Phase 1/2 Study of Tivozanib in Combination With Nivolumab in Subjects With RCC

NCT03136627 | Completed Phase 1

• 1 other identifier: AV-951-16-119
• Study Type: interventional
• Target: 28
• Locations: 1 country
• Sites: 4

Brief Summary

This study will evaluate the safety, tolerability, dose-limiting toxicities, MTD, and preliminary anti-tumor activity of tivozanib in combination with nivolumab in subjects with metastatic renal cell cancer. This will use a standard '3+3' dose-escalation trial design. A cohort of 3 subjects will be enrolled at each dose level. If 1 of 3 subjects experiences a DLT during Cycle 1, that dose level will be expanded to 6 subjects. If 0 of 3 or ≤ 1 of 6 subjects experience a DLT during Cycle 1, escalation to the next dose will occur. If ≥ 2 of 6 subjects experience a DLT during Cycle 1, dose escalation will stop and the prior dose will be considered the MTD. This is a validated trial design for Phase 1 trials. Following completion of the dose-escalation cohorts and determination of MTD, an expansion cohort of up to 20 subjects may be enrolled at MTD to further evaluate safety, tolerability, and preliminary anti-tumor activity of tivozanib in combination with nivolumab in the same target population.

Conditions

Carcinoma, Renal Cell

Keywords

RCC, Tivozanib, Nivolumab, Metastatic Renal Cell Cancer

Outcome Measures

Primary Outcomes (1)

• Maximum Tolerated Dose (MTD) of tivozanib administered orally in combination with Nivolumab in subjects with advanced renal cell carcinoma.

  A traditional escalation rule, also known as "3 + 3" rule, will be used for this study. Subjects are treated in groups of 3 with each receiving the same dose. If none of the 3 subjects experience a DLT within Cycle 1, the next group of 3 subjects receives the next higher dose, otherwise, the group will expand to 6 subjects treated at the same dose level. If ≤ 1 of the 6 subjects treated at that dose level experience a DLT within Cycle 1, the trial will continue to the next higher dose level. If ≥ 2 of the 6 experience a DLT at the dose level within Cycle 1, then escalation stops at that level and the prior dose level will be considered the MTD. If MTD is not identified and both dose levels are tolerated, 1.5 mg will be considered the recommended Phase II dose (RP2D) for the expansion.

  28 days (1 Cycle)

Secondary Outcomes (1)

• Disease status will be summarized by cycle and dose group, including changes from baseline.

  Every 3 months during the first year [beginning from the date of the last scan performed prior to treatment discontinuation], and every 6 months thereafter (up to 24 months) until disease progression or start of another anti-cancer therapy.

Study Arms (1)

Tivozanib (AV-951) plus Nivolumab

EXPERIMENTAL

Tivozanib plus Nivolumab:Tivozanib will be administered once daily for 3 weeks followed by 1 week off. Nivolumab will be administered every 2 weeks starting on Day 1.

Drug: Tivozanib; Drug: Nivolumab

Interventions

Tivozanib DRUG

Tivozanib (AV-951): Phase 1b study and Phase 2a study: Subjects will receive 1 dose of tivozanib daily for 21 days followed by a 7 day rest period (1 cycle = 4 weeks).

Also known as: AV-951

Tivozanib (AV-951) plus Nivolumab

Nivolumab DRUG

Nivolumab: Phase 1b study and Phase 2a study: All subjects will receive IV nivolumab 240 mg every 2 weeks administered over 1 hour.

Also known as: Opdivo (anti-PD-1 monoclonal antibody)

Tivozanib (AV-951) plus Nivolumab

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
• Histologically or cytologically documented renal cell carcinoma with a clear cell component, except in Phase 1b, where any histology will be permitted
• Metastatic renal cell carcinoma. Measurable or evaluable disease by RECIST 1.1 criteria
• No prior exposure to tivozanib or nivolumab
• ECOG performance status ≤ 1 (see Appendix A) and life expectancy ≥ 3 months.
• Signed and dated written informed consent
• Sexually active pre-menopausal female subjects and female partners of male subjects must use adequate contraceptive measures, while on study and for at least 160 days after the last dose of study drug. Sexually active male subjects must use adequate contraceptive measures, while on study and for at least 160 days after the last dose of study drug. All fertile male and female subjects and their partners must agree to use a highly effective method of contraception. Effective birth control includes (a) intrauterine device (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). Note: Oral, implantable, or injectable contraceptives may be affected by cytochrome P450 interactions, and are not considered effective for this study.

You may not qualify if:

• Pregnant or lactating women.
• Subjects with symptomatic CNS metastases. Subjects with treated brain metastases that have remained stable for at least 3 months without steroids are allowed. Subjects with signs or symptoms or history of brain metastasis must have a CT or MRI scan of the brain within 1 month prior to the start of protocol therapy. Subjects with spinal cord or nerve root compression who have completed treatment at least 4 weeks before the start of protocol therapy and are stable without steroid treatment for at least one week before start of protocol therapy are allowed. Subjects with leptomeningeal metastases are not allowed.
• 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 (\>2.5 mg/dL in patients with Gilbert's syndrome)
• AST or ALT \> 2.5 × ULN (or \> 5 × ULN for subjects with liver metastasis)
• Alkaline phosphatase \> 2.5 × ULN (or \> 5 × ULN for subjects with liver or bone metastasis)
• Serum creatinine \> 1.5 × ULN
• Proteinuria \> 2.5 g/24 hours or 3+ with urine dipstick
• Any other ³ Grade 3 laboratory abnormality at baseline (other than those listed above)
• Significant cardiovascular disease, including:
• Clinically symptomatic heart failure. Subjects with a history of heart failure must have an ECHO or MUGA scan to document left ventricular ejection fraction (LVEF) \> 45% prior to start of protocol therapy

Sponsors & Collaborators

• AVEO Pharmaceuticals, Inc.: lead
• Bristol-Myers Squibb: collaborator

Study Sites (4)

Bordeaux Hospital University Center (CHU)

Bordeaux, France

Location

Center Léon Bérard

Lyon, France

Location

Centre Paul Strauss

Strasbourg, 67065, France

Location

Institut Gustave Roussy

Villejuif, 94805, France

Location

Related Publications (1)

• Albiges L, Barthelemy P, Gross-Goupil M, Negrier S, Needle MN, Escudier B. TiNivo: safety and efficacy of tivozanib-nivolumab combination therapy in patients with metastatic renal cell carcinoma. Ann Oncol. 2021 Jan;32(1):97-102. doi: 10.1016/j.annonc.2020.09.021. Epub 2020 Sep 30.

  PMID: 33010459 DERIVED

MeSH Terms

Conditions

Carcinoma, Renal Cell

Interventions

tivozanib; Nivolumab

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Design

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

Model Details: Tivozanib in Combination with Nivolumab

Study Record Dates

• First Submitted: April 7, 2017
• First Posted: May 2, 2017
• Study Start: March 22, 2017
• Primary Completion: December 21, 2017
• Study Completion: June 18, 2021
• Last Updated: December 6, 2021

Record last verified: 2021-12

Data Sharing

• IPD Sharing: Will not share

Locations

FR (4)