Registered purpose of the trial

“This is a multi-center, open-label, randomized, phase 2/3 trial of the bispecific antibody CTX-009 plus paclitaxel versus paclitaxel in patients with previously treated, unresectable advanced or metastatic biliary tract cancers.” (opens the source at this quote in a new tab)

Objective stated in the trial design publication

“COMPANION-002 is a multicenter, randomized, phase II/III study evaluating the efficacy and safety of CTX-009 in combination with paclitaxel as second-line treatment for patients with advanced or metastatic BTC.” (opens the source at this quote in a new tab)

Sponsor-stated purpose and regulatory intent

“Tovecimig (CTX-009), our bispecific antibody targeting DLL4 and VEGF-A, is currently being evaluated in a randomized Phase 2/3 trial in the United States in combination with paclitaxel in patients with biliary tract cancer (“BTC”) who received one prior treatment regimen.” (opens the source at this quote in a new tab)

Study dates and status: registry record

Milestone	Registry record
Study start (actual)	“2023-01-09”
Primary completion (estimated)	“2027-08-31”
Study completion (estimated)	“2027-08-31”
Enrollment (actual)	“168”
Recruitment status	“Active, not recruiting”
Last update posted	“2026-09-02”

Registered sites

“This study has 34 locations” (opens the source at this quote in a new tab)
“United States” (opens the source at this quote in a new tab)

Planned site count in the trial design publication

“The planned sample size is approximately 150 patients. This is a multicenter study with 32 study sites.” (opens the source at this quote in a new tab)

Completion of enrollment

“The trial was fully enrolled in August 2024 with 168 patients randomized in a 2:1 ratio to receive tovecimig plus paclitaxel (n=111) or paclitaxel alone (n=57).” (opens the source at this quote in a new tab)

Data cut-off dates of the reported analyses

“Data cutoff from COMPANION - 002 as of March 2025.” (opens the source at this quote in a new tab)
“Data cutoff from COMPANION - 002 as of April 2026.” (opens the source at this quote in a new tab)

Registered design details

Design feature	Registry record
Primary purpose	“Treatment”
Allocation	“Randomized”
Interventional model	“Parallel Assignment”
Masking	“Single (Outcomes Assessor)”

Blinded independent central review of the primary endpoint

“A blinded independent review committee will be used to assess the primary study endpoint.” (opens the source at this quote in a new tab)

Randomization ratio and stratification factors

“Patients are randomized to a 2:1 ratio, and crossover is allowed to the experimental arm at the time of progression in the control arm for patients that continue to meet eligibility criteria. Stratification factors include stage (locally advanced vs metastatic), anatomic subtype of the primary tumor (intrahepatic cholangiocarcinoma vs other) and ECOG performance status (0 or 1).” (opens the source at this quote in a new tab)

Crossover from the control arm

“Patients randomized to receive paclitaxel only have the option to crossover to the CTX-009 plus paclitaxel arm after documented disease progression per RECIST v1.1.” (opens the source at this quote in a new tab)

“Patients in the paclitaxel-only arm who progressed could cross over to the tovecimig plus paclitaxel arm after centrally confirmed progression if they also still met the enrollment criteria for the study.” (opens the source at this quote in a new tab)

Regulatory origin of the randomized design

“Based on the efficacy data and following discussions with the FDA, while the trial had met the criteria to advance to Part 2, FDA recommended and we agreed to forego the second stage of the study and advance tovecimig directly to a randomized Phase 2/3 study in patients with BTC treated in the second-line setting.” (opens the source at this quote in a new tab)

Independent safety monitoring

“An independent Data Monitoring Committee (DMC) has reviewed safety data at four separate (pre-specified) DMC meetings and, after each meeting, recommended continuation of the study without modification.” (opens the source at this quote in a new tab)

Key inclusion criteria: registry record

Criterion	Quoted registry text
Age	“18 years of age or older”
Diagnosis	“Histologically or cytologically confirmed unresectable advanced, metastatic, or recurrent biliary tract cancers (including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder cancer, and ampullary carcinoma)”
Prior therapy	“Patients must have radiologically documented progression after a prior gemcitabine and platinum containing chemotherapy regimen as first line therapy for locally advanced unresectable or metastatic disease.”
Measurable disease	“At least one lesion measurable as defined by RECIST v1.1”
Performance status	“Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1”
Life expectancy	“Predicted life expectancy of at least 12 weeks”
Hepatic function	“Total bilirubin ≤ 1.5 X ULN”
Renal function	“Estimated creatinine clearance ≥ 30 mL/min based on Cockcroft-Gault”
Proteinuria	“Urine protein ≤ 1+ by Dipstick (Only when urinalysis shows a protein dipstick result of > 1 positive (+), the total protein volume (<1.0 g/24hr) can be confirmed with a 24-hour urine test.)”

Exclusion of participants eligible for an approved targeted therapy

“Patients who are eligible to be treated with a molecularly targeted therapy on a labelled regimen after receiving first-line chemotherapy. Patients who received a molecularly targeted therapy as part of their first line treatment may be eligible, as determined by the Sponsor Medical Monitor.” (opens the source at this quote in a new tab)

Cardiovascular, hemorrhagic, and gastrointestinal exclusions relevant to angiogenesis inhibition

“Congestive heart failure (CHF) that corresponds to Class II or a higher class under New York Heart Association (NYHA) classification, or less than 50% of left ventricular ejection fraction (LVEF)” (opens the source at this quote in a new tab)
“Uncontrolled hypertension (SBP/DBP >140/90 mmHg) (e.g., patient with SBP/DBP >140/90 mmHg despite the best care including optimizing the anti-hypertensive medication regimen)” (opens the source at this quote in a new tab)
“Patients with any history of hypertensive crisis or pre-existing hypertensive encephalopathy” (opens the source at this quote in a new tab)
“Active hemorrhage, hemorrhagic diathesis, coagulopathy or tumor in great arteries” (opens the source at this quote in a new tab)
“History of clinically significant gastroenterological disease, such as peptic ulcer, GI bleeding, GI or non-GI fistula, perforation, abdominal abscess, clinical symptoms, and signs of GI obstruction, need for parenteral hydration or nutrition, or inflammatory bowel disease (IBD)” (opens the source at this quote in a new tab)
“Pre-existing hemoptysis (≥ 1/2 teaspoon of bright red blood per episode) within 28 days prior to screening” (opens the source at this quote in a new tab)
“Patients with percutaneous transhepatic biliary drains (PTBD)” (opens the source at this quote in a new tab)

Dosing of both arms as reported by the sponsor

“All patients were dosed with 80 mg/m2 of paclitaxel on days 1, 8 and 15 of every 28-day cycle. Patients in the tovecimig arm were also dosed with 10 mg/kg of tovecimig on days 1 and 15 of each 28-day cycle.” (opens the source at this quote in a new tab)

Registered intervention schedule

Intervention	Registry description
CTX-009	“IV infusion on day 1 and 14 of every 28 day cycle”
Paclitaxel	“IV infusion on day 1, 8, and 15 of every 28 day cycle”

Adverse event grading and safety follow-up

“Safety will be monitored throughout the study and for 30 days after the end of treatment. Adverse events will be assessed as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0.” (opens the source at this quote in a new tab)

Registered primary outcome measure

Outcome measure	Measure description	Time frame
“Best Overall Response”	“Percentage of patients whose Best Overall Response (BOR) is assessed as Complete Response (CR) or Partial Response (PR) as assessed by RECIST 1.1”	“From randomization to treatment discontinuation for any reason, average 6 months”

Registered secondary outcome measures

Outcome measure	Measure description	Time frame
“Progression Free Survival”	“Time from randomization until the date of objective PD (as assessed by RECIST 1.1) or the date of death (by any cause in the absence of disease progression)”	“From randomization to first documented objective PD or death if PD does not occur, average 6 months”
“Duration of Response”	“The time between the date of the radiological evaluation that first confirmed CR or PR and the date of the radiation evaluation that first confirmed Progressive Disease (PD)”	“From first confirmed CR or PR to confirmed PD, average 6 months”
“Overall Survival”	“Time from randomization until the date of death by any cause. Patients who are still alive at the time of the analysis, or who have become lost to follow-up or withdrawn consent will be censored at their last date known to be alive”	“From randomization to death from any cause, average 12 months”
“Disease Control Rate”	“Percentage of patients whose BOR is assessed as CR, PR, or Stable Disease (SD)”	“From randomization to treatment discontinuation for any reason, average 6 months”
“Incidence of Treatment Emergent Adverse Events (TEAEs) and changes in clinical abnormalities”	“Incidence of Treatment Emergent Adverse Events (TEAEs) and changes in clinical abnormalities for all randomized patients who received at least one dose of study treatment (either CTX-009 or paclitaxel)”	“From randomization to 60 days after the last dose of study treatment, average 7 months”

Endpoint definitions in the trial design publication, including the quality-of-life instrument

“The primary end point is ORR per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by independent central review (ICR). The secondary end points are progression free survival, duration of response, overall survival, disease control rate, safety and quality of life measured with EORTC QLQ-C30.” (opens the source at this quote in a new tab)

Response-rate signal from the preceding phase 2 study that motivated the endpoint

“In a phase II study of patients with advanced biliary tract cancer who had received one or two prior therapies, CTX-009 with paclitaxel demonstrated a 37.5% overall response rate (ORR).” (opens the source at this quote in a new tab)

Low response rate of available second-line regimens against which the endpoint was sized

“For the approximately 85% of patients with BTC whose tumors do not harbor an actionable mutation with an approved targeted therapy, there is currently no FDA-approved treatment in the second line setting. The combinations of therapeutics used in this setting, which are not labeled for this indication, generally have an ORR of ~5% or less and patients face a median overall survival of approximately six months.” (opens the source at this quote in a new tab)

Planned and randomized sample size

“The planned sample size is approximately 150 patients. This is a multicenter study with 32 study sites.” (opens the source at this quote in a new tab)

“The study enrolled 168 adult patients, randomized in a 2:1 ratio to receive tovecimig plus paclitaxel (n=111) or paclitaxel alone (n=57).” (opens the source at this quote in a new tab)

Power and treatment-effect assumption

“This study was designed to detect a 23% absolute difference in response rate between the two arms, with 90% power and a two-sided alpha of 0.05.” (opens the source at this quote in a new tab)

Event threshold triggering the time-to-event analyses

“The trial requires a threshold of events in 80% of patients to trigger the secondary endpoint analyses.” (opens the source at this quote in a new tab)

“In the Phase 2/3 trial, the prespecified event threshold of 80% overall survival (OS) events was reached in Q1 2026; therefore, the analyses of progression-free survival (PFS) and OS are expected to be reported in April 2026.” (opens the source at this quote in a new tab)

Populations analyzed for efficacy and for safety

Analysis set	Tovecimig plus paclitaxel	Paclitaxel
Intent-to-treat population, efficacy analyses	“n=111”	“n=57”
Population reported for treatment-emergent adverse events	“n=108”	“n=53”

Crossover-adjusted overall survival analysis and its assumptions

“In the rank-preserving structural failure time (RPSFT) OS analysis, the combination also had a median OS of 8.9 months compared to 9.4 months for paclitaxel alone (HR=1.13, p=0.65). Though the RPSFT analysis is intended to adjust for crossover, its validity depends on certain assumptions that were not met in this study and thus its results here are largely uninterpretable.” (opens the source at this quote in a new tab)

Prespecified status of the crossover analyses

“An additional, pre-specified secondary endpoint analyzed PFS in the patients in the paclitaxel arm who crossed over to receive tovecimig plus paclitaxel.” (opens the source at this quote in a new tab)

“Although this was a prespecified analysis, statistical assumptions for the RPSFT were not met.” (opens the source at this quote in a new tab)

Crossover from the control arm and total exposure to tovecimig

“Tovecimig did not meet the OS secondary endpoint due to high crossover from the control arm (31 of 57 patients, or 54%) and prolonged survival of those crossover patients after receiving tovecimig, as further described below. As a result of this crossover, 85% (142 of 168) of patients in the study received tovecimig plus paclitaxel with a pooled OS in the study of 8.9 months.” (opens the source at this quote in a new tab)

Participants not evaluable for response

“Not Evaluable: patients who did not receive a Week-8 scan.” (opens the source at this quote in a new tab)

Treatment discontinuation, withdrawal, and follow-up counts

No evidence found.

Balance of baseline characteristics between arms

“Baseline characteristics were well balanced” (opens the source at this quote in a new tab)

Baseline demographics and disease characteristics, n (%) unless stated

Characteristic	Tovecimig plus paclitaxel (n=111)	Paclitaxel (n=57)
Median age, years	“65.0”	“63.0”
Male	“53 (47.7)”	“24 (42.1)”
Female	“58 (52.3)”	“33 (57.9)”
Asian	“17 (15.3)”	“10 (17.5)”
White	“84 (75.7)”	“40 (70.2)”
African American	“4 (3.6)”	“6 (10.5)”
Unknown or other race	“6 (5.4)”	“1 (1.8)”
Intrahepatic primary location	“62 (55.9)”	“30 (52.6)”
Other primary location (extrahepatic, gallbladder, ampullary)	“49 (44.1)”	“27 (47.4)”
ECOG performance status 0	“53 (47.7)”	“27 (47.4)”
ECOG performance status 1	“58 (52.3)”	“30 (52.6)”
Locally advanced disease	“12 (10.8)”	“5 (8.8)”
Metastatic disease	“99 (89.2)”	“52 (91.2)”

Primary endpoint: objective response rate as first reported

“17.1% ORR for tovecimig in combination with paclitaxel (19 of 111 patients) including one complete response, compared to 5.3% for paclitaxel alone (3 of 57 patients), in patients with BTC in the second line setting” (opens the source at this quote in a new tab)
“This 11.8% relative improvement in ORR for those receiving the combination was statistically significant (p=0.031).” (opens the source at this quote in a new tab)

Primary endpoint: objective response rate in the final analysis

“In the final data analysis, the overall response rate (ORR), the primary endpoint in the study, improved to 18.0% (20/111 patients) in the tovecimig combination arm from a previously reported 17.1%.” (opens the source at this quote in a new tab)
“With this change, the p-value improved to 0.0228 compared to paclitaxel alone (ORR of 5.3% in the paclitaxel arm).” (opens the source at this quote in a new tab)

Best overall response by blinded independent central review, intent-to-treat population

Best overall response	Tovecimig plus paclitaxel (n=111)	Paclitaxel (n=57)
Overall response rate (complete plus partial response)	“19 (17.1%)”	“3 (5.3%)”
Complete response	“1 (0.9%)”	“0 (0.0%)”
Partial response	“18 (16.2%)”	“3 (5.3%)”
Stable disease	“49 (44.1%)”	“19 (33.3%)”
Non-complete response / non-progressive disease	“9 (8.1%)”	“2 (3.5%)”
Progressive disease	“18 (16.2%)”	“24 (42.1%)”
Not evaluable	“16 (14.4%)”	“9 (15.8%)”

Central confirmation of responses

“The difference in ORR between the two treatment arms, the primary endpoint of the study, was statistically significant (p=0.031), and all responses have been confirmed by blinded independent central radiology review.” (opens the source at this quote in a new tab)

Key secondary endpoint: progression-free survival

“Tovecimig in combination with paclitaxel demonstrated a statistically significant improvement in median PFS of 4.7 months compared to 2.6 months for paclitaxel alone (HR=0.44, p<0.0001). Progression was confirmed in each case by BICR.” (opens the source at this quote in a new tab)

Key secondary endpoint: overall survival in the intent-to-treat population

“In the ITT OS analysis, tovecimig in combination with paclitaxel had a median OS of 8.9 months compared to 9.4 months for the control arm, which included 26 patients (46%) who received paclitaxel alone and 31 patients (54%) who crossed over to receive tovecimig in combination with paclitaxel (HR=1.05, p=0.78).” (opens the source at this quote in a new tab)

Efficacy summary with hazard ratios and two-sided p values

Endpoint	Tovecimig plus paclitaxel (n=111)	Paclitaxel (n=57)	Hazard ratio	Two-sided p value
Overall response rate	“19 (17.1%)”	“3 (5.3%)”	Not reported	“p=0.031”
Progression-free survival, months	“4.7”	“2.6”	“0.44”	“p<0.0001”
Overall survival, intent-to-treat, months	“8.9”	“9.4”	“1.05”	“p=0.78”
Overall survival, crossover-adjusted by rank-preserving structural failure time, months	“8.9”	“9.4”	“1.13”	“p=0.65”

Prespecified secondary analysis of progression-free survival before and after crossover

“In this analysis, the pre-crossover PFS (PFS1) on paclitaxel alone was compared to PFS with tovecimig post-crossover (PFS2) in the same crossover patients (n=31). In this subset, tovecimig demonstrated a statistically significant improvement with median PFS2 of 3.5 months after treatment with tovecimig compared to median PFS1 of 1.9 months for paclitaxel (HR=0.36, p=0.0016).” (opens the source at this quote in a new tab)

Post hoc analysis of overall survival within the control arm

“In an analysis of OS in all patients randomized to the paclitaxel control arm (n=57), crossover patients who subsequently received tovecimig demonstrated a statistically significant improvement in median OS of 12.8 months compared to 6.1 months for non-crossover patients who received only paclitaxel (HR=0.54, p=0.04).” (opens the source at this quote in a new tab)

Post hoc analysis of progression-free survival within the control arm

“Another analysis of these same patients randomized to the paclitaxel control arm (n=57) demonstrated that the crossover patients initially progressed faster on paclitaxel monotherapy compared to the non-crossover patients, with a median PFS of 1.9 months versus 3.6 months (HR=2.31, p=0.007).” (opens the source at this quote in a new tab)

Post hoc pooled overall survival of all participants who received tovecimig

“For all patients treated with tovecimig, including both crossover patients and patients initially randomized to the tovecimig combination arm (n=142), the pooled median OS was 9.8 months. The median OS for patients randomized to the paclitaxel alone who did not crossover (n=26) was 6.1 months.” (opens the source at this quote in a new tab)

Duration of response

“The complete dataset, including Duration of Response (DoR), will be presented at a medical conference later this year.” (opens the source at this quote in a new tab)

Disease control rate

No evidence found.

Quality of life as a prespecified secondary endpoint

“The secondary end points are progression free survival, duration of response, overall survival, disease control rate, safety and quality of life measured with EORTC QLQ-C30.” (opens the source at this quote in a new tab)

Reported quality-of-life or patient-reported outcome results

No evidence found.

Overall safety conclusion and most frequent events

“Tovecimig was generally well tolerated and the safety profile was consistent with previously reported data from prior studies, with no new safety signals. The most commonly reported treatment emergent adverse events in the tovecimig combination arm were hypertension (69%) and fatigue (67%). The most common related treatment-emergent adverse events of Grade 3 or higher included hypertension (44%) and neutropenia (36%).” (opens the source at this quote in a new tab)

Treatment-emergent adverse events reported in at least 20% of participants, n (%)

Adverse event	Tovecimig plus paclitaxel (n=108), any grade	Tovecimig plus paclitaxel (n=108), grade 3 or higher	Paclitaxel (n=53), any grade	Paclitaxel (n=53), grade 3 or higher
Hypertension	“75 (69)”	“56 (52)”	“10 (19)”	“3 (6)”
Fatigue	“72 (67)”	“16 (15)”	“24 (45)”	“3 (6)”
Neutropenia	“59 (55)”	“40 (37)”	“20 (38)”	“14 (26)”
Diarrhea	“51 (47)”	“6 (6)”	“15 (28)”	“1 (2)”
Anemia	“48 (44)”	“23 (21)”	“17 (32)”	“5 (9)”
Decreased appetite	“44 (41)”	“2 (2)”	“11 (21)”	“-”
Nausea	“43 (40)”	“2 (2)”	“17 (32)”	“-”
Proteinuria	“37 (34)”	“3 (3)”	“5 (9)”	“-”
Vomiting	“36 (33)”	“1 (1)”	“13 (25)”	“1 (2)”
Abdominal pain	“35 (32)”	“9 (8)”	“13 (25)”	“4 (8)”
Dyspnea	“32 (30)”	“5 (5)”	“13 (25)”	“-”
Epistaxis	“32 (30)”	“-”	“4 (8)”	“-”
Alopecia	“32 (30)”	“-”	“28 (53)”	“-”
Thrombocytopenia	“33 (31)”	“7 (7)”	“6 (11)”	“-”
Peripheral edema	“35 (32)”	“-”	“7 (13)”	“-”
Peripheral neuropathy	“29 (27)”	“2 (2)”	“13 (25)”	“1 (2)”
Constipation	“30 (28)”	“-”	“8 (15)”	“-”
Headache	“25 (23)”	“-”	“7 (13)”	“-”
Arthralgia	“25 (23)”	“-”	“6 (11)”	“-”

Consistency of the safety profile across data cuts

“Safety profile generally consistent with previously reported data” (opens the source at this quote in a new tab)

Deaths, serious adverse events, and discontinuations due to adverse events

No evidence found.

Summary

COMPANION-002 randomized 168 participants 2:1 and met its primary endpoint of objective response rate, reported first as 17.1% (19 of 111) versus 5.3% (3 of 57) with p=0.031 and updated in the final analysis to 18.0% (20 of 111) with p=0.0228 after one participant initially classified as non-complete response and non-progressive disease was adjudicated a partial response by blinded independent central review. The trial was powered to detect a 23% absolute difference in response rate with 90% power and a two-sided alpha of 0.05, so the observed difference of about 12 percentage points is smaller than the effect the sample size was planned around, and the planned sample size of approximately 150 was exceeded by the 168 actually randomized. As of September 21, 2026 the complete dataset had not been published or presented; the sponsor stated that it was selected for an oral presentation at the European Society for Medical Oncology Congress in October 2026, so the results available are limited to sponsor announcements and a corporate presentation filed with the U.S. Securities and Exchange Commission, and are not peer reviewed.

Overall survival did not reach statistical significance. Median overall survival was 8.9 months with tovecimig plus paclitaxel versus 9.4 months in the control arm, hazard ratio 1.05 and p=0.78. The sponsor attributes this to crossover: 31 of 57 control participants (54%) crossed over after centrally confirmed progression, so 142 of 168 participants (85%) received tovecimig, and the control arm is not a tovecimig-naive comparator for survival. The prespecified rank-preserving structural failure time adjustment gave 8.9 versus 9.4 months with a hazard ratio of 1.13 and p=0.65, and the sponsor states that the assumptions of that method were not met and that its results here are largely uninterpretable. The crossover comparisons that show benefit, the 12.8 versus 6.1 month survival difference between crossover and non-crossover control participants and the pooled 9.8 month survival of all tovecimig-treated participants, are post hoc subset analyses of non-randomized groups; the same analysis showed crossover participants had progressed faster on paclitaxel alone, with median progression-free survival of 1.9 versus 3.6 months, indicating the two control subgroups differed.

The trial was conducted at 34 sites, all in the United States, and eligibility excluded participants who could receive an approved molecularly targeted therapy after first-line chemotherapy, so the results apply to the population without an actionable alteration rather than to all second-line biliary tract cancer. The registry record and the sponsor announcements describe different tovecimig schedules, day 1 and day 14 in the registry against days 1 and 15 in the press releases. Participant disposition, deaths, serious adverse events, discontinuations due to adverse events, disease control rate, duration of response, and the EORTC QLQ-C30 quality-of-life endpoint listed in the design publication had not been reported. Safety was reported for 108 and 53 participants rather than the 111 and 57 randomized, and grade 3 or higher hypertension occurred in 52% of the tovecimig arm against 6% of the control arm.