Table 2 Summary of published clinical trials using hypoxia targeting strategies

Hypoxia-activated Prodrugs

Evofosfamide (TH-302)

Pazopanib + Evofosfamide

I

30

All solid tumours

Partial response in 10%, stable disease in 57%, progressive disease in 23% of patients

(Riedel et al., 2017) [114]

Evofosfamide monotherapy in relapsed/refractory leukaemia

I

49

Acute myeloid/lymphoid leukaemia

Reduced HIF1a/CAIX but only 6% overall response rate

(Badar et al., 2016) [115]

Gemcitabine Vs Gemcitabine + Evofosfamide

II

214

Pancreatic

Extended progression-free survival (5.6 vs 3.6 months; p = 0.005), greater reduction in tumour burden (p = 0.04) and CA19.9 levels (p = 0.008) with addition of Evofosfamide. No significant difference in overall survival

(Borad et al., 2015) [116]

Evofosfamide + Dexamethasone ± Bortezomib

I-II

59

Multiple myeloma

Stable disease (38/59) or better in 80% patients across all cohorts

(Laubach et al., 2019)

Doxorubicin Vs Doxorubicin + Evofosfamide

III

640

Soft-tissue sarcoma

No survival benefit (18.4 months combination therapy Vs 19.0 months Doxorubicin monotherapy median overall survival)

(Tap et al., 2017) [117]

Gemcitabine Vs Gemcitabine + Evofosfamide

III

693

Pancreatic

Overall survival endpoint not quite met (8.7 months combination therapy Vs 7.6 months Gemcitabine monotherapy; p = 0.059). Median progression-free survival 5.5 months combination therapy V 3.7 months Gemcitabine monotherapy (P = 0.004)

(Van Cutsem et al., 2016) [119]

Tirapazamine (SR-4233)

Tirapazamine (TPZ) + Carboplatin + Paclitaxel

I

42

All solid tumours

8% complete response, 5% partial response, 60% stable disease, 26% progression of disease

(Lara et al., 2003) [120]

Cisplatin + radiotherapy + Tirapazamine

I

16

Oesophageal adenocarcinoma

Three year overall survival 88%, but omission of Tirapazamine needed in latter cycles to avoid dose-limiting toxicity of neutropenia

(Rischin et al., 2001) [121]

Arterial Embolisation + Tirapazamine

I

27

Hepatocellular carcinoma

60% complete response, 84% objective response

(Abi-Jaoudeh et al., 2021) [122]

Cisplatin + Etoposide + radiotherapy + Tirapazamine

II

69

Limited-stage small cell lung cancer

Median progression-free survival 11 months, median overall survival 21 months

(Le et al., 2009) [123]

Paclitaxel + Carboplatin ± Tirapazamine

III

367

Non-small cell lung cancer

Overall survival end-points not reached, significantly more adverse events leading to treatment cessation when Tirapazamine added to combination therapy (p < 0.05), mostly due to myelosuppression

(Williamson et al., 2005) [124]

PR-104

PR-104 + Docetaxel or Gemcitabine

I

42

All solid tumours

9.5% partial response overall, significant myelosuppression prevented further analysis of combo + Gemcitabine

(McKeage et al., 2012) [125]

PR-104

I

27

All solid tumours

No objective responses were observed

(Jameson et al., 2010) [126]

PR-104

I-II

50

Acute myeloid/lymphoid leukaemia

Objective response in 32% AML and 20% ALL patients

(Konopleva et al., 2015) [127]

HIF Signalling

Belzutifan

Belzutifan

I

98

Renal cell carcinoma

Objective response in 25%, median progression-free survival was 14.5 months

(Choueiri et al., 2021) [112]

Belzutifan

II

VHL-associated tumours

Objective response in 49% renal cell carcinomas, 77% pancreatic lesions, 30% CNS haemangioblastomas, 100% retinal haemangioblastomas

(Jonasch et al., 2021) [111]

PT2385

PT2385

I

51

Renal cell carcinoma

2% complete response, 12% partial response, 52% stable disease

(Courtney et al., 2018) [113]

CRLX101

CRLX101 + Bevacizumab

I-II

22

Renal cell carcinoma

23% partial response, 55% achieving progression-free survival of more than four months

(Keefe et al., 2016) [109]

CRLX101 + Bevacizumab Vs standard of care (SOC) therapy

II

111

Renal cell carcinoma

No improvement in progression-free survival (3.7 months CRLX101 + Bevacizumab Vs 3.9 months SOC therapy; p = 0.831) or objective response (5% CRLX101 + Bevacizumab Vs 14% SOC therapy; p = 0.836)

(Voss et al., 2017) [110]

PX-12

PX-12 (thioredoxin-1 inhibitor)

I

38

All solid tumours

18% stable disease, as best response observed

(Ramanathan et al., 2007) [128]

PX-12

I

14

All solid tumours

7% stable disease, as best response observed

(Ramanathan et al., 2012) [129]

Tanespimycin

Tanespimycin + Bortezomib

I

17

All solid tumours

6% stable disease, as best response observed

(Schenk et al., 2013) [102]

CXCR4 (haematological malignancies)

BL-8040

BL-8040 + Ara-C

II

42

Acute myeloid leukaemia

29% complete remission ± incomplete haematological recovery. Median overall survival 8.4 months

(Borthakur et al., 2021) [130]

Plerixafor

Plerixafor + high-dose cytarabine + etoposide

I

19

Acute myeloid/lymphoid leukaemia, myelodysplastic syndrome

16% objective response, exclusively in acute myeloid leukaemia

(Cooper et al., 2017) [131]

Plerixafor + Decitabine

I

69

Acute myeloid/lymphoid leukaemia, myelodysplastic syndrome

43% objective response

(Roboz et al., 2018) [132]

Plerixafor + FLAG-IDA

I-II

41

Acute myeloid leukaemia

Complete remission ± incomplete haematological recovery in 50% and 47% of primary refractory and early relapse groups respectively

(Martínez-Cuadrón et al., 2018) [133]

Ulocuplumab

Ulocuplumab + MEC (mitoxantrone + etoposide + cytarabine)

I

73

Acute myeloid leukaemia

Complete remission ± incomplete haematological recovery in 51% combination therapy compared with 24–28% in those receiving MEC alone

(Becker et al., 2014) [134]