A Study Of Avelumab In Combination With Other Cancer Immunotherapies In Advanced Malignancies (JAVELIN Medley)

Study Overview
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Brief Summary
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This is a Phase 1b/2 dose-optimization study to evaluate safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of avelumab (MSB0010718C) in combination with other cancer immunotherapies in patients with locally advanced or metastatic solid tumors. The primary purpose is to assess the safety and early signs of efficacy of various avelumab combinations with other cancer immunotherapies, optimizing dosing regimens as appropriate, in a limited series of indications.

Detailed Description
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This is a Phase 1b/2, open-label, multi-center, multiple-dose, safety, clinical activity, PK, and PD study of avelumab in combination with other immune modulators in adult patients with locally advanced or metastatic solid tumors (eg, non-small cell lung cancer (NSCLC), melanoma, squamous cell carcinoma of the head and neck (SCCHN), triple-negative breast cancer (TNBC), gastric cancer, platinum resistant ovarian cancer, bladder cancer, small cell lung cancer (SCLC) and progressing tenosynovial giant cell tumor/pigmented villonodular synovitis (TGCT/PVNS) . In Phase 1b, this includes patients whose disease has progressed on standard of care therapy or for whom no standard therapy is available. In Phase 2, enrollment criteria regarding prior treatment(s) received varies by tumor type. Incorporation of the other immune modulators into this study is based on preclinical and clinical data supportive of single-agent tolerability and potential clinical benefit, as well as non-clinical data suggesting safety, tolerability and clinical benefit of the agent(s) in combination with avelumab. Combinations of avelumab plus other immune modulator(s) to be evaluated are as follows: Combination A: avelumab plus utomilumab (4-1BB agonist mAb) Combination B: avelumab plus PF-04518600 (OX40 agonist mAb) Combination C: avelumab plus PD 0360324 (M-CSF mAb) Combination D: avelumab plus utomilumab plus PF-04518600 Combination F: avelumab plus CMP-001 (TLR9 agonist) and avelumab plus CMP-001 plus utomilumab and avelumab plus CMP-001 and PF-04518600 Each combination will be studied individually in 2 study parts: 1) a Phase 1b Lead-in part to evaluate safety, and determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) and RP2D (if applicable), of the combination, and 2) a Phase 2 part to evaluate efficacy and further evaluate safety of the selected dose from the Phase 1b portion in pre-specified patient populations.

Official Title
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A PHASE 1B/2 OPEN-LABEL STUDY TO EVALUATE SAFETY, CLINICAL ACTIVITY, PHARMACOKINETICS AND PHARMACODYNAMICS OF AVELUMAB (MSB0010718C) IN COMBINATION WITH OTHER CANCER IMMUNOTHERAPIES IN PATIENTS WITH ADVANCED MALIGNANCIES

Conditions
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Advanced Cancer

Intervention / Treatment
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* Drug: Avelumab
* Drug: Utomilumab
* Drug: PF-04518600
* Drug: PD 0360324
* Drug: CMP-001


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological or cytological diagnosis of advanced/metastatic solid tumor. Measurable disease by RECIST 1.1 with at least 1 measurable lesion that has not been previously irradiated. Availability of tumor specimen taken within 1 year prior to study entry, with no intervening systemic anti-cancer therapy. No prior PD-1/PDL-1 therapy allowed. Combination A: Phase 1b, patients with NSCLC that have progressed on standard therapy or for which no standard therapy is available, and Phase 2, patients with NSCLC, melanoma, SCCHN, TNBC in any line of therapy, SCLC, 1st line NSCLC. 1st line NSCLC must demonstrate to express PD-L1. Activating EGFR mutation, ALK, ROS1 translocation/rearrangements are not permitted. Combination B: Phase 1b, patients with advanced solid tumors (NSCLC, SCCHN, melanoma) that have progressed on standard therapy or for which no standard therapy is available, and Phase 2, patients with NSCLC, melanoma, or SCCHN. Up to 2 lines of prior therapy in advanced/metastatic disease setting allowed. Activating EGFR mutation, ALK, ROS1 translocation/rearrangements are not permitted. Combination C: Ovarian cancer, SCCHN, NSCLC, gastric cancer, platinum resistant ovarian cancer. Up to 2 lines of prior therapy in advanced/metastatic disease setting allowed. TGCT/PVNS that is either inoperable or requires extensive resection. Prior treatment with agents targeting CSF-1/CSF-1R not allowed. NSCLC activating EGFR mutation, ALK, ROS1 translocation/rearrangements are not permitted. Combination D: NSCLC, melanoma, SCCHN, bladder cancer. NSCLC activating EGFR mutation, ALK, ROS1 translocation/rearrangements are not permitted. Up to 2 lines of prior therapy in advanced/metastatic disease setting allowed. Combination F: Recurrent or metastatic SCCHN. One to three prior lines of systemic therapy for advanced stage or metastatic disease. Patients must have received anti PD-1/PD-L1 containing therapy (requires at least two doses of PD-1/PD-L1 agent).Disease progression no earlier than 6 weeks from initiation of the latest anticancer therapy. Evidence of radiologic progression is required. • Patient must be a candidate for intralesional administration with at least one tumor lesion which can be injected safely. ECOG performance status 0 or 1 Estimated life expectancy of at least 3 months Adequate bone marrow, renal, and liver function Resolved acute effects of prior therapy Negative serum pregnancy test at screening Male and female patients able to have children must agree to use at least 1 highly effective method of contraception throughout the study and for at least 90 days after last dose Signed and dated informed consent Exclusion Criteria: Monoclonal antibody based anti-cancer therapy within 28 days prior to study entry or small-molecule based anti-cancer therapy (targeted therapy or chemotherapy) within 14 days prior to study entry. Combination F:PD-1/PD-L1 agent within 14 days prior study entry. Current or prior use of immunosuppressive medication within 7 days prior to study entry Active autoimmune disease requiring systemic steroids or immunosuppressive agents within 7 days prior to study entry Known prior or suspected hypersensitivity to investigational products Major surgery within 4 weeks or radiation therapy within 14 days prior to study entry Patients with known symptomatic brain metastases requiring steroids Previous high-dose chemotherapy requiring stem cell rescue Prior allogeneic stem cell transplant or organ graft Any of the following within 6 months prior to study entry: myocardial infarction, uncontrolled angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, or transient ischemic attack Symptomatic pulmonary embolism within 6 months prior to study entry Known HIV or AIDS-related illness Active infection requiring systemic therapy Positive HBV or HCV test indicating acute or chronic infection Administration of a live vaccine within 4 weeks prior to study entry Diagnosis of other malignancy within 5 years, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the breast or cervix, or low-grade (Gleason ≤6) prostate cancer Participation in other studies involving investigational drug(s) within 4 weeks prior to study entry and/or during study participation Persisting toxicity related to prior therapy >Grade 1 Other severe acute or chronic medical condition Combo C :Existing periorbital edema. Combo C : Hypocalcemia, clinically significant bone disease or recent bone fracture (within 12 weeks prior study entry)

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: Randomized
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A1<br>NSCLC patients treated with avelumab + utomilumab (Dose level 1) | Drug: Avelumab<br>* Anti-PD-L1 antibody<br>* Other names: MSB0010718C;Drug: Utomilumab<br>* Anti-4-1BB antibody<br>* Other names: PF-05082566;|
| Experimental: Cohort A2<br>NSCLC patients treated with avelumab + utomilumab (Dose level 2) | Drug: Avelumab<br>* Anti-PD-L1 antibody<br>* Other names: MSB0010718C;Drug: Utomilumab<br>* Anti-4-1BB antibody<br>* Other names: PF-05082566;|
| Experimental: Cohort A3<br>NSCLC patients treated with avelumab + utomilumab (Dose level 3) | Drug: Avelumab<br>* Anti-PD-L1 antibody<br>* Other names: MSB0010718C;Drug: Utomilumab<br>* Anti-4-1BB antibody<br>* Other names: PF-05082566;|
| Experimental: Cohort A4<br>Melanoma patients treated with avelumab +utomilumab | Drug: Avelumab<br>* Anti-PD-L1 antibody<br>* Other names: MSB0010718C;Drug: Utomilumab<br>* Anti-4-1BB antibody<br>* Other names: PF-05082566;|
| Experimental: Cohort A5<br>SCCHN patients treated with avelumab + utomilumab | Drug: Avelumab<br>* Anti-PD-L1 antibody<br>* Other names: MSB0010718C;Drug: Utomilumab<br>* Anti-4-1BB antibody<br>* Other names: PF-05082566;|
| Experimental: Cohort A6<br>TNBC patients treated with avelumab + utomilumab | Drug: Avelumab<br>* Anti-PD-L1 antibody<br>* Other names: MSB0010718C;Drug: Utomilumab<br>* Anti-4-1BB antibody<br>* Other names: PF-05082566;|
| Experimental: Cohort A7<br>SCLC that has progressed after at least 1 line of platinum-containing therapy treated with avelumab +utomilumab | Drug: Avelumab<br>* Anti-PD-L1 antibody<br>* Other names: MSB0010718C;Drug: Utomilumab<br>* Anti-4-1BB antibody<br>* Other names: PF-05082566;|
| Experimental: Cohort A8<br>NSCLC first-line Stage IV treated with avelumab +PF-05082566 | Drug: Avelumab<br>* Anti-PD-L1 antibody<br>* Other names: MSB0010718C;Drug: Utomilumab<br>* Anti-4-1BB antibody<br>* Other names: PF-05082566;|
| Experimental: Combination B Dose Escalation<br>PF-04518600 + avelumab in selected tumor types | Drug: Avelumab<br>* Anti-PD-L1 antibody<br>* Other names: MSB0010718C;Drug: PF-04518600<br>* OX40 Agonist<br>|
| Experimental: Combination B Expansion Cohorts<br>PF-04518600 + avelumab in selected tumor types | Drug: Avelumab<br>* Anti-PD-L1 antibody<br>* Other names: MSB0010718C;Drug: PF-04518600<br>* OX40 Agonist<br>|
| Experimental: Combination C Dose escalation cohorts<br>PD 0360324 + avelumab in selected tumor types | Drug: Avelumab<br>* Anti-PD-L1 antibody<br>* Other names: MSB0010718C;Drug: PD 0360324<br>* Anti-M-CSF<br>|
| Experimental: Combination C Dose expansion cohorts<br>PD 0360324 + aveluamb in selected tumor types | Drug: Avelumab<br>* Anti-PD-L1 antibody<br>* Other names: MSB0010718C;Drug: PD 0360324<br>* Anti-M-CSF<br>|
| Experimental: Combination D Dose escalation cohorts<br>PF-05082566 + PF-04518600 + avelumab in selected tumor types | Drug: Avelumab<br>* Anti-PD-L1 antibody<br>* Other names: MSB0010718C;Drug: Utomilumab<br>* Anti-4-1BB antibody<br>* Other names: PF-05082566;Drug: PF-04518600<br>* OX40 Agonist<br>|
| Experimental: Combination D Dose expansion cohorts<br>PF-05082566 + PF-04518600 + avelumab in selected tumor types | Drug: Avelumab<br>* Anti-PD-L1 antibody<br>* Other names: MSB0010718C;Drug: Utomilumab<br>* Anti-4-1BB antibody<br>* Other names: PF-05082566;Drug: PF-04518600<br>* OX40 Agonist<br>|
| Experimental: Cohort A9<br>NSCLC first-line Stage IV treated with avelumab +utomilumab (sequential starting with utomilumab monotherapy followed by combination) | Drug: Avelumab<br>* Anti-PD-L1 antibody<br>* Other names: MSB0010718C;Drug: Utomilumab<br>* Anti-4-1BB antibody<br>* Other names: PF-05082566;|
| Experimental: Cohort A10<br>NSCLC first-line Stage IV treated with avelumab + utomilumab (sequential starting with avelumab monotherapy followed by combination) | Drug: Avelumab<br>* Anti-PD-L1 antibody<br>* Other names: MSB0010718C;Drug: Utomilumab<br>* Anti-4-1BB antibody<br>* Other names: PF-05082566;|
| Experimental: Cohort F1<br>CMP-001 +avelumab in SCCHN | Drug: Avelumab<br>* Anti-PD-L1 antibody<br>* Other names: MSB0010718C;Drug: CMP-001<br>* TLR9 agonist<br>|
| Experimental: Cohort F2<br>CMP-001+avelumab+utomilumab in SCCHN | Drug: Avelumab<br>* Anti-PD-L1 antibody<br>* Other names: MSB0010718C;Drug: Utomilumab<br>* Anti-4-1BB antibody<br>* Other names: PF-05082566;Drug: CMP-001<br>* TLR9 agonist<br>|
| Experimental: Cohort F3<br>CMP-001 +avelumab+PF-04518600 in SCCHN | Drug: Avelumab<br>* Anti-PD-L1 antibody<br>* Other names: MSB0010718C;Drug: PF-04518600<br>* OX40 Agonist<br>Drug: CMP-001<br>* TLR9 agonist<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with Dose-Limiting Toxicities (DLT) | For Phase 1b: DLTs for Combination A (avelumab and PF-05082566) or Combination B (avelumab and PF-04518600) or Combination C (avelumab and PD 0360324) or Combination D (Avelumab and utomilumab and PF-04518600)occurring during the first 8 weeks of treatment (first 2 cycles). For Phase 1b: DLT for Combination F (avelumab plus CMP-001 and utomilumab or PF-04518600) occurring during the first 4 weeks of treatment (first cycle). | First 8 weeks of treatment (Combination A-D) First 4 weeks of treatment (CombinationF) | 
| Objective Response - Number of Participants With Objective Response | For Phase 2: Number of participants with objective response (ie, confirmed complete or partial response according to RECIST Version 1.1). | Baseline up to approximately 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax of avelumab (MSB0010718C) | Cmax defined as the maximum plasma concentration of avelumab (MSB0010718C) | Pre-dose and 1 hour post-dose on Days 1, 8, and 15 of Cycle 1, then on Day 1 of Cycles 2, 4, 6, and 10 | 
| Cmax of PF-05082566 | Cmax defined as the maximum plasma concentration of PF-05082566 | Pre-dose and 1 hour post-dose on Days 1, 8, and 15 of Cycle 1, and then on Day 1 of Cycles 3, 5, 8, and 12 | 
| Ctrough of avelumab (MSB0010718C) | Ctrough is defined as the trough plasma concentration at the end of an avelumab dosage interval. | Pre-dose and 1 hour post-dose on Days 1, 8, and 15 of Cycle 1, then on Day 1 of Cycles 2, 4, 6, and 10 | 
| Ctrough of PF-05082566 | Ctrough is defined as the trough plasma concentration at the end of a PF-05082566 dosage interval. | Pre-dose and 1 hour post-dose on Days 1, 8, and 15 of Cycle 1, and then on Day 1 of Cycles 3, 5, 8, and 12 | 
| Anti-Drug Antibody (ADA) levels of avelumab (MSB0010718C) | Immunogenicity assessment of avelumab (MSB0010718C). | Pre-dose on Day 1 of Cycles 1, 2, 4, 6, and 10 | 
| Anti-Drug Antibody (ADA) levels of PF-05082566 | Immunogenicity assessment of PF-05082566. | Pre-dose on Day 1 of Cycles 1, 3, 5, 8, and 12 | 
| Time to Tumor Response (TTR) | Time to Tumor Response (TTR) is defined for patients with confirmed objective response (CR or PR) as the time from the date of randomization (NSCLC) or date of first dose of study treatment (melanoma and SCCHN) to the first documentation of objective tumor response. | Baseline up to approximately 24 months | 
| Duration of Response (DR) | Duration of Response (DR) is defined for patients with confirmed objective response (CR or PR) as the time from the first documentation of objective tumor response to the first documentation of objective tumor progression or to death due to any cause, whichever occurs first. | Baseline up to approximately 24 months | 
| Progression-Free Survival (PFS) | Progression-Free Survival (PFS) is defined as the time from the date of randomization (NSCLC) or date of first dose of study treatment (melanoma and SCCHN) to the date of disease progression by RECIST v1.1 or death due to any cause, whichever occurs first. | Baseline up to approximately 24 months | 
| Overall Survival (OS) | Overall Survival (OS) is defined as the time from the date of randomization (NSCLC) or date of first dose of study treatment (melanoma and SCCHN) to the date of death. | Baseline up to approximately 24 months | 
| Tumor tissue biomarkers | Tumor tissue biomarkers, including, but not limited to, PD-L1 expression and tumor infiltrating CD8+ T lymphocytes | Baseline | 
| Cmax of PF-04518600 | Cmax defined as the maximum plasma concentration of PF-04518600 | Pre-dose and 1 hour post-dose on Days 1, 8, and 15 of Cycle 1, then on Day 1 of Cycles 2, 4, 6, and 10 | 
| Anti-Drug Antibody (ADA) levels of PF-04518600 | Immunogenicity assessment of PF-04518600. | Pre-dose on Day 1 of Cycles 1, 2, 4, 6, and 10 | 
| Ctrough of PF-04518600 | Ctrough is defined as the trough plasma concentration at the end of a PF-04518600 dosage interval. | Pre-dose and 1 hour post-dose on Days 1, 8, and 15 of Cycle 1, then on Day 1 of Cycles 2, 4, 6, and 10 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Small cell lung cancer (SCLC), bladder cancer, platinum resistant ovarian cancer, TGCT/PVNS, anti PD-L1, anti 4-1BB, OX40 agonist, anti M-CSF, TLR9 agonist, Non-small cell lung cancer (NSCLC), melanoma, squamous cell carcinoma of head and neck (SCCHN), triple negative breast cancer (TNBC), gastric cancer