Palbociclib With Cetuximab and IMRT for Locally Advanced Squamous Cell Carcinoma

NCT03024489 | Active Not Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: RA2016001
• Study Type: interventional
• Target: 27
• Locations: 1 country
• Sites: 1

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 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.

Conditions

Head and Neck Cancer; Locally Advanced

Keywords

Phase I/II

Outcome Measures

Primary Outcomes (1)

• Determination of dose-limiting toxicities (DLTs) and recommended phase II dose (RP2D)

  To describe the dose-limiting toxicities and identify the recommended phase I dose (RP2D) of the combination of palbociclib, cetuximab, and IMRT for locally advanced SCCHN. Recommended Phase II Dose (RP2D) is a maximum tolerated dose (MTD) or the highest dose level when MTD is not reached. Toxicity will be assessed using the NCI Common Toxicity Criteria for Adverse Events (CTCAE), version 4.0. A DLT is defined by the occurrence of any of the following toxicities related to palbociclib and the combination within 8 weeks of treatment duration.

  From baseline to the completion of radiotherapy (up to 8 weeks)

Secondary Outcomes (3)

• Evaluate preliminary efficacy of the combination

  From baseline to 3 months after completion of radiotherapy (up to 5 months)

• Evaluate safety profile of the combination of palbociclib, cetuximab and IMRT

  From baseline to 1 year after completion of radiotherapy (up to 14 months)

• Evaluate anti-tumor activity of the combination depending on Rb status

  From baseline to 3 months after completion of radiotherapy (up to 5 months)

Study Arms (1)

Palbociclib-Cetuximab-IMRT

EXPERIMENTAL

* 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) on 3 dose levels and the MTD.

Drug: Palbociclib; Drug: Cetuximab; Radiation: Intensity Modulated Radiation Therapy

Interventions

Palbociclib DRUG

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).

Also known as: PD-0332991

Palbociclib-Cetuximab-IMRT

Cetuximab DRUG

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.

Also known as: Erbitux

Palbociclib-Cetuximab-IMRT

Intensity Modulated Radiation Therapy RADIATION

5 days on/2 days off with a total dose of 70 Gy for 33-35 fractions.

Also known as: IMRT

Palbociclib-Cetuximab-IMRT

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Locally advanced histology or cytology proven squamous cell carcinoma of oral cavity, oropharynx, larynx, and hypopharynx.
• Locally advanced SCCCH patients who would be considered for concurrent cetuximab and IMRT as a definitive treatment.
• Age ≥ 18 yeas old.
• Available tissue to determine HPV status and the other biomarkers of interest.
• ECOG status ≤ 1.
• Adequate bone marrow, liver, and renal functions, defined as:
• Platelet count ≥150 x 109/L, Absolute Neutrophile Count (ANC) ≥1.5 x 109/L, Hgb ≥9 gm/dL
• ALT and AST ≤ 1.5 upper limit normal (ULN); serum total bilirubin ≤ ULN
• Serum creatinine ≤ 1.5 x ULN, or calculated or measured creatinine clearance (by Cockcroft-Gault Equation) ≥ 50 mL/min
• Magnesium ≥ the lower limit of normal
• Women of childbearing potential must have a negative pregnancy test performed within 7 days prior to the start of study drug.
• Male and female subjects of child-bearing potential must agree to use double-barrier contraceptive measures, oral contraception, or avoidance of intercourse during the study and for 6 months after last investigational drug dose received.
• Subject or legal representative must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure.

You may not qualify if:

• SCCHN patients with distance metastasis.
• Major surgery \< 4 weeks or minor surgery \< 2 weeks prior to the first day of study treatment.
• Patients with previous chemotherapy for cancer treatment and radiation to the head and neck areas.
• Patients who were previously treated with any CDK4/6 inhibitors or cetuximab.
• SCCHN with expressed p16 by IHC (only in expansion cohort).
• Active cardiac disease described as:
• Left ventricular ejection fraction (LVEF) \< 50% by Multiple Grated acquisition (MUGA) scan or echocardiogram (ECHO).
• QTc \> 480 msec on screening EKG (using the QTcF formula).
• Congenital long QT syndrome
• Myocardial infarction or active uncontrolled angina pectoris within the last 6 months prior to the first day of study treatment
• Uncontrolled significant cardiac arrhythmias except for benign premature ventricular contractions (PVC) and premature atrial contractions (PAC).
• Symptomatic pericarditis
• History of cardiomyopathy
• Weight loss more than 10% from baseline body weight before illness.
• Active clinically serious infections or other serious uncontrolled medical conditions.

Sponsors & Collaborators

• Mahidol University: lead

Study Sites (1)

Faculty of Medicine, Ramathibodi Hospital

Bangkok, 10400, Thailand

Location

Related Publications (1)

• Ngamphaiboon N, Pattaranutaporn P, Lukerak S, Siripoon T, Jinawath A, Arsa L, Shantavasinkul PC, Taonam N, Trachu N, Jinawath N, Kositwattanarerk A, Sananmuang T, Jiarpinitnun C. A Phase I Study of the CDK4/6 Inhibitor Palbociclib in Combination with Cetuximab and Radiotherapy for Locally Advanced Head and Neck Squamous Cell Carcinoma. Clin Cancer Res. 2024 Jan 17;30(2):294-303. doi: 10.1158/1078-0432.CCR-23-2303.

  PMID: 37982827 DERIVED

MeSH Terms

Conditions

Head and Neck Neoplasms

Interventions

palbociclib; Cetuximab; Radiotherapy, Intensity-Modulated

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Radiotherapy, Conformal; Radiotherapy, Computer-Assisted; Radiotherapy; Therapeutics

Study Officials

• Nuttapong Ngamphaiboon, MD

  Ramathibodi Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 28, 2016
• First Posted: January 18, 2017
• Study Start: July 19, 2017
• Primary Completion: March 11, 2024
• Study Completion: December 31, 2024
• Last Updated: March 15, 2024

Record last verified: 2024-03

Locations

TH (1)