Introduction
Main Biological Characteristics of Bone Sarcomas
Main Clinical Characteristics of Bone Sarcomas
Tumour type | Ratio male/female | Frequencya
| Peak of incidence (years) | Principal localisations | Survival rate |
---|---|---|---|---|---|
Osteosarcoma | 1.4 | 0.2–0.3/100,000/year (general population) 08–1.1/100,000/year at age 15–19 | Main peak: 18 Secondary peak: 60 | Metaphysis of long bones Distal end of femur + proximal end tibia/fibula (60%) | 60–70% after 5 years 30% after 5 years (with lung metastases) |
Ewing sarcoma | 1.5 | 0.3/100,000/year | 15 | Flat bones (60%) Metaphysis of long bones (40%) and soft tissues | 66% at 5 years and 20% at 5 years for poor responders |
Chondrosarcoma | 1 | 0.2/100,000/year | 45 | Pelvic bone, femur, proximal humerus, scapula | 50–60% at 10 years according the histological grade |
Etiology of Bone Sarcomas: The Microenvironment as the Driver of Cancer Progression
Recent Therapeutic Developments
Drug | Reference | Title | Phase | Experimental plan | Primary outcome | Patients | Status |
---|---|---|---|---|---|---|---|
Temozolomide Irinotecan Vincristine Adriamycin Ifosfamide Etoposide Cyclofosfamide Busulfan Melfalan Celecoxib | NCT02727387 | Study with high doses of chemotherapy, radiotherapy and consolidation therapy With cyclofosfamide and anti-cyclooxygenase 2, for the metastatic Ewing sarcoma | II | Two cycles of temozolomide (500 mg/m2) + irinotecan (250 mg/m2) and two cycles of vincristine (1.4 mg/m2) + adriamycin (90 mg/m2) + Ifosfamide (9 g/m2) alternes with two cycles of cyclofosfamide (4 g/m2) + etoposide (600 mg/m2) followed by radiotherapy (42–54 Gy) and two cycles of Ifosfamide (9 g/m2) + etoposide (300 mg/m2) alternes with to two cycles of vincristine (1.4 mg/m2) + adriamycin (80 mg/m2) + cyclofosfamide (1.2 g/m2) and busulfan (0.8–1.2 mg/kg) + melfalan (140 mg/m2) + PBSCT and 6 months with celecoxib cyclofosfamide | Overall survival Event-free survival | 70 | Recruiting End: 2020 |
Cyclophosphamide Doxorubicin Vincristine Ifosfamide Etoposide Temozolomide Irinotecan | NCT01864109 | A phase II trial of irinotecan and temozolomide in combination with existing high dose alkylator based chemotherapy for treatment of patients with newly diagnosed Ewing sarcoma | II | Patients with localised disease: six cycles of the combination as “maintenance” therapy following standard chemotherapy
Cycles 4–6 including Ifosfamide 2800 mg/m2/day on days 1–5 Etoposide 100 mg/m2/day on days 1–5
Cycle 7 including: Cyclophosphamide on days 1 and 2 at a dose of 2100 mg/m2/day, or for patients < 10 years of age at a dose of 70 mg/kg/day Doxorubicin on days 1 and 2 at a dose of 37.5 mg/m2/day Vincristine on day 1 at a dose of 2 mg/m2 or 0.067 mg/kg (whichever is lower, to a max dose of 2 mg)
Cycles 8–13 including: Irinotecan i.v. on 10 days over weeks 1 and 2 of a cycle at a dose of 20 mg/m2/day Temozolomide daily on the first 5 days of irinotecan administration at a dose of 100 mg/m2/day p.o. or i.v. Patients with metastatic disease: ten cycles of the combination intercalated between the final 4 cycles of standard chemotherapy
Cycles 4, 5, 7, 8, 10, 11, 13, 14, 16 and 17: Irinotecan i.v. on 10 days over weeks 1 and 2 of a cycle at a dose of 20 mg/m2/day Temozolomide daily on the first 5 days of irinotecan 100 mg/m2/day p.o. or i.v.
Cycles 6, 9 and 12
Ifosfamide 2800 mg/m2/day on days 1–5 Etoposide 100 mg/m2/day on days 1–5
Cycle 15: Cyclophosphamide on days 1 and 2 at a dose of 2100 mg/m2/day, or for patients < 10 years of age at a dose of 70 mg/kg/day Doxorubicin on days 1 and 2 at a dose of 37.5 mg/m2/day Vincristine will be given on day 1 at a dose of 2 mg/m2 or 0.067 mg/kg (whichever is lower, to a max dose of 2 mg) | Event-free survival of patients with localised disease Progressive disease according to RECIST 1.1 | 83 | Recruiting End: 2019 |
Zoledronic acid Buslphan Treosulfan | NCT00987636 | Study in localized and disseminated Ewing sarcoma (EWING2008) | III | Zoledronic acid i.v. at 28-day intervals beginning with cycle 6 of VAC/VAI consolidation chemotherapy for a total period of 9 months
Patients < 18 years: 0.05 mg/kg by i.v. infusion 30 min− 1 h
Patients > 18 years will receive a bodyweight-dependent dose: Patients > 40 kg receive 4 mg by i.v. infusion 30 min–1 h. Patients 20–40 kg: 2 mg by i.v. infusion 30 min to 1 h | Improvement of event-free survival compared to the absence of bisphosphonate | 1163 | Recruiting End: 2019 |
Olaparib (PARP inhibitor) Temozolomide Irinotecan | NCT01858168 | Phase I Study of olaparib and temozolomide in adult patients with recurrent/metastatic Ewing sarcoma following failure of prior chemotherapy | I | Arm 1: olaparib, p.o. twice per day on days 1–7 (week 1) of each cycle Temozolomide, p.o. once per day on days 1–7 (week 1) of each cycle irinotecan, given by i.v. once per day on days 1–7 of each cycle Arm 2: olaparib p.o. twice per day on days 1–7 (week 1) of each cycle Temozolomide, p.o. once per day on days 1–7 (week 1) of each cycle | Maximum tolerated dose | 93 | Recruiting End: 2019 |
Niraparib (PARP inhibitor) Irinotecan Temozolomide | NCT02044120 | ESP1/SARC025 global collaboration: a phase I study of a combination of the PARP inhibitor, niraparib and temozolomide or irinotecan in patients with previously treated, incurable Ewing sarcoma | I | Up to 12 cycles of niraparib and temozolomide (Arm 1) or niraparib and irinotecan (Arm 2) | Maximum tolerated dose Dose-limiting toxicity | 50 | Recruiting End: 2019 |
Pbi-shRNA™ EWS/FLI1 Type 1 LPX | NCT02736565 | Phase I trial of Pbi-shRNA™ EWS/FLI1 type 1 lipoplex (LPX) in subjects with advanced Ewing sarcoma | I | Escalation cohorts up to a dose of 0.156 mg/kg of DNA/single dose (i.v. twice a week for 4 weeks for a total of eight infusions of the product per cycle followed by 2 weeks of rest) | Safety | 22 | Recruiting End: 2018 |
TK216 Inhibitor of protein–protein interactions of EWS–FLI1 fusion protein | NCT02657005 | A phase 1, dose escalation study of intravenous TK216 in patients with relapsed or refractory Ewing sarcoma | I | Dose escalation | Maximum tolerated dose Determination of the dose-limiting toxicity | 45 | Recruiting End: 2018 |
Temozolomide Irinotecan Vigil | NCT02511132 | A two-part phase IIb trial of Vigil (Bi-shRNAfurin and GMCSF augmented autologous tumor Cell Immunotherapy) in Ewing’s sarcoma | IIb | Temozolomide p.o. 100 mg/m2 daily (days 1–5, total dose 500 mg/m2/cycle) Irinotecan p.o. 50 mg/m2 daily (days 1–5, total dose 250 mg/m2/cycle), or irinotecan i.v. 20 mg/m2 daily (days 1–5, total dose 100 mg/m2/cycle) Peg-filgrastim 100 μg/kg (day 6) subcutaneously Vigil 1.0 × 107 cells/injection, intradermally on day 15 and every 43 weeks thereafter. One cycle = 21 days | Safety profile of Vigil immunotherapy IFNγ ELISPOT conversion rate of subjects treated with Vigil immunotherapy | 9 | Recruiting End: 2018 |
Cyclophosphamide Doxorubicin Hydrochloride Etoposide Ganitumab Ifosfamide Vincristine Sulfate | NCT02306161 | Combination chemotherapy with or without Ganitumab in treating Patients with newly diagnosed metastatic Ewing sarcoma | III | Time to adverse analytic event (EFS), defined to be disease-related event, diagnosis of a second malignant neoplasm or death | 330 | ||
Liposomal Doxorubicin | NCT02557854 | HIFU hyperthermia with liposomal doxorubicin (DOXIL) for relapsed or refractory pediatric and young adult solid tumors | I | Liposomal doxorubicin (Doxil) 50 mg i.v. every 4 weeks followed by magnetic resonance high-intensity focused ultrasound hyperthermia (MR-HIFU) for 30 min every 4 weeks | Rate of dose-limiting toxicities | 14 | Recruiting End: 2019 |
Irinotecan sucrosofate liposomes Cycophosphamide | NCT02013336 | Phase 1 study of MM-398 plus cyclophosphamide in pediatric solid tumors | I | Maximum tolerated dose | 30 | Recruiting End: 2017 | |
Regorafenib (tyrosine kinase inhibitor) | NCT02048371 | SARC024: a blanket protocol to study oral regorafenib in patients with refractory liposarcoma, osteogenic sarcoma, and Ewing sarcomas | II | Regorafenib 160 mg daily; 21 days on and 7 days off | Progression-free survival | 126 | Recruiting End: 2019 |
Cabozantinib (tyrosine kinase inhibitor) | NCT02867592 | Phase 2 trial of XL184 (Cabozantinib) an oral small-molecule inhibitor of multiple kinases, in children and young adults with refractory sarcomas, Wilms tumor, and other rare tumors | II | Cabozantinib p.o. | Objective response assessed by RECIST1.1 | 110 | Recruiting End: 2018 |
Entrectinib (tyrosine kinase inhibitor) | NCT02650401 | Study of RXDX-101 in children with recurrent or refractory solid tumors and primary CNS tumors, with or without TRK, ROS1 or ALK fusions | I | Escalating doses Entrectinib p.o. | Maximum tolerated dose | 190 | Recruiting End: 2019 |
Erlotinib (EGFR inhibitor) Temozolomide | NCT02689336 | Erlotinib in combination with temozolomide in treating relapsed/recurrent/refractory pediatric solid tumors | II | Erlotinib p.o., 85 mg/m2/dose once a day continuously (every day of a 28-day cycle) Temozolomide p.o. 180 mg/m2/dose once a day on days 1–5 of a 28-day cycle | Overall response rate | 30 | Recruiting End: 2020 |
Enoblituzumab (B7-H3 antibody) | NCT02982941 | Enoblituzumab (MGA271) in children with B7-H3-expressing Solid tumors | I | Enoblituzumab i.v. on a weekly schedule for up to 96 doses (approximately 2 years) in children and young adults with B7-H3-expressing relapsed or refractory malignant solid tumours | Safety Tolerability PK, PD Immunogenicity Preliminary antitumour activity | 112 | Recruiting End: 2022 |
Nivolumab (PD1 inhibitor) Ipilimumab (anti-CTLA4 antibody) | NCT02304458 | Nivolumab With or Without Ipilimumab in Treating Younger Patients With Recurrent or Refractory Solid Tumors or Sarcomas | I–II | Nivolumab i.v. Ipilimumab i.v. | Maximum tolerated dose of nivolumab Response rate of nivolumab combined with ipilimumab according to RECIST | 352 | Recruiting End: 2020 |
Abemaciclib (CD4–CDK6 inhibitors) | NCT02644460 | Abemaciclib in children with DIPG or recurrent/refractory solid tumors (AflacST1501) | I | Escalating doses Abemaciclib (LY2835219) p.o. on a twice daily basis continuously for 28 days, which defines one cycle | Maximum tolerated dose | 50 | Recruiting End: 2020 |
TB-403 (anti-PLGF monoclonal antibody) | NCT02748135 | A two-part study of TB-403 in pediatric subjects with relapsed or refractory medulloblastoma | I–II | Drug: TB-403 20 mg/kg Drug: TB-403 50 mg/kg Drug: TB-403 100 mg/kg Drug: TB-403 ≤ 175 mg/kg | Maximum tolerated dose | 36 | Recruiting End: 2018 |
Expanded NK cells | NCT02409576 | Pilot study of expanded, activated haploidentical natural killer cell infusions for sarcomas (NKEXPSARC) | I–II | Disease response after expanded activated NK cell infusion | 20 | Recruiting End: 2018 | |
hu14.18K322A Human anti GD2 antibody | NCT02159443 | Pretreatment anti-therapeutic antibodies (PATA) in patients treated with hu14.18K322A Antibody | Obs. | To determine whether pretreatment anti-therapeutic antibodies (PATA) represent antibodies reactive against an epitope (allotypic determinant) found on the anti-GD2 antibody hu14.18K322A | 100 | Recruiting End 2019 |
Drug | Reference | Title | Phase | Doses | Primary outcome | Patients | Status |
---|---|---|---|---|---|---|---|
Regorafenib (tyrosine kinase inhibitor) | NCT02389244 | A phase II study evaluating efficacy and safety of regorafenib in patients with metastatic bone sarcomas | II | 160 mg/d once daily for the 3 weeks on/1 week off plus Best Supportive Care (BSC) until progression (according to RECIST 1.1) | Progression-free survival defined using RECIST 1.1 | 132 | 2014–2020 |
Pazopanib (tyrosine kinase inhibitor) | NCT01330966 | Study of pazopanib in the treatment of surgically unresectable or metastatic chondrosarcoma | II | 800 mg p.o. once daily for 28 days | Disease control at week 16 | 47 | 2011–2017 |
Pazopanib | NCT02066285 | Trial of pazopanib in patients with solitary fibrous tumor and extraskeletal myxoid chondrosarcoma | II | 800 mg (2 × 400 mg or 4 × 200 mg) as a single agent once daily continuously | Therapeutic response rate measured using Choi and RECIST 1.1 criteria | 70 | 2014–2018 |
Gemcitabine + pazopanib | NCT01532687 | Gemcitabine hydrochloride with or without pazopanib hydrochloride in treating patients with refractory soft tissue sarcoma | II | Gemcitabine hydrochloride i.v. on days 1 and 8 and pazopanib hydrochloride p.o. on days 1–21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity | Progression-free survival | 80 | 2012–2018 |
Imatinib (tyrosine kinase inhibitor) | NCT00928525 | Imatinib in patients with desmoid tumor and chondrosarcoma | II | 800 mg p.o./day (400 mg b.i.d.) for a maximum of 24 months | Tumour response by imaging techniques | 35 | 2009–2016 |
Dasatinib (tyrosine kinase inhibitor) | NCT00464620 | Trial of dasatinib in advanced sarcomas | II | 70 mg of Dasatinib p.o., twice daily, for 28-day cycles | Response rate and the 6-month progression-free survival rates | 386 | 2007–2017 |
Vismodegib (Hedgehog inhibitor) | NCT01267955 | Vismodegib in treating patients with advanced chondrosarcomas | II | Vismodegib p.o. on days 1–28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity | Objective therapeutic response rate measured using RECIST 1.1 criteria | 45 | 2010–2016 |
Linsitinib (inhibitor of IGF1-R) | NCT01560260 | Linsitinib in treating patients with gastrointestinal stromal tumors | II | Oral linsitinib 150 mg B.I.D. on days 1–28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity | Therapeutic response evaluated according to RECIST 1.1 | 20 including GIST and paraganglioma | 2012–2016 |
Tazemetostat (EZH2 inhibitor) | NCT02601950 | A phase 2 study of the EZH2 inhibitor tazemetostat in pediatric subjects with relapsed or refractory INI1-negative tumors or synovial sarcoma | I | Tazemetostat p.o. 800 mg B.I.D. administered in continuous 28-day cycles | Objective response, progression-free survival | 180 (including INI1-negative tumours or any solid tumour with an EZH2 gain of function mutation) | 2015–2017 |
Metformin + chloroquine | NCT02496741 | Metformin and chloroquine in IDH1/2-mutated solid tumors (MACIST) | Ib | Metformin administered in a 3 + 3 dose-escalation schedule and chloroquine administered in a fixed dose | Maximum tolerated dose of metformin + chloroquine | 20 | 2015–2016 |
Sirolimus (mTOR inhibitor) + cyclophosphamide | NCT02821507 | Sirolimus and cyclophosphamide in metastatic or unresectable myxoid liposarcoma and chondrosarcoma | II | Sirolimus 4 mg p.o. daily and cyclophosphamide p.o. 200 mg day 1–7 and 15–21 in a 4-week schedule | Growth modulation index until disease progression (time frame: 16 weeks) | 105 | 2014–2017 |
Everolimus (mTOR inhibitor) | NCT02008019 | A phase II study of Everolimus in patients with primary or relapsed chondrosarcomas (CHONRAD) | II | 2.5 and 10 mg/day for 30 days | Success rate per dose defined as a decrease of KI67 expression (> 10%) | 57 | (2014–2019) suspended due to the unavailability of Everolimus |
AG-120 (mutant IDH1 inhibitor) | NCT02073994 | Study of orally administered AG-120 in subjects with advanced solid tumors, including glioma, with an IDH1 mutation | I | AG-120 p.o. administered continuously as a single agent on days 1–28 of a 28-day cycle | Safety Maximum tolerated dose | 170 | 2014–2017 |
AG-221 (mutant IDH1 inhibitor) | NCT02273739 | Study of orally administered AG-221 in subjects with advanced solid tumors, including glioma, and with angioimmunoblastic T-cell lymphoma, with an IDH2 mutation | I/II | AG-221 p.o. administered every day of 28-day cycles until disease progression or unacceptable toxicities | Safety Maximum tolerated dose | 21 | 2014–2017 |
Nivolumab (PARP inhibitor) + Ipilimumab (anti-CTLA4 antibody) | NCT02982486 | A phase II of nivolumab plus ipilimumab in non-resectable sarcoma and endometrial carcinoma | II | Nivolumab 240 mg i.v. every 2 weeks plus Ipilimumab 1 mg/m2 i.v. every 6 weeks | Progression-free survival and therapeutic response evaluated by RECIST 1.1 | 60 | 2017–2020 |
Pembrolizumab (anti-PD1) | NCT02301039 | SARC028: a phase II study of the anti-PD1 antibody pembrolizumab (MK-3475) in patients with advanced sarcomas | II | Pembrolizumab i.v. 200 mg every 3 weeks | Objective response rate evaluated according to RECIST 1.1 | 80 | 2015–2018 |