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

Colorectal Cancer Clinical Trial

Official title:

Phase 1/2 Study of ADI-PEG 20 Plus FOLFOX in Subjects With Advanced Gastrointestinal Malignancies Focusing on Hepatocellular Carcinoma

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02102022
• Other study ID #: POLARIS2013-001
• Status: Terminated
• Phase: Phase 1/Phase 2
• Start date: November 2014
• Est. completion date: February 2020

Study information

• Verified date: May 2019
• Source: Polaris Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 140
• Est. completion date: February 2020
• Est. primary completion date: February 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Advanced Gastrointestinal (GI) Malignancies
• Carcinoma
• Carcinoma, Hepatocellular
• Colorectal Cancer
• Gastric Cancer
• Hepatocellular Carcinoma
• Neoplasms

Intervention

Drug:
• ADI-PEG 20 plus modified FOLFOX6

Locations

Country	Name	City	State
China	West China Hospital, Sichuan University	Chengdu	Sichuan
China	The Chinese People's Liberation Army 81 Hospital	Nanjing	Jiangsu
Italy	IRCCS Ca Granda Ospedale Maggiore Policlinico	Milano	Lombardia
Italy	National Cancer Institute of Napoli IRCCS G. Pascale	Napoli
Korea, Republic of	Pusan National University Hospital	Busan
Korea, Republic of	Seoul National University Bundang Hospital	Seongnam-si	Gyeonggi-do
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	The Catholic University of Korea, Seoul ST. Mary's Hospital	Seoul
Taiwan	Changhua Christian Hospital	Changhua
Taiwan	Chang Gung Medical Foundation - Kaohsiung	Kaohsiung
Taiwan	Kaohsiung Medical University Chung-Ho Memorial Hospital	Kaohsiung
Taiwan	Chi Mei Hospital, Liouying	Tainan
Taiwan	Chi Mei Medical Center	Tainan
Taiwan	National Cheng Kung University Hospital	Tainan
Taiwan	Mackay Memorial Hospital	Taipei
Taiwan	Taipei Medical University Hospital	Taipei
Taiwan	Taipei Veterans General Hospital	Taipei
Taiwan	Tri-Service General Hospital	Taipei
Taiwan	Chang Gung Medical Foundation - Linkou	Taoyuan
United Kingdom	The Clatterbridge Cancer Centre NHS Foundation Trust	Bebington	Wirral
United Kingdom	Guy's & St Thomas' NHS Foundation Trust	London
United Kingdom	Royal Free Hospital	London
United Kingdom	The Christie NHS Foundation Trust	Manchester
United States	Emory University	Atlanta	Georgia
United States	The University of Chicago Medical Center	Chicago	Illinois
United States	Masonic Cancer Center	Minneapolis	Minnesota
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	UPMC Hillman Cancer Center	Pittsburgh	Pennsylvania
United States	Oregon Health and Science University	Portland	Oregon
United States	Washington University	Saint Louis	Missouri
United States	California Pacific Medical Center	San Francisco	California
United States	University of Washington	Seattle	Washington
United States	The University of Kansas Cancer Center	Westwood	Kansas

Sponsors (1)

Lead Sponsor	Collaborator
Polaris Group

Countries where clinical trial is conducted

United States,  China,  Italy,  Korea, Republic of,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Objective response rate (ORR)	The percent of subjects who exhibit each level of tumor response, measured by RECIST 1.1 criteria as assessed by blinded independent central review.	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	Progression free survival (PFS)	Time from the first dose until objective tumor progression or death from any cause	Date of first study drug administration to the date of disease progression (measured every 8 weeks) or death (whichever occurs first), 12 months anticipated
Secondary	Overall survival (OS)	The time from first treatment with ADI-PEG 20 until death or censoring	Date of first study drug administration through study completion
Secondary	Duration of response (DoR)	the time in weeks between the first occurrence of objective response and the development of progressive disease or death	From date of first response until the date of documented progression or date of death, 12 month in average
Secondary	Disease control rate (DCR)	the proportion of subjects at each post-baseline assessment who exhibit tumor response of complete response, partial response or stable disease	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	Pharmacodynamics	Blood levels of arginine and citrulline	At week 1, 5, 9, 13, 17, 21 prior to ADI-PEG 20 administration
Secondary	Pharmacokinetics Variable	Peripheral blood levels of ADI-PEG 20	At week 1, 5, 9, 13, 17, 21 prior to ADI-PEG 20 administration
Secondary	Immunogenicity	antibodies to ADI-PEG 20	At week 1, 5, 9, 13, 17, 21 prior to ADI-PEG 20 administration
Secondary	AFP (alpha feto-protein) changes	Maximal percent changes of AFP during the course of study compared to AFP at baseline	At baseline, week3, 7, 11, 15, 19, 23 and end of treatment