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)
- 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
- 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.
- 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
- 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
- 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
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
- 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.