Head and Neck CancerPhase 1NCT03019003
Oral Decitabine (ASTX727) and Durvalumab in Recurrent and/or Metastatic Head and Neck Cancer Patients
A Phase 1 study testing Oral Decitabine, Durvalumab and 5' Azacitidine in people with Head and Neck Cancer, run by Massachusetts General Hospital at 1 site in United States.
Trial summary
This is a non-randomized, open-label, Phase Ib study to assess the safety and efficacy of a DNA methyltransferase inhibitor and immune checkpoint inhibitor(s) (durvalumab and/or tremelimumab) combination therapy in the treatment of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Head and Neck Cancer
- What is being tested?
- Oral Decitabine, Durvalumab and 5' Azacitidine
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 13 participants
- Where
- 1 siteUnited States
- Study dates
- 20 Mar 2017to 24 Sep 2024
- Phase
- Phase 1
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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 are eligible.
- 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
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- 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 guidelines.
- Adequate normal organ and marrow function as defined below (within 28 days prior to study registration):
- 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 physician.
- 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 clearance:
- Males:
- --Creatinine CL (mL/min) = Weight (kg) x (140 - Age) 72 x serum creatinine (mg/dL)
- Females:
- --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
Who cannot join
- 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 of disease
- Adequately treated carcinoma in situ without evidence of disease eg, cervical cancer in situ
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- 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 drug
- 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 criteria.
- 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, ulcerative colitis)
- 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 period
Trial locations and contacts
1 site in 1 country.
United States1 site
Massachusetts General Hospital
Boston, Massachusetts, 02114
About this study
Official title: A Phase IB Rescue Study With Oral Decitabine (AStX727) and Durvalumab (MEDI4736) Combination Therapy in Recurrent and/or Metastatic Head and Neck Cancer Patients Who Have Progressed on Anti-PD-1, Anti-PD-L1, or Anti-CTLA-4 Monotherapy
This is a non-randomized, open-label, Phase Ib study to assess the safety and efficacy of a DNA methyltransferase inhibitor and immune checkpoint inhibitor(s) (durvalumab and/or 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:
- Oral Decitabine (ASTX 727) and 5' Azacytidine
- Durvalumab (MEDI4736) and Tremelimumab
Read the detailed description
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 head and neck cancer.
The FDA (the U.S. Food and Drug Administration) has not approved oral decitabine (ASTX 7272) or 5' Azacytidine 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 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 DNA methyltransferase inhibitors may increase the chance of the immune system to recognize the cancer cells.
In this research study, the investigators are looking for the highest effective dose of DNA methyltransferase inhibitors in combination with durvalumab (MEDI4736) and/or tremelimumab to improve the natural ability of the immune system to recognize and target head and neck cancer cells.
- Conditions
- Head and Neck Cancer
- Being tested
- Oral Decitabine, Durvalumab, 5' Azacitidine, Tremelimumab
- Keywords
- Head and Neck Cancer
- Medical subject headings
- Head and Neck Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Oral DecitabineDrug
Also called ASTX 727
DNA methyltransferase inhibitor
DurvalumabDrug
Also called MEDI4736
anti-PD-L1
5' AzacitidineDrug
Also called Vidaza
DNA methyltransferase inhibitor
TremelimumabDrug
anti-CTLA4
| Study group | Role | What they receive |
|---|---|---|
| Oral Decitabine and Durvalumab | Experimental | Oral decitabine (ASTX 727) will be administered alone in Cycle 1 and the combination of oral decitabine and durvalumab therapy will be given in Cycles 2-12. Receives: Drug: Oral Decitabine; Drug: Durvalumab |
| 5' Azacitidine 40 mg/m2 on Days 1-5, Durvalumab, and Tremelimumab | Experimental | 5' Azacitidine will be administered alone in Cycle 1 and the combination of 5' Azacitidine, durvalumab, and tremelimumab therapy will be given in Cycles 2-12. Receives: Drug: Durvalumab; Drug: 5' Azacitidine; Drug: Tremelimumab |
| 5' Azacitidine 40 mg/m2 on Days 1-5 and 8-12, Durvalumab, and Tremelimumab | Experimental | 5' Azacitidine will be administered alone in Cycle 1 and the combination of 5' Azacitidine, durvalumab, and tremelimumab therapy will be given in Cycles 2-12. Receives: Drug: Durvalumab; Drug: 5' Azacitidine; Drug: Tremelimumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in Immune-based Biomarker Expression at Baseline and 2 Months
Greater than 2-fold change in immune-based biomarker expression within the tumor microenvironment
Measured: 2 months
Secondary outcomes (1)
Number of Participants With Dose Limiting Toxicity
Adverse events were reported using Common Terminology Criteria for Adverse Events (CTCAE) v4.3.
Measured: 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Jan 2017 (estimated)
- Study start20 Mar 2017
- Primary completion24 Sep 2024
- Study completion24 Sep 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Head and Neck CancerStudies of the same condition, open and under way.
- More trials run by Massachusetts General HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 13 participants (actual)
Sponsor and investigators
- Lead sponsor
- Massachusetts General Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- AstraZeneca, Astex Pharmaceuticals, Inc.
- Responsible party
- Principal investigator, Sara Pai, MD, PhD, Massachusetts General Hospital
- Investigators
- Sara Pai, MD, PhD, Principal investigator, Massachusetts General Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03019003
- Sponsor's protocol ID
- 16-425
- Status last verified
- Aug 2025
- First submitted
- 6 Jan 2017
- Last updated
- 16 Sep 2025
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Qin T, Mattox AK, Campbell JS, Park JC, Shin KY, Li S, Sadow PM, Faquin WC, Micevic G, Daniels AJ, Haddad R, Garris CS, Pittet MJ, Mempel TR, ONeill A, Sartor MA, Pai SI. Epigenetic therapy sensitizes anti-PD-1 refractory head and neck cancers to immunotherapy rechallenge. J Clin Invest. 2025 Mar 17;135(6):e181671. doi: 10.1172/JCI181671.
PubMed 40091844