High-Risk Skin Cancers With Atezolizumab Plus NT-I7

Study Overview
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Brief Summary
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The purpose of this study is to test whether the addition of NT-I7 to atezolizumab provides clinically meaningful outcomes for patients with anti-PD-1/PD-L1 naive or relapsed/refractory high-risk melanoma, Merkel Cell Carcinoma (MCC) and cutaneous Squamous Cell Carcinoma (cSCC)

Detailed Description
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This is a Phase 1b/2a, open-label, multicenter study to evaluate the safety, tolerability and anti-tumor effect of NT-I7 (rhIL-7-hyFc) in combination with atezolizumab (MPDL3280A, anti-PD-L1) in patients with anti-PD-1/PD-L1 naïve or relapsed/refractory high-risk skin cancers including cutaneous Squamous Cell Carcinoma (cSCC), Merkel Cell Carcinoma (MCC) and melanoma. This study has been designed to evaluate the safety and tolerability, including the Maximum Tolerated Dose (MTD) or recommended Phase 2 dose (RP2D), of NT-I7 in combination with atezolizumab. There are two phases to this study: Phase 1b, a NT-I7 dose-escalation phase to determine the MTD or RP2D Phase 2a, a non-randomized parallel dose expansion phase to confirm the MTD or RP2D in both arms. Arm I: Anti-PD-1/PD-L1 (checkpoint inhibitors, CPI) naïve patients with cSCC and MCC Arm II: Anti-PD-1/PD-L1 relapsed/refractory patients with cSCC, MCC and melanoma Number of Patients A total of up to 84 patients will be enrolled; Up to 24 patients will be enrolled in the Phase 1b (up to 6 patients per dose level, using 3 + 3 design), and 60 patients will be enrolled in the Phase 2a (24 patients in Arm I, i.e., 12 patients for each indication, and 36 in Arm II, i.e., 12 patients for each indication).

Official Title
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A Phase 1b/2a, Open Label Study to Evaluate Anti-tumor Efficacy and Safety of rhIL-7-hyFc (NT-I7) in Combination With Anti-PD-L1 (Atezolizumab) in Patients With Anti-PD-1/PD-L1 naïve or Relapsed/Refractory High-risk Skin Cancers

Conditions
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Melanoma, Merkel Cell Carcinoma, Cutaneous Squamous Cell Carcinoma

Intervention / Treatment
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* Drug: NT-I7
* Drug: atezolizumab


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Patients must be ≥18 years of age on day of signing informed consent document. Eastern Cooperative Oncology Group (ECOG) performance status ≤2 (Karnofsky ≥60%). Patients must have adequate organ and marrow function. Patients positive for HIV can be considered. Arm I - cSCC: Patients must have biopsy-proven metastatic cSCC or locoregional cSCC that has recurred following standard locoregional therapy with surgery and/or radiation therapy; MCC: Patients must have biopsy-proven metastatic MCC or locoregional MCC in need of systemic therapy, including patients that have not had prior systemic therapy or have recurred following standard locoregional therapy with surgery and/or radiation therapy. Prior chemotherapy is allowed. Arm II - MCC: Patients must have biopsy-proven metastatic MCC or locoregional MCC that has recurred following anti-PD-1 or anti-PD-L1, or has SD following anti-PD-1 or anti-PD-L1, defined as 12 weeks of SD per RECIST 1.1; cSCC: Patients must have biopsy-proven metastatic cSCC or locoregional cSCC that has recurred following anti-PD-1 or anti-PD-L1, or has SD following anti-PD-1 or anti-PD-L1, defined as 12 weeks of SD per RECIST 1.1; Melanoma: Patients must have biopsy-proven metastatic melanoma or locoregional melanoma that has recurred following anti-PD-1, anti-PD-L1, or has SD following anti-PD-1 or anti-PD-L1, defined as 12 weeks of SD per RECIST 1.1. Note: Prior therapy with ipilimumab is allowed (subject to a 6-week washout period) but not required. Note: Progression following targeted therapies (e.g., BRAF inhibitor and/or MEK inhibitor) or other approved (e.g., talimogene laherparepvec [T-VEC]) or investigational therapies is allowed. Key Exclusion Criteria: Pregnancy, lactation, or breastfeeding. Significant cardiovascular disease. Poorly controlled Type 2 diabetes mellitus. Major surgical procedure, other than for diagnosis, within 28 days prior to Cycle 1, Day 1, or anticipation of need for a major surgical procedure during the study. Patients who have had chemotherapy or radiotherapy within 2 weeks (4 weeks for nitrosoureas or systemic mitomycin C) prior to Cycle 1, Day 1. Patients who had prior treatment with immune CPIs, immunomodulatory monoclonal antibodies (mAbs), and/or mAb-derived therapies within 6 weeks before the initiation of study treatment, except for prior anti-PD-L1/anti-PD-1, which requires a 3-week washout period. Patients who have received treatment with any other investigational agent within 4 weeks prior to Cycle 1, Day 1. Patients who have received treatment and failed therapy with checkpoint inhibition plus a T-cell growth factor, e.g., IL-2 (NTKR-204), IL-15 (ALT-803) or IL-7 (CYT107). Patients with known primary central nervous system (CNS) malignancy, untreated CNS metastases, or active CNS metastases (progressing or requiring corticosteroids for symptomatic control) are excluded, with some exceptions. Patients who have leptomeningeal disease. Patients with autoimmune disease history. Patients who have received treatment with systemic immunosuppressive medications within 2 weeks prior to Cycle 1, Day 1. Patients who have a history of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on screening chest CT scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted. Patients with active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] test at screening). Patients with active tuberculosis (TB). Patients who have severe infections within 4 weeks prior to Cycle 1, Day 1. Patients who have signs or symptoms of recent infection (not meeting the above criteria for severe infections) within 2 weeks before initiation of study treatment. Patients with prior allogeneic bone marrow transplantation or prior solid organ transplantation. Patients who have received a live, attenuated vaccine within 4 weeks prior to Cycle 1, Day 1 or anticipate that such a live attenuated vaccine be required during the study.

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Checkpoint Inhibitor-Naive cSCC, MCC Pts<br>Anti-PD-1/PD-L1 naïve patients with cSCC and MCC | Drug: NT-I7<br>* Dose Escalation (Phase 1b) - NT-I7 IM (intramuscular) on Day 1 of each Cycle until MTD or RP2D is achieved. Dose Expansion - NT-I7 IM (intramuscular) on Day 1 of each Cycle, at Maximum Tolerated Dose (MTD) or RP2D defined in escalation phase<br>* Other names: rhIL-7-hyFc;Drug: atezolizumab<br>* Dose Escalation - atezolizumab IV (intravenous) on Day 1 of each Cycle Dose Expansion - atezolizumab IV (intravenous) on Day 1 of each Cycle<br>* Other names: Tecentriq;|
| Experimental: Checkpoint Inhibitor-Relapsed/Refractory cSCC MCC Melanoma Pts<br>Anti-PD-1/PD-L1 relapsed/refractory patients with cSCC, MCC and melanoma | Drug: NT-I7<br>* Dose Escalation (Phase 1b) - NT-I7 IM (intramuscular) on Day 1 of each Cycle until MTD or RP2D is achieved. Dose Expansion - NT-I7 IM (intramuscular) on Day 1 of each Cycle, at Maximum Tolerated Dose (MTD) or RP2D defined in escalation phase<br>* Other names: rhIL-7-hyFc;Drug: atezolizumab<br>* Dose Escalation - atezolizumab IV (intravenous) on Day 1 of each Cycle Dose Expansion - atezolizumab IV (intravenous) on Day 1 of each Cycle<br>* Other names: Tecentriq;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability of NT-I7 in combination with atezolizumab to determine the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) of NT-I7 | Incidence, nature, and severity of adverse events graded according to NCI CTCAE v5.0 Incidence and nature of Dose-Limiting Toxicities (DLTs) Potential correlation with PK, pharmacodynamic, safety, and efficacy parameters | Up to approximately 56 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate immunogenicity of NT-I7 and atezolizumab | To determine and evaluate the incidence of anti-drug antibodies (ADA) to NT-I7 and atezolizumab during the study relative to the prevalence of ADA at baseline | Up to approximately 56 months | 
| Preliminary assessment of the Objective Response Rate (ORR) of NT-I7 in combination with atezolizumab | To preliminarily assess the Objective Response Rate (ORR) defined as percentage of patients who have at least one confirmed partial response (PR) or complete response (CR) according to RECIST v1.1, as determined by the investigator. | Up to approximately 56 months | 
| Preliminary assessment the Disease Control Rate (DCR) of NT-I7 in combination with atezolizumab | To preliminarily assess the Disease Control Rate (DCR) defined as proportion of patients with a best overall response of CR, PR or stable disease (SD). | Up to approximately 56 months | 
| Preliminary assessment the Duration of Objective Response (DOR) of NT-I7 in combination with atezolizumab | To preliminarily assess the Duration of Objective Response (DOR), defined as the time from the first occurrence of a documented objective response to the time of the first documented disease progression or death from any cause, whichever occurs first, per RECIST v1.1 as determined by the investigator. | Up to approximately 56 months | 
| Preliminary assessment the Progression Free Survival (PFS) of NT-I7 in combination with atezolizumab | To preliminarily assess the Progression Free Survival (PFS), defined as the time from the first study treatment (Cycle 1 Day 1) to the first occurrence of progression or death from any cause, whichever occurs first, per RECIST v1.1 as determined by the investigator. | Up to approximately 56 months | 
| Preliminary assessment the Overall Survival (OS) of NT-I7 in combination with atezolizumab | To preliminarily assess the Overall Survival (OS) defined as the time from first study treatment (Cycle 1 Day 1) to death from any cause. | Up to approximately 56 months |