Safety And Efficacy Study Of Palbociclib Plus Cetuximab Versus Cetuximab To Treat Head And Neck Cancer

A RANDOMIZED, MULTICENTER, DOUBLE-BLIND PHASE 2 STUDY OF PALBOCICLIB PLUS CETUXIMAB VERSUS CETUXIMAB FOR THE TREATMENT OF HUMAN PAPILLOMAVIRUS-NEGATIVE, CETUXIMAB-NAÏVE PATIENTS WITH RECURRENT/METASTATIC SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK AFTER FAILURE OF ONE PRIOR PLATINUM-CONTAINING CHEMOTHERAPY REGIMEN

The purpose of this study is to determine whether the combination of palbociclib with cetuximab is superior to cetuximab in prolonging overall survival in HPV-negative, cetuximab-naive patients with recurrent/metastatic squamous cell carcinoma of the head and neck.

Study Overview

• Status: Completed
• Conditions: Squamous Cell Carcinoma of the Head and Neck (SCCHN)
• Intervention / Treatment: Drug: palbociclib; Drug: Cetuximab; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 125
• Phase: Phase 2

Contacts and Locations

Study Locations

• Czechia
  • Olomouc, Czechia, 775 20
    • Fakultni nemocnice Olomouc
  • Olomouc, Czechia, 77520
    • Fakultni nemocnice Olomouc, Lekarna
  • Praha 8, Czechia, 180 81
    • Nemocnice Na Bulovce, Centralni laboratore Pavilon c. 8
  • Praha 8, Czechia, 180 81
    • Nemocnice Na Bulovce, Lekarna, Oddeleni Centralni pripravy
  • Praha 8, Czechia, 180 81
    • Nemocnice Na Bulovce, Ustav radiacni onkologie
• Hungary
  • Debrecen, Hungary, 4032
    • Debreceni Egyetem klinikai Koezpont Onkologiai Intezet
  • Pecs, Hungary, 7623
    • Neuro CT Kft
  • Pecs, Hungary, 7624
    • Pecsi Tudomanyegyetem, Klinikai Kozpont, Laboratoriumi
  • Pecs, Hungary, 7624
    • Pecsi Tudomanyegyetem, Klinikai Kozpont,
  • Szolnok, Hungary, 5000
    • Jasz-Nagykun-Szolnok Megyei Hetenyi Geza Korhaz-Rendelointezet,Onkologiai Kozpont
• Italy
  • Napoli, Italy, 80131
    • Istituto Nazionale Tumori Napoli
• Japan
  • Aichi
    • Nagoya, Aichi, Japan, 464-8681
      • Aichi cancer center central hospital
  • Chiba
    • Kashiwa, Chiba, Japan, 277-8577
      • National Cancer Center Hospital East
  • Hokkaido
    • Sapporo, Hokkaido, Japan, 060-8648
      • Hokkaido University Hospital/Otolaryngology
  • Shizuoka
    • Sunto-gun, Shizuoka, Japan, 411-8777
      • Shizuoka Cancer Center
• Korea, Republic of
  • Seoul, Korea, Republic of, 03080
    • Seoul National University Hospital
  • Seoul, Korea, Republic of, 05505
    • Asan Medical Center
  • Seoul, Korea, Republic of, 06351
    • Samsung Medical Center
• Mexico
  • Oaxaca, Mexico, 68000
    • Oaxaca Site Management Organization S C
  • Distrito Federal
    • Mexico, Distrito Federal, Mexico, 14080
      • Instituto Nacional De Cancerologia
  • Nuevo LEON
    • Monterrey, Nuevo LEON, Mexico, 64460
      • Hospital Universitario Dr. Jose Eleuterio Gonzalez
  • Oaxaca DE Juarez
    • Oaxaca, Oaxaca DE Juarez, Mexico, 68000
      • Cirugia y Ginecobstetricia de Oaxaca S.A de C.V Hospital Reforma
    • Oaxaca, Oaxaca DE Juarez, Mexico, 68020
      • Diaz San Juan Noe, Imagenologia Siglo XXI San Felipe
    • Oaxaca, Oaxaca DE Juarez, Mexico, 68120
      • Daniel Javier Mendez Lopez Imagen y Diagnostico Medico IDM
• Poland
  • Brzozow, Poland, 36200
    • Szpital Specjalistyczny w Brzozowie Podkarpacki Osrodek Onkologiczny im. ks. B. Markiewicza
  • Gdansk, Poland, 80-211
    • Uniwersyteckie Centrum Kliniczne Klinika Onkologii i Radioterapii
  • Lodz, Poland, 93-513
    • Wojewodzki Szpital Specjalistyczny im. M. Kopernika w Lodzi Oddzial Chemioterapii
  • Olsztyn, Poland, 10-228
    • SPZOZ MSWiA z Warminsko-Mazurskim Centrum Onkologii w Olsztynie Oddzial Kliniczny Onkologii
• Romania
  • Sibiu, Romania, 550245
    • Spitalul Clinic Judetean de Urgenta Sibiu, Clinica Oncologie Medicala
  • Cluj
    • Cluj-Napoca, Cluj, Romania, 400058
      • SC Medisprof SRL
  • Dolj
    • Craiova, Dolj, Romania, 200385
      • Sc Oncolab Srl
    • Craiova, Dolj, Romania, 200347
      • Centrul de Oncologie Sf. Nectarie SRL
  • Timis
    • Timisoara, Timis, Romania, 300166
      • S.C. ONCOCENTER Oncologie Clinica S.R.L.
• Russian Federation
  • Saint-Petersburg, Russian Federation, 197758
    • FSBI "National Medical Scientific Centre of Oncology n.a.N.N.Petrov" of the MOH of Russia
  • Arkhangelsk Region
    • Arkhangelsk, Arkhangelsk Region, Russian Federation, 163045
      • State Budgetary Healthcare Institution of Arkhangelsk Region
  • Krasnodar Region
    • Sochi, Krasnodar Region, Russian Federation, 354057
      • State Budgetary Healthcare Institution "Oncology Center #2" of the Ministry of
  • Tatarstan Republic
    • Kazan, Tatarstan Republic, Russian Federation, 420029
      • State Autonomous Healthcare Institution Republican Clinical Oncology Dispensary of the Ministry
• Serbia
  • Belgrade, Serbia, 11000
    • Military Medical Academy
  • Belgrade, Serbia, 11000
    • Institute for Oncology and Radiology of Serbia
• Slovakia
  • Bratislava, Slovakia, 83310
    • Narodny onkologicky ustav
  • Poprad, Slovakia, 05801
    • POKO Poprad, s.r.o.
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitario Vall d'Hebron
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre
  • Navarra
    • Pamplona, Navarra, Spain, 31008
      • Servicio de Oncología
• Taiwan
  • Taichung, Taiwan, 40447
    • China Medical University Hospital
  • Taichung City, Taiwan, 407
    • Taichung Veterans General Hospital
  • Tainan, Taiwan, 70154
    • National Cheng Kung University Hospital
  • Tainan, Taiwan, 704
    • National Cheng Kung University Hospital Department of Pathology
  • Taipei, Taiwan, 114
    • Tri-Service General Hospital
• Ukraine
  • Chernivtsy, Ukraine, 58013
    • Communal Institution "Chernivtsi Regional clinical oncology dispensary",
  • Dnipropetrovsk, Ukraine, 49044
    • SI Dnipropetrovsk Medical Academy of MoH of Ukraine, Chair of Oncology and Medical Radiology
  • Dnipropetrovsk, Ukraine, 49102
    • CI Dnipropetrovsk City Multifunctional Clinical Hospital #4 of Dnipropetrovsk Regional Council
  • Ivano-Frankivsk, Ukraine, 76018
    • Regional Clinical Hospital, Department of microsurgery of otolaryngology organs
  • Kriviy Rig, Ukraine, 50048
    • Communal Institution "Krivorizhskiy Oncology Dispensary" of Dnipropetrovsk Regional Council,
  • Kyiv, Ukraine, 03057
    • Clinic of SI "Institute of Otolaryngology n.a. Prof. O.S. Kolomyichenka of NAMSU"
  • Vinnytsia, Ukraine, 21029
    • Podilskiy Regional Center of Oncology, Chemotherapy Department
  • Kherson Region
    • Antonivka, Kherson Region, Ukraine, 73000
      • Communal Institution of Kherson Regional Council Kherson Regional Oncological Dispensary
• United States
  • California
    • La Jolla, California, United States, 92093
      • UC San Diego Moores Cancer Center
    • La Jolla, California, United States, 92037
      • UC San Diego Medical Center - La Jolla (Thornton Hospital)
    • San Diego, California, United States, 92103
      • UC San Diego Medical Center- Hillcrest
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • University Medical Center, lnc.:DBA University of Louisville Hospital
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • Creve Coeur, Missouri, United States, 63141
      • Siteman Cancer Center - West County
    • Saint Louis, Missouri, United States, 63110
      • Barnes-Jewish Hospital
    • Saint Louis, Missouri, United States, 63129
      • Siteman Cancer Center - South County
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine, Siteman Cancer Center
    • Saint Peters, Missouri, United States, 63376
      • Siteman Cancer Center
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • University of Cincinnati Medical Center
    • Cincinnati, Ohio, United States, 45219
      • University of Cincinnati Investigational Pharmacy
    • West Chester, Ohio, United States, 45069
      • UC Health Physicians Office South
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Henry Joyce Cancer Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

• Histologically or cytologically confirmed squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx or larynx, not amenable for salvage surgery or radiotherapy.
• Measurable disease as defined per RECIST v. 1.1. Tumor lesions previously irradiated or subjected to other locoregional therapy will only be deemed measureable if disease progression at the treated site after completion of therapy is clearly documented.
• HPV- negative SCCHN tumor as determined per institutional standard (eg, p16 IHC; multiplex nucleic acid sequence based amplification [NASBA] or other polymerase chain reaction [PCR]-based assays).
• Documented progressive disease according to RECIST v1.1 (Appendix 2) following receipt of at least 2 cycles of one platinum-containing chemotherapy regimen administered for R/M disease (min. 50 mg/m2 for cisplatin, minimum area under the curve [AUC] > 4 for carboplatin).
• Availability of a tumor tissue specimen (ie, archived formalin fixed paraffin embedded tissue [block preferred, or 15 unstained slides]), which will be used for centralized, retrospective biomarker analysis. If archived tumor tissue is not available, then a de novo biopsy will be required for patient participation.

Key Exclusion Criteria:

• Prior nasopharyngeal cancer, salivary gland or sinus tumors.
• More than one chemotherapeutic regimen given for R/M disease. Prior treatment with immunotherapy is allowed.
• Known active uncontrolled or symptomatic central nervous system (CNS) metastases, carcinomatous meningitis, or leptomeningeal disease as indicated by clinical symptoms, cerebral edema, and/or progressive growth. Patients with a history of CNS metastases or cord compression are eligible if they have been definitively treated with local therapy (eg, radiotherapy, stereotactic surgery) and are clinically stable off anticonvulsants and steroids for at least 4 weeks before randomization.
• Progressive disease within 3 months after completion of curatively intended treatment for locoregionally advanced SCCHN.
• Difficulty swallowing capsules.
• Prior use of cetuximab in the R/M disease treatment setting (except cetuximab during curative radiotherapy)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Palbociclib plus Cetuximab; Palbociclib, 125 mg, orally once daily (QD) with food on Day 1 to Day 21 followed by 7 days off treatment in a 28-day cycle; in combination with Cetuximab, 400 mg/m2 initial dose as a 120-minute IV infusion followed by 250 mg/m2 weekly infused over 60 minutes.	Drug: palbociclib; Palbociclib will be supplied as capsules containing 75 mg, 100 mg, or 125 mg equivalents of palbociclib free base. Administered with food on Day 1 to Day 21 followed by 7 days off treatment in a 28-day cycle.; Other Names: IBRANCE, PD-0332991; Drug: Cetuximab; Cetuximab injection for IV infusion will be provided in 100 mg/50 mL, single-use vials, and 200 mg/100 mL, single-use vials. In Japan, cetuximab will be provided in 100 mg/20 mL, single-use vials. Administered, 400 mg/m2 initial dose as a 120-minute IV infusion followed by 250 mg/m2 weekly infused over 60 minutes.; Other Names: ERBITUX
Active Comparator: Placebo plus Cetuximab; Placebo orally QD with food on Day 1 to Day 21 followed by 7 days off treatment in a 28-day cycle; in combination with Cetuximab, 400 mg/m2 initial dose as a 120-minute IV infusion followed by 250 mg/m2 weekly infused over 60 minutes.	Drug: Cetuximab; Cetuximab injection for IV infusion will be provided in 100 mg/50 mL, single-use vials, and 200 mg/100 mL, single-use vials. In Japan, cetuximab will be provided in 100 mg/20 mL, single-use vials. Administered, 400 mg/m2 initial dose as a 120-minute IV infusion followed by 250 mg/m2 weekly infused over 60 minutes.; Other Names: ERBITUX; Drug: Placebo; Placebo for palbociclib will be indistinguishable from the palbociclib capsules and will be supplied as capsules matching in size and color the various palbociclib formulations. Administered with food on Day 1 to Day 21 followed by 7 days off treatment in a 28-day cycle.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	OS was defined as the time from the date of randomization to the date of death due to any cause. OS (in months) was calculated as (date of death - randomization date +1)/30.4. For participants lacking survival data beyond the date of their last follow-up, the OS time was censored on the last date they were known to be alive. Participants lacking survival data beyond randomization had their OS times be censored at randomization. Estimates of OS and its 95% confidence interval were determined using Kaplan-Meier method.	Baseline up to primary completion date (PCD) (about 34 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS)	PFS was defined as the time from the date of randomization to the date of the first documentation of objective progression of disease (PD) or death due to any cause, whichever was earlier. Estimates of the PFS curves from the Kaplan Meier method were presented.	Baseline up to PCD (about 34 months)
Percentage of Participants With Objective Response (OR)	OR was defined as the overall complete response (CR) or partial response (PR) according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Objective response rate was defined as the proportion of participants with best overall response (BOR) of CR or PR relative to all randomized.	Baseline up to PCD (about 34 months)
Percentage of Participants With Clinical Benefit Response (CBR)	CBR was defined as the overall CR, PR, or stable disease>=24 weeks according to the RECIST version 1.1. Clinical benefit response rate was defined as the proportion of participants with CR, PR, or stable disease>= 24 weeks relative to all randomized participants and randomized participants with measurable disease at baseline.	Baseline up to PCD (about 34 months)
Duration of Response (DR)	DR was defined as the time from the first documentation of objective tumor response (CR or PR) to the first documentation of disease progression or to death due to any cause, whichever occurred first. If tumor progression data included more than 1 date, the first date was used. DR was calculated as [the date response ended (ie, date of PD or death) - first CR or PR date + 1]/30.4.	Baseline up to PCD (about 34 months)
Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30)	The EORTC QLQ-C30 is a 30 item questionnaire composed of 5 multi-item functional subscales (physical, role, cognitive, emotional, and social functioning), 3 multi-item symptom scales (fatigue, nausea/vomiting, and pain), a global health/quality of life (QOL) subscale, and 6 single items assessing other cancer related symptoms (dyspnea, sleep disturbance, appetite, diarrhea, constipation, and the financial impact of cancer). The questionnaire employed twenty-eight 4 point Likert scales with responses from "not at all" to "very much" and two 7 point Likert scales for global health and overall QOL. For functional and global QOL scales, higher scores represented a better level of functioning and all scores were converted to a 0 to 100 scale. For symptom oriented scales, a higher score represented more severe symptoms, and all scores were converted to a 0-100 scale. Negative changes from baseline indicate deterioration in functioning / global QoL scales and improvement in symptom scales.	Baseline up to PCD (about 34 months)
Change From Baseline in European Organization for Research and Treatment of Cancer Head and Neck Module35 (EORTC QLQ-H&N35)	The EORTC QLQ-H&N35 is designed to be used together with the core QLQ-C30. The recall period for the items in the module was "the past week". Items hn1 to hn30 were scored on 4 point Likert type categorical scales ("not at all", "a little", "quite a bit", "very much"). Items hn31 to hn35 had a "no/yes" response format. The scores were transformed into 0 to 100 scales, with a high score implying a high level of symptoms.Negative changes from baseline indicate deterioration in functioning / global QoL scales and improvement in symptom scales.	Baseline up to PCD (about 34 months)
Summary of PFS and OS Based on Investigator Assessment by Rb Expression >= 1%	Rb expression in the palbociclib and cetuximab treatment group, the relationship of the biomarker (individually) with PFS and OS were explored using graphical methods such as box plots, at baseline. The tumors of participants were Rb-positive, which was defined by Rb IHC with>=1% positive tumor cells.	Screening
Ctrough and Cendinf, WPM-Ctrough and WPM-Cendinf at Steady State for Serum Cetuximab	Ctrough is steady-state pre-dose concentration. Cendinf is steady-state end-of-infusion concentration. Ctrough and Cendinf were observed directly from data. WPM-Ctrough and WPM-Cendinf are within-participant mean steady-state pre-dose concentration and end-of-infusion concentration. Acceptance criteria for a steady-state Cendinf was defined as a PK sample that was 1) collected after at least 3 consecutive weeks of cetuximab IV infusions without interruption or prior dose reduction and 2) was collected at the end of cetuximab infusion time +/- 10% of the actual duration of the cetuximab infusion.	Pre-dose and end-of infusion of Day 15 in Cycle 1 and Cycle 2
Number of Participants With Treatment-Emergent Adverse Events(TEAEs)	AE was defined as any untoward medical occurrence in a clinical investigation participant administered a product or medical device, regardless of the causal relationship to study treatment. TEAEs were defined as AEs which occurred for the first time during the effective duration of treatment or AEs that increased in severity during treatment. Serious AEs (SAEs) were defined as any untoward medical occurrence at any dose that resulted in death; was life-threatening (immediate risk of death); required inpatient hospitalization or caused prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduction normal life functions). AEs included SAEs and non-serious AEs. Causality to study treatment was determined by the investigator. Severity was graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.	From the first dose through and including 28 calendar days after the last administration of the study treatment (up to 6.9 years)
Number of Participants With Laboratory Abnormalities	The hematology, chemistry and coagulation tests were included in the laboratory examination. Hematology evaluation included hemoglobin, platelets, white blood cell, absolute neutrophils, absolute lymphocytes. Chemistry evaluation included alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, sodium, potassium, magnesium, chloride, total calcium, total bilirubin, blood urea nitrogen (BUN) or urea, creatinine, uric acid, glucose (non-fasted), albumin, phosphorus or phosphate and hemoglobin A1c (HbA1c). Coagulation evaluation included activated partial thromboplastin time/partial thromboplastin time, international normalized ratio (INR) or prothrombin time.	From the Screening (Day -28) through and including 28 calendar days after the last administration of the study treatment (up to 7 years)
Summary of PFS and OS for P16 Negative (%Positive Tumor Cells < 70%)	A central test was defined as the tumor tissue-based p16 IHC test performed at a central laboratory (Ventana). The analysis of concordance between HPV status as assessed by local or central laboratory included the number and percentage of participants with p16 detected or not detected at the central laboratory, given that all local testing must have been negative for HPV in order for the patient to be eligible for the study. Initial analysis of the p16 status was based on the conventional cutoff of 70% p16-positive tumor cells to call out cases that might be considered HPV-positive. P16 expression was scored as positive if strong and diffuse nuclear and cytoplasmic staining was present in at least 70% of the tumor cells.	Screening
Trough Plasma Concentration (Ctrough) and Within-participant Mean Steady-state Pre-dose Concentration (WPM-Ctrough) at Steady State for Palbociblib	Ctrough is steady-state pre-dose concentration, which was observed directly from data. WPM-Ctrough is within-participant mean steady-state pre-dose concentration. For palbociclib, a steady-state trough was to be defined as a pre-dose plasma concentration following at least 7 consecutive days of 125 mg daily dose without dosing interruption and the time window for the PK collection was to be between 24 hr +/- 2 hr and 24 min post-dose the day prior to PK collection and no more than 1 hr post-dose on the day of PK collection.	Pre-dose of Day 15 in Cycle 1 and Cycle 2

Collaborators and Investigators

• Sponsor: Pfizer
• Investigators: Study Director: Pfizer CT.gov Call Center, Pfizer

Publications and helpful links

General Publications

• Adkins DR, Lin JC, Sacco A, Ley J, Oppelt P, Vanchenko V, Komashko N, Yen CJ, Wise-Draper T, Lopez-Picazo Gonzalez J, Radulovic S, Shen Q, Thurm H, Martini JF, Hoffman J, Huang X, Melichar B, Tahara M. Palbociclib and cetuximab compared with placebo and cetuximab in platinum-resistant, cetuximab-naive, human papillomavirus-unrelated recurrent or metastatic head and neck squamous cell carcinoma: A double-blind, randomized, phase 2 trial. Oral Oncol. 2021 Apr;115:105192. doi: 10.1016/j.oraloncology.2021.105192. Epub 2021 Feb 8.

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start (Actual): September 10, 2015
• Primary Completion (Actual): July 19, 2018
• Study Completion (Actual): September 7, 2022

Study Registration Dates

• First Submitted: July 13, 2015
• First Submitted That Met QC Criteria: July 13, 2015
• First Posted (Estimated): July 15, 2015

Study Record Updates

• Last Update Posted (Actual): September 8, 2023
• Last Update Submitted That Met QC Criteria: August 14, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: palbociclib, cetuximab, human papillomavirus, squamous cell carcinoma, head and neck cancer
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Head and Neck Neoplasms; Neoplasms, Squamous Cell; Carcinoma; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Immunological; Protein Kinase Inhibitors; Palbociclib; Cetuximab
• Other Study ID Numbers: A5481044; 2015-000515-41 (EudraCT Number); PALATINUS (Other Identifier: Alias Study Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.