Abraxane

Disease free survival was defined as the time from the date of randomization to the date of disease recurrence or death, whichever occurred earlier. Disease recurrence was determined by the independent radiological review of computed tomography (CT) or magnetic resonance imaging (MRI) scans. Participants who did not have disease recurrence or did not die were censored at the last tumor assessment date with disease-free status or the randomization date if the last tumor assessment with disease-free status was missing. Disease-free status referred to a status that was neither being disease recurrent nor indeterminate or not evaluable. Participants who received new anti-cancer therapy or cancer-related surgery prior to disease recurrence or death were censored at the date of last tumor assessment with disease-free status prior to the start of new anti-cancer therapy or cancer-related surgery or the randomization date.

Progression-free survival is defined as the time in months from the date of randomization to the date of disease progression based on the investigator's assessment according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 criteria (documented by computerized axial tomography \[CT scan\], not including symptomatic deterioration) or death (any cause) on or prior to 01 Aug 2019. RECIST 1.1 Definition: - Complete response (CR) -disappearance of all target lesions; - Partial response (PR) -at least a 30% decrease in the sum of diameters of target lesions from baseline - Stable disease (SD) -neither sufficient shrinkage to qualify for partial response (PR) nor sufficient increase of lesions to qualify for progressive disease (PD) - Progressive Disease (PD) - At least a 20% increase in the sum of diameters of target lesions from nadir, and/or the appearance of new lesions.

PFS was defined as the time from the randomization date to the start of disease progression or patient death, whichever occurred first. Participants who did not have disease progression or had not died were censored at the last known time that the patient was progression free. In the event of palliative radiotherapy or surgery, they were censored at the last assessment where they were documented to be progression-free prior to the date of radiotherapy or surgery. In follow up, participants who began new anticancer therapy prior to documented progression were censored at the last assessment where they were documented as progression free. Those with two or more missing response assessments prior to a visit with documented disease progression (or death) were censored at the last visit where they were documented to be progression free. RECIST defines progressive disease as a ≥ 20% increase taking as reference the smallest sum of the longest diameters recorded since the treatment began.

Overall survival was defined as the time from the date of randomization to the date of death from all causes. Participants who did not die were censored at the last known time the participant was alive. Patient survival was summarized using Kaplan-Meier methods.

Antitumor response was defined as the percentage of participants who achieved an objective response (Confirmed Response \[CR\] or Partial Response \[PR\]), confirmed by repeat assessments performed no less than 4 weeks after the criteria for response were first met. Response was based on the blinded radiological review using Response Evaluation Criteria in Solid Tumors (RECIST) response guidelines, Version 1.0. A complete response was defined as a disappearance of all target and non-target lesions and no new lesions. Partial response was defined as ≥ 30% decrease in the sum of the longest diameters (SLD) of target lesions, taking as reference the baseline SLD, and the persistence of one or more non-target lesions not qualifying for CR or Progressive Disease (the "unequivocal progression" of existing non-target lesion(s) or appearance of one or more new lesions).

* ORR: Proportion of patients who achieve a complete or partial response to treatment * Complete Response (CR): Disappearance of all target lesions. Disappearance of all non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. * Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

Treatment-emergent adverse events were defined as any adverse event (AE) or serious adverse event (SAE) that occurred or worsened on or after the day of the first dose of the investigational product through 28 days after the last dose of IP. In addition, any SAE with an onset date more than 28 day after the last dose of IP that was assessed by the investigator as related to IP was considered a TEAE. A participant met the primary endpoint if: an AE was the reason for discontinuation as recorded in the electronic Case Report Form (eCRF) and the participant had no doses administered beyond Cycle 4. 95% confidence interval for the percentage was calculated using the Clopper Pearson method.

TTF was defined as the time after the first dose of study therapy to discontinuation of study therapy due to disease progression, death by any cause, or the start of a new non-protocol-defined anticancer therapy/surgery. If a participant does not progress, die or start a new non-protocol-defined anticancer therapy, the participant was censored on the last tumor assessment date. Tumor evaluations of CT or MRI scans were assessed by the investigative sites and response determined according to Response Evaluation Criteria in Solid Tumors (RECIST) guidelines, version 1.1. The definition for progressive disease (PD) was \>= 20% increase in the sum of diameters of target lesions from nadir, and the sum showed an absolute increase of \>= 5 mm; the progression of a non-target lesion or the appearance of any new lesions is also considered progression. Median and its 90% confidence interval (CI) of TTF were estimated using the method of Brookmeyer and Crowley.

PFS is defined as the time from randomization to first radiologic confirmation of disease progression, or death from any cause.

Progression-free survival was defined as the time in months from the date of randomization/assignment to the date of disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 criteria documented by computed tomography (CT) scan, not including symptomatic deterioration, or death (any cause) on or prior to the clinical cut-off date, which ever occurred earlier. Participants who did not have disease progression and had not died, regardless of whether they were discontinued from treatment, were censored at the date of last tumor assessment, on or prior to the clinical cut-off date that the participant was progression free. Progressive Disease was defined as at least a 20% increase in the sum of diameters of target lesions from nadir.

PFS rate was measured by Investigator Assessment according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 from the start of study treatment to disease progression or death from any cause, whichever occurred first.

ORR was defined as the percentage of participants who achieve a complete response (CR) or partial response (PR) based on independent radiological review per Response Evaluation Criteria in Solid Tumors (RECIST) Criteria (V1.0). Using RECIST Version 1.0, participants were to achieve either a complete response defined as the disappearance of all known disease and no new sites or disease related symptoms confirmed at least 4 weeks after initial documentation or partial response defined as at least a 30% decrease in the sum of the longest diameters of target lesions and no progression in non-target lesions based on confirmed responses from the independent radiological review of best overall response during study treatment.

PFS was defined as the time from the date of randomization to the date of disease progression or death from any cause on or prior to the data cutoff date for the statistical analysis, whichever occurred earlier. Tumor responses were assessed every 6 weeks using, Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and defined as: Complete response (CR) is the disappearance of all target lesions; Partial response (PR) occurs when at least a 30% decrease in the sum of diameters of target lesions from baseline; Stable disease is neither sufficient shrinkage to qualify for a PR nor sufficient increase of lesions to qualify for Progressive disease (PD); Progressive Disease- is at least a 20% increase in the sum of diameters of target lesions from nadir.

Count of study participants who had at least one treatment-emergent adverse event (TEAE) defined as any adverse event that began or worsened in grade after the start of study drug through 30 days after the last dose of study drug.

Progression-free survival is defined as the time from first dose of study drug to the start of disease progression or patient death, whichever occurs first. Patients who do not have disease progression or have not died at the end of follow-up were censored at the last known time the patient was progression free. Patients that initiate other anticancer therapy prior to progression were censored at the time when new anticancer therapy was initiated. Response Evaluation Criteria in Solid Tumors (RECIST) defines progressive disease (PD) as a \>= 20% increase taking as reference the smallest sum of the longest diameters recorded since the treatment started; or the appearance of one or more new lesions; or the unequivocal progression of a non-target lesion.

Percentage of participants who achieve an objective confirmed complete or partial overall response based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0. A complete response (CR) is the disappearance of all known disease and no new sites or disease related symptoms. A partial response (PR) is \>= 30% decrease in the sum of the longest diameters of target lesion. PR was also recorded when all measurable disease has completely disappeared, but a non-measurable component (ie, ascites) is still present but not progressing. Overall response (ORR) = CR+PR.

Percentage of participants who achieved an objective confirmed complete or partial overall response based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0. A complete response (CR) is the disappearance of all known disease and no new sites or disease related symptoms confirmed at least 4 weeks after initial documentation. A partial response (PR) is at least a 30% decrease in the sum of the longest diameters of target lesions, taking as a reference the baseline sum of the longest diameters confirmed at least 4 weeks after initial documentation. PR is also recorded when all measurable disease has completely disappeared, but a non-measurable component (i.e., ascites) is still present but not progressing, or with the persistence of one or more non-target lesions and/or the maintenance of tumor marker level above the normal limits.

• Any toxicity starting during the first 28 days of treatment and requiring 14 days or more of treatment interruption • Grade 3 or 4 neutropenia associated with fever \> 38.5°C • Grade 3 anemia requiring a transfusion • Any Grade 4 hematological toxicity lasting \> 7 days • Grade 4 thrombocytopenia or a Grade 3 or 4 thrombocytopenia associated with clinically significant bleeding • Grade 3 or 4 non-hematological toxicity with the exception of fatigue, due to any of the study drugs and unresponsive to medical treatment within 4 days of onset • Subjects who experience Grade ≥ 3 hyperbilirubinemia as an apparent DLT. If a Phase 1 subject experiences a Grade ≥ 3 hyperbilirubinemia due principally to unconjugated bilirubin, it will not be defined as a DLT. The subject will be removed from the study and the Phase 1 subject will be replaced. • Any non-hematologic toxicity delaying the initiation of cycle 2 by \> 21 days • Grade ≥ 2 pneumonitis or interstitial lung disease

1 year survival rate is defined as the time interval between the date of first dose of Investigational Product (IP) and the date of death.

An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a subject during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the subject's health, including laboratory test values, regardless of etiology. All AEs will be recorded by the Investigator from the time the subject signs informed consent until 28 days after the last dose of IP as well as those SAEs made known to the Investigator at any time thereafter that are suspected of being related to Investigational Product.

The number of subjects with dose limiting toxicity in each treatment arm in Part 1.

The percentage of subjects with Grade 3 or 4 Treatment Emergent Adverse Events (TEAEs) or treatment discontinuation due to a TEAE during the study

The percentage of subjects with Grade 3 or 4 TEAEs or treatment discontinuation due to a TEAE during the study.

A DLT was defined as investigational product (IP)-related adverse events occurring during the DLT assessment period that led to treatment discontinuation or met one of the following criteria: - Common Terminology Criteria for Adverse Events (CTCAE) Grade (Gr) 3 or 4 nonhematologic toxicity (excluding transient transaminitis) - CTCAE Gr 3 or 4 nausea or vomiting that persisted \> 5 days despite maximal anti-emetic treatment - CTCAE Gr 4 thrombocytopenia or anemia that persisted \> 7 days or required transfusion \> 7 days - CTCAE Gr 3 thrombocytopenia with bleeding - CTCAE Gr 4 uncomplicated neutropenia lasting \> 7 days - Febrile neutropenia with confirmed bacterial infection - CTCAE Gr 3 hematologic toxicity requiring treatment (tx) delay \> 21 days. Use of "..." in the table rows signifies the continuation of row title per the above list.

An adverse event (AE) was defined as any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participant during the course of a study. A serious AE (SAE) is any AE occurring at any dose that: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; constitutes an important medical event. TEAEs were defined as AEs that began or worsened in severity on or after the date of the first dose of study drug and within 28 days of the date of the last dose of study drug. The severity of an AE was graded according to the CTCAE, Version 4.0.

Overall response rate was defined as the percentage of participants who achieved a complete response (CR; disappearance of all target lesions) or partial response (PR; at least a 30% decrease in the sum of diameters of target lesions) confirmed no less than 4 weeks after the criteria for response were first met using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 guidelines. (For Phase 2 neuroblastoma participants who had both RECIST and Curie Score tumor evaluations, both tumor response results were considered and an overall response was derived.) Confidence interval was obtained using the Clopper-Pearson method.

A dose-limiting toxicity (DLT) is defined as one or more of the following toxicities related to study drug during Cycle 1, according to the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE), Version 3: * Grade 4 neutropenia lasting \>3 days in the absence of growth factor support; * Grade 4 neutropenia associated with fever \>38.5°C; * Any other Grade 4 hematological toxicity; * Grade 3 thrombocytopenia with hemorrhage; * Grade 3 or 4 nausea, vomiting or diarrhea despite prophylaxis or treatment with an optimal anti-emetic or anti-diarrhea regimen; * Any other Grade 3 or higher non-hematological toxicity attributable to the study drug, excluding alopecia and fatigue.