Table 2.

Clinical trials examining targeted therapy-based combination treatments in patients with (soft tissue) sarcoma

CategoryTarget(s)CombinationaPhasePopulationResponseToxicityNCT#/Ref.
RTKs
IGF1RIGF1R + SFKGanitumab + dasatinibI/IIARMS and ERMSNCT03041701
IGF1R + mTORCixutumumab + temsirolimusIIBone and STS patients, allocated based on IGF1R expression (RMS n = 10)PR: 1/57 IGF1R+ STSbGrade 3-4: 8% of adverse events (n = 2546)(13)
IGF1R + mTORCixutumumab + temsirolimusIPediatric and AYA recurrent solid tumors (RMS n = 9)SD: 3/39 (≥ 3 cycles) No mention of RMS.Mostly reversible. Dose-limiting mucositis, fatigue, hypercholesterolemia, transaminitis observed(14)
IGF1R + mTORCixutumumab + temsirolimusIIPediatric and adolescent sarcoma (RMS n = 11)SD: 2/11 RMS1 RMS removed due to toxicity. Others: addition of temsirolimus increased toxicity(15)
IGF1R + mTORDalotuzumab + ridaforolimusIPediatric advanced solid tumors (RMS n = 4)PR: 1/24 No mention of RMSWell tolerated(16)
IGF1R + chemotherapyCixutumumab or temozolomide + combination chemotherapyIIPediatric and adult metastatic ARMS and ERMSCixutumumab vs. temozolomide: 18-months EFS: 68% and 39%, respectivelyCixutumumab: Grade 5 SOS: 1/97 Grade 4 SOS: 2/97 Temozolimide: No toxicity mentionedNCT01055314/(17)
VEGF(R)VEGF + chemotherapyBevacizumab + chemotherapyIIChildhood and AYA metastatic RMS and non-RMS STSChemotherapy vs. chemotherapy + bevacizumab: Median EFS (months): 14.9 vs. 20.6 OR: 36% vs. 54%No increase grade 3/4 toxicity compared to mono chemotherapyNCT00643565/(20)
VEGF + multi-RTK + chemotherapyBevacizumab + sorafenib + low-dose cyclophosphamideIRecurrent/refractory pediatric and YA solid tumors (RMS n = 2)PR: 1/2 RMSWell tolerated(21)
PDGFRαMultikinase + MEKPazopanib + trametinibIb/IIAdvanced STS (sinonasal ERMS with PI3KCA E542K aberration progressed on PI3K monotherapy, n = 1)PR: 1/1 RMS, 59% tumor size reduction18/25: grade 1/2 toxicity 3/25: grade 3 toxicity 1/25: heart problems due to prior treatment(32)
Downstream signaling pathways
mTORmTOR + chemotherapyTemsirolimus + liposomal doxorubicinI/IIRecurrent sarcoma (ARMS n = 2, ERMS n = 2)-Well tolerated(40)
mTOR + chemotherapyTemsirolimus + irinotecan or temozolomideIYA relapsed/refractory solid tumors (RMS n = 4)SD: 1/4 RMSWell tolerated(41)
mTOR + chemotherapySirolimus + vinblastineIPediatric recurrent/refractory solid tumors (RMS n = 2)PR: 1/2 RMS (metastatic ARMS)Well tolerated(42)
mTOR + chemotherapySirolimus + cyclophosphamide + topotecanIPediatric and YA relapsed/refractory solid tumors (RMS n = 3)SD: 6/20 No mention of RMSWell tolerated(43)
Apoptosis pathway
TRAILRTRAILR2 + chemotherapy or IGF1RConatumumab + ongoing chemotherapy or ganitumabIIAdvanced solid tumors, including sarcomasNCT01327612
DNA damage response (DDR)
PARPPARP1 + chemotherapyOlaparib + TrabectedinIMetastatic and advanced adult sarcomasPR: 4/22 SD: 5/22 No mention RMSWell toleratedNCT02398058/(62)
PARP1 + chemotherapyTalazoparib + irinotecan with/without temozolomideIPediatric and AYA refractory or recurrent solid tumorsTalazoparib + irinotecan: SD: 9/22 No mention RMSWell toleratedNCT02392793/(63)
PARP1 + radiotherapyOlaparib + concomitant radiotherapyILocally advanced/unresectable STSNCT02787642
Cell cycle
Wee1Wee1 + chemotherapyAZD1775 + gemcitabine, cisplatin or carboplatinIAdvanced solid tumorsPR: 17/176 Confirmed PR: 7/17 SD: 94/176 No mention RMSWell toleratedNCT00648648/(72)
Wee1 + chemotherapyAZD1775 + irinotecan hydrochlorideI/IIPediatric and AYA relapsed and refractory solid tumors, including RMSNCT02095132
CDKCDK4/6 + chemotherapyRibociclib + doxorubicinIAdult unresectable STSNCT03009201
Epigenome
HDACHDAC + VEGFValproic acid + bevacizumab + gemcitabine + doxetacelI/IIAdvanced STSNCT01106872
HDAC + proteasomeVorinostat + bortezomibIIRecurrent adult STSNCT00937495
HDAC + proteasomeVorinostat + bortezomibIPediatric and adolescent patients with recurrent and refractory solid tumors, including sarcomaNCT01132911
HDAC + chemotherapyVorinostat + etoposideI/IIChildren and adolescents with refractory solid tumors, including sarcomaNCT01294670
HDAC + chemotherapyAbexinostat + doxorubicinIMetastatic sarcomaSD: 5/11 No mention RMSWell manageable(83)
HDAC + chemotherapyBelinostat + doxorubicinI/IIAdvanced STS (RMS n = 1)Phase I: PR: 2/25 SD: 16/25 PD: 7/25Well toleratedNCT00878800/(84)
Phase II: PR: 1/16 CR: 1/16 SD: 9/16 PD: 5/16
No mention RMS
  • Abbreviations: +, IGF1R-positive; —, not mentioned; OR, objective response; PD, progressive disease; SOS, sinusoidal obstructive syndrome; YA, young adult.

  • aPubchem ID available in Supplementary Table S1.

  • bSubtype not specified.