Clinical trial NCT00317772
Conditions: Ovarian Cancer Peritoneal Neoplasms Fallopian Tube Cancer
Keywords: Epithelial Ovarian Cancer Peritoneal Cancer Fallopian Tube Cancer Epidermal Growth Factor Platinum Hypersensitivity Hycamtin Gefitinib Iressa Topotecan EGFR
Sponsor: M.D. Anderson Cancer Center
Start date: 2004-09-02; Completion date: 2020-11-04
Enrollment: 19 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
The purposes of this study are:

1. To determine the dose limiting toxicity (DLT) and the maximum tolerated dose (MTD) weekly of topotecan in combination with standard dose gefitinib in patients with relapsed, platinum-resistant, ovarian, peritoneal or fallopian tube cancers that are epidermal growth factor receptor (EGF-R) positive (\>/= 1+).
2. To determine the response rate and response duration in this patient population treated with the maximum tolerated dose (MTD) of topotecan administered on a weekly schedule in combination with standard dose gefitinib, given by way of the mouth (PO) daily.

Detailed description:
Gefitinib inhibits the activity of a molecule present on the cancer cell that plays a role in cancer cell growth. Topotecan is an FDA approved drug used to treat ovarian cancer that is still present after treatment with chemotherapy. It is also used to treat recurrent ovarian cancer (patients whose cancer returns after they have been cancer-free for a period of time).

Before treatment starts, you will have a complete physical exam, routine blood tests (about 2-3 teaspoons), a chest x-ray, and a CT scan or MRI. Women who are able to have children must have a negative blood pregnancy test.

There are 2 phases to this study. In the first phase, 3 different dose levels of topotecan are being studied. The dose of topotecan that you receive will depend on when you are enrolled. It will also depend on whether or not other participants had side effects from their treatment. Although the dose of topotecan will vary, the dose of gefitinib is the same for all participants. Up to 6 participants may be treated at each dose. The goal of this portion of the study is to find the highest safe dose of this drug combination. Up to 18 patients will be treated on this part of the study.

Once the highest safe dose of topotecan has been found, the second phase of the study will begin. In this phase, all participants will receive the same dose of topotecan and gefitinib. Up to 40 patients will be enrolled in this part of the study (but 6 will be from the 1st portion of the study.

Each treatment cycle is 28 days long. You will take one gefitinib tablet by mouth every day beginning on Day 1. In addition, you will be given topotecan through a catheter (tube) placed in a vein over 30 minutes on Days 1, 8, and 15.

Blood tests to check your kidney, liver, and bone marrow function and a complete checkup (physical examination, including a pelvic and rectal exam) will be done before each course of therapy and a month after treatment ends. About 2-3 teaspoons of blood will be collected for routine blood tests each time blood is drawn during this study. Follow up CT scans or MRI scans will be done after every 2 to 3 cycles to evaluate your response to treatment.

You will be taken off study if your disease gets worse or intolerable side effects occur. If you have a complete response to this therapy (no evidence of cancer) then treatment will continue for an additional 6 months and then stop. All treatment is given on an outpatient basis at UTMDACC.

You will be monitored for at least 30 days after your last dose of therapy. If you have side effects related to this treatment combination, you will be monitored longer (until the side effects have gone away).

This is an investigational study. Both gefitinib and topotecan are FDA approved and commercially available. However, their use together in this study is investigational. A total of up to 52 patients will take part in this study. All will be enrolled at UTMDACC.

Arms: arm 1: Phase I: Topotecan: 2.0, 3.0, or 4.0 mg/m\^2 by vein Days 1, 8 and 15 of 28 day cycle.

Gefitinib: 250 mg by mouth daily.

Phase II: Topotecan starting dose: MTD from Phase I by vein Days 1, 8, and 15 of 28 day cycle.

Gefitinib: 250 by mouth daily for 28 Days.
Interventions: intervention 1: Topotecan intervention 2: Gefitinib
Intervention descriptions: intervention 1: Phase I Starting Dose: 2 mg/m\^2 by vein Weekly Over 30 Minutes on Days 1, 8, and 15.

Phase II: MTD dose from Phase I by vein weekly on Days 1, 8, and 15. intervention 2: Phase I: 250 mg by mouth daily for 28 Days.

Phase II: 250 mg by mouth daily for 28 Days.

Protocol documents:
Prot_SAP_000.pdf: 
2003-0322
Revised, September 7, 2005
Page 1
Protocol Page
A Phase I/II Study of Weekly Topotecan and Gefitinib in Patients with 
Platinum-Resistant Ovarian, Peritoneal, or Fallopian Tube Cancer
2003-0322
Core Protocol Information
Short Title 
Weekly Topotecan and Iressa
Study Chair:
Judith Wolf
Additional Contact:
Maria Jung
Department:
Gynecologic Oncology
Phone:
713-792-7310
Unit:
440
Study Co-Chair(s):
Diane C. Bodurka
John J. Kavanagh
Brian M. Slomovitz
Full Title: 
A Phase I/II Study of Weekly Topotecan and Gefitinib in Patients with Platinum-Resistant 
Ovarian, Peritoneal, or Fallopian Tube Cancer
Protocol Type:
Standard Protocol
Protocol Phase:
Phase I/Phase II
Version Status:
Activated -- Closed to new patient entry as of 01/11/2007
Version:
06
Submitted by:
Maria Jung--10/6/2005 1:29:40 PM
OPR Action:
Accepted by:  Cimetra R. Cox -- 10/7/2005 8:29:27 AM
Which Committee will review this protocol?
The Clinical Research Committee - (CRC)


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Protocol Body
1.0 Objectives
To determine the dose limiting toxicity (DLT) and the maximum tolerated dose (MTD) weekly 
1.
topotecan in combination with standard dose gefitinib in patients with relapsed, platinum-resistant, 
ovarian, peritoneal or fallopian tube cancers that are EGF-R positive (>/= 1+).
To determine the response rate and response duration in this patient population treated with the 
2.
maximum tolerated dose (MTD) of topotecan administered on a weekly schedule in combination with 
standard dose gefitinib, given PO daily.
2.0 Background
Ovarian cancer is the leading cause of death from gynecologic malignancy and the fifth leading cause of 
cancer death in American women. An estimated 25,400 new cases are reported in the United States 
yearly, and approximately 14,300 women die annually from the disease. [1] Unfortunately, ovarian cancer 
often is detected only when it has spread throughout the peritoneal cavity. Despite aggressive surgical 
resection and adjunctive therapy, most patients die in a period of months from malnutrition and small 
bowel obstruction caused by intraperitoneal tumor. The term mullerian cancer refers to carcinomas 
arising from organs developmentally derived from mullerian duct epithelium. In this study we restrict the 
term to epithelial ovarian cancer, fallopian tube cancer and primary surface peritoneal adenocarcinoma. 
The commonly used staging and histology are similar. In fact in some cases of advanced carcinoma it is 
not possible to determine the origin of the carcinoma. Most importantly, the treatment is the same. 
Accordingly, the discussion of epithelial ovarian cancer applies to mullerian carcinoma in general. 
A pivotal Gynecologic Oncology Group (GOG) trial published in 1996 introduced paclitaxel into front line 
therapy in combination with cisplatin. Women with pathologically verified stage III and IV ovarian cancer 
were included. All  patients had sub-optimal tumor reductive surgery. This combination produced a 70% 
response rate with a progression-free survival of 18 months and a median survival of 38 months 
compared with a progression-free survival  of 13 months and a median survival of 24 months with 
cisplatin and cyclophosphamide. [2] Carboplatin-based regimes have equivalent activity and are 
considered the current chemotherapeutic regimen of choice in advanced ovarian cancer. [3] Ovarian 
cancers are often (70-80%) responsive to platinum-based chemotherapy, most become resistant. 
One of the major issues faced by investigators is the optimal treatment of patients with recurrent disease. 
The disease-free interval is the major predictor of response to second-line treatment or reinduction 
treatment with platinum agents. Patients may be classified as platinum-resistant (relapse within 6 months) 
and platinum-sensitive (relapse after 6 months). In a series by Markman et al. [4], the response rate to 
second-line cisplatinum/carboplatin ranged from 27% for patients with a cisplatin-free interval of 5-12 
months to 59% for those with an interval longer than 24 months. Other studies have shown that 
re-treatment with carboplatin for patients with a disease-free interval less than 6 months will yield a 
response rate of approximately 13%. [5] Unfortunately, in spite of the best possible chemotherapy, the 
majority of patients treated will recur within 2 years of treatment and will go on to die of their disease.
Topotecan is a water soluble, semi-synthetic, analogue of camptothecin, and exerts its antitumor activity 
through its inhibition of topoisomerase-I. Topotecan has received FDA approval for the treatment of 
relapsed ovarian and small cell lung carcinomas. The dose and schedule of topotecan administration 
remains under active investigation.
Agents that target topoisomerase-I stabilize a covalent DNA topoisomerase complex, which leads to DNA 
cleavage. Topoisomerase is also important in DNA transcription and replication. [6] High levels of 
topoisomerase can be found in tumor tissue with low, as well as high, growth fractions. As the activity of 
topoisomerase inhibitors is in proportion to the level of the target enzyme, topotecan may be just as 
effective on slowly dividing tumors as more actively dividing tumors. [7]
Two groups have examined the concentration of topoisomerase I following administration of topotecan.


2003-0322
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Page 3
Using a 72 hour continuous infusion of topotecan, Hammond, et al. [8] demonstrated decreases in 
topoisomerase I to 40-60% of baseline in two of six patients on day three, with a return to baseline by day 
seven.  When administered on a daily times five regimen, Murren, et al. [9] noted that topoisomerase 
levels were significantly decreased on days three and five (as compared to baseline) in 62% of 33 cycles 
of therapy administered.  In thirteen patients in this study, seven (54%) demonstrated a greater than 20% 
decrease in topoisomerase I levels on day one of topotecan therapy.  Weekly administration of topotecan 
may allow for maximal interaction with topoisomerase I and prevent down regulation of the enzyme as a 
cellular protective mechanism.
Various doses and schedules of topotecan administration have been studied.  The FDA approved 
schedule of 1.5mg/m
2 daily times five every 21 days was developed from work by Rowinsky, et al. [10] 
where the dose limiting toxicity was determined to be noncummulative neutropenia.  This five day 
regimen requires frequent office visits, and may require colony stimulating factors to mitigate the drug 
induced neutropenia.
Dose limiting neutropenia has also been noted 24 hour continuous infusion schedules (where the 
maximal tolerated dose was 10.5mg/m
2) [11] and 30 minute IV bolus infusion (where the maximal 
tolerated dose was 22.5mg/m
2 ) once every 21 days. [12] In these studies, neutropenia was 
non-cummulative and non-hematologic toxicities were mild.
Modifying the schedule of topotecan administration is an approach to resolution of the myelotoxicity issue 
that has been studied. A weekly schedule appears to be at least as well-tolerated, more convenient and 
efficacious as the daily x 5 schedule. [12] Homesley, et al, reported 4mg/m2/week as a safe well-tolerated 
dose of Topotecan in previously treated ovarian cancer patients. Responses were seen at doses as low 
as 2mg/m
2/week. [13,14]
The epidermal growth factor receptor (EGF-R) is expressed in many types of cancer. Fifty to 70% of epithelial ovarian canc
Importantly, over-expression of EGFR has been correlated with poor prognosis features in many cases. While these tumor
chemosensitive to platinum based therapy, chemoresistance often develops.  Clinical trials in other sites (lung, pancreas, h
cancers) have found that chemoresistance can be overcome in some patients by blocking the EGF-R. Using either an anti
tyrosine kinase inhibitor, such as gefitinib or tarceva. These agents have been combined with several different chemothera
including taxol, platinum and gemcitabine. The major toxicity is an acniform rash. Gefitinib also can cause diarrhea. None o
effect on the chemotherapy toxicities.
Gefitinib (Iressa) is a potent and selective inhibitor of the epidermal growth factor receptor (EGFR) 
tyrosine kinase. Activation of the tyrosine kinase catalyses autophoshorylation and subsequent 
phosphorylation of protein tyrosine residues, which then initiates a cellular signal transduction cascade.
Selective Gefitinib inhibition of the EGFR tyrosine kinase results in interruption of mitogenic and 
anti-apoptotic signals responsible for cellular cancer processes such as proliferation, growth, metastases, 
angiogenesis, and responsiveness to chemotherapy or radiotherapy.
Preclinical evidence in ovarian cancer supports this concept for this site. Combined antisense to EGF-R 
with cisplatin in cell culture of ovarian cancer cell lines that express the EGF-R sensitized the cells the 
effects of cisplatin. In another study, combining an EGF-R tyrosine kinase inhibitor with either cisplatin or 
carboplatin in cell culture of an ovarian cancer cell line also enhanced chemotherapy activity.
Preclinical evidence also exists to support the combination of an EGF-R TK inhibitor with topotecan. 
Erlichman, et al, reported synergistic activity of SN38 (a camptothecin) or topotecan with CI1003, a 
tyrosine kinase inhibitor (not available for clinical trials) in glioblastoma and colon cancer cell lines. Their 
work found that the TK inhibitor increased the intracellular levels of the camptothecins by decreasing 
efflux of the drug from the cell.
Taken together, this information supports evaluating the combination of topotecan and an EGF-R 
antagonist in patients with recurrent ovarian cancer.


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3.0 Background Drug Information
TOPOTECAN
Topotecan is an antineoplastic agent. It acts by inhibiting the enzyme topoisomerase I. Double strand 
DNA damage caused by topotecan cannot be easily repaired by mammalian cells. 
DOSING INFORMATION: The usual dose of topotecan in patients with solid tumors is 1.5 
milligrams/square meter/day (mg/m
2/day) as a 30-minute intravenous infusion for 5 days every three 
weeks. The drug has also been given in numerous prolonged infusion schedules (eg, 24 hrs,  21 days). 
Dose adjustments are indicated in moderate renal impairment. 
PHARMACOKINETICS: Topotecan is absorbed orally, although most clinical studies have employed the 
intravenous route. In vivo, rapid conversion of topotecan (lactone) to the hydroxy acid occurs, although 
the reverse reaction appears minimal; no other metabolic pathways have been confirmed. The protein 
binding of total topotecan is approximately 35%, and the steady-state volume of distribution is 
approximately 90 liters/square meter (L/m(2)) with 30-minute daily infusions. The average urinary 
excretion of total topotecan is about 45% of the dose administered; total body clearance of topotecan 
(lactone) has ranged from 40 to 130 L/hour/m(2) with daily 30-minute infusions. Biliary excretion of 
topotecan may occur. With daily 30-minute infusions for 5 days, the elimination half-life of topotecan is 2 
to 3 hours.
STORAGE AND STABILITY: Unopened vials of topotecan hydrochloride are stable prior to expiration 
date when stored in the original cartons between 20 and 25 degrees Celsius (68 to 77 degrees 
Fahrenheit) and protected from light.  2. While it is recommended that topotecan be used immediately 
after reconstitution, the reconstituted solution is stable for up to 24 hours when stored between 20 and 25 
degrees Celsius (68 to 77 degrees Fahrenheit) in ambient light. Topotecan infusion solution 0.025 mg/mL 
and 0.05 mg/mL in 0.9% sodium chloride or 5% glucose was stable for 28 days (over 95% of original 
topotecan content) when refrigerated or stored at room temperature protected from light
CAUTIONS: Neutropenia is dose-limiting with all administration schedules of topotecan; 
thrombocytopenia and anemia have also been severe in some studies. Other adverse effects include 
alopecia, nausea and vomiting, diarrhea, mucositis, headache, fatigue, rash, liver enzyme abnormalities, 
microscopic hematuria, and proteinuria. Mucositis has been dose-limiting in leukemic patients but not in 
solid tumor patients. Neutropenic fever has been reported in up to 30% of patients receiving daily 
30-minute topotecan infusions. Topotecan has not produced the hemorrhagic cystitis observed with its 
parent compound camptothecin. 
CLINICAL APPLICATIONS: Topotecan is indicated for second-line treatment of refractory small-cell lung 
cancer or metastatic ovarian cancer, and has demonstrated variable antitumor efficacy in non-small cell 
lung cancer, prostate cancer, and colorectal cancer.
PREPARATION: Contents of each 4mg vial should be reconstituted with 4ml sterile water for injection, 
USP, or bacteriostatic water for injection, USP, yielding a l mg/ml solution of topotecan.  Further dilution in 
dextrose 5% in water, or normal saline retains stability for 24 hours at room temperature.
ADMINISTRATION: The diluted solution may be infused via a peripheral or central vein over 30 minutes.
CONTRAINDICATIONS
Breast-feeding
Hypersensitivity to topotecan, irinotecan, or camptothecin 
Neutrophil counts of less than 1500 cells/cubic millimeter 
Pregnancy
PRECAUTIONS
Bone marrow suppression (mild-to-moderate) 


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Page 5
Neutropenia is dose-limiting with all dose schedules 
Extravasation associated with only mild local erythema and bruising 
Hepatic dysfunction (topotecan may have hepatotoxic potential) 
Prior chemotherapy/radiation (possibility of greater myelosuppression) 
Renal impairment (dose reductions) 
ADVERSE REACTIONS 
HEMATOLOGIC EFFECTS: Neutropenia is the main dose-limiting toxicity of topotecan and has been 
severe in 60% of patients during the first course of treatment. Nadir neutrophil counts have occurred at a 
median of 11 days. Higher doses of topotecan can be administered with a short infusion every 3 weeks 
as compared with intermittent or prolonged infusions. THROMBOCYTOPENIA and ANEMIA are also 
observed, and may be dose-limiting. Anemia may occur in all patient groups with or without renal 
impairment.
CARDIOVASCULAR EFFECTS: Topotecan does not appear to produce significant cardiotoxic effects. 
Asymptomatic HYPOTENSION has been reported in up to 15% of patients treated with 30-minute 
infusions for 5 consecutive days. Deep-vein thrombosis was described in 1 of 20 non-small cell lung 
cancer patients during treatment with daily 30-minute infusions of topotecan for 5 days. However, other 
factors may have been contributory or causal. 
CENTRAL NERVOUS SYSTEM EFFECTS: HEADACHE has been reported occasionally during or after 
infusions of topotecan. PERIPHERAL NEUROPATHY or PARESTHESIA has occurred rarely, although a 
causal relationship is uncertain 
FATIGUE: Fatigue has been a frequent complaint with intravenous topotecan, occurring in 54% of 
patients receiving 21-day infusions, 40% receiving 24-hour infusions every 3 weeks, and up to 70% 
receiving 30-minute infusions for 5 days every 3 weeks.
ENDOCRINE/METABOLIC: Neutropenic FEVER has been reported in 4% to 33% of cancer patients 
receiving 30-minute infusions of topotecan for 5 days every 3 weeks. Fever on days of treatment 
(unrelated to infection) has also been reported with this regimen and with 24-hour continuous infusions. 
Fever began within minutes to three hours after the first dose of TOPOTECAN and resolved within 24 
hours of the last dose. Infection was not documented in these cases. High temperatures ranged from 
39.9 to 41.8 degrees Celsius 
GASTROINTESTINAL: Nausea, vomiting, and diarrhea are relatively frequent adverse effects of 
intravenous topotecan in solid tumor patients, but are seldom severe; mucositis is generally infrequent. In 
patients with acute leukemia, however, mucositis is dose-limiting. 
KIDNEY/GENITOURINARY: Occasional increases in serum creatinine, PROTEINURIA, and 
HEMATURIA have been reported 
SKIN: Alopecia has occurred with variable frequency (only rarely to up to 70%) in cancer patients 
receiving daily 30-minute infusions of topotecan for 5 days every 3 weeks; total hair loss has been 
reported occasionally. SKIN RASH, typically maculopapular involving the trunk, scalp, and extremities, 
has been observed in 17% to 25% of cancer patients receiving daily short infusions of topotecan for 5 
days every 3 to 4 weeks. Topotecan-induced skin rashes during daily 5-day regimens or 5-day 
continuous infusion regimens have typically appeared between days 4 and 8, with maximal symptoms 
around day 10; resolution typically occurs by day 15. Skin rashes have not limited therapy with topotecan. 
 SEPSIS: Sepsis or FEBRILE NEUTROPENIA has been attributed to topotecan use in 23% of patients; 
sepsis was fatal in 1%.
DRUG SUPPLY: Commercially available from GalxoSmithKline, Brentford, Middlesex, TW8 9GS


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GEFITINIB
Gefitinib is a selective epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor. 
DOSING INFORMATION: Given orally. Optimal doses/schedules for the treatment of solid tumors have 
not been established. The most common dose in available clinical studies has been 250 or 500 
milligrams (mg) once daily, alone or combined with cytotoxic agents.
Tablets will be packed in high-density polyethylene (HDPE) bottles with child-resistant closures.  Each 
bottle will contain 100 tablets of a single formulation.  The tablets will be dispensed to the patient as a 
3-month supply in the bottle provided by AstraZeneca. 
Each bottle will be labeled with the statement: "Caution: New Drug - Limited by Federal (or USA) Law to 
Investigational Use".  Instructions stating that the tablets should be taken orally “as directed by your 
doctor” will be included.  Information on the label will indicate the identity and quantity of tablets and 
storage conditions.  There will be blank lines for trial number, patient number, center number, and date 
dispensed; this information should be recorded by the investigator at the time the bottle is dispensed.
Gefitinib treatment will be taken once a day, every day about the same time.  It can be taken with or 
without food.  If the subject forgets to take a dose, they should take the last missed dose as soon as they 
remember, as long as it is at least 12 hours before the next dose is due.
PHARMACOKINETICS: Peak plasma levels of gefitinib occur 3 to 7 hours following oral administration; a 
dose of at least 100 mg daily maintains plasma levels above those required in vitro for inhibition of EGF-R 
kinase, although clinical correlations are lacking. Only small amounts of an oral dose appear unchanged 
in the urine (less than 1%); biliary excretion appears significant. An elimination half-life 26 to 49 hours has 
been reported (single or repeat oral dosing). 
CAUTIONS: Gefitinib has been generally well-tolerated in cancer patients. Predominant adverse effects 
are an acne-like skin rash, diarrhea, nausea, vomiting, and mild or moderate myelosuppression. 
CLINICAL APPLICATIONS: Once-daily oral gefitinib has exhibited antitumor efficacy in several 
tumor-types expressing or overexpressing EGF-R, including non-small 
cell lung cancer. Results of larger clinical trials are required to address its place in therapy.
CONTRAINDICATIONS: Prior hypersensitivity
PRECAUTIONS: Hepatic insufficiency (pharmacokinetic data are unavailable (potential need for dose 
adjustment); gefitinib has exhibited hepatotoxic potential; close monitoring of ALT and AST is indicated) 
Gastrointestinal disorders (diarrhea is common during gefitinib therapy) 
Myelosuppression (potential exacerbation) 
Bacterial/viral infection (potential exacerbation) 
Pregnancy (animal/human data lacking) 
Breastfeeding period (animal/human data lacking) 
EFFICACY:
In two Phase II randomized trials (IDEAL 1 and 2), pretreated non-small-cell lung cancer (NSCLC) 
patients received Gefitinib 250 or 500 mg/day.  IDEAL 1 patients (n=210) were recruited across Europe, 
Australia, South Africa and Japan and had received 1 or 2 prior chemotherapy regimens (1 
platinum-based), while IDEAL 2 recruited patients in the US (n=216) who had been given ³ 2 regimens 
(including platinum and docetaxel).  In IDEAL 1, the response rate (RR) was 18.4 and 19.0%, and 
disease control rate (DCR =responses plus stable disease) was 54.4 and 51.4%, in patients who 
received 250 and 500 mg/day Gefitinib, respectively.  Symptom improvement, measured by the LCS 
component of the FACT-L and lasting at least 4 or more weeks occurred in 40.3% for the 250 mg/day 
group and 37.0% for the 500 mg/day group. Median survival for the IDEAL-1 population receiving gefitinib 
as second or third-line therapy was not calculable with the 4 month minimum follow-up at the time of trial 


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closure.
In IDEAL 2, the RR was 11.8 and 8.8%, and DCR was 42.2 and 36.0%, in patients who received 250 and 
500 mg/day, respectively.  Symptom improvement, as measured by the LCS component of the FACT-L 
and lasting at least 4 or more weeks occurred in 43.1% for the 250 mg/day group and 35.1% for the 500 
mg/day group. Median survival for the IDEAL-2 population receiving gefitinib as third-line or greater 
therapy was 6 months.
Symptom-Improvement was associated with objective tumor response and survival in the IDEAL 1 and 2 
trials. Tumor responses occurred in patients predominantly with adenocarcinoma histology but responses 
have been observed in all histologies and irrespective of the number of previous chemotherapy regimens.
In addition to the efficacy findings, quality of life (QOL) improvement was seen in a significant proportion 
of patients and was consistent with disease-related symptom improvement, which reflects the lack of 
significant therapy-related toxicity observed.
Two large trials have been completed in chemo-naïve patients with stage III and IV non-small cell lung 
cancer.  Patients were randomized to receive gefitinib 250 mg daily, gefitinib 500 mg daily, or placebo in 
combination with platinum-based chemotherapy regimens.  The chemotherapies given in these first-line 
trials were gemcitabine and cis-platinum (N=1093) or carboplatin and paclitaxel (N=1037).  The addition 
of gefitinib, did not demonstrate any increase in tumor response rates, time to progression, or overall 
survival beyond that of chemotherapy alone.
TOLERABILITY:
Patients given Gefitinib 250 mg/day (or similar doses) frequently had drug-related gastrointestinal (GI) 
disturbances (mainly diarrhea; sometimes associated with dehydration) and skin reactions (rash, acne, 
dry skin, and pruritus).  The majority of drug-related adverse events are mild and non-cumulative, and 
rarely lead to withdrawal of Gefitinib therapy.
No additional safety concerns were raised for subpopulations of men or women, the elderly, ethnic 
groups, patients with renal impairment, or patients with mild-to-moderate hepatic impairment.  Few 
specific drug-drug interactions were identified that could impact on the safety of Gefitinib.
SIDE EFFECTS:
HEMATOLOGIC EFFECTS: ANEMIA (grade 1) has been relatively common in phase I/II studies. 
NEUTROPENIA and decreases in platelet counts have also been reported with variable frequency. 
CENTRAL NERVOUS SYSTEM EFFECTS: FATIGUE has been described by some cancer patients 
during gefitinib therapy, although this is more likely related to the disease state. 
GASTROINTESTINAL EFFECTS: DIARRHEA, NAUSEA, and VOMITING have been relatively common 
during therapy, occurring in 17% to 45%, 10% to 25%, and 10% to 22% of patients, respectively, in phase 
I/II studies (various doses). Diarrhea (grade 3) has been dose-limiting, usually at 700 mg daily. Anorexia 
has occurred in some patients. 
HEPATOTOXICITY: Increases in transaminases and alkaline phosphatase have been reported 
occasionally; some transaminase elevations reached grade 3 and were dose-limiting. Hepatic effects 
have been reversible. Recent preclinical findings following preliminary results from a carcinogenicity study 
(Study No. 455921, AstraZeneca Reference No. TC2577) in rats. The results have identified an increased 
incidence of benign liver tumors and mesenteric lymph node hemangiosarcomas in rats treated with 
gefitinib, which are suggestive of a possible association with gefitinib treatment. There was no evidence 
that either the benign liver cell tumor and mesenteric lymph node hemangiosarcomas were the cause of 
death of any animal on this study and the majority of findings were at end of life examinations. 
OCULAR EFFECTS: In patients participating in other trials and receiving gefitinib therapy, there were 
infrequent reports of reversible corneal erosion, sometimes in association with aberrant eyelash growth. 
In the event of a patient developing any eye symptoms, patients should be advised to seek medical 
advice promptly (consultation with an optometrist or ophthalmologist is advised).
DERMATOLOGIC EFFECTS: A characteristic skin RASH has accompanied gefitinib therapy in up to 
80% of cancer patients in phase I/II studies, and is the most common adverse effect. Rashes typically 


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Page 8
consist of pustular or acne-like lesions with occasional erythema/pruritus, or dry skin; they are usually 
located on the face, but involve the upper torso at higher doses (eg, 400 or 500 mg daily). Skin rashes 
are grade 1/2 in severity in most instances, although they have occasionally reached grade 3, requiring 
withdrawal of therapy. Rashes resolve rapidly upon cessation of treatment.
PULMONARY EFFECTS:To date, Gefitinib has been administered to over  50,000 people worldwide. 
Interstitial lung disease in patients treated with Gefitinib is uncommon, with a worldwide frequency  of less 
than 1%, which is comparable to that reported with other lung cancer therapies. Interstitial lung disease 
had a fatal outcome, whether deemed Gefitinib related or not, in approximately  0.24% in this medically 
complex group of  over  50,000 patients receiving Gefitinib.  The occurrence of pulmonary toxicity and 
interstitial lung disease was similar across all treatment arms in the first-line NSCLC combination 
chemotherapy (INTACT) trials, which were placebo-controlled first-line trials in over 2000 patients with 
non-small cell lung cancer who received either gemcitabine and cisplatin +/- Gefitinib or carboplatin and 
paclitaxel +/- Gefitinib.  Interstitial lung disease (ILD), including interstitial pneumonitis, is a common 
complication of lung diseases including advanced lung cancer, regardless of treatment. It has been 
widely observed in clinical trials in which chemotherapy and/or radiotherapy has been used for the 
treatment of advanced lung cancer. Interstitial Lung Disease, which may be acute in onset, has been 
observed uncommonly in patients treated with Gefitinib. These patients usually present with a fairly acute 
onset of dyspnea sometimes associated with cough or low grade fever. This may become quite severe 
within a short period of time and usually results in hospitalization. Radiological investigations, often 
including CT scan, frequently show pulmonary infiltrates or interstitial shadowing with ground glass 
appearance. There is often respiratory distress with arterial oxygen desaturation. Cultures are frequently 
negative for bacterial growth. In a number of cases, the event has responded to steroid therapy but this is 
not always so and a significant number of cases have had a fatal outcome.
DRUG SUPPLY: AstraZeneca will supply gefitinib to the investigator as brown, film-coated round shaped 
250mg tablets for use as follows: daily po x28 days in conjunction with intravenous topotecan on days 1, 
8 and 15.
LABELING: Each carton of study material will have an investigational-use label permanently affixed to the 
outside, stating that the drug is for clinical study use only and should be kept out of reach of children.
Instructions stating that the tablets should be taken as a single dose orally at the same time in the 
morning will be included.
STORAGE: All investigational products must be kept in a secure place under appropriate storage 
Conditions.  For US centers, all study treatment will be stored in a lockable storage area, between 
20-25°C (68-77°F).
ACCOUNTABILITY: It is the investigator’s responsibility to establish a system for handling study 
treatments, including investigational products, so as to ensure that:
Deliveries of such products from AstraZeneca are correctly received by a responsible person (e.g., a 
z
pharmacist)
Deliveries are recorded
z
Certificates of delivery and return are signed, preferably by the investigator or a pharmacist, and 
z
copies are retained
Study treatments are handled and stored safely and properly
z
The drug is to be prescribed only by the investigator or sub-investigators named in Form FDA-1572
z
Study treatments are dispensed only to study subjects in accordance with the protocol
z
Subjects must return all unused medication and empty containers to the investigator
z
All unused gefitinib trial treatment and empty bottles at the site or distribution center are destroyed 
z
At the end of the study, it must be possible to reconcile delivery records with records of usage and 
destroyed/returned stock. Records of usage should include the identification of the person to whom the 
trial treatment was dispensed, the quantity and date of dispensing, and unused study treatment returned 
to the investigator. Any discrepancies must be documented.
GUIDELINE FOR DISPENSING WHOLE GEFITINIB TABLETS: Gefitinib tablets cannot be crushed.


2003-0322
Revised, September 7, 2005
Page 9
Experimentation has shown that gefitinib tablets will break up into a fine dispersion within 5 to 7 minutes 
when they are dropped whole into lukewarm water.  There are felt to be no risks to the chemical stability 
of gefitinib providing this process occurs immediately prior to administration by the subject.  The only risk 
is felt to be concerned with ensuring delivery of the whole dose, as a certain amount of deposition of 
powder on the surfaces of the container will occur while the container is being emptied.
Although bio-equivalence has not yet been formally tested in clinical trials the following procedure is 
recommended for administering dispersed whole tablets to subjects who are unable to swallow the 
tablets:
Drop the required number of gefitinib tablets into an appropriate container (ideally glass to help confirm 
removal of all the dispersed material) containing approximately 1-2 ounces (or 50 mls) of lukewarm water. 
Stir the liquid occasionally to ensure complete break-up of the tablet(s).  When the tablet has broken up 
into a fine dispersion (approximately 5 minutes) it can be administered to or by the subject. Administration 
should occur immediately after dispersion is complete.
Rinse the container with a similar amount of water to ensure removal of any material adhering to the walls 
of the container and administer the additional water to the subject.
Since no data are available concerning the stability of the dispersed tablet, administration to the subject 
should occur immediately after dispersion is complete.
Confirmation that the subject has received the whole dose and that it was administered in this fashion 
should be included on the subject dispensing record.
4.0 Patient Eligibility
Inclusion Criteria
Women with platinum-resistant, histologically confirmed epithelial ovarian, fallopian tube or 
1.
peritoneal cancer. Resistance is defined as:
Progression of disease during platinum chemotherapy, or
Progression of disease within 6 months of completing platinum chemotherapy
Failure to achieve a complete response, with persistent macroscopic disease, after an
adequate trial of primary therapy. 
EGF-R expression must be positive (e.g., 1+ or greater) (See Appendix G. Biomarker Collection 
2.
and Analysis). 
Patients with a known hypersensitivity to platinum compounds, who have failed a desensitization 
3.
regimen, or in the opinion of the investigator, are not good candidates for desensitization, are 
eligible.
Patients must have measurable disease.
4.
Unlimited number of prior chemotherapy regimens are allowed.
5.
Zubrod performance status < 2.
6.
Patients must have adequate hepatic, renal, and bone marrow function, defined as serum 
7.
creatinine < 2 mg/dl (estimated creatinine clearance  50 ml/min); total bilirubin < 2.0 X the upper 
limit of normal (ULN); alanine aminotransferase (ALT) < 2X ULN; white blood count (WBC) >
3,000/mm
3; absolute neutrophil count (ANC) > 1,500/mm
3; platelets > 100,000/mm
3.
At least three weeks must have elapsed from completion of chemotherapy or radiation therapy. 
8.
Patients may have been on hormone therapy.
At least 30 days must have elapsed from completion of treatment with a non-approved or 
9.
investigational drug.
Patients must sign an informed consent indicating that they are aware of the investigational 
10.
nature of the study, in keeping with the policies of the hospital. The only approved consent is 
appended to this protocol.
Women of childbearing potential must be willing to practice acceptable methods of birth control to 
11.


2003-0322
Revised, September 7, 2005
Page 10
prevent pregnancy.
Exclusion Criteria
Patients with borderline or low malignant potential tumors are not eligible.
1.
Patients who have had prior therapy with topoisomerase I inhibitors.
2.
Patients who are pregnant or lactating.
3.
Concurrent chemotherapy, radiation therapy, or surgery (excluding palliative radiation).
4.
Concurrent, uncontrolled, medical or psychiatric disorders.
5.
Patients with an active infection.
6.
Patients with a known hypersensitivity to topotecan or gefitinib.
7.
Patients with severe cardiovascular disease (i.e. arrhythmias requiring chronic treatment or 
8.
congestive heart failure) (NYHA classification III or IV).
History of other malignancy (except nonmelanoma skin cancer or carcinoma in situ of the cervix), 
9.
unless in complete remission and off all therapy for that disease for a minimum of 5 years.
Patients with overt psychosis or mental disability or otherwise incompetent to give informed 
10.
consent.
Patients who have had prior anti-EGFR therapy (i.e. Tarceva, Centuximab). 
11.
Evidence of any other significant clinical disorder or laboratory finding that makes it undesirable 
12.
for the subject to participate in the trial.
Concomitant use of phenytoin, carbamazepine, rifampicin, barbiturates, or St. John's Wort.
13.
Any evidence of clinically active interstitial lung disease (patient with chronic stable radiographic
14.
changes who are asymptomatic are eligible).
5.0 Treatment Plan
This is a prospective, Phase I/II, open label, dose escalation study designed to evaluate the maximum 
tolerated dose of topotecan administered in combination with standard dose gefitinib to patients with 
histologically confirmed, platinum resistant ovarian, fallopian tube, or peritoneal cancer. Response rate 
and response duration in this patient population will also be studied.
The Phase I portion of the trial will use the standard dose of gefitinib of 250 mg PO QD with an escalation 
of the topotecan dose. Topotecan 2.0, 3.0, or 4.0 mg/m
2 will be given i.v. on days 1, 8 and 15 of a 28 day 
cycle. A conventional 3 + 3 algorithm will be used. The 2mg/m
2 dose of topotecan was chosen as a 
starting dose because there are reported responses to this level when it has been used as a single agent 
on this schedule. [12]
Cohort 1:  Topotecan 2.0mg/m
2 i.v. over 30 min on days 1, 8 and 15 and Gefitinib 250mg p.o. QD x28 
days
Cohort 2:  Topotecan 3.0mg/m
2 i.v. over 30 min on days 1, 8 and 15 and Gefitinib 250mg p.o. QD x28 
days
Cohort 3:  Topotecan 4.0mg/m
2 i.v. over 30 min on days 1, 8 and 15 and Gefitinib 250mg p.o. QD x28 
days
Definitions:
DLT (dose-limiting toxicity): Any Grade 4 hematological toxicity and any > Grade 3, treatment related, 
1.
non-hematologic toxicity (except Grade 3 fatigue lasting < 7days ).
MTD (maximum tolerated dose): The highest dose level in which we have treated 6 patients with at 
2.
most 1 experiencing the DLT.
Analysis of the Phase I data will be conducted and the results submitted to the Institutional Review Board 
prior to proceeding to the Phase II portion of the study. 
Phase II


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Page 11
The patients treated at the MTD in the Phase I part of the study will be the first 6 patients in this part of 
the trial. We will accrue a minimum of 10 patients and a maximum of 40 patients at a rate of 2 patients 
per month. The primary outcome for this trial is response (CR + PR) rate, which is evaluated at the 
completion of 8 weeks of treatment. 
Dose modifications:
Dose modifications for hematologic and nonhematologic toxicity will be based upon the worst toxicity 
observed during the previous treatment cycle.  The minimum infusion dose of topotecan is 2.0 mg/m
2
/week.  After recovery, standard dose adjustments for toxicity should be applied as follows:
For > Grade 4 hematologic and > Grade 3, treatment related, nonhematologic toxicity (except fatigue 
1.
as noted above) the weekly infusion dose of topotecan will be reduced one dose level.
For patients experiencing neutropenic complications (febrile neutropenia, documented active 
2.
infection during neutropenia, etc.), the dose will be decreased two levels. Patients who require dose 
reductions below the 2.0mg/m
2 dose level will be removed from study.
There will be no dose escalations.
Duration of therapy: Therapy should be continued until progression of disease, patient refusal, or 6 
months following documentation of a complete or partial response.
Growth Factors: 
Routine prophylactic use of G-CSF, erythropoetin or platelets is not permitted.  However, therapeutic use 
in patients with serious neutropenic, anemic, or thrombocytopenic complications such as sepsis or 
bleeding may be considered at the investigator's discretion. 
Other considerations regarding dose and schedule:
No dose shall be given until the absolute neutrophil count is greater than 1,500 and platelet count 
1.
greater than 100,000.
If these criteria are not met for a weekly infusion, the infusion for that week should be eliminated 
2.
without delay or rescheduling.
Failure to recover within two weeks will be cause to remove the patient from study.
3.
If these criteria are not met for a new cycle, the cycle will be delayed until recovery for a maximum of 
4.
two weeks.
Gefitinib treatment will be taken once a day, every day about the same time.  It can be taken with or 
5.
without food.  If the subject forgets to take a dose, they should take the last missed dose as soon as 
they remember, as long as it is at least 12 hours before the next dose is due.
Subjects must return all unused medication and empty containers to the investigator.
6.
Other concomitant treatment
If surgery is considered necessary for the patient, whenever possible, at least 7 days should elapse after 
the last dose of Gefitinib before surgery is performed. Treatment may be restarted after adequate wound 
healing.
No concomitant use of the following drugs is allowed: phenytoin, carbamazepine, rifampicin, barbiturates, 
or St John’s Wort, as these drugs induce CYP3A4 and may decrease levels of Gefitinib.
Concomitant use of CYP3A4 inhibitors, e.g., itraconazole, may result in increased levels of Gefitinib.  This 
exposure may be clinically relevant since adverse experiences are related to dose and exposure. 
Co-administration of drugs that cause significant sustained elevations in gastric pH  5 may reduce plasma 
concentrations of Gefitinib and therefore may reduce efficacy.
Further evaluation of International Normalized Ratio (INR) elevations and/or bleeding events have been 


2003-0322
Revised, September 7, 2005
Page 12
reported in some subjects taking warfarin while also taking Gefitinib.  Subjects taking warfarin 
(Coumadin) should be monitored regularly for changes in their prothrombin time (PT) or INR.
For subjects on steroids at the start of the study, the dose of steroids should not be changed without 
consultation with the Investigator.
The institution of iv and/or oral administration of biphosphonates during the course of the study, if initiated 
specifically for symptomatic bone metastases, is not permitted.
Other medication, which is considered necessary for the subject’s safety and well-being, may be given at 
the discretion of the investigator(s).  The administration of all concurrent medication must be 
documented.
Management of skin toxicity
Subjects with poorly tolerated skin toxicity may be successfully managed by providing a brief (up to 14 
days) interruption of Gefitinib; the daily dose of Gefitinib should then be reinstated. However, the rash 
may improve without the need for interrupting therapy with Gefitinib.
A variety of agents can be used to manage skin rashes. These include mild to moderate strength steroid 
creams, either topical or systemic antibiotics, topical or systemic antihistamines, and occasionally retinoid 
creams.
There is no standard, known or established treatment proven effective for drug-related skin rashes or 
changes due to Gefitinib.  Most commonly, a pustular rash has been observed, which frequently improves 
even though the same dose of Gefitinib therapy is continued uninterrupted.  The need for oral or topical 
antibiotics is a clinical decision of the investigator and should be preceded by a culture of affected areas 
and, if indicated, a dermatology consultation.  Oral retinoids should not be given because of theoretical 
concerns about negatively affecting the Gefitinib mechanism of action.  Oral steroids are also strongly 
discouraged.
Management of GI toxicity
If GI toxicity is not appropriately managed this may be associated with a development of dehydration.
Nausea and/or vomiting
In subjects who have emesis and are unable to retain  Gefitinib, every attempt should be made 
to obtain control of nausea and vomiting.  The dose of Gefinib may be repeated if emesis 
occurs within 30 minutes of taking the tablet(s).
Diarrhea
Diarrhea has been successfully managed with anti-diarrheal agents such as loperamide.
Grade 1-2 diarrhea: No specific supportive care is usually needed or indicated`
Grade 3 or 4 diarrhea: If this occurs, and immediate supportive care measures begun, Gefitinib should be 
discontinued for up to a maximum of 14 days until resolution, or the diarrhea has decreased in severity to 
grade 1.
Grade 2, 3, or 4 diarrhea with rapidly or precipitously declining absolute neutrophil count (ANC), or at 
same time as neutropenia, grade 3 or 4: Gefitinib should be discontinued for up to a maximum of 14 days 
until the ANC is  0.5 x 109/L, or resolution of the diarrhea, or the diarrhea has decreased in severity to 
grade 1.
If a grade 4 diarrhea is associated with hemodynamic collapse, the investigator should report it 
as an SAE and remove patient from trial.
In all cases where the subject is withdrawn due to unusual or unusually severe toxicity considered related 


2003-0322
Revised, September 7, 2005
Page 13
to Gefitinib, the investigator must report it to the sponsor.
Diarrhea can be debilitating and on rare occasions is potentially life threatening.  Guidelines developed by 
an American Society of Clinical Oncology (ASCO) panel for treating chemotherapy-induced diarrhea are 
abstracted below (Wadler 1998).
Pharmacological approaches include the following: 
Loperamide administered as an initial 4-mg dose followed by 2-mg doses every 4 hours.  This dose and 
regimen is moderately effective. Clonidine, non-steroidal anti-inflammatory drugs, and the serotonin 
antagonist cryoheptadine have been shown to be effective in controlling diarrhea associated with 
inflammation of the bowel. The synthetic octapeptide, octreotide has been shown to be effective in the 
control of diarrhea induced by fluoropyrimidine-based chemotherapy regimens when administered as an 
escalating dose by continuous infusion or subcutaneous injection.  Octreotide can be administered at 
doses ranging from 100 micrograms twice daily to 500 micrograms three times daily, with a 
maximum-tolerated dose of 2000 micrograms three times daily in a 5-day regimen.
Management of Interstitial Lung Disease
If patients present with an acute worsening or new onset of respiratory symptoms such as dyspnea, 
cough and fever, Gefitinib should be interrupted and the patient promptly investigated for Interstitial Lung 
Disease. If Interstitial Lung Disease is confirmed, and is believed to be Geftinib-related, Gefitinib should 
be permanently discontinued.
Other Toxicity
For any other grade 3 or 4 toxicity or any clinically significant lower grade toxicity treatment with gefitinib 
should be interrupted for a maximum of 14 days until the patient recovers completely or the toxicity 
reverts to grade 1 or to baseline grade.
6.0 Pretreatment evaluation
Medical history to include review of systems and concurrent therapies, performance status, including 
1.
prior cancer history, cancer therapy and residual toxicities from prior therapies. 
All medications taken within 3 weeks prior to the start of therapy and all concomitant therapy taken 
2.
during the study (with reasons for therapy use) will be recorded in the medical record.
Complete physical examination including vital signs, weight, and pelvic examination.
3.
Pretreatment laboratory tests:
4.
Hematology: CBC, differential and platelet count.
Coagulation panel: PT and INR for patients on therapeutic coumadin.
Chemistry: Albumin, total protein, BUN, 
creatinine, total bilirubin, alkaline phosphatase, alanine aminotransferase (ALT, CA-125 and 
electrolytes. Serum pregnancy test for women of childbearing potential.
Pretreatment exams:
5.
Baseline EKG
Chest x-ray 
CT of the abdomen and pelvis and/or any other pertinent radiologic evaluation to document disease 
status. Radiologic exams must be done within 4 weeks of starting therapy
7.0 Evaluation During Study
Weekly with CBC, platelet count and differential while on study.
1.
CBC, platelet count and differential, chemistries including albumin, total protein, BUN, creatinine, total 
2.
bilirubin, alkaline phosphatase, alanine aminotransferase (ALT), LDH, electrolytes, and CA-125 shall 
be performed prior to each course or as frequently as needed to define drug toxicity.
Interim history and physical exam with performance status and weight prior to each course. 
3.
Assessment of clinically measurable disease (if present) will be recorded before each course. 
4.


2003-0322
Revised, September 7, 2005
Page 14
Imaging studies will be done post cycle 2 and 4 and then every 3rd cycle and at the completion of 
treatment.
At the time a patient is discontinued from protocol participation, medical history, physical exam, 
5.
performance status, weight, hematology and chemistry (as noted above) and response will be 
documented. Any ongoing adverse events deemed treatment-related will be followed until resolution.
8.0 Criteria for Response
Assessment of Tumor Response (RECIST):
Measurable disease is defined as at least one lesion that can be accurately measured in at least one 
dimension (longest dimension to be recorded). Each lesion must be at least >/= 20mm when measured 
by conventional techniques, including palpation and plain x-ray. Lesions must be at least twice the cut 
thickness when measured by MRI or spiral CT. Ultrasound will not be used to define measurable disease.
Baseline documentation of "Target" and "Non-Target" Lesions: All measurable lesions up to a maximum 
of 5 lesions per organ and 10 lesions in total representative of all involved organs should be identified as 
target lesions and will be recorded and measured at baseline. Target lesions should be selected on the 
basis of their size (lesions with the longest dimension) and their suitability for accurate repetitive 
measurements by one consistent method of assessment (either by imaging techniques or clinically). A 
sum of the longest dimension (LD) for all target lesions will be calculated and reported as the baseline 
sum LD. The baseline sum LD will be used as reference to further characterize the objective tumor 
response of the measurable dimension of the disease. 
All other lesions (or sites of disease) should be identified as non-target lesions and should also be 
recorded at baseline. Measurements are not required and these lesions should be followed as "present" 
or "absent".
All baseline evaluations of disease status should be performed as close as possible to the start of 
treatment and never more than 4 weeks before the beginning of therapy.
Best Response:
Measurement of the longest dimension of each lesion size is required for follow-up. Change in the sum of 
these dimensions affords some estimate of change in tumor size and hence therapeutic efficacy. 
All disease must be assessed using the same technique as baseline. Reporting of these changes in an 
individual case should be in terms of the best response achieved by that case since entering the study.
Complete Response (CR):
Disappearance of all target and non-target lesions and no evidence of new lesions documented by two 
disease assessments at least 4 weeks apart. Normalization of CA-125, if elevated at baseline, is 
required.
Partial Response (PR):
At least 30% decrease in sum of the longest dimensions (LD) of all target measurable lesions taking as 
reference the baseline sum of LD. There can be no unequivocal progression of non-target lesions and no 
new lesions. Documentation by two disease assessments at least 4 weeks apart is required. In the case 
where the ONLY target lesion is a solitary pelvic mass measured by physical examination, which is not 
radiographically measurable, a 50% decrease in the LD is required.
Increasing Disease (defined as ANY of the following):
At least a 20% increase in the sum of LD of target lesions taking as reference the smallest sum LD or the 
appearance of new lesions within 8 weeks of study entry. Unequivocal progression on existing non-target 
lesions, other than pleural effusions without cytological proof of neoplastic origin, in the opinion of the 
treating physician within 8 weeks of study entry is also considered increasing disease. In the case where 


2003-0322
Revised, September 7, 2005
Page 15
the only target lesion is the solitary pelvic mass measured by physical examination, which is not 
radiographically measurable, a 50% increase is the LD is required. Death due to disease without prior 
objective documentation of progression. Global deterioration in health status attributable to the disease 
requiring a change in therapy without objective evidence of progression.
Stable disease: Any condition not meeting the above criteria.
Response Duration: Measured from the time of response (not the beginning of treatment) until there is 
evidence of progressive disease. Time to treatment failure will also be measured in responding patients.
Survival Duration: The survival of patients will be measured from protocol entry.
9.0 Criteria for Removal from the Study
The patient has a serious or life-threatening adverse event.
1.
Failure to recover from all treatment-related toxicities after 2 week treatment delay.
2.
The investigator feels that it is in the best interest of the patient.
3.
The patient wishes to withdraw.
4.
The patient fails to comply with the dosing, evaluations or other requirements of the study.
5.
Disease progression.
6.
The development of severe or life threatening hypersensitivity reaction to either topotecan or gefitinib.
7.
All patients will be followed for a minimum of one month from the last dose of study drug.
8.
Any patient who misses 14 or more days of gefitinib in one cycle will be removed from the study, 
9.
regardless of the reason.
10.0 Statistical Considerations
Phase I
The Phase I portion of the trial will use the standard dose of gefitinib of 250 mg PO QD with an escalation 
of the topotecan dose. Topotecan 2.0, 3.0, or 4.0 mg/m
2 will be given i.v. on days 1, 8 and 15 of a 28 day 
cycle. A conventional 3 + 3 algorithm will be used and is described below: 
enroll 3 patients at the lowest dose level
z
proceed to the next higher dose level with a cohort of 3 patients until at least 1 patient experiences 
z
the dose-limiting toxicity (DLT)
if only 1 of 3 patients experiences the DLT at a given dose level, enter 3 additional patients at the 
z
current dose level
if only 1 of 6 patients experiences the DLT at a given dose level, proceed to the next higher dose 
z
level with a cohort of 3 patients
if at least 2 of 3 or 2 of 6 patients experience the DLT at a given dose level, then the MTD has been 
z
exceeded
once the DLT has been exceeded, treat another 3 patients at the previous dose level if there were 
z
only 3 patients treated at that dose level
The DLT (dose-limiting toxicity) is defined as any Grade 4 hematological toxicity and any > Grade 3 
non-hematologic toxicity.
The MTD (maximum tolerated dose) is the highest dose level in which we have treated 6 patients with at 
most 1 experiencing the DLT.
Since there are only 3 doses to be considered, and since we will have only a maximum of 6 patients at 
the MTD, the maximum number of patients enrolled in this phase I part of the trial will be 18.


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Page 16
Phase II
This is a phase II activity trial. We will accrue a minimum of 10 patients and a maximum of 40 patients at 
a rate of 2 patients per month. The primary outcome for this trial is response (CR + PR) rate, which is 
evaluated within 8 weeks of treatment. Our target response rate is 20%. We will monitor the response 
rate as patients accrue and are evaluated, and we will stop the trial if we have evidence that the target 
response rate cannot be met. The patients treated at the MTD in the Phase I part of the study will be the 
first 6 patients in this part of the trial. 
We will stop the trial early if P (response rate > 20% | data from the trial) < 0.10. That is, given the 
outcomes from the patients who have already been evaluated, if we determine that there is less than a 
10% chance that the response rate is 20% or more, we will stop the trial. This decision rule gives the 
following stopping rule. We assume a uniform prior distribution for the response rate. Stop the trial if
[# of patients with response / # of patients evaluated] < 1/10, 2/17, 3/24, 4/31, 5/37
The operating characteristics of this study design are shown in the following table.
Sample Size (Percentile)
Response Rate (CR+PR)
Probability of Stopping Early
25
th
50
th
75
th
5%
0.979
10
10
17
10%
0.784
10
17
37
15%
0.480
17
40
40
20%
0.238
40
40
40
25%
0.104
40
40
40
30%
0.044
40
40
40
11.0 Data Management
Protocol Compliance: The attending physician and oncology research nurse must see each patient prior 
to each cycle of treatment. All required interim and pretreatment data should be available in order to 
evaluate toxicities, assign grade and make a determination regarding continuing therapy.
Data Entry: Data must be entered into the Protocol Data Management System at the completion of each 
course of therapy. A brief explanation for required but missing data should be recorded as a comment.
Accuracy of Data Collection: The Study Chairman will be the final arbiter of response or toxicity should a 
difference of opinion exist.
12.0 Reporting Requirements
This study will utilize the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 for 
adverse event reporting. A copy of the CTCAE version 3.0 can be downloaded from the CTEP home 
page (http:/www.ctep.info.nih.gov/) and is appended to this protocol. Life-threatening toxicities should be 
reported immediately to the Study Chairman, who in turn must notify the IRB. In addition, serious adverse 
events (SAE) will be reported to the IRESSA Safety Representative (fax - 302-886-7483).   Reporting of 
adverse reactions is in addition to and does not supplant the reporting of toxicities as part of the results of 
the clinical trial.
Reporting requirements are defined in Appendix A of this protocol. 
Criteria for response and toxicity: 
Adverse Event: Any unfavorable or unintended symptom, sign, or disease (including abnormal lab) 


2003-0322
Revised, September 7, 2005
Page 17
temporally associated with the use of a medical treatment or procedure that may or may not be 
considered related to the medical treatment or procedure. Such effects can be intervention related, dose 
related, route related, patient related, caused by an interaction with another drug.
Serious Adverse Event:  Any adverse drug experience occurring at any dose that results in any of the 
following outcomes: 
x
Death
x
A life-threatening adverse drug experience – any adverse experience that places the patient, in the 
view of the initial reporter, at immediate risk of death from the adverse experience as it occurred. It 
does not include an adverse experience that, had it occurred in a more severe form, might have 
caused death.
x
Inpatient hospitalization or prolongation of existing hospitalization
x
A persistent or significant disability/incapacity – a substantial disruption of a person’s ability to 
conduct normal life functions.
x
A congenital anomaly/birth defect. 
Eliciting Adverse Event Information: Adverse events will be elicited at each clinic visit during participation 
in the study. Patients will be given a worksheet to record the occurrence of adverse events throughout the 
study. All adverse events which are directly observed and all adverse events which are spontaneously 
reported by the patient are to be documented by the investigator.
Grading/Rating Scale:
All adverse events reported during the study will be evaluated and graded on a scale of 0-5. The 
1.
CTCAE version 3.0 will be used to determine the grade for all toxicities.
For any adverse events which are not listed in the CTCAE version 3.0 the following rating system will 
2.
be used:
Non-NCI Adverse Event Grading Scale
G
r
a
d
e
Description
0 No adverse event (absent) or within normal limits
1 Mild adverse event (minor, no specific medical intervention, asymptomatic laboratory findings only, radiographic findings
clinical relevance)
2 Moderate adverse event (minimal intervention, local intervention, non-invasive intervention [packing, cautery])
3 Severe and undesirable adverse event (significant symptoms requiring hospitalization or invasive intervention; transfusio
interventional radiological procedure; therapeutic endoscopy or operation
4 Life threatening or disabling adverse event (complicated by acute, life threatening metabolic or cardiovascular complicat
circulatory failure, hemmorhage, sepsis. Life-threatening physiologic consequences; need for intensive care or emergen
procedure; emergent interventional radiological procedure therapeutic endoscopy or operation
5 Death related to adverse event
Relationship to Study Treatment: The investigator will use the following definitions to assess the 
relationship of the adverse event to the study treatment:
Definite: Adverse event is clearly related to the study treatment.
1.
Probable: Adverse event is likely related to the study treatment.
2.
Possible: Adverse event may be related to the study treatment.
3.
Unlikely: Adverse event is doubtfully related to the study treatment.
4.


2003-0322
Revised, September 7, 2005
Page 18
Not Related: Adverse event is clearly not related to the study treatment.
5.
13.0 Emergency procedures
Procedures in case of medical emergency
The principal investigator(s) is responsible for ensuring that procedures and expertise are available to 
handle medical emergencies during the study.
Procedures in case of overdose
There is currently no known antidote for gefitinib.  The treatment of AEs associated with overdose 
should be supportive for the underlying adverse symptoms.  To date, no subject has experienced an 
overdose with gefitinib.
Doses of study treatment in excess of that specified in the clinical study protocol are considered to be 
an overdose. Overdose, with or without associated symptoms should be handled in the same way as a 
SAE and sent to AstraZeneca Drug Safety.  Signs or symptoms of an overdose that meet the criteria 
of serious should be reported as a SAE in the appropriate timeframes and be documented as clinical 
sequelae to an overdose.
Procedures in case of pregnancy
Pregnancy in itself is not regarded as an AE unless there is a suspicion that an investigational product 
may have interfered with the effectiveness of a contraceptive treatment. All reports of congenital 
abnormalities/birth defects are SAEs.  Elective terminations for medical reasons, and any serious 
complications of pregnancy (including spontaneous miscarriage) should be reported as SAEs. Elective 
abortions without complications should not be handled as AEs.
 Pregnancy should be reported to AstraZeneca as soon as possible after it has been identified that the 
subject (or subject’s partner) received an AstraZeneca product during pregnancy. It should be sent to 
AstraZeneca, Drug Safety within 45 days. The outcome of the pregnancy  must be sent to 
AstraZeneca, Drug Safety within AE or SAE timeframes if appropriate. Reports of normal outcomes 
should be sent within 45days. 
The time period for collecting information on the occurrence of a pregnancy is from first administration 
of study treatment up to and including the follow up period. 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth or 
congenital abnormality/birth defects) must be followed up and documented (on the pregnancy 
outcome form) even if the subject was discontinued from the study.
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