A Trial of Belinostat in Combination With Erlotinib in Patients With Non-small Cell Lung Cancer

A Clinical Phase I / II Trial of Belinostat in Combination With Erlotinib in Patients With Non-small Cell Lung Cancer

The Belinostat-Erlotinib trial is designed as an open, non randomized phase I / II trial to assess the efficacy and safety of Belinostat in combination with Erlotinib in patients with non-small cell lung cancer who are eligible for treatment with erlotinib.

Belinostat, developed by CuraGen, belongs to a new class of hydroxymat-type histone deacetylase (HDAC) inhibitors. HDAC inhibitors, including Belinostat, has shown marked in vitro and in vivo activity against a number of solid tumors and hematological cancers. Belinostat has proven to be effective as a single agent or in combination with other anticancer agents such as doxorubcin, paclitaxel, carboplatin, fluorouracil, bortezumib, and there has been observed synergy between Belinostat or other HDAC inhibitors and EGFR inhibitors gefinitinib and erlonitib.

Furthermore, the antineoplastic activity of Belinostat seen in preclinical experiments have resulted in only moderate toxicity.

In the two Phase I trials of Belinostat for solid tumors and hematological malignancies Belinostat have been well tolerated at doses up to 2000 mg daily in more than 100 patients.

Fatigue, nausea and vomiting has been the main side effects and with none or very mild hematologic toxicity. Approximately 25% of patients in the study of solid tumors achieved stable disease.

Inclusion Criteria:

1. Signed consent of an approved informed consent form

2. A. For the dose escalation phase: Patients with histological or cytological confirmed non-small cell lung cancer who are rated suitable for treatment with Erlotinib B. For MTD expansion phase: Patients diagnosed with non- small cell lung cancer rated suitable for treatment with Erlotinib and with measurable disease according to RECIST version 1.1

3. Performance status (ECOG) ≤ 2

4. Life expectancy at least 3 months

5. Age ≥ 18 years

6. Acceptable liver, kidney and bone marrow function, defined as:

   • Bilirubin ≤ 1.5 x upper limit of normal (ULN)
   • ASAT, ALAT and alkaline phosphatase ≤ 3 x ULN (if liver metastases is ≤ 5 x ULN allowed)
   • Serum creatinine ≤ 1.5 x upper limit of normal (ULN)
   • WBC> 2.5 x 109 / l, neutrophils> 1.0 x 109 / l, platelets> 100 x 109 / l
   • Hemoglobin> 9.0 g / dl or> 5.6 mmol / l

7. Acceptable coagulation: PT and APTT within ≤ 1.5 x ULN or in the therapeutic range if given anticoagulant

8. A negative pregnancy test for women of childbearing age. In fertile men and women the use of effective contraception methods are required during the trial

9. Serum potassium within normal range

Exclusion Criteria:

1. Treatment with experimental drugs within the last 4 weeks
2. Former anti-cancer therapy within the last 3 weeks before the start of experimental treatment, including chemotherapy, radiotherapy, endocrine therapy or immunotherapy
3. Simultaneous presence of active infection or other concomitant present medical condition likely to affect the experimental procedures, including significant cardiovascular disease (New York Heart Association Class III or IV heart disease, myocardial infarction within the past 6 months, unstable angina, congestive heart failure requiring treatment, unstable arrhythmia or the need for antiarrhythmic drugs or signs of ischemia on ECG, marked baseline prolongation of QT / QTc interval, for example repeated demonstration of a QTc interval> 500 msec; long QT syndrome; required the use of concurrent medication on dosage belinostat days, which may cause torsades de pointes (see Appendix 1).
4. Altered mental status that prevents understanding of the informed consent process and / or execution of the necessary experiments
5. Secondary malignancy present (previous malignancy accepted if cured by treatment for > 3 years ago)
6. Intestinal obstruction or threatening bowel obstruction