Treatment With Dinutuximab Beta, Zoledronic Acid and Low-dose Interleukin (IL-2) in Patients With Leiomyosarcoma (DiTuSarc)

  • STATUS
    Recruiting
  • End date
    Jul 26, 2024
  • participants needed
    10
  • sponsor
    Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
Updated on 20 June 2022
platelet count
cancer
systemic therapy
measurable disease
neutrophil count
cancer chemotherapy
immunomodulators
leiomyosarcoma

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].

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].

Details
Condition Leiomyosarcoma
Treatment Dinutuximab Beta, Zoledronic acid, Interleukin-2
Clinical Study IdentifierNCT05080790
SponsorInstitut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
Last Modified on20 June 2022

Eligibility

Yes No Not Sure

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 2
Measurable disease
Locally advanced/unresectable or metastatic disease
No prior therapy with any agent targeting GD2
Confirmed GD2-Expression proven on cryopreserved tissue tumor samples. A staining score of 2 on cryopreserved tissue is sufficient for enrollment of the patient
No treatment with biologic therapy, immunotherapy, chemotherapy, investigational agent for malignancy, or radiation ≤ 21 days before study registration
No participation in another clinical trial in the period 30 days prior to start of first dose
Patients should have resolution of any toxic effects of prior therapy (except alopecia) to NCI CTCAE, version 5.0, grade 1 or less
Not pregnant and not nursing; for women of childbearing potential who are sexually active, a negative pregnancy test (urinary or serum beta-HCG) done ≤ 7 days prior to treatment start is required
Absolute neutrophil count (ANC) ≥ 1,000/mm3
Platelet count ≥ 70,000/mm3
Creatinine ≤ 1.5 x upper limit of normal (ULN) OR calculated (calc.) creatinine clearance > 45 mL/min
Total bilirubin ≤ 1,5 x upper limit of normal (ULN). If total bilirubin is greater than 1,5 x ULN, measure indirect bilirubin to evaluate for Gilbert's syndrome (if direct bilirubin is within normal range, participant may be eligible)
AST/ALT ≤ 2.5 x upper limit of normal (ULN)
Adequate pulmonary function (FEV1 > 2 liters or ≥ 75% of predicted for height and age)
No clinical significant heart failure (NYHA<III) or ejection fraction (echocardiography or scintigraphy; EF > 40%)
Female participants must be postmenopausal (no spontaneous menses for at least 2 years), surgically sterile (have had a hysterectomy or bilateral oophorectomy, tubal ligation, or otherwise be incapable of pregnancy), abstinent (at the discretion of the investigator), or if sexually active, have agreed to use an highly effective contraceptive method for the duration of their study participation (see Appendix 3 for guidance); patients should maintain adequate contraception for a minimum of 2 months after the last dose of dinutuximab beta. Male participants must agree to use an adequate contraception method as deemed appropriate by the investigator (e.g., vasectomy, double-barrier, partner using effective contraception) and to not donate sperm for a minimum of 5 months after treatment discontinuation

Exclusion Criteria

Symptomatic, untreated, or uncontrolled brain metastases present
Patients with a known history of hypersensitivity to interleukin-2
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
Patients who have received prior anti-GD2 therapy, including chimeric antigen receptor (CAR) T cells directed against GD2 antigen
hypertension or diabetes, ongoing active infection, or psychiatric
Lactating females are not eligible unless they have agreed not to breastfeed their infants
illness/social situation that may potentially impair the participant's
Any condition that, in the opinion of the investigator, would compromise the well-being of the participant or the study or prevent the participant from meeting or performing study requirements
compliance with study procedures
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