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Phase 1b/2 Study of Vorinostat in Combination With Gemcitabine and Docetaxel in Advanced Sarcoma (GemTax)

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ClinicalTrials.gov Identifier: NCT01879085
Recruitment Status : Active, not recruiting
First Posted : June 17, 2013
Last Update Posted : March 3, 2021
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Melissa Burgess, MD, University of Pittsburgh

Brief Summary:

This is a Phase Ib/II experimental, open-label, dose escalation, active treatment study designed to determine the safety, tolerability, and recommended dose of the combination.

During the Phase 2 portion of the study, we will assess progression-free survival (PFS), overall survival (OS),overall response rate (ORR), correlative endpoints, DNA methylation measured by microarray, and expression level of the genes as measured by microarray


Condition or disease Intervention/treatment Phase
Sarcoma Drug: Docetaxel Drug: Gemcitabine Drug: Vorinostat Drug: Pegfilgrastim Phase 1 Phase 2

Detailed Description:

Phase 1b

  • To determine the dose of vorinostat that can be safely combined with gemcitabine and docetaxel in patients with advanced sarcomas.
  • To characterize the Pharmacokinetics (PK) and Pharmacodynamics (PD) of vorinostat when combined with gemcitabine and docetaxel in patients with advanced sarcomas.

Phase 2

  • To determine the safety and efficacy of gemcitabine and docetaxel in combination with vorinostat in patients with advanced sarcomas. The hypothesis is that gemcitabine and docetaxel + vorinostat will be safe and will improve the 6-months progression-free rates (PFR) of the combination by 20% (from 20% to 40%).
  • To determine the objective response rate, progression-free, and overall survival of patients with advanced sarcomas treated with gemcitabine and docetaxel + vorinostat;
  • To develop a predictive molecular signature of response to treatment in advanced sarcomas.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 40 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1b/2 Study of Vorinostat in Combination With Gemcitabine and Docetaxel in Advanced Sarcoma
Actual Study Start Date : September 24, 2013
Estimated Primary Completion Date : July 2021
Estimated Study Completion Date : July 2021


Arm Intervention/treatment
Experimental: Combination therapy
Dose Level\Docetaxel IV\ Gemcitabine IV\Vorinostat PO\Pegfilgrastim 1\75 mg/m2\900 mg/m2\300 mg once daily\6 mg on day 9 2\75 mg/m2\900 mg/m2\200 mg twice daily\6 mg on day 9 3\75 mg/m2\900 mg/m2\300 mg twice daily\6 mg on day 9 4\75 mg/m2\900 mg/m2\400 mg twice daily\6 mg on day 9
Drug: Docetaxel
75 mg/m2 IV over 60 minutes on day 8 every 21 days (1 cycle).
Other Name: Taxotere

Drug: Gemcitabine
given on days 1 and 8 at 900 mg/m2 IV over 90 minutes (fixed dose infusion rate at 10 mg/m2/min) every 21 days (1 cycle). For dose level -2, Gem will be given over 67.5 minutes at 10 mg/m2/min.
Other Name: Gemzar

Drug: Vorinostat
will be given orally at the specified dose levels (Table 2) on days -1 to +2 and days +7-9 every 21 days (treatment for 3 days starting one day prior to chemotherapy on every cycle).
Other Name: Zolinza

Drug: Pegfilgrastim
Administered on day 9 subcutaneously at 6 mg.
Other Name: Neulasta




Primary Outcome Measures :
  1. Phase I: Recommended Phase II Dose of Vorinostat [ Time Frame: Up to 12 months ]
    The dose of vorinostat that can be safely combined with gemcitabine and docetaxel in patients with advanced sarcomas. Gemcitabine and docetaxel will be given at a fixed dose while vorinostat will be dose-escalated using a standard '3+3' design. Dose-limiting toxicity (DLT) is defined as specific study drug-related events experienced during Cycle 1; only DLTs observed in a patient during the first cycle of treatment will be used for the dose escalation decision.

  2. Phase II: Six-month progression-free survival rate (PFR) [ Time Frame: Up to 8 years ]
    Percentage of participants whose disease does not progress within 6 months of start of treatment (number of patients with progressive disease/total number of patients). Per RECIST v1.1, progressive disease (PD) is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. For non-target lesions, PD: Unequivocal progression of existing non-target lesions. The appearance of one or more new lesions is also considered progression.


Secondary Outcome Measures :
  1. Progression-free survival (PFS) [ Time Frame: Up to 8 years ]
    The length from the beginning of study treatment that patients remain alive without progression of their disease (cancer). Per RECIST v1.1, progressive disease (PD) is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. For non-target lesions, PD: Unequivocal progression of existing non-target lesions. The appearance of one or more new lesions is also considered progression.

  2. Overall survival (OS) [ Time Frame: Up to 8 years ]
    The length of time from the start of treatment that diagnosed study participants remain alive.

  3. Objective Response Rate (ORR) [ Time Frame: Up to 8 years ]
    Complete response [CR] + partial response [PR], per RECIST v1.1 criteria . Per RECIST v1.1, CR: Disappearance of all target lesions. Any pathological lymph nodes(whether target or non-target) must have reduction in short axis to <10 mm. For non-target lesions: Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10mm short axis);PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have histologically confirmed soft tissue sarcoma with evidence of metastatic or unresectable disease.
  • Patients must have measurable disease by RECIST 1.1.
  • Up to 32 prior cytotoxic chemotherapy regimens in the metastatic setting are allowed. Adjuvant chemotherapy or targeted therapy will not be considered a prior line of treatment.
  • Age ≥18 years.
  • ECOG performance status ≤2 (Karnofsky ≥60%).
  • Life expectancy of greater than 12 weeks.
  • Patients must have normal organ and marrow function as defined below:

    • leukocytes ≥3,000/µL
    • absolute neutrophil count ≥1,500/µL
    • platelets ≥100,000/µL
    • total bilirubin within normal institutional limits
    • AST(SGOT)/ALT(SGPT) ≤1.5 X institutional upper limit of normal (ULN)
    • creatinine ≤1.5 X institutional upper limit of normal (ULN)
  • Peripheral neuropathy, if present, should be ≤grade 1.
  • Women of Child bearing potential MUST use contraceptives.
  • Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

  • The following specific histologic subtypes of soft tissue sarcomas will be excluded: GIST, Kaposi's sarcoma, mesothelioma, dermatofibrosarcoma, chordoma, alveolar soft-part sarcoma. Also, all bone sarcomas are excluded including Ewing's sarcoma, osteosarcoma, GIST, low grade chondrosarcoma, and chordoma.
  • Patients who have had treatment with chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to starting study treatment or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.
  • Patients who are receiving any other investigational agents.
  • Patients with known brain metastases.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to gemcitabine, docetaxel, vorinostat, or G-CSF.
  • Patients who have received and progressed on the combination of gemcitabine and docetaxel in the metastatic setting.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Pregnant and breastfeeding women
  • Patients taking concomitant HDAC inhibitors.
  • HIV-positive patients on combination antiretroviral treatment

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): NCT01879085


Locations
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United States, Pennsylvania
Hillman Cancer Center
Pittsburgh, Pennsylvania, United States, 15232
Sponsors and Collaborators
Melissa Burgess, MD
Merck Sharp & Dohme Corp.
Investigators
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Principal Investigator: Melissa Burgess, MD University of Pittsburgh
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Responsible Party: Melissa Burgess, MD, Assistant Professor of Medicine Division of Hematology/Oncology, University of Pittsburgh
ClinicalTrials.gov Identifier: NCT01879085    
Other Study ID Numbers: UPCI# 12-104
First Posted: June 17, 2013    Key Record Dates
Last Update Posted: March 3, 2021
Last Verified: February 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Keywords provided by Melissa Burgess, MD, University of Pittsburgh:
advanced
metastatic
unresectable
soft
tissue
sarcomas
Additional relevant MeSH terms:
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Sarcoma
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Gemcitabine
Docetaxel
Vorinostat
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Histone Deacetylase Inhibitors