CD40 Agonistic Antibody APX005M (Sotigalimab) in Combination With Nivolumab

Study Overview
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Brief Summary
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This study is a Phase 1-2 open-label dose escalation study of the immuno-activating monoclonal antibody APX005M administered in combination with nivolumab to adult subjects with non-small cell lung cancer or metastatic melanoma. The Phase 1 portion is intended to establish the maximum tolerated dose and the recommended phase 2 dose of APX005M when administered in combination with nivolumab. The Phase 2 portion of the study will evaluate safety and efficacy of the combination.

Detailed Description
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APX005M-002 is an open-label Phase 1-2 study and comprises a dose-escalation portion (Phase 1) followed by a Phase 2 tumor specific portion. Eligible subjects with non-small cell lung cancer or metastatic melanoma will receive intravenous APX005M in combination with nivolumab until disease progression, unacceptable toxicity or death, whichever occurs first. Study objectives include: Determine the maximum tolerated dose and the recommended phase 2 dose of APX005M when given in combination with nivolumab Evaluate safety of the APX005M and nivolumab combination Evaluate the objective response rate, duration of response and median PFS by RECIST 1.1 in subjects with non-small cell lung cancer or metastatic melanoma receiving APX005M in combination with nivolumab Determine the PK of APX005M

Official Title
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A Study to Evaluate the Safety and Efficacy of the CD40 Agonistic Antibody APX005M Administered in Combination With Nivolumab in Subjects With Non-small Cell Lung Cancer and Subjects With Metastatic Melanoma

Conditions
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Cancer, Non Small Cell Lung Cancer Metastatic, Metastatic Melanoma, Neoplasm of Lung, Melanoma

Intervention / Treatment
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* Drug: APX005M
* Drug: Nivolumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed, immunotherapy naïve or PD-1/PD-L1 pre-treated, metastatic or locally advanced non-small cell lung cancer not amenable to curative treatment. Subjects may be treatment naive or could have received one prior platinum based chemotherapy for non-small cell lung cancer and subjects with a documented activating mutation (e.g., EGFR, ALK, ROS) must also have received the appropriate therapy and progressed Histologically or cytologically confirmed unresectable or metastatic melanoma that progressed during treatment with an anti-PD-1/PD-L1 therapy and had confirmation of PD>=4 weeks later. Subjects with BRAF activating mutation could have also received a BRAF inhibitor and/or MEK inhibitor regimen prior to anti-PD-1/PD-L1 therapy. Measurable disease by RECIST 1.1 ECOG performance status of 0 or 1 Adequate bone marrow, liver and kidney function Negative pregnancy test for women of child bearing potential Agreement to use effective methods of contraception per the protocol requirements Exclusion Criteria: Previous exposure to any immunomodulatory agents (e.g., anti- CD40, anti-PD-1/PD-L1, anti-CTLA-4, IDO inhibitors) except PD-1/PD-L1 targeting agents in the subsets of patients that must have previous treatment with anti-PD-1/PD-L1 therapy Second malignancy (solid or hematologic) within the past 3 years except locally curable cancers that have been apparently cured Active, known, clinically serious infections within the 14 days prior to first dose of investigational product Use of systemic corticosteroids or other systemic immunosuppressive drugs Active, known or suspected autoimmune disease History of (non-infectious) pneumonitis that required corticosteroids or current pneumonitis History of interstitial lung disease History of life-threatening toxicity related to prior anti-PD-1/PD-L1 treatment for subjects with metastatic melanoma or NSCLC.

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: Sequential Assignment
Interventional Model Description: Phase 1b dose escalation with up to 4 sequential dose levels. Followed by Phase 2 dose expansion at Recommended Phase 2 Dose in 3 parallel disease cohorts.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1b escalation 0.03 mg/kg<br>Non-small cell lung cancer (NSCLC) or metastatic melanoma APX005M 0.03 mg/kg and nivolumab 360 mg every 3 weeks | Drug: APX005M<br>* APX005M is a CD40 agonistic monoclonal antibody<br>Drug: Nivolumab<br>* Nivolumab is an immune checkpoint (PD-1) blocking antibody<br>* Other names: Opdivo;|
| Experimental: Phase 1b escalation 0.1 mg/kg<br>Non-small cell lung cancer (NSCLC) or metastatic melanoma APX005M 0.1 mg/kg and nivolumab 360 mg every 3 weeks | Drug: APX005M<br>* APX005M is a CD40 agonistic monoclonal antibody<br>Drug: Nivolumab<br>* Nivolumab is an immune checkpoint (PD-1) blocking antibody<br>* Other names: Opdivo;|
| Experimental: Phase 1b escalation 0.3 mg/kg<br>Non-small cell lung cancer (NSCLC) or metastatic melanoma APX005M 0.3 mg/kg and nivolumab 360 mg every 3 weeks | Drug: APX005M<br>* APX005M is a CD40 agonistic monoclonal antibody<br>Drug: Nivolumab<br>* Nivolumab is an immune checkpoint (PD-1) blocking antibody<br>* Other names: Opdivo;|
| Experimental: Phase 2 expansion Cohort 1<br>Immunotherapy naïve, metastatic or locally advanced NSCLC APX005M 0.3 mg/kg and nivolumab 360 mg every 3 weeks | Drug: APX005M<br>* APX005M is a CD40 agonistic monoclonal antibody<br>Drug: Nivolumab<br>* Nivolumab is an immune checkpoint (PD-1) blocking antibody<br>* Other names: Opdivo;|
| Experimental: Phase 2 expansion Cohort 2<br>Metastatic melanoma progressing during treatment with anti-PD-1/PD-L1 therapy APX005M 0.3 mg/kg and nivolumab 360 mg every 3 weeks | Drug: APX005M<br>* APX005M is a CD40 agonistic monoclonal antibody<br>Drug: Nivolumab<br>* Nivolumab is an immune checkpoint (PD-1) blocking antibody<br>* Other names: Opdivo;|
| Experimental: Phase 2 expansion Cohort 3<br>Metastatic or locally advanced NSCLC progressing during treatment with anti-PD-1/PD-L1: Group A: best response of progressive disease or with stable disease < 16 weeks Group B: tumor response or with stable disease ≥ 16 weeks | Drug: APX005M<br>* APX005M is a CD40 agonistic monoclonal antibody<br>Drug: Nivolumab<br>* Nivolumab is an immune checkpoint (PD-1) blocking antibody<br>* Other names: Opdivo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Experiencing Dose-limiting Toxicities (DLTs) | All toxicities were graded according to the NCI-CTCAE version 4.03. DLT was defined as any of the following events attributed to APX005M and nivolumab combination: Grade 4 hematologic toxicity lasting ≥ 7 days (except asymptomatic lymphopenia) Grade 3 or 4 neutropenia with a single temperature of >38.3◦ C (101◦ F) or a sustained temperature of ≥38◦ C (100.4◦ F) for more than one hour Grade 4 thrombocytopenia or Grade ≥3 thrombocytopenia with signs or symptoms of bleeding or requiring platelet transfusion Grade 4 non-hematologic toxicity Grade 3 non-hematologic toxicity lasting >3 days despite optimal supportive care Any Grade ≥ 3 non-hematologic laboratory value if: medical intervention is required to treat the subject, abnormality leads to hospitalization, or abnormality persists for >1 week Failure to recover from a treatment-related AE to baseline or ≤ Grade 1 within 12 weeks of last dose of investigational product Grade 5 toxicity. | Up to 21 days following first dose of APX005M and nivolumab | 
| Maximum Tolerated Dose (MTD) of APX005M + Nivolumab (Phase 1b) | Establish the MTD dose of APX005M combined with 360 mg of nivolumab for which for which < 33% of DLT- evaluable participants experience a DLT. In Phase 1b, the RP2D was based on the overall safety and tolerability of the combination of APX005M and nivolumab by testing increasing doses up to 0.3 mg/kg APX005M + nivolumab. | Up to 21 days following first dose of APX005M and nivolumab | 
| Phase 2 Evaluate the Objective Response Rate (ORR) by RECIST 1.1 and iRECIST in Each Cohort / Group | ORR defined as the rate of patients who show as best overall response; either a complete response (CR) or a partial response (PR). The ORR can be evaluated by Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. using computed tomography (CT) scans/magnetic resonance imaging (MRI). Per RECIST v1.1, for target lesions and assessed by imaging: Complete Response, (CR), Disappearance of all target lesions and nontarget (NT) lesions; Partial Response (PR), >30% decrease in the sum of the longest diameter of target lesions and no PD in NT lesions or new lesions; Objective Response Rate (ORR)=CR + PR. | From start of the treatment (Day 1) until disease progression, withdrawal of consent, death, initiation of any anticancer therapy, lost to follow-up, or termination by the Sponsor, whichever comes first (for Phase 2: maximum up to 27 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of the APX005M and Nivolumab Combination (Phase 2) | Number of participants with TEAEs are reported. | Day 1 up to 30 days (or 100 days for SAEs and AEs with potential immunologic etiology) following the after the last dose of APX005M and/or nivolumab (from start of treatment up to 27 months) | 
| Duration of Response (DOR) as Per RECIST 1.1(Phase 2) | Duration of Response is defined as the time from the first evidence of confirmed partial response (PR) or better by Per RECIST v1.1 to disease progression or death due to any cause; in subjects alive without progressive disease (PD), DOR was censored on the date of the last tumor assessment. PD is defined using RECIST v1.1, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. | Maximum up to 25 months | 
| Median Progression-free Survival (PFS) (Phase 2) | Progression-free Survival (PFS) in each cohort, measured from first dose to the earlier of PD (by RECIST 1.1) or death due to any cause, whichever occurs first. | From start of treatment (Day 1) up to 27 months | 
| 6-month PFS Rate (Phase 2) | PFS rate in each cohort, measured from first dose to the earlier of PD (by RECIST 1.1) or death due to any cause, whichever occurs first. | * Outcome Measure Time Frame From start of treatment (Day 1) to 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CD40, Immunotherapy, Nivolumab, APX005M, PD-1