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

Study Overview
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Brief Summary
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The purpose of this research study is to determine the best dose of the combination of two approved drugs, intravenous topotecan and oral erlotinib.

Detailed Description
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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.

Official Title
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A Phase I, Dosage-finding and Pharmacokinetic Study of Intravenous Topotecan and Oral Erlotinib in Adults With Refractory Solid Tumors

Conditions
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Metastatic Solid Tumor

Intervention / Treatment
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* Drug: Topotecan
* Drug: Erlotinib


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intravenous Topotecan and Oral Erlotinib<br>All subjects receive treatment with intravenous topotecan and oral erlotinib. | Drug: Topotecan<br>* All subjects receive treatment with intravenous topotecan and oral erlotinib.<br>* Other names: Hycamtin;Drug: Erlotinib<br>* All subjects receive treatment with intravenous topotecan and oral erlotinib.<br>* Other names: Tarceva;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dosage (MTD) of Intravenous Topotecan When Given in Combination With Oral Erlotinib | 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. | MTD was assessed during the first cycle of combination topotecan and erlotinib therapy (days 1-21). | 
| Dosage Limiting Toxicities |  | 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) |  | Day 1 Week 1 and Day 1 Week 3 | 
| Pharmacokinetic Parameters of Intravenous Topotecan With and Without Erlotinib (Renal Clearance) |  | Day 1 Week 1 and Day 1 Week 3 | 
| Pharmacokinetic Parameters of Intravenous Topotecan With and Without Erlotinib (Dose-Normalized AUC) |  | Day 1 Week 1 and Day 1 Week 3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacogenetic Analysis (CYP3A4/5 Polymorphisms, UGT1A1, BCRP, and MDR1 Genotypes) | 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. | Baseline | 
| Objective Response (as Determined Using RECIST 1.0 Criteria) |  | Every 6 weeks until the end of study treatment |