A Phase I/II Study of Erlotinib and Romidepsin in Advanced Non-Small Cell Lung Cancer

Study ID
STU 012011-004

Cancer Related

Healthy Volunteers

Study Sites

Rachael Skelton

Principal Investigator
David Gerber


This is a phase i/ii multi-center trial of the combination of erlotinib and romidepsin, for which uT Southwestern (uTSW) will act as the main study site. additional sites are presently being recruited to assist with timely enrollment and completion of the study. The study is sponsored by uT Southwestern with additional funding provided by Celgene and Genentech, inc. The phase i dose escalation study will use a standard 3+3 dosing scheme. Three dose levels are planned: romidepsin 8 mg/m2, 10 mg/m2 and 14 mg/m2 iV over 4 hours on days 1, 8, and 15 of a 28-day cycle. if unacceptable toxicity occurs at the 8 mg/m2 dose level, the dose may be de-escalated to 5 mg/m2. erlotinib 150 mg Po daily will be administered in all cohorts starting on day 3 of cycle 1. Delaying the start of erlotinib treatment until day 3 of the first cycle will allow comparisons between romidepsin alone and the combination of erlotinib plus romidepsin in pharmacokinetic and correlative studies. Treatment will be continued until disease progression, unacceptable toxicity or another criterion for study termination occurs.

accrual of patients within a dose cohort will be staggered by at least 1 week. There will be no intrapatient dose escalation. Dose escalation may proceed after all patients in the previous dose cohort have completed the day 28 follow-up visit without the observation of a dose-limiting toxicity (DLT) and the recovery of all noted toxicities to [Less Than] Grade 2. it is estimated that 9-15 patients will be needed to determine the maximum tolerated dose of the drug combination in the phase i portion of the study. uTSW as the study coordinating center will assign the patients to a dose cohort and will be in charge of the registration process for all participating sites. By using this method, uTSW will be responsible for ensuring proper registration of subjects to the appropriate dose cohorts.
if tolerated, romidepsin 14 mg/m2 iV on Days 1, 8, and 15 plus erlotinib 150 mg Po daily will be the dose used in the phase ii portion of the study. This will be a single-arm study using a historical control for comparison. approximately 24 subjects will be enrolled to the phase ii portion of the protocol over 18 months.
all subjects whether registered to the phase i or phase ii portion of the study will be followed for approximately 12 months after the accrual period has ended. The total maximum number of patients expected to consent and enroll over the course of both phases is 39. all subjects will be examined for the duration of progression-free survival (PFS) in order to determine overall efficacy of this study and the drug combination.

Following the 2012 review by the DSMC, the Pi feels a maximum tolerated dose has been achieved in Phase i. The Pi discussed the study at length with the study sponsors and it is agreed upon that the study will dose 3 additional patients at the 8 mg/m^2 in order to complete the phase i study and determine the maximum tolerated dose at 8mg/m^2 for Phase ii. The Pi will be in discussion with the sponsors to determine the next steps in regards to starting the phase ii portion of the study.

Participant Eligibility

Criteria for Inclusion of Subjects x Phase I and II:
1. Histologically confirmed locally advanced or metastatic (stage IIIB pleural effusion or stage IV) NSCLC;
2. Age >= 18 years;
3. Written informed consent;
4. Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST);
5. ECOG performance status 0 to 1;
6. Serum potassium and magnesium greater than or equal to the lower limit of institutional normal range (electrolyte abnormalities may be corrected with supplementation to meet inclusion criteria);
7. Negative urine or serum pregnancy test on females of childbearing potential;
8. All women of childbearing potential must use an effective barrier method of contraception (an intrauterine contraceptive device [IUCD] or double barrier method using condoms or a diaphragm plus spermicide) during the treatment period and for at least 1 month thereafter. Male patients should use a barrier method of contraception during the treatment period and for at least 1 month thereafter. Hormonal methods of contraception such as the contraceptive pill or patch (particularly those containing ethinyl-estradiol) should be avoided due to a potential drug interaction.
9. Adequate bone marrow, liver, and renal function as evidenced by

* Hemoglobin >=10 g/dL (transfusions and/or erythropoietin-stimulating agents are permitted)

* Absolute neutrophil count (ANC) >=1.5 x 109 cells/L

* Platelet count >=100 x 109 cells/L

* Total bilirubin <1.5 x upper limit of normal (ULN)

* AST/SGOT and ALT-SGPT <2.0 x upper limit of normal (ULN) or <3.0 x ULN in the presence of demonstrable liver metastases

* Serum creatinine <2.0 x ULN
10. Clinically stable brain metastases are permitted
11. Both male and female patients of all racial and ethnic origins will be eligible for enrollment.
12. Spanish-speaking subjects will also be eligible to enroll.

Criteria for Inclusion of Subjects x Phase I:
1. Prior erlotinib therapy is permitted (with a 3-week washout period)
2. Patients may have received prior anti-cancer therapy (with a 3-week washout period) or, at the discretion of the investigator, may be treatment-naive

Criteria for Inclusion of Subjects x Phase II:
1. Patients must have received at least one and no more than two prior chemotherapy regimens for their advanced NSCLC
2. Patients may not have received prior erlotinib