NOV150101-101 First-in-Human phase 1 dose escalation and expansion

23 evidence topics · 4 sources

Objective

Registered objective

“The purpose of this open-label, dose escalation-dose expansion, Phase 1 clinical trial is to evaluate the safety, pharmacokinetics and anti-tumor activity and determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of NOV1501 (ABL001).” (opens the source at this quote in a new tab)

Objective as reported at the congress

“A phase 1, multicenter, open-label and first-in-human study was conducted to evaluate the safety and tolerability of ABL001 (CTX-009) in patients with advanced solid tumors.” (opens the source at this quote in a new tab)

Location and study date

Study dates and status: registry record

Milestone	Registry record
Study start (actual)	“2017-09-18”
Primary completion (actual)	“2021-03-02”
Study completion (actual)	“2021-03-02”
Enrollment (actual)	“45”
Recruitment status	“Completed”

Study sites

“This study was conducted at three different sites in the Republic of Korea (Seoul National University Hospital Bundang, Samsung Medical Center, and Asan Medical center) and was approved by the Institutional Review Board (IRB) of Seoul National University Hospital Bundang, the IRB of Samsung Medical Center, and the IRB of Asan Medical Center.” (opens the source at this quote in a new tab)

Study design

Registered design details

Design feature	Registry record
Primary purpose	“Treatment”
Allocation	“N/A”
Interventional model	“Single Group Assignment”
Masking	“None (Open Label)”
Phase	“Phase 1”

Dose escalation and expansion structure

“The dose escalation phase had 9 dose cohorts from 0.3 to 17.5 mg/kg (IV every 2 weeks), using a traditional 3+3 design. The study was expanded at dose levels of 7.5, 10, 12.5 and 15 mg/kg. Archived tumor tissue samples were collected to assess DLL4 expression levels using an immunohistochemistry (IHC) method.” (opens the source at this quote in a new tab)

Dose levels, starting dose, and administration schedule

“The initial dose of 0.3 mg/kg was determined based on the no observed adverse effect level (NOAEL) 10 mg/kg in the monkey model, converted to human equivalent dose with the safety factor of 10.” (opens the source at this quote in a new tab)
“After confirming safety in the dose escalation cohort, additional patients were recruited in 7.5, 10, 12.5, and 15 mg/kg dose groups, which were the target dose levels to show clinically meaningful efficacy based on the results of the preclinical study (data on file).” (opens the source at this quote in a new tab)

Eligibility criteria

Key inclusion criteria: registry record

Criterion	Quoted registry text
Age and diagnosis	“≥19 year old patients with histologically or cytologically confirmed metastatic or unresectable advanced solid tumors”
Measurable disease	“Lesions measured by tumor markers or by CT/MRI must be evaluable based on response evaluation criteria in solid tumors (RECIST) version 1.1.”
Life expectancy	“Life expectancy ≥12 weeks”
Performance status	“ECOG performance status ≤2”

Key selection criteria as reported at the congress

“Key selection criteria included: age ≥19 years, metastatic or unresectable advanced solid tumors, ECOG ≤2, and adequate hematologic, hepatic and renal function.” (opens the source at this quote in a new tab)

Exclusion of prior anti-DLL4 therapy and clinically significant cardiovascular disease

“Patients who had clinically significant cardiovascular disease, including pulmonary hypertension and myocardial infarction, hypersensitivity to humanized/human mAb, or who previously received anti‐DLL4 antibody were excluded.” (opens the source at this quote in a new tab)

Treatment

Route, infusion duration, and dosing interval

“Patients received an intravenous infusion of ABL001/CTX‐009 diluted in 0.9% normal saline (250 mL) over 1 h. ABL001/CTX‐009 was administered in a 2‐week cycle, with the exception of the second dose, which had a 3‐week interval. Administration continued until unacceptable toxicity or disease progression was identified according to RECIST version 1.1.” (opens the source at this quote in a new tab)

Registered intervention

“VEGF/DLL4 targeting bispecific antibody” (opens the source at this quote in a new tab)

Study outcomes

Rationale for using dose-limiting toxicity as the primary endpoint

Registered primary outcome measure

Outcome measure	Measure description	Time frame
“Number and percentage of subjects with adverse events (AEs), serious adverse events (SAEs), and dose-limiting toxicities (DLTs)”	“The maximum tolerated dose/maximum administered dose will be determined by the number of participant experiencing DLTs. The safety profile will be assessed through number of participants experiencing AEs, SAEs, abnormal laboratory parameters, vital signs and electrocardiogram (ECG) results.”	“From time of 1st administration of ABL001 until day 21.”

Justification of the primary endpoint

Not applicable.

Statistical analysis description

Number of participants (Planned and analyzed)

Participants enrolled by study part

“A total of 45 patients (31 patients in the dose escalation phase and 14 patients in the dose expansion phase) were enrolled in the study.” (opens the source at this quote in a new tab)

Participants contributing to the population pharmacokinetic analysis

“From the dose escalation cohort, a total of 712 PK samples from 31 patients were included for population PK model development (0.3 mg/kg = 4, 1 mg/kg = 4, 2.5 mg/kg = 3, 5 mg/kg = 4, 7.5 mg/kg = 3, 10 mg/kg = 3, 12 mg/kg = 3, 15 mg/kg = 4, and 17.5 mg/kg = 3).” (opens the source at this quote in a new tab)

Description of analysis sets

Response-evaluable population

“Of the 39 evaluable patients, there were 4 partial responses (PRs) and 3 of those responses were confirmed by RECIST.” (opens the source at this quote in a new tab)

“There were four partial responses (PRs) observed among 40 patients evaluable for response; three of the four responses were confirmed by RECIST.” (opens the source at this quote in a new tab)

Results

Participant disposition

No evidence found.

Baseline characteristics

Prior therapy, performance status, and tumor types

“The patients were heavily pretreated and received a median of 4 lines of prior therapies. 86.7% of the patients were ECOG 1. Gastric cancer (n=19) and colorectal cancer (n=18) were the most common tumors.” (opens the source at this quote in a new tab)

Age and body weight in the dose escalation cohort

Characteristic	Dose escalation cohort (N = 31)
Mean age, years (standard deviation)	“53.5 (12.4)”
Age range, years	“25, 81”
Mean weight, kg (standard deviation)	“64.2 (16.4)”

Biliary tract cancer subset at baseline

No evidence found.

Efficacy results

Responses, dose levels at which they occurred, and DLL4 expression

“Of the 39 evaluable patients, there were 4 partial responses (PRs) and 3 of those responses were confirmed by RECIST. Responses began to appear at the 10 mg/kg dose level. The 3 confirmed partial responses included 2 colorectal cancer patients at 10 mg/kg and 1 gastric cancer patient at 12.5 mg/kg. All 3 patients with PRs exhibited high DLL4 expression by IHC on archived tumor tissue samples. The unconfirmed PR was in a patient with gastric cancer dosed at 15 mg/kg who was also DLL4 IHC positive.” (opens the source at this quote in a new tab)

Response and disease control at the recommended phase 2 doses

“The recommended Phase 2 doses (RP2Ds) were determined to be 10 mg/kg and 12.5 mg/kg and the Overall Response Rate (ORR) at the RP2D was 18.8% (3/16) and the Disease Control Rate (DCR) was 62.5% (11/16).” (opens the source at this quote in a new tab)

Efficacy in the biliary tract cancer subset of the phase 1 monotherapy study

No evidence found.

Health-related quality of life and patient-reported outcomes

No evidence found.

Safety results

Dose-limiting toxicities and treatment-emergent adverse events

“No dose limiting toxicities (DLTs) were observed. The most common Treatment-Emergent Adverse Events (TEAEs) reported in ≥10% patients were hypertension (37.8%), headache (22.2%), anemia (13.3%), asthenia (13.3%) and fatigue (11.1%). Grade 3 or greater TEAEs reported in ≥5% patients were hypertension (15.6%) and anemia (6.7%). The most common Treatment Related Adverse Events (TRAEs) reported in ≥10% patients were hypertension (37.8%) and headache (15.6%).” (opens the source at this quote in a new tab)

Tolerability across the dose range

“ABL001/CTX‐009 showed favorable tolerability in the dose range from 0.3 to 17.5 mg/kg in this first‐in‐human study in patients with advanced solid tumors.” (opens the source at this quote in a new tab)

Study limitations

Summary

The first-in-human study was open-label, single-arm, and enrolled 45 participants at sites in South Korea only, so it supports dose selection rather than efficacy. No maximum tolerated dose was reached because no dose-limiting toxicities were observed across nine dose levels from 0.3 to 17.5 mg/kg, so the recommended phase 2 doses of 10 mg/kg and 12.5 mg/kg rest on activity and pharmacokinetics rather than on toxicity. Participants were heavily pretreated, with a median of four prior lines, and the tumor types enrolled were predominantly gastric (n=19) and colorectal (n=18) cancer; no biliary tract cancer subset result is reported, so the study provides no direct evidence for the indication. Two sources give different response-evaluable denominators for the same analysis, 39 in the congress abstract and 40 in the trial design publication, and the response rate of 18.8% at the recommended phase 2 doses is based on 3 responses among 16 participants. Only three confirmed partial responses occurred, all in participants whose archived tumor tissue showed high DLL4 expression, a finding from a small biomarker subset that was not prospectively tested. The study has been reported only as a congress abstract and, for pharmacokinetics, as a modeling paper using data from 31 dose escalation participants; no full clinical report has been published, and participant disposition and quality-of-life outcomes are not available.