Phase I Trial of Oral Metronomic Topotecan and Oral Pazopanib to Treat Recurrent/Persistent Gynecologic Tumors

This study has been completed.
Sponsor:
Collaborator:
GlaxoSmithKline
Information provided by (Responsible Party):
Vector Oncology
ClinicalTrials.gov Identifier:
NCT00800345
First received: December 1, 2008
Last updated: April 12, 2016
Last verified: April 2016
  Purpose
This is a Phase 1, dose-escalation study in female patients with recurrent or persistent gynecologic tumors.

Condition Intervention Phase
Gynecologic Tumors
Drug: Oral Topotecan
Drug: Pazopanib
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Trial of Oral Metronomic Topotecan in Combination With Oral Pazopanib Utilizing a Daily Dosing Schedule to Treat Recurrent or Persistent Gynecologic Tumors

Resource links provided by NLM:


Further study details as provided by Vector Oncology:

Primary Outcome Measures:
  • Determine the maximum tolerated dose (MTD) of metronomic oral topotecan in combination with oral pazopanib for future phase II evaluation. [ Time Frame: every 28 days ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Identification and incidence of adverse events (AEs) and serious adverse events (SAEs). [ Time Frame: every 28 days ] [ Designated as safety issue: Yes ]
  • Potential signals for response per Response Evaluation Criteria in Solid Tumors (RECIST) v1.0 guidelines. [ Time Frame: after every 2 cycles ] [ Designated as safety issue: No ]

Enrollment: 33
Study Start Date: April 2009
Study Completion Date: September 2015
Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Experimenal
Metronomic oral topotecan and oral pazopanib will be administered by mouth beginning on Cycle 1 Day 1. Patients will be enrolled and observed for dose limiting toxicity (DLT) for 1 cycle of treatment. Dose modification of the combination will depend on the number of patients experiencing DLT(s) at each dose level.
Drug: Oral Topotecan
Starting on Cycle 1 Day 1, each subject will receive the assigned dose of topotecan administered by mouth.
Other Name: Hycamtin capsules
Drug: Pazopanib
Starting on Cycle 1 Day 1, each subject will receive the assigned dose of pazopanib administered by mouth.
Other Names:
  • GW786034
  • Votrient

Detailed Description:
This is a Phase 1, dose-escalation study in female patients with recurrent or persistent gynecologic tumors. The study will include a Screening Phase, a Treatment Phase and a Followup Phase. In the Screening Phase the subject's eligibility for study participation will be determined; this phase can last up to 28 days. The Treatment Phase will begin when the subject starts study treatment and will continue until the subject is removed from study treatment. The Follow-up Phase will last for 30 days after the subject ends study treatment. The study will be conducted at approximately 1 site and will include approximately 41 evaluable patients. Treatment cycle length is 28 days. Radiologic imaging will be repeated after every 2 cycles of treatment.
  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Subjects must provide written informed consent prior to the performance of study specific procedures, and must be willing to comply with treatment and follow-up.
  • Female patients, greater than 18 years of age with a histologically confirmed recurrent/persistent gynecologic malignancy.
  • For patients with recurrent/persistent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma: persistent disease = progression during primary platinum therapy; recurrent disease = disease that recurs ≤ 12 months after discontinuing primary platinum therapy; if disease recurrence occurs > 12 months after discontinuing primary platinum therapy, there must be progression either during a 2nd platinum therapy or < 6 months after discontinuing the 2nd platinum therapy.
  • For patients with other gynecologic malignancies:

    • Malignancy is metastatic or unresectable and no curative or palliative measures exist or are no longer effective.
    • Maximum of two total prior treatments (this includes neoadjuvant, adjuvant, and metastatic settings) for the recurrent or persistent gynecologic tumors including chemotherapy, hormonal therapy, investigational therapy, radiation therapy, etc.)
  • Disease may be measurable or non-measurable according to RECIST version 1.0
  • Gynecologic Oncology Group (GOG) performance status of 0,1,or 2
  • Must have a life expectancy of at least six months
  • Adequate bone marrow, liver, renal, and cardiac function at study entry as assessed by the following:

    • Hemoglobin > 9.0 g/dL.
    • Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L.
    • Platelet count ≥ 100 x 10^9/L.
    • Prothrombin time (PT) or international normalized ratio (INR) < 1.2 x upper limit of normal (ULN).
    • Partial thromboplastin time (PTT) < 1.2 x ULN.
    • Total bilirubin ≤ 1.5 x ULN.
    • Alanine transaminase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN.
    • Creatinine ≤ 1.5 mg/dL or if serum creatinine is greater than 1.5 mg/dL, calculated creatinine clearance must be > 50 mL/min
    • Urine dipstick for protein < 2+ or urine protein creatinine (UPC) ratio < 1.0.
    • Left ventricular ejection fraction (LVEF) ≥ 50% or the institutional lower limit of normal (LLN)
  • Patients must be physiologically incapable of becoming pregnant, be postmenopausal, or have a negative pregnancy test and agree to use adequate contraception.

Exclusion Criteria:

  • Treatment naive patients.
  • Repetitive or prolonged neutropenia or thrombocytopenia during previous therapy.
  • Concurrent malignancy other than malignancies under study. 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.
  • Prior radiation therapy.
  • Myelosuppressive chemotherapy within the past 28 days or has not recovered from the myelosuppressive effects of recent chemotherapy.
  • Use of an investigational agent, including an investigational anti-cancer agent, immunotherapy, biological therapy, or hormonal therapy within 28 days prior to the first dose of study treatment.
  • Prior major surgery or trauma within 28 days prior to the first dose of study treatment and/or presence of any non-healing wound, fracture, or ulcer.
  • History or clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis.
  • Inability to swallow a capsule or clinically significant gastrointestinal abnormalities including, but not limited to:

    • Malabsorption syndrome
    • Major resection of the stomach or small bowel that could affect the absorption of study treatment
    • Active peptic ulcer disease
    • Inflammatory bowel disease
    • Ulcerative colitis, 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.
    • Unresolved bowel obstruction or diarrhea ≥ Grade 1
    • Known intraluminal metastatic lesion(s) with risk of bleeding
  • Known endobronchial lesions or involvement of large pulmonary vessels by tumor.
  • Presence of uncontrolled infection.
  • Prolongation of corrected QT interval > 480 milliseconds.
  • 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
    • 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 of > 140 mmHg or diastolic blood pressure of > 90 mmHg). Initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry.
  • History of cerebrovascular accident, transient ischemic attack, pulmonary embolism, or insufficiently treated deep vein 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
  • Evidence of active bleeding or bleeding diathesis.
  • Recent hemoptysis in excess of 2.5 mL within 8 weeks of 1st dose of study treatment.
  • 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.
  • Use of any prohibited medication within 14 days or 5 half-lives of the drug (whichever is longer) prior to the first dose of study treatment and during the study.
  • Prior use of any investigational or licensed anti-angiogenic agent, including topotecan, bevacizumab, thalidomide, and agents that target vascular endothelial growth factor (VEGF), VEGF receptors, or platelet-derived growth factor (PDGF).
  • Any ongoing toxicity from prior anti-cancer therapy that is > Grade 1 and/or that is progressing in severity, except alopecia.
  • Known hypersensitivity to topoisomerase I inhibitors or pazopanib.
  • Administration of any non-oncologic investigational drug within 30 days or five half-lives of a drug (whichever is longer) prior to the first dose of study treatment.
  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: NCT00800345

Locations
United States, Tennessee
The West Clinic
Memphis, Tennessee, United States, 38120
Sponsors and Collaborators
Vector Oncology
GlaxoSmithKline
Investigators
Principal Investigator: Todd D Tillmanns, MD The West Clinic
  More Information

Responsible Party: Vector Oncology
ClinicalTrials.gov Identifier: NCT00800345     History of Changes
Other Study ID Numbers: ATDTRPST0802 
Study First Received: December 1, 2008
Last Updated: April 12, 2016
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board
Individual Participant Data  
Plan to Share IPD: Undecided

Keywords provided by Vector Oncology:
Gynecologic tumors

Additional relevant MeSH terms:
Genital Neoplasms, Female
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Topotecan
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents

ClinicalTrials.gov processed this record on August 23, 2016