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

Sponsor

Polaris Group (Industry)

Overall Status

Terminated

CT.gov ID

NCT02102022

Collaborator

(none)

140

Enrollment

Locations

Arm

Duration (Months)

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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).

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

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 Design

Study Type:

Interventional

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 :

Nov 1, 2014

Actual Primary Completion Date :

Feb 1, 2020

Actual Study Completion Date :

Feb 1, 2020

Arms and Interventions

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 Other Names: pegargiminase

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

Other Names:

pegargiminase

Outcome Measures

Primary Outcome Measures

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

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Phase 2 HCC Subjects:

Inclusion Criteria:

Advanced histologically or cytologically proven HCC (except with prior liver transplantation).
Treatment with at least 2 prior systemic therapy regimens.
Child-Pugh grade A. Child-Pugh status should be determined based on clinical findings and laboratory data during the screening period (Appendix C).
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.
ECOG performance status of 0 - 1.
Expected survival of at least 3 months.
Age ≥ 18 years.
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.
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.
Informed consent must be obtained prior to study initiation.
No concurrent investigational studies are allowed.
Total bilirubin < 1.5 x upper limit of normal range.
Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5 x upper limit of normal range.
Absolute neutrophil count (ANC) > 1500/μL.
Platelets > 75,000/μL.
Serum uric acid ≤ 8 mg/dL (with or without medication control).
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).
Brain metastases are allowed if well controlled and without seizures.
Serum albumin level ≥ 2.8 g/dL.
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.
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:

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.
Pregnancy or lactation.
Expected non-compliance.
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.
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.
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.
Subjects who had been treated with ADI-PEG 20 previously.
History of seizure disorder not related to underlying cancer.
Known HIV positivity (testing not required).
Known allergy to pegylated compounds.
Known allergy to E. coli drug products (such as GMCSF).
Known allergy to oxaliplatin or other platinum compounds.
Prior grade 2 or higher neuropathy from prior platinum unless neuropathy is currently ≤ grade 1.
Contraindications to fluorouracil
Subjects with poor nutritional state.
Known depressed bone marrow function.
Subjects with potentially serious infections.
Known allergy to fluorouracil.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	California Pacific Medical Center	San Francisco	California	United States	94115
2	Emory University	Atlanta	Georgia	United States	30322
3	The University of Chicago Medical Center	Chicago	Illinois	United States	60637
4	The University of Kansas Cancer Center	Westwood	Kansas	United States	66205
5	Masonic Cancer Center	Minneapolis	Minnesota	United States	55455
6	Washington University	Saint Louis	Missouri	United States	63110
7	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10065
8	Oregon Health and Science University	Portland	Oregon	United States	97239
9	UPMC Hillman Cancer Center	Pittsburgh	Pennsylvania	United States	15232
10	University of Washington	Seattle	Washington	United States	98109
11	The Chinese People's Liberation Army 81 Hospital	Nanjing	Jiangsu	China	210000
12	West China Hospital, Sichuan University	Chengdu	Sichuan	China	610000
13	IRCCS Ca Granda Ospedale Maggiore Policlinico	Milano	Lombardia	Italy	20122
14	National Cancer Institute of Napoli IRCCS G. Pascale	Napoli		Italy	80131
15	Seoul National University Bundang Hospital	Seongnam-si	Gyeonggi-do	Korea, Republic of	13620
16	Pusan National University Hospital	Busan		Korea, Republic of	49241
17	Seoul National University Hospital	Seoul		Korea, Republic of	03080
18	Asan Medical Center	Seoul		Korea, Republic of	05505
19	Samsung Medical Center	Seoul		Korea, Republic of	06351
20	The Catholic University of Korea, Seoul ST. Mary's Hospital	Seoul		Korea, Republic of	06591
21	Changhua Christian Hospital	Changhua		Taiwan	500
22	Kaohsiung Medical University Chung-Ho Memorial Hospital	Kaohsiung		Taiwan	807
23	Chang Gung Medical Foundation - Kaohsiung	Kaohsiung		Taiwan	833
24	National Cheng Kung University Hospital	Tainan		Taiwan	704
25	Chi Mei Medical Center	Tainan		Taiwan	71004
26	Chi Mei Hospital, Liouying	Tainan		Taiwan	73657
27	Mackay Memorial Hospital	Taipei		Taiwan	10491
28	Taipei Medical University Hospital	Taipei		Taiwan	11031
29	Taipei Veterans General Hospital	Taipei		Taiwan
30	Tri-Service General Hospital	Taipei		Taiwan
31	Chang Gung Medical Foundation - Linkou	Taoyuan		Taiwan
32	The Clatterbridge Cancer Centre NHS Foundation Trust	Bebington	Wirral	United Kingdom	CH63 4JY
33	Royal Free Hospital	London		United Kingdom	NW3 2QG
34	Guy's & St Thomas' NHS Foundation Trust	London		United Kingdom	SE1 9RT
35	The Christie NHS Foundation Trust	Manchester		United Kingdom	M20 4BX