Clinical Trials /

ADMIRAL Trial: Adaptive Mediastinal Radiation With Chemo-Immunotherapy

NCT04372927

Description:

This phase II trial studies two questions in patients with stage III NSCLC: 1) does it improve cancer control to add the drug Durvalumab, a type of immunotherapy, earlier in the treatment course; and 2) by intensifying treatment with durvalumab, is it possible to avoid mediastinal radiation to decrease side effects, without decreasing cancer control?

Related Conditions:
  • Non-Squamous Non-Small Cell Lung Carcinoma
  • Squamous Cell Lung Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: ADMIRAL Trial: Adaptive Mediastinal Radiation With Chemo-Immunotherapy
  • Official Title: Adaptive-Dose to Mediastinum With Immunotherapy (Durvalumab MEDI4736) and Radiation in Locally-Advanced Non-Small Cell Lung Cancer

Clinical Trial IDs

  • ORG STUDY ID: RG1007190
  • SECONDARY ID: NCI-2020-02417
  • SECONDARY ID: RG1007190
  • SECONDARY ID: P30CA015704
  • NCT ID: NCT04372927

Conditions

  • Locally Advanced Lung Non-Small Cell Carcinoma
  • Stage III Lung Cancer AJCC v8
  • Stage IIIA Lung Cancer AJCC v8
  • Stage IIIB Lung Cancer AJCC v8
  • Stage IIIC Lung Cancer AJCC v8

Interventions

DrugSynonymsArms
CisplatinAbiplatin, Blastolem, Briplatin, CDDP, Cis-diammine-dichloroplatinum, Cis-diamminedichloridoplatinum, Cis-diamminedichloro Platinum (II), Cis-diamminedichloroplatinum, Cis-dichloroammine Platinum (II), Cis-platinous Diamine Dichloride, Cis-platinum, Cis-platinum II, Cis-platinum II Diamine Dichloride, Cismaplat, Cisplatina, Cisplatinum, Cisplatyl, Citoplatino, Citosin, Cysplatyna, DDP, Lederplatin, Metaplatin, Neoplatin, Peyrone''s Chloride, Peyrone''s Salt, Placis, Plastistil, Platamine, Platiblastin, Platiblastin-S, Platinex, Platinol, Platinol- AQ, Platinol-AQ, Platinol-AQ VHA Plus, Platinoxan, Platinum, Platinum Diamminodichloride, Platiran, Platistin, PlatosinTreatment (chemotherapy, durvalumab, radiation therapy)
DurvalumabImfinzi, Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer, MEDI-4736, MEDI4736Treatment (chemotherapy, durvalumab, radiation therapy)
EtoposideDemethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar, Vepesid, VP 16, VP 16-213, VP-16, VP-16-213, VP16Treatment (chemotherapy, durvalumab, radiation therapy)
PemetrexedMTA, Multitargeted AntifolateTreatment (chemotherapy, durvalumab, radiation therapy)

Purpose

This phase II trial studies two questions in patients with stage III NSCLC: 1) does it improve cancer control to add the drug Durvalumab, a type of immunotherapy, earlier in the treatment course; and 2) by intensifying treatment with durvalumab, is it possible to avoid mediastinal radiation to decrease side effects, without decreasing cancer control?

Detailed Description

      OUTLINE:

      Patients will receive platinum doublet chemotherapy per standard of care with durvalumab for
      8 weeks, concurrent with a short course of radiation to the primary lung tumor. Patients will
      then undergo repeat evaluation of the mediastinal lymph nodes. If there is no cancer in the
      lymph nodes, patients will receive 2 years of adjuvant durvalumab. If there is still cancer
      in the lymph nodes, patients will receive 6 weeks of radiation to the mediastinal lymph
      nodes, and 2 years of adjuvant durvalumab.

      After the completion of study treatment, patients are followed up for 12 months.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (chemotherapy, durvalumab, radiation therapy)ExperimentalPatients with squamous cell cancer receive standard of care chemotherapy consisting of cisplatin on days 1, 8, 29, and 36, and etoposide on days 1-5 and 29-33. Cycles repeat every 4 weeks for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients with non-squamous cell cancer receive standard of care chemotherapy consisting of cisplatin and pemetrexed on days 1, 21, and 42. Cycles repeat every 3 weeks for up to 3 cycles in the absence of disease progression or unacceptable toxicity. All patients receive durvalumab IV over 1 hour Q4W. Radiation to the primary tumor will be given over 8-15 fractions during weeks 1-3 of chemotherapy. For patients who have residual disease in the mediastinal lymph nodes at week 9, radiation will be given to the lymph nodes starting week 11. Durvalumab is given for 2 years after completion of radiationin the absence of disease progression or unacceptable toxicity.
  • Cisplatin
  • Durvalumab
  • Etoposide
  • Pemetrexed

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically or cytologically documented non-small cell lung cancer (NSCLC)

          -  Stage III NSCLC according to American Joint Committee on Cancer (AJCC) staging version
             (v)8

          -  At least one mediastinal site of disease that is discontiguous from all other visible
             sites of disease and can be excluded from primary tumor site radiation (i.e. at least
             10 mm separation between tumors)

          -  A maximum of 20 patients with bulky mediastinal disease will be allowed on this trial,
             defined as at least one contiguous mediastinal mass with minimum diameter > 2 cm, that
             is not contiguous with the primary tumor (and therefore would not be irradiated during
             radiation to the primary tumor)

          -  No surgery for lung cancer for at least 3 years

          -  No other malignancies for at least 3 years, excluding low grade or non-invasive
             malignancies such as skin cancers, prostate cancers, and ductal breast carcinoma in
             situ (DCIS)

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

          -  Life expectancy of >= at least 3 months

          -  Body weight > 30 kg

          -  Hemoglobin >= 9.0 g/dL

          -  Absolute neutrophil count (ANC) 1.5 (or 1.0) x (>= 1500 per mm^3)

          -  Platelet count >= 100,000 per mm^3

          -  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

          -  Aspartate transaminase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine
             transferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x
             institutional upper limit of normal unless liver metastases are present, in which case
             it must be =< 5 x upper limit of normal (ULN)

          -  Measured creatinine clearance (CL) > 60 mL/min or calculated creatinine CL > 50 mL/min
             by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine
             collection for determination of creatinine clearance

          -  Capable of giving signed informed consent which includes compliance with the
             requirements and restrictions listed in the informed consent form (ICF) and in this
             protocol. Written informed consent and any locally required authorization (eg, Health
             Insurance Portability and Accountability Act) obtained from the patient/legal
             representative prior to performing any protocol-related procedures, including
             screening evaluations

          -  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)

          -  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:

          -  Prior anti-CTLA-4, PD-1 or PD-L1 antibodies including durvalumab

          -  Prior chemotherapy in the past 3 years from consent

          -  Any unresolved toxicity National Cancer Institute (NCI) CTCAE grade >= 2 from previous
             anticancer 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
                  after consultation with the study physician

               -  Patients with irreversible toxicity not reasonably expected to be exacerbated by
                  treatment with durvalumab may be included only after consultation with the study
                  physician

          -  Prior thoracic radiation that would preclude curative-intent radiation dose as
             outlined in this study

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

          -  History of allogenic organ transplantation

          -  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

          -  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 adverse events (AEs) or compromise the ability of the patient to
             give written informed consent

          -  History of leptomeningeal carcinomatosis

          -  History of active primary immunodeficiency

          -  Active infection including tuberculosis (clinical evaluation that includes clinical
             history, physical examination and radiographic findings, and tuberculosis (TB) testing
             in line with local practice), hepatitis B (known positive hepatitis B virus [HBV]
             surface antigen [HBsAg] result), hepatitis C. 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 (hepatitis C virus [HCV])
             antibody are eligible only if polymerase chain reaction is negative for HCV
             ribonucleic acid (RNA)

          -  Current or prior use of immunosuppressive medication within 14 days before the first
             dose of durvalumab. 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., computed
                  tomography [CT] scan premedication)

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

          -  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 90 days after the last dose of durvalumab monotherapy

          -  Known allergy or hypersensitivity to any of the study drugs or any of the study drug
             excipients
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-free survival rate (PFS)
Time Frame:From study registration to progression per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, symptomatic deterioration, or death due to any cause, whichever comes first, assessed at 1 year after treatment
Safety Issue:
Description:Will be evaluated using the method of Kaplan-Meier. Confidence intervals for median times will be determined using the Brookmeyer-Crowley method. Confidence intervals around landmark times will be determined using Greenwood's formula for the variance and based on a log-log transformation applied on the survival function. Binary proportions will be calculated with associated confidence intervals for binary outcomes, such as response. Means and/or medians will be calculated for continuous outcomes. Confidence bounds will be provided for means and quartiles and ranges for median values. All confidence bounds will be presented as 95% bounds.

Secondary Outcome Measures

Measure:Frequency and severity of pneumonitis
Time Frame:Up to 12 months after treatment
Safety Issue:
Description:The primary toxicity of interest is grade 3 or higher pneumonitis. The incidence of grade 3 or worse pneumonitis attributable to treatment will be evaluated and compared against the PACIFIC trial results. All toxicities of all grades will be monitored on study and reported. Binary proportions will be calculated with associated confidence intervals for binary outcomes, such as toxicity.
Measure:Overall survival (OS)
Time Frame:From study registration to death due to any cause, assessed up to 12 months after treatment
Safety Issue:
Description:Will be evaluated using the method of Kaplan-Meier. Confidence intervals for median times will be determined using the Brookmeyer-Crowley method. Confidence intervals around landmark times will be determined using Greenwood's formula for the variance and based on a log-log transformation applied on the survival function. Binary proportions will be calculated with associated confidence intervals for binary outcomes, such as response. Means and/or medians will be calculated for continuous outcomes. Confidence bounds will be provided for means and quartiles and ranges for median values. All confidence bounds will be presented as 95% bounds.
Measure:Response rate
Time Frame:Up to 12 months after treatment
Safety Issue:
Description:Will be evaluated using the method of Kaplan-Meier. Confidence intervals for median times will be determined using the Brookmeyer-Crowley method. Confidence intervals around landmark times will be determined using Greenwood's formula for the variance and based on a log-log transformation applied on the survival function. Binary proportions will be calculated with associated confidence intervals for binary outcomes, such as response. Means and/or medians will be calculated for continuous outcomes. Confidence bounds will be provided for means and quartiles and ranges for median values. All confidence bounds will be presented as 95% bounds.
Measure:Incidence of adverse events
Time Frame:Up to 12 months after treatment
Safety Issue:
Description:Frequency and severity of toxicities will be graded with Common Terminology Criteria for Adverse Events (CTCAE), version 5. Toxicities will be summarized as the proportion of patients with such toxicities, in addition to total number of toxicities (allowing for multiple toxicities within a patient) among all patients. All toxicities of all grades will be monitored on study and reported. Binary proportions will be calculated with associated confidence intervals for binary outcomes, such as toxicity.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:University of Washington

Last Updated

April 29, 2020