Neoplasms

Symptoms and General Pathology

All Conditions

Skin and Connective Tissue Diseases

Rare Diseases

Neoplasm Metastasis

Sarcoma

Sarcoma, Ewing

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Osteosarcoma

Neoplasms, Bone Tissue

Neoplasms, Connective Tissue

Soft Tissue Sarcoma

Ewing Sarcoma

Antineoplastic Agents

All Drugs and Chemicals

Bone Density Conservation Agents

Melphalan

Busulfan

Zoledronic Acid

Treosulfan

Diphosphonates

Alkylating Agents

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Standard Risk R1: in a randomised trial, to examine whether add-on treatment with zoledronic acid in addition to induction and maintenance chemotherapy improves event-free survival in patients with localised Ewing sarcoma and good histological response or with initial tumour volume \<200 mL compared to no add-on treatment.

High Risk R2: in a randomised trial, to examine whether high-dose chemotherapy using busulfan-melphalan with autologous stem cell reinfusion, compared with standard chemotherapy, improves event-free survival in patients with localised Ewing sarcoma and poor histological response or tumour volume ≥200 mL (R2loc). In patients with pulmonary metastases high dose busulfan-melphalan chemotherapy with autologous stem cell reinfusion is randomised versus standard chemotherapy plus whole lung irradiation (R2pulm).

Very High Risk R3: in a randomised trial, to examine whether the addition of high dose chemotherapy using treosulfan-melphalan followed by autologous stem cell reinfusion to eight cycles of standard adjuvant chemotherapy, compared to eight cycles of standard adjuvant chemotherapy alone, improves event-free survival in patients with primary disseminated disease.

intravenously at 28 day intervals beginning with cycle 6 of VAC/VAI consolidation chemotherapy for a total period of nine months.

Patients \< 18 years will receive 0.05 mg/kg BW by IV infusion 30 min-1 h.

Patients \>= 18 years will receive a bodyweight-dependent dose:

Patients \>40kg receive 4 mg by IV infusion 30 min-1h Patients 20-40 kg receive 2 mg by IV infusion 30 min-1h

Zoledronic acid

intravenously, day -6 to d -3 adults: 0.8 mg/kg body weight (BW) children and adolescents: \<9 kg= 1mg/kg BW 9 - \<16 kg= 1.2 mg/kg BW 16 - 23 kg= 1.1 mg/kg BW \>23 - 34 kg= 0.95 mg/kg BW \>34 kg = 0.8 mg/kg BW

Uta Dirksen, Prof MD

Alan W Craft, Prof Sir MD

Heribert Jürgens, Prof MD

Ewing Sarcoma

Primary objectives:

Standard Risk R1: in a randomised trial, to examine whether add-on treatment with zoledronic acid in addition to induction and maintenance chemotherapy improves event-free survival in patients with localised Ewing sarcoma and good histological response or with initial tumour volume \<200 mL compared to no add-on treatment.

\*High Risk R2: in a randomised trial, to examine whether high-dose chemotherapy using busulfan-melphalan with autologous stem cell reinfusion, compared with standard chemotherapy, improves event-free survival in patients with localised Ewing sarcoma and poor histological response or tumour volume ≥200 mL (R2loc). In patients with pulmonary metastases high dose busulfan-melphalan chemotherapy with autologous stem cell reinfusion is randomised versus standard chemotherapy plus whole lung irradiation (R2pulm).

Very High Risk R3: in a randomised trial, to examine whether the addition of high dose chemotherapy using treosulfan-melphalan followed by autologous stem cell reinfusion to eight cycles of standard adjuvant chemotherapy, compared to eight cycles of standard adjuvant chemotherapy alone, improves event-free survival in patients with primary disseminated disease.

\*R2 accrual discontinued on December 1st 2015.

EWING 2008 is a joint protocol of European and North American Ewing sarcoma study groups. The protocol is aimed at optimising treatment and treatment results of patients with Ewing sarcomas. The EWING 2008 protocol is open to all patients diagnosed with Ewing sarcomas, localised or metastatic, who are considered eligible for neoadjuvant chemotherapy. All patients registered will receive induction chemotherapy consisting of six cycles of vincristine, ifosfamide, doxorubicin and etoposide (VIDE). The decision regarding local therapy must be made following the fifth cycle of induction treatment, with a preference for surgical intervention with or without additional radiotherapy. Preoperative radiotherapy may be considered to improve the operability of otherwise inoperable lesions. In patients with localised disease or with pulmonary metastases, local treatment should be performed following the 6th cycle of VIDE chemotherapy, and should be a complete tumour resection, whenever feasible. Post-operative radiotherapy is determined by the completeness of surgery and the histological response to chemotherapy.

Standard Risk R1 Good responders (R1) (\< 10% viable tumour cells) with localised disease are allocated to the standard risk arm and will receive a further eight cycles of chemotherapy composed of vincristine, actinomycin D, and cyclophosphamide (VAC) (females) or ifosfamide instead of cyclophosphamide (VAI) (males). They will be randomised to receive add-on treatment with either fenretinide, zoledronic acid, fenretinide plus zoledronic acid, or no add-on treatment.

High Risk R2 \*Poor responders (R2) with localised disease will continue to be randomised as in EURO-E.W.I.N.G. 99 to receive either eight cycles of VAI chemotherapy or high dose treatment with busulfan-melphalan (R2loc).

Patients with primary pulmonary metastases are also allocated to continue to be randomised as in EURO-E.W.I.N.G. 99 to receive either eight cycles of VAI chemotherapy or high dose treatment with busulfan-melphalan (R2pulm).

Very High Risk R3 Patients with disseminated disease, i.e. dissemination to bone and/or other sites and possibly additional pulmonary dissemination (R3), receive six cycles of VIDE induction chemotherapy. Patients are then randomised to either continue with eight cycles of vincristine, actinomycin D and cyclophosphamide (VAC) chemotherapy or high dose treosulfan-melphalan (TreoMel) chemotherapy followed by autologous stem cell reinfusion followed thereafter by eight cycles of VAC chemotherapy. Local therapy in R3 patients is following VIDE induction, whenever feasible prior to high dose therapy (HDT). When long periods of immobilisation following surgery are anticipated, e.g pelvic reconstruction, surgery following HDT may be advisable. Depending on clinical response to induction chemotherapy radiotherapy prior to HDT and surgery may be an option to be considered in such patients. Any delay between VIDE and HDT for reasons of e.g. local treatment must be bridged with VAC cycles. The total number of VAC cycles is not to exceed eight cycles.

\*R2 accrual discontinued on December 1st 2015.

Study in Localized and Disseminated Ewing Sarcoma

Phase 3, Open Label, Multi-centre, Randomised Controlled International Study in Ewing Sarcoma

University Hospital Muenster

Breast Neoplasms

Breast Diseases

Skin Diseases

Gastrointestinal Agents

Denosumab

Sorbitol

Dosage: 120 mg, monthly for total of 6 months, then every 12 weeks for 2 doses, for a total treatment course of one year

Route of administration: subcutaneous injection

Formulation of Dosage forms

The vial presentations of denosumab contain 60 mg/mL denosumab, 17 mM sodium acetate, and 4.7% (w/v) sorbitol, at a pH of 5.2, filled to a target deliverable volume of 1.0 mL; or 70 mg/mL denosumab, 18 mM sodium acetate and 4.6% (w/v) sorbitol, at a pH of 5.2, filled to a target deliverable volume of 1.7 mL. The prefilled syringe (PFS) drug product contains denosumab at 60 mg/mL, 17 mM sodium acetate, 4.7% (w/v) sorbitol, and 0.01% (w/v) polysorbate 20, at a pH of 5.2, filled to a target deliverable volume of 1.0 mL.

Dosage: 120 mg, monthly for total of 6 months, then every 12 weeks for 2 doses, for a total treatment course of one year

Route of administration: subcutaneous injection

Hope Rugo, MD

The purpose of this study is to see whether taking denosumab for 12 months in women with a significant number of disseminated tumor cells in the bone marrow can reduce the number of these cells below a significant level.

The presence of disseminated tumor cells (DTC) in the bone marrow in women with early stage breast cancer is an important prognostic factor associated with an increase in both recurrence and disease-associated death. In a pooled analysis of 4703 invasive breast cancer patients, detection of DTC in the bone marrow was associated with an increase in disease recurrence, distant metastases, and death from breast cancer over a median follow-up period of 5.2 years. Subsequent studies have demonstrated that the presence of DTC in the bone marrow of women with early breast cancer following completion of adjuvant therapy have an even greater impact on the risk of recurrence and death from breast cancer. Multivariate analysis demonstrated that the presence of marrow cells was an independent prognostic factor for reduced breast cancer specific survival with a relative risk of 6.3 (2.3-17.6, p\<0.0001). Clearly, the detection of DTC in women with early stage breast cancer is a marker for increased risk of relapse and death, and this could serve as a unique indicator to select higher risk patients for intervention with targeted therapeutics.

It has long been recognized that there is close relationship between bone and immune system, recent studies also suggests that in addition to monocytes/macrophage, T cells (especially Th17, a subset of T helper cells that produces IL-17), B cells and dendritic cells all play an important role in osteoclast formation. RANKL, in addition to its effect on osteoclasts, also induces local inflammation. Several recent studies have demonstrated that the presence of tumor associate macrophages (TAM) is associated with more aggressive disease, and a worse outcome. Preclinical data suggests that TAM plays an important role in promoting metastases and resistance to therapy. In addition to RANKL, there are other genes secreted by breast cancer cells, including TGF-β, TNF associated factor 6 (TRAF6), Hypoxia Induced Factor -1 (HIF-1) and Bone morphogenetic protein 2 (BMP2), also involve in bone-cancer "vicious cycle" and induce RANKL expression. Cytokines, such as IL-4, IL-6, IL-17, TNF-α and CSF-1, also play an important role in osteolysis and immune response in bone microenvironment by regulating TAM function (CSF-1, IL-4 and IL-17) and RANKL expression. Recently, CD47 and Signal Regulatory Protein α (SIRPA) were also shown to impair macrophage function, and associated with increased risk for recurrence in patients with breast cancer. The investigators hypothesize that patients with higher DTC may have higher expression of RANKL and chronic inflammatory cytokines. The investigators plan to evaluate the expression of RANK, RANKL, TRAF6, BMP2, CSF-1, CD47, IL-17 and SIRPA on isolated DTC and bone marrow hematopoietic cells, and correlate these results to the outcome of patients enrolled in the trial.

The investigators hypothesize that treatment with denosumab will decrease the number of DTC in women with early stage breast cancer who have completed adjuvant or neoadjuvant cytotoxic therapy possibly by preventing cancer cell migration, and by promoting cancer cell death by changing the bone into a "hostile" environment .

The investigators propose to conduct a non-randomized phase II trial testing this hypothesis in women with early stage breast cancer and persistent DTC following adjuvant systemic therapy. Patients with DTC will receive denosumab monthly for 6 months, then every 3 months for a total of one-year treatment, to mirror the schedule utilized in the ongoing randomized phase III denosumab versus placebo D-CARE trial. DTC will be monitored following 6 months and 12 months of therapy. The investigators anticipate that this treatment will reverse the "vicious cycle" between bone and cancer cells.

Pilot Study to Evaluate the Impact of Denosumab on Disseminated Tumor Cells (DTC) in Patients With Early Stage Breast Cancer

Reduction of disseminated tumor cells (DTC)/ mililitre (ml) from \>10DTC/ml to ≤ 10DTC/ml. DTC measured by IE/FC in patients with early stage

Changes from baseline in disseminated tumor cell counts

Correlate breast cancer recurrence risk with individual values for DTC at each time point

University of California, San Francisco

Amgen

Clinical professor

Patients will be treated with denosumab at a dose of 120 mg by subcutaneous injection monthly(-3/+3 days) for total of 6 months, then every 12 weeks (-7/+7 days) for 2 doses, for a total treatment course of one year.

Treatment

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Study terminated early due to low accrual

Low accrual resulted in insufficient data to power statistical analyses for this outcome

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study in Localized and Disseminated Ewing Sarcoma	NCT00987636	Ewing's Sarcoma	Zoledronic acid Busulfan Treosulfan	48 Months - 50 Years	University Hospital Muenster
Study in Localized and Disseminated Ewing Sarcoma	NCT00987636	Ewing's Sarcoma	Zoledronic acid Busulfan Treosulfan	48 Months - 50 Years	University Hospital Muenster
Pilot Study to Evaluate the Impact of Denosumab on Disseminated Tumor Cells (DTC) in Patients With Early Stage Breast Cancer	NCT01545648	Early Stage Bre...	Denosumab	18 Years -	University of California, San Francisco
Pilot Study to Evaluate the Impact of Denosumab on Disseminated Tumor Cells (DTC) in Patients With Early Stage Breast Cancer	NCT01545648	Early Stage Bre...	Denosumab	18 Years -	University of California, San Francisco

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