Phase I study of palbociclib, a cyclin‐dependent kinase 4/6 inhibitor, in Japanese patients

Abstract

This phase I study in Japanese patients evaluated the safety, pharmacokinetics, and preliminary efficacy of palbociclib, a highly selective and reversible oral cyclin‐dependent kinase 4/6 inhibitor, as monotherapy for solid tumors (part 1) and combined with letrozole as first‐line treatment of postmenopausal patients with estrogen receptor‐positive, human epidermal growth factor receptor 2‐negative advanced breast cancer (part 2). Part 1 evaluated palbociclib 100 and 125 mg once daily (3 weeks on/1 week off; n = 6 each group) to determine the maximum tolerated dose. Part 2 evaluated palbociclib maximum tolerated dose (125 mg) plus letrozole 2.5 mg (n = 6). The most common treatment‐related adverse event was neutropenia (all grades/grade 3/4): 100 mg, 83%/67%; 125 mg, 67%/33%; and palbociclib plus letrozole, 100%/83%. Heavier pretreatment with chemotherapy may have resulted in higher neutropenia rates observed with the 100‐mg dose. Palbociclib exposure was higher with 125 vs 100 mg (mean area under the plasma concentration–time curve over dosing interval [τ]: 1322 vs 547.5 ng·h/mL [single dose], 2838 vs 1276 ng·h/mL [multiple dose]; mean maximum plasma concentration: 104.1 vs 41.4 ng/mL [single dose], 185.5 vs 77.4 ng/mL [multiple dose]). Half‐life was 23–26 h. No drug–drug interactions between palbociclib and letrozole occurred. Four patients had stable disease (≥24 weeks in one patient with rectal cancer [100 mg] and one with esophageal cancer [125 mg]) in part 1; two patients had partial response and two had stable disease (both ≥24 weeks) in part 2. Palbociclib at the 125‐mg dose (schedule 3/1) was tolerated and is the recommended dose for monotherapy and letrozole combination therapy in Japanese patients. The trials are registered with www.ClinicalTrials.gov: A5481010 and NCT01684215.

Palbociclib in combination with letrozole as first‐line treatment for advanced breast cancer: A Japanese phase II study

“…The C trough of plasma palbociclib in all patients was 89.4 and 86.8 ng/mL on day 15 of cycles 1 and 2, respectively. These data are highly consistent with the exploratory findings from the phase I portion of this study when the plasma palbociclib C trough was 72.8 ng/mL after multiple oral doses on day 8 of cycles 1 and 2 when coadministered with letrozole . In the phase II portion of PALOMA‐1, the C trough of plasma palbociclib was 63.5 and 62.4 ng/mL on day 14 of cycles 1 and 2, respectively, collectively indicating that the plasma palbociclib mean C trough appeared to be slightly higher in Japanese patients; however, the distribution of plasma C trough in this study and PALOMA‐1 overlap.…”

“…In part 1 of the phase I dose‐finding study, single‐agent palbociclib was given to patients with advanced solid tumors that were refractory to standard therapy. Maximum tolerated dose of palbociclib was 125 mg, and safety findings were consistent with previous studies . In part 2, palbociclib plus letrozole (same dosage regimen as in PALOMA‐1 and PALOMA‐2 trials) was assessed as first‐line therapy in postmenopausal Japanese patients with ER+/HER2− ABC.…”

“…This was the phase II portion of a phase I/II, single‐country, non‐randomized, open‐label, single‐arm, multicenter study in Japanese patients (NCT01684215). The phase I part of this study has been published . The primary objective of the phase II part of the study was to evaluate the efficacy of palbociclib in combination with letrozole using 1‐year PFS probability in postmenopausal Japanese patients with ER+/HER2− ABC.…”

Solute carrier family 35 member F2 is indispensable for papillary thyroid carcinoma progression through activation of transforming growth factor‐β type I receptor/apoptosis signal‐regulating kinase 1/mitogen‐activated protein kinase signaling axis

“…In contrast, CDK inhibitors (CKI), such as the cip/Kip family proteins, p21 Waf/Cip1 and p27 Kip1, bind to and inhibit the activity of the above CDK‐cyclin complexes, which are participated in the negative control of cell cycle progression . Numerous CDK inhibitors were expected to be an effective strategy because many tumorigenic events eventually drive proliferation by subverting CDK4 or CDK6 complexes in the G1 phase of the cell cycle . Therefore, clarifying the mechanism concerning the dysregulation of cell cycle regulator will be of great importance.…”

Untitled

“…Palbociclib also acts as an inhibitor of cyclin-dependent kinases 4 and 6, which are involved in promoting the growth of cancer cells. [2] Addition of palbociclib to letrozole provides a novel treatment for women diagnosed with metastatic breast cancer. Dange et al have established a liquid chromatographic method [3] for the simultaneous determination of palbociclib to letrozole and Song et al developed a reversed-phase high-performance liquid chromatography (RP-HPLC) method for the quantification of palbociclib in capsules.…”