Carcinoma, Renal CellPhase 1/2NCT03136627

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

A Phase 1/2 study testing Tivozanib and Nivolumab in people with Carcinoma, Renal Cell, run by AVEO Pharmaceuticals, Inc. at 4 sites in France.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

Who is it for?: Ages 18 years and older
Conditions the study is for: Carcinoma, Renal Cell
What is being tested?: Tivozanib and Nivolumab
Type of treatment: Injection or infusion
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 28 participants
Where: 4 sitesFrance
Study dates: 22 Mar 2017to 18 Jun 2021
Phase: Phase 1/2
Are there results?: None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 years and older
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

≥ 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.

Who cannot join

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

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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
Uncontrolled hypertension: blood pressure >150/95 mmHg on more than 2 antihypertensive medications, on two consecutive measurements obtained at least 24 hours apart. Subjects with a history of hypertension must have been on stable doses of anti-hypertensive drugs for ≥ 2 weeks prior to start of protocol therapy.
Myocardial infarction within 3 months prior to start of protocol therapy
Subjects with delayed healing of wounds, ulcers, and/or bone fractures
Serious/active infection or infection requiring parenteral antibiotics
Inadequate recovery from any prior surgical procedure; major surgical procedure within 4 weeks prior to start of protocol therapy.
Inability to comply with protocol requirements
Subjects with a "currently active" second primary malignancy other than non-melanoma skin cancers. Subjects are not considered to have a "currently active" malignancy if they have completed anti-cancer therapy and have been disease free for > 2 years.
Known concomitant genetic or acquired immune suppression disease such as HIV
Treatment with systemic hormonal therapy within 3 weeks prior to start of protocol therapy, with the exception of:
Hormonal therapy for appetite stimulation or contraception
Nasal, ophthalmic, inhaled and topical steroid preparations
Oral replacement therapy for adrenal insufficiency
Low-dose maintenance steroid therapy (equivalent of prednisone 10mg/day) for other conditions
Hormone replacement therapy
Herbal preparations/supplements (except for a daily multivitamin/mineral supplement not containing herbal components) or CYP3A4 inhibitors or inducers (see Appendix B) within 2 weeks prior to start of or during protocol therapy.

Trial locations and contacts

4 sites in 1 country.

France4 sites

Bordeaux Hospital University Center (CHU)
Bordeaux
Center Léon Bérard
Lyon
Centre Paul Strauss
Strasbourg, 67065
Institut Gustave Roussy
Villejuif, 94805

Other trials in France

About this study

Official title: A Phase 1b/2, Open-Label, Multi-Center Study of Tivozanib in Combination With Nivolumab in Subjects With Metastatic Renal Cell Carcinoma

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.

Read the detailed description

Tivozanib hydrochloride (tivozanib; previously known as AV-951 and as KRN951) has the chemical name (N-{2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-N'-(5-methyl-3-isoxazolyl)urea hydrochloride monohydrate. Tivozanib is a novel and potent vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor (VEGFR TKI) that has demonstrated significant anti-tumor effects in pre clinical experiments [1]. Tivozanib inhibits phosphorylation of VEGF receptors (VEGFR) -1, -2 and -3 at picomolar concentrations (IC50 of 0.21, 0.16 and 0.24 nM respectively), and inhibits c-Kit and platelet derived growth factor receptor (PDGFR) at 10-times higher concentrations (IC50 of 1.63 and 1.72 nM respectively).

Based on its biochemical profile, tivozanib appears to be one of the most potent and selective VEGF tyrosine kinase inhibitor in clinical development. Other agents used for treatment of renal cell carcinoma (RCC) such as sunitinib and sorafenib inhibit multiple tyrosine kinases in addition to the VEGF receptor tyrosine kinase, leading to off-target toxicities such as fatigue, hand-foot syndrome, stomatitis, and neutropenia. The adverse event (AE) profile of tivozanib demonstrates that it is a selective VEGF tyrosine kinase inhibitor, with reduced off-target toxicities.

Nivolumab is a fully human IgG4 programmed death 1 (PD-1) immune checkpoint inhibitor antibody that selectively blocks the interaction between PD-1, which is expressed on activated T cells, and PD-1 ligand 1 (PD-L1) and 2 (PD-L2) which are expressed on immune cells and tumor cells. Interaction between PD-1 and PD-L1 or PD-L2 normally results in the inhibition of the cellular immune response. Nivolumab has shown activity in renal cell carcinoma. [2]

This study is designed to test the hypothesis that tivozanib can be combined with nivolumab for the treatment of patients with renal cell carcinoma. The purpose of the study is to determine the maximum dose of tivozanib that can be safely combined with nivolumab, and to evaluate the safety profile and tolerability of this combination. Given the different mechanisms of action and a lack of overlapping toxicities this combination may provide an alternative therapy to patients with renal cell carcinoma.

Conditions: Carcinoma, Renal Cell
Being tested: Tivozanib, Nivolumab
Keywords: RCC, Tivozanib, Nivolumab, Metastatic Renal Cell Cancer
Medical subject headings: Carcinoma, Renal Cell

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

TivozanibDrug
Also called AV-951
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).
NivolumabDrug
Also called Opdivo (anti-PD-1 monoclonal antibody)
Nivolumab: Phase 1b study and Phase 2a study: All subjects will receive IV nivolumab 240 mg every 2 weeks administered over 1 hour.

Study groups in NCT03136627
Study group	Role	What they receive
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. Receives: Drug: Tivozanib; Drug: Nivolumab

What is being measured

The primary outcome is the main question the study is designed to answer.

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.
Measured: 28 days (1 Cycle)

Secondary outcomes (1)

Disease status will be summarized by cycle and dose group, including changes from baseline.
Upon determination of MTD, up to 20 additional subjects with measurable disease will be enrolled in the MTD Expansion Cohort for an expanded assessment of safety and activity.
Measured: 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.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

22 Mar 201718 Jun 2021

First posted2 May 2017
Study start22 Mar 2017
Primary completion21 Dec 2017
Study completion18 Jun 2021

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Publications (1)Papers the sponsor has linked to this study.
Other trials for Carcinoma, Renal CellStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 1/2
Primary purpose: Treatment
Allocation: Not applicable
Intervention model: Single group
Model description: Tivozanib in Combination with Nivolumab
Masking: None (open label)
Enrolment: 28 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT03136627
Sponsor's protocol ID: AV-951-16-119
Status last verified: Dec 2021
First submitted: 7 Apr 2017
Last updated: 6 Dec 2021
Results posted: No
Data monitoring committee: No
FDA-regulated drug: No
FDA-regulated device: No
Individual data sharing: No

Publications

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.
PubMed 33010459

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

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Study at a glance

From the registry record, last updated by the sponsor on 6 Dec 2021. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: A Phase 1b/2, Open-Label, Multi-Center Study of Tivozanib in Combination With Nivolumab in Subjects With Metastatic Renal Cell Carcinoma
ClinicalTrials.gov ID: NCT03136627
Acronym / sponsor ID: AV-951-16-119
Conditions: Carcinoma, Renal Cell
Keywords: RCC, Tivozanib, Nivolumab, Metastatic Renal Cell Cancer
Phase: Phase 1/2
Study type: Interventional
Recruitment status: Completed
Enrolment: 28 participants (actual)
Lead sponsor: AVEO Pharmaceuticals, Inc.Industry (pharma, biotech, devices)
Collaborators: Bristol-Myers Squibb
Study start: 22 Mar 2017 (actual)
Primary completion: 21 Dec 2017 (actual)
Study completion: 18 Jun 2021 (actual)
First posted: 2 May 2017 (actual)
Results: Not posted in the source record

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Study design

Primary purpose: Treatment
Allocation: Not applicable
Intervention model: Single group
Masking: None (open label)
Number of arms: 1
Model description: Tivozanib in Combination with Nivolumab

Arm	Type	Receives
Tivozanib (AV-951) plus Nivolumab	Experimental	Drug: Tivozanib, Drug: NivolumabTivozanib 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.

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (7 listed)

≥ 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.

Key exclusion criteria (30 listed)

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:
Any of the following serum chemistry abnormalities:
Significant cardiovascular disease, including:

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
TivozanibAlso: AV-951Tivozanib (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).	Drug	Tivozanib (AV-951) plus Nivolumab
NivolumabAlso: Opdivo (anti-PD-1 monoclonal antibody)Nivolumab: Phase 1b study and Phase 2a study: All subjects will receive IV nivolumab 240 mg every 2 weeks administered over 1 hour.	Drug	Tivozanib (AV-951) plus Nivolumab

Primary outcome

Maximum Tolerated Dose (MTD) of tivozanib administered orally in combination with Nivolumab in subjects with advanced renal cell carcinoma.
Time frame: 28 days (1 Cycle)
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.

1 secondary outcome

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

Results and safety

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 6 Dec 2021.
Derived from this study: PubMed 33010459Albiges 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.
Individual participant dataSharing planned: No

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A Study of Belzutifan (MK-6482) in Combination With Lenvatinib Versus Cabozantinib for Treatment of Renal Cell Carcinoma (MK-6482-011)
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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

The record lists no contact. Use the official record to reach the sponsor.

4 sites in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Tivozanib and Nivolumab in people with Carcinoma, Renal Cell, run by AVEO Pharmaceuticals, Inc. at 4 sites in France.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 30 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 6 Dec 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 4 sites in France. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Maximum Tolerated Dose (MTD) of tivozanib administered orally in combination with Nivolumab in subjects with advanced renal cell carcinoma. (time frame: 28 days (1 Cycle)). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03136627, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Dec 2021.