# Abstract

 

## Background BTH1677, a beta-glucan pathogen-associated molecular pattern molecule, drives an anti-cancer immune response in combination with oncology antibody therapies. This phase II study explored the efficacy, pharmacokinetics (PK), and safety of BTH1677 combined with bevacizumab/carboplatin/paclitaxel in patients with untreated advanced non-small cell lung cancer (NSCLC). 

## Methods Patients were randomized to the BTH1677 arm (*N* = 61; intravenous [IV] BTH1677, 4 mg/kg, weekly; IV bevacizumab, 15 mg/kg, once each 3-week cycle [Q3W]; IV carboplatin, 6 mg/mL/min Calvert formula area-under-the-curve, Q3W; and IV paclitaxel, 200 mg/m^2^, Q3W) or Control arm (*N* = 31; bevacizumab/carboplatin/paclitaxel as above). Carboplatin/paclitaxel was discontinued after 4-6 cycles and patients who responded or remained stable received maintenance therapy with BTH1677/bevacizumab (BTH1677 arm) or bevacizumab (Control arm). Efficacy assessments, based on blinded central radiology review, included objective response rate (ORR; primary endpoint), disease control rate, duration of objective response, and progression-free survival. Overall survival and adverse events (AEs) were also assessed. 

## Results ORR was higher in the BTH1677 vs Control arm but the difference between groups was not statistically significant (60.4% vs 43.5%; *P* = .2096). All other clinical endpoints also favored the BTH1677 arm but none statistically differed between arms. PK was consistent with previous studies. Although a higher incidence of Grade 3/4 AEs occurred in the BTH1677 vs Control arm (93.2% vs 66.7%), no unexpected AEs were observed. Serious AEs and discontinuations due to AEs were lower in the BTH1677 vs Control arm. 

## Conclusions Improvements in tumor assessments and survival were observed with BTH1677/bevacizumab/carboplatin/paclitaxel compared with control treatment in patients with advanced NSCLC. 

## Trial registration ClinicalTrials.gov registration ID: [ NCT00874107](#). Registered 2 April 2009. First participant was enrolled on 29 September 2009. # Results 

## Patient disposition Between 29 September 2009 and 08 March 2013, a total of 92 patients with NSCLC were randomly assigned 2:1 to the BTH1677 or the Control arm. As shown in Fig. [1](#), 59 patients in the BTH1677 arm and 30 patients in the Control arm were treated and included in the safety and survival analyses. The blinded central radiology review primary efficacy population included 50 patients (48 patients response evaluable) in the BTH1677 arm and 23 patients in the Control arm. The primary reason for patient exclusion from the primary efficacy population was that an evaluable baseline or post-baseline CT scan was not available or acceptable to the central radiology reviewers. The primary reason for treatment discontinuation in each arm was disease progression (BTH1677, 45.9%; Control, 41.9%). Patient demographics and disease characteristics at baseline are shown in Table [1](#). The BTH1677 and Control arms were similar with respect to age, sex, race, as well as time from initial tumor diagnosis to diagnosis of stage IIIB/IV NSCLC and diagnosis of stage IIIB/IV NSCLC to randomization. The percentage of patients with ECOG PS status of 1 vs 0 was higher in the BTH1677 arm (47.5%) than in the Control arm (33.3%). The percentage of patients who received prior cancer treatments (radiotherapy, surgery, chemotherapy, hormonal, or other) was also higher in the BTH1677 arm compared with the Control arm. ::::table-wrap

::: caption
Patient demographics and disease characteristics at baseline (Safety
population)
:::

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```
                                                                                BTH1677/                   Bevacizumab/
                                                                                Bevacizumab/Carboplatin/   Carboplatin/
                                                                                Paclitaxel                 Paclitaxel
                                                                                (*N* = 59)                  ( *N* = 30)
```

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Age (years)

Median (range)^a^ 59 (43, 76) 58 (28, 75)

Sex, n (%)

Male 26 (44.1) 14 (46.7)

Female 33 (55.9) 16 (53.3)

Race, n (%)

White 57 (96.6) 30 (100.0)

Black 1 (1.7) 0

Asian or Pacific Islander 1 (1.7) 0

ECOG Performance Status, n (%)

0 31 (52.5) 20 (66.7)

1 28 (47.5) 10 (33.3)

Disease stage at randomization

Stage IIIB 0 0

Stage IV 59 (100.0) 30 (100.0)

Time from initial tumor diagnosis to diagnosis of stage IIIB/IV NSCLC (days)^b^

Median (range) 0 (0, 3158) 0 (0, 0)

Time from diagnosis of stage IIIB/IV NSCLC to randomization (days)^c^

Median (range) 18 (1, 168) 17.5 (7, 77)

Time from initial tumor diagnosis to randomization (days)^d^

Median (range) 20 (1, 3171) 17.5 (7, 77)

Prior cancer treatment, n (%)

Radiotherapy 2 (3.4) 0

Surgery 8 (13.6) 2 (6.7)



## Chemotherapy, hormonal, or other^e^ 2 (3.4) 0

*Abbreviations: ECOG* Eastern Cooperative Oncology Group, *N* overall
sample size, *n* number of patients, *NSCLC* non-small cell lung cancer

^a^Inclusion criteria restricted patients to 18 to 75 years of age but
one 76-year-old patient was inadvertently enrolled in the study

^b^Time from initial tumor diagnosis to diagnosis of Stage IIIB/IV
NSCLC = Stage IIIB/IV diagnosis date - initial tumor diagnosis date

^c^Time from diagnosis of Stage IIIB/IV NSCLC to randomization = Date of
randomization - Stage IIIB/IV diagnosis date

^d^Time from initial tumor diagnosis to randomization = Date of
randomization --initial tumor diagnosis date

^e^Two patients in the BTH1677 arm received prior chemotherapy for lung
cancer. Both patients were previous responders and received the prior
chemotherapy greater than 6 months prior to enrollment:::: 

## Efficacy 

### Tumor-associated assessments Tumor-associated assessments were based on the blinded central radiology review of the primary efficacy population. Although the between-group difference was not statistically significant, compared with the Control arm, patients in the BTH1677 arm had a higher ORR (60.4% vs 43.5%; *P* = .2096) (Table [2](#)). One patient in the BTH1677 arm had a CR while no patients in the Control arm had CR (Table [2](#) and Fig. [2](#)). While on maintenance therapy, continued reduction in the sum of the longest diameters of target lesions of > 20 mm and > 10 mm, respectively, occurred in 7% and 20% of the BTH1677 arm patients, but in none of the Control arm patients (Table [3](#)). One of these continued reductions included a BTH1677 arm patient who had a CR at treatment week 47 (Fig. [3](#)); this patient remained in the study with a CR for an additional 19 weeks until the study was closed for primary analysis. ::::table-wrap
::: caption
Tumor-associated assessments based on a blinded central radiology review
of the primary efficacy population
:::

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```
                                                                  BTH1677/Bevacizumab/     Bevacizumab/                                                
                                                                  Carboplatin/Paclitaxel   Carboplatin/Paclitaxel                                      
                                                                  (*N* = 48)                (*N* = 23)                                                   
```

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n (%) 95% CI n (%) 95% CI *P* value^f^

Objective Response Rate^a,b^ 29 (60.4) (45.3, 74.2) 10 (43.5) (23.2, 65.5) 0.2096

Disease Control Rate^b,c^ 45 (93.8) (82.8, 98.7) 21 (91.3) (72.0, 98.9) 0.6563

Best Observed Response^b^

Complete response 1 (2.1) (0.1, 11.1) 0 NA

Partial response 28 (58.3) (43.2, 72.4) 10 (43.5) (23.2, 65.5) 0.3113

Stable disease 16 (33.3) (20.4, 48.4) 11 (47.8) (26.8, 69.4) 0.2992

Progressive disease 3 (6.3) (1.3, 17.2) 2 (8.7) (1.1, 28.0) 0.6563

Duration of Objective Tumor Response^d^ HR (95% CI)^g^

Patients with objective response (CR + PR) 29 10

Patients (% responding patients) with known duration (uncensored) 9 (31.0) 3 (30.0)

Patients (% responding patients) with unknown duration (censored) 20 (69.0) 7 (70.0)

Duration of objective response (months)

Median (95% CI) 10.3 (5.6, NE) 5.6 (1.5, NE) 0.92 (0.27, 4.20)

Log-rank *P* value 0.9040

Progression-Free Survival^e^ HR (95% CI)^g^

Patients with PD or died, n (%) 17 (34.0) 6 (26.1)

Patients censored, n (%) 33 (66.0) 17 (73.9)

Progression-free survival (months)

Median (95% CI) 11.6 (7.0, NE) 9.6 (7.1, NE) 1.31 (0.54, 3.65)



## Log-rank *P* value 0.5639

*Abbreviations: CI* confidence interval, *CR* complete response, *NA*
not applicable, *PD* progressive disease, *PR* partial response, *HR*
hazard ratio, *n* number of patients, *N* overall sample size, *NE* not
estimable

^a^Objective response rate was defined as the percent of central
radiology review response-evaluable patients experiencing a best overall
tumor

response of either CR or PR at any time on study according to modified
RECIST v1.0 criteria

^b^Tumor response data reported as the number (n) and percent (%) of
response-evaluable patients and the 95% exact binomial confidence
interval

^c^Disease control rate was defined as the percent of blinded central
radiology review response-evaluable patients experiencing a best overall
tumor response of CR, PR, or stable disease (SD) per modified RECIST
v1.0 criteria

^d^Duration of objective response (months) was based on Kaplan-Meier
estimates and was measured from the time at which criteria were met for
CR or PR (whichever status was recorded first) until the first date on
which recurrence or progressive disease (PD) was objectively documented
per modified RECIST v1.0. Patients who did not progress as of the data
cutoff date were censored at their last tumor assessment

^e^Progression-free survival (PFS) (months) was based on Kaplan-Meier
estimates from the total blinded central radiological review population
(BTH1677/Bevacizumab/Carboplatin/Paclitaxel, *n* = 50 and
Bevacizumab/Carboplatin/Paclitaxel, n = 23) and was defined as the time
from randomization to the first date of documented PD or death. PD was
identified by radiologic PD according to modified RECIST v1.0. If a
patient received any further anticancer therapy without prior
documentation of PD, the patient was censored at the date of last
imaging assessment before the treatment. Patients who were lost to
follow-up or who were alive without PD as of the data cut-off date were
censored at the last imaging assessment date or at the analysis data
cut-off date, whichever came first

^f^*P* value was obtained using Fisher's Exact Test

^g^Hazard ratio (95% exact binomial CI) was based on Cox proportional
hazards model with treatment as factor:::: <figure> <p><img src="" /></p> <figcaption>Maximum reduction from baseline in sum of longest diameters (SLD) for target lesions. Blinded central radiology review data from individual patients in the primary efficacy population</figcaption> </figure> ::::table-wrap
::: caption
Change in target lesion sum of longest diameters from post-chemotherapy
baseline to post-chemotherapy nadir
:::

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Length of SLD Reduction (mm) BTH1677/ Bevacizumab/Carboplatin/
Bevacizumab/Carboplatin/ Paclitaxel^a^
Paclitaxel ^a^ (*N* = 13)
(*N* = 30)

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> 20 2 (7%) 0

> 10 6 (20%) 0

> 5 10 (33%) 2 (15%)

______________________________________________________________________

*Abbreviations: N* overall sample size, *SLD* sum of longest diameters

^a^Number of patients continuing in study on maintenance therapy with at
least 2 post-chemotherapy tumor assessments based on blinded central
radiology review of the primary efficacy population:::: <figure> <p><img src="" /></p> <figcaption>CT scans showing continued reduction in tumor burden while on BTH1677 maintenance therapy. Target lesion locations at baseline included left hilum, mediastinal lymph nodes, adrenals, and liver. The patient remained on study and in CR at the time of the primary analysis (19 weeks later). <em>Abbreviations: CR</em> complete response, <em>CT</em> computed tomography</figcaption> </figure> Of the patients with an objective response (BTH1677 *n* = 29; Control *n* = 10), the median DOR was 10.3 months in the BTH1677 arm (95% CI: 5.6, not estimable) vs 5.6 months (95% CI: 1.5, not estimable) in the Control arm (HR 0.92 [95% CI: 0.27, 4.20]; *P* = .9040; Table [2](#) and Fig. [4a](#)). DOR by patient is illustrated in Fig. [4b](#). Of the patients with progressive disease or death (BTH1677 *n* = 17; Control *n* = 6), the PFS was 11.6 months in the BTH1677 arm and 9.6 months in the Control arm (HR 1.31 [95% CI: 0.54, 3.65]; *P* = .5639; Table [2](#)). <figure> <p><img src="" /></p> <figcaption>Duration of objective response. <strong>a</strong> The Kaplan-Meier duration of response (months) curve from patients in the primary efficacy population based on blinded central radiology review. <em>Abbreviations: CI</em> confidence interval, <em>n</em> number of patients, <em>HR</em> hazard ratio. <strong>b</strong> Plot of duration of response for primary efficacy population by patient based on blinded central radiology review. Hatched blue and red bars indicate censoring in the BTH1677 and Control arms, respectively</figcaption> </figure> 

### Overall survival The OS Kaplan-Meier curves for the BTH1677 and Control arms are shown in Fig. [5](#). The median OS of patients in the BTH1677 arm was 16.1 months (95% CI: 11.4, 20.8) compared with 11.6 months (95% CI: 7.7, 22.3) in the Control arm. However, the difference in median OS was not statistically significant between arms (HR 0.75 [95% CI: 0.45, 1.28]; *P*  = .2696). <figure> <p><img src="" /></p> <figcaption>Overall survival. The Kaplan-Meier overall survival (months) curve from patients in the safety population. X indicates censored patients. <em>Abbreviations: CI</em> confidence interval, <em>n</em> number of patients, <em>HR</em> hazard ratio</figcaption> </figure> 

## Safety All patients receiving any treatment (BTH1677 *n* = 59; Control *n* = 30) were included in the safety population, and the majority of these patients (≥98%) experienced at least 1 AE. Grade 3 or Grade 4 AEs occurred at a higher incidence among patients in the BTH1677 arm compared with patients in the Control arm (93.2% vs 66.7%, respectively). However, the incidence of serious AEs (40.7% vs 43.3%) and AEs leading to discontinuation (35.6% vs 40%) was slightly lower in the BTH1677 arm than the Control arm, respectively. In the BTH1677 arm, 22.0% and 28.8% of the AEs were considered probably and possibly related to BTH1677, respectively. These data are summarized in Table [4](#) . ::::table-wrap
::: caption
Overview of safety outcomes (Safety population)
:::

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Adverse events (AEs), n (%) BTH1677/ Bevacizumab/
Bevacizumab/ Carboplatin/
Carboplatin/Paclitaxel Paclitaxel
(*N* = 59) ( *N* = 30)

______________________________________________________________________

Any AE 58 (98.3) 30 (100.0)

NCI/CTCAE Grade 3 or 4 AEs 55 (93.2) 20 (66.7)

Serious AEs 24 (40.7) 13 (43.3)

BTH1677-related AEs

Probably related 13 (22.0) NA

Possibly related 17 (28.8) NA



## AEs leading to discontinuation 21 (35.6) 12 (40.0)

*Abbreviations: AE* adverse events, *N* overall sample size, *n* number
of patients, *NA* not applicable, *NCI/CTCAE* National Cancer Institute
Common Terminology Criteria for Adverse Events:::: AEs of any grade that occurred in ≥10% of patients in the BTH1677 and Control arms are presented in Table [5](#). Gastrointestinal, general, hematological, and skin disorders were commonly reported AEs among both arms. Of the AEs reported in these categories, neutropenia, leukopenia, nausea, constipation, vomiting, abdominal pain upper, stomatitis, pyrexia, and chills occurred at an incidence at least 5% higher in the BTH1677 arm than in the Control arm; of these AEs, stomatitis and chills occurred exclusively in the BTH1677 arm (10.2% vs 0% and 18.6% vs 0%, respectively). In contrast, diarrhea and chest pain occurred at an incidence at least 5% higher in the Control arm than in the BTH1677 arm. ::::table-wrap
::: caption
Any grade AEs (≥10%) and corresponding Grade 3 or 4 AEs (Safety
population)
:::

______________________________________________________________________

```
                                                     BTH1677/                 Bevacizumab/                          
                                                     Bevacizumab/             Carboplatin/Paclitaxel                
                                                     Carboplatin/Paclitaxel   ( *N* = 30)                            
                                                     (*N* = 59)                                                       
```

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Adverse events (AEs), n (%) All AEs Grade 3 or Grade 4 AEs All AEs Grade 3 or Grade 4 AEs

Patients with at least 1 AE 58 (98.3) 55 (93.2) 30 (100.0) 20 (66.7)

Blood and lymphatic system disorders

Neutropenia 26 (44.1) 23 (39.0) 10 (33.3) 8 (26.7)

Thrombocytopenia 20 (33.9) 11 (18.6) 10 (33.3) 5 (16.7)

Anemia 14 (23.7) 2 (3.4) 8 (26.7) 1 (3.3)

Leukopenia 9 (15.3) 3 (5.1) 2 (6.7) 1 (3.3)

Gastrointestinal disorders

Nausea 40 (67.8) 5 (8.5) 16 (53.3) 0

Constipation 25 (42.4) 0 9 (30.0) 0

Vomiting 19 (32.2) 2 (3.4) 7 (23.3) 0

Diarrhea 12 (20.3) 2 (3.4) 8 (26.7) 1 (3.3)

Abdominal pain upper 6 (10.2) 1 (1.7) 1 (3.3) 0

Stomatitis 6 (10.2) 1 (1.7) 0 0

General disorders and administration-site conditions

Fatigue 33 (55.9) 1 (1.7) 18 (60.0) 1 (3.3)

Pyrexia 12 (20.3) 2 (3.4) 3 (10.0) 0

Chills 11 (18.6) 1 (1.7) 0 0

Mucosal inflammation 6 (10.2) 0 3 (10.0) 0

Chest pain 3 (5.1) 0 5 (16.7) 0

Infections and infestations

Nasopharyngitis 6 (10.2) 0 3 (10.0) 0

Urinary tract infection 2 (3.4) 1 (1.7) 3 (10.0) 0

Injury, poisoning, and procedural complications

Infusion-related reaction 7 (11.9) 1 (1.7) 2 (6.7) 1 (3.3)

Investigations

Hemoglobin decreased 4 (6.8) 1 (1.7) 3 (10.0) 2 (6.7)

Platelet count decreased 3 (5.1) 2 (3.4) 3 (10.0) 1 (3.3)

Metabolism and nutritional disorders

Decreased appetite 17 (28.8) 1 (1.7) 11 (36.7) 0

Hypokalemia 6 (10.2) 1 (1.7) 0 0

Musculoskeletal and connective tissue disorders

Arthralgia 19 (32.2) 1 (1.7) 6 (20.0) 0

Pain in extremity 15 (25.4) 0 3 (10.0) 0

Back pain 11 (18.6) 1 (1.7) 4 (13.3) 0

Myalgia 12 (20.3) 1 (1.7) 2 (6.7) 0

Nervous system disorders

Polyneuropathy 16 (27.1) 3 (5.1) 6 (20.0) 0

Headache 9 (15.3) 1 (1.7) 4 (13.3) 0

Neuropathy peripheral 6 (10.2) 0 5 (16.7) 0

Dizziness 7 (11.9) 0 3 (10.0) 0

Paresthesia 7 (11.9) 0 2 (6.7) 0

Dysgeusia 6 (10.2) 0 2 (6.7) 0

Psychiatric disorders

Insomnia 9 (15.3) 0 2 (6.7) 0

Sleep disorder 5 (8.5) 0 4 (13.3) 0

Respiratory, thoracic and mediastinal disorders

Dyspnea 18 (30.5) 3 (5.1) 8 (26.7) 0

Cough 18 (30.5) 2 (3.4) 7 (23.3) 0

Epistaxis 14 (23.7) 0 10 (33.3) 0

Oropharyngeal pain 8 (13.6) 0 2 (6.7) 0

Skin and subcutaneous tissue disorders

Alopecia 28 (47.5) 2 (3.4) 14 (46.7) 0

Vascular disorders



## Hypertension 14 (23.7) 3 (5.1) 7 (23.3) 1 (3.3)

*Abbreviations: AE* adverse events, *N* overall sample size, *n* number
of patients:::: For AEs of any grade that occurred in ≥10% of patients, those that were Grade 3 or Grade 4 are also presented in Table [5](#). For purposes of comparison here, Grade 3 or Grade 4 AEs that occurred in ≥5% of patients in either treatment arm included neutropenia (39.0% BTH1677 vs 26.7% Control), thrombocytopenia (18.6% BTH1677 vs 16.7% Control), leukopenia (5.1% BTH1677 vs 3.3% Control), nausea (8.5% BTH1677 vs 0% Control), hemoglobin decreased (1.7% BTH1677 vs 6.7% Control), polyneuropathy (5.1% BTH1677 vs 0% Control), dyspnea (5.1% BTH1677 vs 0% Control), and hypertension (5.1% BTH1677 vs 3.3% Control). Eight deaths (7 in the BTH1677 arm; 1 in the Control arm) were reported in the treatment phase of within 30 days of the last dose of study medication. Six of the 7 deaths in the BTH1677 arm were due to disease progression or complications of disease progression (e.g., pneumonia due to lung cancer, pneumothorax); the other death was due to intracranial hemorrhage that occurred subsequent to administration of anticoagulant for a blood clot in the lung. The 1 death in the Control arm was due to complications of disease progression (pneumonia due to lung cancer). 

## BTH1677 pharmacokinetics BTH1677 serum concentrations in both cycles were above the limit of quantitation (4.7 ng/mL) for all but 1 patient. Individual t~max~ values generally coincided with the end of infusion or shortly thereafter. Mean serum trough levels of BTH1677 appeared to plateau as of Day 15 of Cycle 1, suggesting that steady state was achieved as of Day 15. Table [6](#) summarizes the PK parameters of BTH1677 from Cycle 1/Day 1 (*n* = 53) and Cycle 3/Day 1 ( *n* = 42). Geometric mean C~max~ of serum BTH1677 was similar in Cycle 1 (49.77 μg/mL) and Cycle 3 (60.50 μg/mL). AUC~0-24~ of BTH1677 was also similar in Cycle 1 (399.8 μg•hr./mL) and Cycle 3 (464.4 μg•hr./mL), with little to no accumulation of BTH1677 being observed. No notable difference in other PK parameters (CL, t ~max~, and V~ss~) between Cycle 1 and Cycle 3 were observed. A longer elimination half-life (t~1/2~) was observed in Cycle 1 (17.56 h) than Cycle 3 (7.17 h); however, these results should be interpreted with caution given the difference in sampling periods between Cycle 1 (up to 168 h post dosing) and Cycle 3 (only up to 24 h post dosing). ::::table-wrap
::: caption
Summary of BTH1677 pharmacokinetics parameters
:::

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Parameters Geometric Mean (CV%)

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BTH1677/Bevacizumab/\
Carboplatin/Paclitaxel

Cycle 1/Day 1 Cycle 3/Day 1

N 53^b^ 42

AUC~0--last~ (μg•hr./mL) 614.6 (52.0) 423.5 (48.1)

AUC~0--24~ (μg•hr./mL) 399.8 (37.3) 464.4 (38.9)^d^

AUC~0--∞~ (μg•hr./mL) 635.9 (49.5)^c^ 518.6 (42.2)^e^

C~max~ (μg/mL) 49.77 (36.1) 60.50 (49.2)

CL (L/h) 0.441 (47.3)^c^ 0.548 (41.6)^e^

t~1/2~ (hr) 17.56 (36.9)^c^ 7.17 (35.3)^e^

t~max~ (hr)^a^ 2.48 (1.52, 5.90) 2.37 (1.92, 6.88)

V~ss~ (L) 5.37 (42.4)^c^ 4.13 (51.5)^e^



## R (AUC) NA 1.10 (27.3)^d^

*Abbreviations: AUC*~*(0-last)*~ area under the serum concentration-time
curve from time 0 to the time of the last measurable concentration,
*AUC*~*0--24*~ area under the serum concentration-time curve from time 0
to 24 h, *AUC*~*0--∞*~ area under the serum concentration-time curve
from time 0 to infinity, *C*~*max*~ maximum serum concentration, *CL*
systemic clearance, *CV* coefficient of variation, *hr.* hour, *L*
liter, *mL* milliliter, *N* overall sample size, *NA* not applicable, *R
(AUC)* accumulation ratio calculated as AUC ~0-24~ (Cycle 3)/AUC~0-24~
(Cycle 1), *t*~*1/2*~ elimination half-life, *t*~*max*~ time of maximum
concentration, μg microgram, *V*~*ss*~ volume of distribution at
steady-state

^a^Median (range)

^b^Although 2 other patients met the basic criteria for inclusion in the
PK population (ie, having at least 75% of the PK measurements available
for any particular treatment cycle data set), 2 patients were
subsequently excluded from analysis. One patient received a second
unplanned BTH1677 infusion on Day 2 of Cycle 1 and a second patient had
a longer infusion time (5.58 h) relative to the other patients for Cycle
1/Day 1. Both of these differences were deemed to likely result in PK
differences relative to other patients in Cycle 1 and were excluded

^c^N = 50

^d^*N* = 37

^e^N = 31::::


Extracted trial result:
Outcome: objective response rate (ORR) (binary)
Intervention: BTH1677 arm ( intravenous [IV] BTH1677, 4 mg/kg, weekly; IV bevacizumab, 15 mg/kg, once each 3-week cycle [Q3W]; IV carboplatin, 6 mg/mL/min Calvert formula area-under-the-curve, Q3W; and IV paclitaxel, 200 mg/m2, Q3W)
Comparator: Control arm ( bevacizumab/carboplatin/paclitaxel as above)
Intervention events: 29
Intervention group size: 48
Comparator events: 10
Comparator group size: 23
Notes: found in table 2