| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| RECURRENT/METASTATIC SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK |
| CARCINOMA A CELLULE SQUAMOSE DELLA TESTA E DEL COLLO RICORRENTE/METASTATICO |
|
| E.1.1.1 | Medical condition in easily understood language |
| RECURRENT/METASTATIC SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK |
CARCINOMA A CELLULE SQUAMOSE DELLA TESTA E DEL
COLLO RICORRENTE/METASTATICO |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10063569 |
| E.1.2 | Term | Metastatic squamous cell carcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To demonstrate that the combination of
palbociclib with cetuximab is superior to cetuximab in prolonging Overall Survival in HPV-negative,
cetuximab-naïve patients with Recurrent/Metastatic Squamous Cell Carcinoma Of The Head and Neck in whom one prior platinumcontaining
chemotherapy has failed. |
Dimostrare che la combinazione di palbociclib con cetuximab è superiore al solo cetuximab nel
prolungare l'OS in pazienti HPV-negativi, cetuximab naïve con SCCHN R/M dopo il fallimento di una precedente chemioterapia
contenente platino. |
|
| E.2.2 | Secondary objectives of the trial |
To compare secondary measure of
efficacy between the treatment arms;
• To compare safety and tolerability between the treatment arms;
-To compare Patient-Reported Outcome (PRO) measures between the treatment arms;
• To characterize the correlations between baseline biomarker (eg, p16, Rb) expression in tumor tissue and clinical efficacy in both
treatment arms;
• To characterize steady state trough concentrations for palbociclib, and trough and maximum concentrations for cetuximib in
patients with Recurrent/Metastatic Squamous Cell Carcinoma Of The Head and Neck |
• Confrontare la misura di efficacia secondaria tra i bracci di trattamento;
• Confrontare la sicurezza e la tollerabilità tra i bracci di trattamento;
• Confrontare le misure di Esito Riferito dal Paziente (PRO, Patient Reported Outcome) tra i bracci di trattamento;
• Caratterizzare le correlazioni tra l'espressione dei biomarcatori (per es. p16, Rb) al basale nel tessuto tumorale e l'efficacia
clinica in entrambi i bracci di trattamento;
• Caratterizzare le concentrazioni di valle allo stato stazionario di palbociclib, e le concentrazioni di valle e massima di cetuximab
in pazienti con SCCHN R/M. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Specify title, date and version of each substudy with relative objectives (specificare il titolo, la data e la versione di ogni
sottostudio con i relativi obiettivi, in inglese): Optional pharmacogenomic sub-study using banked biospeciments for the
following research:
- Investigations of the disease under study in the clinical study, and related conditions;
- Biospecimens may be used as controls. This includes use in case control studies of diseases for which Pfizer is researching drug
therapies; use in characterizing the natural variation among people in genes, RNA, proteins, and metabolites; and use in
developing new technologies related to pharmacogenomics/biomarkers. |
ptional pharmacogenomic sub-study using
banked biospeciments for the following research:
- Investigations of the disease under study in the clinical study, and related conditions;
- Biospecimens may be used as controls. This includes use in case control studies of diseases for which Pfizer is researching drug
therapies; use in characterizing the natural variation among people in genes, RNA, proteins, and metabolites; and use in
developing new technologies related to pharmacogenomics/biomarkers.
|
|
| E.3 | Principal inclusion criteria |
1. Histologically or cytologically confirmed squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx or larynx, not
amenable for
salvage surgery or radiotherapy.
2. Measuarable 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.
3. 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).
4. Documented progressive disease according to RECIST v1.1 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).
5. 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.
6. ECOG performance status (PS) 0 or 1.
7. Adequate organ and marrow function defined as follows:
- Leukocytes >3,000/mm3 (3.0 x 1.000.000.000/L);
- Absolute Neutrophil count (ANC) ≥ 1,200/mm3 (1.2 x 1.000.000.000/L);
- Platelets ≥ 75,000/mm3 (75 x 1.000.000.000/L);
- Hemoglobin (Hb) ≥ 9 g/dL (90 g/L);
- Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or estimated creatinine clearance ≥ 40 mL/min as calculated using the
method
standard for the institution;
- Total serum bilirubin ≤ 1.5 x ULN (≤ 3.0 x ULN if Gilbert's disease);
- Asparate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤ 2 x ULN (≤ 5.0 x ULN if liver metastases present);
- Alkaline phosphatase ≤ 2.5 x ULN (≤ 5.0 x ULN if bone or liver metastases present).
8. Male and female patients of childbearing potential and at risk for pregnancy must agree to use two highly effective methods of
contraception throughout the study and for 6 months after the last dose of cetuximab.
Female subjects who are not of childbearing potential (ie, meet at least 1 of the following criteria):
- Have undergone a documented hysterectomy and/or bilateral oophorectomy;
- Have medically confirmed ovarian failure; or
- Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no
alternative pathological or physiological cause; status may be confirmed by having a serum follicle stimulating hormone (FSH)
level within the laboratory's reference range for postmenopausal women.
9. Age ≥ 18 years (or ≥ 20 years as applicable by local country regulations).
10. Evidence of a personally signed and dated informed consent document indicating that the patient (or a legally acceptable
representative) has been informed of all pertinent aspects of the study.
11. Patients who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study
procedures. |
1. Histologically or cytologically confirmed squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx or larynx, not
amenable for
salvage surgery or radiotherapy.
2. Measuarable 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.
3. 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).
4. Documented progressive disease according to RECIST v1.1 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).
5. 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.
6. ECOG performance status (PS) 0 or 1.
7. Adequate organ and marrow function defined as follows:
- Leukocytes >3,000/mm3 (3.0 x 1.000.000.000/L);
- Absolute Neutrophil count (ANC) ≥ 1,200/mm3 (1.2 x 1.000.000.000/L);
- Platelets ≥ 75,000/mm3 (75 x 1.000.000.000/L);
- Hemoglobin (Hb) ≥ 9 g/dL (90 g/L);
- Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or estimated creatinine clearance ≥ 40 mL/min as calculated using the
method
standard for the institution;
- Total serum bilirubin ≤ 1.5 x ULN (≤ 3.0 x ULN if Gilbert's disease);
- Asparate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤ 2 x ULN (≤ 5.0 x ULN if liver metastases present);
- Alkaline phosphatase ≤ 2.5 x ULN (≤ 5.0 x ULN if bone or liver metastases present).
8. Male and female patients of childbearing potential and at risk for pregnancy must agree to use two highly effective methods of
contraception throughout the study and for 6 months after the last dose of cetuximab.
Female subjects who are not of childbearing potential (ie, meet at least 1 of the following criteria):
- Have undergone a documented hysterectomy and/or bilateral oophorectomy;
- Have medically confirmed ovarian failure; or
- Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no
alternative pathological or physiological cause; status may be confirmed by having a serum follicle stimulating hormone (FSH)
level within the laboratory's reference range for postmenopausal women.
9. Age ≥ 18 years (or ≥ 20 years as applicable by local country regulations).
10. Evidence of a personally signed and dated informed consent document indicating that the patient (or a legally acceptable
representative) has been informed of all pertinent aspects of the study.
11. Patients who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study
procedures. |
|
| E.4 | Principal exclusion criteria |
2. More than one chemotherapeutic regimen given for R/M disease. Prior treatment with immunotherapy is allowed.
3. 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.
4. Progressive disease within 3 months after completion of curatively intended treatment for locoregionally advanced SCCHN.
5. Difficulty swallowing capsules or requirement for a feeding tube.
6. Prior use of cetuximab in the R/M disease treatment setting.
7. Prior treatment with any CDK4/6 or EGFR inhibitor (except cetuximab
during curative radiotherapy).
8. Patients treated within the last 7 days prior to randomization with:
- Food or drugs that are known to be strong CYP (cytochrome P-450) 3A4 inhibitors (ie, amprenavir, atazanavir, boceprevir,
clarithromycin, conivaptan, delavirdine, diltiazem, erythromycin, fosamprenavir, indinavir, itraconazole, ketoconazole, lopinavir,
mibefradil, miconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir,
telithromycin, verapamil, voriconazole, and grapefruit or grapefruit
juice);
- Drugs that are known to be strong CYP3A4 inducers (ie, carbamazepine, felbamate, nevirapine, phenobarbital, phenytoin,
primidone, rifabutin, rifampin, rifapentin, and St. John's wort);
- Drugs that are known to prolong the QT interval.
9. Major surgery, chemotherapy, radiotherapy, any investigational agents, or other anti-cancer therapy within 2 weeks before
randomization. Patients who received prior radiotherapy to ≥ 25% of bone marrow are not eligible independent of when it was
received.
10. Diagnosis of any other malignancy within 3 years prior to randomization, except for adequately treated basal cell or squamous
cell skin cancer, or carcinoma in situ of the cervix.
11. QTc >480 msec (based on the mean value of the triplicate electrocardiograms (ECGs), family or personal history of long or
short QT syndrome, Brugada syndrome or known history of QTc prolongation, or Torsade de Pointes.
12. Uncontrolled electrolyte disorders that can compound the effects of a QTc-prolonging drug (eg, hypocalcemia, hypokalemia,
hypomagnesemia.
13. Any of the following within 6 months of randomization: myocardial infarction, severe/unstable angina, ongoing cardiac
dysrhythmias of NCI CTCAE version 4.03 Grade ≥ 2, atrial fibrillation of any grade, coronary/peripheral artery bypass graft,
symptomatic congestive heart failure, cerebrovascular accident including transient ischemic attack, or symptomatic pulmonary
embolism.
14. Active inflammatory bowel disease or chronic diarrhea, short bowel syndrome, or any upper gastrointestinal surgery including
gastric resection that could impair drug absorption.
15. Known human immunodeficiency virus infection.
16. Other severe acute or chronic medical or psychiatric condition, including recent (within the past year) or active suicidal
ideation or behavior, or laboratory abnormality that may increase the risk associated with study participation or investigational
product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would
make the patient inappropriate for entry into this study.
17. History of allergic reactions attributed to compounds of similar chemical or biologic composition to cetuximab.
18. Pregnant female subjects; breastfeeding female subjects; male and female subjects of childbearing potential who are unwilling
or unable to use two highly effective methods of contraception as outlined in this protocol for the duration of the study and for 6
months after the last dose of cetuximab.
19. Patients who are investigational site staff members directly involved in the conduct of the study and their family members, site
staff members otherwise supervised by the investigator, or patients who are Pfizer employees directly involved in the conduct of
the study.
20. Participation in other studies involving investigational drug(s) (Phases 1-4) within 4 weeks before the current study begins
and/or during study participation. |
2. More than one chemotherapeutic regimen given for R/M disease. Prior treatment with immunotherapy is allowed.
3. 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.
4. Progressive disease within 3 months after completion of curatively intended treatment for locoregionally advanced SCCHN.
5. Difficulty swallowing capsules or requirement for a feeding tube.
6. Prior use of cetuximab in the R/M disease treatment setting.
7. Prior treatment with any CDK4/6 or EGFR inhibitor (except cetuximab
during curative radiotherapy).
8. Patients treated within the last 7 days prior to randomization with:
- Food or drugs that are known to be strong CYP (cytochrome P-450) 3A4 inhibitors (ie, amprenavir, atazanavir, boceprevir,
clarithromycin, conivaptan, delavirdine, diltiazem, erythromycin, fosamprenavir, indinavir, itraconazole, ketoconazole, lopinavir,
mibefradil, miconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir,
telithromycin, verapamil, voriconazole, and grapefruit or grapefruit
juice);
- Drugs that are known to be strong CYP3A4 inducers (ie, carbamazepine, felbamate, nevirapine, phenobarbital, phenytoin,
primidone, rifabutin, rifampin, rifapentin, and St. John's wort);
- Drugs that are known to prolong the QT interval.
9. Major surgery, chemotherapy, radiotherapy, any investigational agents, or other anti-cancer therapy within 2 weeks before
randomization. Patients who received prior radiotherapy to ≥ 25% of bone marrow are not eligible independent of when it was
received.
10. Diagnosis of any other malignancy within 3 years prior to randomization, except for adequately treated basal cell or squamous
cell skin cancer, or carcinoma in situ of the cervix.
11. QTc >480 msec (based on the mean value of the triplicate electrocardiograms (ECGs), family or personal history of long or
short QT syndrome, Brugada syndrome or known history of QTc prolongation, or Torsade de Pointes.
12. Uncontrolled electrolyte disorders that can compound the effects of a QTc-prolonging drug (eg, hypocalcemia, hypokalemia,
hypomagnesemia.
13. Any of the following within 6 months of randomization: myocardial infarction, severe/unstable angina, ongoing cardiac
dysrhythmias of NCI CTCAE version 4.03 Grade ≥ 2, atrial fibrillation of any grade, coronary/peripheral artery bypass graft,
symptomatic congestive heart failure, cerebrovascular accident including transient ischemic attack, or symptomatic pulmonary
embolism.
14. Active inflammatory bowel disease or chronic diarrhea, short bowel syndrome, or any upper gastrointestinal surgery including
gastric resection that could impair drug absorption.
15. Known human immunodeficiency virus infection.
16. Other severe acute or chronic medical or psychiatric condition, including recent (within the past year) or active suicidal
ideation or behavior, or laboratory abnormality that may increase the risk associated with study participation or investigational
product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would
make the patient inappropriate for entry into this study.
17. History of allergic reactions attributed to compounds of similar chemical or biologic composition to cetuximab.
18. Pregnant female subjects; breastfeeding female subjects; male and female subjects of childbearing potential who are unwilling
or unable to use two highly effective methods of contraception as outlined in this protocol for the duration of the study and for 6
months after the last dose of cetuximab.
19. Patients who are investigational site staff members directly involved in the conduct of the study and their family members, site
staff members otherwise supervised by the investigator, or patients who are Pfizer employees directly involved in the conduct of
the study.
20. Participation in other studies involving investigational drug(s) (Phases 1-4) within 4 weeks before the current study begins
and/or during study participation. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Overall Survival |
| Sopravvivenza globale |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Please see the protocol for the timepoints |
| Vedere il protocollo per questo tempo di rilevazione |
|
| E.5.2 | Secondary end point(s) |
| Progression-free Survival (PFS), Objective Response (OR), and Duration of Response (DR), according to Response Evaluation Criteria in Solid Tumours (RECIST verson [v.] 1.1), as assessed by investigator; - Type, incidence, severity (as graded by National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] v.4.03), seriousness and relationship to study medications of AEs and any laboratory abnormalities; - Patient Reported Outcome (PRO) endpoints: European Organisation for Research and Treatment of Cancer Quality of Life Instrument (EORTCQLQ-C30); European Organisation for Research and Treatment of Cancer Head and Neck Module 35 (EORTCQLQ- H&N35); - Tumor tissue biomarkers by IHC(p16 and Rb); - Trough concentrations at steady state for palbociclib; trough and maximum concentrations for cetuximib. |
| Sopravvivenza libera da progressione (PFS), Risposta oggettiva (OR), Durata della risposta (DR), in base ai criteri RECIST v1.1, come valutati dallo sperimentatore; • Tipo, incidenza, serietà (secondo i Common Terminology Criteria for Adverse Events del National Cancer Institute [NCI CTCAE] versione 4.03), gravità e relazione degli eventi avversi (AE) con i farmaci in studio e anomalie di laboratorio; • Endpoint PRO: European Organisation for Research and Treatment of Cancer Quality of Life Instrument (EORTC QLQ C30); European Organisation for Research and Treatment of Cancer Head and Neck Modulo 35 (EORTC QLQ-H&N35); • Biomarcatori del tessuto tumorale mediante immunoistochimica (IHC; p16 e Rb); • Concentrazioni di valle allo stato stazionario del palbociclib; concentrazioni di valle e massima del cetuximab. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Please see the protocol for the timepoints |
| Vedere il protocollo per questi tempi di rilevazione |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 34 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Czech Republic |
| Hungary |
| Italy |
| Japan |
| Korea, Republic of |
| Mexico |
| Montenegro |
| Poland |
| Romania |
| Russian Federation |
| Serbia |
| Spain |
| Taiwan |
| Ukraine |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
