Nab-paclitaxel in Combination With Gemcitabine for Pediatric Relapsed and Refractory Solid Tumors
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|ClinicalTrials.gov Identifier: NCT03507491|
Recruitment Status : Recruiting
First Posted : April 25, 2018
Last Update Posted : July 21, 2020
This is a research study for people who have a solid tumor that was not effectively treated by conventional therapy or for which there is no known effective therapy. This is a phase I study of a drug called nab-paclitaxel used together with gemcitabine. Gemcitabine and nab-paclitaxel will be given intravenously, once a week for 3 out of 4 weeks, for a 28-day cycle.
The goals of this study are:
- To find the highest dose of nab-paclitaxel that can be safely given in combination with gemcitabine without causing severe side effects
- To learn what kind of side effects nab-paclitaxel given in combination with gemcitabine can cause
- To learn more about the pharmacology (how the body handles the drug) of nab-paclitaxel given in combination with gemcitabine
- To evaluate tumor tissue for levels of certain proteins that may help with predicting who will benefit most from treatment with nab-paclitaxel
- To determine whether nab-paclitaxel given in combination with gemcitabine is a beneficial treatment for relapsed and/or refractory solid tumors
|Condition or disease||Intervention/treatment||Phase|
|Cancer||Drug: Gemcitabine Drug: Nab-paclitaxel||Phase 1|
Relapsed and refractory non-central nervous system (non-CNS) solid tumors have poor outcomes, and novel therapies are needed. Many relapsed/refractory solid tumor patients desire further therapy; however, they often wish to also preserve a high quality of life. Thus therapeutic strategies that offer relatively minimal treatment-related toxicities are also desirable. The combination of gemcitabine, a pyrimidine analog, and docetaxel, an antimitotic taxane, is an attractive combination because of non-overlapping toxicities. This combination has shown activity and tolerability in adult Phase II trials for solid tumors. Favorable experiences with this regimen in pediatrics have been described retrospectively by several institutions. Nab-paclitaxel is an albumin-bound, solvent-free taxane that allows higher dosing and shorter infusion duration than solvent-bound taxanes (docetaxel and paclitaxel) by removing exposure to toxic solvent carriers. Albumin binding of the agent also increases drug delivery to tumors through increased albumin-initiated transcytosis, and may also increase tumoral accumulation of drug through binding of secreted protein acidic and rich in cysteine (SPARC). The combination of gemcitabine and nab-paclitaxel has been studied extensively in adults with pancreatic adenocarcinoma, with the combination providing superior outcomes to treatment with gemcitabine alone. There is also preclinical evidence of potent anti-tumor activity of nab-paclitaxel alone and in combination with gemcitabine in pediatric solid tumor models. Therefore, the researchers hypothesize that the combination of nab-paclitaxel with gemcitabine will improve the anti-tumor efficacy observed with gemcitabine/docetaxel in relapsed/refractory solid tumors.
This is a Phase 1 study of nab-paclitaxel in combination with gemcitabine for children, adolescents, and young adults with relapsed or refractory non-central nervous system (CNS) solid tumors in which the researchers will define toxicity, pharmacokinetics, and evaluate SPARC expression in pediatric tumors as a biomarker of disease response.
Nab-paclitaxel will be administered intravenously (IV) once weekly on days 1,8, and 15 of a 28 day cycle. The starting dose of nab-paclitaxel will be 180 mg/m2/dose which is 75% of the pediatric, single agent MTD of 240 mg/m2/dose. The researchers will then dose escalate up to 240 mg/m2/dose. Dose Level 1 of the protocol prior to Amendment 2 utilized nab-paclitaxel at 180 mg/m2/dose and gemcitabine and 1000 mg/m2/dose given on days 1, 8, and 15 of 28 day cycles. The study enrolled 5 patients at Dose Level 1 and two patients experienced hematologic dose limiting toxicities (DLTs). Amendment 2 decreases the starting dose of gemcitabine on Dose Level 1 to 675 mg/m2/dose on days 1, 8, and 15 of the 28 day cycle. If Dose Level 1 is tolerated, then the dose of nab-paclitaxel will escalated on subsequent dose levels. If two or more participants experience DLTs at Dose Level 1, then the study will de-escalate to Dose Level 0 by decreasing the gemcitabine dose to 500 mg/m2/dose IV days 1, 8, and 15. If Dose Level 0 is tolerated, then a dose escalation of nab-paclitaxel will occur.
Participants may continue on therapy until there is evidence of progressive disease or toxicity that requires removal from therapy. Therapy may otherwise continue for up to 24 cycles.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||24 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||AflacST1603: A Phase 1 Study Using Nab-paclitaxel (Abraxane®) in Combination With Gemcitabine for Pediatric Relapsed and Refractory Solid Tumors|
|Actual Study Start Date :||August 27, 2018|
|Estimated Primary Completion Date :||May 2021|
|Estimated Study Completion Date :||May 2022|
Experimental: Gemcitabine + Nab-paclitaxel
Participants receiving gemcitabine and nab-paclitaxel for refractory and/or relapsed solid tumors of childhood.
Gemcitabine will be administered intravenously once weekly over 60 minutes every 3 out of four weeks. The dose of gemcitabine will start at 675 mg/m2/dose. If the MTD has been exceeded at the Dose Level 1, then the subsequent cohort of participants will be treated with gemcitabine at a dose of 500 mg/m2/dose (Dose Level 0).
Other Name: Gemzar
Nab-Paclitaxel will be administered intravenously over 30 minutes once weekly every 3 out of 4 weeks. Nab-paclitaxel will be administered prior to administration of gemcitabine. The starting dose of nab-paclitaxel will be 180 mg/m2/dose (dose level 1). Dose levels for subsequent groups of subjects are 210 mg/m2/dose (for dose level 2) and 240 mg/m2/dose (for dose level 3).
Other Name: Abraxane
- Maximum dose tolerated of nab-paclitaxel [ Time Frame: Up to Day 28 ]The maximum tolerated dose (MTD) of nab-paclitaxel administered intravenously weekly every 3 of 4 weeks in combination with gemcitabine in children with refractory/relapsed non-CNS solid tumors will be determined. The MTD is empirically defined as the highest dose level at which there is no more than one patient experiencing a dose-limiting toxicity (DLT) and the next higher dose level has been determined to be too toxic. The MTD will be determined during Cycle 1 (each cycle is 28 days)
- Toxicity of nab-paclitaxel [ Time Frame: Up to 96 weeks ]The toxicities of nab-paclitaxel in combination with gemcitabine administered intravenously weekly every 3 of 4 weeks will be determined. All toxicities observed will be summarized in terms of type (organ affected or laboratory determination), severity (by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0), and attribution. Data on toxicities will be collected during the entire time a participant is in the study (up to 24 cycles, each cycle is 28 days).
- Antitumor activity of nab-paclitaxel [ Time Frame: Up to 96 weeks ]The antitumor activity (tumor growth) of nab-paclitaxel in combination with gemcitabine will be preliminarily defined, within the confines of a Phase 1 study.
- Change in secreted protein acidic and rich in cysteine (SPARC) expression [ Time Frame: Up to 96 weeks ]The expression of SPARC in tumor tissue from pediatric solid tumors will be evaluated. Archived tumor samples obtained as part of routine subject care will be evaluated for immunohistochemical expression of SPARC. Samples will be evaluated from all surgical procedures to evaluate if expression of these factors changes over time and can predict tumor responsiveness to therapy. Specifically, samples from diagnosis, post-therapy resection, and relapse (when performed for clinical reasons) will be evaluated.
- Blood concentrations of paclitaxel [ Time Frame: Up to Day 3 ]Blood samples will be collected for the first dose (Cycle 1, Day 1) from all patients on study to analyze paclitaxel concentrations in blood. Blood samples will be obtained on Day 1 of Cycle 1 at 1-2 min prior to end of infusion, and 0.25, 1, 3, 5, 7, 24, and 48 hours after end of the nab-paclitaxel infusion.
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): NCT03507491
|Contact: Thomas Cash, MD, MSC||404-785-1200||AflacDevTreferral@choa.org|
|United States, Florida|
|Johns Hopkins All Children's Hospital||Recruiting|
|Saint Petersburg, Florida, United States, 33701|
|Contact: Jessica Crimella 727-767-2423 Jessica.Crimella@jhmi.edu|
|Principal Investigator: Jonathan Metts, MD|
|United States, Georgia|
|Chilldren's Healthcare of Atlanta||Recruiting|
|Atlanta, Georgia, United States, 30322|
|Contact: Thomas Cash, MD, MSc 404-785-1200 AflacDevTreferral@choa.org|
|Principal Investigator: Thomas Cash, MD, MSc|
|United States, Missouri|
|Children's Mercy Hospital||Recruiting|
|Kansas City, Missouri, United States, 64108|
|Contact: Amber Jenkins, MSc 816-302-6891 email@example.com|
|Principal Investigator: Kevin Ginn, MD|
|Study Chair:||Thomas Cash, MD, MSc||Emory University|
|Study Chair:||Jonathan Metts, MD||Johns Hopkins All Children's Hospital|