Table 3.

Clinical trials with combinations in which targeted therapies inhibit resistance mechanisms of cytotoxic drugs.

Signalling Pathway Affected	Targeted Drug/Inhibitor Drug	Cytotoxic Drugs	Clinical Trial Phase	Indications	Obs	References
BCR-ABL	Bosutinib	Pemetrexed	Ongoing phase I	Bladder, cervical, NSCLC, ovarian	Recruiting	[109]
	Dasatinib	Carboplatin + Paclitaxel	Phase I completed	Ovarian	Recommended for phase II	[110]
BCL-2	Venetoclax	Azacitidine	Ongoing phase II	AML	Elderly patients	[111]
		Cyclophosphamide, etoposide, doxorubicin, methotrexate, 6-mercaptopurine, cytarabine	ALL	Ongoing phase II	Older patients with relapsed or refractory ALL	[112]
CDK4/6	Abemaciclib	Pemetrexed, or gemcitabine	Ongoing phase I	NSCLC	For stage IV patients	[113]
		Temozolomide	Ongoing phase II	Glioblastoma		[114]
	Palbociclib	Carboplatin	Ongoing phase II	Metastatic head and neck squamous cell carcinoma		[115]
		Nab-paclitaxel	Phase I completed	mPDAC	No results posted; last update in May 30, 2019.	[116]
		Temozolomide + irinotecan	Ongoing phase I	Solid tumors, neuroblastoma, medulloblastoma	For children, adolescents and young adults	[117]
	Ribociclib	Docetaxel + Prednisone	Ongoing phase Ib/II	mCRPC		[118]
		Gemcitabine	Ongoing phase I	Malignant brain tumors		[119]
		Paclitaxel + Carboplatin	Ongoing phase I	Ovarian cancer, fallopian tube cancer, peritoneal carcinoma		[120]
DNA DAMAGE REPAIR	Niraparib	Temozolomide	Ongoing phase Ib/II	SCLC		[121]
	Olaparib	Cisplatin	Ongoing phase I	Advanced NSCLC		[122]
	Rucaparib	Irinotecan	Ongoing phase Ib	Solid tumors	For patients with DNA repair defects in solid tumors	[123]
	Veliparib	FOLFIRI	Ongoing phase II	Pancreatic (metastatic)	Second line therapy	[124]
			Phase I completed	Gastric	Recommended for further investigation	[124]
		Irinotecan	Ongoing phase I	Breast, lung, ovarian, pancreatic, Hodgkin’s lymphoma	For cancer that is metastatic or cannot be removed	[125]
		Temozolomide	Ongoing phase I	ALL		[126]
			Phase II completed	CRC	Recommended for further investigation	[127]
		Topotecan	Ongoing phase I	Acute leukemias		[128]
EGFR	Cetuximab	FOLFIRI	Ongoing phase II	CRC	For patients with FcγRIIIa polymorphism and wild-type KRAS, NRAS and BRAF	[129]
		FOLFOXIRI	Ongoing phase II	Locally advanced rectal carcinoma	For EGFR wild type patients	[130]
	Necitumumab	Gemcitabine + Cisplatin	Ongoing phase II	Stage IB, II or IIIA squamous NSCLC	Neoadjuvant therapy	[131]
	Panitumumab	FOLFOX/FOLFIRI	Phase II completed	Liver (metastatic)	For patients with wild-type KRAS; no results posted; last update May 14, 2019.	[132]
		mFOLFOX6 + bevacizumab/panitumumab	Ongoing phase III	Advanced/recurrent CRC	First-line therapy for patients with KRAS/NRAS wild-type tumors	[133]
	Pertuzumab	Paclitaxel + Trastuzumab	Ongoing phase I	HER2-positive breast cancer		[134]
PI3K-AKT-MTOR	Copanlisib	Gemcitabine	Phase I completed	Cholangiocarcinoma	No results yet.	[135]
	Duvelisib	Fludarabine + cyclophosphamide + rituximab (FCR)	Ongoing phase Ib/II	CLL		[136]
	Everolimus	Carboplatin + Paclitaxel	Phase II completed	Melanoma	Everolimus failed to improve efficacy	[137]
		Temozolomide	Ongoing phase II	Low-grade glioma		[138]
	Idelalisib	Bendamustine + Rituximab	Phase III completed	Relapsed or refractory CLL	Improved PFS but with serious adverse events and infections	[139]
	Temsirolimus	Carboplatin + Paclitaxel	Phase II completed	Recurrent or metastatic head and neck	Recommended further investigation for PI3K/mTOR mutations	[140]
VEGF	Bevacizumab	Capecitabine	Phase II completed	Advanced or Metastatic Liver Cancer	"All patients presented serious adverse events; only 9.1% presented objective response"	[141]
		Carboplatin + Paclitaxel (CPB)	Phase II completed	Melanoma	Recommended for phase III	[142]
		Carboplatin + Paclitaxel + Everolimus (CPBE)	Phase II completed	Melanoma	Failed to improve PFS compared to CPB
		FOLFIRI (+ Onvansertib)	Ongoing phase Ib/II	mCRC	Second line therapy for patients with KRAS mutation	[143]
		Temozolomide	Phase II completed	Glioma (grade II/III)	Failed to improve 1-year OS	[144]
	Lenvatinib	Paclitaxel	Ongoing phase I	Endometrial, ovarian, fallopian tube, or primary peritoneal cancer		[145]
	Ramucirumab	FOLFIRI	Ongoing phase II	Gastric	For previous failed therapy	[146]
	Regorafenib	Irinotecan	Ongoing phase II	Metastatic gastro-esophageal adenocarcinomas	Second line therapy	[147]
	Sorafenib	Irinotecan	Ongoing phase II	Pediatric solid tumors	Patients with mutations in Raf, PDGFR, VEGFR, Flt-3, KIT, JAK, STAT, RAS, MEK, or ERK	[148]

Abbreviations: OS—overall survival, FOLFIRI—folinic acid, 5-fluorouracil and irinotecan, FOLFIRINOX—folinic acid, 5-fluorouracil, irinotecan and oxaliplatin, CRC—colorectal cancer, mCRC—metastatic colorectal cancer, NSCLC—non-small cell lung cancer, SCLC—small cell lung cancer, ALL—acute lymphoblastic leukemia.