Table 2.
Selected clinical trials investigating radiotherapy in combination with DDR inhibitor and/or other agents.
| Target (drug) & route | Additional therapy | Radiotherapy | Phase | Patient population | n | Response | Toxicity | NCT ID |
|---|---|---|---|---|---|---|---|---|
| DNA repair inhibitors | ||||||||
| ATM kinase inhibitor (AZD1390) |
N/A | 35 Gy over 2 weeks; 30 Gy over two weeks; 60 Gy over 6 weeks |
I | Brain cancer | 120 | Recruiting | Recruiting | NCT03423628 |
| ATR inhibitor (AZD6738) |
None | 20 or 30 Gy | I | Solid tumours | 46 | Active, not recruiting | Active, not recruiting | NCT02223923 |
| ATR kinase inhibitor (BAY1895344) | Pembrolizumab | SBRT 3 fractions with 2-3 days between fractions | I | Recurrent head and neck squamous cell carcinoma | 37 | Recruiting | Recruiting | NCT04576091 |
| ATR inhibitor (M6620) |
Cisplatin; capecitabine | Not specified | I | Oesophageal cancer and other solid cancers | 65 | Recruiting | Recruiting | NCT03641547 |
| DNA- PK inhibitor (M3814) | Avelumab | Hypofractionated in 5 fractions | I/II | Advanced hepatobiliary malignancies |
92 | Not yet recruiting | Not yet recruiting | NCT04068194 |
| DNA- PK inhibitor (M3814) | Cisplatin | 3 Gy x 10; 2 Gy x 33-35 | I | Locally advanced tumours | 52 | Preliminary efficacy: in-field response (n=16): one patient had pCR, 4 PR, 7 SD, and 3 have not yet been evaluated. One patient was not evaluable. | Dose-escalation results reported (n=16 patients enrolled). The most frequent AEs were fatigue in 12/16 and nausea 8/16. No patients discontinued due to DLTs. Four DLTs were reported: grade 3 mucositis lasting > 7 days in 3/16 and odynophagia in 1/16, all recovered without sequelae. One fatal suspected unexpected serious AE considered as radiation pneumonitis occurred. | NCT02516813 |
| DNA- PK inhibitor (M3814) | Capecitabine | 45–50 Gy in 25–28 fractions over 5 weeks |
Ib/II | Rectal cancer | 165 | Recruiting | Recruiting | NCT03770689 |
| DNA- PK inhibitor (M3814) | Avelumab | 30 Gy in 10 fractions over 2 weeks | I | Various advanced solid tumours |
24 | Recruiting | Recruiting | NCT03724890 |
| DNA- PK inhibitor (M3814) | Temozolomide | 60 Gy in 30 fractions over 6 weeks | I | MGMT promoter unmethylated glioblastoma or gliosarcoma | 29 | Recruiting | Recruiting | NCT04555577 |
| DNA- PK inhibitor (M3814) | N/A | Not specified | I | Advanced head and neck cancer | 42 | Recruiting | Recruiting | NCT04533750 |
| DNA-PK inhibitor (XRD-0394) |
N/A | 20 Gy in 5 fractions over 1 week | I | Various advanced solid tumours |
38 | Recruiting | Recruiting | NCT05002140 |
| Dual ATM and DNA-PK inhibitor (XRD-0394) |
N/A | 20 Gy in 5 fractions over 1 week | I | Metastatic, locally advanced, or recurrent cancer | 38 | Recruiting | Recruiting | NCT05002140 |
| PARP inhibitor (olaparib) | Durvalumab; Tremelimumab | 30 Gy in 10 fractions over 2 weeks |
I/II | Extensive stage small cell lung cancer | 54 | Recruiting | Recruiting | NCT03923270 |
| PARP inhibitor (olaparib) | N/A | Not specified | I | Triple-negative breast cancer | 24 | Awaiting report | 2/24 (8.7%) patients experienced acute grade 3 dermatitis related to RT. Olaparib-related toxicity grade 3-4 haematological toxicity was lymphopenia in 11/24 (45.8%) patients. | NCT03109080 |
| PARP inhibitor (olaparib) | N/A | Unspecified standard radiotherapy treatment 5 days per week for 6 weeks | II | Inflammatory breast cancer | 300 | Recruiting | Recruiting | NCT03598257 |
| PARP inhibitor (olaparib) | Durvalumab; carboplatin; etoposide | Not specified consolidative thoracic radiotherapy | I/II | Extensive-stage small cell lung cancer | 63 | Recruiting | Recruiting | NCT04728230 |
| PARP inhibitor (olaparib) | N/A | High-dose 70 Gy in 35 fractions; elective neck 54.25 Gy in 35 fractions | I | Head and neck cancer | 12 | Active, not recruiting | Active, not recruiting | NCT02229656 |
| PARP inhibitor (olaparib) | Temozolomide | 2 Gy per fraction given once daily five days per week over 6 weeks, for a total dose of 60 Gy | I/IIa | High-grade gliomas | 79 | Recruiting | Recruiting | NCT03212742 |
| PARP inhibitor (niraparib) | N/A | Not specified | I | Triple-negative breast cancer | 20 | Recruiting | Recruiting | NCT03945721 |
| PARP inhibitor (niraparib) | Dostarlimab | Not specified | II | Triple-negative breast cancer | 32 | Recruiting | Recruiting | NCT04837209 |
| PARP inhibitor (veliparib) |
Temozolomide | 30 daily fractions of radiation therapy 5 days per week for 6-7 weeks | II | Newly diagnosed malignant glioma without H3 K27M or BRAFV600 mutations | 115 | Active, not recruiting | Active, not recruiting | NCT03581292 |
| PARP inhibitor (Veliparib) |
N/A | 50 Gy to the chest wall and regional lymph nodes plus a 10-Gy boost | I | Inflammatory or loco-regionally recurrent breast cancer | 30 | 15 disease control failures during the 3 years of follow-up. 13 died (all after recurrence) | 5 dose-limiting AEs occurred: 4 moist desquamation, 1 neutropenia. Crude Grade 3 toxicity was 10% at year 1, 16.7% at year 2, and 46.7% at year 3. At year 3, 6 of 15 surviving patients had severe fibrosis in the treatment field. | NCT01477489 |
| PARP inhibitor (Veliparib) |
Capecitabine | 50·4 Gy in 1.8 Gy fractions daily, 5 consecutive days per week for 5·5 weeks | !b | Locally advanced rectal cancer | 32 | Tumour downstaging at surgery was noted in 22 (71%) of 31 patients; nine (29%) of 31 patients achieved a pathological complete response. | Common AEs included nausea in 17 patients (53%), diarrhoea in 16 (50%), and fatigue in 16 (50%). Grade 3 diarrhoea in three (9%) of 32 patients; no Grade 4 events. | NCT01589419 |
| Wee 1 inhibitor | ||||||||
| Adavosertib (AZD1775) | Cisplatin | IMRT 5 days a week, once daily, Monday to Friday, for 6 weeks | I | Head and neck cancer | 9 | Completed | Completed | NCT03028766 |
| Adavosertib (AZD1775) | Cisplatin | 45 Gy or greater | I | Cervical, upper vaginal and uterine Cancers | 33 | Active, not recruiting | Active, not recruiting | NCT03345784 |
| Adavosertib (AZD1775) |
Cisplatin | 70 Gy at 2Gy per fraction, 35 fractions, Monday to Friday over 7 weeks | I | Intermediate/high risk squamous cell carcinoma of head and neck | 12 | Completed | Completed | NCT02585973 |
| Adavosertib (AZD1775) |
Gemcitabine | 52.5Gy in 25 fractions (2.1Gy/fraction), using intensity-modulated radiation therapy (IMRT) after chemotherapy | I/II | Unresectable adenocarcinoma of the pancreas | 34 | Median overall survival for all patients was 21.7 months (90% CI, 16.7 to 24.8 months) which was substantially higher than prior results combining gemcitabine with radiation therapy. | 8/34 patients (24%) experienced a dose-limiting toxicity, most commonly anorexia, nausea, or fatigue. | NCT02037230 |
| Toll-like receptor agonists | ||||||||
| TLR9 agonist (SD-101) intratumoural | N/A | 4 Gy in 2 fractions over 2 days |
I/II | Untreated indolent lymphoma | 29 | 26/29 (89.7%) patients had tumour reduction at treated site. 24 (82.8%) patients had tumour reduction at non-treated sites. | Grade 1-2 drug-related AEs reported by all patients. Most common treatment-related side effect was a flu-like systemic reaction. 8/29 patients (27.6%) had grade 3 drug-related AEs. No drug-related grade 4 or serious AEs. | NCT02266147 |
| TLR9 agonist (SD-101) intratumoural | Anti-OX40 (BMS-986178) | Low-dose not specified over 2 fractions | I | Low-grade B cell non-Hodgkin lymphoma |
15 | Recruiting | Recruiting | NCT03410901 |
| TLR9 agonist (SD-101) intratumoural | Epacadostat | 24 Gy in 8 fractions, 20 Gy in 5 fractions, 4 Gy in 2 fractions |
I/II | Advanced solid tumours |
20 | Early outcome reported for 7 patients refractory to prior therapy with anti-PD-L1 checkpoint inhibition. In these patients, disease control rate (DCR) and abscopal DCR was 86% (6/7) and 100% (7/7), response rate was 43% (3/7), and abscopal response rate was 29% (2/7) including 2 patients with long-term durable complete responses. | Awaiting report | NCT03322384 |
| TLR9 agonist (SD-101) intratumoural | Pembrolizumab; leuprolide acetate; abiraterone Acetate; prednisone | 35 Gy in 7 fractions | II | Oligometastatic prostate cancer |
42 | Recruiting | Recruiting | NCT03007732 |
| TLR9 agonist (SD-101) intratumoural | Ibrutinib | Not specified | Ib/II | Lymphoma | 30 | Early outcome reported for 13 patients treated with a median follow-up of 7.7 months. 6 of 12 evaluable patients had achieved a partial response (50% ORR) and 3 had achieved >50% reduction in distal tumour burden. Eight of 12 patients (66.7%) had experienced at least a 30% reduction in distal tumour burden. | AEs were consistent with known effects of ibrutinib and of CpG with no unexpected AEs to suggest synergistic toxicity. There were no grade 4 or 5 events. AEs led to ibrutinib dose reduction or discontinuation in 3 patients. | NCT02927964 |
| TLR9 agonist (SD-101) intratumoural | Nivolumab | 6-10 Gy per fraction to the injected lesion given on days 1, 3, 5, 8, and 10 | I | Metastatic pancreatic adenocarcinoma |
6 | Active, not recruiting | Active, not recruiting | NCT04050085 |
| CMP-001 intratumoural |
Nivolumab; ipilimumab | Radiosurgery | I | Colorectal cancer metastatic to liver | 19 | Recruiting | Recruiting | NCT03507699 |
| SD-101 intratumoural |
Ipilimumab | Low-dose radiation therapy to 1 site of disease | I/II | Recurrent low-grade B-cell lymphoma | 9 | Completed | Completed | NCT02254772 |
| Imiquimod (topical) | Cyclophosphamide | 30 Gy in 5 fractions | I/II | Metastatic breast cancer |
31 | Completed | Completed | NCT01421017 |
| Poly(ICLC) intratumoural | rhuFlt3L/CDX-301 | 2 Gy x 2 | I/II | Lymphoma | 11 | Partial or complete response of treated tumour in 8/11 (72.7%). Six (54.5%) had stable disease/minor regressions at non-treated sites and three (27.3%) showed significant distant disease regression. | All AEs Grade 1 apart from 1 patient with G2 fever | NCT01976585 |
| CpG- enriched TLR9 agonist (PF-3512676) intratumoural |
4 Gy in 2 fractions over 2 days |
I/II | Mycosis fungoides | 15 | One (6.7%) patient with complete clinical response, distant site clinical response seen in 5 patients (33.3%). |
Mild injection site reaction and mild flu- like symptoms |
NCT00185965 | |
AEs, Adverse effects; DLTs, Dose-limiting toxicities; NCT, National Clinical Trial; N/A, Not Applicable.