A Study of Tremelimumab and IV Durvalumab Plus Poly-ICLC in Subjects With Biopsy-accessible Cancers

Study Overview
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Brief Summary
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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 poly-ICLC, a TLR3 agonist, in subjects with advanced, measurable, biopsy-accessible cancers.

Detailed Description
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This is an open-label, multicenter, Phase 1/2 study of the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody, tremelimumab, and the programmed cell death ligand-1 (PD-L1) antibody, durvalumab (MEDI4736), in combination with the tumor microenvironment (TME) modulator poly-ICLC, a toll-like receptor 3 (TLR3) agonist, in subjects with advanced, measurable, biopsy-accessible cancers. Subjects will receive intratumoral and intramuscular (IM) administration of poly-ICLC and intravenous (IV) administration of durvalumab, together with either IV or intratumoral administration of tremelimumab. The study will be conducted in 2 phases. Phase 1: There will be enrollment to 3 subject cohorts in Phase 1, with staggered initiation of enrollment. Cohort 1A: IV Durvalumab + Intratumoral/IM Poly-ICLC. After safety is demonstrated in the first 3-6 subjects in Cohort 1A, Cohorts 1B and 1C will open to enrollment. Cohort 1B: IV Durvalumab + IV Tremelimumab + Intratumoral/IM Poly-ICLC. Cohort 1C: IV Durvalumab + Intratumoral Tremelimumab + Intratumoral/IM Poly-ICLC. Phase 2: Upon determination of the recommended combination dose in Cohort 1C, up to 66 evaluable subjects will be treated in Phase 2. Up to 6 subjects will be initially enrolled by tumor type (head and neck squamous cell carcinoma, locally recurrent or metastatic breast cancer, sarcoma, Merkel cell carcinoma, cutaneous T-cell lymphoma, melanoma after failure of available therapies, genitourinary cancers and solid tumors with accessible metastases). Subjects enrolled in Cohort 1C will be included in Phase 2 in the applicable tumor type. Data from all subjects in each Phase 2 tumor type will be reviewed for safety/efficacy to select up to 3 tumor types that demonstrate an efficacy signal, defined as at least 1 of 6 subjects within a tumor type who achieve a partial response (PR) or complete response (CR) by immune-related RECIST (irRECIST) or RECIST 1.1, or stable disease (SD) for at least 6 months. Up to 6 additional subjects in each of the selected tumor types may be enrolled in the expansion.

Official Title
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A Phase 1/2 Study of In Situ Vaccination With Tremelimumab and IV Durvalumab (MEDI4736) Plus the Toll-like Receptor Agonist Poly-ICLC in Subjects With Advanced, Measurable, Biopsy-accessible Cancers

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

Intervention / Treatment
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* Drug: Durvalumab
* Drug: Tremelimumab
* Drug: Poly-ICLC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 human papillomavirus (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 Genitourinary (GU) cancers with accessible metastases (e.g., bladder, renal) Any solid tumors with masses that are accessible Subjects with measurable disease, must have at least 2 lesions (1 measurable lesion and 1 biopsy/injectable lesion, which does not need to be measurable). Any number of prior systemic therapies. Eastern Cooperative Oncology Group (ECOG) performance status 0-1. Laboratory parameters for vital functions should be in the normal range or not clinically significant. Exclusion Criteria: Prior treatment with combination CTLA-4 and PD-1/PD-L1 blockade, with the exception of subjects with melanoma. Participants may not have been treated intratumorally with poly-ICLC. 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. Active, suspected or prior documented autoimmune disease, clinically significant cardiovascular disease or clinically uncontrolled hypertension. History of pneumonitis or interstitial lung disease or any unresolved immune-related adverse events following prior biological therapy. 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). Subjects with clinical symptoms or signs of gastrointestinal obstruction and/or who require drainage gastrostomy tube and/or parenteral hydration or nutrition. Known immunodeficiency or HIV, Hepatitis B, or Hepatitis C positivity. Antibody to Hepatitis B or C without evidence of active infection may be allowed. History of severe allergic reactions to any unknown allergens or any components of the study drugs. Other serious illnesses (e.g., serious infections requiring antibiotics, bleeding disorders). History of allogeneic organ transplant.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: In Phase 1, Cohort 1A was opened first and after the safety of durvalumab and poly-ICLC was demonstrated, Cohorts 1B and 1C were open in parallel. In Phase 2, all tumor types were opened in parallel, and subjects included in Cohort 1C were included and reported in their respective tumor type in Phase 2.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1, Cohort 1A<br>Subjects received durvalumab (1500 mg IV every 4 weeks [Q4W] for 12 cycles). Poly-ICLC (1 mg) was administered intratumorally on days 1, 3, 5, 8, 10 and 15 and intramuscularly on days 17, 22, and 24 of Cycle 1 as well as intramuscularly on days 1, 3, 8, 10, 15, 17, 22 and 24 of Cycle 2 and on days 1 and 4 of Cycle 3. | Drug: Durvalumab<br> <br> * Other names: Imfinzi®;Drug: Poly-ICLC<br> <br> * Other names: Hiltonol®;|
| Experimental: Phase 1, Cohort 1B<br>Subjects received durvalumab (1500 mg IV Q4W for 12 cycles) and tremelimumab (75 mg IV Q4W for the first 4 cycles). Poly-ICLC (1 mg) was administered intratumorally on days 1, 3, 5, 8, 10 and 15 and intramuscularly on days 17, 22, and 24 of Cycle 1 as well as intramuscularly on days 1, 3, 8, 10, 15, 17, 22 and 24 of Cycle 2 and on days 1 and 4 of Cycle 3. | Drug: Durvalumab<br> <br> * Other names: Imfinzi®;Drug: Tremelimumab<br> <br> Drug: Poly-ICLC<br> <br> * Other names: Hiltonol®;|
| Experimental: Cohort 1C + Phase 2; Head + Neck Squamous Cell Carcinoma<br>Subjects received durvalumab (1500 mg IV Q4W for 12 cycles) and tremelimumab (10 mg) intratumorally on days 1, 8, and 15 of Cycle 1, days 1 and 15 of Cycle 2 and day 1 of Cycles 3 and 4. Poly-ICLC (1 mg) was administered intratumorally on days 1, 3, 5, 8, 10 and 15 and intramuscularly on days 17, 22, and 24 of Cycle 1 as well as intramuscularly on days 1, 3, 8, 10, 15, 17, 22 and 24 of Cycle 2 and on days 1 and 4 of Cycle 3. | Drug: Durvalumab<br> <br> * Other names: Imfinzi®;Drug: Tremelimumab<br> <br> Drug: Poly-ICLC<br> <br> * Other names: Hiltonol®;|
| Experimental: Cohort 1C + Phase 2; Locally Recurrent or Metastatic Breast Cancer<br>Subjects received durvalumab (1500 mg IV Q4W for 12 cycles) and tremelimumab (10 mg) intratumorally on days 1, 8, and 15 of Cycle 1, days 1 and 15 of Cycle 2 and day 1 of Cycles 3 and 4. Poly-ICLC (1 mg) was administered intratumorally on days 1, 3, 5, 8, 10 and 15 and intramuscularly on days 17, 22, and 24 of Cycle 1 as well as intramuscularly on days 1, 3, 8, 10, 15, 17, 22 and 24 of Cycle 2 and on days 1 and 4 of Cycle 3. | Drug: Durvalumab<br> <br> * Other names: Imfinzi®;Drug: Tremelimumab<br> <br> Drug: Poly-ICLC<br> <br> * Other names: Hiltonol®;|
| Experimental: Cohort 1C + Phase 2; Sarcoma<br>Subjects received durvalumab (1500 mg IV Q4W for 12 cycles) and tremelimumab (10 mg) intratumorally on days 1, 8, and 15 of Cycle 1, days 1 and 15 of Cycle 2 and day 1 of Cycles 3 and 4. Poly-ICLC (1 mg) was administered intratumorally on days 1, 3, 5, 8, 10 and 15 and intramuscularly on days 17, 22, and 24 of Cycle 1 as well as intramuscularly on days 1, 3, 8, 10, 15, 17, 22 and 24 of Cycle 2 and on days 1 and 4 of Cycle 3. | Drug: Durvalumab<br> <br> * Other names: Imfinzi®;Drug: Tremelimumab<br> <br> Drug: Poly-ICLC<br> <br> * Other names: Hiltonol®;|
| Experimental: Cohort 1C + Phase 2; Merkel Cell Carcinoma<br>Subjects received durvalumab (1500 mg IV Q4W for 12 cycles) and tremelimumab (10 mg) intratumorally on days 1, 8, and 15 of Cycle 1, days 1 and 15 of Cycle 2 and day 1 of Cycles 3 and 4. Poly-ICLC (1 mg) was administered intratumorally on days 1, 3, 5, 8, 10 and 15 and intramuscularly on days 17, 22, and 24 of Cycle 1 as well as intramuscularly on days 1, 3, 8, 10, 15, 17, 22 and 24 of Cycle 2 and on days 1 and 4 of Cycle 3. | Drug: Durvalumab<br> <br> * Other names: Imfinzi®;Drug: Tremelimumab<br> <br> Drug: Poly-ICLC<br> <br> * Other names: Hiltonol®;|
| Experimental: Cohort 1C + Phase 2; Cutaneous T-cell Lymphoma<br>Subjects received durvalumab (1500 mg IV Q4W for 12 cycles) and tremelimumab (10 mg) intratumorally on days 1, 8, and 15 of Cycle 1, days 1 and 15 of Cycle 2 and day 1 of Cycles 3 and 4. Poly-ICLC (1 mg) was administered intratumorally on days 1, 3, 5, 8, 10 and 15 and intramuscularly on days 17, 22, and 24 of Cycle 1 as well as intramuscularly on days 1, 3, 8, 10, 15, 17, 22 and 24 of Cycle 2 and on days 1 and 4 of Cycle 3. | Drug: Durvalumab<br> <br> * Other names: Imfinzi®;Drug: Tremelimumab<br> <br> Drug: Poly-ICLC<br> <br> * Other names: Hiltonol®;|
| Experimental: Cohort 1C + Phase 2; Melanoma After Failure of Available Therapies<br>Subjects received durvalumab (1500 mg IV Q4W for 12 cycles) and tremelimumab (10 mg) intratumorally on days 1, 8, and 15 of Cycle 1, days 1 and 15 of Cycle 2 and day 1 of Cycles 3 and 4. Poly-ICLC (1 mg) was administered intratumorally on days 1, 3, 5, 8, 10 and 15 and intramuscularly on days 17, 22, and 24 of Cycle 1 as well as intramuscularly on days 1, 3, 8, 10, 15, 17, 22 and 24 of Cycle 2 and on days 1 and 4 of Cycle 3. | Drug: Durvalumab<br> <br> * Other names: Imfinzi®;Drug: Tremelimumab<br> <br> Drug: Poly-ICLC<br> <br> * Other names: Hiltonol®;|
| Experimental: Cohort 1C + Phase 2; Genitourinary Cancers with Accessible Metastases<br>Subjects received durvalumab (1500 mg IV Q4W for 12 cycles) and tremelimumab (10 mg) intratumorally on days 1, 8, and 15 of Cycle 1, days 1 and 15 of Cycle 2 and day 1 of Cycles 3 and 4. Poly-ICLC (1 mg) was administered intratumorally on days 1, 3, 5, 8, 10 and 15 and intramuscularly on days 17, 22, and 24 of Cycle 1 as well as intramuscularly on days 1, 3, 8, 10, 15, 17, 22 and 24 of Cycle 2 and on days 1 and 4 of Cycle 3. | Drug: Durvalumab<br> <br> * Other names: Imfinzi®;Drug: Tremelimumab<br> <br> Drug: Poly-ICLC<br> <br> * Other names: Hiltonol®;|
| Experimental: Cohort 1C + Phase 2; Solid Tumors with Accessible Masses<br>Subjects received durvalumab (1500 mg IV Q4W for 12 cycles) and tremelimumab (10 mg) intratumorally on days 1, 8, and 15 of Cycle 1, days 1 and 15 of Cycle 2 and day 1 of Cycles 3 and 4. Poly-ICLC (1 mg) was administered intratumorally on days 1, 3, 5, 8, 10 and 15 and intramuscularly on days 17, 22, and 24 of Cycle 1 as well as intramuscularly on days 1, 3, 8, 10, 15, 17, 22 and 24 of Cycle 2 and on days 1 and 4 of Cycle 3. | Drug: Durvalumab<br> <br> * Other names: Imfinzi®;Drug: Tremelimumab<br> <br> Drug: Poly-ICLC<br> <br> * Other names: Hiltonol®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Treatment-emergent Adverse Events (TEAEs) | Toxicity was graded in accordance with the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. Adverse events (AEs) were reported based on clinical laboratory tests, vital signs, physical examinations, and any other medically indicated assessments, including subject interviews, from the time informed consent was signed through 90 days after the last dose of study treatment. Treatment-emergent AEs were those that occurred or worsened after administration of the first dose of study treatment. | up to 15 months | 
| Number of Subjects With Best Overall Tumor Response by Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) | Tumor responses were evaluated using appropriate imaging and categorized according to irRECIST at Screening (up to 21 days before the first dose of study treatment), and in Cycles 4, 7, 9 and 11, when a subject discontinued treatment prematurely and 28 days after the last dose of study treatment. Per irRECIST, measurable lesions were categorized as follows: Complete Response (irCR): Complete disappearance of all target lesions; Partial Response (irPR): ≥ 30% decrease from baseline in the Total Measured Tumor Burden (TMTB); Progressive Disease (irPD): ≥ 20% increase from nadir in Total Measured Tumor Burden (TMTB); Stable Disease (irSD): not meeting above criteria. | up to 15 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Progression-free Survival (PFS) by Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) as Estimated Using the Kaplan-Meier Method | Tumor responses were evaluated using appropriate imaging and categorized according to irRECIST at Screening (up to 21 days before the first dose of study treatment), and in Cycles 4, 7, 9 and 11, when a subject discontinued treatment prematurely and 28 days after the last dose of study treatment. PFS was measured from the date of the first dose of study treatment to the date of earliest disease progression according to irRECIST or to the date of death, if disease progression did not occur. Per irRECIST, Progressive Disease (irPD) was defined as a ≥ 20% increase from nadir in the Total Measured Tumor Burden (TMTB). | up to 15 months | 
| Overall Disease Control Rate as Measured by Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) | Tumor responses were evaluated using appropriate imaging and categorized according to irRECIST at Screening (up to 21 days before the first dose of study treatment), and in Cycles 4, 7, 9 and 11, when a subject discontinued treatment prematurely and 28 days after the last dose of study treatment. Per irRECIST, measurable lesions were categorized as follows: Complete Response (irCR): Complete disappearance of all target lesions; Partial Response (irPR): ≥ 30% decrease from baseline in the Total Measurable Tumor Burden (TMTB); Progressive Disease (irPD): ≥ 20% increase from nadir in Total Measured Tumor Burden (TMTB); Stable Disease (irSD): not meeting above criteria. Overall Disease Control Rate was defined as the percentage of subjects who had irSD for at least 6 months, or irPR or irCR over a period of at least 4 weeks. Subjects who dropped out prior to meeting the responder criteria were considered non-responders. | Up to 24 weeks | 
| Number of Subjects With Best Overall Tumor Response by Response Evaluation Criteria in Solid Tumors (RECIST 1.1) | Tumor responses were evaluated using appropriate imaging and categorized according to RECIST 1.1 at Screening (up to 21 days before the first dose of study treatment), and in Cycles 4, 7, 9 and 11, when a subject discontinued treatment prematurely and 28 days after the last dose of study treatment. Per RECIST 1.1, target lesions are categorized as follows: Complete Response (CR): disappearance of all target lesions; Partial Response (PR): ≥ 30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD): ≥ 20% increase in the sum of the longest diameter of target lesions or presence of new lesions; Stable Disease (SD): small changes that did not meet above criteria. | up to 13 months | 
| Median PFS by Response Evaluation Criteria in Solid Tumors (RECIST 1.1) as Estimated Using the Kaplan-Meier Method | Tumor responses were evaluated using appropriate imaging and categorized according to RECIST 1.1 at Screening (up to 21 days before the first dose of study treatment), and in Cycles 4, 7, 9 and 11, when a subject discontinued treatment prematurely and 28 days after the last dose of study treatment. PFS was measured from the date of the first dose of study treatment to the date of earliest disease progression according to RECIST 1.1 or to the date of death, if disease progression did not occur. Per RECIST 1.1, Progressive disease (PD) was defined as a ≥ 20% increase in the sum of the longest diameter of target lesions or the presence of new lesions. | Up to 15 months | 
| Overall Disease Control Rate as Measured by Response Evaluation Criteria in Solid Tumors (RECIST 1.1) | Tumor responses were evaluated using appropriate imaging and categorized according to RECIST 1.1 at Screening (up to 21 days before the first dose of study treatment), and in Cycles 4, 7, 9 and 11, when a subject discontinued treatment prematurely and 28 days after the last dose of study treatment. Per RECIST 1.1, target lesions are categorized as follows: Complete Response (CR): disappearance of all target lesions; Partial Response (PR): ≥ 30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD): ≥ 20% increase in the sum of the longest diameter of target lesions or presence of new lesions; Stable Disease (SD): small changes that did not meet above criteria. Overall Disease Control Rate was defined as the percentage of subjects who had SD for at least 6 months, or PR or CR over a period of at least 4 weeks. Subjects who dropped out prior to meeting the responder criteria were considered non-responders. | up to 24 weeks | 
| Median Overall Survival (OS) as Estimated Using the Kaplan-Meier Method | After completion of treatment, all subjects were followed for survival every 3 months for 2 years after completion of treatment; then every 6 months until 5 years from study entry; then yearly until 10 years from study entry. OS was measured from the date of the first dose of study treatment to the date of death or last follow-up. Subjects lost to follow-up were censored on the date when they were last known to be alive. Per protocol amendment 6.0, all post study follow-up for the collection of survival data was discontinued as of February 28, 2022. The last collection of survival data was on February 23, 2022. | up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Durvalumab, MEDI4736, Tremelimumab, Poly-ICLC, Hiltonol®, Breast Cancer, Melanoma, In Situ, CTLA-4 Antibody, PD-L1 Antibody, TLR3 Agonist, CTCL, Imfinzi®