Clinical Trials /

Radiotherapy With Durvalumab Prior to Surgical Resection for HPV Negative Squamous Cell Carcinoma

NCT03635164

Description:

This is a multi-center, prospective, single-arm phase I/Ib safety trial. Patients eligible for treatment must be diagnosed with non-metastatic, biopsy-proven p16-negative histology squamous cell carcinoma of the oral cavity, oropharynx, larynx, or hypopharynx, and must be eligible and amenable to surgical resection.

Related Conditions:
  • Head and Neck Squamous Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Radiotherapy With Durvalumab Prior to Surgical Resection for HPV Negative Squamous Cell Carcinoma
  • Official Title: Phase I/Ib Trial of Radiotherapy in Combination With Durvalumab (MEDI4736) Prior to Surgical Resection for HPV Negative Squamous Cell Carcinoma of the Head and Neck (HNSCC)

Clinical Trial IDs

  • ORG STUDY ID: 18-0606.cc
  • NCT ID: NCT03635164

Conditions

  • Squamous Cell Carcinoma of the Head and Neck

Interventions

DrugSynonymsArms
DurvalumabDose Escalation and Expansion

Purpose

This is a multi-center, prospective, single-arm phase I/Ib safety trial. Patients eligible for treatment must be diagnosed with non-metastatic, biopsy-proven p16-negative histology squamous cell carcinoma of the oral cavity, oropharynx, larynx, or hypopharynx, and must be eligible and amenable to surgical resection.

Detailed Description

      Head and neck cancer is a disease that is known to have poor survival outcomes and response
      to combination chemoradiation. This study will feature a dose escalation and dose expansion
      phases of durvalumab. It will also feature surgical resection 3-6 weeks after radiation as
      recommended by the ENT surgeon.
    

Trial Arms

NameTypeDescriptionInterventions
Dose Escalation and ExpansionExperimentalPart 1 of this trial will use a traditional 3+3 design will be used for this trial (i.e. cohort sizes of 3 patients for the first and second cohort at each dose level). Dose escalation will occur as long as there are minimal dose limiting toxicities.The expectation is that 9 patients will be enrolled to the trial during part 1.This is based on the expectation that all dose levels are safe (i.e. patients will not experience DLTs at all dose levels). The range of patients needed will be 6-12 patients. Part 2 of this trial will be an expansion cohort. A total of 8 additional patients will be enrolled at the dose level determined to be the MTD in part 1 of the study. These 8 patients will be used to confirm that the MTD is a safe combination, as well as provide additional patients to investigate the efficacy for the treatment combination. Note: Standard of care surgery will follow 3-6 weeks after medication and radiation treatment.
  • Durvalumab

Eligibility Criteria

        Inclusion Criteria:

          1. Histologically or cytologically confirmed stage III or IV HNSCC oral cavity,
             hypopharynx, oropharynx, or larynx

          2. Measurable disease defined as lesions that can be accurately measured in at least one
             dimension (longest diameter to be recorded) as >10 mm with CT scan or >10 mm with
             calipers by clinical exam by RECIST 1.1

          3. Patients who are deemed resectable by ENT surgeon without pre-existing medical
             conditions that could inhibit surgery following neoadjuvant therapy, and do not refuse
             surgery

          4. Written informed consent and HIPAA authorization obtained from the patient prior to
             performing any protocol-related procedures, including screening evaluations

          5. Age > 18 years at time of study entry

          6. ECOG performance status ≤ 1

          7. Life expectancy ≥ 24 weeks

          8. Body weight >30kg

          9. Adequate normal organ and marrow function as defined below:

               -  Hemoglobin ≥9.0 g/dL

               -  Absolute neutrophil count (ANC) 1.0 x 109/L (> 1000 per mm3)

               -  Platelet count ≥75 x 109/L (>75,000 per mm3)

               -  Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). This will not
                  apply to patients 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

               -  Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine 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)

        10. 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 follicle-stimulating hormone levels in the
             post-menopausal range for the institution or underwent surgical sterilization
             (bilateral oophorectomy or hysterectomy)

          -  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 menopause with last menses >1 year ago, had
             chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical
             sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy) 11.
             Patient is willing and able to comply with the protocol for the duration of the study
             including undergoing treatment and scheduled visits and examinations including follow
             up

        Exclusion Criteria:

          1. Participation in another clinical study with an investigational product during the
             last 3 months

          2. Patients with active ILD / pneumonitis or with a history of ILD/ pneumonitis requiring
             steroids

          3. Concurrent enrollment in another clinical study, unless it is an observational
             (non-interventional) clinical study or during the follow-up period of an
             interventional study

          4. Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab,
             anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4)
             antibody (including ipilimumab or any other antibody or drug specifically targeting
             T-cell co-stimulation or checkpoint pathways)

          5. Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapy, endocrine
             therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal
             antibodies, other investigational agent) 30 days prior to the first dose of study drug
             for patients who have received prior TKIs [e.g., erlotinib, gefitinib and crizotinib]
             and within 6 weeks for nitrosourea or mitomycin C. (If sufficient wash-out time has
             not occurred due to the schedule or PK properties of an agent, a longer wash-out
             period may be required.)

          6. Patients with QTc interval > 470 msec during screening

          7. Current or prior use of immunosuppressive medication within 14 days before the first
             dose of durvalumab, 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. The following are exceptions to this
             criterion:

               -  Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra
                  articular injection)

               -  Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
                  prednisone or its equivalent

               -  Steroids as premedication for hypersensitivity reactions (e.g., CT scan
                  premedication)

          8. Any concurrent chemotherapy, IP, biologic, or hormonal therapy that is not part of
             standard NCCN indicated HNSCC adjuvant concurrent CRT. Concurrent use of hormonal
             therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is
             acceptable.

          9. History of allogenic organ or bone marrow transplantation

         10. Active or prior documented autoimmune or inflammatory disorders (including
             inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with
             the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome,
             or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid
             arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this
             criterion:

               -  Patients with vitiligo or alopecia

               -  Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on
                  hormone replacement

               -  Any chronic skin condition that does not require systemic therapy

               -  Patients without active disease in the last 5 years may be included but only
                  after consultation with the study physician

               -  Patients with celiac disease controlled by diet alone

         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, serious chronic
             gastrointestinal conditions associated with diarrhea, or psychiatric illness/social
             situations that would limit compliance with study requirement, substantially increase
             risk of incurring AEs 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 ≥3 years
                  before the first dose of IP 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

         13. History of leptomeningeal carcinomatosis

         14. History of active primary immunodeficiency

         15. Active infection including tuberculosis (clinical evaluation that includes clinical
             history, physical examination and radiographic findings, and TB testing in line with
             local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result),
             hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients
             with a past or resolved HBV infection (defined as the presence of hepatitis B core
             antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for
             hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative
             for HCV RNA.

         16. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note:
             Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to
             30 days after the last dose of IP.

         17. Female patients who are pregnant or breastfeeding or male or female patients of
             reproductive potential who are not willing to employ highly effective birth control
             from screening to 90 days after the last dose of durvalumab monotherapy. Patient must
             have a negative serum or urine pregnancy test within 72 hours of study entry.

         18. Known allergy or hypersensitivity to any of the study drugs or any of the study drug
             excipients

         19. Prior randomisation or treatment in a previous durvalumab clinical study

         20. Prior treatment for head and neck cancer. Note: patients with synchronous head and
             neck cancer primaries are an exception to this criterion and may qualify for the
             study.

         21. Patients with HPV-positive or p16-positive oropharyngeal SCCA

         22. Patients with sinonasal SCCAs

         23. Patients with metastatic SCCA neck disease with an unknown primary tumor site

         24. Patients with distant metastatic disease on initial screening imaging

         25. Judgment by the investigator that the patient is unsuitable to participate in the
             study and the patient is unlikely to comply with study procedures, restrictions and
             requirements
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose and Dose Limiting Toxicities
Time Frame:Study start date to study end date, or death, whichever comes first, up to 24 months
Safety Issue:
Description:The Maximum Tolerated Dose (MTD) and Dose Limiting Toxicities (DLT) will be discovered by using the 3+3 study design.

Secondary Outcome Measures

Measure:Pathologic Response
Time Frame:Study start date to study end date, or death, whichever comes first, up to 24 months
Safety Issue:
Description:Tumor response to neoadjuvant therapy (durvalumab + SBRT) will be assessed by pathology review of the surgical specimen. Response will be labeled as complete pathologic remission, microscopic residual tumor (only scattered foci of residual tumor cells) or macroscopic residual tumor.
Measure:Clinical Response
Time Frame:Study start date to study end date, or death, whichever comes first, up to 24 months
Safety Issue:
Description:Overall survival (OS), along with locoregional control and distant control will be determined from the time of enrollment to date of death due to any cause. OS will be evaluated by Kaplan-Meier estimate.
Measure:Evaluate Biomarkers: Gene Expression
Time Frame:Study start date to study end date, or death, whichever comes first, up to 24 months
Safety Issue:
Description:Analysis of gene expression of RNA levels and entire genome sequences using the 10X Genomics single-cell RNA-sequencing platform.
Measure:Evaluate Biomarkers: Phenotypic Analysis
Time Frame:Study start date to study end date, or death, whichever comes first, up to 24 months
Safety Issue:
Description:Phenotypic analysis of T cells and assessment of intracellular and circulating cytokines using multiplex mass flow cytometry to analyze phenotypic changes, functional response of cytokine production, and activation status of tumor infiltrating lymphocytes (TILs), circulating T cells (especially CD8 and PD-1 expression), and peripheral blood mononuclear cells (PBMCs).
Measure:Evaluate Biomarkers: Immune Cell Infiltration
Time Frame:Study start date to study end date, or death, whichever comes first, up to 24 months
Safety Issue:
Description:Examination of intratumoral immune cell infiltration using the Perkin Elmer Vectra 3 and tissue microarrays.
Measure:Toxicity Profile
Time Frame:Study start date to study end date, or death, whichever comes first, up to 24 months
Safety Issue:
Description:Grading of adverse effects (AEs) will follow the guidelines provided in the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
Measure:Short Term Quality of Life
Time Frame:Study start date to study end date, or death, whichever comes first, up to 24 months
Safety Issue:
Description:Short- and long-term quality of life will be obtained using FACT H&N v4 and will be assessed at baseline, with each cycle, post-SBRT, post-surgically, and throughout adjuvant therapy on a standard schedule.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:University of Colorado, Denver

Trial Keywords

  • HPV Negative
  • Durvalumab
  • Surgical Resection
  • Neoadjuvant
  • Radiation

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