This is a non-randomized, open-label, Phase Ib/II study to assess the safety and efficacy of
azacitidine, durvalumab (MEDI4736), and tremelimumab combination therapy in the treatment of
patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck
(SCCHN) who have progressed during or after treatment with anti-PD-1, anti-PD-L1, or
anti-CTLA-4 monotherapy for recurrent and/or metastatic disease. The clinical trial is
studying drugs that can boost the participant's immune system against the cancer cells as a
possible treatment for head and neck cancer.
The study interventions involved in this study are:
- Azacitidine (Vidaza)
- Durvalumab (MEDI4736)
This research study is a Phase I clinical trial, which tests the safety of an investigational
drug and also tries to define the appropriate dose of the investigational drug to use for
further studies. "Investigational" means that the drugs are still being studied.
The FDA (the U.S. Food and Drug Administration) has not approved durvalumab (MEDI4736) or
tremelimumab as a treatment for any disease.
The FDA (the U.S. Food and Drug Administration) has not approved azacitidine for the
participant's specific disease but it has been approved for other uses.
This is a first in human study evaluating the safety of combining these three different
drugs. Durvalumab (MEDI4736) and tremelimumab are part of a family of proteins that make up
the immune system. The body generates these proteins, or antibodies, in response to foreign
substances (particles not typically found in the body such as bacteria and viruses) and these
antibodies can protect against infection. Durvalumab (MEDI4736) and tremelimumab are
antibodies that are being studied in several other clinical trials to see if it has an effect
in helping the immune system to recognize and eliminate abnormal cells in the body.
Investigators hope that azacitidine may increase the chance of the immune system to recognize
the cancer cells. Azacitidine has been tested in other research studies for similar reasons.
In this research study, the investigators are looking for the highest effective dose of
azacitidine in combination with durvalumab (MEDI4736) and tremelimumab to improve the natural
ability of the immune system to recognize and target head and neck cancer cells.
- Written informed consent and any locally-required authorization (e.g., HIPAA in the
UEU Data Privacy Directive in the EU) obtained from the subject prior to performing
any protocol-related procedures, including screening evaluations
- Age ≥ 18 years at time of study entry or adult male or female (according to age of
majority as defined as ≥18 years)
- 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
- Tumor progression or recurrence during or after treatment with anti-PD1, anti-PDL1,
anti-PDL2, anti-CTLA4, or other immune checkpoint inhibitor where the most recent dose
was given within 3 months prior to study registration.
- Must give valid written consent to provide archival FFPE and/or newly acquired tumor
tissue for the purpose of establishing baseline PD-L1 status as well as consent to
provide on- and/or post-treatment tumor biopsy sample.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at enrollment
- Life expectancy of > 6 months
- At least 1 lesion 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
- Adequate normal organ and marrow function as defined below (within 28 days prior to
- Hemoglobin ≥ 9.0 g/dL
- Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (> 1500 per mm3)
- Platelet count ≥ 100 x 109/L (>100,000 per mm3)
- Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN). This will not
apply to subjects with confirmed Gilbert's syndrome (persistent or recurrent
hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis
or hepatic pathology), who will be allowed only in consultation with their
- 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
- Serum creatinine level <1.5 x ULN and CL>40 mL/min by the Cockcroft-Gault formula
(Cockcroft and Gault 1976) or by 24-hour urine collection for determination of
--Creatinine CL (mL/min) = Weight (kg) x (140 - Age) 72 x serum creatinine (mg/dL)
--Creatinine CL (mL/min) = Weight (kg) x (140 - Age) x 0.85 72 x serum creatinine (mg/dL)
- Female subjects must either be of non-reproductive potential (ie, post-menopausal by
history: ≥60 years old and no menses for ≥1 year without an alternative medical cause;
OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of
bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry.
- Male subjects with a female partner of childbearing potential must commit to true
abstinence from heterosexual contact or commit to the use of male condom plus
spermicide throughout the course of the study, and avoid fathering a child during the
course of the study (including dose interruptions) and for 6 months following the last
dose of azacitidine.
- All men and women of childbearing potential must use acceptable methods of birth
control throughout the study as described below:
Females of childbearing potential: Recommendation is for at least one highly effective
contraceptive methods during the study and must agree to continue using such precautions
for 180 days after the last dose of investigational product.
Non-sterilized males : Non-sterilized male patients who are sexually active with a female
partner of childbearing potential must use male condom plus spermicide from screening
through 180 days after the last dose of investigational product.
-Subject is willing and able to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits and examinations including follo
- Involvement in the planning and/or conduct of the study (applies to AstraZeneca staff
and/or staff at the study site)
- Histologically confirmed squamous cell carcinoma of any other primary anatomic
location in the head and neck (eg. paranasal cavity) and non-squamous histologies (eg.
nasopharynx or salivary gland)
- 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
- Adequately treated carcinoma in situ without evidence of disease eg, cervical
cancer in situ
- Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy,
endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal
antibodies, other investigational agent) ≤ 21days prior to the first dose of study
- Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3
electrocardiograms (ECGs) using Fredericia's Correction
- Current or prior use of immunosuppressive medication within 28 days before the first
dose of durvalumab (MEDI4736) or tremelimumab, with the exceptions of intranasal and
inhaled corticosteroids or systemic corticosteroids at physiological doses, which are
not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid
- Any unresolved toxicity NCI CTCAE grade 2 from previous anti-cancer therapy with the
exception of alopecia, vitiligo, and the laboratory values defined in the inclusion
- 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.
- Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous
immunotherapy agent, or any unresolved irAE >Grade 1
- Abnormal coagulation parameters (PT >15 seconds, PTT>40 seconds, and/or INR >1.5)
- Active or prior documented autoimmune disease within the past 2 years NOTE: Subjects
with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within
the past 2 years) are not excluded.
- Active or prior documented inflammatory bowel disease (e.g., Crohn's disease,
- History of primary immunodeficiency
- History of allogeneic organ transplant
- History of hypersensitivity to durvalumab (MEDI4736), tremelimumab, or any excipient
- Known or suspected hypersensitivity to azacitidine or mannitol
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
angina pectoris, cardiac arrhythmia, myocardial infarction in the past 6 months,
active peptic ulcer disease or gastritis, active bleeding diatheses including any
subject known to have evidence of acute or chronic hepatitis B, hepatitis C or human
immunodeficiency virus (HIV), or psychiatric illness/social situations that would
limit compliance with study requirements or compromise the ability of the subject to
give written informed consent
- Known history of previous clinical diagnosis of tuberculosis
- Uncontrolled systemic fungal, bacterial or viral infection (defined as ongoing
signs/symptoms related to the infection without improvement despite appropriate
antibiotics, antiviral therapy and/or other treatment)
- History of leptomeningeal carcinomatosis
- Receipt of live attenuated vaccination within 30 days prior to study entry or within
30 days of receiving durvalumab (MEDI4736) or tremelimumab
- Female subjects who are pregnant, breast-feeding or male or female patients of
reproductive potential who are not employing an effective method of birth control
- Any condition that, in the opinion of the investigator, would interfere with
evaluation of study treatment or interpretation of patient safety or study results
- Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive
of but not limited to surgery, radiation and/or corticosteroids.
- Subjects with uncontrolled seizures.
- Female patients who are pregnant or breastfeeding or male or female patients of
reproductive potential who are not willing to employ effective birth control from
screening to 180 days after the last dose of azacitidine, durvalumab (MEDI4736) and/or
tremelimumab therapy. Lactating females must agree not to breast feed throughout this