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Study of ADI-PEG 20 in Patients With Advanced Melanoma

Primary Purpose

Metastatic Melanoma, Skin Cancer, Neoplasm

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

ADI PEG 20

About this trial

This is an interventional treatment trial for Metastatic Melanoma focused on measuring metastatic melanoma, ADI, ADI-PEG 20, ADI SS PEG 20,000mw, arginine, enzyme therapy

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Histologically confirmed malignant melanoma, American Joint Committee on Cancer (AJCC) stage III (unresectable) or IV. Subjects with uveal and mucosal melanomas were eligible.
Measurable disease using the Response Evaluation Criteria in Solid Tumors (RECIST).
Pathology slides reviewed by the Memorial Hospital Department of Pathology or New York University (NYU) Department of Pathology for confirmation of melanoma diagnosis.
Karnofsky performance status of 80% or more.
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
Expected survival of at least 3 months.
Age ≥ 18 years.
Able and willing to give valid written informed consent.

Exclusion Criteria:

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.
Any other malignancy that required concomitant therapy.
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.
Metastatic disease to the central nervous system, unless treated and stable.
Known human immunodeficiency virus (HIV) positivity.
Mental impairment that may have compromised the ability to give informed consent and comply with the requirements of the study.
Lack of availability for clinical follow-up assessments.
Participation in any other clinical trial involving another investigational agent within 3 weeks prior to enrollment.
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.
History of seizure disorder.

Sites / Locations

NYU Cancer Institute
Memorial Sloan-Kettering Cancer Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Arm Label

Cohort 1

Cohort 2

Cohort 3

Arm Description

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

Outcomes

Primary Outcome Measures

Assessment of Safety and Tolerability of ADI-PEG 20

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

Best Overall Clinical Tumor Response

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

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

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

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

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

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

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.

Full Information

NCT ID

NCT00520299

First Posted

August 22, 2007

Last Updated

October 3, 2022

Sponsor

Ludwig Institute for Cancer Research

Collaborators

Memorial Sloan Kettering Cancer Center, NYU Langone Health

1. Study Identification

Unique Protocol Identification Number

NCT00520299

Brief Title

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

2. Study Status

Record Verification Date

October 2022

Overall Recruitment Status

Completed

Study Start Date

July 2007 (undefined)

Primary Completion Date

March 2010 (Actual)

Study Completion Date

March 2010 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Ludwig Institute for Cancer Research

Collaborators

Memorial Sloan Kettering Cancer Center, NYU Langone Health

4. Oversight

Data Monitoring Committee

5. 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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Metastatic Melanoma, Skin Cancer, Neoplasm

Keywords

metastatic melanoma, ADI, ADI-PEG 20, ADI SS PEG 20,000mw, arginine, enzyme therapy

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Sequential Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

31 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Cohort 1

Arm Type

Experimental

Arm Description

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

Arm Title

Cohort 2

Arm Type

Experimental

Arm Description

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

Arm Title

Cohort 3

Arm Type

Experimental

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

ADI PEG 20

Other Intervention Name(s)

ADI-SS PEG 20,000 mw, ADI

Intervention Description

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

Primary Outcome Measure Information:

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

Title

Best Overall Clinical Tumor Response

Description

Time Frame

Every 8 to 9 weeks for up to 12 months

Secondary Outcome Measure Information:

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

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

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

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

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

Title

Correlation Between ASS Tumor Expression and Clinical Response

Description

Time Frame

Up to 12 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Histologically confirmed malignant melanoma, American Joint Committee on Cancer (AJCC) stage III (unresectable) or IV. Subjects with uveal and mucosal melanomas were eligible. Measurable disease using the Response Evaluation Criteria in Solid Tumors (RECIST). Pathology slides reviewed by the Memorial Hospital Department of Pathology or New York University (NYU) Department of Pathology for confirmation of melanoma diagnosis. Karnofsky performance status of 80% or more. 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 Expected survival of at least 3 months. Age ≥ 18 years. Able and willing to give valid written informed consent. Exclusion Criteria: 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. Any other malignancy that required concomitant therapy. 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. Metastatic disease to the central nervous system, unless treated and stable. Known human immunodeficiency virus (HIV) positivity. Mental impairment that may have compromised the ability to give informed consent and comply with the requirements of the study. Lack of availability for clinical follow-up assessments. Participation in any other clinical trial involving another investigational agent within 3 weeks prior to enrollment. 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. History of seizure disorder.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Jedd Wolchok, MD, PhD

Organizational Affiliation

Memorial Sloan Kettering Cancer Center

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Anna Pavlick, DO

Organizational Affiliation

New York University Cancer Institute

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Gary Schwartz, MD

Organizational Affiliation

Memorial Sloan Kettering Cancer Center

Official's Role

Principal Investigator

Facility Information:

Facility Name

NYU Cancer Institute

City

New York

State/Province

New York

ZIP/Postal Code

10016

Country

United States

Facility Name

Memorial Sloan-Kettering Cancer Center

City

New York

State/Province

New York

ZIP/Postal Code

10021

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Yes

Citations:

PubMed Identifier

22864522

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.

Results Reference

result

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Study of ADI-PEG 20 in Patients With Advanced Melanoma

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