Table 6 The clinical trials studied the combination therapy with HIF inhibitors

Chemotherapy

RAD001 (everolimus)

FOLFOX (oxaliplatin + 5 FU + leucovorin)

Bevacizumab

Phase I/II

Metastatic CRC

Complete

MTD: 10 mg/d

ORR: 53%

PFS (6 mths): 96%

NCT01047293

[162]

Topotecan

Cisplatin

Bevacizumab

Phase II

Cervical Cancer

Complete

PFS (6 mths): 59%

mPFS: 7.1 mths

mOS:13.2 mths

NCT00548418

[163]

(T)PubChem CID:

60700

URL:

https://pubchem.ncbi.nlm.nih.gov/compound/60700

Topotecan

Ziv-Aflibercept

5-Fluorouracil

Folinic Acid

Phase II

Metastatic CRC

Complete

PFS (12 mths): 21.9%

mPFS: 8.4 mths

mOS: 20.9 mths

NCT02129257

[164]

Ganetespib

(Hsp90 inhibitor)

Carboplatin

Paclitaxel

Radiation Therapy

Phase I

Stage II-III Esophageal Cancer

Complete

MTD (70 days)

NCT02389751

Ganetespib

Doxorubicin

Phase I/II

SCLC

Terminated

MTD: ganetespib 150 mg/m² + doxorubicin 50 mg/m²

RR: 25%

NCT02261805

[165]

Ganetespib

Paclitaxel

Phase I/II

Metastatic, p53-mutant, Platinum-resistant Ovarian Cancer

Terminated

ORR: 20% (2 out of 10)

DCR: 60% (4 out of 10)

mPFS: 2.9 mths

A: ganetespib 100 mg/m² + paclitaxel

B:

ganetespib 150 mg/m² + paclitaxel

NCT02012192

[166]

Targeted therapy

SN-38

Cetuximab

Phase II

Metastatic or locally recurrent CRC

Complete

ORR: 10.7%

PFS:4.9 mths

NCT00437268 [167]

PubChem CID:104842

URL: https://pubchem.ncbi.nlm.nih.gov/compound/104842

Camptothecin

Bevacizumab

Phase II

Ovarian Cancer

Fallopian Tube Cancer

Primary Peritoneal Cancer

Complete

PFS (6 mths): 56%

Camptothecin 15 mg/m² + Avastin 10 mg/kg

NCT01652079

[168]

PubChem CID: 184196

URL: https://pubchem.ncbi.nlm.nih.gov/compound/184196

RAD001

Sorafenib

Phase I/II

Advanced Solid Tumors

Suspended (toxicity)

MTD (6 wks)

PFS (3mths)

NCT01226056

Ganetespib

Ziv-Aflibercept (VEGF-A and VEGF-B inhibitor)

Phase I

Metastatic gastrointestinal carcinomas,

NSCLC,

Urothelial carcinomas

Sarcomas

Terminated (Drug supplier suspend)

MTD (28 days): ganetespib 100 mg/m² + Ziv-Aflibercept 3 mg/kg

NCT02192541

[169]

Everolimus

Lenvatinib (RTK inhibitor)

Phase I

Advanced or metastatic RCC

Recruiting

Surgical complication

NCT03324373

(L)PubChem CID:

9823820

URL:

https://pubchem.ncbi.nlm.nih.gov/compound/9823820

PT2977

PubChem CID:

117947097

URL:

https://pubchem.ncbi.nlm.nih.gov/compound/117947097

Cabozantinib (TKI)

PubChem CID:

25102847

URL:

https://pubchem.ncbi.nlm.nih.gov/compound/25102847

Phase II

Advanced ccRCC

Complete

ORR: 22%

DCR: 90%

Median PFS: 16.8 months

PFS rate(12mth): 65%

OS rate (12mth): 81%

NCT03634540

[170]

PT2977

Abemaciclib (CDK4/6 inhibitors)

Phase I

Advanced refractory ccRCC

Recruiting

PR or CR

MTD

NCT04627064

(A)PubChem CID:

46220502

URL:

https://pubchem.ncbi.nlm.nih.gov/compound/46220502

Radiotherapy

RAD001

Radiotherapy

Erlotinib

Phase I

Recurrent head and neck cancer

Withdrawn

MTD

NCT01332279

Immunotherapy

PT2385

Nivolumab

Phase I

Advanced or metastatic ccRCC

Active, not recruiting

MTD

NCT02293980

[171]

DFF332

Spartalizumab (anti-PD1) + Taminadenant (adenosine A2A receptor antagonist)

Phase I

Advanced or metastatic ccRCC

Recruiting

AEs

DLT

NCT04895748

Metformin

Sintilimab (PD-1 inhibitor)

Phase II

ED-stage SCLC

Recruiting

ORR

NCT03994744

[172]