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Neoadjuvant AXITINIB and AVELUMAB for Patients With Localized Clear-cell RCC

Primary Purpose

Renal Cell Carcinoma

Status

Recruiting

Phase

Phase 2

Locations

Netherlands

Study Type

Interventional

Intervention

Axitinib

Avelumab

About this trial

This is an interventional treatment trial for Renal Cell Carcinoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Signed and written informed consent

Male or female patients age ≥ 18 years
Histologically confirmed diagnosis of non-metastatic clear-cell renal cell carcinoma of intermediate to high risk with completely resectable primary tumours.
World Health Organization performance status of 0-1.
Adequate coagulation function as defined in protocol
Adequate hematological function as defined in protocol
Adequate hepatic function as defined in protocol
Adequate renal function as defined in protocol
Negative serum pregnancy test at screening for women of childbearing potential.
Highly effective contraception for both male and female subjects if the risk of conception exists.

Exclusion Criteria:

Renal tumors of low risk or M1

Non-clear cell histology at biopsy
Clinically significant gastrointestinal abnormalities that may affect absorption of investigational product
Corrected QT interval (QTc) > 480 msecs
History of any of the cardiovascular conditions defined in the protocol within the past 6 months
Poorly controlled hypertension
History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months.
Major surgery or trauma within 28 days prior to first dose of investigational product and/or presence of any non-healing wound, fracture, or ulcer
Evidence of active bleeding or bleeding diathesis.
Any serious and/or unstable pre-existing medical, psychiatric, or other condition that could interfere with subject's safety, provision of informed consent, or compliance to study procedures.
Unable or unwilling to discontinue use of prohibited medications to be listed in protocol for at least 14 days or five half-lives of a drug (whichever is longer) prior to the first dose of study drug and for the duration of the study
Treatment with any of the following anti-cancer therapies: chemotherapy, immunotherapy, biologic therapy, investigational therapy or hormonal therapy within 14 days or five half-lives of a drug (whichever is longer) prior to the first dose of axitinib or avelumab
Administration of any non-oncologic investigational drug within 30 days or 5 half lives whichever is longer prior to receiving the first dose of study treatment
Prior organ transplantation, including allogeneic stem cell transplantation
Significant acute or chronic infections as defined in protocol
Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent
Known severe hypersensitivity reactions to monoclonal antibodies
Pregnancy or lactation
Known alcohol or drug abuse

Sites / Locations

Antoni van LeeuwenhoekRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

axitinib and avelumab

Arm Description

axitinib 5MG BID and avelumab 10mg/kg Q2W

Outcomes

Primary Outcome Measures

number of patients with partial remission

according to RECIST 1.1.

Secondary Outcome Measures

toxicity

measured by number and grade of adverse events

event free survival and overall survival

Time from registration to disease progression or death

Full Information

NCT ID

NCT03341845

First Posted

November 9, 2017

Last Updated

May 18, 2018

Sponsor

The Netherlands Cancer Institute

Collaborators

Pfizer

1. Study Identification

Unique Protocol Identification Number

NCT03341845

Brief Title

Neoadjuvant AXITINIB and AVELUMAB for Patients With Localized Clear-cell RCC

Official Title

Neoadjuvant AXITINIB and AVELUMAB for Patients With Localized Clear-cell RCC and a Moderate to High Risk

Study Type

Interventional

2. Study Status

Record Verification Date

April 2018

Overall Recruitment Status

Recruiting

Study Start Date

March 28, 2018 (Actual)

Primary Completion Date

January 31, 2023 (Anticipated)

Study Completion Date

January 31, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

The Netherlands Cancer Institute

Collaborators

Pfizer

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

a monocenter, open label, single arm, phase II study of the combination of axitinib with avelumab as neoadjuvant therapy in patients with intermediate to high-risk non-metastatic RCC.

Detailed Description

Renal cell carcinoma (RCC) accounts for 3% of adult malignancies and constitutes 95% of renal tumors. Surgical complete resection is currently the only curative treatment of RCC, including patients with locally advanced RCC or limited metastatic disease. However, these patients carry a high risk to develop locally recurrent disease and systemic progression. High risk patients with no evidence of disease following complete resection may therefore benefit from adjuvant and neo-adjuvant systemic treatment strategies which primarily aim to prolong disease free (DFS) and ultimately overall survival (OS). Neoadjuvant studies are a unique opportunity to further investigate the way in which immune checkpoint inhibition works and to identify predictors of treatment response. Recent research on intratumoral immune components after pretreatment of human renal cell carcinoma suggest a potential synergism for TKI with anti-PD-L1 therapy that could be exploited. In terms of downsizing tumours by pretreatment, axitinib has been shown to be more effective than sunitinib when comparing trials that have been performed with each drug. However, the immunemodulatory effect of axitinib has been ill defined. Since axitinib and anti-PD-L1 therapy would make for a potential synergism, two phase Ib dose-finding studies to evaluate safety, pharmacokinetics and pharmacodynamics of avelumab, an anti-PD-L1 monoclonal antibody, or pembrolizumab, an anti-PD1 monoclonal antibody, in combination with axitinib were performed. First results on response rate and safety profile presented at ESMO 2016 were promising with objective response rates of 67-70 % and toxicity profiles as seen with VEGFR-treatment. The investigator proposes a monocenter, open label, single arm, phase II study of the combination of axitinib with avelumab as neoadjuvant therapy in patients with intermediate to high-risk non-metastatic RCC. The statistical calculation of the primary endpoint is based on efficacy on the local tumour. The safety of this combination prior to surgery will be an important secondary endpoint.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Renal Cell Carcinoma

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Model Description

simon's two stage design

Masking

None (Open Label)

Allocation

N/A

Enrollment

40 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

axitinib and avelumab

Arm Type

Experimental

Arm Description

axitinib 5MG BID and avelumab 10mg/kg Q2W

Intervention Type

Drug

Intervention Name(s)

Axitinib

Intervention Description

axitinib in combination with avelumab

Intervention Type

Drug

Intervention Name(s)

Avelumab

Intervention Description

axitinib in combination with avelumab

Primary Outcome Measure Information:

Title

number of patients with partial remission

Description

according to RECIST 1.1.

Time Frame

week 12 of neoadjuvant treatment

Secondary Outcome Measure Information:

Title

toxicity

Description

measured by number and grade of adverse events

Time Frame

up to 90 days after end of treatment

Title

event free survival and overall survival

Description

Time from registration to disease progression or death

Time Frame

assessed up to 10 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Signed and written informed consent Male or female patients age ≥ 18 years Histologically confirmed diagnosis of non-metastatic clear-cell renal cell carcinoma of intermediate to high risk with completely resectable primary tumours. World Health Organization performance status of 0-1. Adequate coagulation function as defined in protocol Adequate hematological function as defined in protocol Adequate hepatic function as defined in protocol Adequate renal function as defined in protocol Negative serum pregnancy test at screening for women of childbearing potential. Highly effective contraception for both male and female subjects if the risk of conception exists. Exclusion Criteria: Renal tumors of low risk or M1 Non-clear cell histology at biopsy Clinically significant gastrointestinal abnormalities that may affect absorption of investigational product Corrected QT interval (QTc) > 480 msecs History of any of the cardiovascular conditions defined in the protocol within the past 6 months Poorly controlled hypertension History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months. Major surgery or trauma within 28 days prior to first dose of investigational product and/or presence of any non-healing wound, fracture, or ulcer Evidence of active bleeding or bleeding diathesis. Any serious and/or unstable pre-existing medical, psychiatric, or other condition that could interfere with subject's safety, provision of informed consent, or compliance to study procedures. Unable or unwilling to discontinue use of prohibited medications to be listed in protocol for at least 14 days or five half-lives of a drug (whichever is longer) prior to the first dose of study drug and for the duration of the study Treatment with any of the following anti-cancer therapies: chemotherapy, immunotherapy, biologic therapy, investigational therapy or hormonal therapy within 14 days or five half-lives of a drug (whichever is longer) prior to the first dose of axitinib or avelumab Administration of any non-oncologic investigational drug within 30 days or 5 half lives whichever is longer prior to receiving the first dose of study treatment Prior organ transplantation, including allogeneic stem cell transplantation Significant acute or chronic infections as defined in protocol Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent Known severe hypersensitivity reactions to monoclonal antibodies Pregnancy or lactation Known alcohol or drug abuse

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Axel Bex, MD

Phone

003120512

Ext

9111

a.bex@nki.nl

First Name & Middle Initial & Last Name or Official Title & Degree

Hans van Thienen, MD

Phone

003120512

Ext

9111

h.v.thienen@nki.nl

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Axel Bex, MD

Organizational Affiliation

NKI-AvL

Official's Role

Principal Investigator

Facility Information:

Facility Name

Antoni van Leeuwenhoek

City

Amsterdam

ZIP/Postal Code

1066CX

Country

Netherlands

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Axel Bex, MD, PhD

Phone

0205129111

a.bex@nki.nl

12. IPD Sharing Statement

Plan to Share IPD

Undecided

IPD Sharing Plan Description

decided by PI at each request for data

Citations:

PubMed Identifier

31023100

Citation

Bex A, van Thienen JV, Schrier M, Graafland N, Kuusk T, Hendricksen K, Lagerveld B, Zondervan P, van Moorselaar JA, Blank C, Wilgenhof S, Haanen J. A Phase II, single-arm trial of neoadjuvant axitinib plus avelumab in patients with localized renal cell carcinoma who are at high risk of relapse after nephrectomy (NEOAVAX). Future Oncol. 2019 Jul;15(19):2203-2209. doi: 10.2217/fon-2019-0111. Epub 2019 Apr 26. Erratum In: Future Oncol. 2019 Aug;15(22):2667.

Results Reference

derived

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Neoadjuvant AXITINIB and AVELUMAB for Patients With Localized Clear-cell RCC

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