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Ph 1-2 Study ADI-PEG 20 Plus FOLFOX in Subjects With Advanced GI Malignancies Focusing on Hepatocellular Carcinoma

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. Identifier: NCT02102022
Recruitment Status : Terminated
First Posted : April 2, 2014
Last Update Posted : March 9, 2021
Information provided by (Responsible Party):
Polaris Group

Brief Summary:
Assessment of safety and tolerability of ADI-PEG 20 in combination with folinic acid (leucovorin), fluorouracil and oxaliplatin (FOLFOX) in advanced GI malignancies.

Condition or disease Intervention/treatment Phase
Advanced Gastrointestinal (GI) Malignancies Hepatocellular Carcinoma Gastric Cancer Colorectal Cancer Drug: ADI-PEG 20 plus modified FOLFOX6 Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 140 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1/2 Study of ADI-PEG 20 Plus FOLFOX in Subjects With Advanced Gastrointestinal Malignancies Focusing on Hepatocellular Carcinoma
Study Start Date : November 2014
Actual Primary Completion Date : February 2020
Actual Study Completion Date : February 2020

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: ADI-PEG 20 plus modified FOLFOX6

Dose: 36 mg/m2 given weekly

Route of Administration: Intramuscular (IM)

In combination with modified FOLFOX6, every 2 weeks, intravenous (IV) / IV bolus

Drug: ADI-PEG 20 plus modified FOLFOX6

Primary Outcome Measures :
  1. Objective response rate (ORR) [ Time Frame: Date of first study drug administration to the date of disease progression (measured every 8 weeks) or death (whichever occurs first), up to 24 months ]
    The percent of subjects who exhibit each level of tumor response, measured by RECIST 1.1 criteria as assessed by blinded independent central review.

Secondary Outcome Measures :
  1. Progression free survival (PFS) [ Time Frame: Date of first study drug administration to the date of disease progression (measured every 8 weeks) or death (whichever occurs first), 12 months anticipated ]
    Time from the first dose until objective tumor progression or death from any cause

  2. Overall survival (OS) [ Time Frame: Date of first study drug administration through study completion ]
    The time from first treatment with ADI-PEG 20 until death or censoring

  3. Duration of response (DoR) [ Time Frame: From date of first response until the date of documented progression or date of death, 12 month in average ]
    the time in weeks between the first occurrence of objective response and the development of progressive disease or death

  4. Disease control rate (DCR) [ Time Frame: Date of first study drug administration to the date of disease progression (measured every 8 weeks) or death (whichever occurs first), up to 24 months. ]
    the proportion of subjects at each post-baseline assessment who exhibit tumor response of complete response, partial response or stable disease

  5. Pharmacodynamics [ Time Frame: At week 1, 5, 9, 13, 17, 21 prior to ADI-PEG 20 administration ]
    Blood levels of arginine and citrulline

  6. Pharmacokinetics Variable [ Time Frame: At week 1, 5, 9, 13, 17, 21 prior to ADI-PEG 20 administration ]
    Peripheral blood levels of ADI-PEG 20

  7. Immunogenicity [ Time Frame: At week 1, 5, 9, 13, 17, 21 prior to ADI-PEG 20 administration ]
    antibodies to ADI-PEG 20

  8. AFP (alpha feto-protein) changes [ Time Frame: At baseline, week3, 7, 11, 15, 19, 23 and end of treatment ]
    Maximal percent changes of AFP during the course of study compared to AFP at baseline

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Phase 2 HCC Subjects:

Inclusion Criteria:

  1. Advanced histologically or cytologically proven HCC (except with prior liver transplantation).
  2. Treatment with at least 2 prior systemic therapy regimens.
  3. Child-Pugh grade A. Child-Pugh status should be determined based on clinical findings and laboratory data during the screening period (Appendix C).
  4. Measurable disease using RECIST 1.1 criteria (Appendix A). At least 1 measurable lesion must be present. Subjects who have received local-regional therapies are eligible, provided that they have either a target lesion which has not been treated with local therapy and/or the target lesion(s) within the field of the local regional therapy has shown an increase of ≥ 20% in size. Local-regional therapy must be completed at least 4 weeks prior to the baseline CT scan.
  5. ECOG performance status of 0 - 1.
  6. Expected survival of at least 3 months.
  7. Age ≥ 18 years.
  8. Fully recovered from any prior surgery and no major surgery within 4 weeks of initiating treatment. Surgery or procedure for placement of vascular access devices is exempt from this period.
  9. Subjects must agree to use at least one form of highly effective contraception or agree to refrain from intercourse for the duration of the study. Contraceptive use must be continued until at least 30 days after the last administration of ADI-PEG 20 and at least 90 days after the last administration of FOLFOX. For female subjects, a serum human chorionic gonadotropin (HCG) pregnancy test must be negative before entry into the study. If HCG pregnancy test is positive, further evaluation to rule out pregnancy must be performed according to GCP before this patient is claimed eligible.
  10. Informed consent must be obtained prior to study initiation.
  11. No concurrent investigational studies are allowed.
  12. Total bilirubin < 1.5 x upper limit of normal range.
  13. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5 x upper limit of normal range.
  14. Absolute neutrophil count (ANC) > 1500/μL.
  15. Platelets > 75,000/μL.
  16. Serum uric acid ≤ 8 mg/dL (with or without medication control).
  17. Serum creatinine ≤ 1.5 x the upper limit of normal range, or, if serum creatinine >1.5 x the upper limit of normal range, then the creatinine clearance must be ≥ 60 mL/min/1.73 m2 (calculated using the Jelliffe equation: calculated creatinine clearance = 98 - 0.8 [age (yrs.) - 20] /serum creatinine (x 0.9 if female).
  18. Brain metastases are allowed if well controlled and without seizures.
  19. Serum albumin level ≥ 2.8 g/dL.
  20. Prothrombin time (PT)-international normalized ratio (INR): PT <6 seconds above control or INR <1.7. Subjects on Coumadin anti-coagulants are to receive only 1 point for their INR status.
  21. Subjects with active hepatitis B or C on anti-viremic compounds may remain on such treatment, except for interferon.

Exclusion Criteria:

A subject will not be eligible for study participation if he/she meets any of the exclusion criteria:

  1. Serious infection requiring treatment with systemically administered antibiotics at the time of study entrance, or an infection requiring systemic antibiotic therapy within 7 days prior to the first dose of study treatment.
  2. Pregnancy or lactation.
  3. Expected non-compliance.
  4. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure (New York Heart Association Class III or IV), cardiac arrhythmia, or psychiatric illness.
  5. Subjects who have had any anticancer treatment prior to entering the study and have not recovered to baseline (except alopecia) or ≤ Grade 1 AEs, or deemed irreversible from the effects of prior cancer therapy. AEs > Grade 1 that are not considered a safety risk by the Sponsor and investigator may be allowed upon agreement with both.
  6. Subjects with history of another primary cancer, including co-existent second malignancy, with the exception of: a) curatively resected non-melanoma skin cancer; b) curatively treated cervical carcinoma in situ; or c) other primary solid tumor with no known active disease present or in the opinion of the investigator will not affect patient outcome.
  7. Subjects who had been treated with ADI-PEG 20 previously.
  8. History of seizure disorder not related to underlying cancer.
  9. Known HIV positivity (testing not required).
  10. Known allergy to pegylated compounds.
  11. Known allergy to E. coli drug products (such as GMCSF).
  12. Known allergy to oxaliplatin or other platinum compounds.
  13. Prior grade 2 or higher neuropathy from prior platinum unless neuropathy is currently ≤ grade 1.
  14. Contraindications to fluorouracil

    1. Subjects with poor nutritional state.
    2. Known depressed bone marrow function.
    3. Subjects with potentially serious infections.
    4. Known allergy to fluorouracil.

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 identifier (NCT number): NCT02102022

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Sponsors and Collaborators
Polaris Group
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Principal Investigator: James Harding, MD Memorial Sloan-Kettering Cancer Center (MSKCC)
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Responsible Party: Polaris Group Identifier: NCT02102022    
Other Study ID Numbers: POLARIS2013-001
First Posted: April 2, 2014    Key Record Dates
Last Update Posted: March 9, 2021
Last Verified: May 2019

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Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Polaris Group:
argininosuccinate synthetase
arginine deiminase
Additional relevant MeSH terms:
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Carcinoma, Hepatocellular
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Neoplasms
Liver Diseases