Clinical Trials /

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

NCT01532687

Description:

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.

Related Conditions:
  • Soft Tissue Sarcoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Gemcitabine Hydrochloride With or Without Pazopanib Hydrochloride in Treating Patients With Refractory Soft Tissue Sarcoma
  • Official Title: A Randomized, Double-Blind Phase II, Study of Gemcitabine Alone or in Combination With Pazopanib for Refractory Soft Tissue Sarcoma

Clinical Trial IDs

  • ORG STUDY ID: 7943
  • SECONDARY ID: NCI-2012-00052
  • SECONDARY ID: 7943
  • SECONDARY ID: P30CA069533
  • NCT ID: NCT01532687

Conditions

  • 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 Mesenchymoma
  • Adult Malignant Peripheral Nerve Sheath Tumor
  • Adult Rhabdomyosarcoma
  • Adult Synovial Sarcoma
  • Adult Undifferentiated Pleomorphic Sarcoma
  • Malignant Adult Hemangiopericytoma
  • Recurrent Adult Soft Tissue Sarcoma
  • Stage III Adult Soft Tissue Sarcoma
  • Stage IV Adult Soft Tissue Sarcoma

Interventions

DrugSynonymsArms
Gemcitabine HydrochloridedFdCyd, Difluorodeoxycytidine Hydrochloride, Gemzar, LY-188011Arm I (gemcitabine hydrochloride and pazopanib hydrochloride)
Pazopanib HydrochlorideGW786034B, VotrientArm I (gemcitabine hydrochloride and pazopanib hydrochloride)

Purpose

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

Detailed Description

      PRIMARY OBJECTIVES:

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

      SECONDARY OBJECTIVES:

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

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

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

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

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

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

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

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

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

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

Trial Arms

NameTypeDescriptionInterventions
Arm I (gemcitabine hydrochloride and pazopanib hydrochloride)ExperimentalPatients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and pazopanib hydrochloride PO on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • Gemcitabine Hydrochloride
  • Pazopanib Hydrochloride
Arm II (gemcitabine hydrochloride, placebo)Active ComparatorPatients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and placebo PO on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients who experience disease progression may receive single-agent pazopanib hydrochloride PO daily. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • Gemcitabine Hydrochloride
  • Pazopanib Hydrochloride

Eligibility Criteria

        Inclusion Criteria:

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

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

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

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

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

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

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

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

          -  Platelets >= 100 x 10^9/L

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

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

          -  Total bilirubin =< 1.5 x ULN

          -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN;
             concomitant elevations in bilirubin and AST/ALT above 1.0 x ULN (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
             milliinternational units per milliliter (mIU/mL) and an estradiol value < 40 pg/mL (<
             140 pmol/L)

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

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

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

               -  Oral contraceptive, either combined or 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 bladder cancer are eligible

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

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

               -  Active peptic ulcer disease

               -  Known intraluminal metastatic lesion/s with risk of bleeding

               -  Inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease), or other
                  gastrointestinal conditions with increased risk of perforation

               -  History of abdominal fistula, gastrointestinal perforation, or intra-abdominal
                  abscess within 28 days prior to beginning study treatment

          -  Clinically significant gastrointestinal abnormalities that may affect absorption of
             investigational product including, but not limited to:

               -  Malabsorption syndrome

               -  Major resection of the stomach or small bowel

          -  Presence of uncontrolled infection

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

          -  History of any one or more of the following cardiovascular conditions within the past
             6 months:

               -  Cardiac angioplasty or stenting

               -  Myocardial infarction

               -  Unstable angina

               -  Coronary artery bypass graft surgery

               -  Symptomatic peripheral vascular disease

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

          -  Poorly controlled hypertension (defined as systolic blood pressure (SBP) of >= 140
             mmHg or diastolic blood pressure (DBP) of >= 90mmHg); note: initiation or adjustment
             of antihypertensive medication(s) is permitted prior to study entry; following
             antihypertensive medication initiation or adjustment, blood pressure (BP) must be
             re-assessed three times at approximately 2-minute intervals; at least 24 hours must
             have elapsed between anti-hypertensive medication initiation or adjustment and BP
             measurement; these three values should be averaged to obtain the mean diastolic blood
             pressure and the mean systolic blood pressure; the mean SBP/DBP ratio must be < 140/90
             mmHg

          -  History of cerebrovascular accident including transient ischemic attack (TIA),
             pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months;
             note: subjects with recent DVT who have been treated with therapeutic anti-coagulating
             agents for at least 6 weeks are eligible

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

          -  Evidence of active bleeding or bleeding diathesis

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

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

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

          -  Unable or unwilling to discontinue use of prohibited medications for at least 14 days
             or five half-lives of a drug (whichever is longer) prior to the first dose of study
             drug and for the duration of the study; administration of any non-oncologic
             investigational drug within 30 days or 5 half-lives whichever is longer prior to
             receiving the first dose of study treatment

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

               -  Radiation therapy, surgery or tumor embolization within 14 days prior to the
                  first dose of pazopanib OR

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

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

               -  Any prior treatment with gemcitabine

          -  Any ongoing toxicity from prior anti-cancer therapy that is > grade 1 and/or that is
             progressing in severity, except alopecia
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-free survival (PFS)
Time Frame:Calculated as the time from randomization to the first documented progression or death whichever occurs first, or until time of last contact if no progression or death occurred, assessed up to 3 years
Safety Issue:
Description:Compared using a one-sided log-rank test stratified by sarcoma subtype and study site. Kaplan-Meier estimates and the survival curves for each treatment arm will be presented with the estimated hazard ratios and their associated confidence intervals.

Secondary Outcome Measures

Measure:Best overall response rate
Time Frame:Best response recorded from the start of treatment until disease progression/recurrence assessed up to 3 years
Safety Issue:
Description:Estimated odds ratio of treatment response will be reported with 95% confidence interval for the two histologic sarcoma subgroups (liposarcoma vs. all other eligible soft tissue sarcoma subtypes). Exact one-sided CMH test will be used to determine whether the response rates differ for the subgroups in general.
Measure:Incidence of adverse events and serious adverse events, defined using the Common Terminology Criteria for Adverse Events (CTCAE) version (v) 4.0.
Time Frame:Up to 3 years
Safety Issue:
Description:Toxicities will be descriptively tabulated. Frequency and severity of adverse events will be tabulated for each treatment arm based on the actual treatment the patient receives. Toxicity and adverse events will be summarized according to each major organ group and grade outline in the CTCAE v4.0 criteria.
Measure:Overall survival
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
Safety Issue:
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.
Measure:PFS (for a sub-group of patients treated with single-agent pazopanib hydrochloride following administration of gemcitabine hydrochloride in the cross-over portion of this study)
Time Frame:Calculated as the time from receiving open-labeled pazopanib hydrochloride to the next documented progression or death whichever occurs first, assessed up to 3 years
Safety Issue:
Description:Statistical analysis is exploratory—Kaplan-Meier estimate and the survival curve will be presented with the estimated hazard ratio and its associated 95% confidence interval.
Measure:Response rate
Time Frame:Assessed up to 3 years
Safety Issue:
Description:Categorized into complete response, partial response, progressive disease, and stable disease following RECIST version 1.1. Estimated odds ratio of treatment response will be reported with 95% confidence interval for the two histologic sarcoma subgroups (liposarcoma vs. all other eligible soft tissue sarcoma subtypes). Exact one-sided Cochran-Mantel-Haenszel (CMH) test will be used to determine whether the response rates differ for the subgroups in general.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:OHSU Knight Cancer Institute

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