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Phase I Study To Determine The Safety, Tolerance And Preliminary Antineoplastic Activity Of Combined EGFR (erbB1) And HER2 (erbB2) Blockade, With OSI-774 And Trastuzumab, In Combination With Weekly Paclitaxel


Phase 1
18 Years
N/A
Not Enrolling
Both
Unspecified Adult Solid Tumor, Protocol Specific

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Trial Information

Phase I Study To Determine The Safety, Tolerance And Preliminary Antineoplastic Activity Of Combined EGFR (erbB1) And HER2 (erbB2) Blockade, With OSI-774 And Trastuzumab, In Combination With Weekly Paclitaxel


OBJECTIVES:

I. Determine the safety, quantitative and qualitative toxic effects, maximum tolerated dose,
and dose-limiting toxic effects of erlotinib when combined with paclitaxel and trastuzumab
(Herceptin) in patients with advanced solid tumors.

II. Determine the relevant pharmacokinetic interactions between these agents in these
patients.

III. Determine, preliminarily, the antitumor activity of this regimen in these patients.

OUTLINE: This is an open-label, non-randomized, multicenter, dose-escalation study of
erlotinib.

Intermittent schedule: Patients receive paclitaxel IV over 1 hour followed 30 minutes later
by trastuzumab (Herceptin) IV over 30 minutes on days 1, 8, and 15 of each course. Patients
also receive oral erlotinib once daily on days 3-28 of course 1 and on days 1-28 of
subsequent courses. Courses repeat every 28 days in the absence of disease progression or
unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of erlotinib until the maximum tolerated
dose (MTD) is determined. The MTD is defined as the dose preceding that at which at least 2
of 3 or 2 of 6 patients experience dose-limiting toxicity.

Continuous schedule: Once the MTD is determined using the intermittent schedule, an
additional 12 patients are accrued to study the tolerability of a continuous schedule
comprising paclitaxel and trastuzumab as above on days 1, 8, 15, and 22 and oral erlotinib
once daily on days 3-28 during course 1 and on days 1-28 of subsequent courses using the
same dose-escalation scheme as above. Courses repeat as above.

Patients are followed every 30 days.

PROJECTED ACCRUAL: A maximum of 40 patients will be accrued for this study within 10-13.3
months.


Inclusion Criteria:



- Histologically confirmed metastatic solid tumor for which there are no effective
standard treatment options

- HER2 positive (1+ to 3+)

- Tumor has a high likelihood of expressing epidermal growth factor receptor (EGFR)

- No evidence of leptomeningeal disease or brain metastases unless previously treated,
currently asymptomatic, and off both antiepileptics and dexamethasone

- Patients with treated brain metastases are eligible if they are without any
clinical change in their brain disease status for at least 4 weeks after whole
brain irradiation

- Performance status - ECOG 0-2

- Performance status - Karnofsky 60-100%

- At least 12 weeks

- Absolute neutrophil count at least 1,500/mm^3

- Platelet count at least 100,000/mm^3

- Bilirubin normal

- AST/ALT no greater than 2.5 times upper limit of normal (ULN) (5 times ULN if liver
has tumor involvement)

- Creatinine normal

- Creatinine clearance at least 60 mL/min

- LVEF more than 50% by radionuclide ventriculogram or MUGA scan

- No significant cardiovascular disease

- No prior congestive heart failure requiring therapy

- No unstable angina pectoris

- No myocardial infarction within the past 6 months

- No gastrointestinal tract disease resulting in an inability to take oral medication
or a requirement for IV alimentation

- Patients who are unable to swallow tablets and/or who have silicon-based G-tubes
may dissolve the tablets in distilled water

- No active peptic ulcer disease

- HIV negative

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- No known or suspected hypersensitivity to paclitaxel

- No prior allergic reactions attributed to compounds of similar chemical or biologic
composition to erlotinib or other study agents

- No concurrent active infection

- No other concurrent medical condition that would preclude study participation

- No persistent grade 2 or greater neurotoxicity/neuropathy from any cause

- No psychiatric disorders or altered mental status that would preclude study
participation

- No other concurrent immunotherapy

- No concurrent cytokine growth factors (e.g., colony-stimulating factors)

- At least 4 weeks since prior chemotherapy (6 weeks for mitomycin or nitrosoureas) and
recovered

- No other concurrent chemotherapy

- See Disease Characteristics

- No concurrent hormonal therapy except megestrol as an appetite stimulant or
luteinizing hormone-releasing hormone agonists for prostate cancer

- See Disease Characteristics

- No concurrent radiotherapy

- No prior surgical procedures affecting absorption

- No prior EGFR-targeting therapy

- No other concurrent experimental medications or other specific antitumor therapy

- No concurrent immunosuppressant therapy

- No concurrent antiarrhythmic therapy for a ventricular arrhythmia

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximally tolerated dose (MTD), graded according to the National Cancer Institute Common Toxicity Criteria (NCI CTC) v2.0

Outcome Time Frame:

Up to day 28

Safety Issue:

Yes

Principal Investigator

Muralidhar Beeram

Investigator Role:

Principal Investigator

Investigator Affiliation:

Cancer Therapy and Research Center at The UT Health Science Center at San Antonio

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2012-02477

NCT ID:

NCT00042809

Start Date:

May 2002

Completion Date:

Related Keywords:

  • Unspecified Adult Solid Tumor, Protocol Specific

Name

Location

Cancer Therapy and Research Center at The UT Health Science Center at San AntonioSan Antonio, Texas  78229