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

Sponsor
OHSU Knight Cancer Institute (Other)
Overall Status
Completed
CT.gov ID
NCT01532687
Collaborator
Novartis Pharmaceuticals (Industry), Oregon Health and Science University (Other)
54
Enrollment
2
Locations
2
Arms
91.6
Actual Duration (Months)
27
Patients Per Site
0.3
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Detailed Description

PRIMARY OBJECTIVES:
  1. To investigate whether treatment with gemcitabine (gemcitabine hydrochloride) plus pazopanib (pazopanib hydrochloride) improves the median progression-free survival (PFS) of patients with metastatic soft tissue sarcoma when compared to gemcitabine plus placebo.
SECONDARY OBJECTIVES:
  1. To assess overall response in this population to gemcitabine plus pazopanib compared to gemcitabine plus placebo.

  2. To assess overall survival (OS) in this population to gemcitabine plus pazopanib compared to gemcitabine plus placebo.

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

  4. To evaluate the safety and tolerability of the combination of gemcitabine plus pazopanib.

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

  6. 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. Cycles 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. Cycles 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 daily. Cycles 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.

Study Design

Study Type:
Interventional
Actual Enrollment :
54 participants
Allocation:
Randomized
Intervention Model:
Crossover Assignment
Masking:
Double (Participant, 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
Actual Study Start Date :
Mar 13, 2012
Actual Primary Completion Date :
Oct 31, 2019
Actual Study Completion Date :
Oct 31, 2019

Arms and Interventions

ArmIntervention/Treatment
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. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Drug: Gemcitabine
Given IV
Other Names:
  • dFdC
  • dFdCyd
  • Difluorodeoxycytidine
  • Drug: Gemcitabine Hydrochloride
    Given IV
    Other Names:
  • dFdCyd
  • Difluorodeoxycytidine Hydrochloride
  • FF 10832
  • FF-10832
  • FF10832
  • Gemcitabine HCI
  • Gemzar
  • LY-188011
  • LY188011
  • Other: Laboratory Biomarker Analysis
    Correlative studies

    Drug: Pazopanib
    Given PO
    Other Names:
  • GW786034
  • Drug: Pazopanib Hydrochloride
    Given PO
    Other Names:
  • GW786034B
  • Votrient
  • 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. Cycles 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 daily. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

    Drug: Gemcitabine
    Given IV
    Other Names:
  • dFdC
  • dFdCyd
  • Difluorodeoxycytidine
  • Drug: Gemcitabine Hydrochloride
    Given IV
    Other Names:
  • dFdCyd
  • Difluorodeoxycytidine Hydrochloride
  • FF 10832
  • FF-10832
  • FF10832
  • Gemcitabine HCI
  • Gemzar
  • LY-188011
  • LY188011
  • Other: Laboratory Biomarker Analysis
    Correlative studies

    Drug: Pazopanib
    Given PO
    Other Names:
  • GW786034
  • Drug: Pazopanib Hydrochloride
    Given PO
    Other Names:
  • GW786034B
  • Votrient
  • Other: Placebo Administration
    Given PO

    Outcome Measures

    Primary Outcome Measures

    1. Progression-free Survival (PFS) [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]

      Compared using a one-sided Gehan-Wilcoxon test stratified by sarcoma subtype. Kaplan-Meier estimates for each treatment arm will be presented with the estimated hazard ratios and their associated confidence intervals. Progression is defined using Response Evaluation Criteria in Solid Tumors (RECIST) v1.0 as at least a 20% increase in the sum of the longest diameters of target lesions (taking as reference the smallest sum on study) with an absolute increase of at least 5 mm (target lesions), or measurable increase in non-target lesions (unequivocal progression), or appearance of one or more new lesions.

    Secondary Outcome Measures

    1. Progression-free Survival (PFS) for a Sub-group of Patients Treated With Open-label Pazopanib Hydrochloride Following Administration of Gemcitabine Hydrochloride in the Cross-over Portion of This Study [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]

      Participants who progress during treatment and are found to be part of the gemcitabine+placebo arm after unblinding are eligible to receive open-label pazopanib with gemcitabine. This is the crossover population. Statistical analysis is exploratory and requires sufficient crossover participants to assess Kaplan-Meier estimated hazard ratio and associated 95% confidence interval. This represents the participants second progression. In both cases progression is defined using Response Evaluation Criteria in Solid Tumors (RECIST) v1.0 as at least a 20% increase in the sum of the longest diameters of target lesions with an absolute increase of at least 5 mm (target lesions), or measurable increase in non-target lesions (unequivocal progression), or appearance of one or more new lesions. First progression uses the smallest sum on study as a reference; progression for the crossover population uses first progression measurements as the reference.

    2. Percentage of Participants Achieving Best Overall Objective Response (CR+PR) [Best overall objective response recorded from the start of treatment until disease progression/recurrence assessed up to 3 years]

      Response is evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, where RECIST combines assessments for target, non-target and presence of new lesions. Best Overall Objective Response is the sum of all CR+PR divided by all randomized participants, where the strongest recorded response is used for the evaluation (CR>PR>SD>PD). Objective response (CR+PR) requires at least a 30% decrease in the sum of the largest diameter target lesions (with respective to the baseline sum); disappearance of all or persistence of one or more non-target lesions, maintenance of tumor marker levels above normal limits, and no new lesions. Estimated odds ratio of best overall objective response are reported with 95% confidence interval for the two histologic sarcoma subgroups (liposarcoma vs all other eligible soft tissue sarcoma subtypes). One-sided proportions test is used to determine whether best overall objective response is greater for the gemcitabine plus pazopanib group.

    3. Overall Survival [From randomization to death due to any cause, or until last patient contact if the patient did not die, assessed up to 3 years]

      Two treatment arms will be 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 interval.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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 the neoadjuvant, adjuvant, or metastatic setting unless medically inappropriate for the patient

    • Neoadjuvant or adjuvant therapy will not count towards prior treatment for metastatic disease, unless the patient relapsed within 2 years of completing such therapy.

    • Absolute neutrophil count (ANC) >= 1.5 x 10^9/L

    • Hemoglobin >= 8 g/dL; 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 (upper limit of normal) are not permitted

    • Serum creatinine =< 1.5 mg/dL (133 umol/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 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 progesterone alone

    • Injectable progesterone

    • 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 superficial 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 28 days in the case of monoclonal antibody therapy) prior to the first dose of pazopanib.

    • Any prior treatment with pazopanib.

    • Prior treatment with vascular endothelial growth factor (VEGF) or vascular endothelial growth factor receptor (VEGFR)-targeting agents other than pazopanib (eg. sorafenib, sunitinib, and bevacizumab) in the metastatic setting. Prior use of such agents in the neoadjuvant or adjuvant setting is permitted.

    • Any prior treatment with gemcitabine for metastatic disease. Prior use of gemcitabine in the neoadjuvant or adjuvant setting is permitted.

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

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1OHSU Knight Cancer InstitutePortlandOregonUnited States97239
    2Fred Hutch/University of Washington Cancer ConsortiumSeattleWashingtonUnited States98109

    Sponsors and Collaborators

    • OHSU Knight Cancer Institute
    • Novartis Pharmaceuticals
    • Oregon Health and Science University

    Investigators

    • Principal Investigator: Christopher W Ryan, OHSU Knight Cancer Institute

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Christopher Ryan, Principal Investigator, OHSU Knight Cancer Institute
    ClinicalTrials.gov Identifier:
    NCT01532687
    Other Study ID Numbers:
    • IRB00007943
    • NCI-2012-00052
    • IRB00007943
    First Posted:
    Feb 14, 2012
    Last Update Posted:
    Sep 27, 2021
    Last Verified:
    Sep 1, 2021

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment DetailDouble-blinded randomization (1:1) was stratified by subtypes of sarcoma (liposarcoma vs. all other eligible soft tissue sarcoma subtypes). Patients were randomized to either experimental arm or placebo arm prior to starting treatment. Those who discontinued treatment on the placebo arm due to disease progression were eligible for treatment with open-label pazopanib (unblinded, cross-over treatment); those who developed disease progression on the Experimental arm (pazopanib arm) were not.
    Arm/Group TitleGemcitabine Hydrochloride Plus Pazopanib HydrochlorideGemcitabine Hydrochloride Plus Placebo
    Arm/Group DescriptionPatients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and pazopanib hydrochloride PO on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Gemcitabine: Given IV Gemcitabine Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Pazopanib: Given PO Pazopanib Hydrochloride: Given POPatients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and placebo PO on days 1-21. Cycles 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 daily. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Gemcitabine: Given IV Gemcitabine Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Pazopanib: Given PO Pazopanib Hydrochloride: Given PO Placebo Administration: Given PO
    Period Title: Overall Study
    STARTED2925
    Crossover to Open-label Pazopanib014
    COMPLETED1523
    NOT COMPLETED142

    Baseline Characteristics

    Arm/Group TitleGemcitabine Hydrochloride Plus Pazopanib HydrochlorideGemcitabine Hydrochloride Plus PlaceboTotal
    Arm/Group DescriptionPatients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and pazopanib hydrochloride PO on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Gemcitabine: Given IV Gemcitabine Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Pazopanib: Given PO Pazopanib Hydrochloride: Given POPatients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and placebo PO on days 1-21. Cycles 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 daily. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Gemcitabine: Given IV Gemcitabine Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Pazopanib: Given PO Pazopanib Hydrochloride: Given PO Placebo Administration: Given POTotal of all reporting groups
    Overall Participants292554
    Age (years) [Median (Inter-Quartile Range) ]
    Median (Inter-Quartile Range) [years]
    63
    56
    60
    Sex: Female, Male (Count of Participants)
    Female
    14
    48.3%
    16
    64%
    30
    55.6%
    Male
    15
    51.7%
    9
    36%
    24
    44.4%
    Race/Ethnicity, Customized (Count of Participants)
    Asian
    1
    3.4%
    0
    0%
    1
    1.9%
    White
    25
    86.2%
    24
    96%
    49
    90.7%
    Unknown/Not Reported
    3
    10.3%
    1
    4%
    4
    7.4%
    Histology (Count of Participants)
    Liposarcoma
    9
    31%
    7
    28%
    16
    29.6%
    Leiomyosarcoma (LMS)
    9
    31%
    5
    20%
    14
    25.9%
    Undifferentiated Pleomorphic Sarcoma (UPS)
    3
    10.3%
    5
    20%
    8
    14.8%
    Synovial Sarcoma
    3
    10.3%
    3
    12%
    6
    11.1%
    Other Sarcoma(s)
    5
    17.2%
    5
    20%
    10
    18.5%
    Number Prior Treatments (Treatments) [Median (Full Range) ]
    Median (Full Range) [Treatments]
    1
    1
    1

    Outcome Measures

    1. Primary Outcome
    TitleProgression-free Survival (PFS)
    DescriptionCompared using a one-sided Gehan-Wilcoxon test stratified by sarcoma subtype. Kaplan-Meier estimates for each treatment arm will be presented with the estimated hazard ratios and their associated confidence intervals. Progression is defined using Response Evaluation Criteria in Solid Tumors (RECIST) v1.0 as at least a 20% increase in the sum of the longest diameters of target lesions (taking as reference the smallest sum on study) with an absolute increase of at least 5 mm (target lesions), or measurable increase in non-target lesions (unequivocal progression), or appearance of one or more new lesions.
    Time FrameCalculated 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

    Outcome Measure Data

    Analysis Population Description
    All randomized participants
    Arm/Group TitleGemcitabine Hydrochloride Plus Pazopanib HydrochlorideGemcitabine Hydrochloride Plus Placebo
    Arm/Group DescriptionPatients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and pazopanib hydrochloride PO on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Gemcitabine: Given IV Gemcitabine Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Pazopanib: Given PO Pazopanib Hydrochloride: Given POPatients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and placebo PO on days 1-21. Cycles 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 daily. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Gemcitabine: Given IV Gemcitabine Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Pazopanib: Given PO Pazopanib Hydrochloride: Given PO Placebo Administration: Given PO
    Measure Participants2925
    All randomized
    4.5
    1.6
    Liposarcoma
    8.9
    1.5
    Other Sarcoma
    4.4
    2.2
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Gemcitabine Hydrochloride Plus Pazopanib Hydrochloride, Gemcitabine Hydrochloride Plus Placebo
    Comments Statistical results are for the full randomized population (n = 54). The study was originally designed with overall one-sided alpha of 5%, where a total of 73 patients (36 in the gemcitabine + placebo arm, and 37 in the gemcitabine + pazopanib arm) were required to achieve 80% power to detect a 2.5 month increase in median PFS (a hazard ratio of 0.55) between the two treatment arms. Study was closed early by the sponsor due to slow accrual and funds and thus was under powered.
    Type of Statistical Test Superiority
    Comments Log-log plots revealed crossing of the curves at late time points, indicating a possible interaction between treatment arms over time. We used the Gehan-Wilcoxon test, which weights early differences between groups, to test whether there is a difference between the treatment arms early in the study.
    Statistical Test of Hypothesisp-Value0.017
    Comments
    MethodGehan-Wilcoxon
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Gemcitabine Hydrochloride Plus Pazopanib Hydrochloride, Gemcitabine Hydrochloride Plus Placebo
    Comments Comparison between the two arms for the liposarcoma subgroup
    Type of Statistical Test Other
    Comments Log-log plots revealed crossing of the curves at late time points, indicating a possible interaction between treatment arms over time. We used the Gehan-Wilcoxon test, which weights early differences between groups, to test whether there is a difference between the treatment arms early in the study.
    Statistical Test of Hypothesisp-Value0.195
    Comments
    MethodGehan-Wilcoxon
    Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Gemcitabine Hydrochloride Plus Pazopanib Hydrochloride, Gemcitabine Hydrochloride Plus Placebo
    Comments Statistical results are for the 'other' sarcoma subgroup (n = 38)
    Type of Statistical Test Other
    Comments Log-log plots revealed crossing of the curves at late time points, indicating a possible interaction between treatment arms over time. We used the Gehan-Wilcoxon test, which weights early differences between groups, to test whether there is a difference between the treatment arms early in the study.
    Statistical Test of Hypothesisp-Value0.079
    Comments
    MethodGehan-Wilcoxon
    Comments
    2. Secondary Outcome
    TitleProgression-free Survival (PFS) for a Sub-group of Patients Treated With Open-label Pazopanib Hydrochloride Following Administration of Gemcitabine Hydrochloride in the Cross-over Portion of This Study
    DescriptionParticipants who progress during treatment and are found to be part of the gemcitabine+placebo arm after unblinding are eligible to receive open-label pazopanib with gemcitabine. This is the crossover population. Statistical analysis is exploratory and requires sufficient crossover participants to assess Kaplan-Meier estimated hazard ratio and associated 95% confidence interval. This represents the participants second progression. In both cases progression is defined using Response Evaluation Criteria in Solid Tumors (RECIST) v1.0 as at least a 20% increase in the sum of the longest diameters of target lesions with an absolute increase of at least 5 mm (target lesions), or measurable increase in non-target lesions (unequivocal progression), or appearance of one or more new lesions. First progression uses the smallest sum on study as a reference; progression for the crossover population uses first progression measurements as the reference.
    Time FrameCalculated as the time from receiving open-labeled pazopanib hydrochloride to the next documented progression or death whichever occurs first, assessed up to 3 years

    Outcome Measure Data

    Analysis Population Description
    Participants randomized to the gemcitabine + placebo arm who progressed and elected to receive gemcitibine + open-label pazopanib
    Arm/Group TitleCrossover From Gemcitabine + Placebo to Gemcitabine + Open-label Pazopanib
    Arm/Group DescriptionParticipants randomized to the gemcitabine + placebo arm who progressed can be moved into the crossover arm, receiving gemcitabine + open-label pazopanib
    Measure Participants14
    Median (95% Confidence Interval) [months]
    3.0
    3. Secondary Outcome
    TitlePercentage of Participants Achieving Best Overall Objective Response (CR+PR)
    DescriptionResponse is evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, where RECIST combines assessments for target, non-target and presence of new lesions. Best Overall Objective Response is the sum of all CR+PR divided by all randomized participants, where the strongest recorded response is used for the evaluation (CR>PR>SD>PD). Objective response (CR+PR) requires at least a 30% decrease in the sum of the largest diameter target lesions (with respective to the baseline sum); disappearance of all or persistence of one or more non-target lesions, maintenance of tumor marker levels above normal limits, and no new lesions. Estimated odds ratio of best overall objective response are reported with 95% confidence interval for the two histologic sarcoma subgroups (liposarcoma vs all other eligible soft tissue sarcoma subtypes). One-sided proportions test is used to determine whether best overall objective response is greater for the gemcitabine plus pazopanib group.
    Time FrameBest overall objective response recorded from the start of treatment until disease progression/recurrence assessed up to 3 years

    Outcome Measure Data

    Analysis Population Description
    All randomized participants.
    Arm/Group TitleGemcitabine Hydrochloride Plus Pazopanib HydrochlorideGemcitabine Hydrochloride Plus Placebo
    Arm/Group DescriptionPatients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and pazopanib hydrochloride PO on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Gemcitabine: Given IV Gemcitabine Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Pazopanib: Given PO Pazopanib Hydrochloride: Given POPatients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and placebo PO on days 1-21. Cycles 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 daily. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Gemcitabine: Given IV Gemcitabine Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Pazopanib: Given PO Pazopanib Hydrochloride: Given PO Placebo Administration: Given PO
    Measure Participants2925
    All randomized participants
    6.9
    23.8%
    8.0
    32%
    Liposarcoma participants
    22.2
    76.6%
    0
    0%
    Other sarcoma participants
    0
    0%
    11.1
    44.4%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Gemcitabine Hydrochloride Plus Pazopanib Hydrochloride, Gemcitabine Hydrochloride Plus Placebo
    Comments Statistical results are for the full randomized population (n = 54). The study tests whether gemcitabine plus pazopanib is superior to gemcitabine plus placebo (one-sided proportion test with Yate's continuity correction)
    Type of Statistical Test Superiority
    Comments Analysis was not powered for secondary endpoints. Given the study closed early due to slow enrollment, we do not anticipate detecting a statistical difference between the two groups
    Statistical Test of Hypothesisp-Value0.5
    CommentsYate's continuity correction was applied because of the number of subjects and successes (n = 4)
    MethodOne-sided Proportions Test
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Gemcitabine Hydrochloride Plus Pazopanib Hydrochloride, Gemcitabine Hydrochloride Plus Placebo
    Comments Statistical results are for the Liposarcoma group (n = 16). The study tests whether gemcitabine plus pazopanib is superior to gemcitabine plus placebo (one-sided proportion test with Yate's continuity correction). Analysis was not powered for the secondary endpoints. Given the study closed early due to slow enrollment we do not anticipate detecting a statistical difference between the groups.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value0.3
    CommentsYate's continuity correction was applied because of small number of participants (n = 16) and successes (n = 2).
    MethodOne-sided Proportion Test
    Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Gemcitabine Hydrochloride Plus Pazopanib Hydrochloride, Gemcitabine Hydrochloride Plus Placebo
    Comments Statistical results are for the Other Sarcoma group (n = 38). The study tests whether gemcitabine plus pazopanib is superior to gemcitabine plus placebo (one-sided proportion test with Yate's continuity correction). Analysis was not powered for secondary endpoints. Given the study closed early due to slow enrollment, we do not anticipate detecting a statistical difference between the two groups.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value0.8
    CommentsYate's continuity correction was applied because of the small number of participants and successes (n = 2).
    MethodOne-sided Proportion Test
    Comments
    4. Secondary Outcome
    TitleOverall Survival
    DescriptionTwo treatment arms will be 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 interval.
    Time FrameFrom randomization to death due to any cause, or until last patient contact if the patient did not die, assessed up to 3 years

    Outcome Measure Data

    Analysis Population Description
    All randomized participants
    Arm/Group TitleGemcitabine Hydrochloride Plus Pazopanib HydrochlorideGemcitabine Hydrochloride Plus Placebo
    Arm/Group DescriptionPatients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and pazopanib hydrochloride PO on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Gemcitabine: Given IV Gemcitabine Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Pazopanib: Given PO Pazopanib Hydrochloride: Given POPatients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and placebo PO on days 1-21. Cycles 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 daily. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Gemcitabine: Given IV Gemcitabine Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Pazopanib: Given PO Pazopanib Hydrochloride: Given PO Placebo Administration: Given PO
    Measure Participants2925
    All Randomized
    11.0
    15.6
    Liposarcoma participants
    20.5
    5.7
    Other Sarcoma participants
    10.2
    17.7
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Gemcitabine Hydrochloride Plus Pazopanib Hydrochloride, Gemcitabine Hydrochloride Plus Placebo
    Comments Overall survival estimated among all randomized participants (n = 54)
    Type of Statistical Test Other
    Comments Log-log plots revealed crossing of the curves at late time points, indicating a possible interaction between treatment arms over time. We used the Gehan-Wilcoxon test, which weights early differences between groups, to test whether there is a difference between the treatment arms early in the study.
    Statistical Test of Hypothesisp-Value0.481
    Comments
    MethodGehan-Wilcoxon
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Gemcitabine Hydrochloride Plus Pazopanib Hydrochloride, Gemcitabine Hydrochloride Plus Placebo
    Comments Overall survival compared between the two arms for the liposarcoma subgroup (n = 16)
    Type of Statistical Test Other
    Comments Log-log plots revealed crossing of the curves at late time points, indicating a possible interaction between treatment arms over time. We used the Gehan-Wilcoxon test, which weights early differences between groups, to test whether there is a difference between the treatment arms early in the study.
    Statistical Test of Hypothesisp-Value0.353
    Comments
    MethodGehan-Wilcoxon
    Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Gemcitabine Hydrochloride Plus Pazopanib Hydrochloride, Gemcitabine Hydrochloride Plus Placebo
    Comments Overall survival comparison between the two treatment arms for the other sarcoma group (n = 38)
    Type of Statistical Test Other
    Comments Log-log plots revealed crossing of the curves at late time points, indicating a possible interaction between treatment arms over time. We used the Gehan-Wilcoxon test, which weights early differences between groups, to test whether there is a difference between the treatment arms early in the study.
    Statistical Test of Hypothesisp-Value0.408
    Comments
    MethodGehan-Wilcoxon
    Comments

    Adverse Events

    Time FrameAdverse events were collected up 30 days after the last dose of study drugs while participant was in that Arm/Group. All-Cause Mortality was assessed up to 3 years. For SAEs and OAEs, the Gem+Pazo group was assessed up to 32.1 months; Gem+Placebo participants were assessed up to 36.0 months (30 days after progression). If Gem+Placebo participants crossed over to open-label Pazo after progression, any additional AEs were collected under the crossover arm (up to 16.6 months).
    Adverse Event Reporting Description All Serious Adverse Events (SAEs) are reported, irrespective of grade or attribution. For other Adverse Events (AEs), only those grade 3 or higher are collected with a threshold set at 3.5% within any arm. AEs and SAEs are assessed using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Assessments are made by laboratory tests, physical exam, and other clinical measurements (e.g. ECGs, radiological scans, vital signs, etc.)
    Arm/Group TitleGemcitabine Hydrochloride Plus Pazopanib HydrochlorideGemcitabine Hydrochloride Plus PlaceboCrossover From Gemcitabine Plus Placebo to Gemcitabine Plus Open-label Pazopanib
    Arm/Group DescriptionPatients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and pazopanib hydrochloride PO on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Gemcitabine: Given IV Gemcitabine Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Pazopanib: Given PO Pazopanib Hydrochloride: Given POPatients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and placebo PO on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients who experience disease progression, are unblinded and found randomized to placebo arm may crossover to receive open-label pazopanib hydrochloride PO daily. AEs and deaths reported only while participant is in placebo arm/group. Gemcitabine: Given IV Gemcitabine Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Pazopanib: Given PO Pazopanib Hydrochloride: Given PO Placebo Administration: Given POPatients who progress and found randomized to the placebo arm after unblinding are eligible for receipt of open-label gemcitabine plus pazopanib. Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and pazopanib hydrochloride PO on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. AEs and deaths collected during this treatment period
    All Cause Mortality
    Gemcitabine Hydrochloride Plus Pazopanib HydrochlorideGemcitabine Hydrochloride Plus PlaceboCrossover From Gemcitabine Plus Placebo to Gemcitabine Plus Open-label Pazopanib
    Affected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total23/29 (79.3%) 10/11 (90.9%) 11/14 (78.6%)
    Serious Adverse Events
    Gemcitabine Hydrochloride Plus Pazopanib HydrochlorideGemcitabine Hydrochloride Plus PlaceboCrossover From Gemcitabine Plus Placebo to Gemcitabine Plus Open-label Pazopanib
    Affected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total8/29 (27.6%) 6/25 (24%) 5/14 (35.7%)
    Blood and lymphatic system disorders
    Febrile neutropenia1/29 (3.4%) 0/25 (0%) 0/14 (0%)
    Cardiac disorders
    Heart failure2/29 (6.9%) 1/25 (4%) 1/14 (7.1%)
    Supraventricular tachycardia0/29 (0%) 1/25 (4%) 0/14 (0%)
    Acute coronary syndrome0/29 (0%) 1/25 (4%) 0/14 (0%)
    Atrial fibrillation2/29 (6.9%) 0/25 (0%) 0/14 (0%)
    Gastrointestinal disorders
    Abdominal pain0/29 (0%) 1/25 (4%) 1/14 (7.1%)
    Gastric perforation0/29 (0%) 0/25 (0%) 1/14 (7.1%)
    Colitis1/29 (3.4%) 0/25 (0%) 0/14 (0%)
    General disorders
    Pain0/29 (0%) 0/25 (0%) 1/14 (7.1%)
    Fever1/29 (3.4%) 0/25 (0%) 1/14 (7.1%)
    Edema limbs1/29 (3.4%) 0/25 (0%) 0/14 (0%)
    Edema trunk1/29 (3.4%) 0/25 (0%) 0/14 (0%)
    Hepatobiliary disorders
    Cholecystitis0/29 (0%) 0/25 (0%) 1/14 (7.1%)
    Hepatic failure1/29 (3.4%) 0/25 (0%) 0/14 (0%)
    Infections and infestations
    Skin infection0/29 (0%) 1/25 (4%) 0/14 (0%)
    Lung infection1/29 (3.4%) 1/25 (4%) 0/14 (0%)
    Investigations
    Alanine aminotransferase increased2/29 (6.9%) 1/25 (4%) 0/14 (0%)
    Aspartate aminotransferase increased2/29 (6.9%) 1/25 (4%) 0/14 (0%)
    Ejection fraction decreased2/29 (6.9%) 0/25 (0%) 1/14 (7.1%)
    Cardiac troponin I increase1/29 (3.4%) 0/25 (0%) 0/14 (0%)
    Neutrophil count decreased1/29 (3.4%) 0/25 (0%) 0/14 (0%)
    Platelet count decreased1/29 (3.4%) 0/25 (0%) 0/14 (0%)
    Metabolism and nutrition disorders
    Hypoglycemia0/29 (0%) 1/25 (4%) 0/14 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumor pain0/29 (0%) 0/25 (0%) 1/14 (7.1%)
    Renal and urinary disorders
    Proteinuria0/29 (0%) 1/25 (4%) 0/14 (0%)
    Respiratory, thoracic and mediastinal disorders
    Dyspnea1/29 (3.4%) 0/25 (0%) 1/14 (7.1%)
    Pleural effusion0/29 (0%) 0/25 (0%) 1/14 (7.1%)
    Pneumothorax1/29 (3.4%) 0/25 (0%) 0/14 (0%)
    Pulmonary edema1/29 (3.4%) 0/25 (0%) 0/14 (0%)
    Vascular disorders
    Hypertension1/29 (3.4%) 0/25 (0%) 0/14 (0%)
    Thromboembolic event1/29 (3.4%) 0/25 (0%) 0/14 (0%)
    Other (Not Including Serious) Adverse Events
    Gemcitabine Hydrochloride Plus Pazopanib HydrochlorideGemcitabine Hydrochloride Plus PlaceboCrossover From Gemcitabine Plus Placebo to Gemcitabine Plus Open-label Pazopanib
    Affected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total25/29 (86.2%) 14/25 (56%) 9/14 (64.3%)
    Blood and lymphatic system disorders
    Anemia2/29 (6.9%) 3/25 (12%) 0/14 (0%)
    Febrile neutropenia2/29 (6.9%) 2/25 (8%) 0/14 (0%)
    Cardiac disorders
    Heart failure2/29 (6.9%) 1/25 (4%) 1/14 (7.1%)
    Gastrointestinal disorders
    Abdominal pain0/29 (0%) 1/25 (4%) 2/14 (14.3%)
    Diarrhea2/29 (6.9%) 0/25 (0%) 0/14 (0%)
    Gastric perforation0/29 (0%) 0/25 (0%) 1/14 (7.1%)
    General disorders
    Fatigue2/29 (6.9%) 0/25 (0%) 2/14 (14.3%)
    Hepatobiliary disorders
    Cholecystitis0/29 (0%) 0/25 (0%) 1/14 (7.1%)
    Investigations
    Alanine aminotransferase increased3/29 (10.3%) 1/25 (4%) 0/14 (0%)
    Aspartate aminotransferase increased2/29 (6.9%) 1/25 (4%) 0/14 (0%)
    Lymphocyte count decreased4/29 (13.8%) 0/25 (0%) 0/14 (0%)
    Neutrophil count decreased12/29 (41.4%) 9/25 (36%) 1/14 (7.1%)
    Platelet count decreased4/29 (13.8%) 0/25 (0%) 0/14 (0%)
    White blood cell decreased4/29 (13.8%) 1/25 (4%) 0/14 (0%)
    Ejection fraction decreased2/29 (6.9%) 0/25 (0%) 1/14 (7.1%)
    Metabolism and nutrition disorders
    Hyperglycemia2/29 (6.9%) 0/25 (0%) 0/14 (0%)
    Hypoalbuminemia1/29 (3.4%) 1/25 (4%) 2/14 (14.3%)
    Hypophosphatemia2/29 (6.9%) 0/25 (0%) 0/14 (0%)
    Hyponatremia1/29 (3.4%) 0/25 (0%) 1/14 (7.1%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumor pain0/29 (0%) 0/25 (0%) 1/14 (7.1%)
    Respiratory, thoracic and mediastinal disorders
    Dyspnea1/29 (3.4%) 0/25 (0%) 1/14 (7.1%)
    Hypoxia0/29 (0%) 0/25 (0%) 1/14 (7.1%)
    Pulmonary edema0/29 (0%) 0/25 (0%) 1/14 (7.1%)
    Vascular disorders
    Hypertension5/29 (17.2%) 0/25 (0%) 1/14 (7.1%)
    Thromboembolic event3/29 (10.3%) 0/25 (0%) 0/14 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/TitleDr. Christopher Ryan
    OrganizationOHSU Knight Cancer Institute
    Phone503-494-9000
    Emailryanc@ohsu.edu
    Responsible Party:
    Christopher Ryan, Principal Investigator, OHSU Knight Cancer Institute
    ClinicalTrials.gov Identifier:
    NCT01532687
    Other Study ID Numbers:
    • IRB00007943
    • NCI-2012-00052
    • IRB00007943
    First Posted:
    Feb 14, 2012
    Last Update Posted:
    Sep 27, 2021
    Last Verified:
    Sep 1, 2021