Ignite Creation Date:
2024-05-06 @ 9:37 AM
Last Modification Date:
2024-10-26 @ 12:17 PM
Study NCT ID:
NCT03024489
Status:
ACTIVE_NOT_RECRUITING
Last Update Posted:
2024-03-15
First Post:
2016-11-28
Brief Title:
Palbociclib With Cetuximab and IMRT for Locally Advanced Squamous Cell Carcinoma
Sponsor:
Mahidol University
Organization:
Mahidol University
Study Overview
Official Title:
A Phase III Dose Escalation Study of the CDK46 Inhibitor Palbociclib in Combination With Cetuximab and Intensity Modulated Radiation Therapy IMRT for Locally Advanced Squamous Cell Carcinoma of the Head and Neck
Status:
ACTIVE_NOT_RECRUITING
Status Verified Date:
2024-03
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Cyclin D kinase 4 CDK4 is a key regulator of the G1-S transition in the cell cycle Alterations in CDK4-cyclin D-retinoblastoma Rb pathway may lead to carcinogenesis in many cancers Several mechanisms have been described i Amplification or overexpression of cyclin D1 ii Amplification of CDK4 iii Activating mutation of CDK4 and iv Loss of the CDK4 inhibitor p16 CDKN2A Human Papilloma Virus HPV plays a major role in squamous cell carcinoma of head and neck SCCHN carcinogenesis It induces many alterations in the CDK4-Cyclin D-Rb and apoptotic pathways such as up-regulation of p16 loss of Rb and p53 functions A novel therapy for HPV-negative SCCHN is clearly an unmet medical need
Palbociclib PD 0332991 is an orally active highly selective inhibitor of the CDK46 with ability to block Rb phosphorylation in the low nanomolar range The most advanced development is in a treatment of metastatic breast cancer In addition palbociclib showed a radiosensitization property Since combination of cetuximab and radiation improved PFS and overall survival OS in locally advanced SCCHN when compared with radiation alone these provide a strong rationale to evaluate a combination of palbociclib cetuximab and radiation for locally advanced SCCHN Because many genetic alterations in SCCHN significantly involve in the CDK4-cyclin D-Rb pathway predictive biomarkers of palbociclib in this combination will be explored
Thus the investigators propose a non-randomized dose escalation phase I study designed to determine the maximum tolerated dose MTD and toxicity of palbociclib cetuximab and IMRT for locally advanced SCCHN
Palbociclib PD 0332991 is an orally active highly selective inhibitor of the CDK46 with ability to block Rb phosphorylation in the low nanomolar range The most advanced development is in a treatment of metastatic breast cancer In addition palbociclib showed a radiosensitization property Since combination of cetuximab and radiation improved PFS and overall survival OS in locally advanced SCCHN when compared with radiation alone these provide a strong rationale to evaluate a combination of palbociclib cetuximab and radiation for locally advanced SCCHN Because many genetic alterations in SCCHN significantly involve in the CDK4-cyclin D-Rb pathway predictive biomarkers of palbociclib in this combination will be explored
Thus the investigators propose a non-randomized dose escalation phase I study designed to determine the maximum tolerated dose MTD and toxicity of palbociclib cetuximab and IMRT for locally advanced SCCHN
Detailed Description:
The enrollment of an initial patient cohort of 3 or 6 patients will follow the traditional 3 3 dose escalation scheme see table below The patients will be treated with palbociclib cetuximab and IMRT at starting at Dose Level DL 1 Subsequent patient cohorts will be enrolled depending on the safety and tolerability of the initial cohort If 33 patients treated at Dose Level 1 experience DLT see definition below by the end of treatment 56 days then next cohort of 3 patients will be enrolled and treated at Dose Level 2 If 2 treatment-related DLTs are observed at Dose Level 1 patients will be accrued to Dose Level -1 The MTD is defined as the maximum dose level at which 16 patients have DLTs
At the MTD or RP2D we will accrue up to 15 locally advanced unresectable p16-negative SCCHN patients to allow for definitive evaluation of tolerability correlative endpoints and preliminary efficacy CTPET scan will be performed at 3 months after the last dose of radiation to evaluate residual disease Patients with residual disease will be considered for salvage surgery following standard of care
IMRT will be administered 5 days on2 days off with a total dose of 70 Gy for 33-35 fractions
Cetuximab will be administered 400 mgm2 IV at 7 days before day -7 starting radiation and then 250 mgm2 IV weekly for 7 weeks
Palbociclib will be administered orally daily 3 week-on and 1-week of during IMRT Day 1-21 and Day 29-49
At the MTD or RP2D we will accrue up to 15 locally advanced unresectable p16-negative SCCHN patients to allow for definitive evaluation of tolerability correlative endpoints and preliminary efficacy CTPET scan will be performed at 3 months after the last dose of radiation to evaluate residual disease Patients with residual disease will be considered for salvage surgery following standard of care
IMRT will be administered 5 days on2 days off with a total dose of 70 Gy for 33-35 fractions
Cetuximab will be administered 400 mgm2 IV at 7 days before day -7 starting radiation and then 250 mgm2 IV weekly for 7 weeks
Palbociclib will be administered orally daily 3 week-on and 1-week of during IMRT Day 1-21 and Day 29-49
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
True
Is an FDA AA801 Violation?:
None