Pancreatic Cancer
Conditions
Brief summary
This trial will include 2 portions (phase 1 and phase 2). The first portion will be a Phase I, open label, dose escalation study to establish the maximum tolerated dose (MTD) of XB2001 as measured by Dose-Limiting Toxicity (DLT), in combination with ONIVYDE + LV + 5-FU chemotherapy regimen in patients with advanced pancreatic cancer and to determine the recommended dose for the subsequent Phase 2 study. The phase 2 portion will be implemented with the maximum established tolerated dose (MTD) of XB2001. The target enrollment in the phase 2 portion is 60 patients which will be randomized on a 1:1 basis to XB2001 plus ONIVYDE + LV + 5-FU (Arm 1) or placebo plus ONIVYDE + LV + 5-FU (Arm 2).
Detailed description
Study Title: A Phase I/II randomized, double-blind, placebo-controlled trial (1-BETTER) examining XB2001 (anti-IL-1⍺ True Human antibody) in combination with ONIVYDE + 5-FU/LV (+folinic acid) in advanced pancreatic cancer Sponsor: XBiotech USA, Inc. Sample Size: Approximately 69 patients will be enrolled in the USA (at least 9 patients in the open label phase 1 portion and 60 patients in the randomized phase 2 portion) Approximate Duration: This trial will include 2 phases. The first portion will be a Phase I, open label, dose escalation study evaluating the safety, tolerability and establishing the Maximum Tolerated Dose (MTD) of XB2001 in at least nine patients with metastatic pancreatic adenocarcinoma who are receiving ONIVYDE + Leucovorin l + d racemic + 5-Fluorouracil chemotherapy treatment. The duration for each patient in the Phase I portion will be 14 days (1 treatment cycle) in which they will be given one intravenous dose of XB2001 prior to receiving ONIVYDE + Leucovorin l + d racemic + 5-Fluorouracil chemotherapy treatment and assessed for Dose Limited Toxicities (DLT). The Phase II portion will be implemented following the completion of the Phase I portion and declaration of the MTD. The duration of subject participation in the randomized, double-blind, placebo-controlled Phase II portion of the trial is approximately 28 weeks: including a screening period of up to 30 days, and 24-week treatment period. All study subjects can continue treatment with XB2001 in an open label extension, for as long as they are judged to be benefitting clinically and have had no unacceptable toxicities.
Interventions
BIOLOGICALPhase I: XB2001 250 mg
Subjects were administered one intravenous (IV) dose of XB2001 250 mg prior to receiving ONIVYDE 70 mg/m2 IV over 90 minutes, followed by leucovorin 400 mg/m2 IV over 30 minutes, followed by 5-Fluorouracil 2400 mg/m2 intravenously over 46 hours at each cycle.
BIOLOGICALPhase I: XB2001 500 mg
Subjects were administered one intravenous (IV) dose of XB2001 500 mg prior to receiving ONIVYDE 70 mg/m2 IV over 90 minutes, followed by leucovorin 400 mg/m2 IV over 30 minutes, followed by 5-Fluorouracil 2400 mg/m2 intravenously over 46 hours at each cycle.
BIOLOGICALPhase I: XB2001 1000 mg
Subjects were administered one intravenous (IV) dose of XB2001 1000 mg prior to receiving ONIVYDE 70 mg/m2 IV over 90 minutes, followed by leucovorin 400 mg/m2 IV over 30 minutes, followed by 5-Fluorouracil 2400 mg/m2 intravenously over 46 hours at each cycle.
BIOLOGICALPhase II: XB2001 1000 mg
Subjects were administered one intravenous (IV) dose of XB2001 1000 mg prior to receiving ONIVYDE 70 mg/m2 IV over 90 minutes, followed by leucovorin 400 mg/m2 IV over 30 minutes, followed by 5-Fluorouracil 2400 mg/m2 intravenously over 46 hours at each cycle.
BIOLOGICALPhase II: Placebo
Subjects were administered one intravenous (IV) dose of placebo 1000 mg prior to receiving ONIVYDE 70 mg/m2 IV over 90 minutes, followed by leucovorin 400 mg/m2 IV over 30 minutes, followed by 5-Fluorouracil 2400 mg/m2 intravenously over 46 hours at each cycle.
Sponsors
XBiotech, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double-blinded study
Intervention model description
Subjects in phase II portion will be randomized on a 1:1 basis to XB2001 plus ONIVYDE + LV + 5-FU (Arm 1) or placebo plus ONIVYDE + LV + 5-FU (Arm 2).
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically confirmed pancreatic adenocarcinoma of exocrine pancreas that is metastatic, unresectable, or recurrent * At least one measurable lesion according to Response Evaluation Criteria in Solid Tumor V1.1 * Documented disease progression after one prior gemcitabine-based therapy OR one FOLFIRINOX and gemcitabine combination therapy * Eastern Cooperative Oncology Group (ECOG) performance of 0 or 1 or Karnofsky performance status (KPS) ≥ 70 * Adequate hepatic, renal and bone marrow function
Exclusion criteria
* Clinically significant decrease in performance status (medical records) within 2 weeks of intended first dose administration * Clinically significant GI disorders * Severe arterial thromboembolic events less than 6 months before inclusion * Prior Whole Brain Radiation Therapy (WBRT) * Evidence of brain metastases * NYHA Class III or IV congestive heart failure, ventricular arrhythmias or uncontrolled blood pressure (defined as ≥ 160/100 mm Hg) * Use of strong CYP3A4 inducers or inhibitors and/or UGT1A1 inhibitors within 14 days prior to Visit 1/Baseline visit.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To Establish the Maximum Tolerated Dose (MTD) of XB2001 as Measured by Dose-Limiting Toxicity (DLT), in Combination With ONIVYDE + LV + 5-FU Chemotherapy Regimen in Patients With Advanced Pancreatic Cancer. | 28 days (consisting of the first two 14-day treatment cycles or the formal DLT observation window). | The primary objective of the Phase I portion is to identify the MTD of XB2001 when administered in combination with ONIVYDE + LV + 5-FU. The MTD is defined as the highest dose level at which no more than one out of six subjects experience a DLT. If two or more subjects in a cohort of six experience a DLT, the MTD is considered exceeded, and the previous lower dose level will be identified as the MTD. If no DLTs are observed at the highest dose level studied, that dose will be used for Phase II. A DLT is defined as any Grade 3-4 adverse event (per NCI CTCAE v5.0) occurring within the first 28 days that is deemed possibly related to the combination regimen, unless the toxicity is clearly attributable to a single non-XB2001 component. Specific DLT criteria include: 1. Inability to deliver all scheduled doses during the 28-day window due to unexpected drug-related toxicity. 2. Inability to deliver the intended dose of XB2001 due to drug-related toxicity. |
| Safety and Tolerability of XB2001 in Combination With ONIVYDE + LV + 5-FU | From post-infusion visit 1(week 0) through visit 13 (week 24), which is two weeks after the last infusion. | This endpoint evaluates the cumulative safety profile and patient tolerance of XB2001 when administered at the Maximum Tolerated Dose (MTD) or the maximum dose studied in Phase I, in combination with the ONIVYDE + LV + 5-FU regimen. Safety is characterized by the total number of participants in each cohort who experienced one or more adverse events. For the purpose of this count, each participant is counted only once, regardless of the total number of individual adverse events experienced. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | From baseline until the date of first documented disease progression or date of death (from any cause), whichever come first. | Progression free survival (PFS) was defined as the time from randomization to first progression based on RECIST v1.1 criteria or death from any cause, whichever occurred first. Subjects who had no baseline and post-baseline tumor assessment and no death, or no adequate post-baseline tumor assessment and no death were censored at the date of randomization. Subjects alive and without documented disease progression at the time of data analysis are censored at the date of the last adequate tumor assessment. |
| Overall Survival (OS) | From baseline until death from any cause | OS was defined as the duration from the date of randomization until death irrespective of the cause. Subjects who were alive at the time of analysis were censored at the last known date alive. Subjects without any data after baseline were censored on the randomization day. |
| Objective Response Rate (ORR) | Analyses performed at Visit 5 (Week 8), Visit 9 (Week 16), and Visit 13 (Week 24). This outcome measure was reported for Visit 13. | Objective Response Rate (ORR) is defined as the proportion of subjects in the Phase II Population who achieved a Best Overall Response (BOR) of either Complete Response (CR) or Partial Response (PR), as defined by RECIST v1.1 criteria. |
| Time to Treatment Failure(TTF) | From baseline until treatment failure assessed up to Visit 13 (Week 24) | TTF measures the time from randomization to discontinuation of treatment for any reason, including, but not limited to, disease progression, treatment-related toxicity, and/or death during study. |
| Number of Serious Adverse Events (SAEs) | From post-infusion visit 1(week 0) through visit 13 (week 24), which is two weeks after the last infusion. | This outcome measure calculates the total number of unique participants who reported serious adverse events (SAEs) in each group. An SAE is defined as any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect. |
| Incidence of Grade 3-4 Diarrhea | From post-infusion visit 1(week 0) through visit 13 (week 24), which is two weeks after the last infusion. | This measure tracks the overall burden of severe (Grade 3) or life-threatening (Grade 4) diarrhea as defined by the NCI CTCAE v5.0. Grade 3 events are severe enough to require medical intervention or significantly limit a person's ability to care for themselves, while Grade 4 events represent urgent, life-threatening clinical situations. |
| Duration of Hospitalization | From post-infusion visit 1(week 0) through visit 13 (week 24), which is two weeks after the last infusion. | This outcome measure calculates the sum of duration of hospitalizations during the study period in phase II population for both groups. |
| Plasma Concentration of Natrunix | Reported results Natrunix: Phase I: V1 post-dose collected at 30 min post-infusion at visit 1(Week 0), which represents Cmax of Cycle 1. Phase II: V6 pre-dose, at Visit 6 (Week 10), represents the trough of steady state concentration. | Measurement of the concentration of Natrunix in plasma samples to evaluate the pharmacokinetic profile. Due to reporting limitations on this portal, results from only one time point are reported here. For Phase 1, samples were collected at V1 pre-dose, V1 post-dose, V2 pre-dose, V3 follow up. For phase 2, samples were collected at V1 pre-dose, V1 post-dose, V1 Day 4, V1 Day 7, V2 pre-dose, V3 pre-dose, V4 pre-dose, V6 pre-dose, V8 pre-dose, and V13 follow up. Placebo patients were tested at V1 post-dose only for verification. |
| Number of Treatment Cycles | From randomization to end of study or study discontinuation for any reasons, up to 24 weeks | This measures the total number of cycles (total number of doses) received by subjects after randomization in each arm. |
Countries
United States
Contacts
STUDY_CHAIRDavid J Park
Providence St. Joseph Heritage
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 20 Participants |
| Age, Categorical Between 18 and 65 years | 30 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) White | 55 Participants |
| Region of Enrollment United States | 3 participants |
| Sex: Female, Male Female | 17 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 3 | 2 / 5 | 0 / 3 | 21 / 33 | 23 / 32 |
| other Total, other adverse events | 3 / 3 | 4 / 5 | 3 / 3 | 32 / 33 | 32 / 32 |
| serious Total, serious adverse events | 1 / 3 | 1 / 5 | 0 / 3 | 10 / 33 | 14 / 32 |
Outcome results
None listed