| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Recurrent or metastatic PD-L1-positive or negative squamous cell carcinoma of the head and neck (SCCHN). |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 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 versus SoC in terms of OS |
|
| E.2.2 | Secondary objectives of the trial |
- To further assess the efficacy of MEDI4736 + tremelimumab
combination therapy versus SoC in terms of OS.
- To assess the efficacy of MEDI4736 monotherapy versus SoC in terms
of OS
- To further assess the efficacy of MEDI4736 monotherapy versus SoC in
terms of OS
- To further assess the efficacy of MEDI4736 + tremelimumab
combination therapy and MEDI4736 monotherapy versus SoC in terms of PFS, ORR, DoR, DCR, APF6, APF12, OS12, OS18, and OS24
- To explore symptoms and HRQoL in patients treated with MEDI4736 +
tremelimumab combination therapy and MEDI4736 monotherapy versus SoC 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 obtained from the patient/legal
representative prior to performing any protocol-related procedures, including screening evaluations. (For patients aged <20 years and enrolling in Japan, a written informed consent should be obtained from the patient and his or her legally acceptable representative.)
3. Histologically or cytologically 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 only one pallative
systemic treatment regimen for recurrent or metastatic disease that
must have contained a platinum agent OR progression within 6 months
of completion of platinum-containing multimodality therapy with
curative intent.
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 fresh
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-positive or -negative SCCHN by the Ventana PD-L1
SP263 IHC 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
Ventana PD-L1 SP263 IHC assay as a part of the screening process for
another AstraZeneca/MedImmune study, this test result can be used for the determination of eligibility, provided the PD-L1 status was obtained on tissue within the last 3 years.
7. WHO/Eastern Cooperative Oncology Group (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 a short axis ≥15 mm) with CT or MRI and that is suitable for accurate repeated measurements as per RECIST 1.1 guidelines. Lesions in a previously irradiated field can be used as measurable disease provided that there has been demonstrated progression in the lesion.
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 below. Patients
requiring routine transfusions should be discussed with the Sponsor. -Hemoglobin ≥9 g/dL
-Absolute neutrophil count ≥1500/mm3
-Platelet count ≥100000/mm3
-Serum bilirubin ≤1.5 × the 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.
- 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
(using actual body weight)
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.
The following age-specific requirements apply:
- 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.
-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 have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution, 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). |
|
| E.4 | Principal exclusion criteria |
1. Histologically or cytologically confirmed squamous cell carcinoma of any other primary anatomic location in the head and neck not specified in the inclusion criteria, patients with SCCHN of unknown primary, and non-squamous histologies (eg, nasopharynx or salivary gland)
2. Received more than 1 palliative systemic 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 (eg, hormone replacement therapy) is acceptable.
4. Receipt of any investigational anticancer therapy within 28 days or 5 half-lives, whichever is longer, prior to the first dose of study treatment. Receipt of last dose of an approved 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 AZ and the Investigator.
5. Major surgical procedure (as defined by the Investigator) within 28 days prior to the
first dose of IP.
6. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, lymphopenia and the laboratory values defined in the inclusion criterion
(i) Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis and may be included after consultation with the Study Physician. (ii) Patients with a toxicity not reasonably expected to be exacerbated by treatment with their assigned IP (eg, hearing loss) may be included after consultation with the Study Physician.
7. 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:
(i) Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular injection) (ii)Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent (iii) Steroids as pre-medication for hypersensitivity reactions (eg, CT scan pre-medication)
8. History of allogeneic organ transplantation
9. Active or prior documented autoimmune or inflammatory disorders (including colitis, Crohn’s 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 [granulomatosis with polyangiitis]; 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:
(i) Patients with vitiligo or alopecia; (ii) Patients with hypothyroidism stable on hormone replacement or any skin condition not requiring systemic treatment.
10. 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 IP, or compromise the ability of the patient to give written informed consent
11.History of another primary malignancy except for
(i) 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 (ii) Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease (iii) Adequately treated carcinoma in situ without evidence of disease e.g. cervical cancer in situ
12. 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.
13. Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 electrocardiograms (ECGs) using Friderica’s Correction
14. History of active primary immunodeficiency
15. Active tuberculosis
16. Active infection including hepatitis B, hepatitis C, or human immunodeficiency virus (HIV)
17. Receipt of live, attenuated vaccine within 30 days prior to the first dose of IP.
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 from screening to 90 days after the last dose of randomized to the monotherapy MEDI4736 arm and 180 days after the last dose of IP for those randomized to the MEDI4736 + tremelimumab arm.
19. Known allergy or hypersensitivity to IP or any IP excipient |
20. Any condition that, in the opinion of the Investigator, would interfere with evaluation of the IP or interpretation of patient safety or study results
21. For subjects randomized to the standard of care arm: Any contraindication to a specific standard of care agent as specified by the accompanying package insert/SmPC will require subjects to receive an alternate SOC agent specified in the protocol.
22. Prior randomization or treatment in a previous MEDI4736 and/or
tremelimumab clinical study, regardless of treatment arm assignment |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- 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.
- Progression-free survival: PFS (per RECIST 1.1 as assessed by the BICR) 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 randomized 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. However, if the patient progresses or dies after 2 or more missed visits, the patient will be censored at the time of the latest evaluable RECIST 1.1 assessment. If the patient has no evaluable visits or does not have baseline data, they will be censored at 0 days unless they die within 2 visits of baseline. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
-OS: time from the date of randomization until death due to any cause.
-PFS: time from the date of randomization until the date of objective disease progression or death. |
|
| E.5.2 | Secondary end point(s) |
- Progression-free survival: PFS PFS (per RECIST 1.1 as assessed by the
site Investigator) 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 (ie, date of event or censoring - date of randomization +1). 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. However, if the patient progresses or dies after 2 or more missed visits, the patient will be censored at the time of the latest evaluable RECIST 1.1 assessment prior to the 2 missed visits. If the patient has no evaluable visits or does not have baseline data, they will be censored at Day 1 unless they die within 2 visits of baseline, then they will be treated as an event with date of death as the event date.
- Objective response rate: ORR (per RECIST 1.1 as assessed by the site
Investigator) is defined as the number (%) of patients with at least 1
visit response of CR or PR and will be based on a subset of all randomized patients
- Duration of response: DoR is 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.
- Disease control rate: DCR at 6 months is defined as the percentage of
patients who have a best objective response (BoR) of CR or PR in the
first 6 months or who have demonstrated SD for a minimum interval of
24 weeks (-7 days, ie, 161 days) following the start of treatment with
IP. DCR at 12 months is defined as the percentage of patients who have
a BoR of CR or PR in the first 12 months or who have demonstrated SD
for a minimum interval of 48 weeks (-7 days, ie, 329 days) following the
start of treatment with IP.
- Proportion of patients alive and progression free at 6 months
- Proportion of patients alive and progression free at 12 months
- Proportion of patients alive at 12 months
- Proportion of patients alive at 18 months
- Proportion of patients alive at 24 months
- Best objective response: BoR is the best response a patient has had
during their time in the
study up until RECIST 1.1 or confirmed progression or the last evaluable
assessment. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
-PFS: time from the date of randomization until the date of objective
disease progression or death.
Other secondary endpoints: Duration of study for individual patients
|
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | 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 | 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 96 |
| 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 |
| Argentina |
| Australia |
| Belgium |
| Brazil |
| Bulgaria |
| Chile |
| Croatia |
| Czech Republic |
| France |
| Germany |
| Hungary |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Peru |
| 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
|
| Last visit of the last patient undergoing the study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| 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 | 3 |
| 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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