neoplasm Refractory Malignant Neoplasm Stage IV Hepatocellular Carcinoma AJCC v7 Unresectable Solid Neoplasm||Other: Laboratory Biomarker Analysis Biological: Navitoclax Other: Pharmacological Study Drug: Sorafenib Tosylate||Phase 1|
I. To determine the maximum tolerated dose (MTD) of the combination of navitoclax and sorafenib tosylate (sorafenib) in patients with advanced solid tumors. (Dose escalation cohort) II. To better characterize the toxicity profile of the combination of navitoclax and sorafenib. (Dose expansion cohort)
I. To identify any activity of this treatment combination in patients with metastatic cancer. (Dose escalation cohort) II. To seek preliminary evidence of activity of this treatment combination in patients with hepatoma. (Dose expansion cohort)
I. To determine whether the combination of navitoclax and sorafenib induces apoptosis that can be detected by peripheral blood biomarker analysis. (Dose escalation cohort) II. To assess peripheral blood biomarkers and pharmacokinetics in a more homogenous population. (Dose expansion cohort) III. To determine whether treatment is associated with Mcl-1 down regulation in hepatocellular carcinoma (HCC) at the maximum tolerated dose (MTD). (Dose expansion cohort) IV. To assess in a preliminary fashion whether pretreatment tumor cell levels of Mcl-1 predict response to this regimen through serial biopsies. (Dose expansion cohort)
OUTLINE: This is a dose-escalation study of navitoclax.
Patients receive navitoclax orally (PO) once daily (QD) on days 1-21 (days 1-28 cycle of 1 only) and sorafenib tosylate PO twice daily (BID) on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||44 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase I Trial of ABT-263 (Navitoclax), a Bcl-2 Inhibitor, and Sorafenib (Nexavar) in Patients With Relapsed or Refractory Solid Organ Tumors|
|Actual Study Start Date :||November 7, 2014|
|Estimated Primary Completion Date :||May 7, 2020|
Experimental: Treatment (navitoclax, sorafenib tosylate)
Patients receive navitoclax PO QD on days 1-21 (days 1-28 cycle of 1 only) and sorafenib tosylate PO BID on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Other: Laboratory Biomarker Analysis
Other: Pharmacological Study
Drug: Sorafenib Tosylate
- Maximum tolerated dose (MTD) of navitoclax [ Time Frame: 28 days ]Will be defined as the dose level below the lowest dose that induces dose-limiting toxicity in at least one-third of patients (at least 2 of a maximum of 6 new patients) per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v.) 4.0.
- Incidence of adverse events [ Time Frame: Up to 3 months ]Will be graded per NCI CTCAE v. 4.0. The number and severity of all adverse events (overall, by dose-level, and by tumor group) will be tabulated and summarized in this patient population. The grade 3+ adverse events will also be described and summarized in a similar fashion.
- Tumor response [ Time Frame: Up to 3 months ]Will be assessed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline version 1.1. Response will be summarized by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease. The waterfall plot may be used to display best tumor response. Exploratory analysis of the relationship between response and other clinical endpoints may be performed.
- Time until any treatment related toxicity [ Time Frame: Up to 3 months ]The data on time-related variables will be summarized descriptively.
- Time until treatment related grade 3+ toxicity [ Time Frame: Up to 3 months ]The data on time-related variables will be summarized descriptively.
- Time until hematologic nadirs (white blood cell, absolute neutrophil count, platelets) [ Time Frame: Up to 3 months ]The data on time-related variables will be summarized descriptively.
- Time to progression [ Time Frame: Up to 3 months ]The data on time-related variables will be summarized descriptively.
- Time to treatment failure [ Time Frame: From registration to documentation of progression, unacceptable toxicity, or refusal to continue participation by the patient, assessed up to 3 months ]The data on time-related variables will be summarized descriptively.
- Changes in levels of cleaved cytokeratin 18 (expansion cohort only) [ Time Frame: Day -7 up to day 8 ]To assess changes in each antigen, dot plots will be constructed with H-score on the Y axis and pre-or post-treatment status on the X axis, looking for patterns of change that emerge. To assess whether changes occur predominantly in one direction, a sign test will be applied.
- Changes in hepatoma Mcl-1 expression level in tumor tissue (expansion cohort only) [ Time Frame: Baseline to up to day 8 ]Will be assessed by immunohistochemistry. The relationship between pretreatment Mcl-1 expression and clinical response will be examined in a post hoc and exploratory fashion. To assess the relationship between Mcl-1 and response the H score (0-300) vs. response will be graphed. Chi-squared tests will be used to assess significance of relationships between these dichotomous variables and response. In addition, associations between molecular markers and time-to-event variables (progression-free-survival [PFS]) will be illustrated graphically using Kaplan-Meier curves and log-rank tests in an exploratory fashion.
- Change in cleaved and total CK18 levels in serum [ Time Frame: Day -7 to up to day 8 ]Will be assessed by enzyme-linked immunosorbent assay (ELISA). Will be summarized descriptively and plotted along time by dose levels and as a whole. The changes of the serum levels of cleaved and total CK18 at each time point against pre-treatment baseline will be correlated with toxicity and clinical endpoints. The relationships between cleaved and total CK18, caspase 3 and cytochrome c at various time points and dose levels will be explored in longitudinal data analysis. Tissue expression of Mcl-1 will be correlated with serum levels of cleaved and total CK18 at different time points and clinical toxicity and tumor response.
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): NCT02143401
|United States, Arizona|
|Mayo Clinic in Arizona|
|Scottsdale, Arizona, United States, 85259|
|United States, California|
|University of California Davis Comprehensive Cancer Center|
|Sacramento, California, United States, 95817|
|United States, Colorado|
|University of Colorado Hospital|
|Aurora, Colorado, United States, 80045|
|United States, Florida|
|Mayo Clinic in Florida|
|Jacksonville, Florida, United States, 32224-9980|
|United States, Iowa|
|University of Iowa/Holden Comprehensive Cancer Center|
|Iowa City, Iowa, United States, 52242|
|United States, Maryland|
|University of Maryland/Greenebaum Cancer Center|
|Baltimore, Maryland, United States, 21201|
|United States, Minnesota|
|Rochester, Minnesota, United States, 55905|
|United States, New York|
|NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center|
|New York, New York, United States, 10032|
|United States, Pennsylvania|
|Thomas Jefferson University Hospital|
|Philadelphia, Pennsylvania, United States, 19107|
|United States, Texas|
|M D Anderson Cancer Center|
|Houston, Texas, United States, 77030|
|Principal Investigator:||Brian A Costello||Mayo Clinic Cancer Center LAO|