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Pazopanib and Paclitaxel as First-Line Treatment for Subjects With Unresectable Stage III and Stage IV Melanoma

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
GlaxoSmithKline
Information provided by (Responsible Party):
John P. Fruehauf, University of California, Irvine
ClinicalTrials.gov Identifier:
NCT01107665
First received: April 19, 2010
Last updated: December 6, 2016
Last verified: November 2016
  Purpose
This is a Phase II single-arm, open-label, clinical trial evaluating the efficacy and safety of pazopanib in combination with paclitaxel as first line therapy for subjects with unresectable Stage III and Stage IV melanoma. Previous cytokine therapy is permitted. Subjects must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST). Subjects who are not candidates for curative intent treatments are eligible for this study.

Condition Intervention Phase
Stage III Melanoma
Stage IV Melanoma
Unresectable Melanoma
Drug: Pazopanib and Paclitaxel
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: A Phase II, Single-Arm Study of Pazopanib and Paclitaxel as First-Line Treatment for Subjects With Unresectable Stage III and Stage IV Melanoma

Resource links provided by NLM:


Further study details as provided by University of California, Irvine:

Primary Outcome Measures:
  • Progression-free survival [ Time Frame: 6 Months ] [ Designated as safety issue: Yes ]

    This is defined as the percentage of subjects who are free of RECIST-defined objective disease progression at 6 months after study treatment start.

    Subjects in the Intent-to-Treat (ITT) population who discontinue the study prior to 6 months will be included in the denominator when calculating the percentage.



Secondary Outcome Measures:
  • Survival [ Time Frame: At 1 year after enrollment ] [ Designated as safety issue: No ]
    This is defined as the percentage of subjects who are alive at 1 year after enrollment. For subjects who do not die, time to death will be censored at the time of last contact.

  • Survival [ Time Frame: At 2 years after enrollment ] [ Designated as safety issue: No ]
    This is defined as the percentage of subjects who are alive at 2 years after enrollment. For subjects who do not die, time to death will be censored at the time of last contact.

  • Objective response rate (ORR) [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]

    This is defined as the percentage of subjects achieving either a complete or partial tumor response per RECIST criteria. The response rate will be calculated from the review of best response which records confirmed cases of PR and CR only. Confirmation will occur at least 4 weeks after the initial response. Stable disease (SD) will also be defined by 8 weeks or greater and will be summarized by less than 6 months vs. equal or greater than 6 months.

    Subjects in the ITT population with unknown or missing response will be treated as non-responders, i.e. they will be included in the denominator when calculating the percentage.


  • Clinical benefit response (CBR) [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]

    This is defined as the percentage of subjects achieving either a complete, partial tumor or stable disease response per RECIST criteria. Confirmation will occur at least 4 weeks after the initial response for partial and complete responders. Stable disease (SD) will also be defined by 8 weeks or greater.

    Subjects in the ITT population with unknown or missing response will be treated as non-responders, i.e. they will be included in the denominator when calculating the percentage.


  • Duration of response (DR) [ Time Frame: Time from first documented evidence of response (CR/PR) until the first documented sign of disease progression or death, assessed up to 2 years ] [ Designated as safety issue: No ]

    Duration of response analyses will be restricted to the subgroup of the population who experience a response during the study. Duration of response will be defined as the time from first documented evidence of response (CR/PR) until the first documented sign of disease progression or death, if sooner.

    For subjects who do not progress or die, duration of response will be censored on the date of last assessment.

    Duration of response will be summarized using a Kaplan-Meier methods and displayed graphically where appropriate.


  • Incidence, severity of adverse events (AE), serious adverse events (SAEs) and other safety parameters [ Time Frame: Up to 28 days ] [ Designated as safety issue: Yes ]

    AEs and toxicities will be graded according to the National Cancer Institute-common toxicity criteria (NCI-CTC), Version 4.0. Summaries of the number of toxicity grades for both laboratory and non-laboratory data will be presented. If the AE is listed in the NCI-CTC, the maximum grade will be summarized. Otherwise, the maximum intensity will be summarized.

    AEs will be coded using the standard dictionary (MedDRA), and grouped by system organ class. They will be summarized by frequency and proportion of total subjects, by system organ class and preferred term. Separate summaries will be given for all AEs, for drug-related AEs, for SAEs, and for AEs leading to withdrawal from the study treatment.

    The incidence of deaths will also be reported.



Other Outcome Measures:
  • Concentrations of plasma proteins (serum VEGF, soluble VEGF receptor 2, serum Hypoxia-inducible factor (HIF) and serum TSP1) that may be associated to angiogenesis and tumor proliferation [ Time Frame: Day 1 ] [ Designated as safety issue: No ]
    Categorical statistical analysis will be performed to determine the relationship between PD and pharmacokinetic (PK) markers and outcomes. Univariate summary statistics will be calculated, such as the sample median, standard deviation, minimum, and maximum observations. The dichotomized variables were tabulated as high and low levels or positive and negative expression. Changes over time in continuously distributed biomarker levels will be investigated with the sign's test because of the heavy degree of skewness observed in some of the marginal distributions.

  • Tissue levels of angiogenic markers including protein (p)53, HIF, cluster of differentiation (CD)31, neuronal nitric oxide synthase (nNOS), TSP1, and VEGF [ Time Frame: Day 1 ] [ Designated as safety issue: No ]
    Categorical statistical analysis will be performed to determine the relationship between PD and PK markers and outcomes. Univariate summary statistics will be calculated, such as the sample median, standard deviation, minimum, and maximum observations. The dichotomized variables were tabulated as high and low levels or positive and negative expression. Changes over time in continuously distributed biomarker levels will be investigated with the sign's test because of the heavy degree of skewness observed in some of the marginal distributions.

  • V-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutation status [ Time Frame: Day 1 ] [ Designated as safety issue: No ]
    Associations between interval quality data with ordinal data will be examined with Spearman's correlation coefficient. Associations between dichotomized biomarkers among themselves and with ordinal subject characteristics such as tumor grade or performance status will be characterized with Kendall's tau-b correlation

  • In vitro response of tumor cells grown in culture with vascular endothelial cells to pazopanib, paclitaxel, topotecan and resveratrol [ Time Frame: Day 1 ] [ Designated as safety issue: No ]

Enrollment: 60
Study Start Date: August 2010
Estimated Study Completion Date: January 2018
Estimated Primary Completion Date: January 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Pazopanib and Paclitaxel
Treatment on study will be administered in 4-week cycles. Paclitaxel will be administered intravenously at a starting dose of 80mg/m2 weekly for 3 weeks followed by a 1-week rest. Pazopanib will be administered orally, in a continuous regimen, with a starting dose of 800mg daily.
Drug: Pazopanib and Paclitaxel
Paclitaxel will be administered intravenously at a starting dose of 80mg/m2 weekly for 3 weeks followed by a 1-week rest. Pazopanib will be administered orally, in a continuous regimen, with a starting dose of 800mg daily.
Other Name: Pazopanib monohydrochloride salt and Taxol

Detailed Description:

Treatment on study will be administered in 4-week cycles. Paclitaxel will be administered intravenously at a starting dose of 80mg/m2 weekly for 3 weeks followed by a 1-week rest. Pazopanib will be administered orally, in a continuous regimen, with a starting dose of 800mg daily.

Approximately 60 eligible subjects will be enrolled over a 24 month period. 21 subjects will be entered into the first stage of a 2-stage Simon Minimax design. If there are 3 or more responses, 39 additional subjects will be enrolled in Stage 2. The minimum number of responses required to move to the second stage, > 3, were noted after the first 9 patients on treatment, and the study then proceeded towards the goal of accruing 60 total patients. Subjects are permitted to receive supportive care throughout the study including transfusion of blood and blood products, treatment with antibiotics, anti-emetics, anti-diarrheal agents, analgesics, erythropoietin, filgrastim (Neupogen), or bisphosphonates, when appropriate. Subjects should continue treatment on study until objective disease progression is documented according to RECIST or withdrawal from the study for other reasons. Subjects discontinuing treatment with paclitaxel prior to disease progression should continue treatment with pazopanib. Subjects discontinuing both agents prior to progressive disease (PD) will be followed for tumor assessment until PD, or until the initiation of a subsequent anti-cancer therapy in the absence of documented PD, or until death, whichever occurs first. Subjects may continue treatment beyond the time of RECIST-defined progression at the discretion of the investigator if the subject is perceived to be experiencing clinical benefit. Overall survival will be assessed for 2 years from first study treatment.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
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. 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. Note: It is not necessary that informed consent be obtained within the protocol-specified screening window.
  2. Histologically confirmed cutaneous melanoma with 1) unresectable Stage III disease, or 2) Stage IV disease by American Joint Committee on Cancer (AJCC) criteria.
  3. Must have measurable disease [i.e. with at least one measurable lesion, per RECIST]. A measurable lesion is defined as a lesion that can be accurately measured in at least one dimension with the longest diameter ≥20mm using conventional techniques or ≥10mm with spiral CT scan.

    Note: Subjects should be excluded if all baseline measurable lesions are within previously irradiated areas. Subjects participating in the exploratory analysis shall not have the biopsied lesion(s) as the only sites of measurable disease.

  4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  5. Age 18 years old or older
  6. 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 unit (mIU)/mL and an estradiol value <40pg/mL (<140 pmol/L).

    Subjects must discontinue HRT prior to study enrollment due to the potential for inhibition of Cytochrome P450 (CYP) enzymes that metabolize estrogens and progestins. For most forms of HRT, at least 2-4 weeks must elapse between the cessation of HRT and determination of menopausal status; length of this interval depends on the type and dosage of HRT. If a female subject is determined not to be post-menopausal, they must use adequate contraception, as defined immediately below.

    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. Acceptable contraceptive methods, when used consistently and in accordance with both the product label and the instructions of the physician, are as follow:

    • An intrauterine device with a documented failure rate of less than 1% per year.
    • Vasectomized partner who is sterile prior to the female subject's entry and is the sole sexual partner for that female.
    • 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.
    • Double-barrier contraception (condom with spermicidal jelly, foam suppository, or film; diaphragm with spermicide; or male condom and diaphragm with spermicide).

    Note: Oral contraceptives are not reliable due to potential drug drug interactions.

    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.

    A male with a female partner of childbearing potential is eligible to enter and participate in the study if he uses a barrier method of contraception or abstinence during the study.

  7. Adequate organ system functions as defined below:

    System:Laboratory Values

    Hematologic

    • Absolute neutrophil count (ANC) >= .5 X 10^9/L
    • Hemoglobin >= 9 g/dL
    • International normalized ratio (INR) <= 1.2 X upper limit of normal (ULN)
    • Partial thromboplastin time (PTT) <= 1.2 X ULN

    Hepatic

    • Total bilirubin <= 1.5 X ULN
    • Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) <=2.5 x ULN

    Renal

    • Calculated creatinine clearance >= 30 mL/min Note: Subjects may not have had a transfusion within 7 days of screening assessment.
    • Platelets >= 100 X 10^9/L
    • Urine Protein to Creatinine Ratio (UPC) < 1 Note: If UPC is more than 1, then a 24-hour urine protein must be assessed. Subjects must have a 24-hour urine protein value <1g to be eligible.
  8. Corrected serum calcium concentration within normal range per local clinical laboratory standard.
  9. Left ventricular ejection fraction (LVEF) more or equal lower limit of normal (LLN) as assessed by echocardiography or multigated acquisition (MUGA) scan.

Exclusion Criteria:

  • Subjects meeting any of the following criteria must not be enrolled in the study:

    1. Prior treatment with cytotoxic anti-cancer therapy. (Previous cytokine or investigational immunotherapy are permitted, but must be completed 28 days prior to first dose of study medication).
    2. Prior use of other investigational or licensed tyrosine kinase inhibitors (TKIs), or agents which target vascular endothelial growth factor (VEGF) or VEGF receptors (ie. bevacizumab, VEGF-Trap).
    3. Known history of dose-limiting hypersensitivity reactions to paclitaxel/Cremophor EL.
    4. Pregnant or lactating female. Female subjects who are lactating are eligible if they discontinue nursing prior to the first dose of study drug and refrain from nursing throughout the treatment period and for 14 days following the last dose of study drug.
    5. Melanoma of ocular origin.
    6. History of another 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 or successfully treated in situ carcinoma are eligible.
    7. Life expectancy less than 3 months.
    8. History or clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis except for subjects who have previously-treated CNS metastases (surgery with or without radiotherapy, radiosurgery, or gamma knife) and meet all 3 of the following criteria:

      1. Are asymptomatic
      2. Have had no evidence of active CNS metastases for more or equal 6 months prior to enrollment
      3. Have no requirement for steroids or enzyme-inducing anticonvulsants (EIAC)
    9. Clinically significant gastrointestinal abnormalities including, but not limited to:

      1. Malabsorption syndrome
      2. Major resection of the stomach or small bowel that could affect the absorption of study drug
      3. Active peptic ulcer disease
      4. Inflammatory bowel disease
      5. Ulcerative colitis, or other gastrointestinal conditions with increased risk of perforation
      6. History of abdominal fistula, gastrointestinal perforation, or intra abdominal abscess within 28 days prior to beginning study treatment.
    10. Presence of uncontrolled infection.
    11. Prolongation of corrected QT interval (QTc) >480 milliseconds (ms).
    12. History of any one or more of the following cardiovascular conditions within the past 6 months:

      1. Cardiac angioplasty or stenting
      2. Myocardial infarction
      3. Unstable angina
      4. Symptomatic peripheral vascular disease
      5. Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA)
    13. History of cerebrovascular accident, 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.
    14. Poorly controlled hypertension [defined as systolic blood pressure (SBP) of ≥150 millimeters of mercury (mmHg)or diastolic blood pressure (DBP) of ≥ 90 mmHg].

      Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry. Blood pressure must be re-assessed on two occasions that are separated by a minimum of 24 hours. The mean SBP/DBP values from each blood pressure assessment must be less or equal 150 systolic and 90 diastolic mmHg in order for a subject to be eligible for the study.

    15. Prior major surgery or trauma within 14 days of the first dose of study drug and/or presence of any non-healing wound, fracture, or ulcer.
    16. Evidence of active bleeding or bleeding diathesis
    17. Hemoptysis within 6 weeks of first dose of study drug.
    18. Any serious and/or unstable pre-existing medical, psychiatric, or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study.
    19. Use of any prohibited medications within 14 days of the first dose of study medication.
    20. Radiation therapy within 28 days of the first dose of study drug.
    21. Any ongoing toxicity from prior anti-cancer therapy that is >Grade 1 and/or that is progressing in severity.
    22. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to pazopanib.
  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: NCT01107665

Locations
United States, California
Chao Family Comprehensive Cancer Center
Orange, California, United States, 92868
Sponsors and Collaborators
University of California, Irvine
GlaxoSmithKline
Investigators
Principal Investigator: John Fruehauf, MD, PhD Chao Family Comprehensive Cancer Center
  More Information

Responsible Party: John P. Fruehauf, Professor of Clinical Medicine, University of California, Irvine
ClinicalTrials.gov Identifier: NCT01107665     History of Changes
Other Study ID Numbers: UCI 09-53  2010-7443  PZP113567  NCI-2010-00748 
Study First Received: April 19, 2010
Last Updated: December 6, 2016
Health Authority: United States: Institutional Review Board
United States: Food and Drug Administration

Keywords provided by University of California, Irvine:
pazopanib
paclitaxel
melanoma

Additional relevant MeSH terms:
Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Paclitaxel
Albumin-Bound Paclitaxel
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on December 09, 2016