Dendritic Cell Vaccine With or Without Gemcitabine Pre-Treatment for Adults and Children With Sarcoma

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by University of Miami
Sponsor:
Information provided by (Responsible Party):
John Goldberg, University of Miami
ClinicalTrials.gov Identifier:
NCT01803152
First received: February 27, 2013
Last updated: July 24, 2014
Last verified: July 2014
  Purpose

The use of adjuvant vaccination with autologous dendritic cells (DC) matured in situ after being loaded with tumor lysates derived from autologous refractory sarcoma tissue will be safe, feasible and potentially beneficial for patients diagnosed with sarcoma. This vaccination will result in evidence of immune stimulation against tumor antigens. In addition, combining myeloid derived supressor cells (MDSC) inhibition using gemcitabine with DC vaccination in this method will be safe and feasible and show improved immune parameters over DC vaccination without MDSC inhibition.


Condition Intervention Phase
Sarcoma
Soft Tissue Sarcoma
Bone Sarcoma
Biological: Dendritic Cells Vaccine
Biological: Lysate of Tumor
Drug: Gemcitabine
Other: Imiquimod
Procedure: Leukapheresis
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Trial of Dendritic Cell Vaccination With and Without Inhibition of Myeloid Derived Suppressor Cells by Gemcitabine Pre-Treatment For Children And Adults With Sarcoma

Resource links provided by NLM:


Further study details as provided by University of Miami:

Primary Outcome Measures:
  • Number of Participants with Adverse Events as a Measure of Safety and Tolerability [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]
    To demonstrate that DC vaccination loaded with tumor lysate is feasible and that therapy with the vaccine with topical imiquimod (as final step in vaccine maturation), with or without the inhibition of MDSC by gemcitabine pre-treatment, is safe in pediatric and adult subjects with metastatic and refractory sarcoma.


Secondary Outcome Measures:
  • Measurement levels of Myeloid Derived Supressor Cells before and after treatment [ Time Frame: 3 years ] [ Designated as safety issue: No ]
    To explore biomarkers of immune response. Assessment will include measurement of levels of Myeloid Derived Supressor Cells before and after treatment and T and B cell subsets before and after treatment.

  • Progression-free survival [ Time Frame: 3 years ] [ Designated as safety issue: No ]
    To obtain preliminary clinical benefit by evaluating progression-free survival (PFS)in patients receiving this DC vaccine with or without gemcitabine pre-treatment.

  • Overall Survival [ Time Frame: 3 years ] [ Designated as safety issue: No ]
    To obtain preliminary clinical benefit by evaluating overall survival in patients receiving this DC vaccine with or without gemcitabine pre-treatment.

  • The rate of Complete Response (CR) or Partial Response (PR) in subjects receiving treatment [ Time Frame: 3 years ] [ Designated as safety issue: No ]
    To obtain preliminary clinical benefit by evaluating response rate (RR) in patients receiving this DC vaccine with or without gemcitabine pre-treatment.

  • Measurement levels of Myeloid Derived Supressor Cells after Gemcitabine treatment [ Time Frame: 3 years ] [ Designated as safety issue: No ]
    To determine if gemcitabine is effective in the inhibition and depletion of Myeloid Derived Supressor Cells in the study patients.


Estimated Enrollment: 56
Study Start Date: July 2012
Estimated Primary Completion Date: July 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: DC Vaccine + Lysate Biological: Dendritic Cells Vaccine
Subjects will begin to receive Dendritic Cells vaccination alone, approximately 2 weeks after pheresis and continue weekly for a total of four vaccinations.
Other Name: DC Vaccine
Biological: Lysate of Tumor
After completion of DC vaccination course, lysate of tumor will be administered during weeks 8, 12, 16, and 28. Lysate dose will be up to 1.5 mg of tumor lysate, divided into 4 equal doses. All lysate will be injected into one arm intradermally in alternating arms/thigh
Other Names:
  • Lysate
  • Tumor Lysate
Other: Imiquimod
Subjects will self-apply imiquimod one night before and each night for two nights after the scheduled administration of DC or lysate. Investigator will instruct the subject to apply a thin layer of imiquimod on the selected area (approximately the area of a silver dollar) of both arms,or thigh. Subjects are advised to rinse the selected area with water (where imiquimod is applied) the morning after application. Subjects will be given a medication diary when supplied with imiquimod in which they will record both the time of application of the imiquimod, and the time of rinse of the imiquimod.
Other Name: Aldara
Procedure: Leukapheresis
Blood draw post-surgery via central venous catheter to obtain peripheral blood mononuclear cells (PBMCs) from which dendritic cells will be obtained.
Other Name: Pheresis
Active Comparator: Gemcitabine + DC Vaccine + Lysate Biological: Dendritic Cells Vaccine
Subjects will begin to receive Dendritic Cells vaccination alone, approximately 2 weeks after pheresis and continue weekly for a total of four vaccinations.
Other Name: DC Vaccine
Biological: Lysate of Tumor
After completion of DC vaccination course, lysate of tumor will be administered during weeks 8, 12, 16, and 28. Lysate dose will be up to 1.5 mg of tumor lysate, divided into 4 equal doses. All lysate will be injected into one arm intradermally in alternating arms/thigh
Other Names:
  • Lysate
  • Tumor Lysate
Drug: Gemcitabine
After surgery and leukapheresis is completed and subject is cleared, gemcitabine 1000 mg/m2 IV wil be administered weekly x 3 followed by a week rest.
Other Name: Gemzar
Other: Imiquimod
Subjects will self-apply imiquimod one night before and each night for two nights after the scheduled administration of DC or lysate. Investigator will instruct the subject to apply a thin layer of imiquimod on the selected area (approximately the area of a silver dollar) of both arms,or thigh. Subjects are advised to rinse the selected area with water (where imiquimod is applied) the morning after application. Subjects will be given a medication diary when supplied with imiquimod in which they will record both the time of application of the imiquimod, and the time of rinse of the imiquimod.
Other Name: Aldara
Procedure: Leukapheresis
Blood draw post-surgery via central venous catheter to obtain peripheral blood mononuclear cells (PBMCs) from which dendritic cells will be obtained.
Other Name: Pheresis

Detailed Description:

This is a dose finding / dose escalation study of dendritic cell (DC) vaccination administered through imiquimod (Aldara®) treated skin for refractory sarcoma patients, which includes a subsequent cohort of subjects who will receive DC and gemcitabine (Gemzar®) therapy. There are three intended dose levels for cell number of DC per treatment - 3, 6 and 12 million cells per treatment. There will be 5 subjects accrued per dose level. If one subject in the first 5 patients per dose level experiences a dose limiting toxicity (DLT), then the dose level will be expanded to 8 subjects. If 2 or more of the subjects at a given dose level experience a DLT, then the maximum tolerated dose (MTD) will be considered to have been exceeded. The MTD will be the cell dose level at which less than 1 in 5 or less than 2 in 8 subjects experience a DLT. Provision will be made to de-escalate to dose level 0, or 1.5 million cells per treatment, should dose level 1 be too toxic. This is a 5+3 design modified from the conventional 3+3 dose escalation schema used for testing cytotoxic agents in Phase I trials. A lower rate of DLTs is therefore potentially to be accepted on this study than on such a conventional dose escalation trial of a cytotoxic agent. If no MTD is reached, we will consider the third dose level to be the recommended phase 2 dose (RP2D) going forward and expand this dose level to 8 subjects in total.

After the MTD/RP2D is reached, we will commence with the addition of gemcitabine pre-treatment to the study therapy with the cell dose held at the dose determined for the DC alone. This will include weekly gemcitabine infusion for three weeks out of four before the initiation of vaccination. Gemcitabine treatment will commence as soon as the subject has safely recovered from pheresis, but within 2 weeks of completion of pheresis. DC vaccination will begin two weeks after the third administration of gemcitabine. Gemcitabine dosing will be constant, but should the combination of gemcitabine with the MTD/RP2D of DC alone prove too toxic, we will de-escalate the dose of DC on the gemcitabine containing levels. This de-escalation will mirror the dose escalation for DC alone, and the MTD for the DC plus gemcitabine will be defined as the dose level at which less than 1 in 5 or less than 2 in 8 subjects experience a DLT.

At least two children, defined as subjects who were initially diagnosed with sarcoma before the age of 21 years, must be included on each dose level to insure that the experience is representative of the distribution of age levels found in sarcoma patients.

Subjects will undergo resection of tumor followed by pheresis to acquire monocytes which will be separated and used to grow out DC. Subjects not undergoing gemcitabine therapy will begin vaccination approximately two weeks after pheresis, depending on the manufacture time of their DC. All subjects will undergo lysate boost administration.

  Eligibility

Ages Eligible for Study:   1 Year and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age: 1 - 100 years old.
  • Histologically or cytologically confirmed sarcoma either relapsed or without known curative therapies. Both bone sarcomas and soft tissue sarcomas are eligible. Osteosarcoma, chondrosarcoma, Ewing's sarcoma and any other diagnoses of sarcoma are eligible as long as there is soft tissue that can be excised and be used to prepare lysate. Subjects presenting only with lesions that are only comprised of bone are excluded. Any number of prior therapies is allowed, including zero.
  • No radiotherapy to other sites planned and/or other chemotherapy planned for the study period. No radiotherapy or chemotherapy to have been received for at least 4 weeks before study entry. To allow for better local control without introducing undue toxicity into the trial, brachytherapy at time of surgery scheduled to end by one week before first vaccination is allowed. In the event of positive margins being determined after surgical resection, but not determined in time for the placement of brachytherapy catheters, external beam radiotherapy may start after the last DC vaccination is administered but before the lysate boosts begin.
  • No treatment with corticosteroids, antihistamines or salicylates for at least 1 week before first vaccination.
  • Adequate organ function (to be measured at enrollment)

    • Absolute neutrophil count (ANC) >750/L
    • Lymphocytes > 500/L
    • Platelets > 75,000/L
    • Hemoglobin > 9 g/dL
    • AST/ALT < 2.5 X ULN; if liver metastases, < 5 X ULN
    • Serum Creatinine < 1.5 X ULN
    • Total Bilirubin < 3 X ULN
    • Albumin > 2 g/dL
  • ECOG performance status of 0 or 1
  • Subjects must agree to use adequate method of contraception or abstinence throughout and up to 4 weeks after the study treatment completion.
  • Life expectancy of > 3 months.
  • Capable of understanding the investigational nature, potential risks and benefits of the study and able to provide valid informed consent.
  • Written consent by patient or parent(s) (if patient is < 18 years) on an institutional review board (IRB)-approved informed consent form prior to any study-specific evaluation. Assent is required from children as per UM IRB guidelines.

Exclusion Criteria:

  • Pregnancy
  • Breast feeding females.
  • Any concomitant participation in other therapeutic trials
  • Virus serology known to be positive for HIV (testing is not required in the absence of clinical suspicion)
  • Documented immunodeficiency
  • Documented autoimmune disease
  • Concomitant treatment with corticosteroids, antihistamines (H1 and H2 inhibitors) or salicylates. Patients may be eligible if the treatment is stopped at least 1 week before the first vaccination.
  • Brain metastases unless they have been stable for 3 months off of treatment directed specifically at them.
  • Known allergy to gemcitabine or its formulation components. Intolerant to gemcitabine

    • Does not apply to cohorts to be treated without gemcitabine
    • Prior therapy with gemcitabine is allowed on all cohorts
  • Refusal to use adequate contraception for fertile patients (females and males) during the study and for 30 days after the last dose of study treatment.
  • Any serious or uncontrolled medical or psychiatric condition that in the opinion of the investigator makes the patient not able to participate in the study.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01803152

Locations
United States, Florida
University of Miami Recruiting
Miami, Florida, United States, 33136
Contact: John Goldberg, MD    305-243-2795    jgoldberg2@med.miami.edu   
Contact: Emil Kamar       e.kamar@med.miami.edu   
Principal Investigator: John Goldberg, MD         
Sub-Investigator: Ofelia Alvarez, MD         
Sub-Investigator: Martin Andreasky, MD, PhD         
Sub-Investigator: Antonello Podda, MD         
Sub-Investigator: Julio Barredo, MD         
Sub-Investigator: Pasquale Benedetto, MD         
Sub-Investigator: Sheila Conway, MD         
Sub-Investigator: Joanna Davis, MD         
Sub-Investigator: Cristina Fernandes, MD         
Sub-Investigator: Jonathan Gottlieb, MD         
Sub-Investigator: Holly Neville, MD         
Sub-Investigator: Dao Nguyen, MD         
Sub-Investigator: Juan Sola, MD         
Sub-Investigator: H. Thomas Temple, MD         
Sponsors and Collaborators
University of Miami
Investigators
Principal Investigator: John Goldberg, MD University of Miami
  More Information

No publications provided

Responsible Party: John Goldberg, Assistant Professor of Clinical, University of Miami
ClinicalTrials.gov Identifier: NCT01803152     History of Changes
Other Study ID Numbers: 20110462
Study First Received: February 27, 2013
Last Updated: July 24, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by University of Miami:
Metastatic Sarcoma
Relapsed Sarcoma
Dendritic Cell
Myeloid Derived Suppressor Cells
MDSC
MDSC Inhibition

Additional relevant MeSH terms:
Sarcoma
Osteosarcoma
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Bone Tissue
Neoplasms, Connective Tissue
Gemcitabine
Imiquimod
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Radiation-Sensitizing Agents
Adjuvants, Immunologic
Interferon Inducers

ClinicalTrials.gov processed this record on September 18, 2014