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

• Sponsor: Ludwig Institute for Cancer Research (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01266018
• Collaborator: Memorial Sloan Kettering Cancer Center (Other), Duke University (Other), St. Bartholomew's Hospital (Other), Krankenhaus Nordwest (Other), Saint-Luc University Hospital (Other), National Taiwan University Hospital (Other), National Cheng-Kung University Hospital (Other), Chang Gung Memorial Hospital (Other), Austin Health (Other), Polaris Group (Industry)
• Enrollment: 22
• Locations: 8
• Arms: 2
• Duration (Months): 36
• Patients Per Site: 2.8
• Patients Per Site Per Month: 0.1

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Small Cell Lung Cancer	Drug: ADI-PEG 20 (Arginine deiminase pegylated)	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 22 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study of ADI-PEG 20 in Patients With Relapsed Sensitive or Refractory Small Cell Lung Cancer
• Study Start Date: Jan 1, 2011
• Actual Primary Completion Date: Jan 1, 2014
• Actual Study Completion Date: Jan 1, 2014

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Best Overall Response [Every 4 to 8 weeks for up to 16 weeks]

   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

1. Assessment of Safety of Arginine Deiminase Pegylated (ADI-PEG) 20 [Every 1 to 4 weeks for up to 16 weeks]

   Analysis of treatment-emergent adverse events (TEAEs) reported from clinical laboratory tests, physical examinations, and vital signs.

2. Assessment of Pharmacodynamics of ADI-PEG 20 [Every 1 to 4 weeks for up to 16 weeks]

   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.

3. Assessment of Immunogenicity of ADI-PEG 20 [Every 1 to 4 weeks for up to 16 weeks]

   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.

4. Assessment of Overall Survival [Every 4 weeks for up to 16 months]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

1. Age ≥ 18 years

2. 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10065
2	Duke University Medical Center	Durham	North Carolina	United States	27710
3	University Clinic Saint-Luc	Brussels		Belgium	B-1200
4	Krankenhaus Nordwest	Frankfurt		Germany	D-60488
5	National Cheng Kung University Hospital	Tainan City		Taiwan	704
6	National Taiwan University Hospital	Taipei City		Taiwan	10002
7	Chang Gung Memorial Hospital - LinKou Branch	Taoyuan		Taiwan	333
8	St. Bartholomew's Hospital	West Smithfield	London	United Kingdom	EC1A 7BE

Sponsors and Collaborators

• Ludwig Institute for Cancer Research
• 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

Investigators

• Study Chair: Lee M Krug, MD, Memorial Sloan Kettering Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Ludwig Institute for Cancer Research
• ClinicalTrials.gov Identifier: NCT01266018
• Other Study ID Numbers: LUD2009-007; Pro00022622
• First Posted: Dec 24, 2010
• Last Update Posted: Jan 29, 2019
• Last Verified: Jan 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Ludwig Institute for Cancer Research: small cell lung cancer; SCLC; ADI-PEG 20; arginine deiminase pegylated
• Additional relevant MeSH terms: Lung Neoplasms; Small Cell Lung Carcinoma

Study Results

Participant Flow

Arm/Group Title	Cohort 1: Sensitive Disease	Cohort 2: Refractory Disease
Arm/Group 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.	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
Period Title: Overall Study
STARTED	9	13
COMPLETED	8	12
NOT COMPLETED	1	1

Baseline Characteristics

Arm/Group Title	All Enrolled Subjects
Arm/Group Description	Includes all subjects enrolled in Cohort 1 (n = 9) and Cohort 2 (n = 13).
Overall Participants	22
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63.4 (9.4)
Sex: Female, Male (Count of Participants)
Female	8 36.4%
Male	14 63.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	21 95.5%
Unknown or Not Reported	1 4.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	6 27.3%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 4.5%
White	14 63.6%
More than one race	0 0%
Unknown or Not Reported	1 4.5%
Region of Enrollment (participants) [Number]
Belgium	1 4.5%
United States	11 50%
Taiwan	6 27.3%
United Kingdom	3 13.6%
Germany	1 4.5%
Body mass index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	28.3 (5.6)
Argininosuccinate Synthetase (ASS) Assay Result (participants) [Number]
Negative	11 50%
<5% cells positive	11 50%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Includes all patients who were evaluable for tumor response allocation.

Arm/Group Title	Cohort 1: Sensitive Disease	Cohort 2: Refractory Disease
Arm/Group Description	Includes 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.	Includes 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.
Measure Participants	8	12
Stable disease	2 9.1%	2 NaN
Progressive disease	6 27.3%	10 NaN

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The Safety Analysis Set comprises all subjects who received at least 1 dose of study drug.

Arm/Group Title	Cohort 1: Sensitive Disease	Cohort 2: Refractory Disease
Arm/Group Description	Includes 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.	Includes 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.
Measure Participants	9	13
Any TEAE	9 40.9%	12 NaN
Grade 3 TEAE	5 22.7%	1 NaN
Grade 4 TEAE	1 4.5%	2 NaN
Grade 5 TEAE (Death)	0 0%	3 NaN
Treatment-related TEAE	4 18.2%	7 NaN
Serious TEAE	5 22.7%	5 NaN
TEAE leading to withdrawal	0 0%	3 NaN

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The Pharmacodynamic Analysis Set comprises all subjects who received at least 1 dose of study drug and provided plasma samples for pharmacodynamic analyses. A total of 121 plasma samples from 21 subjects were analyzed. Summary data are presented through Day 58, i.e., the last time point with at least 3 samples available for calculation of a mean.

Arm/Group Title	All Subjects (Pharmacodynamic Analysis Set)
Arm/Group Description	Includes all subjects in Cohort 1 (n = 9) and Cohort 2 (n = 12) who received at least 1 dose of study drug and provided plasma samples for pharmacodynamic analyses.
Measure Participants	21
Arginine (Day 0)	69
Arginine (Day 1)	110
Arginine (Day 8)	2
Arginine (Day 15)	2
Arginine (Day 22)	3
Arginine (Day 29)	2
Arginine (Day 36)	16
Arginine (Day 43)	11
Arginine (Day 50)	29
Arginine (Day 58)	52
Citrulline (Day 0)	26
Citrulline (Day 1)	46
Citrulline (Day 8)	546
Citrulline (Day 15)	684
Citrulline (Day 22)	495
Citrulline (Day 29)	409
Citrulline (Day 36)	223
Citrulline (Day 43)	222
Citrulline (Day 50)	222
Citrulline (Day 58)	119

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The Pharmacodynamic Analysis Set comprises all subjects who received at least 1 dose of study drug and provided plasma samples for pharmacodynamic analyses. A total of 121 plasma samples from 21 subjects were analyzed. Summary data are presented through Day 58, i.e., the last time point with at least 3 samples available for calculation of a mean.

Arm/Group Title	All Subjects (Pharmacodynamic Analysis Set)
Arm/Group Description	Includes all subjects in Cohort 1 (n = 9) and Cohort 2 (n = 12) who received at least 1 dose of study drug and provided plasma samples for pharmacodynamic analyses.
Measure Participants	21
Antibody titer (Day 0)	0.7
Antibody titer (Day 1)	0.5
Antibody titer (Day 8)	0.4
Antibody titer (Day 15)	1.4
Antibody titer (Day 22)	1.5
Antibody titer (Day 29)	1.3
Antibody titer (Day 36)	1.9
Antibody titer (Day 43)	2.2
Antibody titer (Day 50)	3.4
Antibody titer (Day 58)	4.0

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Subjects who had survival status recorded during post-study follow-up.

Arm/Group Title	Cohort 1: Sensitive Disease	Cohort 2: Refractory Disease
Arm/Group Description	Includes 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.	Includes 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.
Measure Participants	6	11
Alive at last follow-up	4 18.2%	4 NaN
Not alive at last follow-up	2 9.1%	7 NaN

Adverse Events

Time Frame	All adverse events (AEs) occurring between the signing of informed consent and the off-study date were documented, regardless of the causal relationship to study drug. AEs occurring after the first dose of study drug were considered treatment emergent (i.e., TEAEs).
Adverse Event Reporting Description	AE documentation included onset/resolution dates, severity using NCI CTCAE (v4.0), seriousness, study drug action taken, treatment, and outcome. In summaries, treatment-related AEs included those with a "possible", "probable", or "definite" relationship to study drug; preferred terms were counted only once per subject at the maximum reported grade.
Arm/Group Title	All Subjects (Safety Analysis Set)
Arm/Group Description	Includes all subjects in Cohort 1 (n = 9) and Cohort 2 (n = 13) who received at least 1 dose of study drug.
All Cause Mortality
	All Subjects (Safety Analysis Set)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	All Subjects (Safety Analysis Set)
	Affected / at Risk (%)	# Events
Total	10/22 (45.5%)
Blood and lymphatic system disorders
Febrile neutropenia	1/22 (4.5%)
Leukopenia	1/22 (4.5%)
Lymphopenia	1/22 (4.5%)
Neutropenia	1/22 (4.5%)
Cardiac disorders
Cardiac arrest	1/22 (4.5%)
General disorders
Non-cardiac chest pain	1/22 (4.5%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant neoplasm progression	2/22 (9.1%)
Nervous system disorders
Hypoaesthesia	1/22 (4.5%)
Paraesthesia	1/22 (4.5%)
Somnolence	1/22 (4.5%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	3/22 (13.6%)
Other (Not Including Serious) Adverse Events
	All Subjects (Safety Analysis Set)
	Affected / at Risk (%)	# Events
Total	21/22 (95.5%)
Cardiac disorders
Tachycardia	2/22 (9.1%)
Gastrointestinal disorders
Constipation	4/22 (18.2%)
Nausea	4/22 (18.2%)
Vomiting	4/22 (18.2%)
Diarrhoea	3/22 (13.6%)
General disorders
Fatigue	10/22 (45.5%)
Asthenia	4/22 (18.2%)
Chest discomfort	2/22 (9.1%)
Infections and infestations
Lower respiratory tract infection	2/22 (9.1%)
Investigations
White blood cell count decreased	4/22 (18.2%)
Platelet count decreased	3/22 (13.6%)
Blood creatinine increased	2/22 (9.1%)
Haemoglobin decreased	2/22 (9.1%)
Metabolism and nutrition disorders
Decreased appetite	7/22 (31.8%)
Dehydration	2/22 (9.1%)
Hyperglycaemia	2/22 (9.1%)
Musculoskeletal and connective tissue disorders
Back pain	2/22 (9.1%)
Muscular weakness	2/22 (9.1%)
Pain in extremity	2/22 (9.1%)
Nervous system disorders
Dysgeusia	2/22 (9.1%)
Headache	2/22 (9.1%)
Psychiatric disorders
Insomnia	2/22 (9.1%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	2/22 (9.1%)
Cough	4/22 (18.2%)
Wheezing	3/22 (13.6%)
Productive cough	2/22 (9.1%)
Skin and subcutaneous tissue disorders
Pruritus	2/22 (9.1%)

Limitations/Caveats

The study was terminated early due to lack of efficacy and slow enrollment; therefore, only 22 of the planned 45 subjects were enrolled, treated, and evaluated for study endpoints.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.