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

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.

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.

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.

Safety: In the Phase 1b only, the incidence of treatment discontinuations, modifications, and interruptions due to adverse events.

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.

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.

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.

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.

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.

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.

Cabiralizumab serum concentration was determined using a validated enzyme-linked immunosorbent assay (ELISA) method.

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).

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.

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.