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

• ClinicalTrials.gov Identifier: NCT00800345
• Recruitment Status: Completed
• First Posted: December 2, 2008
• Results First Posted: February 23, 2017
• Last Update Posted: March 28, 2017
• Sponsor: Vector Oncology
• Collaborator: GlaxoSmithKline
• Information provided by (Responsible Party): Vector Oncology

Study Description

Brief Summary:

This is a Phase 1, dose-escalation study in female patients with recurrent or persistent gynecologic tumors.

Condition or disease	Intervention/treatment	Phase
Gynecologic Tumors	Drug: Oral Topotecan; Drug: Pazopanib	Phase 1

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. Treatment cycle length is 28 days. Radiologic imaging will be repeated after every 2 cycles of treatment.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 33 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (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
• Study Start Date: April 2009
• Actual Primary Completion Date: June 2015
• Actual Study Completion Date: September 2015

Arms and Interventions

Arm	Intervention/treatment
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

Outcome Measures

Primary Outcome Measures :

1. Dose Limiting Toxicity (DLT) [ Time Frame: Cycle 1 (28 days) ]

Secondary Outcome Measures :

1. Treatment Response [ Time Frame: After every 2 cycles of treatment beginning on Cycle 1 Day 1, up to 38 months ]
   Treatment response was evaluated using RECIST version 1.0 guidelines, where complete response (CR) is the disappearance of all target lesions; partial response (PR) is >=30% decrease in the sum of the longest diameter (LD) of target lesions; Stable Disease (SD) is neither sufficient shrinkage in sum of LD of target lesions to be PR nor increase of >=20%; Progressive Disease (PD) is the increase in existing lesions or new lesions.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes 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

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
• Other Study ID Numbers: ATDTRPST0802
• First Posted: December 2, 2008
• Results First Posted: February 23, 2017
• Last Update Posted: March 28, 2017
• Last Verified: December 2016

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

Keywords provided by Vector Oncology:

Gynecologic tumors

Additional relevant MeSH terms:

Genital Neoplasms, Female; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Topotecan; Topoisomerase I Inhibitors; Topoisomerase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents