| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| resectable, locally advanced squamous cell carcinoma of the oral cavity |
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| E.1.1.1 | Medical condition in easily understood language |
| resectable, locally advanced squamous cell carcinoma of the oral cavity |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 |
| Evaluate the biological response in the tumor upon treatment with durvalumab, and in parallel, with combination of durvalumab and tremelimumab. |
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| E.2.2 | Secondary objectives of the trial |
The feasibility to use a 68 Ga-ligand CXCR4 immunotracer PET-MR to measure immune response in the tumor
Safety analysis of addition of durvalumab with or without tremelimumab to standard of care treatment
LRC, TTF and OS after treatment, combining durvalumab (arm 1) or durvalumab + tremelimumab (arm 2) with SOC treatment (radiotherapy with or without chemotherapy)
PD-L1 testing before and after single dose of durvalumab and/or tremelimumab
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Age ≥18 years at the time of screening
• Written informed consent obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations.
• Histologically or cytologically confirmed resectable locally advanced stage IV SCC of the oral cavity. Staging will be performed according to 7th Edition of the AJCC/UICC Staging System.
• No prior systemic therapy for SCCHN disease is allowed.
• No prior radiation therapy in the head and neck is allowed
• No active second malignancy during the last five years except non-melanomatous skin cancer or carcinoma in situ
• Able and willing to give valid written consent to provide newly acquired tumor tissue for the purpose of the analyses defined in the protocol.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at enrollment
• Body weight > 30 kg
• Patients must have no prior exposure to immune-mediated therapy, including anti-CTLA-4,including tremelimumab anti-PD-1, anti–PD-L1including durvalumab, or anti–programmed cell death ligand 2 antibodies, excluding therapeutic anticancer vaccines.
• Adequate organ and marrow function:
o Adequate bone marrow function demonstrated by neutrophils count ≥ 1,500/mm3, platelet count ≥ 100,000/mm3, Haemoglobin ≥ 9.0 g/dL
Adequate hepatic function: AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be ≤ 5x ULN; bilirubin ≤ 1.5 times upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia [predominantly unconjugated bilirubin] in the absence of evidence of hemolysis or hepatic pathology), who will be allowed in consultation with their physician.
o Adequate renal function as demonstrated by serum creatinine ≤ 1.5 mg/dL (< 133 μmol/L) or calculated creatinine clearance ≥ 50 ml/min as determined by CKD-EPI [51] –
o Prothrombin time (PT) or international normalized ratio (INR) < or = 1.2 times (ULN)
o Partial thromboplastin time (PTT) < or = 1.2 times ULN
• Adequate cardiac function assessed by 12-lead ECG
• Availability of blood samples for Translational research
• Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and 6 months beyond stop of treatment in such a manner that the risk of pregnancy is minimized. In general, the decision for appropriate methods to prevent pregnancy should be determined by discussions between the investigator and the study subject. WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal. Females should not be pregnant or breast feeding. Males should not father a baby while on this study and 6 months beyond because the drugs in this study can affect an unborn baby.
o Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments or if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution.
o Women <50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution, or had radiation-induced oophorectomy with last menses >1 year ago, or had chemotherapy-induced menopause with >1 year interval since last menses, or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
• No participation in another interventional clinical trial in the preceding 30 days prior to randomization
• Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
Before patient registration, written informed consent must be given according to ICH/GCP, and national/local regulations
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| E.4 | Principal exclusion criteria |
• Histologically or cytologically confirmed head and neck cancer of any other primary anatomic location in the head and neck not specified in the inclusion criteria including patients with SCCHN of unknown primary or non-squamous histologies (eg, salivary gland)
• Receipt of:
o any radiotherapy or hormonal therapy for cancer treatment within 30 days prior to first dose of study treatment.
o any previous radiation therapy in the head and neck
o any previous systemic therapy for SCCHN
o any investigational anticancer therapy within 28 days or 5 half-lives, whichever is longer, prior to the first dose of study treatment.
• Current or prior use of immunosuppressive medication within 14 days before the first dose of their assigned IP. The following are exceptions to this criterion unless otherwise indicated:
o Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular injection)
o Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
o Steroids as pre-medication for hypersensitivity reactions (eg, CT scan pre-medication) and/or as anti-emetics for the SoC arm
• History of allogeneic organ transplantation
• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, Crohn’s disease] with the exception of a prior episode that has resolved; systemic lupus erythematosus; Wegener syndrome [granulomatosis with polyangiitis]; myasthenia gravis; Graves’ disease; rheumatoid arthritis) within the past 3 years prior to the start of treatment. The following are exceptions to this criterion:
o Patients with vitiligo or alopecia
o Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement
o Psoriasis not requiring systemic treatment
• 11. Uncontrolled intercurrent illness, including, but not limited to ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, or psychiatric illness or social situations that would limit compliance with study requirements or substantially increase the risk of incurring AEs from IP
• Active second malignancy during the last five years except for the following: non melanomatous skin cancer that has been surgically cured, non-invasive malignancies, such as carcinoma in situ. Other in situ carcinomas that have been adequately treated may be permitted.
• Mean QT interval corrected for heart rate ≥470 ms
• History of active primary immunodeficiency
• Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
• Receipt of live, attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine during the study and up to 30 days after the last dose of IP.
• Female patients of childbearing potential who are pregnant or breast-feeding or who are not willing to employ a highly effective method of birth control from screening to 90 days after the last dose of IP therapy and non-sterilized male patients who are sexually active with a female partner of childbearing potential who are not willing to employ male condom plus spermicide from screening to 90 days after the last dose of IP therapy
• Known allergy or hypersensitivity to IP or any IP excipient
• Any condition that, in the opinion of the Investigator, would interfere with evaluation of the IP or interpretation of patient safety or study results
• Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria
Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician.
Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab may be included only after consultation with the Study Physician.
• Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable.
• Distant metastasis
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary objective is to evaluate the biological response by means of CD8 infiltration density in the tumor upon treatment with durvalumab, and in parallel, with combination of durvalumab and tremelimumab on the biopsy (before treatment) and on the resection specimen (after 1 cycle of treatment). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| CD8 infiltration density will be assessed by immunohistochemistry on the biopsy and on the resection specimen. A >1.5-fold increase of CD8 infiltration density would be considered a treatment success. |
|
| E.5.2 | Secondary end point(s) |
1 imaging:Response after 14 days of treatment, prior to surgery, evaluated by 68Ga-CXCR-4 PET/MR. RECIST v1.1 will be used to compare MRI images (as part of the 68Ga-CXCR-4 PET/MR) to preoperative imaging.
2 Locoregional control, time to treatment failure and overall survival->will be evaluated up to 2 years after surgery
3 safety analysis
4 endpoints involve the evaluation of outcome prediction by several biomarkers |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1 after 14 days of treatment, prior to surgery
2will be evaluated up to 2 years after surgery
3 if the first 3 patients in arm 1 do not develop unexpected severe toxicity related to concurrent treatment with cisplatin and radiotherapy, new patients are allowed to be treated according to the protocol |
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| 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 | No |
| 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 | 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| 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
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| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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