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Phase I, Dosage-finding and PK Study of IV Topotecan and Erlotinib With Refractory Solid Tumors

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00611468
First Posted: February 11, 2008
Last Update Posted: August 22, 2011
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborators:
GlaxoSmithKline
Genentech, Inc.
Information provided by (Responsible Party):
Accelerated Community Oncology Research Network
  Purpose
The purpose of this research study is to determine the best dose of the combination of two approved drugs, intravenous topotecan and oral erlotinib.

Condition Intervention Phase
Metastatic Solid Tumor Drug: Topotecan Drug: Erlotinib Phase 1

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I, Dosage-finding and Pharmacokinetic Study of Intravenous Topotecan and Oral Erlotinib in Adults With Refractory Solid Tumors

Resource links provided by NLM:


Further study details as provided by Accelerated Community Oncology Research Network:

Primary Outcome Measures:
  • Maximum Tolerated Dosage (MTD) of Intravenous Topotecan When Given in Combination With Oral Erlotinib [ Time Frame: MTD was assessed during the first cycle of combination topotecan and erlotinib therapy (days 1-21). ]
    The MTD of topotecan was determined using a standard 3 + 3 dose escalation cohort design. The total sample and the number of patients who receive each dose in this design depends on the frequency of dose limiting toxicities (DLT) at each dosage. If 0 out of 3 patients experience a DLT at a given dosage level, 3 patients will be enrolled at the next dosage level. If greater than or equal to 2 patients experience a DLT at a given dosage level, dosage escalation will be stopped. If 1 out of 3 patients experience a DLT at a given dosage level, 3 patients are enrolled at the same dosage level.

  • Dosage Limiting Toxicities [ Time Frame: DLT were assessed during the first cycle of combination topotecan and erlotinib therapy (days 1-21) ]
  • Pharmacokinetic Parameters of Intravenous Topotecan With and Without Erlotinib (Mean Clearance) [ Time Frame: Day 1 Week 1 and Day 1 Week 3 ]
  • Pharmacokinetic Parameters of Intravenous Topotecan With and Without Erlotinib (Renal Clearance) [ Time Frame: Day 1 Week 1 and Day 1 Week 3 ]
  • Pharmacokinetic Parameters of Intravenous Topotecan With and Without Erlotinib (Dose-Normalized AUC) [ Time Frame: Day 1 Week 1 and Day 1 Week 3 ]

Secondary Outcome Measures:
  • Pharmacogenetic Analysis (CYP3A4/5 Polymorphisms, UGT1A1, BCRP, and MDR1 Genotypes) [ Time Frame: Baseline ]
    Each subgroup lists the gene on which a polymorphism occurred (e.g., CYP3A4), the name of the polymorphism (e.g., *1), whether it was heterozygous or a variant, the number of subjects with available data, and the number who had the polymorphism.

  • Objective Response (as Determined Using RECIST 1.0 Criteria) [ Time Frame: Every 6 weeks until the end of study treatment ]

Enrollment: 29
Study Start Date: June 2006
Study Completion Date: August 2009
Primary Completion Date: August 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Intravenous Topotecan and Oral Erlotinib
All subjects receive treatment with intravenous topotecan and oral erlotinib.
Drug: Topotecan
All subjects receive treatment with intravenous topotecan and oral erlotinib.
Other Name: Hycamtin
Drug: Erlotinib
All subjects receive treatment with intravenous topotecan and oral erlotinib.
Other Name: Tarceva

Detailed Description:

The primary objectives of this trial include:

  • To determine the maximum tolerated dosage (MTD) of intravenous topotecan when given in combination with oral erlotinib.
  • To define the dosage-limiting toxicities (DLT) of this combination.
  • To evaluate the pharmacokinetic (PK) parameters of intravenous topotecan with and without erlotinib

The secondary objectives include:

  • To evaluate the pharmacodynamic effect of the topotecan and erlotinib combination
  • To evaluate for any correlations between the presence of CYP3A4/5 polymorphisms and topotecan / erlotinib disposition and to measure the frequency of MDR1 and BCRP in peripheral blood samples and correlate these results with topotecan pharmacokinetics
  • To measure the frequency of UGT genotypes in peripheral blood samples
  • To evaluate the objective response rate using the RECIST criteria.
  Eligibility

Information from the National Library of Medicine

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, Learn About Clinical Studies.


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

Inclusion Criteria:

  • Patients must have a histologically confirmed malignancy that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective.
  • Prior chemotherapy must have been completed at least 3 weeks prior to enrollment (6 weeks for nitrosureas and mitomycin) and the patient must have recovered from all associated toxicities (except alopecia and neuropathy grade 1 according to the NCI-CTC, version 3.0 classification). Radiation must have been completed 8 weeks prior to enrollment. Major surgery must have been completed 4 weeks prior to enrollment. Hormonal therapy must have been completed at least 2 weeks prior.
  • Age >18 years.
  • ECOG performance status <1 (Karnofsky >70%)
  • Life expectancy of greater than 12 weeks.
  • Patients must have normal organ and marrow function as defined below: White blood cell count >2,500/mm3, Absolute neutrophil count (ANC) >1,500/ mm3, Platelet count >100,000/ mm3, Hemoglobin > 10 g/dL, Albumin >2.5 g/dL, Total bilirubin <1.5 X institutional upper limit of normal (ULN), AST/ALT <1.5 X institutional ULN, Serum creatinine <2.0 g/dL, Creatinine clearance >40 mL/min
  • Patients must be able to swallow and retain oral medication
  • Female patients must be nonpregnant and nonlactating. All patients of childbearing potential must implement an effective method of contraception during the study. All female patients (except those who are postmenopausal or surgically sterilized) must have a negative pre-study serum or urine pregnancy test obtained within 7 days of study enrollment.
  • All patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines.

Exclusion Criteria:

  • Patients may not be receiving any other investigational agents. Participation in other clinical trials with any investigational drugs must have been completed ≥ 28 days prior to enrollment on this trial (or longer based on the halflife of the investigational agent).
  • Patients must have no more than 3 prior lines of therapy. The patient may have only received carboplatin and/or gemcitabine in one of the prior lines of therapy.
  • Patients must not be receiving concurrent cancer therapy (chemotherapy, radiation therapy, immunotherapy, biologic therapy, hormonal therapy for cancer). Low dose maintenance steroids are acceptable if the patient will remain on a stable dose during cycles 1, 2 and 3 (to ensure continuity for topotecan pharmacokinetic studies).
  • Patient may not have a history of serious allergic reactions attributed to compounds of similar chemical composition to topotecan (camptothecins) and/or erlotinib (tyrosine kinase inhibitors).
  • Patients must not have malabsorption syndrome, any disease significantly altering gastrointestinal function, or resection of the stomach or small bowel.
  • Patients must not be taking warfarin (including low dose anticoagulants).
  • Patients must not be taking concurrent treatment with potent inhibitors of cytochrome P450 3A4. For patients who were receiving treatment with such agents, a one-week washout period is required prior to beginning the protocol.
  • Patients must not be taking concurrent treatment with potent inducers of cytochrome P450 3A4, such as phenytoin, carbamazepine, rifampin, barbiturates, or St. John's Wort. For patients who were receiving treatment with such agents, a one week washout period is required prior to beginning the protocol.
  • Patients must have no active serious infection, fever > 38.2 degrees Celsius, or other serious underlying medical condition that would otherwise impair their ability to receive protocol treatment (i.e., documented HIV infection, uncontrolled hypertension, uncontrolled CNS metastases, unstable angina, congestive heart failure, poorly controlled diabetes, coronary angioplasty within 6 months, myocardial infarction within 6 months, uncontrolled atrial or ventricular arrhythmias).
  • Patients should not have psychological, familial, sociological geographical conditions that do not permit medical follow-up and compliance with the study protocol.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00611468


Locations
United States, Tennessee
The West Clinic
Memphis, Tennessee, United States, 38120
Sponsors and Collaborators
Accelerated Community Oncology Research Network
GlaxoSmithKline
Genentech, Inc.
Investigators
Principal Investigator: Lee S. Schwartzberg, MD, FACP Accelerared Community Oncology Research Network, Inc.
  More Information

Responsible Party: Accelerated Community Oncology Research Network
ClinicalTrials.gov Identifier: NCT00611468     History of Changes
Other Study ID Numbers: ACORN ALSSRST0501
First Submitted: January 29, 2008
First Posted: February 11, 2008
Results First Submitted: July 1, 2010
Results First Posted: July 19, 2011
Last Update Posted: August 22, 2011
Last Verified: August 2011

Additional relevant MeSH terms:
Erlotinib Hydrochloride
Topotecan
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Topoisomerase I Inhibitors
Topoisomerase Inhibitors