Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN)

Primary objective: -To assess the efficacy of MEDI4736 monotherapy and MEDI4736 + tremelimumab combination therapy versus SoC in terms of PFS and OS Secondary objectives: -To further assess the efficacy of MEDI4736 monotherapy and MEDI4736 + tremelimumab combination therapy 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 monotherapy and MEDI4736 + tremelimumab combination therapy versus SoC using the EORTC QLQ-C30 v3 and the H&N35 module Safety objective: -To assess the safety and tolerability profile of MEDI4736 monotherapy and MEDI4736 + tremelimumab combination therapy compared to SoC

MEDI4736

MEDI4736
Tremelimumab

Vial
vial

500mg
400mg

Primary Outcome Measures :
1. Overall Survival (OS) [ Time Frame: September 2015 to September 2018 (36 months) ]
OS is defined as the time from the date of randomization until death due to any cause. OS was analyzed for the full analysis set, regardless of programmed death-ligand 1 (PD-L1) status.


Secondary Outcome Measures :
1. Overall Survival (OS) in PD-L1 Negative Participants [ Time Frame: September 2015 to September 2018 (36 months) ]
OS is defined as the time from the date of randomization until death due to any cause. PD-L1 negative was defined as <25% of tumor cells with membrane staining for PD-L1 at any intensity.

2. Overall Survival (OS) in PD-L1 Positive Participants [ Time Frame: September 2015 to September 2018 (36 months) ]
OS is defined as the time from the date of randomization until death due to any cause. PD-L1 positive was defined as ≥25% of tumor cells with membrane staining for PD-L1 at any intensity.

3. Progression Free Survival (PFS) [ Time Frame: September 2015 to September 2018 (36 months) ]
PFS was defined as the time from the date of randomization until the date of objective disease progression or death based on investigator assessments, according to response evaluation criteria in solid tumors 1.1 (RECIST1.1). Objective disease progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

4. Objective Response Rate (ORR) [ Time Frame: Assessed at randomization and every 8 weeks thereafter ]
The percentage of participants who experienced an objective response (complete response [CR] or partial response [PR]), based on investigator assessments according to response evaluation criteria in solid tumors 1.1 (RECIST1.1). A CR was defined as the disappearance of all target lesions (TLs) since baseline. Any pathological lymph nodes selected as TLs must have a reduction in short axis to <10 mm. A PR was defined as at least a 30% decrease in the sum of the diameters of TLs, taking as reference the baseline sum of diameters.

5. Duration of Response (DoR) [ Time Frame: September 2015 to September 2018 (36 months) ]
Median DoR, in months, based on investigator assessments, according to response evaluation criteria in solid tumors 1.1 (RECIST1.1). A complete response was defined as the disappearance of all target lesions (TLs) since baseline. Any pathological lymph nodes selected as TLs must have a reduction in short axis to <10 mm. A partial response was defined as at least a 30% decrease in the sum of the diameters of TLs, taking as reference the baseline sum of diameters.

6. Disease Control Rate (DCR) [ Time Frame: Baseline up to 6 months; baseline up to 12 months ]
6 Months: The percentage of participants who had a best objective response of complete response (CR) or partial response (PR) in the first 6 months or had demonstrated stable disease (SD) for a minimum interval of 24 weeks following randomization.
12 Months: The percentage of participants who had a best objective response of CR or PR within 12 months or had demonstrated SD for a minimum interval of 48 weeks following randomization.
Objective response was based on investigator assessments, according to response evaluation criteria in solid tumors 1.1 (RECIST1.1). A CR was defined as the disappearance of all target lesions (TLs) since baseline. Any pathological lymph nodes selected as TLs must have a reduction in short axis to <10 mm. A PR was defined as at least a 30% decrease in the sum of the diameters of TLs, taking as reference the baseline sum of diameters.

7. Percentage of Participants Alive and Progression Free (APF) [ Time Frame: Baseline up to 6 months; baseline up to 12 months ]
APF is defined as the percentage of participants who are alive and progression free at 6 months and 12 months after randomization. Estimates of progression free survival were based on investigator assessments according to response evaluation criteria in solid tumors 1.1 (RECIST1.1). Objective disease progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

8. Percentage of Participants Alive [ Time Frame: 12, 18 and 24 months ]
Percentage of participants alive at 12, 18 and 24 months using a Kaplan Meier estimate.

9. Progression Free Survival (PFS) in PD-L1 Negative Participants [ Time Frame: September 2015 to September 2018 (36 months) ]
Number of participants with confirmed objective disease progression (PD) at the time of the participant's last evaluable response evaluation criteria in solid tumors 1.1 (RECIST1.1) assessment. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. PD-L1 negative was defined as <25% of tumor cells with membrane staining for PD-L1 at any intensity.

10. Objective Response Rate (ORR) in PD-L1 Negative Participants [ Time Frame: September 2015 to September 2018 (36 months) ]
The percentage of PD-L1 negative participants who experienced an objective response (complete response [CR] or partial response [PR]), based on investigator assessments according to response evaluation criteria in solid tumors 1.1 (RECIST1.1). A CR was defined as the disappearance of all target lesions (TLs) since baseline. Any pathological lymph nodes selected as TLs must have a reduction in short axis to <10 mm. A PR was defined as at least a 30% decrease in the sum of the diameters of TLs, taking as reference the baseline sum of diameters. PD-L1 negative was defined as <25% of tumor cells with membrane staining for PD-L1 at any intensity.

11. Time to Deterioration in European Organisation for Research and Treatment of Cancer 30-item Core Quality of Life Questionnaire, Version 3 (EORTC QLQ-C30) [ Time Frame: September 2015 to September 2018 (36 months) ]
The EORTC QLQ-C30 consists of 30 questions that can be combined to produce functional scales (e.g. physical), symptom scales (e.g. fatigue), and a global measure of health status. Each of the scales are measured from 0 to 100. Deterioration was defined as a 10-point decrease from baseline in a functioning or global health status/ quality of life score or a 10-point increase from baseline in a symptom score.

12. Time to Deterioration for European Organisation for Research and Treatment of Cancer 35-item Head and Neck Quality of Life Questionnaire (EORTC QLQ-H&N35) [ Time Frame: September 2015 to September 2018 (36 months) ]
The EORTC QLQ-H&N35 comprises of 35 questions to assess head and neck cancer symptoms (e.g. pain, swallowing). Deterioration was defined as a 10-point increase from baseline in the symptom score.

13. Number of Participants Reporting One or More Adverse Events (AE) [ Time Frame: First dose to last dose + 90 days or data cut off (up to 36 months) ]
An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. Inclusive of AEs and serious AEs.

Inclusion criteria
For inclusion in the study, patients should fulfill the following criteria:
1. Age ≥18 years at the time of screening
2. Written informed consent and any locally required authorization (eg, Health
Insurance Portability and Accountability Act in the United States, European Union
[EU] Data Privacy Directive in the EU) 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 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 1 regimen for
recurrent or metastatic disease that must have contained platinum OR progression
within 6 months from multimodality therapy containing platinum (for either locally
advanced disease or recurrent/metastatic disease).
5. Able and willing to give valid written consent to undergo a fresh tumor biopsy for
the purpose of screening for this clinical trial or to provide an available archival
tumor sample taken less than 3 months ago if a fresh tumor biopsy is not feasible
with an acceptable clinical risk. Tumor lesions used for fresh biopsies should not
be the same lesions used as RECIST target lesions, unless there are no other lesions
suitable for biopsy.
6. Confirmed PD-L1-positive or -negative SCCHN by a specified IHC assay on a
recent sample (<3 months) or fresh tumor biopsy
- Regardless of the age of the test result, if the patient’s PD-L1 status has
already been assessed using the Ventana 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 no intervening therapy has
been administered.
- Note: A positive PD-L1 sample is measured using a defined cut-off based on
≥25% of tumor cells with membrane staining of any intensity for PD-L1. A
negative PD-L1 sample is determined by 0% to 24% of tumor cells with
membrane staining for PD-L1.
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
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 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 and if they have luteinizing hormone and folliclestimulating 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, had radiation-induced oophorectomy with last menses
>1 year ago, had chemotherapy-induced menopause with >1 year interval since
last menses, or underwent surgical sterilization (bilateral oophorectomy or
hysterectomy).

Exclusion criteria
Patients should not enter the study if any of the following exclusion criteria are fulfilled:
1. Histologically 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 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. Note: Local treatment of isolated
lesions for palliative intent is acceptable (eg, local surgery or radiotherapy).
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 (marketed) anticancer therapy (chemotherapy, targeted therapy,
biologic therapy, mAbs, etc.) 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.
5. 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.
6. 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 (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:
 Intranasal, inhaled, topical steroids, or local steroid injections
(eg, intra-articular injection)
 Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
prednisone or its equivalent
 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
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
[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:
 Patients with vitiligo or alopecia
 Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on
hormone replacement or psoriasis 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
 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
12. Patients with a 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 Fridericia’s Correction
14. History of active primary immunodeficiency
15. Known history of previous clinical diagnosis of 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.
Note: Patients, if enrolled, should not receive live vaccine during the study and up
to 30 days after the last 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 IP for those 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