Clinical trial NCT02102022: Ph 1-2 Study ADI-PEG 20 Plus FOLFOX in Subjects With Advanced GI Malignancies Focusing on Hepatocellular Carcinoma
Official title: Phase 1/2 Study of ADI-PEG 20 Plus FOLFOX in Subjects With Advanced Gastrointestinal Malignancies Focusing on Hepatocellular Carcinoma
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Advanced Gastrointestinal (GI) Malignancies
Hepatocellular Carcinoma
Gastric Cancer
Colorectal Cancer
Keywords: argininosuccinate synthetase
arginine
arginine deiminase
Lead sponsor: Polaris Group
Sponsor class: INDUSTRY
First posted: 2014-04-02
Enrollment: 140
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Phase 1: Assessment of safety and tolerability of ADI-PEG 20 in combination with folinic acid (leucovorin), fluorouracil and oxaliplatin (FOLFOX) in advanced GI malignancies.

Phase 2: Assessment of the objective response rate (ORR), measured by RECIST 1.1 criteria as assessed by blinded independent central review (BICR).

Detailed description: Phase 1:The primary objective of the dose escalation portion of this study was to assess the safety and tolerability of ADI-PEG 20 in combination with folinic acid (leucovorin), fluorouracil (5-FU), and oxaliplatin (mFOLFOX6) in advanced GI malignancies. The primary objective of the maximum tolerated dose (MTD) expansion phase (recommended phase 2 dose \[RP2D\]) of this study was to determine preliminary estimates of efficacy, measured by RECIST 1.1 criteria, for ADI-PEG 20 in combination with FOLFOX in hepatocellular carcinoma (HCC), gastro-esophageal cancer (GEC), and colorectal cancer (CRC).

Phase 2: The primary objective of this single arm trial is ORR. Based on a two-sided exact test of a one-sample proportion with an alpha of 0.05, under a presumed ORR of 22%, there is 80% power to yield 95% confidence interval of 15-26%, which will require 46 objective responses in 225 subjects. A futility analysis will be described in the Statistical Analysis Plan.

Eligibility criteria: 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.

Primary outcomes:
measure: Objective response rate (ORR)
timeFrame: 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
Secondary outcomes:
measure: Progression free survival (PFS)
timeFrame: Date of first study drug administration to the date of disease progression (measured every 8 weeks) or death (whichever occurs first), 12 months anticipated
measure: Overall survival (OS)
timeFrame: Date of first study drug administration through study completion
measure: Duration of response (DoR)
timeFrame: From date of first response until the date of documented progression or date of death, 12 month in average
measure: Disease control rate (DCR)
timeFrame: 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.
measure: Pharmacodynamics
timeFrame: At week 1, 5, 9, 13, 17, 21 prior to ADI-PEG 20 administration
measure: Pharmacokinetics Variable
timeFrame: At week 1, 5, 9, 13, 17, 21 prior to ADI-PEG 20 administration
measure: Immunogenicity
timeFrame: At week 1, 5, 9, 13, 17, 21 prior to ADI-PEG 20 administration
measure: AFP (alpha feto-protein) changes
timeFrame: At baseline, week3, 7, 11, 15, 19, 23 and end of treatment
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: California Pacific Medical Center
state: California
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Chicago
country: United States
facility: The University of Chicago Medical Center
state: Illinois
city: Westwood
country: United States
facility: The University of Kansas Cancer Center
state: Kansas
city: Minneapolis
country: United States
facility: Masonic Cancer Center
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Pittsburgh
country: United States
facility: UPMC Hillman Cancer Center
state: Pennsylvania
city: Seattle
country: United States
facility: University of Washington
state: Washington
city: Nanjing
country: China
facility: The Chinese People's Liberation Army 81 Hospital
state: Jiangsu
city: Chengdu
country: China
facility: West China Hospital, Sichuan University
state: Sichuan
city: Milano
country: Italy
facility: IRCCS Ca Granda Ospedale Maggiore Policlinico
state: Lombardia
city: Napoli
country: Italy
facility: National Cancer Institute of Napoli IRCCS G. Pascale
city: Seongnam-si
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
state: Gyeonggi-do
city: Busan
country: Korea, Republic of
facility: Pusan National University Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea, Seoul ST. Mary's Hospital
city: Changhua
country: Taiwan
facility: Changhua Christian Hospital
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Medical University Chung-Ho Memorial Hospital
city: Kaohsiung
country: Taiwan
facility: Chang Gung Medical Foundation - Kaohsiung
city: Tainan
country: Taiwan
facility: National Cheng Kung University Hospital
city: Tainan
country: Taiwan
facility: Chi Mei Medical Center
city: Tainan
country: Taiwan
facility: Chi Mei Hospital, Liouying
city: Taipei
country: Taiwan
facility: Mackay Memorial Hospital
city: Taipei
country: Taiwan
facility: Taipei Medical University Hospital
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital
city: Taipei
country: Taiwan
facility: Tri-Service General Hospital
city: Taoyuan
country: Taiwan
facility: Chang Gung Medical Foundation - Linkou
city: Bebington
country: United Kingdom
facility: The Clatterbridge Cancer Centre NHS Foundation Trust
state: Wirral
city: London
country: United Kingdom
facility: Royal Free Hospital
city: London
country: United Kingdom
facility: Guy's & St Thomas' NHS Foundation Trust
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
Study officials:
affiliation: Memorial Sloan-Kettering Cancer Center (MSKCC)
name: James Harding, MD
role: PRINCIPAL_INVESTIGATOR
References: