Table 3.
Recently completed clinical trials targeting ECM (not including already approved and marketed drugs).
| Trial No and Phase |
Cancer Type | Drug | Target | Mechanism of Action | Preliminary Results and Adverse Events |
|---|---|---|---|---|---|
| NCT00431561; Phase 2b | Recurrent and refractory glioma | Trabedersen (AP 12009) |
TGFβ2 |
Antisense oligodeoxynucleotide specifically inhibits TGF-beta2 and suppresses key mechanisms of tumour development, specifically immunosuppression, metastasis, angiogenesis, and proliferation. |
19/89 pts had CR or PR following robust lesion size reduction (med. time for 90% reduction of baseline tumour volume = 11.7 mo, 4.9–57.7 mo). 7 pts had an SD for ≥6 mo. For the group of 26 AA/GBM patients with favourable responses, the median PFS: 1109 days and OS: 1280 days (significantly better than seen in the group including non-responders (n = 89; p < 0.00001) (https://doi.org/10.3390/cancers11121892) |
| NCT00761280; Phase 3 | Recurrent or refractory AA and secondary glioblastoma | Trabedersen + Temozolomide + Carmustine + Lomustine | Terminated due to inability to recruit the projected patient number. | ||
| NCT01401062; Phase 2 | m-Breast cancer | Fresolimumab + Focal irradiation |
TGFβ |
Human IgG4-κ monoclonal antibody neutralises all TGFβ isoforms (i.e., β1, β2, and β3) with half-life ranging from 21–30 days. |
7 grade 3/4 AE in 5/11 pts (1 mg/kg arm) and in 2/12 pts (10 mg/kg arm), respectively. SD = 3. At 12 months follow-up, 20/23 pts deceased. Patients receiving the 10 mg/kg had a significantly higher OS than those receiving 1 mg/kg fresolimumab (HR: 2.73 with 95% CI: 1.02, 7.30; p = 0.039). (https://doi.org/10.1158/1078-0432.CCR-17-3322) |
| NCT01112293; Phase 2 | Relapsed malignant pleural mesothelioma | Fresolimumab (GC1008) | SD: 3/13 pts; serum from 5 patients showed increased levels of antibodies against MPM tumour lysates. Had increased OS (15 vs. 7.5 mo, p < 0.03) (https://doi.org/10.4161/onci.26218) | ||
| NCT01246986; Phase 2 | HCC | Galunisertib + Sofarenib + Ramucirumab |
TGFβ-R1 |
Galunisertib (LY2157299) acts as a small-molecule selective inhibitor of the TGF-β receptor type I, which is a serine/threonine kinase. |
Median time-to-tumour progression was 4.1 mo for 150 mg Galunisertib cohort; OS: 18.8 mo; PR: 2 pts; SD: 21; and progressive disease: 13. TGF-β1 responders showed better OS compared to non-responders (22.8 vs. 12.0 months, p = 0.038). (https://doi.org/10.14309/ctg.0000000000000056) |
| NCT01373164; Phase 1, 2 | m-Neoplasms, pancreatic cancer | Galunisertib + Gemcitabine/ Placebo + Gemcitabine | OS: 10.9 vs. 7.2 mos (GG vs. GP) in the subgroup with baseline TGFβ1 levels ≤ 4224 pg/mL (n = 117). PFS: 3.65 vs. 2.79 mos (p = 0.215). ORR: 8.7 vs. 1.9 (p = 0.116). Grade 3/4 TR-AE (GG vs GP) were anaemia (7.8% vs. 13.5%), neutropenia (32.0% vs. 26.9%) and thrombocytopenia (7.8% vs. 9.6%). | ||
| NCT02149108; Phase 3 | Refractory m-CRC | Nintedanib (BIBF1120)/ Placebo |
RTK |
Oral small-molecule inhibitors of RTK, including FGFR-1 to 3, PDGFR-α and β, and VEGFR-1 to 3. It inhibits the release of proinflammatory and profibrotic mediators, migration and differentiation of fibrocytes and fibroblasts, and deposition of ECM. |
OS 6.4 mo vs. 6.0 mo with placebo; HR 1.01; 95% CI 0.86–1.19; p = 0.8659. PFS 1.5 mo vs. 1.4 mo; HR 0.58; 95% CI 0.49–0.69; p < 0.0001). No CR or PR. AEs occurred in 97% of the treatment group (n = 384) and 93% of the placebo group (381). The most frequent grade ≥ 3 AEs were liver-related AEs (nintedanib 16%; placebo 8%) and fatigue (nintedanib 9%; placebo 6%). (https://doi.org/10.1093/annonc/mdy241) |
| NCT01015118; Phase 3 | Ovarian and peritoneal neoplasms |
Nintedanib/Placebo + Carboplatin + Paclitaxel | 53% of nintedanib grp (486/911) had disease progression or death compared with 58% of placebo grp (266). PFS: 17.2 mo vs. 16.6 mo, HR 0.84; 95% CI 0.72–0.98; p = 0.024. The most common AE were diarrhoea, neutropenia, anaemia, and thrombocytopenia. SAE in 376/902 pts in nintedanib grp and 155/450 pts in placebo grp. 29 pts in the nintedanib group had SAE compared with 16 in the placebo group. TR-AE-related death in 3 vs. 1 pts in treatment vs the placebo group. | ||
| NCT01195415; Phase 2 | m-Pancreatic cancer | Vismodegib/Placebo + Gemcitabine |
SMO |
Vismodegib selectively binds to and inhibits the transmembrane G protein-coupled receptor protein, SMO, to inhibit the Hedgehog signalling pathway and reduce desmoplasia. |
75% pts had elevated SHH expression pretreatment. Post-treatment, GLI1 and PTCH1 decreased in 95.6% and 82.6% of 23 pts, fibrosis decreased in 45.4% of 22 and Ki-67 in 52.9% of 17 evaluable pts. PFS and OS for all pts was 2.8 and 5.3 mos. DCR: 65.2%. Grade > 3 AE seen in 56% pts. (n = 23) (https://doi.org/10.1158/1078-0432.CCR-14-1269) |
| NCT02667574; Phase 2 | laBCC | Vismodegib + Surgery | 44/55 patients had a procedure after vismodegib treatment (80.0%, 95% CI [67 to 90]). CR: 27/44. The main AEs were dysgeusia, muscle spasms, alopecia, fatigue, and weight loss (20% pts with grade ≥ 3). Vismodegib helps with downstaging before surgery for laBCC. (https://doi.org/10.1200/JCO.2018.36.15_suppl.9509) | ||
| NCT01130142, Phase 1, 2 | m-Pancreatic cancer | Patidegib (IPI-926) + Gemcitabine | SMO | Small-molecule, semi-synthetic cyclopamine analogue that inhibits SMO | Preliminary results: 3/9 radiographic PR with post-baseline scans. No Grade 4/5 AE and no TR-AEs. The most common TR-AEs: fatigue (40% total, 0% Grade 3), nausea (40%, 0%), ALT increased (13%, 7%), AST increased (13%, 7%), anaemia (13%, 0%), and vomiting (13%, 0%). The study was terminated early due to a lack of benefits. |
| NCT01479465; Phase 2a | m-CRC | A. Simtuzumab 700 mg + FOLFIRIB. Simtuzumab 200 mg + FOLFIRIC. Placebo + FOLFIRI |
LOXL2 | A humanised IgG4 monoclonal antibody against LOXL2 inhibits its enzymatic activity and ECM remodelling required for tumour progression. | PFS: A. 5.5 mo, B. 5.4 mo, and C. 5.8 mo. OS: 11.4 mo (1.23 [0.80, 1.91]; p = 0.25), 10.5 mo (1.50 [0.98, 2.30]; p = 0.06), and 16.3 mo. ORR was 11.9%, 5.9%, and 10%. Simtuzumab was well tolerated; however, clinical outcomes did not improve. (https://doi.org/10.1634/theoncologist.2016-0479) |
| NCT00195091, Phase 2 | Breast Cancer, TNBC | Tetrathiomolybdate | LOX | TM is a copper chelator that targets the catalytic activity of LOX by binding to copper and depleting it. | Disease progression was seen in 14/74, and 17 died. EFS: 71.4% and OS: 64.7% for all patients. Cancer-specific OS: 79.9%. TNBC: EFS: 71.7%, and OS: 74.2%. non-TNBC: EFS: 71.2% and OS: 64.6% |
| NCT01839487, Phase 2 | m-PDAC | PEGPH20 plus nab-paclitaxel/gemcitabine (PAG) or nab-paclitaxel/gemcitabine (AG) | Hyaluronic acid | PEGPH20 degrades tumour-associated HA and increases the efficacy of chemo- and immuno-therapeutic agents. | PFS significantly improved with PAG (HR, 0.73; 95% CI, 0.53–1.00; p = 0.049) and for patients with HA-high tumours. ORR: 45% vs. 31% (PAG vs. AG). OS: 11.5 vs. 8.5 mos (HR, 0.96; 95% CI, 0.57–1.61). The most common grade 3/4 TR-AE with significant differences between arms (PAG vs. AG): muscle spasms (13% vs. 1%), neutropenia (29% vs. 18%), and myalgia (5% vs. 0%) (https://doi.org/10.1200/JCO.2017.74.9564) |
AA: anaplastic astrocytoma; AE: adverse events; AMPK: AMP-activated protein kinase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; BTC: biliary tract cancer; laBCC: locally advanced basal cell carcinoma; CI: confidence interval; CR: complete response; CRC: colorectal cancer; DCR: disease control rate; FGFR: fibroblast growth factor receptor; GBM: glioblastoma multiforme; GG: gemcitabine plus galunisertib; GP: gemcitabine plus placebo; GIST: gastrointestinal solid tumors; HIF: hypoxia inducing factor; HCC: hepatocellular carcinoma; HNSCC: head and neck squamous cell carcinoma; HR: hazard ratio; LOXL2: lysyl oxide like 2; ICI: immune checkpoint inhibitor; IGFR: insulin-like growth factor receptor; IRTK: insulin receptor tyrosine kinase LUSC: squamous cell lung carcinoma; m: metastatic; MET: hepatocyte growth factor receptor; mTOR: mammalian target of rapamycin; mTORC1/2: mTOR complex 1/2; NFE2L2/NRF2: Nuclear factor erythroid 2-related factor 2; NSCLC: non-small cell lung cancer; ORR: overall response rate; OS: overall survival; PD1: programmed cell death protein 1; PDL1: programmed death ligand 1; PDGFR: platelet-derived growth factor receptor; PR: partial response; RCC: renal cell carcinoma; RTK: receptor tyrosine kinase; SD: stable disease; SMO: smoothened TGFβ transforming growth factor-beta; TNBC: triple negative breast cancer; TRKB: tropomyosin-related kinase B; TR-AE: treatment related AE; VEGFR: vascular endothelial growth factor receptor.