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Phase I Study of Erlotinib (Tarceva) in Combination With AT-101 in Patients With Advanced Non-Small Cell Lung Cancer (NSCLC)

Phase 1
19 Years
Not Enrolling
Carcinoma, Non Small Cell Lung

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Trial Information

Phase I Study of Erlotinib (Tarceva) in Combination With AT-101 in Patients With Advanced Non-Small Cell Lung Cancer (NSCLC)

Lung cancer is the leading cause of death in the United States as well as worldwide. It is
estimated that approximately 215,020 new cases of lung cancer will be diagnosed in the
United States in 2008, with approximately 161,840 deaths (1). The great majority of the
lung cancers are grouped as non small cell lung cancer (NSCLC), and only 13% as small cell
lung cancer. Most patients with NSCLC present with advanced disease (55% with stage IIIB or
IV). The overall median survival of patients with advanced NSCLC treated with first line
platinum based doublets is less than 12 months (8 10 months) with a 1 year and 2 year
survival of 33% and 11%, respectively (2-4). Agents targeting epidermal growth factor
receptor (EGFR), matrix metalloproteinase, farnesyl transferase, protein kinase C and
retinoic X receptor have so far shown no survival benefit in combination with chemotherapy
in advanced NSCLC (5-10).

More recently, 2 trials have shown clinical evidence of anti tumor activity with the
addition of bevacizumab to first line chemotherapy in patients with advanced NSCLC (11,12).
The pivotal study (EGOC 4599) responsible for the approval of bevacizumab in combination
with carboplatin plus paclitaxel in selective patients with advanced non squamous cell lung
cancers demonstrated a 2 month improvement in the median survival (12.3 months versus 10.3
months), and a higher objective response rate (12).

Patients with disease progression on or after first line therapy may be candidates for
second line chemotherapy with either docetaxel or pemetrexed, which results in a modest
improvement in survival. More recently, 2 EGFR tyrosine kinase inhibitors (TKIs), gefitinib
and erlotinib, have been approved for second and third line therapy in advanced NSCLC
(13,14). The effect on overall survival in genotypically uncharacterized patients was
observed with erlotinib (BR21 trial), but not with gefitinib (ISEL trial), contributing to
the withdrawal of gefitinib from the United States, and the approval of erlotinib as second
and third line therapy in NSCLC irrespective of tumor genotype (15).

It is proposed that the effects of AT-101 on the downstream signaling pathways of the EGFR,
particularly inhibition of the anti-apoptotic members Bcl-2 family of proteins, may provide
an opportunity to improve the clinical benefit of erlotinib in patients with advanced NSCLC.

The safety of the combination of erlotinib with AT-101 has not been assessed. It is
therefore proposed that a phase I study be performed using standard (FDA approved) dose of
erlotinib (150 mg/day) with an effective dose of AT-101 (40 mg twice daily for 3 days) of a
3 week cycle.

Inclusion Criteria:

- Pathological proven diagnosis of NSCLC with positive EGFR status by
immunohistochemistry. Patients will be considered as positive if greater than 10% of
the tumor cells are positively stained by the EGFR pharmDX assay kit.

- Disease that is locally advanced, metastatic, or recurrent.

- Prior treatment with 1 or 2 chemotherapy regimens, including a platinum based regimen
for advanced disease (stage IIIB with malignant pleural effusion or stage IV).

- Evidence of unidimensionally measurable disease as per Response Evaluation Criteria
in Solid Tumors [RECIST].

- Radiographic evidence of disease progression during or following previous
chemotherapy treatment.

- Formalin fixed, paraffin embedded tumor tissue from the initial diagnoses will be

- Male or female, 19 years of age or older.

- ECOG performance status 0 2.

- Resolution of all acute toxic effects of prior therapy or surgical procedures (except
for alopecia).

- Bisphosphonate therapy for bone metastases is allowed; however, treatment must be
initiated prior to the first dose of therapy. Prophylactic use of bisphosphonates in
patients without bone disease, except for the treatment of osteoporosis, is not

- Ability to swallow and retain oral medication.

- Adequate organ function as defined by the following criteria:

- Hemoglobin >9.0 g/dL.

- Absolute neutrophil count (ANC) >1500/μL.

- Platelet >100,000/μL.

- Serum creatinine <1.75 × ULN.

- Serum albumin >3.0 g/dL.

- Total serum bilirubin <1.5 × ULN.

- Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) <2.5 ×
ULN, or AST and ALT <5 × ULN if liver function abnormalities are due to
underlying malignancy

- Signed and dated informed consent indicating that the subject (or legally acceptable
representative) has been informed of all pertinent aspects of the trial prior to

- Willingness and ability to comply with scheduled visits, treatment plans, laboratory
tests, and other study procedures.

- Males and non-pregnant, non-lactating females age 19 years or older.

Exclusion Criteria:

- Prior treatment with >2 systemic chemotherapy based regimens for advanced disease
(stages IIIB/IV).

- Prior treatment with any EGFR inhibitors (TK inhibitor or monoclonal antibody).

- Symptomatic brain metastases or spinal cord compression; subjects will be eligible
after adequate treatment (radiotherapy, surgery) and having stable disease not
requiring steroids.

- Diagnosis of any second malignancy within the last 3 years, except basal cell
carcinoma, squamous cell skin cancer, or in situ carcinoma that has been adequately

- Any significant acute or chronic medical (e.g., gastrointestinal complications,
myocardial infarction, unstable angina, congestive heart failure, cerebrovascular
accident, infection, metabolic complications, etc.) or psychiatric conditions that
would impart, in the judgment of the investigator, excess risk associated with study
participation, or study drug administration.

- Known human immunodeficiency virus (HIV) infection.

- Current treatment on other therapeutic clinical trials.

- Known hypersensitivity to gossypol, its enantiomers, or its excipients.

- Any other condition or circumstance that would, in the opinion of the Investigator,
make the patient unsuitable for participation in the study.

- Patients with symptomatic hypercalcemia or hypercalcemia that is > grade 2.

- Patients with malabsorption syndrome, disease significantly affecting
gastrointestinal function, or resection of the stomach or small bowel are excluded.
Subjects with ulcerative colitis, inflammatory bowel disease, or partial or complete
small bowel obstruction are also excluded.

- Pregnancy or breastfeeding. Female patients must be surgically sterile or be
postmenopausal, or must agree to use effective contraception during the period of
therapy. All female patients with reproductive potential must have a negative
pregnancy test within 3 days prior to enrollment. Male patients must be surgically
sterile or must agree to use effective contraception during the period of therapy.

Type of Study:


Study Design:

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

Outcome Measure:

To determine the safety and tolerability of erlotinib plus AT-101

Outcome Time Frame:

Assessment of toxicity will be performed on day 15 of the first cycle, and then on day 1 of every cycle of treatment.

Safety Issue:


Principal Investigator

Francisco Robert, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Alabama at Birmingham


United States: Food and Drug Administration

Study ID:




Start Date:

February 2010

Completion Date:

June 2015

Related Keywords:

  • Carcinoma, Non Small Cell Lung
  • Carcinoma
  • Carcinoma, Non-Small-Cell Lung
  • Lung Neoplasms