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

Primary Purpose

Small Cell Lung Cancer

Status
Terminated
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
ADI-PEG 20 (Arginine deiminase pegylated)
Sponsored by
Ludwig Institute for Cancer Research
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Small Cell Lung Cancer focused on measuring small cell lung cancer, SCLC, ADI-PEG 20, arginine deiminase pegylated

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Memorial Sloan-Kettering Cancer Center
  • Duke University Medical Center
  • University Clinic Saint-Luc
  • Krankenhaus Nordwest
  • National Cheng Kung University Hospital
  • National Taiwan University Hospital
  • Chang Gung Memorial Hospital - LinKou Branch
  • St. Bartholomew's Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Cohort 1: Sensitive Disease

Cohort 2: Refractory Disease

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
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.
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.

Full Information

First Posted
December 22, 2010
Last Updated
October 3, 2022
Sponsor
Ludwig Institute for Cancer Research
Collaborators
Memorial Sloan Kettering Cancer Center, Duke University, St. Bartholomew's Hospital, Krankenhaus Nordwest, Saint-Luc University Hospital, National Taiwan University Hospital, National Cheng-Kung University Hospital, Chang Gung Memorial Hospital, Austin Health, Polaris Group
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1. Study Identification

Unique Protocol Identification Number
NCT01266018
Brief Title
Study of ADI-PEG 20 in Patients With Relapsed Sensitive or Refractory Small Cell Lung Cancer
Official Title
Phase II Study of ADI-PEG 20 in Patients With Relapsed Sensitive or Refractory Small Cell Lung Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
October 2022
Overall Recruitment Status
Terminated
Why Stopped
Lack of efficacy in Cohort 2; slow enrollment in Cohort 1
Study Start Date
January 2011 (undefined)
Primary Completion Date
January 2014 (Actual)
Study Completion Date
January 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Ludwig Institute for Cancer Research
Collaborators
Memorial Sloan Kettering Cancer Center, Duke University, St. Bartholomew's Hospital, Krankenhaus Nordwest, Saint-Luc University Hospital, National Taiwan University Hospital, National Cheng-Kung University Hospital, Chang Gung Memorial Hospital, Austin Health, Polaris Group

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Small Cell Lung Cancer
Keywords
small cell lung cancer, SCLC, ADI-PEG 20, arginine deiminase pegylated

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
22 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Cohort 1: Sensitive Disease
Arm Type
Experimental
Arm Description
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.
Arm Title
Cohort 2: Refractory Disease
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
ADI-PEG 20 (Arginine deiminase pegylated)
Other Intervention Name(s)
ADI, Arginine deiminase pegylated
Intervention Description
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)
Primary Outcome Measure Information:
Title
Best Overall Response
Description
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.
Time Frame
Every 4 to 8 weeks for up to 16 weeks
Secondary Outcome Measure Information:
Title
Assessment of Safety of Arginine Deiminase Pegylated (ADI-PEG) 20
Description
Analysis of treatment-emergent adverse events (TEAEs) reported from clinical laboratory tests, physical examinations, and vital signs.
Time Frame
Every 1 to 4 weeks for up to 16 weeks
Title
Assessment of Pharmacodynamics of ADI-PEG 20
Description
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.
Time Frame
Every 1 to 4 weeks for up to 16 weeks
Title
Assessment of Immunogenicity of ADI-PEG 20
Description
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.
Time Frame
Every 1 to 4 weeks for up to 16 weeks
Title
Assessment of Overall Survival
Description
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.
Time Frame
Every 4 weeks for up to 16 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Subjects must have had histologically documented SCLC 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 Measurable disease using RECIST version 1.1 Argininosuccinate synthetase (ASS) tumor expression was either negative or < 5% + tumor cells by immunohistochemistry analysis Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 2 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 Age ≥ 18 years Able and willing to give valid written informed consent Exclusion Criteria: Previous treatment with ADI-PEG 20 Known allergy to pegylated products History of uncontrolled seizures 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 Metastatic disease to the central nervous system, unless treated and stable Known immunodeficiency or human immunodeficiency virus (HIV) positivity Participation in another clinical trial involving another investigational agent within 3 weeks prior to first dosing of study agent Any other malignancy that required protocol-specified restricted concomitant therapy Mental impairment that may have compromised the ability to give informed consent and comply with the requirements of the study Lack of availability for clinical follow-up assessment Pregnancy or breast feeding Refusal or inability to use effective means of contraception for men and women of childbearing potential for the duration of the study
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Lee M Krug, MD
Organizational Affiliation
Memorial Sloan Kettering Cancer Center
Official's Role
Study Chair
Facility Information:
Facility Name
Memorial Sloan-Kettering Cancer Center
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Facility Name
Duke University Medical Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Facility Name
University Clinic Saint-Luc
City
Brussels
ZIP/Postal Code
B-1200
Country
Belgium
Facility Name
Krankenhaus Nordwest
City
Frankfurt
ZIP/Postal Code
D-60488
Country
Germany
Facility Name
National Cheng Kung University Hospital
City
Tainan City
ZIP/Postal Code
704
Country
Taiwan
Facility Name
National Taiwan University Hospital
City
Taipei City
ZIP/Postal Code
10002
Country
Taiwan
Facility Name
Chang Gung Memorial Hospital - LinKou Branch
City
Taoyuan
ZIP/Postal Code
333
Country
Taiwan
Facility Name
St. Bartholomew's Hospital
City
West Smithfield
State/Province
London
ZIP/Postal Code
EC1A 7BE
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
Yes

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

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