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

• ClinicalTrials.gov Identifier: NCT02643303
• Recruitment Status: Recruiting
• First Posted: December 31, 2015
• Last Update Posted: February 23, 2021
• Sponsor: Ludwig Institute for Cancer Research
• Collaborators: MedImmune LLC; Cancer Research Institute, New York City
• Information provided by (Responsible Party): Ludwig Institute for Cancer Research

Tracking Information

• First Submitted Date: December 18, 2015
• First Posted Date: December 31, 2015
• Last Update Posted Date: February 23, 2021
• Actual Study Start Date: December 28, 2016
• Estimated Primary Completion Date: December 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 12, 2019)

Progression-Free Survival (PFS) at 24 weeks [ Time Frame: up to 24 weeks ]

Analyzed by irRECIST

Original Primary Outcome Measures (submitted: December 28, 2015)

• 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.
• 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 ]

Current Secondary Outcome Measures (submitted: March 12, 2019)

• Safety and tolerability [ Time Frame: up to 15 months ]
  Adverse events according to CTCAE V4.03
• Clinical Efficacy by objective response rate (ORR) [ Time Frame: up to 15 months ]
  assessed by irRECIST
• Clinical Efficacy by progression-free survival (PFS) [ Time Frame: up to 15 months ]
  assessed by irRECIST
• Clinical Efficacy by overall survival (OS) [ Time Frame: up to 15 months ]
  assessed by irRECIST

Original Secondary Outcome Measures (submitted: December 28, 2015)

• Individual durvalumab concentrations [ Time Frame: First dose of durvalumab through 3 months after the last dose of study medication ]
• Individual tremelimumab concentrations after IV and IT administration [ Time Frame: First dose of tremelimumab through 3 months after the last dose of study medication ]
• 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 ]
• 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 ]
• 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.

• Current Other Pre-specified Outcome Measures: Not Provided

Original Other Pre-specified Outcome Measures (submitted: December 28, 2015)

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.

Descriptive Information

• Brief Title: A Phase 1/2 Study of In Situ Vaccination With Tremelimumab and IV Durvalumab Plus PolyICLC in Subjects With Advanced, Measurable, Biopsy-accessible Cancers
• 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
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Head and Neck Squamous Cell Carcinoma
• Breast Cancer
• Sarcoma
• Merkel Cell Carcinoma
• Cutaneous T-Cell Lymphoma
• Melanoma
• Renal Cancer
• Bladder Cancer
• Prostate Cancer
• Testicular Cancer
• Solid Tumor

Intervention

• Drug: Durvalumab
  Other Name: MEDI4736
• Drug: Tremelimumab
• Drug: Poly ICLC
  Other Name: Hiltonol

Study Arms

• Experimental: Phase 1, Cohort 1A
  IV Durvalumab + IT/IM polyICLC
  Interventions:

  • Drug: Durvalumab
  • Drug: Poly ICLC
• Experimental: Phase 1, Cohort 1B
  IV Durvalumab + IV Tremelimumab + IT/IM polyICLC
  Interventions:

  • Drug: Durvalumab
  • Drug: Tremelimumab
  • Drug: Poly ICLC
• Experimental: Phase 1, Cohort 1C
  IV Durvalumab + IT Tremelimumab + IT/IM polyICLC
  Interventions:

  • Drug: Durvalumab
  • Drug: Tremelimumab
  • Drug: Poly ICLC
• 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.
  Interventions:

  • Drug: Durvalumab
  • Drug: Tremelimumab
  • Drug: Poly ICLC

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: December 28, 2015): 102
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 2022
• Estimated Primary Completion Date: December 2021 (Final data collection date for primary outcome measure)

Eligibility 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 or metastatic 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
2. Subjects with measurable disease, must have at least 2 lesions (1 measurable lesion and 1 biopsy/injectable lesion, which will not need to be measurable).
3. Any number of prior systemic therapies.
4. ECOG performance status 0-1.
5. Laboratory parameters for vital functions should be in the normal range or not clinically significant.

Exclusion Criteria:

1. Prior treatment with combination CTLA-4 and PD-1/PD-L1 blockade, with the exception of subjects with melanoma.
2. Participants may not have been treated intratumorally with polyICLC.
3. 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 active 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.
4. Active, suspected or prior documented autoimmune disease, clinically significant cardiovascular disease or clinically uncontrolled hypertension.
5. History of pneumonitis or interstitial lung disease or any unresolved immune-related adverse events following prior biological therapy.
6. 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).
7. Subjects with clinical symptoms or signs of gastrointestinal obstruction and/or who require drainage gastrostomy tube and/or parenteral hydration or nutrition.
8. Known immunodeficiency or HIV, Hepatitis B, or Hepatitis C positivity. Antibody to Hepatitis B or C without evidence of active infection may be allowed.
9. History of severe allergic reactions to any unknown allergens or any components of the study drugs.
10. Other serious illnesses (e.g., serious infections requiring antibiotics, bleeding disorders).
11. History of allogeneic organ transplant.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Kristen Aufiero Ramirez; 212-450-1515; clintrialinformation@licr.org

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02643303
• Other Study ID Numbers: LUD2014-011
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Ludwig Institute for Cancer Research
• Study Sponsor: Ludwig Institute for Cancer Research

Collaborators

• 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

• PRS Account: Ludwig Institute for Cancer Research
• Verification Date: February 2021