Combined Treatment With Dinutuximab Beta, Zoledronic Acid and Low-dose Interleukin (IL-2) in Patients With Metastatic or Inoperable Leiomyosarcoma - DiTuSarc Study
Overview
- Phase
- Phase 2
- Intervention
- Dinutuximab Beta, Zoledronic acid, Interleukin-2
- Conditions
- Leiomyosarcoma
- Sponsor
- Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
- Enrollment
- 7
- Locations
- 2
- Primary Endpoint
- The primary objective of this study is to assess the feasibility of the combined treatment with dinutuximab beta, zoledronic acid and low-dose interleukin 2.
- Status
- Completed
- Last Updated
- 8 months ago
Overview
Brief Summary
Dinutuximab beta was designed to bind to neuroblastoma cells and other cancer cells that express the GD2 antigen, such as STS/LMS cells, and it is believed that this binding "labels" the cells an makes them a better target.
In addition, γδ T cells can safely be expanded in-vivo using intravenous zoledronic acid and subcutaneous interleukin-2 (IL-2) in patients with different types of solid tumors [Dieli et al., 2007; Pressey et al., 2016].
It is supposed that combination treatment using dinutuximab beta, zoledronic acid and IL-2 is more effective than their use in isolation. The already-established safety profiles of these agents make testing of the combination in GD2 positive cancers such as GD2 expressing LMS both rational and feasible [Fisher et al., 2015].
Detailed Description
Soft-tissue sarcomas (STS) are a heterogeneous group of malignancies characterized by both their relatively low incidence and their poor prognosis, encompassing more than 60 distinct diagnoses. Leiomyosarcoma (LMS), together with liposarcoma, is one of the most frequent sub-types amongst STS and accounts for up to 25% of all newly diagnosed STS \[Guo et al., 2015\]. The absence of definite causative risk factors for LMS, whether genetic, epigenetic or environmental, make this disease particularly difficult to understand and difficult to treat. Classically, soft-tissue sarcomas (STS) have been treated as a single disease and with LMS as one of the most frequent sub-types the results with conventional therapies have been rather disappointing, especially in the advanced setting. The use of novel therapeutic approach such immunotherapy has also not yielded the same success compared to other tumor entities, whereas the heterogeneity of this malignancy certainly plays a role. Current immunotherapy trials mostly use monoclonal antibodies to target those molecules or interactions, that essentially "take the brakes off" the immune system. If the underlying immune response however is poor, simply taking the brakes off will be insufficient. In tumors that do not trigger a sufficient immune response, it might be an advantages strategy to try make the tumor a better target and thus trigger a better antitumor immune response. Strategies that incorporate the tumoricidal properties of gammadelta T cells (γδ T cells) represent a promising immunotherapeutic strategy for treatment of solid malignancies including neuroblastoma (NB) \[Dieli et al., 2007\]. An evaluation of pooled data from 132 published in vitro experiments shows a consistent improvement in the cytotoxicity of γδ T cells in the presence of antitumor antibodies. Immunotherapy using γδ T cells alone shows promising clinical activity, but there is a strong preclinical rationale for combining this treatment modality with cancer-targeting antibodies to augment its efficacy \[Fisher et al., 2014\]. Dinutuximab beta was designed to bind to neuroblastoma cells and other cancer cells that express the GD2 antigen, such as STS/LMS cells, and it is believed that this binding "labels" the cells an makes them a better target. In addition, γδ T cells can safely be expanded in-vivo using intravenous zoledronic acid and subcutaneous interleukin-2 (IL-2) in patients with different types of solid tumors \[Dieli et al., 2007; Pressey et al., 2016\]. It is supposed that combination treatment using dinutuximab beta, zoledronic acid and IL-2 is more effective than their use in isolation. The already-established safety profiles of these agents make testing of the combination in GD2 positive cancers such as GD2 expressing LMS both rational and feasible \[Fisher et al., 2015\].
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients must have histologically confirmed leiomyosarcoma.
- •≥ 1 prior systemic therapy for sarcoma, including adjuvant systemic therapy (anthracycline-containing regimen).
- •Patients must have a cryopreserved and formalin-fixed paraffin-embedded tumor sample available for submission to central pathology review.
- •Signed Written Informed Consent.
- •Men and women aged ≥ 18 years.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 to
- •Measurable disease.
- •Locally advanced/unresectable or metastatic disease.
- •No prior therapy with any agent targeting GD
- •Confirmed GD2-Expression proven on cryopreserved tissue tumor samples. A staining score of 2 on cryopreserved tissue is sufficient for enrollment of the patient.
Exclusion Criteria
- •Symptomatic, untreated, or uncontrolled brain metastases present.
- •Patients with a known history of hypersensitivity to interleukin-
- •Patients with a hypersensitivity to zoledronic acid or to other bisphosphonates.
- •Need for invasive dental procedures. Preventive dental exams should be performed before starting zoledronic acid.
- •Patients after allogenic stem cell transplantation or other allogenic organ transplantation (e.g., liver, kidney etc.).
- •Patients with different malignant diseases other than sarcoma (measurable manifestations in the last 12 months or active therapy against the other malignant disease in the last 12 months).
- •Known active pulmonary disease with hypoxia defined as:
- •Oxygen saturation \< 85% on room air or
- •Oxygen saturation \< 88% despite supplemental oxygen.
- •Uncontrolled intercurrent illness including, but not limited to, poorly controlled hypertension or diabetes, ongoing active infection, or psychiatric illness/social situation that may potentially impair the participant's compliance with study procedures.
Arms & Interventions
5 cycles (Q5W) of dinutuximab beta, interleukin-2 and zoledronic acid
5 cycles (Q5W) of dinutuximab beta, 20mg/m2/day, interleukin-2, 5.4x10\^6, and zoledronic acid, 4 mg
Intervention: Dinutuximab Beta, Zoledronic acid, Interleukin-2
Outcomes
Primary Outcomes
The primary objective of this study is to assess the feasibility of the combined treatment with dinutuximab beta, zoledronic acid and low-dose interleukin 2.
Time Frame: 3 years, at EOS
Feasibility rate, defined as the number of patients still on treatment and progression-free at Cycle 4 Day 5 divided by the number of all treated subjects.
Secondary Outcomes
- A secondary objective of this study is to assess the safety and tolerability of the combined treatment with dinutuximab beta, zoledronic acid and low-dose interleukin 2.(3 years, at EOS)
- An additional secondary objective of this study is to assess the efficacy of the combined treatment with dinutuaseximab beta, zoledronic acid and low-dose interleukin 2.(3 years, at EOS)