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A Randomized, Double-Blind Phase II, Study of Gemcitabine Alone or in Combination With Pazopanib for Refractory Soft Tissue Sarcoma

Phase 2
15 Years
Open (Enrolling)
Adult Alveolar Soft-part Sarcoma, Adult Angiosarcoma, Adult Desmoplastic Small Round Cell Tumor, Adult Epithelioid Hemangioendothelioma, Adult Epithelioid Sarcoma, Adult Extraskeletal Chondrosarcoma, Adult Extraskeletal Osteosarcoma, Adult Fibrosarcoma, Adult Leiomyosarcoma, Adult Liposarcoma, Adult Malignant Fibrous Histiocytoma, Adult Malignant Hemangiopericytoma, Adult Malignant Mesenchymoma, Adult Neurofibrosarcoma, Adult Rhabdomyosarcoma, Adult Synovial Sarcoma, Childhood Alveolar Soft-part Sarcoma, Childhood Angiosarcoma, Childhood Desmoplastic Small Round Cell Tumor, Childhood Epithelioid Hemangioendothelioma, Childhood Epithelioid Sarcoma, Childhood Fibrosarcoma, Childhood Leiomyosarcoma, Childhood Liposarcoma, Childhood Malignant Hemangiopericytoma, Childhood Malignant Mesenchymoma, Childhood Neurofibrosarcoma, Childhood Synovial Sarcoma, Dermatofibrosarcoma Protuberans, Metastatic Childhood Soft Tissue Sarcoma, Nonmetastatic Childhood Soft Tissue Sarcoma, Recurrent Adult Soft Tissue Sarcoma, Recurrent Childhood Soft Tissue Sarcoma, Stage III Adult Soft Tissue Sarcoma, Stage IV Adult Soft Tissue Sarcoma

Thank you

Trial Information

A Randomized, Double-Blind Phase II, Study of Gemcitabine Alone or in Combination With Pazopanib for Refractory Soft Tissue Sarcoma


I. To investigate whether treatment with gemcitabine (gemcitabine hydrochloride) plus
pazopanib (pazopanib hydrochloride) improves the median progression-free survival of
patients with metastatic soft tissue sarcoma when compared to gemcitabine plus placebo.


I. To assess response rate in this population to gemcitabine plus pazopanib compared to
gemcitabine plus placebo.

II. To assess overall survival in this population to gemcitabine plus pazopanib compared to
gemcitabine plus placebo.

III. To investigate differences in treatment response in different histologic subgroups
(liposarcoma vs. all other eligible soft tissue sarcoma subtypes).

IV. To evaluate the safety and tolerability of the combination of gemcitabine plus

V. To assess the progression-free survival and response rate in patients treated with single
agent pazopanib following administration of gemcitabine in the cross-over portion of this

VI. To collect specimens for an exploratory analysis of potential biomarkers that predict
response in patients receiving combination therapy with gemcitabine plus pazopanib.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive gemcitabine hydrochloride intravenously (IV) over 30 minutes on days
1 and 8 and pazopanib hydrochloride orally (PO) on days 1-21. Courses repeat every 21 days
in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and
placebo PO on days 1-21. Courses repeat every 21 days in the absence of disease progression
or unacceptable toxicity. Patients who experience disease progression may receive
single-agent pazopanib hydrochloride PO once daily. Courses repeat every 21 days in the
absence of disease progression or unacceptable toxicity.

After the completion of study treatment, patients are followed up every 3 months.

Inclusion Criteria:

- Subjects must provide written informed consent prior to performance of study-specific
procedures or assessments, and must be willing to comply with treatment and
follow-up; procedures conducted as part of the subject's routine clinical management
(e.g., blood count, imaging study) and obtained prior to signing of informed consent
may be utilized for screening or baseline purposes provided these procedures are
conducted as specified in the protocol

- Histologically confirmed diagnosis of metastatic or unresectable soft tissue sarcoma,
excluding gastrointestinal stromal tumors, Kaposi's sarcoma, Ewing's family of
tumors, and embryonal or alveolar rhabdomyosarcoma

- Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

- Measurable disease per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1

- Patients must have received at least one, but not more than three, systemic regimens
for treatment of metastatic soft tissue sarcoma; patients must have had a prior
anthracycline in either the adjuvant or metastatic setting unless medically
inappropriate for the patient

- Adjuvant therapy will not count towards prior treatment for metastatic disease,
unless the patient relapsed within 1 year of completing adjuvant therapy

- Absolute neutrophil count (ANC) >= 1.5 X 10^9/L

- Hemoglobin >= 9 g/dL (5.6 mmol/L); subjects may not have had a transfusion within 7
days of screening assessment

- Platelets >= 100 X 10^9/L

- Prothrombin time (PT) or international normalized ratio (INR) =< 1.2 X upper limit of
normal (ULN); subjects receiving anticoagulation therapy are eligible if their INR is
stable and within the recommended range for the desired level of anticoagulation

- Activated partial thromboplastin time (aPTT) =< 1.2 X ULN

- Total bilirubin =< 1.5 X ULN

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 X ULN;
concomitant elevations in bilirubin and AST/ALT above 1.0 x ULN are not permitted

- Serum creatinine =< 1.5 mg/dL (133 μmol/L) Or, if > 1.5 mg/dL: calculated creatinine
clearance (ClCR) >= 30 mL/min

- Urine Protein to Creatinine Ratio (UPC) < 1; if UPC >= 1, then a 24-hour urine
protein must be assessed; subjects must have a 24-hour urine protein value < 1 g to
be eligible; use of urine dipstick for renal function assessment is not acceptable Or
24-hour urine protein < 1 g

- A female is eligible to enter and participate in this study if she is of:

* Non-childbearing potential (i.e., physiologically incapable of becoming pregnant),
including any female who has had:

- A hysterectomy

- A bilateral oophorectomy (ovariectomy)

- A bilateral tubal ligation

- Is post-menopausal

- Subjects not using hormone replacement therapy (HRT) must have experienced total
cessation of menses for >= 1 year and be greater than 45 years in age, OR, in
questionable cases, have a follicle stimulating hormone (FSH) value > 40 mIU/mL and
an estradiol value < 40 pg/mL (< 140 pmol/L)

- Subjects using HRT must have experienced total cessation of menses for >= 1 year and
be greater than 45 years of age OR have had documented evidence of menopause based on
FSH and estradiol concentrations prior to initiation of HRT

- Childbearing potential, including any female who has had a negative serum pregnancy
test within 7 days prior to the first dose of study treatment, preferably as close to
the first dose as possible, and agrees to use adequate contraception; defined as

- Complete abstinence from sexual intercourse for 14 days before exposure to
investigational product, through the dosing period, and for at least 21 days
after the last dose of investigational product

- Oral contraceptive, either combined or progestogen alone

- Injectable progestogen

- Implants of levonorgestrel

- Estrogenic vaginal ring

- Percutaneous contraceptive patches

- Intrauterine device (IUD) or intrauterine system (IUS) with a documented failure
rate of less than 1% per year

- Male partner sterilization (vasectomy with documentation of azoospermia) prior
to the female subject's entry into the study, and this male is the sole partner
for that subject

- Double barrier method: condom and an occlusive cap (diaphragm or cervical/vault
caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository)

- Female subjects who are lactating should discontinue nursing prior to the first dose
of study drug and should refrain from nursing throughout the treatment period and for
14 days following the last dose of study drug

Exclusion Criteria:

- Prior malignancy; Note: subjects who have had another malignancy and have been
disease-free for > 3 years, or subjects with a history of completely resected
non-melanomatous skin carcinoma, successfully treated in situ carcinoma, or
successfully treated bladder cancer are eligible

- History or clinical evidence of central nervous system (CNS) metastases or
leptomeningeal carcinomatosis, except for individuals who have previously-treated CNS
metastases, are asymptomatic, and have had no requirement for steroids or
anti-seizure medication for 6 months prior to first dose of study drug; screening
with CNS imaging studies (computed tomography [CT] or magnetic resonance imaging
[MRI]) is required only if clinically indicated or if the subject has a history of
CNS metastases

- Clinically significant gastrointestinal abnormalities that may increase the risk for
gastrointestinal bleeding including, but not limited to:

- Active peptic ulcer disease

- Known intraluminal metastatic lesion/s with risk of bleeding

- 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

- 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

- Presence of uncontrolled infection

- Corrected QT interval (QTc) > 480 msecs using Bazett's formula

- 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

- Class III or IV congestive heart failure, as defined by the New York Heart
Association (NYHA)

- 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; following
antihypertensive medication initiation or adjustment, blood pressure (BP) must be
re-assessed three times at approximately 2-minute intervals; at least 24 hours must
have elapsed between anti-hypertensive medication initiation or adjustment and BP
measurement; these three values should be averaged to obtain the mean diastolic blood
pressure and the mean systolic blood pressure; the mean SBP/DBP ratio must be <
140/90 mmHg

- 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
anti-coagulating agents for at least 6 weeks are eligible

- Prior major surgery or trauma within 28 days prior to first dose of study drug and/or
presence of any non-healing wound, fracture, or ulcer (procedures such as catheter
placement not considered to be major)

- Evidence of active bleeding or bleeding diathesis

- Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels that
increase the risk of pulmonary hemorrhage

- Hemoptysis in excess of 2.5 mL (or one half teaspoon) within 8 weeks of first dose of
study drug

- Any serious and/or unstable pre-existing medical, psychiatric, or other condition
that could interfere with subject's safety, provision of informed consent, or
compliance to study procedures

- Unable or unwilling to discontinue use of prohibited medications for at least 14 days
or five half-lives of a drug (whichever is longer) prior to the first dose of study
drug and for the duration of the study; 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

- Treatment with any of the following anti-cancer therapies:

- Radiation therapy, surgery or tumor embolization within 14 days prior to the
first dose of pazopanib OR* Chemotherapy, immunotherapy, biologic therapy,
investigational therapy or hormonal therapy within 14 days or five half-lives of
a drug (whichever is longer) prior to the first dose of Pazopanib

- Any prior treatment with pazopanib or vascular endothelial growth factor (VEGF)
or vascular endothelial growth factor receptor (VEGFR)-targeting agents (eg.
sorafenib, sunitinib, and bevacizumab)

- Any prior treatment with gemcitabine

- Any ongoing toxicity from prior anti-cancer therapy that is > Grade 1 and/or that is
progressing in severity, except alopecia

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Outcome Measure:

Progression-free survival (PFS)

Outcome Description:

Compared using a one-sided log-rank test stratified by sarcoma subtype and study site. Kaplan-Meier estimates and the survival curves for each treatment arm will be presented with the estimated hazard ratios and their associated confidence intervals.

Outcome Time Frame:

Calculated as the time from randomization to the first documented progression or death whichever occurs first, or until time of last contact if no progression or death occurred, assessed up to 3 years

Safety Issue:


Principal Investigator

Christopher Ryan

Investigator Role:

Principal Investigator

Investigator Affiliation:

OHSU Knight Cancer Institute


United States: Federal Government

Study ID:




Start Date:

March 2012

Completion Date:

Related Keywords:

  • Adult Alveolar Soft-part Sarcoma
  • Adult Angiosarcoma
  • Adult Desmoplastic Small Round Cell Tumor
  • Adult Epithelioid Hemangioendothelioma
  • Adult Epithelioid Sarcoma
  • Adult Extraskeletal Chondrosarcoma
  • Adult Extraskeletal Osteosarcoma
  • Adult Fibrosarcoma
  • Adult Leiomyosarcoma
  • Adult Liposarcoma
  • Adult Malignant Fibrous Histiocytoma
  • Adult Malignant Hemangiopericytoma
  • Adult Malignant Mesenchymoma
  • Adult Neurofibrosarcoma
  • Adult Rhabdomyosarcoma
  • Adult Synovial Sarcoma
  • Childhood Alveolar Soft-part Sarcoma
  • Childhood Angiosarcoma
  • Childhood Desmoplastic Small Round Cell Tumor
  • Childhood Epithelioid Hemangioendothelioma
  • Childhood Epithelioid Sarcoma
  • Childhood Fibrosarcoma
  • Childhood Leiomyosarcoma
  • Childhood Liposarcoma
  • Childhood Malignant Hemangiopericytoma
  • Childhood Malignant Mesenchymoma
  • Childhood Neurofibrosarcoma
  • Childhood Synovial Sarcoma
  • Dermatofibrosarcoma Protuberans
  • Metastatic Childhood Soft Tissue Sarcoma
  • Nonmetastatic Childhood Soft Tissue Sarcoma
  • Recurrent Adult Soft Tissue Sarcoma
  • Recurrent Childhood Soft Tissue Sarcoma
  • Stage III Adult Soft Tissue Sarcoma
  • Stage IV Adult Soft Tissue Sarcoma
  • Histiocytoma
  • Chondrosarcoma
  • Fibrosarcoma
  • Hemangioendothelioma
  • Hemangiopericytoma
  • Hemangiosarcoma
  • Leiomyosarcoma
  • Liposarcoma
  • Mesenchymoma
  • Osteosarcoma
  • Rhabdomyosarcoma
  • Sarcoma, Synovial
  • Sarcoma
  • Histiocytoma, Benign Fibrous
  • Dermatofibrosarcoma
  • Sarcoma, Alveolar Soft Part
  • Neurofibrosarcoma
  • Neurilemmoma
  • Hemangioendothelioma, Epithelioid
  • Desmoplastic Small Round Cell Tumor
  • Histiocytoma, Malignant Fibrous
  • Liver Neoplasms



OHSU Knight Cancer Institute Portland, Oregon  97239