Study of Cabiralizumab in Combination With Nivolumab in Patients With Selected Advanced Cancers

Study Overview
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Brief Summary
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Phase 1a/1b does-escalation study of cabiralizumab alone and with nivolumab in advanced solid tumors.

Detailed Description
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This is a phase 1a/b single-arm, open-label study to evaluate safety, tolerability, pharmacokinetics (PK), and clinical benefit of cabiralizumab in combination with nivolumab in patients with selected advanced cancers.

Official Title
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A Phase 1a/1b Study of Cabiralizumab in Combination With Nivolumab in Patients With Selected Advanced Cancers

Conditions
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Advanced Solid Tumors, Head and Neck Cancer, Pancreatic Cancer, Ovarian Cancer, Renal Cell Carcinoma, Malignant Glioma, Non-small Cell Lung Cancer

Intervention / Treatment
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* Biological: Cabiralizumab
* Biological: Nivolumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have at least one measurable lesion at baseline by computed tomography (CT) or magnetic resonance imaging (MRI) as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria. Patients must have had progressive disease on, after, or refused, appropriate approved therapy for their tumor type. Patients must have histologically or cytologically confirmed solid tumor that is locally recurrent or metastatic and has progressed following standard treatment or is not appropriate for standard treatment Understand and sign an Institutional review board/Independent ethics committee (IRB/IEC)-approved informed consent form (ICF) prior to any study-specific evaluation Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Willing and able to comply with all study procedures Exclusion Criteria: Current or history of clinically significant muscle disorders (e.g., myositis), recent unresolved muscle injury, or any condition known to elevate serum creatine kinase (CK) levels Decreased cardiac function with New York Heart Association (NYHA) > Class 2 Uncontrolled or significant heart disorder such as unstable angina Significant abnormalities on electrocardiogram (ECG) at screening. Fridericia's correction formula for QT interval (QTcF) > 450 msec for males or > 470 msec for females at screening History of anti-drug antibodies, severe allergic, anaphylactic, or other infusion-related reaction to a previous biologic agent Positive test for latent tuberculosis (TB) at screening (Quantiferon test) or evidence of active TB Patients with abnormal serum chemistry values, which in the opinion of the Investigator is considered to be clinically significant, will be excluded from the study Lack of peripheral venous or central venous access or any condition that would interfere with drug administration or collection of study samples Any uncontrolled medical condition or psychiatric disorder which, in the opinion of the Investigator, would pose a risk to patient safety or interfere with study participation or interpretation of individual patient results Pregnant or breastfeeding Current unresolved infection or history of chronic, active, clinically significant infection (viral, bacterial, fungal, or other) which, in the opinion of the Investigator, would preclude the patient from exposure to a biologic agent or pose a risk to patient safety Prior exposure to any colony stimulating factor 1 receptor (CSF1R) pathway inhibitors

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1a Monotherapy Dose Escalation<br>Cabiralizumab administered at 2 mg/kg every 2 weeks (Q2W), 4 mg/kg Q2W and 6 mg/kg Q2W in participants with any solid tumor. | Biological: Cabiralizumab<br>* Solution for IV administration<br>* Other names: FPA008;|
| Experimental: Phase 1a Combination Therapy Dose Escalation<br>Nivolumab 3 mg/kg Q2W + cabiralizumab at the following doses: 1 mg/kg, 2 mg/kg, 4 mg/kg, and 6 mg/kg Q2W. Also nivolumab 3 mg/kg + cabiralizumab 4 mg/kg every 3 weeks (Q3W). Participants with any solid tumor. | Biological: Cabiralizumab<br>* Solution for IV administration<br>* Other names: FPA008;Biological: Nivolumab<br>* Solution for IV administration<br>* Other names: BMS-936558;|
| Experimental: Phase 1b Combination Therapy Dose Expansion<br>The expansion phase would use the recommended dose determined in Phase 1a: cabiralizumab 4 mg/kg + nivolumab 3 mg/kg Q2W. Participants are enrolled for the following advanced cancer types: non-small cell lung cancer (anti-programmed cell death 1 [PD1] targeted drug naïve), non-small cell lung cancer (prior treatment with anti-PD-1), pancreatic cancer, ovarian cancer, renal cell cancer, glioblastoma, and melanoma. | Biological: Cabiralizumab<br>* Solution for IV administration<br>* Other names: FPA008;Biological: Nivolumab<br>* Solution for IV administration<br>* Other names: BMS-936558;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety: Number of Participants With Grade 3 or Grade 4 Adverse Events (AEs) and Laboratory Abnormalities Defined as Dose Limiting Toxicities (DLT) (Phase 1a) | A DLT was defined as a study drug-related ≥ Grade 3 AE (using National Cancer Institute Common Terminology Criteria for Adverse Events v 4.03) occurring during the first 28-days, excluding Grade 3 tumor flare (defined as local pain, irritation, or rash localized at sites of known or suspected tumor), rash, immune-related adverse event (irAE) that resolved to ≤ Grade 1 by 14 days or a transient (resolving within 6 hours of onset) Grade 3 infusion-related AE. Any recurrence of Grade 3 rash, irAE or infusion-related AE was considered a DLT. The protocol was amended such that in the absence of clinical symptoms and other accompanying changes in bilirubin or alanine aminotransferase (ALT), serum elevation of aspartate aminotransferase (AST)/ALT > 12 × upper limit of normal (ULN) and ≤ 20 × ULN that lasted for < 7 days and serum elevation of creatine kinase (CK) and/or lactate dehydrogenase (LDH) > 15 × ULN and ≤ 20 × ULN that lasted for < 7 days were not considered DLTs. | 28 days | 
| Recommended Dose (RD) of Cabiralizumab in Combination With Nivolumab (Phase 1a) | Using both the incidence of dose limiting toxicities (first 28 days on therapy) as well as overall tolerability and toxicities observed beyond 28 days, the RD was chosen as 4 mg/kg of cabiralizumab + 3 mg/kg nivolumab every 2 weeks to be the dose used in the Phase 1b (dose expansion). No maximum tolerated dose was identified. | 28 days | 
| Safety: Number of Participants With Adverse Events and Serious Adverse Events (Phase 1a and 1b) | An AE is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation, patient-administered study drug and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: Resulted in death; Was life-threatening; Required inpatient hospitalization or causes prolongation of existing hospitalization; Resulted in persistent or significant disability/incapacity; Was a congenital anomaly/birth defect; Was an important medical event that may jeopardize the patient or may require intervention (e.g., medical, surgical) to prevent one of the other serious outcomes listed in the definition above. | From first dose of study drug up to 100 days after last dose. Median (range) duration of exposure was 6 (2-32) weeks in the monotherapy cohorts and 8 (2-108) weeks for cabiralizumab and 8 (2-156) weeks for nivolumab in the combination groups. | 
| Safety: Number of Participants With Treatment Discontinuations, Modifications, or Interruptions Due to Adverse Events (Phase 1b) | Safety: In the Phase 1b only, the incidence of treatment discontinuations, modifications, and interruptions due to adverse events. | From first dose of study drug up to last dose; median (range) duration of exposure was 8 (2-108) weeks for cabiralizumab and 8 (2-156) weeks for nivolumab. | 
| Efficacy: Objective Response Rate - Investigator Assessment (Phase 1b) | Objective response rate (ORR) is defined as the percentage of participants with confirmed responses of either complete response (CR) or partial response (PR). Response was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 by investigator review. Complete Response: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. | Tumor response was assessed every 8 weeks from first dose for the first 12 months and then every 12 weeks thereafter until end of treatment; maximum duration of treatment was 156 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy: Overall Survival (Phase 1b) | Overall survival (OS) was defined as the time from first dose of study drug to death due to any cause. OS was calculated using the Kaplan-Meier method. Participants who did not die while on study were censored on the date they were last known to be alive. | From first dose of study drug up to the end of study; maximum time on study in Phase 1b was 35.9 months. | 
| Efficacy: Overall Survival (OS) at One Year (Phase 1b) | Overall survival at one-year is defined as the percentage of participants who were alive one year after receiving their first dose of study drug. | 52 weeks | 
| Efficacy: Duration of Response (Phase 1b) | Duration of response (DOR) is defined as the time from the date of the first documentation of confirmed response (CR or PR) to the first objective documentation of progressive disease (PD) per RECIST v1.1 per Investigator assessment or to death due to any cause in the absence of documented PD. DOR was analyzed using Kaplan-Meier methods. Participants who discontinued from the study, did not die or have disease progression, or who received new anticancer therapy were censored on the date of last evaluable assessment prior to initiation of subsequent therapy. Participants with no evaluable baseline or post-baseline assessments were censored on the date of first dose. Progressive Disease (PD): The appearance of one or more new lesions or at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. | From first dose of study drug up to the end of study; maximum time on study in Phase 1b was 35.9 months. | 
| Efficacy: Progression Free Survival (Phase 1b) | Progression-free survival (PFS) was defined as as the time from the first dose to the first objectively documented disease progression per RECIST v1.1 per Investigator assessment or death due to any cause in the absence of documented progressive disease (PD). PFS was analyzed using Kaplan-Meier methods. Participants who discontinued from the study, did not die or have disease progression, or who received new anticancer therapy were censored on the date of last evaluable assessment prior to initiation of subsequent therapy. Participants with no evaluable baseline or post-baseline assessments were censored on the date of first dose. | From first dose of study drug up to the end of study; maximum time on study in phase 1b was 35.9 months. | 
| Efficacy: Objective Response Rate - Central Review Assessment (Phase 1b) | Objective response rate is defined as the percentage of participants with confirmed responses of either complete response (CR) or partial response (PR). Response was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 by independent central review. Complete Response: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. | Tumor response was assessed every 8 weeks from first dose for the first 12 months and then every 12 weeks thereafter until end of treatment; maximum duration of treatment was 156 weeks. | 
| Pharmacokinetics (PK) of Cabiralizumab: Area Under the Concentration Curve From Time Zero to Time of Last Quantifiable Concentration (AUC0-t) Normalized by Dose (Phase 1a and 1b) | Cabiralizumab serum concentration was determined using a validated enzyme-linked immunosorbent assay (ELISA) method. | Cycles 1 and 8, Day 1 predose, and at 0.25, 4, 24, 72, 168, and 336 hours after the end of infusion. | 
| PK of Cabiralizumab: Maximum Observed Concentration (Cmax) and Minimum Observed Concentration (Cmin) | Cabiralizumab serum concentration was determined using a validated enzyme-linked immunosorbent assay method. Cmax is the maximum observed serum concentration of cabiralizumab during the dosing period. Cmin is the minimum observed serum concentration of cabiralizumab during a dosing interval (excluding pre-dose concentration before the first dose). | Cycles 1 and 8, Day 1 predose, and at 0.25, 4, 24, 72, 168, and 336 hours after the end of infusion. | 
| Immunogenicity of Cabiralizumab: Number of Participants With Anti-Cabiralizumab Antibodies (Phase 1a and 1b) | Anti-drug antibodies (ADA) to cabiralizumab in serum were measured by a validated bridging electrochemiluminescence assay (ECLA). Baseline ADA Positive is defined as participants who had a baseline ADA sample which tested as positive for an anti-drug antibody against cabiralizumab; Post baseline ADA Positive is defined as participants that either had 1) an ADA detected (positive seroconversion) sample in a participant for whom ADA was not detected at baseline, or (2) an ADA detected sample with ADA titer at least 4-fold or greater than the baseline positive titer; Post baseline ADA Negative: Participants who never reported an ADA-positive sample after the initiation of treatment. | Blood samples were collected before the infusion on Cycles 1 (Baseline), 2, 3, 4, 5, 9, 13, and 21, and at 28 days and 100 days after the end of treatment | 
| Immunogenicity of Nivolumab: Number of Participants With Anti-Nivolumab Antibodies (Phase 1a and 1b) | Anti-drug antibodies (ADA) to nivolumab in serum were measured by a validated electrochemiluminescence assay. Baseline ADA Positive is defined as participants who had a baseline ADA sample which tested as positive for an anti-drug antibody against cabiralizumab; Post baseline ADA Positive is defined as participants that either had 1) an ADA detected (positive seroconversion) sample in a participant for whom ADA was not detected at baseline, or (2) an ADA detected sample with ADA titer at least 4-fold or greater than the baseline positive titer; Post baseline ADA Negative: Participants who never reported an ADA-positive sample after the initiation of treatment. | Blood samples were collected before the infusion on Cycles 1 (Baseline), 2, 3, 4, 5, 9, 13, and 21, and at 28 days and 100 days after the end of treatment |