| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with recurrent or metastatic PD-L1-negative squamous cell carcinoma of the head and neck (SCCHN) |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 | 10067821 |
| E.1.2 | Term | Head and neck cancer |
| 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 MEDI4736 + tremelimumab combination therapy in terms of ORR |
|
| E.2.2 | Secondary objectives of the trial |
To further assess the efficacy of MEDI4736 + tremelimumab combination therapy in terms of ORR, TTR, DoR, DCR, BoR, PFS, and OS;
To assess the efficacy of MEDI4736 + tremelimumab combination therapy compared with a) MEDI4736 monotherapy and b) tremelimumab monotherapy, in terms of ORR, PFS and OS;
To explore symptoms and health-related QoL in patients with MEDI4736 monotherapy, tremelimumab monotherapy, and MEDI4736 + tremelimumab combination therapy using the EORTC QLQ-C30 v3 and the H&N35 module
|
|
| 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 |
AstraZeneca intends to perform genetic research in the MEDI4736
clinical development program to explore how genetic variations may
affect the clinical parameters associated with this drug. Collection of
DNA samples from populations with well-described clinical
characteristics may lead to improvements in the design and
interpretation of clinical trials and, possibly, to genetically guided
treatment strategies.
The objective of this research is to collect and store DNA, derived from a
blood sample, for
future exploratory research into genes/genetic variations that may
influence response, ie,
distribution, safety, tolerability, and efficacy of MEDI4736, and/or
susceptibility to SCCHN.
All enrolled patients who take part in the main study will be asked to
participate in this genetic
research. Participation is voluntary. For inclusion in this genetic research, patients must fulfil all of the inclusion criteria described in the
main body of the Clinical Study Protocol and provide informed consent
for the genetic sampling and analyses.
Blood samples will ideally be collected during the screening/baseline
period. If for any reason
the sample is not drawn during the screening/baseline period, it should
be taken as soon as
possible, but not later than the last study visit. Only 1 sample should be
collected per patient for genetics during the study. |
|
| E.3 | Principal inclusion criteria |
1) Age ≥18 years at the time of screening;
2) Written informed consent and any locally required authorization;
3) Histologically confirmed recurrent or metastatic SCCHN (oral cavity, oropharynx, hypopharynx, or larynx) not amenable to therapy with curative intent (surgery or radiation therapy with or without chemotherapy). Patients who refuse radical resection are eligible;
4) Tumor progression or recurrence during or after treatment with only 1 systemic palliative regimen for recurrent or metastatic disease that must have contained a platinum agent. Patients who have only received chemo-radiation with curative intent for treatment of their locally advanced disease or recurrent disease are not eligible. Patients who received concurrent chemo-radiation aas part of treatment of their recurrent disease are also not eligible;
5) Able and willing to give valid written consent to provide newly acquired tumor tissue (preferred) or archival tissue (<3 years old) for the purpose of establishing PD-L1 status. Tumor lesions used for newly acuired biopsies should not be the same lesions used as RECIST 1.1 target lesions, unless there are no other lesions suitable for biopsy;
6) Confirmed PD-L1-negative SCCHN by the Ventana SP263 assay on newly acquired tumor tissue (preferred) or archival tissue (<3 years old). If the patient's PD-L1 status has already been assessed using the analytically validated Ventana assay as part of the Screening process for another AstraZeneca/Medimmune study, this test can be used for the determination of eligibility;
7) WHO/ECOG performance status of 0 or 1 at enrollment;
8) At least 1 lesion, not previously irradiated, that can be accurately measured at baseline as ≥10 mm in the longest diameter (except lymph nodes which must have short axis ≥15 mm) with CT or MRI and that is suitable for accurate repeated measurements as per RECIST 1.1 guidelines;
9) Patients must have no prior exposure to immune-mediated therapy, including other anti-CTLA-4, anti-PD-1, anti-PD-L1, or anti-PD-L2 antibodies, excluding therapeutic anticancer vaccines. Exposure to other investigational agents may be permitted after discussion with the Sponsor;
10) Adequate organ and marrow function independent of transfusion for at least 7 days prior to screening and independent of growth factor support for at least 14 days prior to screening, defined as: Hemoglobin ≥9 g/dL, Absolute neutrophil count ≥1500/mm3, Platelet count ≥100000/mm3, Serum bilirubin ≤1.5 × the upper limit of normal (ULN), ALT and AST ≤2.5 × ULN; for patients with hepatic metastases, ALT and AST≤5 × ULN, Calculated creatinine clearance ≥40 mL/min as determined by Cockcroft-Gault;
11) Evidence of post-menopausal status, or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. |
|
| E.4 | Principal exclusion criteria |
1) Histologically confirmed squamous cell carcinoma of any other primary anatomic location in the head and neck, patients with squamous cell carcinoma of the head and neck of unknown primary, and non squamous histologies;
2) Received more than 1 systemic palliative regimen for recurrent or metastatic disease; 3) Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions is acceptable;
4) Prior randomization or treamtent in a previous MEDI4736 and / or tremelimumab clinical study regardless of treamtent arm assignement or receipt of any investigational anticancer therapy within 28 days or 5 half-lives, whichever is longer, prior to the first dose of study treatment;
5) Receipt of last dose of an approved (marketed) anticancer therapy within 21 days prior to the first dose of study treatment. If sufficient washout time has not occurred due to the schedule or PK properties of an agent, a longer washout period will be required, as agreed upon by AstraZeneca and the Investigator;
6) 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;
7) 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 criterion: *- Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis and may be included after consultation with the Study Physician, **- Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with their assigned IP may be included after consultation with the Study Physician;
8) 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: * - Intranasal, inhaled, topical steroids, or local steroid injections, ** - Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent, *** - Steroids as pre-medication for hypersensitivity reactions;
9) History of allogeneic organ transplantation;
10) Active or prior documented autoimmune or inflammatory disorders (eg, inflammatory bowel disease, diverticulitis with the exception of a prior episode that has resolved or diverticulosis, celiac disease, , or other serious GI chronic conditions associated with diarrhea; systemic lupus erythematosus; Wegener syndrome; myasthenia gravis; Graves’ disease; rheumatoid arthritis, hypophysitis, uveitis, etc) within the past 3 years prior to the start of treatment. The following are exceptions to this criterion: * - Patients with vitiligo or alopecia, ** - Patients with hypothyroidism stable on hormone replacement or other chronic skin conditions 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, substantially increase the risk of incurring AEs from MEDI4736 or tremelimumab, or compromise the ability of the patient to give written informed consent;
12) History of another primary malignancy except for: * - Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of study drug and of low potential risk for recurrence, ** - Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease, *** - Adequately treated carcinoma in situ without evidence of disease eg, cervical cancer in situ;
13) Patients with history of brain metastases, spinal cord compression, or leptomeningeal carcinomatosis, or involvement of any other anatomic area that, in the opinion of the Investigator, may cause significant symptoms if an inflammatory reaction occurs;
14) History of active primary immunodeficiency;
15) Known history of previous clinical diagnosis of tuberculosis;
16) Active infection including hepatitis B, hepatitis C or HIV;
17) 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 both IPs;
18) Female patients who are pregnant or breast-feeding or male or female patients of reproductive potential who are not willing to employ effective birth control;
19) Mean QT interval corrected for heart rate ≥470 ms calculated from 3 ECGs using Fridericia’s Correction;
20) Known allergy or hypersensitivity to IP or any IP excipient;
|
| 21) Any condition that, in the opinion of the Investigator, would interfere with evaluation of the IP or interpretation of patient safety or study results. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is ORR. ORR is defined as the number (%) of patients with a confirmed overall response of CR (complete response) or PR (partial response) and will be based on all treated patients who have measurable disease at baseline per BICR (Evaluable Analysis Set). A confirmed response of CR/PR means that a response of CR/PR is recorded at one visit and confirmed by repeat imaging not less than 4 weeks after the visit when the response was first observed with no evidence of progression between the initial and CR/PR confirmation visit. Therefore, data obtained up until progression, or the last evaluable assessment in the absence of progression, will be included in the assessment of ORR. Any patient who discontinues treatment without progression, receives a subsequent therapy, and then responds will not be included as responders in the ORR. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The initial data cut-off will take place approximately 6 months after the last patient is first dosed. All study endpoints will be analyzed at this time with the exception of OS (overall survival). A further analysis of all study endpoints including OS will take place approximately 12 months after the last patient is dosed. A final analysis of OS and safety will be conducted approximately 18 months after the last patient is dosed. |
|
| E.5.2 | Secondary end point(s) |
1) Duration of response (DoR) will be defined as the time from the date of first documented response until the first date of documented progression or death in the absence of disease progression. The end of response should coincide with the date of progression or death from any cause used for the RECIST 1.1 PFS (Progression-free survival) endpoint. The denominator for DoR will be defined as described for ORR.
2) Disease control rate (DCR) at 4, 6 or 12 months is defined as the percentage of patients who have a best objective response (BoR) of CR or PR in the first 4, 6 or 12 months, respectively, or who have demonstrated SD (Stable disease) for a minimum interval of 16, 24 or 52 weeks, following randomization. As additional analysis, DCR at 6 months will also be assessed as % of patients who have a BoR of CR or PR in the first 6 months or who have demonstrated SD for a minimum interval of 12 weeks following randomization.
3) Progression-free survival (PFS) will be defined as the time from the date of randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from therapy or receives another anticancer therapy prior to progression. Patients who have not progressed or died at the time of analysis will be censored at the time of the latest date of assessment from their last evaluable RECIST 1.1 assessment.
4) Overall survival (OS) is defined as the time from the date of randomization until death due to any cause. Any patient not known to have died at the time of analysis will be censored based on the last recorded date on which the patient was known to be alive.
Survival calls will be made in the week following the date of data cut-off (DCO) for the analysis, and if patients are confirmed to be alive or if the death date is post the DCO date, these patients will be censored at the date of DCO. Death dates may be found by checking publicly available death registries.
5) Best objective response (BoR) is calculated based on the overall visit responses from each RECIST assessment. It is the best response a patient has had during their time in the study up until RECIST progression (or confirmed progression where applicable) or the last evaluable assessment in the absence of RECIST progression. CR or PR must be confirmed. BoR will be determined programmatically based on RECIST using ICR data using all data up until the first progression event. It will also be assessed using the irRC (Immune-related response criteria) data obtained from ICR.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) DoR - will be defined as the latest of the dates contributing towards the first visit response of CR or PR;
2) DCR - in the first 4, 6 or 12 mos;
3) PFS - from the date of randomization until the date of objective disease progression or death. PFS time will always be derived based on scan/assessment dates not visit dates;
4) OS - the final analysis of OS will be conducted following the OS Extension DCO (data cut off), which will occur approx. 30 month after LPD (last patient dosed);
5) BoR - if the death occurs ≤17 weeks after enrollment, then BoR will be assigned to PD category, if the death occurs >17 weeks BoR will be assigned to the NE category.
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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 | 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 | Yes |
| 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 | No |
| E.8.1.1 | Randomised | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 45 |
| 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 |
| Belgium |
| Canada |
| Czech Republic |
| France |
| Germany |
| Hungary |
| Spain |
| United Kingdom |
| United States |
|
| 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
|
| The study will continue until the last patient completes 90 days of follow-up after re-treatment or the last patient withdraws from the progression-free follow-up, whichever occurs first. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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