臨床研究等提出・公開システム

-

-

125

The demographic characteristics (intent-to-treat population) were well balanced in both treatment arms. The majority of patients were male (113 [90.4%]). The mean age for palbociclib + cetuximab arm was 58.3 years (range: 38 to 83 years) and mean body mass index (BMI) was 22.9 kg/m2 (range: 14.35 to 34.52 kg/m2). The mean age for placebo + cetuximab arm was 60.9 years (range: 32 to 80 years) and mean BMI was 21.9 kg/m2 (range: 15.40 to 38.97 kg/m2). The majority of patients (93 [74.4%]) were of White race. The primary diagnosis for all patients (125) was squamous cell carcinoma of the head and neck (SCCHN). The median (range) duration of the disease under study since histopathological diagnosis was 1.7 years (0.2 to 16.7 years) for patients in the palbociclib + cetuximab arm and 2.3 years (0.6 to 32.2 years) for patients in the placebo + cetuximab arm. All patients (125) had a measurable disease presented at baseline and an adequate baseline assessment. Baseline characteristics were generally well balanced between both treatment arms, except some unbalance between treatment arms observed in primary diagnosis sites at hypopharynx and oropharynx, and in initial diagnosis at Stage II and III. For the location of SCCHN, oral cavity was the most common site of disease (palbociclib + cetuximab arm: 25 [38.5%] vs placebo + cetuximab arm: 25 [41.7%]), followed by larynx (palbociclib + cetuximab arm: 18 [27.7%] vs placebo + cetuximab arm: 16 [26.7%]), oropharynx (palbociclib + cetuximab arm: 9 [13.8%] vs placebo + cetuximab arm: 14 [23.3%]), and hypopharynx (palbociclib + cetuximab arm: 13 [20.0%] vs placebo + cetuximab arm: 5 [8.3%]). About 31 (24.8%) patients had >4 disease sites involved (palbociclib + cetuximab arm: 16 [24.6%] vs placebo + cetuximab arm: 15 [25.0%]). Most patients already had advanced SCCHN at the time of initial diagnosis with 23 (18.4%) patients in Stage III (palbociclib + cetuximab arm: 15 [23.1%] vs placebo + cetuximab arm: 8 [13.3%]), 45 (36.0%) patients in Stage IVA (25 [38.5%] vs 20 [33.3%]), 4 (3.2%) patients in Stage IVB (3 [4.6%] vs 1 [1.7%]) and 14 (11.2%) patients in Stage IVC (7 [10.8%] vs 7 [11.7%]). For the disease stage at baseline, majority of patients (92 [73.6%]) had SCCHN in Stage IVC (45 [69.2%] vs 47 [78.3%]). At the time of recurrence, most patients (58 [46.4%]) exhibited both distant and locoregional recurrence of disease (28 [43.1%] vs 30 [50.0%]).

A total of 125 patients were randomized to palbociclib + cetuximab and placebo + cetuximab arms with 65 and 60 patients, respectively; among them, 124 patients received study treatments. One (1) patient in the palbociclib + cetuximab treatment arm was randomized but not treated. Twenty-six (26) patients were ongoing on the study as of data cutoff (19 July 2018). Participants continued to receive their assigned treatment until objective disease progression, symptomatic deterioration unacceptable toxicity, death, or withdrawal of consent, whichever occurred first.

Overall, 116 (93.5%) of all patients (as-treated population) experienced a total of 884 treatment-emergent adverse events (TEAEs): 60 (93.8%) patients in the palbociclib + cetuximab arm experienced 512 TEAEs and 56 (93.3%) patients in the placebo + cetuximab arm experienced 372 TEAEs. A higher percentage of patients reported Grade 3 or 4 TEAEs in the palbociclib + cetuximab arm than in the placebo + cetuximab arm (palbociclib + cetuximab arm: 33 [51.6%] vs placebo + cetuximab arm: 18 [30.0%]). The proportion of patients with Grade 5 TEAEs (palbociclib + cetuximab arm: 15 [23.4%] vs placebo + cetuximab arm: 11 [18.3%]) and serious adverse events (SAEs) (palbociclib + cetuximab arm: 25 [39.1%] vs placebo + cetuximab arm: 19 [31.7%]) were slightly higher in the palbociclib + cetuximab arm. Similar percentages of patients in each treatment arm had TEAEs that were associated with permanent discontinuation of study (palbociclib + cetuximab arm: 14 [21.9%] vs placebo + cetuximab arm: 10 [16.7%]) and permanent discontinuation of treatment (palbociclib + cetuximab arm: 17 [26.6%] vs placebo + cetuximab arm: 12 [20.0%]); 15 (23.4%) of the patients discontinued palbociclib in the palbociclib + cetuximab arm, and 12 (20.0%) of patients discontinued placebo in the placebo + cetuximab arm. A comparable percentage of patients permanently discontinued the treatment with cetuximab due to TEAEs in both treatment arms (palbociclib + cetuximab arm: 16 [25.0%] vs placebo + cetuximab arm: 11 [18.3%]). A larger proportion of patients in the palbociclib + cetuximab arm (57 [89.1%]) had treatment-related TEAEs when compared with the patients in the placebo + cetuximab arm (47 [78.3%]). The percentages of patients with treatment-related Grade 3 or Grade 4 TEAEs and SAEs were higher in the palbociclib + cetuximab arm (34 [53.1%] and 7 [10.9%]) than in the placebo + cetuximab arm (9 [15.0%] and 2 [3.3%]). There was 1 (1.6%) Grade 5 treatment-related TEAE was reported in palbociclib + cetuximab arm and no patient in the placebo + cetuximab arm reported Grade 5 treatment-related TEAEs. The patient with Grade 5 treatment-related TEAE died due to cardio-respiratory arrest, which was considered to be related to cetuximab as well as disease under study. In the palbociclib + cetuximab treatment arm, 5 (7.8%) of patients discontinued palbociclib treatment and 6 (9.4%) of patients discontinued cetuximab treatment due to treatment-related TEAEs. In the placebo + cetuximab arm, only 1 (1.7%) patient discontinued placebo and cetuximab treatments due to treatment-related TEAEs. There was 1 (1.6%) patient in the palbociclib + cetuximab treatment arm discontinued the study due to treatment-related TEAEs while no patient in the placebo + cetuximab arm discontinued the study due to treatment-related TEAEs. The proportion of patients had at least 1 TEAE was comparable between the palbociclib + cetuximab treatment arm and the placebo + cetuximab treatment arm (60 [93.8%] vs 56 [93.3%]). The most frequently reported TEAEs (>=25%) in the palbociclib + cetuximab arm were RASH* (39 [60.9%]), rash (27 [42.2%]), NEUTROPENIA* (27 [42.2%]), LEUKOPENIA* (24 [37.5%]), ANEMIA* (23 [35.9%]), anaemia (23 [35.9%]), and neutropenia (18 [28.1%]). The most frequently reported TEAEs (>=25%) in the placebo + cetuximab arm were RASH* (34 [56.7%]) and rash (21 [35.0%]). The following TEAEs were reported at a >=20% higher frequency in the palbociclib + cetuximab arm compared with the placebo + cetuximab arm: NEUTROPENIA* (27 [42.2%] vs 0), LEUKOPENIA* (24 [37.5%] vs 0), neutropenia (18 [28.1%] vs 0), THROMBOCYTOPENIA* (15 [23.4%] vs 0), ANEMIA* (23 [35.9%] vs 9 [15.0%]), anemia (23 [35.9%] vs 9 [15.0%]), and leukopenia (13 [20.3%] vs 0). The most frequently reported treatment-related TEAEs (>=25%) in the palbociclib + cetuximab arm were RASH* (39 [60.9%]), rash (27 [42.2%]), NEUTROPENIA* (26 [40.6%]), LEUKOPENIA* (22 [34.4%]), and neutropenia (18 [28.1%]). The most frequently reported treatment-related TEAEs (>=25%) in the placebo + cetuximab arm were RASH* (32 [53.3%]) and rash (19 [31.7%]). The following treatment-related TEAEs were reported at a >=20% higher frequency in the palbociclib + cetuximab arm compared with the placebo + cetuximab arm: NEUTROPENIA* (26 [40.6%] vs 0), LEUKOPENIA* (22 [34.4%] vs 0), neutropenia (18 [28.1%] vs 0), and THROMBOCYTOPENIA* (14 [21.9%] vs 0). Between the start of treatment and 28 days after last dose, 15 (23.1%) patients in the palbociclib + cetuximab arm died, of which majority deaths were due to the disease under study (13 [20.0%]). While in the placebo + cetuximab arm, 11 (18.3%) patients died and most deaths were due to the disease under study (8 [13.3%]). Following the 28-day observation period after last dose until the date of data cutoff (19 July 2018), 30 (46.2%) patients in the palbociclib + cetuximab arm died, of which majority deaths were due to the disease under study (28 [43.1%]). While in the placebo + cetuximab arm, 31 (51.7%) patients died and most deaths were due to the disease under study (29 [48.3%]). Overall, a higher percentage of patients in the palbociclib + cetuximab arm than in the placebo + cetuximab arm experienced at least 1 SAE (25 [39.1%] vs 19 [31.7%]). The most frequently reported SAEs in the palbociclib + cetuximab arm were disease progression (7 [10.9%]), pneumonia (4 [6.3%]), and febrile neutropenia (2 [3.1%]); all the other SAEs were reported in 1 (1.6%) patient each. The most frequently reported SAEs in the placebo + cetuximab arm were disease progression (6 [10.0%]), pulmonary embolism (2 [3.3%]), and sepsis (2 [3.3%]); all the other SAEs were reported in 1 (1.7%) patient each. The most frequently reported laboratory test abnormalities in both treatment arms were hemoglobin decreased (40 [64.5%] vs 22 [37.3%]), lymphocytes decreased (absolute) (45 [88.2%] vs 30 [55.6%]), lymphocytes decreased (%) (43 [74.1%] vs 48 [84.2%]), and magnesium decreased (27 [43.5%] vs 24 [40.7%]). A higher proportion of patients had white blood cells (WBC) count decreased in palbociclib + cetuximab arm (32 [51.6%]) comparing to placebo + cetuximab arm (1 [1.7%]) and total neutrophils decreased (33 [63.5%] vs 1 [1.8%]). TEAEs of weight decreased were reported by 5 (7.8%) patients in palbociclib + cetuximab arm and 3 (5.0%) patients in the placebo + cetuximab arm. There were no clinically relevant changes from baseline in any vital signs neither in the palbociclib + cetuximab arm nor in the placebo + cetuximab arm. One (1) patient in palbociclib + cetuximab arm had Grade 4 TEAE of electrocardiogram (ECG) QT prolonged after discontinued from study treatments due to disease progression. The Grade 4 TEAE of ECG QT prolonged was considered related to disease under study. One (1) patient in placebo + cetuximab arm had Grade 1 TEAE of ECG QT prolonged, which was considered related to placebo. The overall change from baseline in symptoms of dry mouth, sticky saliva and feeding tube was found to be statistically significant favoring palbociclib + cetuximab arm compared with placebo + cetuximab arm. * Cluster term

Overall Survival (OS): At the data cutoff date (19 July 2018), there were 45 (69.2%) deaths in the palbociclib + cetuximab treatment arm and 42 (70.0%) deaths in the placebo + cetuximab treatment arm. The estimated median OS was 9.7 months (95% confidence interval [CI] [7.3, 13.9]) in the palbociclib + cetuximab treatment arm and 7.8 months (95% CI [6.7, 10.6]) in the placebo + cetuximab treatment arm. The estimated hazard ratio (HR) using stratified (by ECOG per randomization) analysis was 0.820 (95% CI [0.536, 1.253]; p-value = 0.180), which showed a numerical trend in favor of palbociclib + cetuximab but was not statistically significant. The study did not meet its primary endpoint of OS with palbociclib + cetuximab treatment arm when compared with placebo + cetuximab treatment arm.

Progression Free Survival (PFS): At the data cutoff date (19 July 2018), 50 (76.9%) out of 65 patients in the palbociclib + cetuximab treatment arm and 47 (78.3%) out of 60 patients in the placebo + cetuximab treatment arm had experienced disease progression or death. The estimated HR using stratified (by ECOG per randomization) analysis was 1.000 (95% CI [0.669, 1.495]; p-value = 0.495), which showed no difference between the 2 treatment arms. The median PFS was 3.9 months (95% CI [3.6, 5.6]) in the palbociclib + cetuximab treatment arm and 4.6 months (95% CI [2.3, 5.5]) in the placebo + cetuximab treatment arm. The study did not meet its key secondary endpoint of PFS based on the investigator’s assessment. Objective Response (OR) and Clinical Benefit Response: Complete response was observed in 2 (3.1%) patients in palbociclib + cetuximab arm and none in the placebo + cetuximab arm. Partial response was seen in 16 (24.6%) patients in palbociclib + cetuximab arm and 15 (25.0%) patients in placebo + cetuximab arm. OR rate was 27.7% (95% CI [17.3, 40.2]) in palbociclib + cetuximab arm and 25.0% (95% CI [14.7, 37.9]) in placebo + cetuximab arm. Clinical benefit response was 36.9% (95% CI [25.3, 49.8]) in palbociclib + cetuximab arm and 36.7% (95% CI [24.6, 50.1]) in placebo + cetuximab arm. The odds ratio using stratified analysis was 1.013 (95% CI [0.461, 2.230]; p-value = 0.5605), which showed no difference between the 2 treatment arms. Duration of Objective Response (DR): DR is summarized only on the 18 patients in the palbociclib + cetuximab arm and 15 patients in the placebo + cetuximab arm who had objective tumor response (unconfirmed CR or PR). The estimated median DR showed no differences between the 2 treatment arms. Pharmacokinetic (PK) Results: Palbociclib exposure following administration of daily 125 mg oral doses with concomitant treatment with cetuximab in patients with recurrent/metastatic (R/M) SCCHN, as measured by within-patient mean steady-state trough concentration (WPM-Ctrough), was consistent with prior reported palbociclib PK data in patients with advanced cancer indicating that concomitant cetuximab use did not have a clinically meaningful impact on palbociclib PK. Cetuximab exposure in patients with R/M SCCHN, as measured by WPM-Ctrough and within-patient mean steady-state end of-infusion concentration (WPM-Cendinf) in patients without prior dose modifications, was consistent across treat ment arms indicating that concomitant treatment with palbociclib did not have a clinically meaningful impact on cetuximab PK. Biomarker Results: Tumor tissue p16 immunohistochemistry (IHC) suggested that a certain proportion of the patients enrolled in the study exhibited characteristics associated with HPV-related SCCHN. Use of p16 IHC as a retrospective selection marker with an optimized cutpoint did not significantly change the study overall outcome. Patient-Reported Outcomes Results (PRO): The PRO results showed similar profiles with European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) scales. No statistically significant differences were observed in global quality of life (QOL), functioning and symptoms. No statistically significant difference was observed between treatment arms in delay in deterioration in pain and swallowing difficulty.

The study did not meet its primary endpoint of OS with palbociclib + cetuximab treatment arm when compared with placebo + cetuximab treatment arm, although the estimated HR using stratified analysis showed a numerical trend in favor of palbociclib + cetuximab. The study did not meet secondary endpoint of PFS (investigator’s assessment). Overall, the combination of palbociclib + cetuximab was well tolerated and the safety findings were aligned with the safety profile of both palbociclib and cetuximab.

Nov. 30, 2023

Feb. 08, 2021

https://www.sciencedirect.com/science/article/pii/S1368837521000154?via%3Dihub

Yes

Pfizer provides an environment which enables researchers to access de-identified individual subject data and related documents (protocol, statistical analysis plan, clinical study report, etc.). Details of our clinical trial data sharing standards and access requests are available at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

-

-

clinical-trials@pfizer.com

-

-

-

clinical-trials@pfizer.com

completed

Sept. 10, 2015

Interventional

-

treatment purpose

2

-

-

Both

-

investigational material(s)
Generic name etc : -
INN of investigational material : palbociclib
Therapeutic category code : 429 Other antitumor agents
Dosage and Administration for Investigational material : -

control material(s)
Generic name etc : -
INN of investigational material : -
Therapeutic category code : --- Other
Dosage and Administration for Investigational material : -

efficacy
-

efficacy
pharmacokinetics
safety
-

-

Aug. 05, 2015