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

• ClinicalTrials.gov Identifier: NCT02499120
• Recruitment Status: Completed
• First Posted: July 15, 2015
• Results First Posted: September 20, 2019
• Last Update Posted: September 8, 2023
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

Tracking Information

• First Submitted Date: July 13, 2015
• First Posted Date: July 15, 2015
• Results First Submitted Date: June 23, 2019
• Results First Posted Date: September 20, 2019
• Last Update Posted Date: September 8, 2023
• Actual Study Start Date: September 10, 2015
• Actual Primary Completion Date: July 19, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 18, 2019)

Overall Survival (OS) [ Time Frame: Baseline up to primary completion date (PCD) (about 34 months) ]

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.

Original Primary Outcome Measures (submitted: July 13, 2015)

Overall Survival (OS) [ Time Frame: Baseline to date of death from any cause (up to 12 months) ]

Overall survival was the duration from enrollment to death. For participants who are alive, overall survival was censored at the last contact.

Current Secondary Outcome Measures (submitted: August 14, 2023)

• Progression Free Survival (PFS) [ Time Frame: Baseline up to PCD (about 34 months) ]
  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.
• Percentage of Participants With Objective Response (OR) [ Time Frame: Baseline up to PCD (about 34 months) ]
  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.
• Percentage of Participants With Clinical Benefit Response (CBR) [ Time Frame: Baseline up to PCD (about 34 months) ]
  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.
• Duration of Response (DR) [ Time Frame: Baseline up to PCD (about 34 months) ]
  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.
• Number of Participants With Treatment-Emergent Adverse Events(TEAEs) [ Time Frame: From the first dose through and including 28 calendar days after the last administration of the study treatment (up to 6.9 years) ]
  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.
• Number of Participants With Laboratory Abnormalities [ Time Frame: From the Screening (Day -28) through and including 28 calendar days after the last administration of the study treatment (up to 7 years) ]
  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.
• Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) [ Time Frame: Baseline up to PCD (about 34 months) ]
  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.
• Change From Baseline in European Organization for Research and Treatment of Cancer Head and Neck Module35 (EORTC QLQ-H&N35) [ Time Frame: Baseline up to PCD (about 34 months) ]
  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.
• Summary of PFS and OS for P16 Negative (%Positive Tumor Cells < 70%) [ Time Frame: Screening ]
  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.
• Summary of PFS and OS Based on Investigator Assessment by Rb Expression >= 1% [ Time Frame: Screening ]
  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.
• Trough Plasma Concentration (Ctrough) and Within-participant Mean Steady-state Pre-dose Concentration (WPM-Ctrough) at Steady State for Palbociblib [ Time Frame: Pre-dose of Day 15 in Cycle 1 and Cycle 2 ]
  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.
• Ctrough and Cendinf, WPM-Ctrough and WPM-Cendinf at Steady State for Serum Cetuximab [ Time Frame: Pre-dose and end-of infusion of Day 15 in Cycle 1 and Cycle 2 ]
  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.

Original Secondary Outcome Measures (submitted: July 13, 2015)

• Patient-Reported Outcome (PRO) measures, EORTC QLQ-C30, between the treatment arms [ Time Frame: 22 months (estimated length of study) ]
  EORTC QLQ-C30: included functional scales (physical, role, cognitive, emotional, and social), global health status, symptom scales (fatigue, pain, nausea/vomiting) and single items (dyspnoea, appetite loss, insomnia, constipation/diarrhea and financial difficulties). Most questions used 4 point scale (1 'Not at all' to 4 'Very much'; 2 questions used 7-point scale (1 'very poor' to 7 'Excellent'). Scores averaged, transformed to 0-100 scale; higher score=better level of functioning or greater degree of symptoms.
• Progression-free survival measure of efficacy between the treatment arms [ Time Frame: 22 months (estimated length of study) ]
  The period from study entry until disease progression, death or date of last contact.
• Correlations between baseline biomarker (eg, p16, Rb) expression in tumor tissue and clinical efficacy in both treatment arms [ Time Frame: 22 months (estimated length of study) ]
  Tumor tissue biomarkers by IHC (p16 and Rb)
• Steady state trough concentrations for palbociclib, and trough and maximum concentrations for cetuximab in patients with R/M SCCHN [ Time Frame: 22 months (estimated length of study) ]
  Trough concentrations at steady state for palbociclib; trough and maximum concentrations for cetuximab
• Duration of response measure of efficacy between the treatment arms [ Time Frame: 22 months (estimated length of study) ]
  Time in weeks/months from the first documentation of objective tumor response to objective tumor progression or death due to any cancer. Duration of tumor response was calculated as (the date of the first documentation of objective tumor progression or death due to cancer minus the date of the first CR or PR [which ever occurred first] that was subsequently confirmed plus 1) divided by 7 (or 30.44 if in months). DR was calculated for the subgroup of participants with a confirmed objective tumor response. DR is usually categorized by the median with its 95% Confidence Interval (CI), range and 25% and 75% percentiles.
• Objective response measure of efficacy between the treatment arms [ Time Frame: 22 months (estimated length of study) ]
  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 (ORR) is defined as the proportion of patients with CR or PR relative to (1) all randomized patients and (2) randomized patients with measurable disease at baseline. Designation of best response of SD requires the criteria to be met at least 12 weeks after randomization. Patients who do not have on-study radiographic tumor re-evaluation, who receive anti-tumor treatment other than the study medication prior to reaching a CR or PR, or who die, progress, or drop out for any reason prior to reaching a CR or PR will be counted as non-responders in the assessment of ORR. Tumor response will be determined from tumor assessment data (where data meet the criteria for CR or PR).
• Patient-Reported Outcome (PRO) measures, EORTC QLQ-H&N35, between the treatment arms [ Time Frame: 22 months (estimated length of study) ]
  The EORTC QLQ-H&N35 is designed to be used together with the core QLQ-C30. The time frame of the module is ''during the past week,'' and the format is similar to that of the core questionnaire. Items hn 1 to hn30 are scored on four-point Likert-type categorical scales (''not at all,'' ''a little,'' ''quite a bit,'' ''very much''). Items hn31 to hn35 have a ''no/yes'' response format. The scores are transformed into 0-to-100 scales, with a high score implying a high level of symptoms or problems, in the same way as scoring for symptom scales and single items of the QLQ-C30.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Safety And Efficacy Study Of Palbociclib Plus Cetuximab Versus Cetuximab To Treat Head And Neck Cancer
• Official Title: 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
• Brief Summary: 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Squamous Cell Carcinoma of the Head and Neck (SCCHN)

Intervention

• 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 Name: 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 Name: 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.

Study Arms

• 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.
  Interventions:

  • Drug: palbociclib
  • Drug: Cetuximab
• 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.
  Interventions:

  • Drug: Cetuximab
  • Drug: Placebo

• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 14, 2023): 125
• Original Estimated Enrollment (submitted: July 13, 2015): 120
• Actual Study Completion Date: September 7, 2022
• Actual Primary Completion Date: July 19, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

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)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Czechia, Hungary, Italy, Japan, Korea, Republic of, Mexico, Poland, Romania, Russian Federation, Serbia, Slovakia, Spain, Taiwan, Ukraine, United States
• Removed Location Countries: Czech Republic

Administrative Information

• NCT Number: NCT02499120
• Other Study ID Numbers: A5481044; 2015-000515-41 ( EudraCT Number ); PALATINUS ( Other Identifier: Alias Study Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes
• 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.
• URL: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests

• Current Responsible Party: Pfizer
• Original Responsible Party: Same as current
• Current Study Sponsor: Pfizer
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

• PRS Account: Pfizer
• Verification Date: August 2023