Study of ADI-PEG 20 in Patients With Relapsed Sensitive or Refractory Small Cell Lung Cancer

Phase II Study of ADI-PEG 20 in Patients With Relapsed Sensitive or Refractory Small Cell Lung Cancer

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.

Study Overview

• Status: Terminated
• Conditions: Small Cell Lung Cancer
• Intervention / Treatment: Drug: ADI-PEG 20 (Arginine deiminase pegylated)

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium, B-1200
    • University Clinic Saint-Luc
• Germany
  • Frankfurt, Germany, D-60488
    • Krankenhaus Nordwest
• Taiwan
  • Tainan City, Taiwan, 704
    • National Cheng Kung University Hospital
  • Taipei City, Taiwan, 10002
    • National Taiwan University Hospital
  • Taoyuan, Taiwan, 333
    • Chang Gung Memorial Hospital - Linkou Branch
• United Kingdom
  • London
    • West Smithfield, London, United Kingdom, EC1A 7BE
      • St. Bartholomew's Hospital
• United States
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan-Kettering Cancer Center
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1: Sensitive Disease; Cohort 1 comprised subjects with "sensitive" disease, defined as subjects who were treated with 1 previous line of chemotherapy and maintained an appropriate response for 90 days or more. Subjects received 4 administrations of ADI-PEG 20 (320 IU/m^2) followed by 1 week of follow-up in each treatment cycle.	Drug: ADI-PEG 20 (Arginine deiminase pegylated); ADI-PEG 20 was administered intramuscularly (IM) at a fixed dose of 320 IU/m^2 (36.8 mg/m^2) once weekly for 4 weeks followed by a 1-week follow-up (1 cycle); Other Names: ADI; Arginine deiminase pegylated
Experimental: Cohort 2: Refractory Disease; Cohort 2 comprised subjects with "refractory" disease, defined as subjects who either (a) were treated with 1 previous line of chemotherapy and either had no response or progressed < 90 days after completing treatment or (b) required third-line therapy, i.e., had completed 2 previous lines of chemotherapy, regardless of response. Subjects received 4 administrations of ADI-PEG 20 (320 IU/m^2) followed by 1 week of follow-up in each treatment cycle.	Drug: ADI-PEG 20 (Arginine deiminase pegylated); ADI-PEG 20 was administered intramuscularly (IM) at a fixed dose of 320 IU/m^2 (36.8 mg/m^2) once weekly for 4 weeks followed by a 1-week follow-up (1 cycle); Other Names: ADI; Arginine deiminase pegylated

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Best Overall Response	Tumor responses were evaluated using any appropriate imaging type and were categorized according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Per RECIST for target lesions and assessed by MRI: Complete Response (CR): Disappearance of all target lesions [no evidence of disease]; Partial Response (PR): ≥ 30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD): ≥ 20% increase in the sum of the longest diameter of target lesions; Stable Disease (SD): small changes that do not meet above criteria.	Every 4 to 8 weeks for up to 16 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assessment of Safety of Arginine Deiminase Pegylated (ADI-PEG) 20	Analysis of treatment-emergent adverse events (TEAEs) reported from clinical laboratory tests, physical examinations, and vital signs.	Every 1 to 4 weeks for up to 16 weeks
Assessment of Pharmacodynamics of ADI-PEG 20	Blood samples were collected from all subjects at enrollment, prior to each treatment, and at the end of study to evaluate changes in plasma arginine and citrulline levels following administration of ADI-PEG 20. Disease state (ie, relapsed sensitive vs refractory) was not considered relevant to this analysis and as such samples were collected without regard for cohort assignment.	Every 1 to 4 weeks for up to 16 weeks
Assessment of Immunogenicity of ADI-PEG 20	Blood samples were collected for all subjects at enrollment, prior to each treatment, and at the end of study to evaluate changes in ADI-PEG 20 antibody titer in peripheral blood over time. Disease state (ie, relapsed sensitive vs refractory) was not considered relevant to this analysis and as such samples were collected without regard for cohort assignment.	Every 1 to 4 weeks for up to 16 weeks
Assessment of Overall Survival	Overall survival was measured from the initial date of treatment to the recorded date of death. Because the study was terminated prematurely, no statistical analyses of overall survival data were performed.	Every 4 weeks for up to 16 months

Collaborators and Investigators

• Sponsor: Ludwig Institute for Cancer Research
• Collaborators: Memorial Sloan Kettering Cancer Center; National Taiwan University Hospital; Duke University; Chang Gung Memorial Hospital; National Cheng-Kung University Hospital; Austin Health; St. Bartholomew's Hospital; Saint-Luc University Hospital; Krankenhaus Nordwest; Polaris Group
• Investigators: Study Chair: Lee M Krug, MD, Memorial Sloan Kettering Cancer Center

Study record dates

Study Major Dates

• Study Start: January 1, 2011
• Primary Completion (Actual): January 1, 2014
• Study Completion (Actual): January 1, 2014

Study Registration Dates

• First Submitted: December 22, 2010
• First Submitted That Met QC Criteria: December 23, 2010
• First Posted (Estimate): December 24, 2010

Study Record Updates

• Last Update Posted (Actual): October 25, 2022
• Last Update Submitted That Met QC Criteria: October 3, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: small cell lung cancer; SCLC; ADI-PEG 20; arginine deiminase pegylated
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Small Cell Lung Carcinoma
• Other Study ID Numbers: LUD2009-007; Pro00022622 (Duke University Medical Center)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes