Topotecan and Gefitinib (Iressa) for Ovarian, Peritoneal, or Fallopian Tube Cancer

• Sponsor: M.D. Anderson Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00317772
• Collaborator: AstraZeneca (Industry), GlaxoSmithKline (Industry)
• Enrollment: 19
• Location: 1
• Arm: 1
• Actual Duration (Months): 194.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Ovarian Cancer; Peritoneal Neoplasms; Fallopian Tube Cancer	Drug: Topotecan; Drug: Gefitinib	Phase 1/Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 19 participants
• Allocation: N/A
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Study of Weekly Topotecan and Gefitinib (Iressa) in Patients With Platinum-Resistant Ovarian, Peritoneal, of Fallopian Tube Cancer
• Actual Study Start Date: Sep 2, 2004
• Actual Primary Completion Date: Nov 4, 2020
• Actual Study Completion Date: Nov 4, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Topotecan + Gefitinib 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.	Drug: Topotecan; 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.; Drug: Gefitinib; Phase I: 250 mg by mouth daily for 28 Days. Phase II: 250 mg by mouth daily for 28 Days.; Other Names: Iressa

Outcome Measures

Primary Outcome Measures

1. Dose Limiting Toxicity (DLT) [Continual reassessment method, prior to each 28 day cycle, an average of 60 days]

   Dose-limiting toxicity defined as any Grade 4 hematological toxicity and any > Grade 3 non-hematologic toxicity. The DLT (dose-limiting toxicity) is defined as any Grade 4 hematological toxicity and any > Grade 3 non-hematologic toxicity.

2. Maximum Tolerated Dose (MTD) of Topotecan [At end of first course, prior to each new course (28 day cycle). Continual reassessment method (CRM) during each course for toxicity, an average of 60 days]

   Maximum tolerated dose is highest dose level in which 6 patients treated with at most 1 experiencing DLT.

Secondary Outcome Measures

1. Response Rate [61 weeks]

   Measurable disease defined as at least one lesion that can be accurately measured in at least one dimension. Complete Response (CR): disappearance of all target and non-target lesions and no evidence of new lesions. Partial Response (PR): At least 30% decrease in sum of longest dimensions (LD) of all target measurable lesions. Increasing Disease: At least a 20% increase in sum of LD of target lesions taking as reference smallest sum LD or appearance of new lesions within 8 weeks of study entry. Progression on existing non-target lesions, other than pleural effusions without cytological proof of neoplastic origin. Death due to disease without prior objective documentation of progression. Global deterioration in health status attributable to disease requiring a change in therapy without objective evidence of progression.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Women with platinum-resistant, histologically confirmed epithelial ovarian, fallopian tube or peritoneal cancer. Resistance is defined as: Progression of disease during platinum chemotherapy, or progression of disease within 6 months of completing platinum chemotherapy, or 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.

• Patients with a known hypersensitivity to platinum compounds, who have failed a desensitization regimen, or in the opinion of the investigator, are not good candidates for desensitization, are eligible.

• Patients must have measurable disease.

• Unlimited number of prior chemotherapy regimens are allowed.

• Zubrod performance status </= 2.

• Patients must have adequate hepatic, renal, and bone marrow function, defined as serum 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/mm3; absolute neutrophil count (ANC) >/= 1,500/mm3; platelets >/= 100,000/mm3.

• At least three weeks must have elapsed from completion of chemotherapy or radiation therapy.

• At least 30 days must have elapsed from completion of treatment with a non-approved or investigational drug.

• Patients must sign an informed consent indicating that they are aware of the investigational 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 prevent pregnancy.

Exclusion Criteria:

• Patients with borderline or low malignant potential tumors are not eligible.

• Patients who have had prior therapy with topoisomerase I inhibitors.

• Patients who are pregnant or lactating.

• Concurrent chemotherapy, radiation therapy, or surgery (excluding palliative radiation).

• Concurrent, uncontrolled, medical or psychiatric disorders.

• Patients with an active infection.

• Patients with a known hypersensitivity to topotecan or iressa.

• Patients with severe cardiovascular disease (i.e. arrhythmias requiring chronic treatment or congestive heart failure) (NYHA classification III or IV).

• History of other malignancy (except nonmelanoma skin cancer or carcinoma in situ of the cervix), 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 consent.

• Patients who have had prior anti-EGFR therapy (i.e. Tarceva, Cetuximab).

• Evidence of any other significant clinical disorder or laboratory finding that makes it undesirable for the subject to participate in the trial.

• Concomitant use of phenytoin, carbamazepine, rifampicin, barbiturates, or St. John's Wort.

• Any evidence of clinically active interstitial lung disease (patient with chronic stable radiographic changes who are asymptomatic are eligible).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030

Sponsors and Collaborators

• M.D. Anderson Cancer Center
• AstraZeneca
• GlaxoSmithKline

Investigators

• Principal Investigator: Charles Levenback, MD, M.D. Anderson Cancer Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Sep 7, 2005

More Information

Additional Information:

• University of Texas MD Anderson Cancer Center Website

Publications

None provided.

• Responsible Party: M.D. Anderson Cancer Center
• ClinicalTrials.gov Identifier: NCT00317772
• Other Study ID Numbers: 2003-0322
• First Posted: Apr 25, 2006
• Last Update Posted: Feb 7, 2022
• Last Verified: Jan 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by M.D. Anderson Cancer Center: Epithelial Ovarian Cancer; Peritoneal Cancer; Fallopian Tube Cancer; Epidermal Growth Factor; Platinum Hypersensitivity; Hycamtin; Gefitinib; Iressa; Topotecan; EGFR
• Additional relevant MeSH terms: Ovarian Neoplasms; Fallopian Tube Neoplasms; Peritoneal Neoplasms; Topotecan; Gefitinib

Study Results

Participant Flow

Recruitment Details	The study was activated on 09/02/2004 and closed to new patient entry on 01/10/2007. All recruitments were done in a medical clinic setting.

Arm/Group Title	Phase 1 Dose Level 1	Phase 1 Dose Level 2	Phase 1 Dose Level 3	Expansion Phase
Arm/Group Description	Topotecan 2 mg/m2 IV on Days 1, 8, and 15 plus daily Gefitinib 250 mg given PO	Topotecan 3 mg/m2 IV on Days 1, 8, and 15 plus daily Gefitinib 250 mg given PO	Topotecan 4 mg/m2 IV on Days 1, 8, and 15 plus daily Gefitinib 250 mg given PO	Topotecan 4 mg/m2 IV on Days 1, 8, and 15 plus daily Gefitinib 250 mg given PO
Period Title: Overall Study
STARTED	3	3	3	10
COMPLETED	1	1	2	1
NOT COMPLETED	2	2	1	9

Baseline Characteristics

Arm/Group Title	Phase 1 Dose Level 1	Phase 1 Dose Level 2	Phase 1 Dose Level 3	Expansion Phase	Total
Arm/Group Description	Topotecan 2 mg/m2 IV on Days 1, 8, and 15 plus daily Gefitinib 250 mg given PO	Topotecan 3 mg/m2 IV on Days 1, 8, and 15 plus daily Gefitinib 250 mg given PO	Topotecan 4 mg/m2 IV on Days 1, 8, and 15 plus daily Gefitinib 250 mg given PO	Topotecan 4 mg/m2 IV on Days 1, 8, and 15 plus daily Gefitinib 250 mg given PO	Total of all reporting groups
Overall Participants	3	3	3	10	19
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	3 100%	2 66.7%	1 33.3%	7 70%	13 68.4%
>=65 years	0 0%	1 33.3%	2 66.7%	3 30%	6 31.6%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	55	55	68	60	60
Sex: Female, Male (Count of Participants)
Female	3 100%	3 100%	3 100%	10 100%	19 100%
Male	0 0%	0 0%	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%	1 10%	1 5.3%
Not Hispanic or Latino	3 100%	3 100%	3 100%	9 90%	18 94.7%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	1 10%	1 5.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	1 10%	1 5.3%
White	3 100%	3 100%	3 100%	7 70%	16 84.2%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	1 10%	1 5.3%
Region of Enrollment (participants) [Number]
United States	3 100%	3 100%	3 100%	10 100%	19 100%

Outcome Measures

1. Primary Outcome

Title	Dose Limiting Toxicity (DLT)
Description	Dose-limiting toxicity defined as any Grade 4 hematological toxicity and any > Grade 3 non-hematologic toxicity. The DLT (dose-limiting toxicity) is defined as any Grade 4 hematological toxicity and any > Grade 3 non-hematologic toxicity.
Time Frame	Continual reassessment method, prior to each 28 day cycle, an average of 60 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 1 Dose Level 1	Phase 1 Dose Level 2	Phase 1 Dose Level 3
Arm/Group Description	Topotecan 2 mg/m2 IV on Days 1, 8, and 15 plus daily Gefitinib 250 mg given PO	Topotecan 3 mg/m2 IV on Days 1, 8, and 15 plus daily Gefitinib 250 mg given PO	Topotecan 4 mg/m2 IV on Days 1, 8, and 15 plus daily Gefitinib 250 mg given PO
Measure Participants	3	3	3
Number [Dose Limiting Toxicities]	2	3	4

2. Primary Outcome

Title	Maximum Tolerated Dose (MTD) of Topotecan
Description	Maximum tolerated dose is highest dose level in which 6 patients treated with at most 1 experiencing DLT.
Time Frame	At end of first course, prior to each new course (28 day cycle). Continual reassessment method (CRM) during each course for toxicity, an average of 60 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Phase 1 Participants
Arm/Group Description	Topotecan 4 mg/m2 IV on Days 1, 8, and 15 plus daily Gefitinib 250 mg given PO
Measure Participants	9
Number [mg/m^2]	4

3. Secondary Outcome

Title	Response Rate
Description	Measurable disease defined as at least one lesion that can be accurately measured in at least one dimension. Complete Response (CR): disappearance of all target and non-target lesions and no evidence of new lesions. Partial Response (PR): At least 30% decrease in sum of longest dimensions (LD) of all target measurable lesions. Increasing Disease: At least a 20% increase in sum of LD of target lesions taking as reference smallest sum LD or appearance of new lesions within 8 weeks of study entry. Progression on existing non-target lesions, other than pleural effusions without cytological proof of neoplastic origin. Death due to disease without prior objective documentation of progression. Global deterioration in health status attributable to disease requiring a change in therapy without objective evidence of progression.
Time Frame	61 weeks

Outcome Measure Data

Analysis Population Description

Two patients received only one cycle of treatment and therefore were not evaluable for response to therapy.

Arm/Group Title	Phase 1 Dose Level 1	Phase 1 Dose Level 2	Phase 1 Dose Level 3	Expansion Phase
Arm/Group Description	Topotecan 2 mg/m2 IV on Days 1, 8, and 15 plus daily Gefitinib 250 mg given PO	Topotecan 3 mg/m2 IV on Days 1, 8, and 15 plus daily Gefitinib 250 mg given PO	Topotecan 4 mg/m2 IV on Days 1, 8, and 15 plus daily Gefitinib 250 mg given PO	Topotecan 4 mg/m2 IV on Days 1, 8, and 15 plus daily Gefitinib 250 mg given PO
Measure Participants	3	3	3	10
Complete response	0 0%	0 0%	0 0%	0 0%
Partial response	1 33.3%	0 0%	1 33.3%	0 0%
Stable disease	0 0%	1 33.3%	1 33.3%	1 10%
Progressive disease	2 66.7%	2 66.7%	1 33.3%	7 70%
Not evaluable	0 0%	0 0%	0 0%	2 20%

Adverse Events

Time Frame	adverse events were accessed from baseline to 30 days following the last dose of study medication received, up to 2 years
Arm/Group Title	Phase 1 Dose Level 1		Phase 1 Dose Level 2		Phase 1 Dose Level 3		Expansion Phase
Arm/Group Description	Topotecan 2 mg/m2 IV on Days 1, 8, and 15 plus daily Gefitinib 250 mg given PO		Topotecan 3 mg/m2 IV on Days 1, 8, and 15 plus daily Gefitinib 250 mg given PO		Topotecan 4 mg/m2 IV on Days 1, 8, and 15 plus daily Gefitinib 250 mg given PO		Topotecan 4 mg/m2 IV on Days 1, 8, and 15 plus daily Gefitinib 250 mg given PO
All Cause Mortality
	Phase 1 Dose Level 1		Phase 1 Dose Level 2		Phase 1 Dose Level 3		Expansion Phase
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/3 (0%)		0/3 (0%)		0/10 (0%)
Serious Adverse Events
	Phase 1 Dose Level 1		Phase 1 Dose Level 2		Phase 1 Dose Level 3		Expansion Phase
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/3 (0%)		0/3 (0%)		0/10 (0%)
Other (Not Including Serious) Adverse Events
	Phase 1 Dose Level 1		Phase 1 Dose Level 2		Phase 1 Dose Level 3		Expansion Phase
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		3/3 (100%)		3/3 (100%)		9/10 (90%)
Blood and lymphatic system disorders
Hemoglobin	2/3 (66.7%)		3/3 (100%)		3/3 (100%)		9/10 (90%)
Neutrophils	2/3 (66.7%)		3/3 (100%)		2/3 (66.7%)		6/10 (60%)
Platelets	0/3 (0%)		1/3 (33.3%)		2/3 (66.7%)		4/10 (40%)
Gastrointestinal disorders
Dehydration	0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/10 (0%)
Abdominal pain	2/3 (66.7%)		3/3 (100%)		2/3 (66.7%)		9/10 (90%)
Mucositis	1/3 (33.3%)		2/3 (66.7%)		0/3 (0%)		1/10 (10%)
Constipation	3/3 (100%)		2/3 (66.7%)		1/3 (33.3%)		9/10 (90%)
Diarrhea	3/3 (100%)		3/3 (100%)		3/3 (100%)		9/10 (90%)
Nausea	2/3 (66.7%)		1/3 (33.3%)		2/3 (66.7%)		6/10 (60%)
Vomiting	1/3 (33.3%)		2/3 (66.7%)		2/3 (66.7%)		3/10 (30%)
Anorexia	1/3 (33.3%)		3/3 (100%)		1/3 (33.3%)		3/10 (30%)
General disorders
Fatigue	3/3 (100%)		3/3 (100%)		3/3 (100%)		9/10 (90%)
Infections and infestations
Febrile neutropenia	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		2/10 (20%)
Metabolism and nutrition disorders
Hyponatremia	1/3 (33.3%)		1/3 (33.3%)		0/3 (0%)		4/10 (40%)
Hypokalemia	1/3 (33.3%)		2/3 (66.7%)		0/3 (0%)		0/10 (0%)
Hypomagnesemia	1/3 (33.3%)		3/3 (100%)		0/3 (0%)		6/10 (60%)
Hyperglycemia	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		4/10 (40%)
ALT increase	0/3 (0%)		0/3 (0%)		0/3 (0%)		2/10 (20%)
AST increase	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/10 (10%)
Blood bilirubin increase	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/10 (10%)
Hypoalbuminemia	2/3 (66.7%)		3/3 (100%)		1/3 (33.3%)		2/10 (20%)
Nervous system disorders
Mood alterations	3/3 (100%)		2/3 (66.7%)		2/3 (66.7%)		2/10 (20%)
Neuropathy	2/3 (66.7%)		2/3 (66.7%)		2/3 (66.7%)		5/10 (50%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/3 (33.3%)		2/3 (66.7%)		1/3 (33.3%)		3/10 (30%)
Skin and subcutaneous tissue disorders
Acne	3/3 (100%)		2/3 (66.7%)		0/3 (0%)		6/10 (60%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.