Study of ADI-PEG 20 in Patients With Advanced Melanoma

• Sponsor: Ludwig Institute for Cancer Research (Other)
• Overall Status: Completed
• CT.gov ID: NCT00520299
• Collaborator: Memorial Sloan Kettering Cancer Center (Other), NYU Langone Health (Other)
• Enrollment: 31
• Locations: 2
• Arms: 3
• Duration (Months): 32
• Patients Per Site: 15.5
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

This was a phase 1/2, open-label, dose-escalation study of arginine deiminase linked via succinimidyl succinate to polyethylene glycol of 20,000 molecular weight (ADI-PEG 20) in subjects with advanced melanoma. ADI-PEG 20 was administered intramuscularly (IM) at escalating doses weekly for 9 weeks (cycle 1) or 8 weeks (subsequent cycles). The primary objectives were to the establish the safety, tolerability, and clinical efficacy of ADI-PEG 20. Secondary objectives included evaluation of the metabolic activity by [18F]-fluorodeoxyglucose positron emission tomography (FDG PET), pharmacodynamics, correlation of immunogenicity with clinical response, and correlation of argininosuccinate synthetase (ASS) tumor expression with clinical response.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Melanoma; Skin Cancer; Neoplasm	Drug: ADI PEG 20	Phase 1/Phase 2

Detailed Description

A 3+3 design was implemented during phase 1, in which 3 to 6 subjects were enrolled sequentially into the following escalating dose cohorts:

• Cohort 1 (40 IU/m^2)

• Cohort 2 (80 IU/m^2)

• Cohort 3 (160 IU/m^2)

Subjects were monitored for dose-limiting toxicity (DLT) during the first 2 weeks of cycle 1, with DLT defined as any grade 3 or higher toxicity. The maximum tolerated dose (MTD) was defined as the cohort in which < 33% of subjects (ie, 0/3 or 1/6 subjects in a cohort) experienced DLT. In phase 2, the MTD cohort was expanded in up to 25 patients.

Subjects who completed treatment in cycle 1 without DLT were eligible to initiate cycle 2 at week 10 provided that a computed tomography (CT) scan showed either enlargement of existing disease without accompanying symptoms OR stable disease or improvement with no unacceptable toxicity. The same radiologic criteria applied for initiation of subsequent cycles. Subjects could continue to receive study treatment until disease progression.

Study Design

• Study Type: Interventional
• Actual Enrollment: 31 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase 1/2 Study of ADI-SS PEG 20,000mw in Patients With Advanced Melanoma
• Study Start Date: Jul 1, 2007
• Actual Primary Completion Date: Mar 1, 2010
• Actual Study Completion Date: Mar 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort 1 Subjects received ADI-PEG 20 at a dose of 40 IU/m^2	Drug: ADI PEG 20; Intramuscular injections were administered into the deltoid, gluteal, or quadricep muscles once weekly (± 2 days) for 9 weeks during cycle 1 and 8 weeks during subsequent cycles; Other Names: ADI-SS PEG 20,000 mw ADI
Experimental: Cohort 2 Subjects received ADI-PEG 20 at a dose of 80 IU/m^2	Drug: ADI PEG 20; Intramuscular injections were administered into the deltoid, gluteal, or quadricep muscles once weekly (± 2 days) for 9 weeks during cycle 1 and 8 weeks during subsequent cycles; Other Names: ADI-SS PEG 20,000 mw ADI
Experimental: Cohort 3 Subjects received ADI-PEG 20 at a dose of 160 IU/m^2	Drug: ADI PEG 20; Intramuscular injections were administered into the deltoid, gluteal, or quadricep muscles once weekly (± 2 days) for 9 weeks during cycle 1 and 8 weeks during subsequent cycles; Other Names: ADI-SS PEG 20,000 mw ADI

Outcome Measures

Primary Outcome Measures

1. Assessment of Safety and Tolerability of ADI-PEG 20 [Every 1 to 2 weeks for up to 12 months]

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

2. Best Overall Clinical Tumor Response [Every 8 to 9 weeks for up to 12 months]

   Clinical tumor responses were evaluated using disease imaging (CT preferred) performed at baseline and at the end of every cycle. Responses were categorized according to RECIST. 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. Metabolic Tumor Response [Every 8 to 9 weeks for up to 12 months]

   Metabolic tumor responses were evaluated using fluorodeoxyglucose (FDG) positron emission tomography (PET) at baseline, on day 4, and at the end of every cycle.

2. Summary of ADI-PEG 20 Plasma Concentrations Over Time [Up to 12 months]

   Blood samples were collected on day 1 (pre-injection), day 4, day 8, and every 7 days thereafter for ADI-PEG 20 plasma concentrations.

3. Summary of Plasma Arginine Levels Over Time [Up to 9 months]

   Blood samples were collected at baseline, day 1 (pre-injection), day 4, day 8, and every 7 days thereafter for plasma arginine levels.

4. Summary of Plasma Citrulline Levels Over Time [Up to 9 months]

   Blood samples were collected at baseline, day 1 (pre-injection), day 4, day 8, and every 7 days thereafter for plasma citrulline levels.

5. Summary of ADI-PEG 20 Immunogenicity Over Time [Up to 12 months]

   Blood samples were collected at baseline, day 1 (pre-injection), day 4, day 8, and every 7 days thereafter for detection of anti-ADI antibodies.

6. Correlation Between ASS Tumor Expression and Clinical Response [Up to 12 months]

   Expression of ASS was analyzed by immunohistochemistry in tumor samples (archived or biopsy) at baseline and compared with overall best clinical response per RECIST. ASS tumor expression is categorized as either negative or ≤ 5% positive tumor cells.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Histologically confirmed malignant melanoma, American Joint Committee on Cancer (AJCC) stage III (unresectable) or IV. Subjects with uveal and mucosal melanomas were eligible.

2. Measurable disease using the Response Evaluation Criteria in Solid Tumors (RECIST).

3. Pathology slides reviewed by the Memorial Hospital Department of Pathology or New York University (NYU) Department of Pathology for confirmation of melanoma diagnosis.

4. Karnofsky performance status of 80% or more.

5. Adequate organ and marrow function, as defined below:

• white blood cell count ≥ 3000/µL

• absolute neutrophil count ≥ 1500/µL

• platelet count ≥ 100,000/µL

• total bilirubin ≤ 2.5 x institutional upper limit of normal (ULN)

• lactate dehydrogenase ≤ 1.5 x institutional ULN

• albumin ≥ 3.0 mg/dL

• creatinine ≤ 2.0 mg/dL

1. Expected survival of at least 3 months.

2. Age ≥ 18 years.

3. Able and willing to give valid written informed consent.

Exclusion Criteria:

1. Receipt of chemotherapy, immunotherapy, or radiotherapy within 3 weeks prior to first dosing of study agent or lack of recovery from adverse events (AEs) due to agents administered more than 3 weeks earlier. For nitrosoureas, at least 6 weeks must have elapsed.

2. Any other malignancy that required concomitant therapy.

3. Any medical condition that could have made it difficult for the subject to complete the full course of treatments, at the discretion of the Principal Investigator or co-Principal Investigators.

4. Metastatic disease to the central nervous system, unless treated and stable.

5. Known human immunodeficiency virus (HIV) positivity.

6. Mental impairment that may have compromised the ability to give informed consent and comply with the requirements of the study.

7. Lack of availability for clinical follow-up assessments.

8. Participation in any other clinical trial involving another investigational agent within 3 weeks prior to enrollment.

9. Pregnant women or women who were nursing. Women of child-bearing potential and sexually active men must have used appropriate contraception during the course of this study. Women of child-bearing potential must not have been pregnant (negative β human chorionic gonadotropin within 2 weeks of treatment) or nursing during treatment.

10. History of seizure disorder.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	NYU Cancer Institute	New York	New York	United States	10016
2	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10021

Sponsors and Collaborators

• Ludwig Institute for Cancer Research
• Memorial Sloan Kettering Cancer Center
• NYU Langone Health

Investigators

• Principal Investigator: Jedd Wolchok, MD, PhD, Memorial Sloan Kettering Cancer Center
• Principal Investigator: Anna Pavlick, DO, New York University Cancer Institute
• Principal Investigator: Gary Schwartz, 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: NCT00520299
• Other Study ID Numbers: LUD2005-007; MSKCC IRB #06-165; NYU IRB #07-053
• First Posted: Aug 24, 2007
• Last Update Posted: Nov 21, 2017
• Last Verified: Oct 1, 2017

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Ludwig Institute for Cancer Research: metastatic melanoma; ADI; ADI-PEG 20; ADI SS PEG 20,000mw; arginine; enzyme therapy
• Additional relevant MeSH terms: Melanoma

Study Results

Participant Flow

Arm/Group Title	Cohort 1: ADI-PEG 20 40 IU/m^2/Week	Cohort 2: ADI-PEG 20 80 IU/m^2/Week	Cohort 3: ADI-PEG 20 160 IU/m^2/Week
Arm/Group Description	Includes subjects enrolled to receive 40 IU/m^2/week of ADI-PEG 20	Includes subjects enrolled to receive 80 IU/m^2/week of ADI-PEG 20	Includes subjects enrolled to receive 160 IU/m^2/week of ADI-PEG 20
Period Title: Overall Study
STARTED	6	6	19
COMPLETED	6	3	13
NOT COMPLETED	0	3	6

Baseline Characteristics

Arm/Group Title	Cohort 1: ADI-PEG 20 40 IU/m^2/Week	Cohort 2: ADI-PEG 20 80 IU/m^2/Week	Cohort 3: ADI-PEG 20 160 IU/m^2/Week	Total
Arm/Group Description	Includes subjects enrolled to receive 40 IU/m^2/week of ADI-PEG 20	Includes subjects enrolled to receive 80 IU/m^2/week of ADI-PEG 20	Includes subjects enrolled to receive 160 IU/m^2/week of ADI-PEG 20	Total of all reporting groups
Overall Participants	6	6	19	31
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.7 (18.2)	61.2 (14.7)	67.2 (11.2)	64.9 (13.2)
Sex: Female, Male (Count of Participants)
Female	5 83.3%	3 50%	6 31.6%	14 45.2%
Male	1 16.7%	3 50%	13 68.4%	17 54.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	1 5.3%	1 3.2%
Not Hispanic or Latino	6 100%	6 100%	17 89.5%	29 93.5%
Unknown or Not Reported	0 0%	0 0%	1 5.3%	1 3.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	1 5.3%	1 3.2%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%
White	6 100%	6 100%	18 94.7%	30 96.8%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
BMI (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	22.0 (4.1)	24.7 (1.8)	26.9 (4.7)	25.5 (4.5)
ASS Assay Result (participants) [Number]
Negative	4 66.7%	6 100%	14 73.7%	24 77.4%
≤5% positive	2 33.3%	0 0%	3 15.8%	5 16.1%
Not done	0 0%	0 0%	2 10.5%	2 6.5%

Outcome Measures

1. Primary Outcome

Title	Assessment of Safety and Tolerability of 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 2 weeks for up to 12 months

Outcome Measure Data

Analysis Population Description

Safety Analysis Set (all subjects who received at least 1 dose of ADI-PEG 20)

Arm/Group Title	Cohort 1: ADI-PEG 20 40 IU/m^2/Week	Cohort 2: ADI-PEG 20 80 IU/m^2/Week	Cohort 3: ADI-PEG 20 160 IU/m^2/Week
Arm/Group Description	Includes subjects enrolled to receive 40 IU/m^2/week of ADI-PEG 20	Includes subjects enrolled to receive 80 IU/m^2/week of ADI-PEG 20	Includes subjects enrolled to receive 160 IU/m^2/week of ADI-PEG 20
Measure Participants	6	6	19
Any TEAE	6 100%	6 100%	19 100%
Grade 3 TEAE	1 16.7%	2 33.3%	4 21.1%
Grade 4 TEAE	0 0%	1 16.7%	1 5.3%
Grade 5 TEAE (Death)	0 0%	0 0%	1 5.3%
Treatment-related TEAE	5 83.3%	5 83.3%	17 89.5%
SAE	4 66.7%	1 16.7%	6 31.6%
TEAE leading to withdrawal	0 0%	1 16.7%	3 15.8%

2. Primary Outcome

Title	Best Overall Clinical Tumor Response
Description	Clinical tumor responses were evaluated using disease imaging (CT preferred) performed at baseline and at the end of every cycle. Responses were categorized according to RECIST. 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 8 to 9 weeks for up to 12 months

Outcome Measure Data

Analysis Population Description

Includes all subjects who completed the study as planned or had tumor progression during the study

Arm/Group Title	Cohort 1: ADI-PEG 20 40 IU/m^2/Week	Cohort 2: ADI-PEG 20 80 IU/m^2/Week	Cohort 3: ADI-PEG 20 160 IU/m^2/Week
Arm/Group Description	Includes subjects enrolled to receive 40 IU/m^2/week of ADI-PEG 20	Includes subjects enrolled to receive 80 IU/m^2/week of ADI-PEG 20	Includes subjects enrolled to receive 160 IU/m^2/week of ADI-PEG 20
Measure Participants	6	6	17
Complete/partial response	0 0%	0 0%	0 0%
Stable disease	3 50%	2 33.3%	4 21.1%
Progressive disease	3 50%	4 66.7%	13 68.4%

3. Secondary Outcome

Title	Metabolic Tumor Response
Description	Metabolic tumor responses were evaluated using fluorodeoxyglucose (FDG) positron emission tomography (PET) at baseline, on day 4, and at the end of every cycle.
Time Frame	Every 8 to 9 weeks for up to 12 months

Outcome Measure Data

Analysis Population Description

Includes all subjects who completed the study as planned or had tumor progression during the study

Arm/Group Title	Cohort 1: ADI-PEG 20 40 IU/m^2/Week	Cohort 2: ADI-PEG 20 80 IU/m^2/Week	Cohort 3: ADI-PEG 20 160 IU/m^2/Week
Arm/Group Description	Includes subjects enrolled to receive 40 IU/m^2/week of ADI-PEG 20	Includes subjects enrolled to receive 80 IU/m^2/week of ADI-PEG 20	Includes subjects enrolled to receive 160 IU/m^2/week of ADI-PEG 20
Measure Participants	6	6	17
Cycle 1 Day 4: Partial metabolic response	1 16.7%	0 0%	6 31.6%
Cycle 1 Day 4: Stable metabolic disease	2 33.3%	3 50%	6 31.6%
Cycle 1 Day 4: Progressive metabolic disease	3 50%	2 33.3%	4 21.1%
Cycle 1 Day 4: Missing	0 0%	1 16.7%	1 5.3%
Cycle 1 Day 50: Partial metabolic response	0 0%	1 16.7%	0 0%
Cycle 1 Day 50: Stable metabolic disease	4 66.7%	3 50%	5 26.3%
Cycle 1 Day 50: Progressive metabolic disease	2 33.3%	1 16.7%	9 47.4%
Cycle 1 Day 50: Missing	0 0%	1 16.7%	3 15.8%

4. Secondary Outcome

Title	Summary of ADI-PEG 20 Plasma Concentrations Over Time
Description	Blood samples were collected on day 1 (pre-injection), day 4, day 8, and every 7 days thereafter for ADI-PEG 20 plasma concentrations.
Time Frame	Up to 12 months

Outcome Measure Data

Analysis Population Description

Includes all subjects who had at least 1 post-baseline blood sample with associated pharmacokinetic analysis. Means are presented for time points at which >1 subject in any arm contributed data.

Arm/Group Title	Cohort 1: ADI-PEG 20 40 IU/m^2/Week	Cohort 2: ADI-PEG 20 80 IU/m^2/Week	Cohort 3: ADI-PEG 20 160 IU/m^2/Week
Arm/Group Description	Includes subjects enrolled to receive 40 IU/m^2/week of ADI-PEG 20	Includes subjects enrolled to receive 80 IU/m^2/week of ADI-PEG 20	Includes subjects enrolled to receive 160 IU/m^2/week of ADI-PEG 20
Measure Participants	6	5	19
Day 0	3.3 (2.9)	4.4 (5.2)	1.9 (1.7)
Day 4	35.5 (16.0)	59.8 (35.7)	57.2 (39.9)
Day 8	33.2 (17.2)	46.3 (33.8)	60.9 (35.5)
Day 15	37.7 (27.2)	49.8 (59.4)	54.0 (36.4)
Day 22	24.1 (16.9)	61.2 (63.8)	47.5 (40.2)
Day 29	16.8 (11.1)	54.0 (58.2)	40.9 (42.3)
Day 36	11.2 (11.7)	50.0 (65.3)	27.1 (42.3)
Day 43	12.0 (10.7)	34.9 (47.2)	11.9 (20.2)
Day 50	11.0 (14.9)	19.0 (26.2)	13.2 (25.7)
Day 57	8.4 (10.5)	9.3 (10.3)	10.0 (15.6)
Day 64	8.0 (9.1)	14.7 (17.3)	10.0 (16.2)
Day 71	2.6 (1.3)	1.5 (0.7)	3.8 (2.9)
Day 78	2.8 (1.1)	0.6 (0.8)	2.6 (1.2)
Day 85	0.5 (0.7)	0.2 (0.0)	2.2 (1.9)
Day 92	0.9 (0.8)	0.6 (0.4)	2.6 (2.9)
Day 99	0.9 (1.1)	2.2 (NA)	2.4 (1.7)
Day 106	1.0 (1.7)	3.1 (NA)	0.9 (0.8)
Day 113	0.9 (0.1)	2.0 (NA)	1.6 (1.8)
Day 120	2.1 (0.7)	3.0 (NA)	4.0 (2.4)

5. Secondary Outcome

Title	Summary of Plasma Arginine Levels Over Time
Description	Blood samples were collected at baseline, day 1 (pre-injection), day 4, day 8, and every 7 days thereafter for plasma arginine levels.
Time Frame	Up to 9 months

Outcome Measure Data

Analysis Population Description

Includes all subjects who had at least 1 post-baseline blood sample with associated pharmacokinetic analysis. Means are presented for time points at which >1 subject in any arm contributed data.

Arm/Group Title	Cohort 1: ADI-PEG 20 40 IU/m^2/Week	Cohort 2: ADI-PEG 20 80 IU/m^2/Week	Cohort 3: ADI-PEG 20 160 IU/m^2/Week
Arm/Group Description	Includes subjects enrolled to receive 40 IU/m^2/week of ADI-PEG 20	Includes subjects enrolled to receive 80 IU/m^2/week of ADI-PEG 20	Includes subjects enrolled to receive 160 IU/m^2/week of ADI-PEG 20
Measure Participants	6	5	19
Day 0	55 (17)	62 (22)	49 (11)
Day 4	2 (0)	9 (20)	4 (11)
Day 8	2 (0)	12 (18)	3 (7)
Day 15	4 (6)	29 (22)	7 (16)
Day 22	9 (11)	22 (23)	21 (33)
Day 29	14 (24)	19 (24)	23 (32)
Day 36	20 (28)	29 (26)	31 (34)
Day 43	23 (34)	35 (31)	48 (44)
Day 50	58 (46)	24 (21)	44 (37)
Day 57	38 (30)	27 (22)	40 (31)
Day 64	30 (29)	30 (26)	42 (35)
Day 71	68 (33)	63 (13)	50 (34)
Day 78	78 (39)	105 (2)	60 (26)
Day 85	75 (38)	64 (28)	74 (24)
Day 92	98 (42)	95 (6)	71 (23)
Day 99	67 (11)	89 (NA)	52 (16)
Day 106	52 (34)	43 (NA)	77 (28)
Day 113	59 (15)	53 (NA)	59 (7)
Day 120	64 (34)	59 (NA)	60 (16)

6. Secondary Outcome

Title	Summary of Plasma Citrulline Levels Over Time
Description	Blood samples were collected at baseline, day 1 (pre-injection), day 4, day 8, and every 7 days thereafter for plasma citrulline levels.
Time Frame	Up to 9 months

Outcome Measure Data

Analysis Population Description

Includes all subjects who had at least 1 post-baseline blood sample with associated pharmacokinetic analysis. Means are presented for time points at which >1 subject in any arm contributed data.

Arm/Group Title	Cohort 1: ADI-PEG 20 40 IU/m^2/Week	Cohort 2: ADI-PEG 20 80 IU/m^2/Week	Cohort 3: ADI-PEG 20 160 IU/m^2/Week
Arm/Group Description	Includes subjects enrolled to receive 40 IU/m^2/week of ADI-PEG 20	Includes subjects enrolled to receive 80 IU/m^2/week of ADI-PEG 20	Includes subjects enrolled to receive 160 IU/m^2/week of ADI-PEG 20
Measure Participants	6	5	19
Day 0	38 (17)	29 (8)	23 (14)
Day 4	195 (89)	158 (84)	225 (106)
Day 8	152 (40)	121 (51)	280 (125)
Day 15	127 (71)	125 (122)	280 (150)
Day 22	141 (102)	174 (165)	245 (175)
Day 29	99 (59)	126 (126)	169 (148)
Day 36	116 (75)	104 (115)	139 (149)
Day 43	106 (81)	135 (149)	71 (72)
Day 50	58 (31)	77 (88)	66 (76)
Day 57	71 (51)	47 (29)	64 (76)
Day 64	76 (80)	108 (133)	60 (54)
Day 71	35 (9)	19 (9)	45 (34)
Day 78	40 (12)	44 (29)	30 (19)
Day 85	50 (30)	23 (6)	32 (11)
Day 92	44 (21)	27 (2)	29 (18)
Day 99	33 (13)	31 (NA)	23 (12)
Day 106	33 (21)	33 (NA)	29 (10)
Day 113	35 (12)	22 (NA)	23 (10)
Day 120	37 (14)	47 (NA)	22 (8)

7. Secondary Outcome

Title	Summary of ADI-PEG 20 Immunogenicity Over Time
Description	Blood samples were collected at baseline, day 1 (pre-injection), day 4, day 8, and every 7 days thereafter for detection of anti-ADI antibodies.
Time Frame	Up to 12 months

Outcome Measure Data

Analysis Population Description

Includes all subjects who had at least 1 post-baseline blood sample with associated pharmacokinetic analysis. Means are presented for time points at which >1 subject in any arm contributed data.

Arm/Group Title	Cohort 1: ADI-PEG 20 40 IU/m^2/Week	Cohort 2: ADI-PEG 20 80 IU/m^2/Week	Cohort 3: ADI-PEG 20 160 IU/m^2/Week
Arm/Group Description	Includes subjects enrolled to receive 40 IU/m^2/week of ADI-PEG 20	Includes subjects enrolled to receive 80 IU/m^2/week of ADI-PEG 20	Includes subjects enrolled to receive 160 IU/m^2/week of ADI-PEG 20
Measure Participants	6	5	19
Day 0	0.2 (0.4)	0.2 (0.5)	0.1 (0.3)
Day 4	0.2 (0.4)	0.0 (0.0)	0.4 (0.5)
Day 8	0.2 (0.4)	0.4 (0.5)	0.4 (0.5)
Day 15	0.5 (0.5)	0.6 (0.5)	0.8 (0.4)
Day 22	0.5 (0.5)	1.0 (0.6)	0.7 (0.5)
Day 29	0.8 (0.4)	1.4 (0.5)	1.3 (0.9)
Day 36	0.8 (0.8)	1.8 (0.4)	1.9 (1.1)
Day 43	1.2 (1.2)	1.8 (0.4)	2.4 (1.2)
Day 50	1.5 (1.2)	2.2 (0.4)	2.9 (1.5)
Day 57	1.5 (0.8)	2.4 (0.5)	3.0 (1.2)
Day 64	2.0 (1.0)	2.0 (0.0)	3.0 (1.3)
Day 71	2.3 (0.6)	2.5 (0.7)	3.5 (0.6)
Day 78	2.7 (0.6)	2.5 (0.7)	4.0 (0.8)
Day 85	2.7 (0.6)	2.0 (0.0)	4.0 (0.8)
Day 92	3.0 (0.0)	3.0 (0.0)	4.0 (0.8)
Day 99	3.0 (1.0)	3.0 (NA)	3.8 (1.3)
Day 106	3.0 (1.0)	3.0 (NA)	4.0 (0.8)
Day 113	3.0 (0.0)	2.0 (NA)	4.0 (1.4)
Day 120	3.0 (0.0)	4.0 (NA)	4.5 (1.3)

8. Secondary Outcome

Title	Correlation Between ASS Tumor Expression and Clinical Response
Description	Expression of ASS was analyzed by immunohistochemistry in tumor samples (archived or biopsy) at baseline and compared with overall best clinical response per RECIST. ASS tumor expression is categorized as either negative or ≤ 5% positive tumor cells.
Time Frame	Up to 12 months

Outcome Measure Data

Analysis Population Description

Includes all subjects who had an ASS antigen assay performed at Baseline

Arm/Group Title	Cohort 1: ADI-PEG 20 40 IU/m^2/Week	Cohort 2: ADI-PEG 20 80 IU/m^2/Week	Cohort 3: ADI-PEG 20 160 IU/m^2/Week
Arm/Group Description	Includes subjects enrolled to receive 40 IU/m^2/week of ADI-PEG 20	Includes subjects enrolled to receive 80 IU/m^2/week of ADI-PEG 20	Includes subjects enrolled to receive 160 IU/m^2/week of ADI-PEG 20
Measure Participants	6	6	17
≤5% Positive ASS & Progressive Disease	2 33.3%	0 0%	3 15.8%
Negative ASS & Stable Disease	1 16.7%	1 16.7%	0 0%
Negative ASS & Progressive Disease	3 50%	5 83.3%	12 63.2%
Negative ASS & Missing Response	0 0%	0 0%	2 10.5%

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	Cohort 1: ADI-PEG 20 40 IU/m^2/Week		Cohort 2: ADI-PEG 20 80 IU/m^2/Week		Cohort 3: ADI-PEG 20 160 IU/m^2/Week
Arm/Group Description	Includes subjects who received 40 IU/m^2/week of ADI-PEG 20		Includes subjects who received 80 IU/m^2/week of ADI-PEG 20		Includes subjects who received 160 IU/m^2/week of ADI-PEG 20
All Cause Mortality
	Cohort 1: ADI-PEG 20 40 IU/m^2/Week		Cohort 2: ADI-PEG 20 80 IU/m^2/Week		Cohort 3: ADI-PEG 20 160 IU/m^2/Week
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		0/6 (0%)		1/19 (5.3%)
Serious Adverse Events
	Cohort 1: ADI-PEG 20 40 IU/m^2/Week		Cohort 2: ADI-PEG 20 80 IU/m^2/Week		Cohort 3: ADI-PEG 20 160 IU/m^2/Week
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/6 (66.7%)		1/6 (16.7%)		6/19 (31.6%)
Gastrointestinal disorders
Nausea	1/6 (16.7%)		0/6 (0%)		1/19 (5.3%)
Vomiting	1/6 (16.7%)		0/6 (0%)		1/19 (5.3%)
Abdominal pain	0/6 (0%)		0/6 (0%)		1/19 (5.3%)
Musculoskeletal and connective tissue disorders
Musculoskeletal pain	1/6 (16.7%)		0/6 (0%)		0/19 (0%)
Musculoskeletal chest pain	1/6 (16.7%)		0/6 (0%)		0/19 (0%)
Pain in extremity	0/6 (0%)		0/6 (0%)		1/19 (5.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasm progression	0/6 (0%)		0/6 (0%)		1/19 (5.3%)
Nervous system disorders
Headache	2/6 (33.3%)		0/6 (0%)		0/19 (0%)
Convulsion	0/6 (0%)		0/6 (0%)		1/19 (5.3%)
Cerebral haemorrhage	0/6 (0%)		0/6 (0%)		1/19 (5.3%)
Grand mal convulsion	0/6 (0%)		0/6 (0%)		1/19 (5.3%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/6 (16.7%)		0/6 (0%)		1/19 (5.3%)
Surgical and medical procedures
Skin neoplasm excision	0/6 (0%)		1/6 (16.7%)		0/19 (0%)
Lymphadenectomy	0/6 (0%)		0/6 (0%)		1/19 (5.3%)
Other (Not Including Serious) Adverse Events
	Cohort 1: ADI-PEG 20 40 IU/m^2/Week		Cohort 2: ADI-PEG 20 80 IU/m^2/Week		Cohort 3: ADI-PEG 20 160 IU/m^2/Week
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/6 (100%)		6/6 (100%)		19/19 (100%)
Cardiac disorders
Tachycardia	0/6 (0%)		0/6 (0%)		2/19 (10.5%)
Gastrointestinal disorders
Nausea	4/6 (66.7%)		1/6 (16.7%)		5/19 (26.3%)
Diarrhea	2/6 (33.3%)		2/6 (33.3%)		4/19 (21.1%)
Abdominal pain	2/6 (33.3%)		1/6 (16.7%)		2/19 (10.5%)
Vomiting	1/6 (16.7%)		1/6 (16.7%)		3/19 (15.8%)
Constipation	0/6 (0%)		1/6 (16.7%)		2/19 (10.5%)
Abdominal discomfort	0/6 (0%)		0/6 (0%)		2/19 (10.5%)
General disorders
Injection site pain	2/6 (33.3%)		1/6 (16.7%)		11/19 (57.9%)
Fatigue	1/6 (16.7%)		2/6 (33.3%)		10/19 (52.6%)
Injection site rash	1/6 (16.7%)		2/6 (33.3%)		2/19 (10.5%)
Pyrexia	1/6 (16.7%)		0/6 (0%)		4/19 (21.1%)
Injection site erythema	1/6 (16.7%)		0/6 (0%)		3/19 (15.8%)
Oedema peripheral	1/6 (16.7%)		1/6 (16.7%)		1/19 (5.3%)
Chest pain	0/6 (0%)		0/6 (0%)		2/19 (10.5%)
Chills	0/6 (0%)		0/6 (0%)		2/19 (10.5%)
Injection site discomfort	0/6 (0%)		0/6 (0%)		2/19 (10.5%)
Injection site reaction	0/6 (0%)		0/6 (0%)		2/19 (10.5%)
Investigations
Weight decreased	1/6 (16.7%)		0/6 (0%)		1/19 (5.3%)
Metabolism and nutrition disorders
Decreased appetite	2/6 (33.3%)		1/6 (16.7%)		5/19 (26.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/6 (16.7%)		1/6 (16.7%)		4/19 (21.1%)
Back pain	0/6 (0%)		1/6 (16.7%)		4/19 (21.1%)
Pain in extremity	1/6 (16.7%)		1/6 (16.7%)		3/19 (15.8%)
Myalgia	1/6 (16.7%)		1/6 (16.7%)		2/19 (10.5%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour pain	1/6 (16.7%)		2/6 (33.3%)		2/19 (10.5%)
Nervous system disorders
Dizziness	2/6 (33.3%)		0/6 (0%)		4/19 (21.1%)
Headache	0/6 (0%)		1/6 (16.7%)		2/19 (10.5%)
Psychiatric disorders
Insomnia	0/6 (0%)		2/6 (33.3%)		1/19 (5.3%)
Respiratory, thoracic and mediastinal disorders
Cough	1/6 (16.7%)		1/6 (16.7%)		4/19 (21.1%)
Dyspnoea	0/6 (0%)		0/6 (0%)		4/19 (21.1%)
Skin and subcutaneous tissue disorders
Rash	1/6 (16.7%)		2/6 (33.3%)		4/19 (21.1%)
Alopecia	1/6 (16.7%)		0/6 (0%)		1/19 (5.3%)
Erythema	0/6 (0%)		0/6 (0%)		2/19 (10.5%)
Hyperhidrosis	0/6 (0%)		0/6 (0%)		2/19 (10.5%)
Pruritus	1/6 (16.7%)		0/6 (0%)		1/19 (5.3%)
Rash pruritic	0/6 (0%)		1/6 (16.7%)		1/19 (5.3%)

Limitations/Caveats

[Not Specified]

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.