Clinical trial NCT00520299: Study of ADI-PEG 20 in Patients With Advanced Melanoma
Official title: Phase 1/2 Study of ADI-SS PEG 20,000mw in Patients With Advanced Melanoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Metastatic Melanoma
Skin Cancer
Neoplasm
Keywords: metastatic melanoma
ADI
ADI-PEG 20
ADI SS PEG 20,000mw
arginine
enzyme therapy
Lead sponsor: Ludwig Institute for Cancer Research
Sponsor class: OTHER
Collaborators: name: Memorial Sloan Kettering Cancer Center
name: NYU Langone Health
First posted: 2007-08-24
Enrollment: 31
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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
6. Expected survival of at least 3 months.
7. Age ≥ 18 years.
8. 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.

Primary outcomes:
measure: Assessment of Safety and Tolerability of ADI-PEG 20
timeFrame: Every 1 to 2 weeks for up to 12 months
measure: Best Overall Clinical Tumor Response
timeFrame: Every 8 to 9 weeks for up to 12 months
Secondary outcomes:
measure: Metabolic Tumor Response
timeFrame: Every 8 to 9 weeks for up to 12 months
measure: Summary of ADI-PEG 20 Plasma Concentrations Over Time
timeFrame: Up to 12 months
measure: Summary of Plasma Arginine Levels Over Time
timeFrame: Up to 9 months
measure: Summary of Plasma Citrulline Levels Over Time
timeFrame: Up to 9 months
measure: Summary of ADI-PEG 20 Immunogenicity Over Time
timeFrame: Up to 12 months
measure: Correlation Between ASS Tumor Expression and Clinical Response
timeFrame: Up to 12 months
Other outcomes:
Locations:
city: New York
country: United States
facility: NYU Cancer Institute
state: New York
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
Study officials:
affiliation: Memorial Sloan Kettering Cancer Center
name: Jedd Wolchok, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: New York University Cancer Institute
name: Anna Pavlick, DO
role: PRINCIPAL_INVESTIGATOR
affiliation: Memorial Sloan Kettering Cancer Center
name: Gary Schwartz, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ott PA, Carvajal RD, Pandit-Taskar N, Jungbluth AA, Hoffman EW, Wu BW, Bomalaski JS, Venhaus R, Pan L, Old LJ, Pavlick AC, Wolchok JD. Phase I/II study of pegylated arginine deiminase (ADI-PEG 20) in patients with advanced melanoma. Invest New Drugs. 2013 Apr;31(2):425-34. doi: 10.1007/s10637-012-9862-2. Epub 2012 Aug 5.