| 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 |
|
| E.1.1.1 | Medical condition in easily understood language |
| very advanced head and neck cancer |
|
| 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10060121 |
| E.1.2 | Term | Squamous cell carcinoma of head and neck |
| 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 assess the efficacy of molecular targeted drugs or immunotherapy in patients with non-curable recurrent/metastatic SCCHN harboring pre-defined biomarkers. |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the feasibility of a biomarker-driven trial in recurrent/metastatic SCCHN that will utilize a central biomarker screening platform to integrate genomic and proteomic testing in the clinical setting
• To determine the safety profile of targeted drugs/immunotherapy in patients with SCCHN (adverse events according to CTCAE version 4.03)
• To further investigate activity and efficacy of each compound |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1- General inclusion criteria
• Histologically confirmed recurrent and/or metastatic SCCHN of the oral cavity, oropharynx, hypopharynx or larynx not amenable to curative treatment.
• At least one measurable lesion by MRI or CT-scan according to RECIST 1.1, evaluated within 2 weeks prior to registration.
• Progressive disease after first line platinum-based chemotherapy with or without cetuximab given as palliative treatment or progressive disease within 1 year if platinum-based chemotherapy was given as a part of the multimodal curative treatment. Patients pre-treated with anti-PD1/anti-PDL1 are allowed.
• ECOG performance status 0 -1.
• Tumor core biopsy from any accessible tumor site available for central testing.
• Patients must have adequate organ function, evaluated within 14 days prior to cohort allocation:
• Hemoglobin ≥ 9 g/100 ml,
• Neutrophils ≥ 1,500/mm3,
• Platelets ≥ 100,000/mm3,
• Total bilirubin <1.5 time the upper limit of normal (ULN) (< 3 time the upper limit of normal for Gilbert’s disease),
• Serum ALT and AST < 1.5 x ULN for age,
• Creatinine clearance > 45ml / min using the Cockcroft and Gault formula,
• International Normalized Ratio (INR) or Prothrombin Time (PT) must be within the normal ranges as per institution's standard. A window of 5% is allowed.
• Patients receiving prophylactic/short-term low molecular weight heparin are allowed to participate as long as the PT/INR values are within the expected target range of their current dose.
• Clinically normal cardiac function based on -left ventricular ejection fraction (≥ 50%) as assessed either by multi-gated acquisition scan or cardiac ultrasound and 12 lead ECG without clinically relevant abnormalities.
• Patients ≥ 18 years old and must be able to give written informed consent.
• Women of child-bearing potential must have a negative pregnancy test.
• Patients of childbearing / reproductive potential must agree to use highly effective methods of contraception based on the Clinical Trial Facilitation Group (CTFG) guidance as of registration and up to 6 months after the last treatment dose.
• Female subjects who are breast feeding should agree to discontinue nursing prior to the first dose of study treatment and up to 6 months after the last study treatment.
• Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations.
2 - Specific inclusion criteria
2.1 - Inclusion criteria for cohort I1
• no specific criteria
2.2 - Inclusion criteria for cohort B1 (p16 negative and EGFR amplification/mutation or PTEN high or HER2 amplification/mutation patients)
• Confirmed p16 negative immunohistochemistry (p16 positive is defined as H-score ≥ 210) on the fresh biopsy
• One of the following criteria:
- Confirmed EGFR amplification (amplification is defined as minimum 8 copies for 90% of the amplicons and > median + 2*standard deviations after normalization compared to population of reference)
- Activating/damaging EGFR mutation
- Confirmed HER2 amplification (amplification is defined as minimum 8 copies for 90% of the amplicons and > median + 2*standard deviations after normalization compared to population of reference)
- Activating/damaging HER2 mutation
- PTEN high (IHC: H-score > 150)
• Wild type for the known activating mutations in KRAS, NRAS and HRAS
2.3 - Inclusion criteria for cohort B2 (p16 negative and cetuximab naïve patients)
• Confirmed p16 negative immunohistochemistry (p16 positive is defined as H-score ≥ 210) on the fresh biopsy
• Cetuximab-naïve patient
• Wild type for the known activating/damaging mutations in KRAS, NRAS and HRAS
2.5 - Inclusion criteria for cohort B3 (p16 negative and CCND1 amplification patients)
• Confirmed p16 negative immunohistochemistry (p16 positive is defined as H-score ≥ 210) on the fresh biopsy
• Cyclin D1 amplification (amplification is defined as minimum 8 copies for 90% of the amplicons and > median + 2*standard deviation after normalization compared to population of reference) |
|
| E.4 | Principal exclusion criteria |
1 - General exclusion criteria
• Unresolved and significant toxicity CTCAE version 4.03 grade ≥ 2 from previous anticancer therapy other than alopecia.
• History of any of the following cardiovascular conditions within 6 months prior to registration:
• myocardial infarction,
• severe/unstable angina,
• ongoing cardiac dysrhythmias of CTCAE version 4.03 Grade 2 or more,
• atrial fibrillation of any grade,
• coronary/peripheral artery bypass graft,
• symptomatic congestive heart failure according to NYHA Class III or Class IV,
• Significant active cardiac disease including uncontrolled high blood pressure according to the CTCAE v 4.03 grade 3.
• Cerebrovascular accident including transient ischemic attack and thromboembolic event like symptomatic pulmonary embolism.
• Nasopharynx and sino-nasal tumor.
• Surgery or investigational drugs or chemotherapy or other anticancer therapy within 4w before registration. Curative radiation therapy (60-70 Gy) within 8w of registration. Palliative radiation therapy will be allowed.
• Known untreated and uncontrolled brain metastases or carcinomatous meningitis.
• Known diagnosis of immune deficiency or a known history of HIV (HIV 1/2 antibodies).
• Known active Hepatitis B or Hepatitis C or pre-existing liver cirrhosis.
• Known pre-existing ILD.
• Other uncontrolled active illnesses.
• Any psychiatric, psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
• Any malignancy (other than SCCHN, non-melanoma skin cancer or localized cervical cancer or localized and presumed cured prostatic cancer or basal cell carcinoma of the skin and carcinoma in situ of the cervix or bladder) within the last 3 years prior to registration.
2 - Specific exclusion criteria
2.1 - Exclusion criteria for cohort I1
• Prior treatment with anti-PD1 or anti-PD-L1 compounds
• Systemic treatment with steroids or other immunosuppressive agents within 7d prior to starting the study drug. The intermittent use of inhaled corticosteroids, local steroids, topical applications of steroids, eye drops, or local steroid injections is allowed. Physiological replacement with hydrocortisone or equivalent is also acceptable
• Active auto-immune disease treated with systemic immunosuppressive drugs within the last 3m or history of clinically severe auto-immune disease. Patients with stable diabetes type 1, resolved childhood asthma/atopy, Sjorgren syndrome are allowed to participate.
• Treatment with cytokines or growth factors
• Known hypersensitivity to monalizumab or its excipients.
2.2 - Exclusion criteria for cohort B1 (p16 negative and EGFR amplification/mutation or PTEN high or HER2 amplification/mutation patients)
• Patients with hereditary conditions of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
• Unresolved skin toxicities CTCAE v4.03 grade >1 caused by prior treatment with EGFR targeted antibodies.
• Treatment with any of the prohibited concomitant medications related to afatinib that cannot be stopped at the time of trial participation.
• Significant or recent acute gastrointestinal disorders with diarrhea as major symptom .
• Known hypersensitivity to afatinib or the excipients of any of the trial drugs.
2.3 - Exclusion criteria for cohort B2 (p16 negative and cetuximab naïve patients)
refer to 2.2
2.4 Exclusion criteria for cohort B3 (p16 negative and CCND1 amplification patients)
• Food or drugs that are known to be CYP3A4 inhibitors or inducers listed in Appendix I related to palbociclib.
• Drugs that are known to prolong the QT interval. QTc >480 msec, personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation, or Torsade de Pointes (TdP).
• Uncontrolled electrolyte disorders that can compound the effects of a QTc-prolonging drug.
• Known hypersensitivity to palbociclib and its excipients.
• Patients who received prior radiotherapy to 25% of bone marrow are not eligible independent of when it was received.
• Inability to swallow or feeding tube.
• Significant acute gastro-intestinal disorders with diarrhea as a major symptom. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Depending on the patient cohort
1 - cohorts I1: objective response rate (ORR) according to RECIST 1.1
2 - cohort B1 to B3: progression free survival rate (PFSR) at 16 weeks |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Depending on the patient cohort
1 - cohorts I1: every 8 weeks
2 - cohort B1 to B3: at 16 weeks. |
|
| E.5.2 | Secondary end point(s) |
1 - The percentage of patients included in each patient cohort according the biomarker testing (number of patients included/number of patients screened).
2 - Description of the genetic abnormalities of the screened population
3 - The percentage of patients with an evaluable fresh tumor biopsy
4 - Progression free survival
5 - Objective response rate according to RECIST 1.1, if not primary endpoint
6 - Response duration
7 - Objective response rate according to iRECIST (for immunotherapy patient cohort)
8 - Toxicity according CTCAE version 4.03
9 - Overall survival |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1 - at randomization/treatment allocation
2 - at randomization/treatment allocation
3 - at randomization/treatment allocation
4 - every 8 weeks
5 - every 8 weeks
6 - every 8 weeks
7 - at 6 months
8 - every 8 weeks
9 - every 8 weeks |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Umbrella trial - cohorts B1 to B3 are controlled and randomized, cohorts I1 is not |
|
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
| Only for cohorts B1 to B: Best treatment of choice of the investigator (may be best supportive care) |
|
| E.8.2.4 | Number of treatment arms in the trial | 7 |
| 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 | 7 |
| 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 |
|
| 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
|
1. At least thirty days after the end of the protocol treatment of the last patient
2. Provided all patients have finished protocol specific procedures, not being otherwise part of the standard clinical practice.
3. Provided the trial is mature for the analysis of the primary endpoint of all patient cohorts
4. The database has been fully cleaned and frozen for this analysis |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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