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

NCT02086721 | Completed Phase 1

• 1 other identifier: L19-IL2
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

Brief 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

Outcome Measures

Primary Outcomes (1)

• Toxicity (CTCAE 4.0)

  three months

Secondary Outcomes (7)

• Progression-Free survival

  3 months

• Local control rate

  3 months

• non-invasive response evaluation using PET

  3 months

• Quality of life

  3 months

• Correlation of outcome measures with PET-imaging

  3 months

Study Arms (1)

Oligometastatic cancer patients; N=18

EXPERIMENTAL

Drug: L19-IL2

Interventions

L19-IL2 DRUG

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.

Oligometastatic cancer patients; N=18

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histological or cytological confirmed oligometastatic originating from NSCLC, HNSCC, CRC, RCC and melanoma occurring synchronous (at time of diagnosis) or metachronous (\> 6 months after radical treatment for primary tumor; i.e., surgically. A biopsy could be omitted in selected cases if a biopsy is medically contraindicated or unfeasable (e.g. fear of ent-metastasis, lesion not accessible). In this case the diagnosis of metastatic disease should be certified using an alternative approach (e.g. imaging..)
• determination of possible activating mutations (e.g., ALK/EGFR/ROS in NSCLC, and BRAF, NRAS and KIT in melanoma);
• All oligometastatic tumor sites (including brain) are eligible;
• ≤ 5 metastases, or 4 if the primary tumor is to be treated concomitantly;
• ≤ 3 metastatic lesions confined to one organ;
• ≤ 2 organ systems affected with metastases;
• WHO performance status 0-2;
• Adequate bone marrow: Normal white blood cell count and formula, normal platelet count, no anemia requiring blood transfusion or erythropoietin;
• Adequate hepatic function: total bilirubin ≤ 1.5 x upper limit of normal (ULN) for the institution; ALT, AST, and alkaline phosphatase ≤ 2.5 x ULN for the institution);
• Adequate renal function: calculated creatinine clearance at least 60 ml/min;
• The patient is capable of complying with study procedures;
• Signed and dated written informed consent;
• Life expectancy of at least 12 weeks;
• For women of childbearing potential, a negative pregnancy test prior to the first dose of study treatment;
• Men and women with reproductive potential must be willing to practice acceptable methods of birth control during the study and for up to 12 weeks after the last dose of study medication.

You may not qualify if:

• Other oligometastatic (hormone-sensitive) solid tumors;
• Previous radiotherapy to an area that would be re-treated by SABR;
• Previous systemic treatment to treat recurrent disease;
• Other active malignancy or malignancy within the last 2 years (with exception of localized skin basal/squamous cell carcinoma, bladder in situ carcinoma);
• History of allergy to intravenously administered proteins/peptides/antibodies;
• HIV infection, active infection, or active hepatitis;
• Chronic use of corticosteroids used in the management of cancer or non-cancer-related illness;
• Acute or sub-acute coronary syndromes within the last year, accute inflammatory heart disease, heart insufficiency or irreversible cardiac arrhythmias;
• Impaired cardiac function defined as left ventricular ejection fraction (LVEF) \<50% (or below the study site's lower limit of normal) as measured by MUGA of ECHO. (LVEF measurements dating back up to 8 weeks will be acceptable in the absence of intercurrent use of potentially cardiotoxic treatment of cardiac medical history
• Uncontrolled hypertensive disease
• History or evidence of active autoimmune disease;
• Severe diabetic retinopathy (38);
• Major trauma including surgery within 4 weeks prior to entering the study;
• Any underlying medical or psychiatric condition which in the opinion of the investigator will make administration of study drug hazardous or hinder the interpretation of study results (e.g., AE);
• Unstable or serious concurrent uncontrolled medical conditions;

Sponsors & Collaborators

• Maastricht Radiation Oncology: lead

Study Sites (1)

MAASTRO clinic

Maastricht, Limburg, 6229 ET, Netherlands

Location

MeSH Terms

Interventions

L19-IL2 immunocytokine

Study Officials

• Philippe Lambin, MD, PhD.

  MAASTR clinic

  PRINCIPAL INVESTIGATOR

Study Design

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

Study Record Dates

• First Submitted: September 3, 2013
• First Posted: March 13, 2014
• Study Start: December 1, 2015
• Primary Completion: May 1, 2017
• Study Completion: May 1, 2017
• Last Updated: May 31, 2017

Record last verified: 2017-05

Locations

NL (1)