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)
• Enrollment: 54
• Locations: 2
• Arms: 2
• Actual Duration (Months): 91.6
• Patients Per Site: 27
• Patients Per Site Per Month: 0.3

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.

Condition or Disease	Intervention/Treatment	Phase
Adult Alveolar Soft Part Sarcoma; Adult Angiosarcoma; Adult Desmoplastic Small Round Cell Tumor; Adult Epithelioid Hemangioendothelioma; Adult Epithelioid Sarcoma; Adult Extraskeletal Myxoid Chondrosarcoma; Adult Extraskeletal Osteosarcoma; Adult Fibrosarcoma; Adult Leiomyosarcoma; Adult Liposarcoma; Adult Malignant Peripheral Nerve Sheath Tumor; Adult Rhabdomyosarcoma; Adult Synovial Sarcoma; Adult Undifferentiated Pleomorphic Sarcoma; Malignant Adult Hemangiopericytoma; Recurrent Adult Soft Tissue Sarcoma; Sarcoma; Stage III Adult Soft Tissue Sarcoma AJCC v7; Stage IV Adult Soft Tissue Sarcoma AJCC v7	Drug: Gemcitabine; Drug: Gemcitabine Hydrochloride; Other: Laboratory Biomarker Analysis; Drug: Pazopanib; Drug: Pazopanib Hydrochloride; Other: Placebo Administration	Phase 2

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

Arm	Intervention/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

	Site	City	State	Country	Postal Code
1	OHSU Knight Cancer Institute	Portland	Oregon	United States	97239
2	Fred Hutch/University of Washington Cancer Consortium	Seattle	Washington	United States	98109

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)

• Study Protocol and Statistical Analysis Plan - Aug 20, 2017

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

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Sarcoma; Osteosarcoma; Rhabdomyosarcoma; Leiomyosarcoma; Liposarcoma; Chondrosarcoma; Sarcoma, Synovial; Hemangiosarcoma; Nerve Sheath Neoplasms; Neurofibrosarcoma; Desmoplastic Small Round Cell Tumor; Fibrosarcoma; Sarcoma, Alveolar Soft Part; Hemangiopericytoma; Solitary Fibrous Tumors; Histiocytoma, Malignant Fibrous; Hemangioendothelioma; Hemangioendothelioma, Epithelioid; Gemcitabine

Study Results

Participant Flow

Pre-assignment Detail

Double-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 Title	Gemcitabine Hydrochloride Plus Pazopanib Hydrochloride	Gemcitabine Hydrochloride Plus Placebo
Arm/Group Description	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. Gemcitabine: Given IV Gemcitabine Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Pazopanib: Given PO Pazopanib Hydrochloride: Given PO	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. 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
STARTED	29	25
Crossover to Open-label Pazopanib	0	14
COMPLETED	15	23
NOT COMPLETED	14	2

Baseline Characteristics

Arm/Group Title	Gemcitabine Hydrochloride Plus Pazopanib Hydrochloride	Gemcitabine Hydrochloride Plus Placebo	Total
Arm/Group Description	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. Gemcitabine: Given IV Gemcitabine Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Pazopanib: Given PO Pazopanib Hydrochloride: Given PO	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. Gemcitabine: Given IV Gemcitabine Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Pazopanib: Given PO Pazopanib Hydrochloride: Given PO Placebo Administration: Given PO	Total of all reporting groups
Overall Participants	29	25	54
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

Title	Progression-free Survival (PFS)
Description	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.
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

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	Gemcitabine Hydrochloride Plus Pazopanib Hydrochloride	Gemcitabine Hydrochloride Plus Placebo
Arm/Group Description	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. Gemcitabine: Given IV Gemcitabine Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Pazopanib: Given PO Pazopanib Hydrochloride: Given PO	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. Gemcitabine: Given IV Gemcitabine Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Pazopanib: Given PO Pazopanib Hydrochloride: Given PO Placebo Administration: Given PO
Measure Participants	29	25
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 Hypothesis	p-Value	0.017
	Comments
	Method	Gehan-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 Hypothesis	p-Value	0.195
	Comments
	Method	Gehan-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 Hypothesis	p-Value	0.079
	Comments
	Method	Gehan-Wilcoxon
	Comments

2. Secondary Outcome

Title	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
Description	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.
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

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 Title	Crossover From Gemcitabine + Placebo to Gemcitabine + Open-label Pazopanib
Arm/Group Description	Participants randomized to the gemcitabine + placebo arm who progressed can be moved into the crossover arm, receiving gemcitabine + open-label pazopanib
Measure Participants	14
Median (95% Confidence Interval) [months]	3.0

3. Secondary Outcome

Title	Percentage of Participants Achieving Best Overall Objective Response (CR+PR)
Description	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.
Time Frame	Best 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 Title	Gemcitabine Hydrochloride Plus Pazopanib Hydrochloride	Gemcitabine Hydrochloride Plus Placebo
Arm/Group Description	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. Gemcitabine: Given IV Gemcitabine Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Pazopanib: Given PO Pazopanib Hydrochloride: Given PO	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. Gemcitabine: Given IV Gemcitabine Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Pazopanib: Given PO Pazopanib Hydrochloride: Given PO Placebo Administration: Given PO
Measure Participants	29	25
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 Hypothesis	p-Value	0.5
	Comments	Yate's continuity correction was applied because of the number of subjects and successes (n = 4)
	Method	One-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 Hypothesis	p-Value	0.3
	Comments	Yate's continuity correction was applied because of small number of participants (n = 16) and successes (n = 2).
	Method	One-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 Hypothesis	p-Value	0.8
	Comments	Yate's continuity correction was applied because of the small number of participants and successes (n = 2).
	Method	One-sided Proportion Test
	Comments

4. Secondary Outcome

Title	Overall Survival
Description	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.
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

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	Gemcitabine Hydrochloride Plus Pazopanib Hydrochloride	Gemcitabine Hydrochloride Plus Placebo
Arm/Group Description	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. Gemcitabine: Given IV Gemcitabine Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Pazopanib: Given PO Pazopanib Hydrochloride: Given PO	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. Gemcitabine: Given IV Gemcitabine Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Pazopanib: Given PO Pazopanib Hydrochloride: Given PO Placebo Administration: Given PO
Measure Participants	29	25
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 Hypothesis	p-Value	0.481
	Comments
	Method	Gehan-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 Hypothesis	p-Value	0.353
	Comments
	Method	Gehan-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 Hypothesis	p-Value	0.408
	Comments
	Method	Gehan-Wilcoxon
	Comments

Adverse Events

Time Frame	Adverse 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 Title	Gemcitabine Hydrochloride Plus Pazopanib Hydrochloride		Gemcitabine Hydrochloride Plus Placebo		Crossover From Gemcitabine Plus Placebo to Gemcitabine Plus Open-label Pazopanib
Arm/Group Description	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. Gemcitabine: Given IV Gemcitabine Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Pazopanib: Given PO Pazopanib Hydrochloride: Given PO		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, 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 PO		Patients 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 Hydrochloride		Gemcitabine Hydrochloride Plus Placebo		Crossover From Gemcitabine Plus Placebo to Gemcitabine Plus Open-label Pazopanib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	23/29 (79.3%)		10/11 (90.9%)		11/14 (78.6%)
Serious Adverse Events
	Gemcitabine Hydrochloride Plus Pazopanib Hydrochloride		Gemcitabine Hydrochloride Plus Placebo		Crossover From Gemcitabine Plus Placebo to Gemcitabine Plus Open-label Pazopanib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/29 (27.6%)		6/25 (24%)		5/14 (35.7%)
Blood and lymphatic system disorders
Febrile neutropenia	1/29 (3.4%)		0/25 (0%)		0/14 (0%)
Cardiac disorders
Heart failure	2/29 (6.9%)		1/25 (4%)		1/14 (7.1%)
Supraventricular tachycardia	0/29 (0%)		1/25 (4%)		0/14 (0%)
Acute coronary syndrome	0/29 (0%)		1/25 (4%)		0/14 (0%)
Atrial fibrillation	2/29 (6.9%)		0/25 (0%)		0/14 (0%)
Gastrointestinal disorders
Abdominal pain	0/29 (0%)		1/25 (4%)		1/14 (7.1%)
Gastric perforation	0/29 (0%)		0/25 (0%)		1/14 (7.1%)
Colitis	1/29 (3.4%)		0/25 (0%)		0/14 (0%)
General disorders
Pain	0/29 (0%)		0/25 (0%)		1/14 (7.1%)
Fever	1/29 (3.4%)		0/25 (0%)		1/14 (7.1%)
Edema limbs	1/29 (3.4%)		0/25 (0%)		0/14 (0%)
Edema trunk	1/29 (3.4%)		0/25 (0%)		0/14 (0%)
Hepatobiliary disorders
Cholecystitis	0/29 (0%)		0/25 (0%)		1/14 (7.1%)
Hepatic failure	1/29 (3.4%)		0/25 (0%)		0/14 (0%)
Infections and infestations
Skin infection	0/29 (0%)		1/25 (4%)		0/14 (0%)
Lung infection	1/29 (3.4%)		1/25 (4%)		0/14 (0%)
Investigations
Alanine aminotransferase increased	2/29 (6.9%)		1/25 (4%)		0/14 (0%)
Aspartate aminotransferase increased	2/29 (6.9%)		1/25 (4%)		0/14 (0%)
Ejection fraction decreased	2/29 (6.9%)		0/25 (0%)		1/14 (7.1%)
Cardiac troponin I increase	1/29 (3.4%)		0/25 (0%)		0/14 (0%)
Neutrophil count decreased	1/29 (3.4%)		0/25 (0%)		0/14 (0%)
Platelet count decreased	1/29 (3.4%)		0/25 (0%)		0/14 (0%)
Metabolism and nutrition disorders
Hypoglycemia	0/29 (0%)		1/25 (4%)		0/14 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain	0/29 (0%)		0/25 (0%)		1/14 (7.1%)
Renal and urinary disorders
Proteinuria	0/29 (0%)		1/25 (4%)		0/14 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/29 (3.4%)		0/25 (0%)		1/14 (7.1%)
Pleural effusion	0/29 (0%)		0/25 (0%)		1/14 (7.1%)
Pneumothorax	1/29 (3.4%)		0/25 (0%)		0/14 (0%)
Pulmonary edema	1/29 (3.4%)		0/25 (0%)		0/14 (0%)
Vascular disorders
Hypertension	1/29 (3.4%)		0/25 (0%)		0/14 (0%)
Thromboembolic event	1/29 (3.4%)		0/25 (0%)		0/14 (0%)
Other (Not Including Serious) Adverse Events
	Gemcitabine Hydrochloride Plus Pazopanib Hydrochloride		Gemcitabine Hydrochloride Plus Placebo		Crossover From Gemcitabine Plus Placebo to Gemcitabine Plus Open-label Pazopanib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	25/29 (86.2%)		14/25 (56%)		9/14 (64.3%)
Blood and lymphatic system disorders
Anemia	2/29 (6.9%)		3/25 (12%)		0/14 (0%)
Febrile neutropenia	2/29 (6.9%)		2/25 (8%)		0/14 (0%)
Cardiac disorders
Heart failure	2/29 (6.9%)		1/25 (4%)		1/14 (7.1%)
Gastrointestinal disorders
Abdominal pain	0/29 (0%)		1/25 (4%)		2/14 (14.3%)
Diarrhea	2/29 (6.9%)		0/25 (0%)		0/14 (0%)
Gastric perforation	0/29 (0%)		0/25 (0%)		1/14 (7.1%)
General disorders
Fatigue	2/29 (6.9%)		0/25 (0%)		2/14 (14.3%)
Hepatobiliary disorders
Cholecystitis	0/29 (0%)		0/25 (0%)		1/14 (7.1%)
Investigations
Alanine aminotransferase increased	3/29 (10.3%)		1/25 (4%)		0/14 (0%)
Aspartate aminotransferase increased	2/29 (6.9%)		1/25 (4%)		0/14 (0%)
Lymphocyte count decreased	4/29 (13.8%)		0/25 (0%)		0/14 (0%)
Neutrophil count decreased	12/29 (41.4%)		9/25 (36%)		1/14 (7.1%)
Platelet count decreased	4/29 (13.8%)		0/25 (0%)		0/14 (0%)
White blood cell decreased	4/29 (13.8%)		1/25 (4%)		0/14 (0%)
Ejection fraction decreased	2/29 (6.9%)		0/25 (0%)		1/14 (7.1%)
Metabolism and nutrition disorders
Hyperglycemia	2/29 (6.9%)		0/25 (0%)		0/14 (0%)
Hypoalbuminemia	1/29 (3.4%)		1/25 (4%)		2/14 (14.3%)
Hypophosphatemia	2/29 (6.9%)		0/25 (0%)		0/14 (0%)
Hyponatremia	1/29 (3.4%)		0/25 (0%)		1/14 (7.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain	0/29 (0%)		0/25 (0%)		1/14 (7.1%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/29 (3.4%)		0/25 (0%)		1/14 (7.1%)
Hypoxia	0/29 (0%)		0/25 (0%)		1/14 (7.1%)
Pulmonary edema	0/29 (0%)		0/25 (0%)		1/14 (7.1%)
Vascular disorders
Hypertension	5/29 (17.2%)		0/25 (0%)		1/14 (7.1%)
Thromboembolic event	3/29 (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.