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Study of ADI-PEG 20 in Patients With Advanced Melanoma

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00520299
First Posted: August 24, 2007
Last Update Posted: May 30, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborators:
Memorial Sloan Kettering Cancer Center
New York University School of Medicine
Information provided by (Responsible Party):
Ludwig Institute for Cancer Research
  Purpose
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 Intervention Phase
Metastatic Melanoma Skin Cancer Neoplasm Drug: ADI PEG 20 Phase 1 Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group 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

Resource links provided by NLM:


Further study details as provided by Ludwig Institute for Cancer Research:

Primary Outcome Measures:
  • Assessment of Safety and Tolerability of ADI-PEG 20 [ Time Frame: 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.

  • Best Overall Clinical Tumor Response [ Time Frame: 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:
  • Metabolic Tumor Response [ Time Frame: 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.

  • Summary of ADI-PEG 20 Plasma Concentrations Over Time [ Time Frame: 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.

  • Summary of Plasma Arginine Levels Over Time [ Time Frame: 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.

  • Summary of Plasma Citrulline Levels Over Time [ Time Frame: 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.

  • Summary of ADI-PEG 20 Immunogenicity Over Time [ Time Frame: 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.

  • Correlation Between ASS Tumor Expression and Clinical Response [ Time Frame: 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.


Enrollment: 31
Study Start Date: July 2007
Study Completion Date: March 2010
Primary Completion Date: March 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 80IU/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

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

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00520299


Locations
United States, New York
NYU Cancer Institute
New York, New York, United States, 10016
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
New York University School of Medicine
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
  More Information

Publications:
Responsible Party: Ludwig Institute for Cancer Research
ClinicalTrials.gov Identifier: NCT00520299     History of Changes
Other Study ID Numbers: LUD2005-007
MSKCC IRB #06-165 ( Other Identifier: MSKCC IRB )
NYU IRB #07-053 ( Other Identifier: NYU School of Medicine IRB )
First Submitted: August 22, 2007
First Posted: August 24, 2007
Results First Submitted: November 30, 2016
Results First Posted: April 26, 2017
Last Update Posted: May 30, 2017
Last Verified: April 2017
Individual Participant Data (IPD) Sharing Statement:
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
Skin Neoplasms
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Neoplasms by Site
Skin Diseases