Table 2.
Summary of clinical studies in relation to circadian-modulated cancer therapy
| Treatments/drugs (targets) | Study design | Cancer type | Main findings | Ref |
|---|---|---|---|---|
| LYC-55716 (RORγ agonist) | Phase 1 clinical trials treating patients with LYC-55716 alone or in combination with pembrolizumab | Relapsed metastatic cancer (NSCLC, gastroesophageal, renal cell, urothelial, and ovarian) | Confirmed its safety and tolerability and choice of 450 mg BID dose for a phase 2a study | [289] |
| MLN4924 (RORα stabilization) | A phase 1b study of MLN4924 plus docetaxel, gemcitabine, or combination of carboplatin and paclitaxel | Solid tumors | MLN4924 with docetaxel or with carboplatin plus paclitaxel was tolerable without cumulative toxicity | [435] |
| Phase 1, dose escalation study of MLN4924 in adult patients | Lymphoma and multiple myeloma | The population pharmacokinetic of MLN4924 was profiled | [436] | |
| BTX-A51 (CKIα inhibitor) | Phase 1a study to evaluate the safety, toxicity, pharmacokinetics and preliminary efficacy | Relapsed or refractory acute myeloid leukemia | Ongoing | / |
| Chrono-modulated capecitabine | Phase 2 study to evaluate the feasibility and tolerability of capecitabine according to a specific time schedule | Locally advanced primary rectal cancer | Chrono-modulated capecitabine combined with adjuvant radiation therapy is tolerated and feasible | [345] |
| Chronotherapy with oxaliplatin, fluorouracil, and folinic acid | Phase 3 study to test chrono-modulated infusion of oxaliplatin, fluorouracil, and folinic acid compared with a constant-rate infusion method | Metastatic colorectal cancer | Chronotherapy was significantly less toxic and more effective than constant-rate infusion | [329] |
| Chrono-modulated infusion of 5-fluorouracil and 5-fluorodeoxyuridine | Randomized phase II trial comparing flat versus chrono-modulated infusion | Hepatic metastases from colorectal cancer | Supporting the use of chronotherapy in treating colorectal cancer liver metastases with combined arterial and venous fluoropyrimidine chemotherapy | [437] |
| Chrono-modulated infusion of 5-fluorouracil and mitomycin-C | Phase 3 study of mitomycin-C with protracted venous infusion or circadian-timed infusion of 5-fluorouracil | Advanced colorectal carcinoma | Dose intensification of 5-FU using a circadian-timed infusion did not lead to improved response or survival | [438] |
| Vinorelbine combined with chrono-modulated 5-fluorouracil | Phase 1 trial to study the optimal circadian time of vinorelbine combined with 5- fluorouracil | Metastatic breast cancer | Future optimal time-finding trials should have tolerability and/or activity as the primary endpoint in place of a particular toxicity | [439] |
| 4'-O-tetrahydropyranyl doxorubicin and cisplatin | Randomized phase 2 trial to evaluate the circadian timing and dose-intensity | Advanced ovarian cancer | Dosing doxorubicin in the early morning and cisplatin in the late afternoon could decrease toxicities | [434] |
| Sunitinib | Phase 2 study of sunitinib administered in a continuous once-daily dosing regimen | Metastatic renal cell carcinoma | Administration of 37.5 mg sunitinib on a continuous once-daily dosing regimen has a manageable safety profile | [440] |
| Chrono-modulated infusion of oxaliplatin in combination with capecitabine | A randomized phase 2/3 trial to compare short-time and chrono-modulated infusion of oxaliplatin in combination with capecitabine | Advanced colorectal cancer | Infusion of 30-min oxaliplatin is safe and does not increase the severity of chronic neuropathy | [441] |
| Cisplatin-based chronotherapy | A randomized controlled study to evaluate the superiority of cisplatin-based chronotherapy and pharmacokinetics for cisplatin | Advanced non-small cell lung cancer | Cisplatin-based chronotherapy has advantage in relieving side effects of chemotherapy | [442] |
| Chronotherapy of interleukin-2 | A phase 1/2 study to evaluate the safety of IL-2 chronotherapy and determine the maximum tolerated dose | Metastatic renal cell carcinoma | IL-2 chronotherapy is safe, moderately toxic and active in metastatic RCC | [443] |
| Chrono-modulated capecitabine treatment | A phase 1 study to evaluate the pharmacology of continuous chrono-modulated capecitabine treatment | Advanced solid tumors | Chrono-modulated treatment with capecitabine can lead to improved tolerability and efficacy | [444] |
| Cetuximab and circadian chrono-modulated chemotherapy | A clinical trial to study safety, efficacy and improved secondary surgical resectability of combinational treatment | Metastatic colorectal cancer | Cetuximab combined with chronotherapy shows safe and effective therapeutic control of metastases | [445] |
| Chrono-modulated treatment of oxaliplatin, 5-fluorouracil and sodium folinate | A clinical trial to evaluate non-hematological toxicity and patient characteristics treated with chrono-modulated chemotherapy | Metastatic gastrointestinal cancer | The chrono-modulated regimen with oxaliplatin, 5-FU and sodium folinate displays a manageable toxicity which depends on the patient characteristics | [446] |