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A Phase 1/2 Study of In Situ Vaccination With Tremelimumab and IV Durvalumab Plus PolyICLC in Subjects With Advanced, Measurable, Biopsy-accessible Cancers

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ClinicalTrials.gov Identifier: NCT02643303
Recruitment Status : Recruiting
First Posted : December 31, 2015
Last Update Posted : September 13, 2018
Sponsor:
Collaborators:
MedImmune LLC
Cancer Research Institute, New York City
Information provided by (Responsible Party):
Ludwig Institute for Cancer Research

Brief Summary:
This is an open-label, multicenter Phase 1/2 study of the CTLA-4 antibody, tremelimumab, and the PD-L1 antibody, durvalumab (MEDI4736), in combination with the tumor microenvironment (TME) modulator polyICLC, a TLR3 agonist, in subjects with advanced, measurable, biopsy-accessible cancers.

Condition or disease Intervention/treatment Phase
Head and Neck Squamous Cell Carcinoma Breast Cancer Sarcoma Merkel Cell Carcinoma Cutaneous T-Cell Lymphoma Melanoma Renal Cancer Bladder Cancer Prostate Cancer Drug: Durvalumab Drug: Tremelimumab Drug: Poly ICLC Phase 1 Phase 2

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 102 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/2 Study of In Situ Vaccination With Tremelimumab and IV Durvalumab (MEDI4736) Plus the Toll-like Receptor Agonist PolyICLC in Subjects With Advanced, Measurable, Biopsy-accessible Cancers
Actual Study Start Date : December 28, 2016
Estimated Primary Completion Date : August 2022
Estimated Study Completion Date : August 2022


Arm Intervention/treatment
Experimental: Phase 1, Cohort 1A
IV Durvalumab + IT/IM polyICLC
Drug: Durvalumab
Other Name: MEDI4736

Drug: Poly ICLC
Other Name: Hiltonol

Experimental: Phase 1, Cohort 1B
IV Durvalumab + IV Tremelimumab + IT/IM polyICLC
Drug: Durvalumab
Other Name: MEDI4736

Drug: Tremelimumab
Drug: Poly ICLC
Other Name: Hiltonol

Experimental: Phase 1, Cohort 1C
IV Durvalumab + IT Tremelimumab + IT/IM polyICLC
Drug: Durvalumab
Other Name: MEDI4736

Drug: Tremelimumab
Drug: Poly ICLC
Other Name: Hiltonol

Experimental: Phase 2 Cohort
Once the recommended combination doses of the triplet dosing regimen has been determined in Cohort 1C, subsequent subjects will be enrolled into Cohort 2 to receive the recommended combination doses of both checkpoint antibodies in combination with polyICLC.
Drug: Durvalumab
Other Name: MEDI4736

Drug: Tremelimumab
Drug: Poly ICLC
Other Name: Hiltonol




Primary Outcome Measures :
  1. To determine the recommended combination doses of the dosing regimen, based on assessment of toxicity and tolerability. [ Time Frame: 12 months ]
    In the Dose-finding Phase, Cohorts 1A - 1C, the safety and tolerability of each regimen will be evaluated to determine the tolerability of IT or systemic tremelimumab and/or IV durvalumab in combination with polyICLC.

  2. Clinical Efficacy will be determined by objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) and will be assessed by irRECIST and RECIST1.1. [ Time Frame: up to 6 years ]

Secondary Outcome Measures :
  1. Individual durvalumab concentrations [ Time Frame: First dose of durvalumab through 3 months after the last dose of study medication ]
  2. Individual tremelimumab concentrations after IV and IT administration [ Time Frame: First dose of tremelimumab through 3 months after the last dose of study medication ]
  3. Number of subjects that develop changes in detectable antidrug antibodies to durvalumab [ Time Frame: First dose of durvalumab through 6 months after the last dose of study medication ]
  4. Number of subjects that develop changes in detectable antidrug antibodies to tremelimumab [ Time Frame: First dose of tremelimumab through 6 months after the last dose of study medication ]
  5. Durvalumab and Tremelimumab Immunogenicity [ Time Frame: up to 39 months ]
    Anti-drug antibody samples for the assessment of anti-tremelimumab and anti- durvalumab antibodies will be collected at each time point. Validated electrochemiluminescence assays using the MSD platform will be used for the detection of anti-tremelimumab and antidurvalumab antibodies in human serum.


Other Outcome Measures:
  1. Changes in Biomarkers [ Time Frame: Screening through 1 months after the last dose of study medication ]
    Evaluate biomarkers that may correlate with clinical activity of durvalumab monotherapy plus Poly ICLC, tremelimumab IV and IT monotherapy plus PolyICLC and durvalumab, tremelimumab and PolyICLC in combination.



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

Inclusion Criteria:

  1. Subjects must have histologic confirmation of advanced, biopsy-accessible, measurable cancers of the following histologies:

    • Non-viral-associated head and neck squamous cell carcinoma (HNSCC) or HPV-associated HNSCC after failure of prior therapy
    • Locally recurrent breast cancer
    • Sarcoma
    • Merkel Cell Carcinoma (MCC)
    • Cutaneous T cell Lymphoma (CTCL)
    • Melanoma after failure of available therapies
    • GU cancers with accessible metastases (e.g., bladder, renal)
    • Any solid tumors with masses that are accessible without imaging
  2. Subjects with measurable disease.
  3. Any number of prior systemic therapies.
  4. Performance status 0-1.
  5. Laboratory parameters:

    • Absolute neutrophil count (ANC) ≥ 1000/mm3;
    • Platelets ≥ 100,000/mm3;
    • Hemoglobin (Hgb) ≥ 9 g/dL;
    • Hgb-A1C ≤ 7.5%;
    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × upper limit of normal (ULN);
    • Bilirubin ≤ 2.5 × ULN (≤ 4 × ULN for subjects with Gilbert's disease);
    • Alkaline phosphatase ≤ 2.5 × ULN;
    • Creatinine ≤ 1.5 × ULN.
  6. Age ≥ 18 years.
  7. Able and willing to give valid written informed consent.

Exclusion Criteria:

  1. Prior treatment with combination CTLA-4 and PD-1/PD-L1 blockade.
  2. Participants may not have been treated intratumorally with polyICLC.
  3. Unresolved irAEs following prior biological therapy, except that stable and managed irAEs may be acceptable (e.g., hypothyroidism or hypopituitarism on appropriate replacement).
  4. Subjects with history or evidence upon physical examination of central nervous system (CNS) disease, including primary brain tumor, seizures not controlled with standard medical therapy, any brain metastases, or, within 6 months of the first date of treatment on this study, history of cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA) or subarachnoid hemorrhage.
  5. Subjects with clinically significant cardiovascular disease, including:

    1. Uncontrolled hypertension, defined as systolic blood pressure (BP) > 150 mmHg or diastolic BP > 90 mmHg.
    2. Myocardial infarction or unstable angina within 6 months of the first date of treatment on this study.
    3. History of serious ventricular arrhythmia (i.e., ventricular tachycardia or ventricular fibrillation) or cardiac arrhythmias requiring anti-arrhythmic medications, except for atrial fibrillation that is well controlled with anti arrhythmic medication.
    4. Baseline ejection fraction ≤ 50% as assessed by echocardiogram or multi-gated acquisition (MUGA) scan.
    5. New York Heart Association (NYHA) Class II or higher congestive heart failure.
    6. Grade 2 or higher peripheral ischemia [brief (< 24 hours) episode of ischemia managed non-surgically and without permanent deficit].
  6. History of pneumonitis or interstitial lung disease.
  7. Active, suspected or prior documented autoimmune disease (including inflammatory bowel disease, celiac disease, irritable bowel syndrome, Wegner's granulomatosis and Hashimoto's thyroiditis). Participants with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
  8. Other malignancy within 2 years prior to entry into the study, except for those treated with surgical therapy only (e.g., localized low-grade cervical or prostate cancers).
  9. Subjects with clinical symptoms or signs of gastrointestinal obstruction and/or who require drainage gastrostomy tube and/or parenteral hydration or nutrition.
  10. Known immunodeficiency or HIV, Hepatitis B, or Hepatitis C positivity. Antibody to Hepatitis B or C without evidence of active infection may be allowed.
  11. History of severe allergic reactions to any unknown allergens or any components of the study drugs.
  12. Other serious illnesses (e.g., serious infections requiring antibiotics, bleeding disorders).
  13. Participation in any other clinical trial involving another investigational agent within 4 weeks prior to Day 1 of the study.
  14. Mental impairment that may compromise the ability to give informed consent and comply with the requirements of the study.
  15. Lack of availability for immunological and clinical follow-up assessment.
  16. Women of child bearing potential who are pregnant as evidenced by positive serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) or nursing.
  17. Females of childbearing potential not using a medically acceptable means of contraception.
  18. Any condition that, in the clinical judgment of the treating physician, is likely to prevent the subject from complying with any aspect of the protocol or that may put the subject at unacceptable risk.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02643303


Contacts
Contact: Sunita Hack, MS 212-450-1515 clintrialinformation@licr.org

Locations
United States, Georgia
Research Facility Not yet recruiting
Atlanta, Georgia, United States, 30322
United States, New York
Research Facility Recruiting
Buffalo, New York, United States, 14263
Research Facility Recruiting
New York, New York, United States, 10029
United States, Virginia
Research Facility Recruiting
Charlottesville, Virginia, United States, 22908
Contact: Emily H. Allred, PhD, CCRC       eh4m@virginia.edu   
Sponsors and Collaborators
Ludwig Institute for Cancer Research
MedImmune LLC
Cancer Research Institute, New York City
Investigators
Study Chair: Craig L Slingluff, Jr., MD University of Virginia
Study Chair: Nina Bhardwaj, MD, PhD Tisch Cancer Institute Ichan School of Medicine at Mount Sinai

Responsible Party: Ludwig Institute for Cancer Research
ClinicalTrials.gov Identifier: NCT02643303     History of Changes
Other Study ID Numbers: LUD2014-011
First Posted: December 31, 2015    Key Record Dates
Last Update Posted: September 13, 2018
Last Verified: September 2018

Keywords provided by Ludwig Institute for Cancer Research:
Durvalumab
MEDI4736
Tremelimumab
PolyICLC
Hiltonol
Locally Recurrent Breast Cancer
Metastatic Melanoma
In Situ
CTLA-4 Antibody
PD-L1 Antibody
TLR3 Agonist

Additional relevant MeSH terms:
Carcinoma
Melanoma
Carcinoma, Squamous Cell
Urinary Bladder Neoplasms
Lymphoma, T-Cell
Head and Neck Neoplasms
Lymphoma, T-Cell, Cutaneous
Kidney Neoplasms
Carcinoma, Renal Cell
Carcinoma, Merkel Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms, Nerve Tissue
Nevi and Melanomas
Neoplasms, Squamous Cell
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Urinary Bladder Diseases
Urologic Diseases
Lymphoma, Non-Hodgkin
Lymphoma
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases