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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 : August 31, 2018
Sponsor:
Collaborator:
Celgene Corporation
Information provided by (Responsible Party):
Thomas Cash, MD, Emory University

Brief Summary:

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

Detailed Description:

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. Participants will also receive gemcitabine 1000 mg/m2/dose IV once weekly on days 1, 8, and 15. 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)
Primary Purpose: Treatment
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


Arm Intervention/treatment
Experimental: Gemcitabine + Nab-paclitaxel
Participants receiving gemcitabine and nab-paclitaxel for refractory and/or relapsed solid tumors of childhood.
Drug: Gemcitabine
Gemcitabine will be administered intravenously once weekly over 60 minutes every 3 out of four weeks. The dose of gemcitabine will be fixed at 1000 mg/m2/dose throughout the study.
Other Name: Gemzar

Drug: Nab-paclitaxel
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). If the MTD has been exceeded at the first dose level, then the subsequent cohort of subjects will be treated with nab-paclitaxel at a dose of 150 mg/m2/dose (dose level 0).
Other Name: Abraxane




Primary Outcome Measures :
  1. 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)

  2. Toxicity of nab-paclitaxel [ Time Frame: Up to 24 months ]
    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 4.0), 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).


Secondary Outcome Measures :
  1. Antitumor activity of nab-paclitaxel [ Time Frame: Up to 24 months ]
    The antitumor activity (tumor growth) of nab-paclitaxel in combination with gemcitabine will be preliminarily defined, within the confines of a Phase 1 study.

  2. Change in secreted protein acidic and rich in cysteine (SPARC) expression [ Time Frame: Up to 24 months ]
    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.

  3. 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.



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Ages Eligible for Study:   6 Months to 30 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Subjects must be ≥ than 6 months and ≤ 30 years of age at the time of study enrollment.
  • Subjects must have had histologic verification of a malignancy at original diagnosis or relapse. All subjects with relapsed or refractory solid tumors are eligible, excluding CNS tumors.
  • Subjects must have either measurable or evaluable disease.
  • Subject's current disease state must be one for which there is no known curative therapy, or in the case of a new diagnosis there must be ≤15% chance of cure if given standard-of-care chemotherapy. (Prognosis to be determined at the discretion of the treating physician.)
  • Karnofsky ≥ 60 for subjects > 16 years of age and Lansky ≥ 50 for subjects ≤ 16 years of age. Subjects who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
  • Subjects must have fully recovered from the acute toxic effects of all prior anti-cancer chemotherapy.

    • At least 21 days after the last dose of myelosuppressive chemotherapy (42 days if prior nitrosourea).
    • At least 14 days after the last dose of a long-acting growth factor (e.g. Pegfilgrastim) or 7 days for short acting growth factor. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair.
    • At least 7 days after the last dose of a biologic agent. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair.
    • ≥ 42 days must have elapsed from last dose of any type of cellular therapy (e.g. modified T cells, natural killer (NK) cells, dendritic cells, etc.)
    • ≥ 21 days must have elapsed from the last dose of interleukins, interferon or cytokines (other than Hematopoietic Growth Factors).
    • ≥ 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to Grade ≤ 1.
    • At least 28 days after local palliative radiation therapy (XRT) (small port); 6 weeks must have elapsed since treatment with therapeutic doses of iodine-131 metaiodobenzylguanidine (131I-MIBG); At least 42 days must have elapsed if other substantial bone marrow (BM) radiation.
    • No evidence of active graft vs. host disease and at least 84 days must have elapsed after transplant and 42 days for autologous stem cell infusion after 131I-MIBG therapy.
    • Patients who have previously received a taxane, including nab-paclitaxel, or a nucleoside analogue, including gemcitabine, are eligible as long as they have not received gemcitabine in combination with nab-paclitaxel.
    • ≥72 hours must have elapsed since the last administration of medical cannabis and cannabidiol (CBD Oil).
    • ≥30 days must have elapsed since the last dose of any agents not specified above. For agents with an uncertain washout period or for any questions or uncertainty the study PI should be notified.
  • Adequate bone marrow function defined as:

    • For subjects with solid tumors without known bone marrow involvement: Peripheral absolute neutrophil count (ANC) ≥ 750/mm3. Platelet count ≥ 75,000/mm3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
    • Subjects with known bone marrow metastatic disease will be eligible for study provided they meet the blood counts of peripheral absolute neutrophil count (ANC) ≥ 750/mm3 and platelet count ≥ 75,000/mm3 (may receive transfusions provided they are not known to be refractory to red cell or platelet transfusions). These subjects will not be evaluable for hematologic toxicity. At least 5 of every cohort of 6 patients must be evaluable for hematologic toxicity for the dose-escalation part of the study. If dose-limiting hematologic toxicity is observed, all subsequent subjects enrolled must be evaluable for hematologic toxicity.
  • Adequate renal function defined as:

    • Creatinine clearance or radioisotope glomerular filtration rate (GFR) 70ml/min/1.73 m2 or
    • A serum creatinine based on age/gender using threshold creatinine values derived from the Schwartz formula for estimating GFR utilizing child length and stature data published by the Centers for Disease Control and Prevention (CDC).
  • Adequate liver function defined as:

    • Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of normal (ULN) for age
    • Serum glutamic pyruvic transaminase (SGPT) (ALT) ≤ 5 x the ULN. For the purpose of this study, the ULN for SGPT is 45 U/L.

Exclusion Criteria:

  • Female patients who are pregnant are ineligible for study. Lactating females are not eligible unless they have agreed not to breastfeed their infants from the time of informed consent through the duration and at least 1 month following the study. Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained. Sexually active patients of reproductive potential are not eligible unless they have agreed to use an effective contraceptive method from the time of informed consent through the duration and for 1 month following study participation. The definition of an effective contraceptive method will be at the discretion of the institutional investigator.
  • Patients taking any the following concomitant medications are not eligible:

    • Subjects who are currently receiving another investigational drug.
    • Subjects who are currently receiving other anti-cancer agents.
    • Subjects who are receiving cyclosporine, tacrolimus, or other agents to prevent graft-versus-host disease post bone marrow transplant.
    • Subjects using medications which interfere with CYP3A4 and CYP2C8 metabolism, which metabolize nab-paclitaxel. Paclitaxel is metabolized by CYP3A4 and CYP2C8, so strong inhibitors or inducers of these enzymes should be avoided.
  • Patients with any of the following adverse events at the time of enrollment are not eligible:

    • Grade ≥ 2 Motor, sensory or peripheral neuropathy
    • Grade ≥3 Hyponatremia (serum Na ≤ 130 mmol/L)
  • Subjects who have an uncontrolled infection are not eligible.
  • Subjects who have received prior solid organ transplantation are not eligible.
  • Subjects who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible.

Information from the National Library of Medicine

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


Contacts
Contact: Kate Glasscox 404-785-0002 Katherine.GlasscoxSuggs@choa.org
Contact: Amy Autry-Bush 404-785-6011 Amy.Autry-Bush@choa.org

Locations
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: Kate Glasscox    404-785-0002    Katherine.GlasscoxSuggs@choa.org   
Principal Investigator: Thomas Cash, MD, MSc         
Sponsors and Collaborators
Emory University
Celgene Corporation
Investigators
Study Chair: Thomas Cash, MD, MSc Emory University
Study Chair: Jonathan Metts, MD Johns Hopkins All Children's Hospital

Responsible Party: Thomas Cash, MD, Assistant Professor, Emory University
ClinicalTrials.gov Identifier: NCT03507491     History of Changes
Other Study ID Numbers: IRB00098777
First Posted: April 25, 2018    Key Record Dates
Last Update Posted: August 31, 2018
Last Verified: August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Thomas Cash, MD, Emory University:
Pediatric
Sarcoma
Neuroblastoma
Ewing sarcoma
Osteosarcoma
Rhabdomyosarcoma
Wilms tumor
Hepatoblastoma
Adolescent and young adult
Germ cell tumor

Additional relevant MeSH terms:
Paclitaxel
Gemcitabine
Albumin-Bound Paclitaxel
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antimetabolites
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs