Phase I Clinical Study Combining L19-IL2 With SABR in Patients With Oligometastatic Solid Tumor

Summary

The formation of metastasis is responsible for as much as 90% of cancer-associated mortality. In spite of recent advances in oncologic therapy, approximately 50 % of the lung cancer patients have already overt disseminated cancer at diagnosis. Additionally, numerous patients with locoregional disease initially treated with curative intent develop (oligo)metastases during the course of disease. In both instances, these stage IV patients are generally considered to be incurable and mostly treated palliatively.

Oligometastases, defined as 1-5 sites of active disease on whole body imaging, was coined to refer to isolated sites of metastasis resembling limited tumor metastatic capacity. The implication of this concept is that local cancer treatments are curative in a proportion of patients with metastases and that incorporating local therapy is a conceptually attractive approach. In several, but not all, academic centers the standard treatment of patients with oligometastases in good general health is standard chemotherapy followed by surgery or by Stereotactic Ablative Body Radiotherapy (SABR) with radical dose on the macroscopic visible tumors.

The widespread introduction of SABR and of minimally invasive surgery has fuelled research in treating patients with oligometastases. Indeed, local control of metastases can be obtained in virtually all parts of the body with a low proportion of patients experiencing severe side effects. In the few prospective studies published to date, approximately 20% of patients remained free of recurrence several years after treatment when all sites of disease were targeted by radiation.

Along with standard anti-cancer therapeutic modalities like chemotherapy and radiotherapy (RT), immunotherapy has recently gained a lot of attention.

Angiogenesis is one of the hallmarks of cancer, and therefore, considerable efforts have been made to exploit this unique target for selective drug delivery. One of the appealing targets for both approaches is the splice variant of fibronectin containing extra domain B (EDB), which is abundantly expressed in vascular endothelial cells of a variety of primary tumors as well as metastases , but virtually absent in normal tissues. Recently, a human recombinant scFv fragment directed against EDB, designated L19, was developed and subsequently combined with the pro-inflammatory interleukin-2 (IL2), resulting in the immunocytokine L19-IL2. L19-IL2 delivers high doses of IL2 to the (metastatic) tumor site(s) exploiting the selective expression of EDB on newly formed blood vessels. Interleukin-2 (IL2) plays an essential role in the activation phases of both specific and natural immune responses. Even though it has no direct cytotoxic effects on cancer cells, it can induce tumor regression by stimulating a potent cell-mediated response. In summary, L19-IL2 is an immunocytokine which will stimulate immune response specifically in tumors with angiogenesis and tissue remodeling.

Radiotherapy is a particularly interesting partner for immunotherapy, since it can be harnessed to specifically modify the immunogenicity of the primary tumors and their microenvironment, in the attempt to generate an in situ immunization of the host against a patient's own cancer. Our hypothesis is that three independent therapeutic approaches will synergize to improve dramatically survival in patients with oligometastases of solid tumors.

Conditions

• Solid Tumour

Interventions

DRUG

L19-IL2

Patients receive a schedule of 1 x 30 Gy, 3 x 15-20 Gy; 5 x 12 Gy; 8 x 7.5 Gy; to the 80 % or 100 % isodose. Step -1: Toxicity of 10 Mio IU of L19-IL2 (n=3-6)10 Mio IU of L19-IL2 (max. 6 cycles) via i.v. bolus injection. Toxicity scored at every i.v. drug administration and on day 7, 14 and 21. Step 1: Toxicity of 15 Mio IU of L19-IL2 (n=3-6)(max. 6 cycles) via i.v. bolus injection. Step 2: Toxicity of 22.5 Mio IU of L19-IL2 (n=3-6)(max. 6 cycles) via i.v. bolus injection. Toxicity scored at every i.v. drug administration and on day 7, 14 and 21 of the cycle. Step 3: Expansion cohort of the maximally tolerable dose (n=10) Administration of the maximally tolerable dose of L19-IL2(max. 6 cycles) via i.v. bolus injection. Toxicity scored at every i.v. drug administration and on day 7, 14 and 21 of the cycle.

Sponsors & Collaborators

• Maastricht Radiation Oncology

  lead OTHER

Principal Investigators

• Philippe Lambin, MD, PhD. · MAASTR clinic

Study Design

Allocation

NA

Purpose

TREATMENT

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2015-12-31

Primary Completion

2017-05-31

Completion

2017-05-31

Countries

• Netherlands

Study Locations