Study of Tivozanib (AV-951) Plus FOLFOX6 in Subjects With Advanced Colorectal Cancer and Other Gastrointestinal Cancers

NCT00660153 | Completed Phase 1

• 1 other identifier: AV-951-103
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 2

Brief Summary

The FOLFOX6 regimen is a standard chemotherapy regimen for the treatment of patients with colorectal cancer and other gastrointestinal cancers. Tivozanib (AV-951) is a targeted anti-angiogenesis agent that has demonstrated acceptable tolerability in a phase I clinical trial. This study is designed to test the hypothesis that tivozanib (AV-951) can be combined with standard FOLFOX6 chemotherapy for the treatment of patients with colorectal and other gastrointestinal cancers. The purpose of this study is to determine the maximum dose of tivozanib (AV-951) that can be safely combined with FOLFOX6 chemotherapy, and to evaluate the safety profile, tolerability, and pharmacokinetics of this combination.

Conditions

Colorectal Cancer; Gastrointestinal Cancer

Keywords

Advanced Colorectal Cancer and Other Gastrointestinal Cancers; tivozanib; AV-951

Outcome Measures

Primary Outcomes (1)

• To determine the safety, tolerability, and maximum tolerated dose of tivozanib (AV-951) in combination with FOLFOX6 chemotherapy.

  • Minimum of 4 weeks for assessment of tolerability, minimum of 8 weeks (2 consecutive dosing cycles) for assessment of anti-tumor activity. Extended therapy may continue for up to 1 year from the subject's start of Cycle 1.

Secondary Outcomes (1)

• To characterize the pharmacokinetic profile of tivozanib (AV-951) and FOLFOX6 chemotherapy when administered together, and to assess the antineoplastic activity of the combination of tivozanib (AV-951) and FOLFOX6 chemotherapy.

  • Minimum of 4 weeks for assessment of tolerability, minimum of 8 weeks (2 consecutive dosing cycles) for assessment of anti-tumor activity. Extended therapy may continue for up to 1 year from the subject's start of Cycle 1.

Study Arms (1)

single arm; multiple cohort

EXPERIMENTAL

Single arm; multiple cohort

Drug: Tivozanib (AV-951) plus FOLFOX6

Interventions

Tivozanib (AV-951) plus FOLFOX6 DRUG

Investigational product, dosage and mode of administration (1 cycle = 4 weeks of treatment): Tivozanib (AV-951): 0.5 mg, 1.0 mg, and 1.5 mg oral once daily On Day -5 (± 2 days) subjects will receive a single dose of tivozanib (AV-951) for pharmacokinetic sampling. Beginning on Day 1 of Cycle 1, subjects will receive tivozanib (AV-951) once daily for 3 weeks followed by 1 week off. Tivozanib (AV-951) dosing repeats every cycle in the absence of disease progression or unacceptable toxicity. On days when both tivozanib (AV-951) and the FOLFOX6 chemotherapy regimen are co-administered, tivozanib (AV-951) will be administered immediately prior to the start of the FOLFOX6 chemotherapy regimen. Subjects will receive FOLFOX6 chemotherapy every 2 weeks starting on Day 1 of Cycle 1. Subjects will receive 2 treatments of FOLFOX6 in each treatment cycle, starting on Day 1 and Day 15.

single arm; multiple cohort

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• ≥ 18-year-old males or females
• Histologically or cytologically confirmed metastatic colorectal cancer or other gastrointestinal malignancy for which FOLFOX6 chemotherapy is a standard treatment. Other gastrointestinal cancers include, but are not limited to, esophageal, gastric, and small intestine, appendiceal, and pancreatico-biliary cancers.
• Documented progressive disease
• Measurable or evaluable disease by RECIST. (Note: Subjects enrolled in the MTD Expansion Cohort are required to have measurable disease, according to RECIST.)
• No more than 2 prior chemotherapy regimens for metastatic disease (This does not include prior adjuvant chemotherapy with fluorouracil and/or oxaliplatin.)
• At least 3 weeks since prior treatment with:
• Chemotherapy (at least 6 weeks for nitrosoureas, mitomycin C, and liposomal doxorubicin)
• Agents targeting the VEGF pathway (eg, bevacizumab, sunitinib, sorafenib, etc.)
• Other signal transduction inhibitors and monoclonal antibodies
• Immunotherapy or biological response modifiers
• Systemic hormonal anti-cancer therapy, with the exception of LHRH agonists for prostate cancer
• Any experimental therapy
• Resolution of toxicities associated with prior chemotherapy to ≤ Grade 1 (except for Grade 2 alopecia)
• ECOG performance status ≤ 2 (see Appendix A) and life expectancy ≥ 3 months
• No childbearing potential or use of effective contraception by all fertile male and female subjects during the study and for 30 days after the last dose of study drug. All subjects must agree to use a highly effective method of contraception (including their partner). Effective birth control includes (a) IUD plus one barrier method; or (b) 2 barrier methods. Effective barrier methods are male or female condoms, diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm). Oral, implantable, or injectable contraceptives may be affected by cytochrome P450 interactions, and are therefore not considered effective for this study.

You may not qualify if:

• Primary CNS malignancies or clinically active CNS metastases
• Hematologic malignancies (includes leukemia in any form, lymphoma, and multiple myeloma)
• Any of the following hematologic abnormalities:
• Hemoglobin \< 9.0 g/dL
• ANC \< 1500 per mm3
• Platelet count \< 100,000 per mm3
• Any of the following serum chemistry abnormalities:
• Total bilirubin \> 1.5 × ULN
• AST or ALT \> 2.5 × ULN (or \> 5 x ULN for subjects with liver metastasis)
• GGT \> 2.5 x ULN (or \> 5 x ULN for subjects with liver metastasis)
• Alkaline Phosphatase \> 2.5 x ULN (or \> 5 x ULN for subjects with liver or bone metastasis)
• Serum albumin \< 3.0 g/dL
• Creatinine \> 1.5 × ULN (or calculated CLCR \<50 mL/min/1.73 m2)
• Proteinuria \> 2.5 g/24 hours or 3+ with urine dipstick
• Any other ≥ Grade 3 laboratory abnormality at baseline (other than those listed above)

Sponsors & Collaborators

• AVEO Pharmaceuticals, Inc.: lead

Study Sites (2)

University Medical Center Groningen; Internal Medicine, Department of Medical Oncology

Groningen, Netherlands

Location

Erasmus Medical Center; Department of Medical Oncology

Rotterdam, Netherlands

Location

Related Publications (1)

• Oldenhuis CN, Loos WJ, Esteves B, van Doorn L, Cotreau MM, Strahs AL, den Hollander MW, Gietema JA, de Vries EG, Eskens FA. A phase Ib study of the VEGF receptor tyrosine kinase inhibitor tivozanib and modified FOLFOX-6 in patients with advanced gastrointestinal malignancies. Clin Colorectal Cancer. 2015 Mar;14(1):18-24.e1. doi: 10.1016/j.clcc.2014.12.001. Epub 2014 Dec 16.

  PMID: 25591799 DERIVED

MeSH Terms

Conditions

Colorectal Neoplasms; Gastrointestinal Neoplasms

Interventions

tivozanib

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Study Officials

• Ferry Eskens, MD, PhD

  Erasmus Medical Center; Department of Medical Oncology

  PRINCIPAL INVESTIGATOR

• E.G.E de Vries, Prof, MD

  University Medical Center Groningen

  PRINCIPAL INVESTIGATOR

• Jaroslow Jac, MD

  AVEO Pharmaceuticals, Inc.

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 15, 2008
• First Posted: April 17, 2008
• Study Start: June 1, 2008
• Primary Completion: June 1, 2012
• Study Completion: June 1, 2012
• Last Updated: August 28, 2012

Record last verified: 2012-08

Locations

NL (2)