Gemcitabine Hydrochloride With or Without Pazopanib Hydrochloride in Treating Patients With Refractory Soft Tissue Sarcoma

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by OHSU Knight Cancer Institute
Sponsor:
Collaborator:
GlaxoSmithKline
Information provided by (Responsible Party):
OHSU Knight Cancer Institute
ClinicalTrials.gov Identifier:
NCT01532687
First received: February 6, 2012
Last updated: July 26, 2014
Last verified: July 2014
  Purpose

This randomized phase II trial studies how well gemcitabine hydrochloride works with or without pazopanib hydrochloride in treating patients with refractory soft tissue sarcoma. Drugs used in chemotherapy, such as gemcitabine hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Pazopanib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Pazopanib hydrochloride may also stop the growth of tumor cells by blocking blood flow to the tumor. It is not yet known whether gemcitabine hydrochloride is more effective with or without pazopanib hydrochloride in treating patients with soft tissue sarcoma


Condition Intervention Phase
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
Drug: gemcitabine hydrochloride
Drug: pazopanib hydrochloride
Other: placebo
Other: laboratory biomarker analysis
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: A Randomized, Double-Blind Phase II, Study of Gemcitabine Alone or in Combination With Pazopanib for Refractory Soft Tissue Sarcoma

Resource links provided by NLM:


Further study details as provided by OHSU Knight Cancer Institute:

Primary Outcome Measures:
  • Progression-free survival (PFS) [ 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 ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • PFS (for a sub-group of patients treated with single-agent pazopanib hydrochloride following administration of gemcitabine hydrochloride in the cross-over portion of this study) [ Time Frame: Calculated as the time from receiving open-labeled pazopanib hydrochloride to the next documented progression or death whichever occurs first, assessed up to 3 years ] [ Designated as safety issue: No ]
  • Response rate (RR) [ Time Frame: Assessed up to 3 years ] [ Designated as safety issue: No ]
  • Best overall response rate (ORR) [ Time Frame: Assessed up to 3 years ] [ Designated as safety issue: No ]
  • Overall survival (OS) [ Time Frame: From randomization to death due to any cause, or until last patient contact if the patient did not die, assessed up to 3 years ] [ Designated as safety issue: No ]
  • Adverse events and serious adverse events, defined using the Common Terminology Criteria for Adverse Events (CTCAE) v 4.0. [ Time Frame: The duration of the study, up to 3 years ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 80
Study Start Date: March 2012
Estimated Primary Completion Date: March 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I (gemcitabine hydrochloride and pazopanib hydrochloride)
Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and pazopanib hydrochloride PO on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Drug: gemcitabine hydrochloride
Given IV
Other Names:
  • dFdC
  • difluorodeoxycytidine hydrochloride
  • gemcitabine
  • Gemzar
Drug: pazopanib hydrochloride
Given PO
Other Names:
  • GW786034
  • Votrient
Other: laboratory biomarker analysis
Correlative studies
Active Comparator: Arm II (gemcitabine hydrochloride, placebo)
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.
Drug: gemcitabine hydrochloride
Given IV
Other Names:
  • dFdC
  • difluorodeoxycytidine hydrochloride
  • gemcitabine
  • Gemzar
Drug: pazopanib hydrochloride
Given PO
Other Names:
  • GW786034
  • Votrient
Other: placebo
Given PO
Other Name: PLCB
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

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.

SECONDARY OBJECTIVES:

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 pazopanib.

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 study.

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.

  Eligibility

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

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 milli-international units per milliliter (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 follows:

    • 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 milliseconds (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
  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: NCT01532687

Contacts
Contact: Dave Boody-Alter 503-418-9655 boodyalt@ohsu.edu

Locations
United States, Oregon
OHSU Knight Cancer Institute Recruiting
Portland, Oregon, United States, 97239
Contact: David Boody-Alter       boodyalt@ohsu.edu   
Principal Investigator: Christopher W. Ryan         
Sponsors and Collaborators
OHSU Knight Cancer Institute
GlaxoSmithKline
Investigators
Principal Investigator: Christopher Ryan OHSU Knight Cancer Institute
  More Information

No publications provided

Responsible Party: OHSU Knight Cancer Institute
ClinicalTrials.gov Identifier: NCT01532687     History of Changes
Other Study ID Numbers: 7943, NCI-2012-00052, IRB# 7943
Study First Received: February 6, 2012
Last Updated: July 26, 2014
Health Authority: United States: Federal Government
United States: Institutional Review Board

Additional relevant MeSH terms:
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
Neoplasms, Fibrous Tissue
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Hemangioma
Neoplasms, Vascular Tissue
Neoplasms, Muscle Tissue

ClinicalTrials.gov processed this record on August 27, 2014