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

Netherlands Cancer Institute (NKI)

Status and phase

Enrolling

Phase 2

Conditions

Renal Cell Carcinoma

Treatments

Drug: Avelumab

Drug: Axitinib

Study type

Interventional

Funder types

Other

Industry

Identifiers

NCT03341845

N17JAV

Details and patient eligibility

About

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.

Full 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.

Enrollment

40 estimated patients

Sex

All

Ages

18+ years old

Volunteers

No 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