Advanced Gastrointestinal (GI) Malignancies, Colorectal Cancer, Gastric Cancer, Hepatocellular Carcinoma
Conditions
Keywords
argininosuccinate synthetase, arginine, arginine deiminase
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.
Interventions
DRUGADI-PEG 20 plus modified FOLFOX6
Sponsors
Polaris Group
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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 |
| 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 |
| Pharmacodynamics | At week 1, 5, 9, 13, 17, 21 prior to ADI-PEG 20 administration | Blood levels of arginine and citrulline |
Countries
China, Italy, South Korea, Taiwan, United Kingdom, United States
Outcome results
None listed