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

Phase 1

Terminated

• Conditions: Gastric Cancer; Colorectal Cancer; Advanced Gastrointestinal (GI) Malignancies; Hepatocellular Carcinoma
• Interventions: Drug: ADI-PEG 20 plus modified FOLFOX6

• Registration Number: NCT02102022
• Lead Sponsor: Polaris Group

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.

Study Timeline

• Study First Submitted: 2014-03-28
• Study First Submitted QC: 2014-03-28
• Study First Posted: 2014-04-02
• Study Start: 2014-11
• Status Verified: 2019-05
• Primary Completion: 2020-02
• Study Completion: 2020-02
• Last Update Submitted: 2022-04-18
• Last Update Posted: 2022-04-25

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 140

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
ADI-PEG 20 plus modified FOLFOX6	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

Primary Outcome Measures

Name	Time	Method
Objective response rate (ORR)	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

Name	Time	Method
Progression free survival (PFS)	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
Overall survival (OS)	Date of first study drug administration through study completion	The time from first treatment with ADI-PEG 20 until death or censoring
Duration of response (DoR)	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
Disease control rate (DCR)	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
Pharmacodynamics	At week 1, 5, 9, 13, 17, 21 prior to ADI-PEG 20 administration	Blood levels of arginine and citrulline
Pharmacokinetics Variable	At week 1, 5, 9, 13, 17, 21 prior to ADI-PEG 20 administration	Peripheral blood levels of ADI-PEG 20
Immunogenicity	At week 1, 5, 9, 13, 17, 21 prior to ADI-PEG 20 administration	antibodies to ADI-PEG 20
AFP (alpha feto-protein) changes	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

Trial Locations

Locations (35)

Memorial Sloan-Kettering Cancer Center; 🇺🇸 New York, New York, United States

Kaohsiung Medical University Chung-Ho Memorial Hospital; 🇨🇳 Kaohsiung, Taiwan

Chang Gung Medical Foundation - Kaohsiung; 🇨🇳 Kaohsiung, Taiwan

National Cheng Kung University Hospital; 🇨🇳 Tainan, Taiwan

Chi Mei Medical Center; 🇨🇳 Tainan, Taiwan

Mackay Memorial Hospital; 🇨🇳 Taipei, Taiwan

Taipei Medical University Hospital; 🇨🇳 Taipei, Taiwan

Chang Gung Medical Foundation - Linkou; 🇨🇳 Taoyuan, Taiwan

The Clatterbridge Cancer Centre NHS Foundation Trust; 🇬🇧 Bebington, Wirral, United Kingdom

Tri-Service General Hospital; 🇨🇳 Taipei, Taiwan

Masonic Cancer Center; 🇺🇸 Minneapolis, Minnesota, United States

Changhua Christian Hospital; 🇨🇳 Changhua, Taiwan

The Catholic University of Korea, Seoul ST. Mary's Hospital; 🇰🇷 Seoul, Korea, Republic of

Samsung Medical Center; 🇰🇷 Seoul, Korea, Republic of

California Pacific Medical Center; 🇺🇸 San Francisco, California, United States

Emory University; 🇺🇸 Atlanta, Georgia, United States

The University of Kansas Cancer Center; 🇺🇸 Westwood, Kansas, United States

Royal Free Hospital; 🇬🇧 London, United Kingdom

The Christie NHS Foundation Trust; 🇬🇧 Manchester, United Kingdom

Oregon Health and Science University; 🇺🇸 Portland, Oregon, United States

UPMC Hillman Cancer Center; 🇺🇸 Pittsburgh, Pennsylvania, United States

West China Hospital, Sichuan University; 🇨🇳 Chengdu, Sichuan, China

Guy's & St Thomas' NHS Foundation Trust; 🇬🇧 London, United Kingdom

Pusan National University Hospital; 🇰🇷 Busan, Korea, Republic of

National Cancer Institute of Napoli IRCCS G. Pascale; 🇮🇹 Napoli, Italy

The Chinese People's Liberation Army 81 Hospital; 🇨🇳 Nanjing, Jiangsu, China

Seoul National University Hospital; 🇰🇷 Seoul, Korea, Republic of

Asan Medical Center; 🇰🇷 Seoul, Korea, Republic of

The University of Chicago Medical Center; 🇺🇸 Chicago, Illinois, United States

Washington University; 🇺🇸 Saint Louis, Missouri, United States

University of Washington; 🇺🇸 Seattle, Washington, United States

IRCCS Ca Granda Ospedale Maggiore Policlinico; 🇮🇹 Milano, Lombardia, Italy

Seoul National University Bundang Hospital; 🇰🇷 Seongnam-si, Gyeonggi-do, Korea, Republic of

Chi Mei Hospital, Liouying; 🇨🇳 Tainan, Taiwan

Taipei Veterans General Hospital; 🇨🇳 Taipei, Taiwan