Table 5.
Clinical trials exploring the role of PI3K, AKT and/or mTOR inhibitors radiosensitising various cancer.
| Author | Year | Type of Cancer | No. of Patients | Stage of Disease | Experimental Model | Drug (s) Tested | Drug Category | Radiotherapy Dose | Summary Outcome |
|---|---|---|---|---|---|---|---|---|---|
| de Melo et al. [112] | 2016 | Cervical Cancer | 13 | Primary stage IIB, IIIA or IIIB | Phase-I clinical trial | Everolimus + cisplatin + radiotherapy | mTOR inhibitor with traditional chemoradiotherapy | External Beam 4500 cGy, 25 fractionsBrachytherapy: 2400 cGy, 4 insertions | Maximum tolerated dose (MTD) of everolimus with radiotherapy and cisplatin is 5 mg/day |
| Chinnaiyan et al. [103] | 2018 | GBM | 171 | Newly diagnosed | Phase-II clinical trial | Everolimus (10mg/day) + temozolomide (TMZ) + radiotherapy | mTOR inhibitor with traditional chemoradiotherapy | 60 Gy in 30 fractions of 2 Gy each | Increased toxicity. Overall survival of everolimus group worse (p = 0.008) |
| Ma et al. [102] | 2015 | GBM | 100 | Newly diagnosed | Phase-II clinical trial | Everolimus (70mg/wk) + temozolomide + radiotherapy | mTOR inhibitor | Total dose: 60 Gy |
Moderate toxicity observed following everolimus radiotherapy and TMZ No appreciable survival benefit over control |
| Wen et al. [104] | 2015 | GBM | 54 | Newly diagnosed | Phase-I clinical trial | XL 765 (30–90 mg once daily or 20–50 mg twice daily) + temozolomide + radiotherapy | PI3K and mTOR inhibitor |
Total dose of 60 Gy (1.8–2 Gy a day, 5 days a week) | Drug + temozolomide with or without radiotherapy feasible with favourable safety profile Moderate level of PI3K/mTOR pathway inhibition observed on skin biopsies MTD = 90 mg/day |
| Sarkaria et al. [101] | 2011 | GBM | 18 | Newly diagnosed | Phase-I clinical trial | Everolimus (30 mg/wk or 50 mg/wk or 70 mg/wk) + temozolomide + radiotherapy | mTOR inhibitor | Total dose: 60 Gy in 30 fractions |
Favourable safety profile following TMZ + radiotherapy Changes in tumour metabolism following everolimus MTD = 70 mg/wk (10 mg/day) |
| NCT00858663 | - | Head and Neck SCC | Not known | Not known | Phase-I | Everolimus | mTOR inhibitor | Not known | N/A |
| NCT02113878 | - | Head and Neck SCC | Not known | Not known | Phase-Ib | BKM120 | PI3K inhibitor | Not known | N/A |
| Deutsch et al. [87] | 2015 | NSCLC | 26 | Primary NSCLC (Stage III-IV) | Phase-I clinical trial | Everolimus | mTOR inhibitor | Median total dose of 66 Gy (range, 28–66), Median number of 33 fractions (range, 14–33) |
Treatment feasible and safe Authors recommend close observation for pulmonary toxicity |
|
NCT00374140 (In progress) |
- | NSCLC | Not known | Not known | Everolimus | mTOR inhibitor | Not known | N/A | |
|
NCT02128724 (In progress) |
- | NSCLC | Not known | Not known | BKM120 | PI3K inhibitor | Not known | N/A | |
| Azria et al. [61] | 2017 | Prostate Cancer (high risk locally advanced) |
14 | Primary locally advanced non metastatic prostate cancer (≥T3, Gleason score ≥ 8) | Phase-I clinical trial | Everolimus (5 or 7.5 or 10 mg)+hormone therapy + Radiotherapy |
mTOR inhibitor | 74 Gy in 37 fractions of 2 Gy | Everolimus was tolerated with hormone and radiotherapy with minimal side effects MTD = 7.5 mg/day. Recommended dose for phase-II studies is 5mg/day |
| Narayan et al. [62] | 2017 | Prostate Cancer (recurrent) |
18 | Biochemical recurrence following prostatectomy | Phase-I clinical trial | Everolimus (5 or 7.5 or 10 mg) + radiotherapy | mTOR inhibitor | 66.6 Gy in 37 fractions of 1.8 Gy | Everolimus dose of ≤10mg/day is safe and toleration in combination with radiotherapy |
| Gelsomino F [52] | 2017 | Rectal Cancer | 12 | Primary resectable rectal cancer (T3-4, N0-2) | Phase-I/II clinical trial (n = 12) | Everolimus (2.5 or 5 or 7.5 or 10 mg) + 5FU + radiotherapy | mTOR inhibitor with traditional chemoradiotherapy | 1.8 Gy/fraction 50.4 Gy in 28 daily fractions, 5 days/week | No increase in toxicity at any of the doses with 5-FU and radiotherapy No significant increase in pCR MTD—10 mg |
| Buijsen et al. [51] | 2015 | Rectal Cancer | 13 | Primary resectable rectal cancer (T2-3, N0-1) | Phase-I/II clinical trial Phase-I (n = 13) Phase-II (n = 31) |
Rapamycin (2 mg or 4 mg or 6 mg) + radiotherapy | mTOR inhibitor | 5 × 5 Gy | Neoadjuvant radiotherapy and rapamycin feasible with no significant increase in toxicity (MTD = 6mg) No increase in post-operative complications rates after delaying duration to surgery to 6 weeks Significant reduction in tumour metabolic activity but pCR rate was still 10% within small sample sized study |