Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Rare Diseases

Melanoma

Skin Neoplasms

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Diseases

Neuroendocrine Tumor

Neuroepithelioma

Amino Acids

All Drugs and Chemicals

Arginine

Subjects received ADI-PEG 20 at a dose of 40 IU/m\^2

Subjects received ADI-PEG 20 at a dose of 80 IU/m\^2

Subjects received ADI-PEG 20 at a dose of 160 IU/m\^2

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

ADI PEG 20

Jedd Wolchok, MD, PhD

Anna Pavlick, DO

Gary Schwartz, MD

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.

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 of ADI-PEG 20 in Patients With Advanced Melanoma

Phase 1/2 Study of ADI-SS PEG 20,000mw in Patients With Advanced Melanoma

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

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.

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

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

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

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

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.

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.

Memorial Sloan Kettering Cancer Center

NYU Langone Health

Ludwig Institute for Cancer Research

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

Includes subjects who received 40 IU/m\^2/week of ADI-PEG 20

Cohort 1: ADI-PEG 20 40 IU/m^2/Week

Includes subjects who received 80 IU/m\^2/week of ADI-PEG 20

Cohort 2: ADI-PEG 20 80 IU/m^2/Week

Includes subjects who received 160 IU/m\^2/week of ADI-PEG 20

Cohort 3: ADI-PEG 20 160 IU/m^2/Week

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

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Negative

≤5% positive

Not done

Argininosuccinate synthetase (ASS) tumor expression, as determined by immunohistochemistry, is categorized as either negative or ≤ 5% positive tumor cells.

ASS Assay Result

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

Jonathan Skipper PhD

Any TEAE

Grade 3 TEAE

Grade 4 TEAE

Grade 5 TEAE (Death)

Treatment-related TEAE

TEAE leading to withdrawal

Assessment of Safety and Tolerability of ADI-PEG 20

Complete/partial response

Stable disease

Progressive disease

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

Best Overall Clinical Tumor Response

Cycle 1 Day 4: Partial metabolic response

Cycle 1 Day 4: Stable metabolic disease

Cycle 1 Day 4: Progressive metabolic disease

Cycle 1 Day 4: Missing

Cycle 1 Day 50: Partial metabolic response

Cycle 1 Day 50: Stable metabolic disease

Cycle 1 Day 50: Progressive metabolic disease

Cycle 1 Day 50: Missing

Metabolic Tumor Response

Day 0

Day 4

Day 8

Day 15

Day 22

Day 29

Day 36

Day 43

Day 50

Day 57

Day 64

Day 71

Day 78

Day 85

Day 92

Day 99

Day 106

Day 113

Day 120

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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Study of ADI-PEG 20 in Patients With Advanced Melanoma	NCT00520299	Metastatic Mela... Skin Cancer Neoplasm	ADI PEG 20	18 Years -	Ludwig Institute for Cancer Research
Study of ADI-PEG 20 in Patients With Advanced Melanoma	NCT00520299	Metastatic Mela... Skin Cancer Neoplasm	ADI PEG 20	18 Years -	Ludwig Institute for Cancer Research

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