Trial record 9 of 80 for:    liposarcoma

Activity and Tolerability of Pazopanib in Advanced and/or Metastatic Liposarcoma. A Phase II Clinical Trial

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by Grupo Espanol de Investigacion en Sarcomas
Sponsor:
Collaborator:
GlaxoSmithKline
Information provided by (Responsible Party):
Grupo Espanol de Investigacion en Sarcomas
ClinicalTrials.gov Identifier:
NCT01692496
First received: September 14, 2012
Last updated: August 25, 2014
Last verified: August 2014
  Purpose

Soft tissue and bone sarcomas are rare malignant tumors, which encompasses a large family of more than 50 histologically distinct tumor subtypes, all of which share a putative mesenchymal origin. In the case of soft tissue sarcomas (STS) surgical excision is the mainstay of treatment, but despite curative surgery, around half of patients develop distant metastases and die from disease. Few therapeutic approaches are currently available to patients with unresectable, locally advanced, or metastatic STS and only anthracyclines, ifosfamide and trabectedin have shown activity, with response rates of 20-40% in previously untreated patients. Recent and ongoing trials have investigated a variety of combination chemotherapeutic regimens (variously employing ifosfamide, doxorubicin, gemcitabine, temozolomide, vincristine, cisplatin, and dacarbazine, among others) as well as targeted therapies, which in some cases have yielded improvements in response rate but which have had little impact on survival. No other medical option is currently available, and the median survival of patients with soft-tissue sarcoma with non-resectable metastases is around 12-15 months, and approximately 8 months after second line chemotherapy.

Liposarcomas are STS which account for at least 20% of all STS in adults. They can be further classified into 3 histologically and biologically different subtypes: well-differentiated liposarcoma/dedifferentiated liposarcoma (ALT-WD), myxoid or round cell liposarcoma and pleomorphic liposarcoma.

ALT-WD liposarcomas are locally aggressive rarely metastasizing tumors characterized by ring or giant marker chromosomes on the cytogenetic analysis and by amplification of the 12q13-21 region on FISH (MDM2, CDK4 and HMGIC). They account for about 40% iv of liposarcomas with a 5 year OS around 80%. In a series of WD/DD treated with several regimens response rate was 12.5% OS 15 months and median PFS 3.6 months(95 CI: 3.3-5.9) Mixoid /round cell liposarcoma accounts for 45-50% of all liposarcomas. They tend to metastasize to unusual soft tissue and bone locations. High histologic grade with more than 5% of round cell component is associated with a 5-year OS of 50% approximately. They are characterized by t(23;16)(q13-14;p11) which leads to the fusion of CHOP and TLS genes Pleomorphic liposarcoma accounts for approximately 5-10% of all liposarcomas, characterized by high grade features with frequent and early lung metastasis and cytogenetically by high chromosome counts and complex structural rearrangements.

VEGF is expressed in many STS in which increased expression is associated with higher grade and worse prognosis.

Pazopanib is an oral angiogenesis inhibitor that targets mainly VEGFR, PDGFR and c-kit. Recently the results of a phase II trial of pazopanib in STS have been published. It was a four-cohort 2-stages study. The liposarcoma stratum was closed after the first stage because of a PFS at 12 weeks of 17% (3 out of 17 patients did not progressed after 12 weeks). After central pathologic review, 2 other patients initially classified as other STS were found to have liposarcoma with stable disease at 12 weeks (5/19: 26% PFS12w), thus fulfilling criteria for cohort expansion. Phase II study had been completed and in phase III study patients with liposarcomas were excluded so therefore data on the liposarcoma cohort are inconclusive.

Furthermore the positive results of the phase III study PALETTE have been recently communicated, encouraging this treatment in other sarcomas: progression-free survival (PFS) per independent review was significantly prolonged with pazopanib (median: 4.6 vs 1.5 months; HR=0.31, 95% CI 0.24-0.40; P<0.0001). The interim analysis for overall survival shows a statistically non-significant improvement of pazopanib vs placebo (median: 11.9 vs 10.4 months, HR=0.83, 95% CI 0.62-1.09).

Soluble factors associated with efficacy and toxicity of pazopanib in these patients had been also reported. Decreases in VEGFR2 and increase in PlGF were both associated with toxicity (HTA and TSH elevation) and poorer prognosis.


Condition Intervention Phase
Advanced and / or Metastatic Liposarcoma
Drug: Pazopanib
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase II Clinical Trial of Pazopanib to Evaluate the Activity and Tolerability in Patients With Advanced and/or Metastatic Liposarcoma Who Have Relapsed Following Standard Therapies or for Whom no Standard Therapy Exists

Resource links provided by NLM:


Further study details as provided by Grupo Espanol de Investigacion en Sarcomas:

Primary Outcome Measures:
  • Progression-free survival (PFS) assessed 12 weeks after start of treatment [ Time Frame: 12 weeks after start of treatment ] [ Designated as safety issue: No ]
    The primary objective of this study is to evaluate the activity of Pazopanib in patients with advanced and/or metastatic liposarcoma by means of progression-free survival (PFS) assessed 12 weeks after start of treatment. (According the RECIST criteria 1.1 and central radiology review).


Secondary Outcome Measures:
  • Overall progression free survival (median PFS) [ Time Frame: Imaging studies repeated every 6 weeks for the first 12 weeks and every 8 weeks up to 36 months. ] [ Designated as safety issue: No ]
    Overall progression free survival will be computed from the date of start of treatment to the first documented date of progression or the date of death, whatever the cause. Patients alive and free from progression at the time of the analysis will be censored at the date of last follow-up.

  • Objective tumor response [ Time Frame: Imaging studies required to investigate known disease should be repeated every 6 weeks for the first 12 weeks and every 8 weeks up to 36 months ] [ Designated as safety issue: No ]

    Objective tumor response, measured according to the RECIST 1.1 criteria, will be used as secondary end-point in this trial.

    Response criteria are essentially based on a set of measurable lesions identified at baseline as target lesions, and followed until disease progression.


  • Time to onset of response [ Time Frame: Imaging studies required to investigate known disease should be repeated every 6 weeks for the first 12 weeks and every 8 weeks up to 36 months. ] [ Designated as safety issue: No ]
    It will be computed from the date of start of treatment to the time of first documented response

  • Duration of response [ Time Frame: Imaging studies required to investigate known disease should be repeated every 6 weeks for the first 12 weeks and every 8 weeks up to 36 months. ] [ Designated as safety issue: No ]
    It will be computed from time of attaining response to the time of first documented progression or death.

  • Overall survival (OS) [ Time Frame: Every 12 weeks from disease progression up to 36 months. ] [ Designated as safety issue: No ]
    It will be computed from the date of start of treatment to the date of death, whatever the cause. Patients alive or lost for follow-up at the time of the analysis will be censored at the date of last follow-up.

  • Clinical benefit rate [ Time Frame: Imaging studies required to investigate known disease should be repeated every 6 weeks for the first 12 weeks and every 8 weeks up to 36 months. ] [ Designated as safety issue: No ]
    Patients who achieve CR, PR, or SD for 6 months or more and an improvement of symptoms will be considered as having derived clinical benefit.

  • Growth Modulation Index (GMI) [ Time Frame: Imaging studies required to investigate known disease should be repeated every 6 weeks for the first 12 weeks and every 8 weeks up to 36 months. At patient progression confirmed by means RECIST criteria V 1.1 ] [ Designated as safety issue: No ]
    GMI is the ratio between time to progression (TTP) with pazopanib (TTPp) divided by the TTPp-1 with the previous line of therapy.

  • Safety profile (according CTCAE, version 4.0) [ Time Frame: Every week during the first month, week 6, week 9, week 12, every 4 weeks until end of treatment and at the end of treatment visit (28 days after the end of treatment). ] [ Designated as safety issue: Yes ]
    The safety and tolerability of Pazopanib will be determined by means of type, incidence, severity, timing, seriousness, and relatedness; of reported AEs, physical examinations, and laboratory tests. Toxicity will be graded and tabulated by the NCI-CTCAE v 4.0.


Estimated Enrollment: 74
Study Start Date: January 2013
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Pazopanib
Patients will receive oral pazopanib, 800mg once daily and treatment will continue until disease progression, development of unacceptable toxicity, noncompliance, withdrawal of consent by the patient or investigator decision.
Drug: Pazopanib
Patients will receive oral pazopanib, 800mg once daily and treatment will continue until disease progression, development of unacceptable toxicity, noncompliance, withdrawal of consent by the patient or investigator decision.

  Eligibility

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

Inclusion Criteria:

  1. 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.

    Informed consent must be obtained prior to start of the specified screening window.

    Procedures conducted as part of the subject's routine clinical management (e.g., blood count, imaging study such as bone scan) 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.

  2. Age ≥ 18 years or legal age of consent if greater than 18 years
  3. Histological confirmed diagnosis of high or intermediate grade malignant liposarcoma with metastatic or locally advanced disease. Formalin fixed paraffin embedded tumour block and/or representative H/E (haematoxylin/eosin) slides must be available for central pathologic review to classify tumors in the 2 eligible subtypes:

    Well-differentiated liposarcoma/de-differentiated liposarcoma (ALT-WD) Myxoid/round cell liposarcoma

  4. Patient must have documentation of disease progression within 6 months prior to study entry.
  5. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
  6. Measurable disease by RECIST v1.1 criteria. At least one measurable lesion located outside of a previously irradiated area. If the only measurable lesion is in a previously irradiated area, RECIST progression should be documented after radiotherapy, in the previous 6 months before study entry.
  7. The patient should not be considered eligible for surgery or radical radiotherapy. e.g. Patients to whom surgery/radiotherapy can not be performed with a curative intent due to the extension of the disease. In the case of radiotherapy, it may also be limited due to a previous treatment with radiotherapy in the same area.
  8. The patient must have either been considered ineligible for systemic chemotherapy or received at least one previous regimen for relapsed, refractory or metastatic disease. A maximum of three previous lines for advanced/metastatic disease are allowed.

    Patients not eligible for systemic chemotherapy:

    Because of age, a biological condition or patient-refusal Generally, patients that received anthracyclines in the adjuvant setting are not eligible for first line therapy with this agent for advanced disease.

    Patients with a solitary kidney or >60 years old are usually not the best candidates for treatment with regular doses of ifosfamide.

  9. Tumor tissue must be provided for all subjects for biomarker analysis before/during treatment with investigational product.
  10. The patient should be able to swallow and retain study drug
  11. Adequate organ system function as defined:

    Absolute neutrophil count (ANC)≥ 1.5 X 109/L Hemoglobin ≥ 9 g/dL (5.6 mmol/L) Platelets ≥ 100 X 109/L Prothrombin time (PT) or international normalized ratio (INR)≤ 1.2 X ULN Activated partial thromboplastin time (aPTT)≤ 1.2 X ULN Total bilirubin≤ 1.5 X ULN Alanine amino transferase (ALT) and Aspartate aminotransferase (AST) ≤ 2.5 X ULN Serum creatinine ≤ 1.5 mg/dL (133 µmol/L)Or, if >1.5 mg/dL: Calculated creatinine clearance (ClCR)≥ 30 mL/min to ≥ 50 mL/min Urine Protein to Creatinine Ratio (UPC) <1 Or, 24-hour urine protein <1g

    1. Subjects may not have had a transfusion within 7 days of screening assessment.
    2. Subjects receiving anticoagulant therapy are eligible if their INR is stable and within the recommended range for the desired level of anticoagulation.
    3. Concomitant elevations in bilirubin and AST/ALT above 1.0 x ULN (upper limit of normal) are not permitted.
    4. 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 baseline renal function assessment is not acceptable.
  12. 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 Female 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 < 40pg/mL (<140 pmol/L).

    Female 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 2 weeks prior to the first dose of study treatment, preferably as close to the first dose as possible, and agrees to use adequate contraception. The acceptable contraceptive methods, when used consistently and in accordance with both the product label and the instructions of the physician, are as follows:

    Complete abstinence from sexual intercourse for 14 days before exposure to investigational product, through the dosing period, and for at least 21 days after the last dose of investigational product Oral contraceptive, either combined or progestogen alone Injectable progestogen Implants of levonorgestrel Estrogenic vaginal ring Percutaneous contraceptive patches Intrauterine device (IUD) or intrauterine system (IUS) with a documented failure rate of less than 1% per year Male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject's entry into the study, and this male is the sole partner for that subject Double barrier method: condom and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository) Female subjects who are lactating should discontinue nursing prior to the first dose of study drug and should refrain from nursing throughout the treatment period and for 14 days following the last dose of study drug

  13. LVEF above the lower limit of normal for the institution, based on ECHO or MUGA.

Exclusion Criteria:

  1. Prior history of malignancies other than liposarcoma. 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 or successfully treated in situ carcinoma are eligible.
  2. 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.
  3. 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.

  4. 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.

  5. Corrected QT interval (QTc) > 480 msecs
  6. 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)

  7. Poorly controlled hypertension [defined as systolic blood pressure (SBP) of ≥140 mmHg or diastolic blood pressure (DBP) of ≥ 90mmHg].

    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 (OR 150/90 mm Hg, if this criterion is approved by Safety Review Team) in order for a subject to be eligible for the study.

  8. History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months.

    Subjects with recent DVT who have been treated with therapeutic anti-coagulating agents for at least 6 weeks are eligible

  9. Major surgery or trauma within 28 days prior to first dose of investigational product and/or presence of any non-healing wound, fracture, or ulcer (procedures such as catheter placement not considered to be major surgery).
  10. Evidence of active bleeding or bleeding diathesis.
  11. Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels that increase the risk of pulmonary hemorrhage.

    Lesions infiltrating major pulmonary vessels (contiguous tumour and vessels) are excluded; however, the presence of a tumor that is touching, but not infiltrating (abutting) the vessels is acceptable (CT with contrast is strongly recommended to evaluate such lesions).

  12. Recent hemoptysis (≥ ½ teaspoon of red blood within 8 weeks before first dose of study drug).
  13. 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.
  14. Unable or unwilling to discontinue use of prohibited medications listed in section 7.4 of this protocol or 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.
  15. 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 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

  16. 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
  17. Any ongoing toxicity from prior anti-cancer therapy that is >Grade 1 and/or that is progressing in severity, except alopecia.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01692496

Contacts
Contact: Claudia Valverde, MD +34 93 434 44 12 secretaria@grupogeis.org
Contact: Federico Nepote, PhD +34934344412 ext 119 federico.nepote@mfar.net

Locations
Germany
HELIOS Klinikum Berlin-Buch (Sarkomzentrum Berlin-Brandenburg) Recruiting
Berlin, Germany, D-10707
Principal Investigator: Peter Reichardt, MD         
Universitätsklinikum EssenInnere Klinik (Tumorforschung) Recruiting
Essen, Germany, D-45147
Principal Investigator: Sebastian Bauer, MD         
Medizinische Hochschule Hannover (Zentrum Innere Medizin) Recruiting
Hannover, Germany, D-30625
Principal Investigator: Viktor Grünwald, MD         
Universitätsmedizin Mannheim (Sarkomzentrum) Recruiting
Manheim, Germany, D-68169
Principal Investigator: Bernd Kasper, MD         
Klinikum Großhadern der LMU Universität München (Med. Klinik und Poliklinik II) Recruiting
Munich, Germany, D-80336
Principal Investigator: Lars Lindner, MD         
Spain
Hospital Central de Asturias Not yet recruiting
Oviedo, Asturias, Spain, 33011
Principal Investigator: Pilar Blay, MD         
Hospital Universitario de Canarias Recruiting
La Laguna, Islas Canarias, Spain, 38320
Principal Investigator: Josefina Cruz, MD         
Hospital de Navarra Recruiting
Pamplona, Navarra, Spain, 31008
Principal Investigator: María José Lecumberri, MD         
Complejo Hospitalario Universitario de Vigo Recruiting
Vigo, Pontevedra, Spain, 36204
Principal Investigator: Juan Antonio Carrasco, MD         
Hospital Vall d'Hebrón Recruiting
Barcelona, Spain, 08035
Principal Investigator: Claudia Valverde, MD         
Hospital 12 de Octubre Recruiting
Madrid, Spain, 28041
Principal Investigator: José López Martín, MD         
Hospital Universitari Son Espases Recruiting
Palma de Mallorca, Spain, 07010
Principal Investigator: Javier Martín Broto, MD         
Hospital Universitario Virgen del Rocío Recruiting
Sevilla, Spain, 41013
Principal Investigator: Pilar Sancho Marques, MD         
Instituto Valenciano de Oncología Recruiting
Valencia, Spain, 46009
Principal Investigator: Andres Poveda, MD         
Hospital Miguel Servet Recruiting
Zaragoza, Spain, 50009
Principal Investigator: Javier Martínez, MD         
Sponsors and Collaborators
Grupo Espanol de Investigacion en Sarcomas
GlaxoSmithKline
Investigators
Study Chair: Claudia Valverde, MD Hospitals de la Vall de Hebron
Principal Investigator: Bernd Kasper, MD University Medical Centre Mannheim
  More Information

No publications provided

Responsible Party: Grupo Espanol de Investigacion en Sarcomas
ClinicalTrials.gov Identifier: NCT01692496     History of Changes
Other Study ID Numbers: GEIS-30, 2012-002745-38
Study First Received: September 14, 2012
Last Updated: August 25, 2014
Health Authority: Spain: Agencia Española de Medicamentos y Productos Sanitarios
Spain: Comité Ético de Investigación Clínica
Germany: Ethics Commission
Germany: Federal Institute for Drugs and Medical Devices

Keywords provided by Grupo Espanol de Investigacion en Sarcomas:
Advanced
Metastatic
Liposarcoma
Pazopanib

Additional relevant MeSH terms:
Liposarcoma
Neoplasms, Adipose Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Sarcoma

ClinicalTrials.gov processed this record on September 16, 2014