Gemcitabine and Docetaxel in Combination With Pazopanib (Gem/Doce/Pzb) for the Neoadjuvant Treatment of Soft Tissue Sarcoma (STS)

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by Memorial Sloan-Kettering Cancer Center
Sponsor:
Collaborators:
National Comprehensive Cancer Network
University of California, Los Angeles
Washington University School of Medicine
Northwestern University
Information provided by (Responsible Party):
Memorial Sloan-Kettering Cancer Center
ClinicalTrials.gov Identifier:
NCT01418001
First received: August 15, 2011
Last updated: August 5, 2014
Last verified: August 2014
  Purpose

The purpose of this study is to see the effects, good and/or bad, of the drug combination of gemcitabine, docetaxel and pazopanib on sarcoma. This is a phase Ib-phase II clinical trial. The goal of a phase Ib part of the clinical trial is to confirm a dose of the drugs that is safe. The investigators determine this by closely checking for side effects that the patient may experience.


Condition Intervention Phase
Sarcoma
Leiomyosarcoma
Malignant Peripheral Nerve Sheath Tumor
Malignant Fibrous
Histiocytoma/Undifferentiated Pleomorphic Sarcoma
Drug: Gemcitabine and Docetaxel in Combination with Pazopanib
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase IB/II Study of Gemcitabine and Docetaxel in Combination With Pazopanib (Gem/Doce/Pzb) for the Neoadjuvant Treatment of Soft Tissue Sarcoma (STS)

Resource links provided by NLM:


Further study details as provided by Memorial Sloan-Kettering Cancer Center:

Primary Outcome Measures:
  • maximum tolerated dose (MTD) [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    standard 3+3 format

  • To assess the effectiveness of in improving distant relapse free survival (DRFS) [ Time Frame: 2 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • pathologic response [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    will be assessed by both MRI and by pathologic review after surgery. An estimate of each response rate and the 95% CI will be provided

  • time to distant recurrence [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • time to local recurrence [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • pathologic response to the combination therapy based in post-treatment specimen [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    Histologic response to the combination of pazopanib /gemcitabine/docetaxel will be assessed as a percentage and will be graded, based on the gross and microscopic amounts of necrosis and fibrosis, using a previously proposed grading scheme47: 1, minimal (0-10% response); 2, low (>10% and ≤50% response); 3, moderate (>50% and ≤90% response); and 4, high (>90% response). Other histologic variables, including the type of tumor (spindle/epithelioid) and mitotic count (per 50 high-power fields), were recorded.


Estimated Enrollment: 61
Study Start Date: August 2011
Estimated Study Completion Date: August 2015
Estimated Primary Completion Date: August 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Gemcitabine and Docetaxel in Combination with Pazopanib
This will be a multicenter single arm phase IB/II trial to evaluate the clinical safety and efficacy of gemcitabine/docetaxel and pazopanib in the neoadjuvant treatment of soft tissue sarcoma.
Drug: Gemcitabine and Docetaxel in Combination with Pazopanib

Patients who meet the eligibility criteria above will be treated with the combination therapy of Gemcitabine, Docetaxel, and Pazopanib for two cycles and subsequently re-evaluated for treatment effect. If no progression of the tumor is seen, patients will continue with two more cycles of treatment (total four cycles). Those patients who have progression of disease will proceed directly to surgical resection.

Following completion of neoadjuvant treatment, all patients will have definitive surgical resection. Following recovery from surgery, patients will proceed with adjuvant radiation therapy. Patients will then be followed for up to 2 years.


  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have histologically or cytologically confirmed extremity only, ≥8 cm, high grade STS (MPNST, MFH/UPS, LMS) at MSKCC or locally for participating sites.
  • Subjects must have only localized disease that is potentially amenable to definitive resection.
  • The first 15 MSKCC patients on the Phase II portion of the protocol must undergo either an open incisional or core tumor biopsy prior to the initiation of therapy.
  • Patients must have measurable disease by RECIST 1.1, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >20 mm with conventional techniques or as >10 mm with spiral CT scan. See Section 10 for the evaluation of measurable disease.
  • Age >18 years. ECOG performance status 0 or 1.
  • Patients must have normal organ and marrow function as defined below (ULN indicates institutional upper limit of normal): Absolute neutrophil count (ANC) ≥1.5 X 109/L Hemoglobin ≥9 g/dL (5.6 mmol/L) Platelets ≥100 X 109/L International normalized ratio (INR) ≤1.2 X ULN Activated partial thromboplastin time (aPTT)≤1.2 X ULN Total bilirubin ≤1.5 X ULN Alanine amino, transferase (ALT) and Aspartate aminotransferase (AST) ≤2.5 X ULN Serum creatinine ≤1.5 mg/dL (133 μmol/L) Or, if serum creatinine, >1.5 mg/dL: Calculated creatinine clearance (ClCR)

    ≥30 mL/min to ≥50 mL/min Urine Protein to Creatinine Ratio (UPC; appropriate appendix) <1 Or, 24-hour urine protein <1g

  • Patients must not have current evidence of another malignancy.
  • Pazopanib, gemcitabine and docetaxel all carry category D (positive evidence of risk) pregnancy status. For this reason women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) during therapy and for at least 8 weeks after completion of therapy and have pregnancy testing prior to study entry and after two cycles of treatment. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately.

Exclusion Criteria:

  • Patients who have had major surgery 4 weeks prior to entering the study, or those who have not recovered from adverse events to ≤ NCI CTC AE Grade 1, associated with surgery. Excluded from such considerations are surgical changes not expected to improve, e.g. removal of muscle tissue.
  • Patients must not have had been treated previously with radiation, chemotherapy or other anti-cancer agent for the current disease.
  • History of allergic reactions or hypersensitivity reactions attributed to compounds of similar chemical or biologic composition to pazopanib, gemcitabine, docetaxel or other agents used in the study.
  • Patients with a contraindication to MRIs.
  • Patients who required concomitant treatment with medications that are known to be inhibitors or strong inducers of isoenzyme CYP3A4, CYP2C8, and CYP2D6 unless the drugs are medically necessary and no substitutes are available. If there are no acceptable substitutes, special precautions should be taken in these patients. Similarly, co-administration with CYP3A inhibitors (e.g. Ergot derivatives, Neuroleptics, Antiarrhythmics, Immune modulators and miscellaneous agents such quetiapine, risperidone, clozapine, atomoxetine, and inducers (e.g. Glucocorticoids, Anticonvulsants, HIV antivirals, Antibiotics, miscellaneous agents such as St. John's Wort, modafinil, pioglitazone, troglitazone, simvastatin, should also be avoided if possible, or otherwise subject to caution (e.g. increased frequency of safety monitoring). Strong CYP3A4 inhibitors are PROHIBITED within 14 days prior to the first dose of pazopanib including: Antibiotics, HIV protease inhibitors, Antifungals and Antidepressants
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, including HIV, active hepatitis B or C, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, poorly controlled diabetes or psychiatric illness/social situations that would limit compliance with study requirements. Hepatitis B and C will be screened for in all patients prior to initiating treatment via hepatitis B serologic markers, that is, HBsAg, HBs Ab, HBc Ab and Hep C Antibody. If patients have positive serologic markers, viral load markers (HBV-DNA and Hepatitis C RNA-PCR) will be performed during screening to confirm disease as well as screening for hepatitis C via quantitative RNA-PCR.
  • Pregnant women and women who are breast-feeding.
  • HIV -positive patients on combination antiretroviral therapy due to the potential for pharmacokinetic interactions with pazopanib.
  • Patients with significant respiratory compromise or an active and unexplained pneumonitis given that these patients would have an increased risk of pneumonitis from gemcitabine, and would also confuse the evaluation of pneumonitis on the trial
  • Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding including, but not limited to:

Active peptic ulcer disease

  • Inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease), or other gastrointestinal conditions with increased risk of perforation
  • History of abdominal fistula, gastrointestinal perforation, or intra-abdominal
  • abscess within 28 days prior to beginning study treatment Active diarrhea of any grade
  • Clinically significant gastrointestinal abnormalities that may affect absorption of investigational product including, but not limited to:
  • Malabsorption syndrome
  • Major resection of the stomach or small bowel
  • History of any one or more of the following cardiovascular conditions within the past 6 months:

Cardiac angioplasty or stenting Myocardial infarction Unstable angina Coronary artery bypass graft surgery Symptomatic peripheral vascular disease

  • History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months.
  • Note: Subjects with recent DVT who have been treated with therapeutic anticoagulating agents for at least 6 weeks are eligible
  • Corrected QT interval (QTc) ≥ 450 msecs using Bazett's formula (append formula); for subjects with bundle branch block (BBB), QTc ≥480 msecs using Bazett's formula.)
  • Poorly controlled hypertension, defined as systolic blood pressure (SBP) of ≥140 mmHg or diastolic blood pressure (DBP) of ≥ 90mmHg.
  • Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry.

History of Class III or IV congestive heart failure, as defined by the New York Heart Association Classification of Congestive Heart Failure [see Appendix D for description]

  • Evidence of active bleeding or bleeding diathesis
  • Administration of any non-oncologic investigational drug within 30 days or 5 half lives whichever is longer prior to receiving the first dose of study treatment.
  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: NCT01418001

Contacts
Contact: William Tap, MD 646-888-4163
Contact: Sandra D'Angelo, MD 646-888-4159

Locations
United States, California
UCLA Recruiting
Los Angeles, California, United States, 90095
Contact: Arun Singh, MD         
Principal Investigator: Arun Singh, MD         
United States, Illinois
Northwestern University Recruiting
Evanston, Illinois, United States, 60208
Contact: Mark Agulnik, MD         
Principal Investigator: Mark Agulnik, MD         
United States, Missouri
Washington University School of Medicine Recruiting
St Louis, Missouri, United States, 63110
Contact: Brian Van Tine, MD         
Principal Investigator: Brian Van Tine, MD         
United States, New York
Memorial Sloan-Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: William Tap, MD    646-888-4163      
Contact: Sandra D'Angelo, MD    646-888-4159      
Principal Investigator: William Tap, MD         
Sponsors and Collaborators
Memorial Sloan-Kettering Cancer Center
National Comprehensive Cancer Network
University of California, Los Angeles
Washington University School of Medicine
Northwestern University
Investigators
Principal Investigator: William Tap, MD Memorial Sloan-Kettering Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: Memorial Sloan-Kettering Cancer Center
ClinicalTrials.gov Identifier: NCT01418001     History of Changes
Other Study ID Numbers: 11-104
Study First Received: August 15, 2011
Last Updated: August 5, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Memorial Sloan-Kettering Cancer Center:
GEMCITABINE
GW786034 (PAZOPANIB)
TAXOTERE (DOCETAXEL)
11-104

Additional relevant MeSH terms:
Sarcoma
Histiocytoma
Leiomyosarcoma
Nerve Sheath Neoplasms
Neurofibrosarcoma
Neurilemmoma
Histiocytoma, Malignant Fibrous
Neoplasms, Fibrous Tissue
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Muscle Tissue
Neoplasms, Nerve Tissue
Peripheral Nervous System Neoplasms
Nervous System Neoplasms
Nervous System Diseases
Peripheral Nervous System Diseases
Neuromuscular Diseases
Fibrosarcoma
Neurofibroma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neuroma
Gemcitabine
Docetaxel
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on August 27, 2014