NCT03024489

Palbociclib With Cetuximab and IMRT for Locally Advanced Squamous Cell Carcinoma

A Phase I/II Dose Escalation Study of the CDK4/6 Inhibitor, Palbociclib in Combination With Cetuximab and Intensity Modulated Radiation Therapy (IMRT) for Locally Advanced Squamous Cell Carcinoma of the Head and Neck

• Status: Unknown
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 27 (actual)
• Sponsor: Mahidol University · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

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 CDK4/6 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 biomarker(s) 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 cohort(s) 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 ≤1/6 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. CT/PET 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 on/2 days off with a total dose of 70 Gy for 33-35 fractions. * Cetuximab will be administered 400 mg/m2 IV at 7 days before (day -7) starting radiation and then 250 mg/m2 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).

Conditions

• Head and Neck Cancer
• Locally Advanced

Interventions

Type	Name	Description
DRUG	Palbociclib	Dose Level -1: 100 mg oral every other day 3 week-on and 1-week of during IMRT (Day 1-21 and Day 29-49).
DRUG	Palbociclib	Dose Level 1: 75 mg per oral daily 3 week-on and 1-week of during IMRT (Day 1-21 and Day 29-49).
DRUG	Palbociclib	Dose Level 2: 100 mg per oral daily 3 week-on and 1-week of during IMRT (Day 1-21 and Day 29-49).
DRUG	Palbociclib	Dose Level 3: 125 mg per oral daily 3 week-on and 1-week of during IMRT (Day 1-21 and Day 29-49).
DRUG	Cetuximab	All dose levels: 400 mg/m2 IV at 7 days before (day -7) starting radiation and then 250 mg/m2 IV weekly for 7 weeks.
RADIATION	Intensity Modulated Radiation Therapy	5 days on/2 days off with a total dose of 70 Gy for 33-35 fractions.

Timeline

• Start date: 2017-07-19
• Primary completion: 2024-03-11
• Completion: 2024-12-31
• First posted: 2017-01-18
• Last updated: 2024-03-15

Locations

1 site across 1 country: Thailand

Regulatory

• FDA-regulated drug study