Lack of efficacy in Cohort 2; slow enrollment in Cohort 1

This was a 2-arm, open-label, phase 2 study of pegylated arginine deiminase (ADI-PEG) 20 in subjects with relapsed sensitive or refractory small cell lung cancer (SCLC). ADI-PEG 20 was administered intramuscularly (IM) at a fixed dose of 320 IU/m^2 once weekly for a 4-week cycle. The primary objective was to assess clinical efficacy with a primary endpoint of tumor response by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 after 4 weeks. Secondary objectives were to assess the safety, pharmacodynamics, and immunogenicity of ADI-PEG 20, as well as clinical efficacy with a secondary endpoint of overall survival.

Subjects were enrolled sequentially (non-randomized) into two separate cohorts in parallel. Cohort 1 comprised subjects with "sensitive" disease and Cohort 2 comprised subjects with "refractory" disease. Both cohorts received the same treatment regimen consisting of 4 weekly IM administrations of ADI-PEG 20 (320 IU/m^2), followed by a 1-week follow-up (1 cycle). No dose adjustment was allowed. Additional treatment cycles were permitted in the absence of disease progression requiring other therapeutic interventions.

Each cohort was to be enrolled in 2 stages. In the first stage, 15 subjects were to be accrued in Cohort 1 and 12 subjects in Cohort 2. If ≥ 3 subjects met the primary endpoint in Cohort 1, then an additional 13 subjects were to be accrued in the second stage. If ≤ 2 subjects met the primary endpoint in Cohort 1, then the study was to be terminated and declared negative for Cohort 1. If ≥ 1 subject met the primary endpoint in Cohort 2, then an additional 4 subjects were to be accrued in the second stage. If no subjects met the primary endpoint in Cohort 2, then the study was to be terminated and declared negative. Additionally, if at any time a death or two grade 4 adverse events (AEs) that were definitely related or probably related to the study drug occurred, then the study was to be stopped.

Inclusion Criteria:

1. Subjects must have had histologically documented SCLC

2. Assigned to one of two cohorts based on the following characteristics: Cohort 1: "Sensitive" disease subjects who had 1 previous line of chemotherapy and maintained an appropriate response for 90 days or more; or Cohort 2: "Refractory" disease subjects, who had (a) 1 previous line of chemotherapy and either had no response or progressed in less than 90 days after completing treatment or (b) any subject ("sensitive" or "refractory") in need of third-line therapy, i.e., who completed or failed 2 previous lines of chemotherapy

3. Measurable disease using RECIST version 1.1

4. Argininosuccinate synthetase (ASS) tumor expression was either negative or < 5% + tumor cells by immunohistochemistry analysis

5. Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 2

6. Laboratory parameters for vital functions in the normal range. Laboratory abnormalities that were not clinically significant were generally permitted, except for the following laboratory parameters, which were to be within the ranges specified:

   • Neutrophil count: ≥ 1.5 x 10^9/L
   • Lymphocyte count: ≥ 0.5 x 10^9/L
   • Platelet count: ≥ 50 x 10^9/L
   • Serum creatinine: ≤ 1.5 x upper limit of normal (ULN) (or creatinine clearance ≥ 60 mL/min)
   • Serum bilirubin: ≤ 2 mg/dL (or ≤ 34 µmol/L)
   • Serum uric acid: ≤ 8 mg/dL (or ≤ 0.48 mmol/L)
   • International normalized ratio (INR): ≤ 1.5
   • Partial thromboplastin time: ≤ 1.5 x ULN

7. Age ≥ 18 years

8. Able and willing to give valid written informed consent

Exclusion Criteria:

1. Previous treatment with ADI-PEG 20
2. Known allergy to pegylated products
3. History of uncontrolled seizures
4. Serious illnesses, e.g., serious infections requiring antibiotics, bleeding disorders, or any condition that in the opinion of the Investigator would interfere with the ability of the patient to fulfill the study requirements
5. Metastatic disease to the central nervous system, unless treated and stable
6. Known immunodeficiency or human immunodeficiency virus (HIV) positivity
7. Participation in another clinical trial involving another investigational agent within 3 weeks prior to first dosing of study agent
8. Any other malignancy that required protocol-specified restricted concomitant therapy
9. Mental impairment that may have compromised the ability to give informed consent and comply with the requirements of the study
10. Lack of availability for clinical follow-up assessment
11. Pregnancy or breast feeding
12. Refusal or inability to use effective means of contraception for men and women of childbearing potential for the duration of the study