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MEDI4736 (Durvalumab) in Patients With Brain Metastasis From Epithelial-derived Tumors

This study is currently recruiting participants. (see Contacts and Locations)
Verified January 2017 by Washington University School of Medicine
Sponsor:
Information provided by (Responsible Party):
Washington University School of Medicine
ClinicalTrials.gov Identifier:
NCT02669914
First received: January 22, 2016
Last updated: January 23, 2017
Last verified: January 2017
  Purpose

Brain metastases are the most common intracranial malignancy occurring in 20-40% of all cancers, and the presence of CNS metastases is associated with a poor prognosis. As such, the median overall survival of patients with symptomatic brain lesions is a dismal 2-3 months regardless of tumor type. Because standard chemotherapy largely does not cross the blood brain barrier at a meaningful concentration, standard treatment is limited and usually involves surgical resection and/or stereotactic radiosurgery for isolated lesions and whole brain radiation for multiple lesions. Unfortunately, the median overall survival is only improved by about 6 months with this multimodality approach2, and there is a paucity of second-line therapies to treat recurrence. Furthermore, re-resection and re-radiation are often not feasible options due to concern for increasing complications or neurotoxicity, respectively. Thus, there is a dire clinical need for additional treatment options for this patient population.

Checkpoint blockade therapy, in particular PD-1 and PD-L1 inhibition, has recently shown clinical efficacy in multiple types of solid tumors. The investigators propose to study the efficacy of checkpoint blockade therapy in patients with solid tumors and refractory/recurrent brain metastases. The investigators will assess the efficacy of MEDI4736, a novel PD-L1 inhibitory monoclonal antibody, in this study.


Condition Intervention Phase
Non-Small Cell Lung Cancer
Nonsmall Cell Lung Cancer
Breast Cancer
Cancer of Breast
Cancer of the Breast
Gastroesophageal Cancer
Pancreatic Cancer
Cancer of the Pancreas
Colorectal Cancer
Colorectal Carcinoma
Renal Cancer
Kidney Cancer
Cancer of the Kidney
Cancer of Kidney
Ovarian Cancer
Ovary Cancer
Cancer of the Ovary
Cancer of Ovary
Drug: MEDI4736
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: A Phase II Study of MEDI4736 (Durvalumab) in Patients With Brain Metastasis From Epithelial-derived Tumors

Resource links provided by NLM:


Further study details as provided by Washington University School of Medicine:

Primary Outcome Measures:
  • Overall response rate of intracranial disease [ Time Frame: Completion of treatment (estimated to be 6 months) ]
    • Defined as the proportion of subjects who achieve a complete response or partial response based on assessment of brain lesions
    • Response and progression will be evaluated using the updated response assessment criteria for high-grade gliomas: Response Assessment in Neuro-Oncology (RANO) working group guideline


Secondary Outcome Measures:
  • Safety of MEDI4736 in advanced solid epithelial-derived tumor patients with brain metastases as measured by frequency and grade of treatment-emergent adverse events [ Time Frame: 30 days after completion of treatment (estimated to be 7 months) ]
    -The severity of AEs will be graded by the investigator according to the CTCAE, Version 4.03

  • Overall disease control rate of intracranial disease [ Time Frame: Completion of treatment (estimated to be 6 months) ]
    • Defined as the proportion of patients who achieve a complete response, partial response, or stable disease based on assessment of brain lesions
    • Intracranial disease: response and progression will be evaluated using the updated response assessment criteria for high-grade gliomas: Response Assessment in Neuro-Oncology (RANO) working group guideline

  • Overall response rate of extracranial disease [ Time Frame: Completion of treatment (estimated to be 6 months) ]
    • Defined as the proportion of patients who achieve a complete response or partial response based on assessment of systemic lesions
    • Extracranial disease: response and progression will be evaluated using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1)

  • Overall disease control rate of extracranial disease [ Time Frame: Completion of treatment (estimated to be 6 months) ]
    • Defined as the proportion of patients who achieve a complete response, partial response, or stable disease based on assessment of systemic lesions
    • Extracranial disease: response and progression will be evaluated using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1)

  • Overall response rate considering both intracranial and extracranial disease [ Time Frame: Completion of treatment (estimated to be 6 months) ]
    • Defined as the proportion of patients who achieve a complete response or partial response based on assessment of brain and systemic lesions
    • Intracranial disease: response and progression will be evaluated using the updated response assessment criteria for high-grade gliomas: Response Assessment in Neuro-Oncology (RANO) working group guideline
    • Extracranial disease: response and progression will be evaluated using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1)

  • Overall disease control rate considering both intracranial and extracranial disease [ Time Frame: Completion of treatment (estimated to be 6 months) ]
    • Defined as the proportion of subjects who achieve a complete response, partial response, or stable disease based on assessment of brain and systemic lesions
    • Intracranial disease: response and progression will be evaluated using the updated response assessment criteria for high-grade gliomas: Response Assessment in Neuro-Oncology (RANO) working group guideline
    • Extracranial disease: response and progression will be evaluated using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1)

  • Duration of response of intracranial disease [ Time Frame: Completion of treatment (estimated to be 6 months) ]
    • Defined as the interval from the first documentation of objective response to the earlier of the first documentation of disease progression or death from any cause
    • Intracranial disease: response and progression will be evaluated using the updated response assessment criteria for high-grade gliomas: Response Assessment in Neuro-Oncology (RANO) working group guideline

  • Duration of response of extracranial disease [ Time Frame: Completion of treatment (estimated to be 6 months) ]
    • Defined as the interval from the first documentation of objective response to the earlier of the first documentation of disease progression or death from any cause
    • Extracranial disease: response and progression will be evaluated using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1)

  • Duration of response considering both intracranial and extracranial disease [ Time Frame: Completion of treatment (estimated to be 6 months) ]
    • Defined as the interval from the first documentation of objective response to the earlier of the first documentation of disease progression or death from any cause
    • Intracranial disease: response and progression will be evaluated using the updated response assessment criteria for high-grade gliomas: Response Assessment in Neuro-Oncology (RANO) working group guideline
    • Extracranial disease: response and progression will be evaluated using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1)

  • Progression-free survival (PFS) [ Time Frame: Up to 2 years after completion of treatment (estimated to be 2 years and 6 months) ]
    -PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first.

  • Overall survival (OS) [ Time Frame: Up to 2 years after completion of treatment (estimated to be 2 years and 6 months) ]
    -Defined as the interval from the start of study therapy to death from any cause

  • Safety of MEDI4736 in patients with intracranial epithelial-derived tumor metastases as measured by frequency and grade of treatment-emergent adverse events [ Time Frame: 30 days after completion of treatment (estimated to be 7 months) ]
    -The severity of AEs will be graded by the investigator according to the CTCAE, Version 4.03


Estimated Enrollment: 136
Actual Study Start Date: September 12, 2016
Estimated Study Completion Date: December 31, 2021
Estimated Primary Completion Date: December 31, 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cohort 1: Non-small cell lung cancer w/o corticosteroids
-MEDI4736 will be given to all patients > 30 kg actual body weight intravenously at a fixed dose 750 mg every 2 weeks over the course of 60 minutes on an outpatient basis on Days 1 and 15 of each 28-day cycle. Patients < 30 kg actual body weight will be dosed at 10 mg/kg every 2 weeks.
Drug: MEDI4736
Other Name: Durvalumab
Experimental: Cohort 2: Epithelial origin solid tumors w/o corticosteroids
-MEDI4736 will be given to all patients > 30 kg actual body weight intravenously at a fixed dose 750 mg every 2 weeks over the course of 60 minutes on an outpatient basis on Days 1 and 15 of each 28-day cycle. Patients < 30 kg actual body weight will be dosed at 10 mg/kg every 2 weeks.
Drug: MEDI4736
Other Name: Durvalumab
Experimental: Cohort 3: NSCLC or non-NSCLC w/corticosteroids
-MEDI4736 will be given to all patients > 30 kg actual body weight intravenously at a fixed dose 750 mg every 2 weeks over the course of 60 minutes on an outpatient basis on Days 1 and 15 of each 28-day cycle. Patients < 30 kg actual body weight will be dosed at 10 mg/kg every 2 weeks.
Drug: MEDI4736
Other Name: Durvalumab

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Cohort A: Histologically confirmed metastatic non-small cell lung cancer (all histologic subtypes allowed) with radiographic evidence by MRI of at least one measurable brain lesion as defined by RANO criteria that does not require corticosteroids for symptomatic control.
  • Cohort B: Histologically confirmed metastatic solid tumor of epithelial origin, excluding NSCLC, including but not limited to ovarian cancer, colorectal cancer, pancreatic cancer, gastric cancer, renal cancer, bladder cancer, or breast cancer with radiographic evidence by MRI of at least one measurable brain lesion as defined by RANO criteria that does not require corticosteroids for symptomatic control.
  • Cohort C: Histologically confirmed metastatic solid tumor of epithelial origin, including both NSCLC and non-NSCLC, with radiographic evidence by MRI of at least one measurable brain lesion as defined by RANO criteria that requires corticosteroids for symptomatic control.
  • At least one prior treatment to a CNS-based lesion is required. Prior therapy must be completed > 2 weeks prior to enrollment. A previously treated lesion must be demonstrated by MRI to have progressed following treatment in order to be eligible. The subsequent development of a new CNS lesion that was not previously treated will be permitted and dose not require treatment followed by progression prior to enrollment. Treatment of a single CNS lesion with local therapy in the context of multifocal disease is permitted as long as at least one untreated lesions meets criteria for measurable disease. Patients should have received minimum of one line of systemic therapy.
  • At least 18 years of age.
  • ECOG performance status of 0 to 2
  • Adequate bone marrow and organ function as defined below:

    • Absolute neutrophil count ≥ 1,500/mcL
    • Platelets ≥ 100,000/mcL
    • Hemoglobin ≥ 8.0 g/dL
    • Serum bilirubin ≤ 1.5 x IULN
    • AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN
    • Creatinine clearance ≥ 40 mL/min/1.73 m2 by the Cockcroft-Gault formula or by 24-hour urine collection for determination of creatinine clearance
  • Negative antiviral serology:

    • Negative human immunodeficiency virus (HIV) antibody.
    • Negative hepatitis B surface antigen (HBsAg) and negative hepatitis B core (HBc) antibody or undetectable hepatitis B (HBV) DNA by quantitative polymerase chain reaction (PCR) testing.
    • Negative hepatitis C virus (HCV) antibody or negative HCV ribonucleic acid (RNA) by quantitative PCR.
  • Mean QT interval corrected for heart rate (QTc) < 470 msec calculated from 3 ECGs performed at least 2 minutes apart using Frediricia's Correction.
  • Female subjects must either be of non-reproductive potential (i.e., 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.
  • Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).

Exclusion Criteria:

  • Diagnosis of leptomeningeal carcinomatosis.
  • Diagnosis of melanoma or other non-epithelial based malignancy such as sarcoma, neuroendocrine tumor, small cell lung cancer.
  • Presence of unstable systemic disease (e.g., visceral crisis or rapid progression) in the judgment of the investigator.
  • A history of other malignancy ≤ 5 years previous with the exception of basal cell or squamous cell carcinoma of the skin which were treated with local resection only or carcinoma in situ of the cervix.
  • Currently receiving any other investigational agents.
  • A history of allergic reactions attributed to compounds of similar chemical or biologic composition to MEDI4736 or other agents used in the study.
  • Previous treatment with a PD-1 or PD-L1 inhibitor, including MEDI4736, or a CTLA-4 inhibitory agent.
  • Current or prior use of immunosuppressive medication within 28 days before the first dose of MEDI4736 with the exceptions of intranasal and inhaled corticosteroids, or systemic corticosteroids in Cohort C.
  • Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies, other investigational agent) 21 days prior to the first dose of study drug.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension (>180/110), unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses, or psychiatric illness/social situations that would limit compliance with study requirements.
  • 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 prior immunodeficiency.
  • History of allogeneic organ transplant.
  • Known history of previous clinical diagnosis of tuberculosis.
  • Receipt of live attenuated vaccination within 30 days prior to first dose of MEDI4736.
  • Pregnant and/or breastfeeding 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02669914

Contacts
Contact: Ramaswamy Govindan, M.D. 314-362-5737 rgovindan@wustl.edu

Locations
United States, Missouri
Washington University School of Medicine Recruiting
St. Louis, Missouri, United States, 63110
Contact: Ramaswamy Govindan, M.D.    314-362-5737    rgovindan@wustl.edu   
Principal Investigator: Ramaswamy Govindan, M.D.         
Sub-Investigator: Gavin Dunn, M.D., Ph.D.         
Sub-Investigator: Tanner Johanns, M.D., Ph.D.         
Sub-Investigator: Maria Q Baggstrom, M.D.         
Sub-Investigator: Daniel Morgensztern, M.D.         
Sub-Investigator: Saiama Waqar, M.D.         
Sub-Investigator: George Ansstas, M.D.         
Sub-Investigator: Jian Campian, M.D.         
Sub-Investigator: Milan Chheda, M.D.         
Sub-Investigator: Michael Chicoine, M.D.         
Sub-Investigator: Ralph Dacey, M.D.         
Sub-Investigator: Joshua Dowling, M.D.         
Sub-Investigator: Ashiq Masood, M.D.         
Sub-Investigator: Michael Naughton, M.D.         
Sub-Investigator: A. Craig Lockhart, M.D.         
Sub-Investigator: Haeseong Park, M.D.         
Sub-Investigator: Peter Oppelt, M.D.         
Sub-Investigator: Katrina Pedersen, M.D.         
Sponsors and Collaborators
Washington University School of Medicine
Investigators
Principal Investigator: Ramaswamy Govindan, M.D. Washington University School of Medicine
  More Information

Additional Information:
Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT02669914     History of Changes
Other Study ID Numbers: 201602169
Study First Received: January 22, 2016
Last Updated: January 23, 2017
Individual Participant Data  
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Carcinoma, Non-Small-Cell Lung
Lung Neoplasms
Colorectal Neoplasms
Pancreatic Neoplasms
Kidney Neoplasms
Carcinoma, Renal Cell
Breast Neoplasms
Ovarian Neoplasms
Carcinoma, Bronchogenic
Bronchial Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Endocrine Gland Neoplasms
Pancreatic Diseases
Endocrine System Diseases
Urologic Neoplasms
Urogenital Neoplasms
Kidney Diseases

ClinicalTrials.gov processed this record on April 27, 2017