CD40 Agonistic Antibody APX005M (Sotigalimab) in Combination With Nivolumab

Phase 1

Completed

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

Interventions: Drug: APX005M
Drug: Nivolumab

Registration Number: NCT03123783

Lead Sponsor: Apexigen America, Inc.

Brief Summary: 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: 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

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 140

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Phase 2 expansion Cohort 1	APX005M	Immunotherapy naïve, metastatic or locally advanced NSCLC APX005M 0.3 mg/kg and nivolumab 360 mg every 3 weeks
Phase 2 expansion Cohort 3	APX005M	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
Phase 1b escalation 0.03 mg/kg	APX005M	Non-small cell lung cancer (NSCLC) or metastatic melanoma APX005M 0.03 mg/kg and nivolumab 360 mg every 3 weeks
Phase 2 expansion Cohort 2	APX005M	Metastatic melanoma progressing during treatment with anti-PD-1/PD-L1 therapy APX005M 0.3 mg/kg and nivolumab 360 mg every 3 weeks
Phase 1b escalation 0.1 mg/kg	APX005M	Non-small cell lung cancer (NSCLC) or metastatic melanoma APX005M 0.1 mg/kg and nivolumab 360 mg every 3 weeks
Phase 1b escalation 0.3 mg/kg	APX005M	Non-small cell lung cancer (NSCLC) or metastatic melanoma APX005M 0.3 mg/kg and nivolumab 360 mg every 3 weeks
Phase 1b escalation 0.03 mg/kg	Nivolumab	Non-small cell lung cancer (NSCLC) or metastatic melanoma APX005M 0.03 mg/kg and nivolumab 360 mg every 3 weeks
Phase 1b escalation 0.1 mg/kg	Nivolumab	Non-small cell lung cancer (NSCLC) or metastatic melanoma APX005M 0.1 mg/kg and nivolumab 360 mg every 3 weeks
Phase 1b escalation 0.3 mg/kg	Nivolumab	Non-small cell lung cancer (NSCLC) or metastatic melanoma APX005M 0.3 mg/kg and nivolumab 360 mg every 3 weeks
Phase 2 expansion Cohort 1	Nivolumab	Immunotherapy naïve, metastatic or locally advanced NSCLC APX005M 0.3 mg/kg and nivolumab 360 mg every 3 weeks
Phase 2 expansion Cohort 2	Nivolumab	Metastatic melanoma progressing during treatment with anti-PD-1/PD-L1 therapy APX005M 0.3 mg/kg and nivolumab 360 mg every 3 weeks
Phase 2 expansion Cohort 3	Nivolumab	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

Primary Outcome Measures

Name	Time	Method
Number of Participants Experiencing Dose-limiting Toxicities (DLTs)	Up to 21 days following first dose of APX005M and nivolumab	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.
Phase 2 Evaluate the Objective Response Rate (ORR) by RECIST 1.1 and iRECIST in Each Cohort / Group	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)	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.
Maximum Tolerated Dose (MTD) of APX005M + Nivolumab (Phase 1b)	Up to 21 days following first dose of APX005M and nivolumab	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.

Secondary Outcome Measures

Name	Time	Method
6-month PFS Rate (Phase 2)	* Outcome Measure Time Frame From start of treatment (Day 1) to 6 months	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.
Duration of Response (DOR) as Per RECIST 1.1(Phase 2)	Maximum up to 25 months	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.
Safety of the APX005M and Nivolumab Combination (Phase 2)	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)	Number of participants with TEAEs are reported.
Median Progression-free Survival (PFS) (Phase 2)	From start of treatment (Day 1) up to 27 months	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.

Trial Locations

Locations (23): H. Doce de Octubre
🇪🇸
Madrid, Spain
H. Vall d'Hebron
🇪🇸
Barcelona, Spain
H. Lucus Augusti
🇪🇸
Lugo, Spain
Hospital Quirón Dexeus
🇪🇸
Barcelona, Spain
H. Insular de Gran Canaria
🇪🇸
Las Palmas De Gran Canaria, Spain
H. La Fe
🇪🇸
Valencia, Spain
H. HM Sanchinnarro
🇪🇸
Madrid, Spain
H. Clinic i Provincial
🇪🇸
Barcelona, Spain
H. de Málaga
🇪🇸
Málaga, Spain
City of Hope
🇺🇸
Duarte, California, United States
Hem-Onc Associates of the Treasure Coast
🇺🇸
Port Saint Lucie, Florida, United States
University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center (UMGCCC)
🇺🇸
Baltimore, Maryland, United States
SUNY Upstate Medical Hospital
🇺🇸
Syracuse, New York, United States
University Hospitals Seidman Cancer Center
🇺🇸
Cleveland, Ohio, United States
Abramson Cancer Center of The University of Pennsylvania
🇺🇸
Philadelphia, Pennsylvania, United States
Fox Chase Cancer Center
🇺🇸
Philadelphia, Pennsylvania, United States
H. General de Valencia
🇪🇸
Valencia De Alcántara, Spain
Fox Chase Center
🇺🇸
Rockledge, Pennsylvania, United States
Nebraska Cancer Specialists
🇺🇸
Omaha, Nebraska, United States
University of Nebraska Medical Center
🇺🇸
Omaha, Nebraska, United States
Tennessee Oncology
🇺🇸
Nashville, Tennessee, United States
University of Arizona Cancer Center
🇺🇸
Tucson, Arizona, United States
Yale University
🇺🇸
New Haven, Connecticut, United States