This study has been transitioned to CTIS with ID 2023-508267-69-00 check the CTIS register for the current data. Cohort-Expansion Stage (Single-Agent and Combination Therapy Cohorts):Primary:• To evaluate the preliminary efficacy of XB002 when…
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Source
Brief title
Condition
- Other condition
Synonym
Health condition
Inoperable Locally Advanced or Metastatic Solid Tumors
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Cohort-Expansion Stage (Single-Agent and Combination Therapy Cohorts):
To evaluate preliminary efficacy of XB002 when administered alone and in
combination therapy by determining the ORR per RECIST 1.1 (or other applicable
response criteria, eg, RANO or PCWG3 criteria) as assessed by the Investigator.
Secondary outcome
• To evaluate the safety and tolerability of XB002 when administered alone and
in combination therapy
• To further evaluate the PK of XB002 (antibody conjugated to payload), total
antibody (unconjugated and conjugated antibody), and free payload following IV
administration alone and in combination therapy
• To assess the immunogenicity of XB002
• To evaluate the anti-tumor activity of XB002 alone and in combination therapy
as measured by DOR and PFS per RECIST 1.1 (or other applicable response
criteria, eg, RANO or PCWG3 criteria) as assessed by the Investigator
• To evaluate the anti-tumor activity of XB002 alone and in combination therapy
as measured by ORR, DOR, and PFS per RECIST 1.1 (or other applicable response
criteria, eg, RANO or PCWG3 criteria) as assessed by a BIRC for selected cohorts
• To evaluate overall survival
• To evaluate changes in tumor markers from baseline for selected tumor
indications
Background summary
See protocol page 57 (1. Background and Rationale)
Study objective
This study has been transitioned to CTIS with ID 2023-508267-69-00 check the CTIS register for the current data.
Cohort-Expansion Stage (Single-Agent and Combination Therapy Cohorts):
Primary:
• To evaluate the preliminary efficacy of XB002 when administered alone and in
combination therapy by determining the ORR per RECIST 1.1 (or other applicable
response criteria, eg, RANO or PCWG3 criteria) as assessed by the Investigator
Additional:
• To evaluate the safety and tolerability of XB002 when administered alone and
in combination therapy
• To further evaluate the PK of XB002 (antibody conjugated to payload), total
antibody (unconjugated and conjugated antibody), and free payload following IV
administration alone and in combination therapy
• To assess the immunogenicity of XB002
• To evaluate the anti-tumor activity of XB002 alone and in combination therapy
as measured by DOR and PFS per RECIST 1.1 (or other applicable response
criteria, eg, RANO or PCWG3 criteria) as assessed by the Investigator
• To evaluate the anti-tumor activity of XB002 alone and in combination therapy
as measured by ORR, DOR, and PFS per RECIST 1.1 (or other applicable response
criteria, eg, RANO or PCWG3 criteria) as assessed by a Blinded Independent
Radiology Committee (BIRC) for selected cohorts
• To evaluate overall survival
• To evaluate changes in tumor markers from baseline for selected tumor
indications
Exploratory:
• To assess the effects of XB002 on tumor and blood biomarkers
• To evaluate the exposure of nivolumab or bevacizumab in combination with XB002
• To assess the immunogenicity of nivolumab or bevacizumab in combination with
XB002
• To evaluate the association between TF expression and efficacy outcomes
• To evaluate the safety, tolerability, and anti-tumor activity of XB002 when
administered alone at the RD and RD-low doses in SCCHN, NSCLC, EOC, and
cervical cancer
• To evaluate patient-reported outcomes and the impact of ocular symptoms on
vision-related function
Study design
This is a Phase 1, open-label, multicenter, dose-escalation and expansion study
evaluating the safety, tolerability, PK, pharmacodynamics, and clinical
antitumor activity of XB002 administered IV q3w alone and in combination with
nivolumab or bevacizumab to subjects with advanced solid tumors. This study
consists of Dose-Escalation and Cohort-Expansion Stages for the evaluation of
XB002 as monotherapy and in combination with nivolumab or bevacizumab. First,
the safety and PK of XB002 monotherapy will be evaluated in the Single-Agent
Dose-Escalation Stage. In this stage, subjects with advanced solid tumors will
be treated with XB002 in dose-escalation cohorts using the i3+3 design (Liu et
al 2020).
Dose-escalation steps of XB002 will be tailored by monitoring safety and PK
data. The safety and PK of XB002 combination therapy will be evaluated in the
Combination Therapy Cohort-Expansion Stage for nivolumab or bevacizumab. A
Cohort Review Committee (described in Section 3.7.1) will determine the MTD and
the RD of XB002 from both Dose Escalation Stages (single-agent XB002 and in
combination with nivolumab or bevacizumab) for use in the corresponding
Cohort-Expansion Stages. After the RD of XB002 has been identified in the
Dose-Escalation Stage, safety and efficacy of XB002, both as a single-agent and
in combination with nivolumab or bevacizumab may be further evaluated in the
Cohort-Expansion Stage. The opening or closing of each Expansion Cohort will be
determined by the Sponsor. The TA TF+ cohort may be opened at selected sites
and/or countries.
Subjects in the Dose-Escalation Stage will provide available archival tumor
tissue during the screening period (if archival tissue is not available, fresh
tumor biopsy material can be provided if the biopsy can be safely performed per
investigator discretion). Subjects in the Cohort-Expansion Stage are required
to provide tissue samples (archival or fresh biopsy tumor tissue) during the
screening period. Fresh tumor biopsy during the screening period should not be
performed for the TA TF+ cohort. Subjects in both stages may also provide tumor
tissue from a fresh biopsy optionally during the treatment period. All subjects
will receive XB002 as a single 30-minute IV infusion q3w. Subjects will
continue treatment until a discontinuation criterion is met. After the last
follow-up visit subjects will be followed every 12 weeks to obtain information
on subsequent anticancer therapy and survival.
Note: XB002 plus bevacizumab combination therapy was terminated in light of
recent safety data reviewed as of 20 Dec 2023.
Intervention
XB002 Injection Drug Product will be administered IV over approximately 30
minutes (see Table 11) every three weeks (q3w). Dosing of XB002 will be based
on actual body weight (mg/kg). For subjects with a body weight > 100 kg, the
maximum total dose will be calculated based on 100 kg body weight. Standard
institutional dose rounding rules can be applied. If not available, rounding
should be based on the nearest milligram.
Nivolumab will be administered in the clinic at a dose of 360 mg as an IV
infusion over approximately 30 minutes q3w for a maximum of 2 years. Nivolumab
should be administered prior to XB002. The time in between infusions is
expected to be at least 30 minutes (from the end of the nivolumab infusion to
the start of the XB002 infusion). The initial infusions of nivolumab and XB002
will be given without premedication for potential IRRs. Premedication for IRRs
is allowed after the initial infusions. No bolus or IV push of nivolumab is
allowed.
Study burden and risks
Effects of XB002 in Animals:
In studies in animals done to understand possible XB002 side effects, XB002
caused changes in the eye and eyelids, including changes in the conjunctiva and
cornea. Symptoms at higher doses included swelling around the eye, eyelid
swelling, eye discharge, eye redness, dry eye, ulceration (ulcer), inflammation
and changes which might result in blurry vision. In addition, inflammation was
seen in lungs, and dry and/or red skin. In some animals, particularly at high
doses, the eye symptoms persisted within 6 weeks after the last treatment,
though longer term recovery was not assessed and improvement may occur with
time.
Effects of XB002 in Humans
There is limited experience with XB002 in humans, so the risks are not
completely known. As of 21 December 2023, a total of 109 patients have been
dosed in the Dose Escalation and Cohort Expansion stages of the study and
received XB002 alone or in combination therapy at various dosages (up to 2.5
mg/kg). To date, the following side effects have been stablished for XB002:
Very common (may affect more than 1 in 10 people)
• Inflammation of the membranes protecting your eye (conjunctiva)
• Protein loss in the urine
Common (may affect up to 1 in 10 people)
• Nephrotic syndrome, a kidney disease which results in protein loss in the
urine, low protein levels in the blood and fluid collection in your body (eg in
the ankles off the legs). This disease may cause kidney injury and may require
hospitalization. It also may increase the risk of infections and may lead to
blood clotting problems (thromboses). The observation of this disease led to a
XB002 dose reduction to 1.75 mg/kg maximally. In light of this, it is very
important that frequent urine samples are collected and analyzed.
Effects of Nivolumab in Humans:
Be aware of important symptoms of inflammation. Nivolumab acts on your immune
system (the body*s own defense) and may cause inflammation in parts of your
body. Inflammation may cause serious damage to your body and some inflammatory
conditions may be life-threatening and need treatment or withdrawal of
nivolumab.
The following side effects have been reported with nivolumab alone:
Very common (may affect more than 1 in 10 people)
• Infections of the upper respiratory airway
• A decreased number of red blood cells (which carry oxygen), white blood cells
(which are important in fighting infection) or platelets (cells which help the
blood to clot)
• High (hyperglycaemia) or low (hypoglycaemia) sugar levels in the blood
• Diarrhea (watery, lose or soft stools), vomiting, nausea, constipation,
stomach pain
• Skin rash sometimes with itching
• Feeling tired or weak, fever, oedema (swelling)
• Decreased appetite
• Headache
• Shortness of breath (dyspnoea), cough
• Pain in the muscles, bones (musculoskeletal pain) and joints (arthralgia)
Please refer to the ICF for risks and discomforts associated with study
procedures (Section 7).
Harbor Bay Parkway 1851
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US
Listed location countries
Age
Inclusion criteria
1. Cytologically or histologically and radiologically confirmed solid tumor
that is inoperable, locally advanced, metastatic, or recurrent.
2. Subjects in the Cohort-Expansion Stage must have measurable disease per
RECIST 1.1 as determined by the investigator. Note: Measurable disease at
screening is not required for the following subjects:
a. Subjects in the Dose-Escalation Stage.
b. Subjects with prostate cancer (Cohort I) without soft tissue disease
(RECIST 1.1 assessments are not required for these subjects).
c. Subjects with primary brain tumors, such as glioblastoma (RECIST
assessments are not required for these subjects).
3. Available archival tumor tissue collected no more than 3 years prior to
consent, if possible. If archival tumor tissue is not available, a fresh tumor
biopsy may be collected from subjects enrolled in the Dose-Escalation Stage and
should be collected from subjects in the Cohort-Expansion Stage. Fresh tumor
biopsy during the screening period should not be performed for the TA TF+
cohort. Specific requirements for tumor tissue samples are provided in the
Laboratory Manual.
4. Recovery to baseline or <= Grade 1 severity (Common Terminology Criteria for
Adverse Events version 5 [CTCAE v5]) from AEs, unless AEs are clinically
nonsignificant (eg, alopecia) or stable (eg, peripheral neuropathy not limiting
subjects* instrumental activities of daily life).
5. Age 18 years or older or meeting country definition of adult, whichever is
older on the day of consent.
6. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1
7. Adequate organ and marrow function, based upon meeting of laboratory
criteria within 10 days before first dose of study treatment:
a. Absolute neutrophil count (ANC) >= 1500/mm3 (>= 1.5 GI/L) without granulocyte
colony-stimulating factor (G-CSF) support within 2 weeks prior to screening
laboratory sample collection.
b. Platelets >= 100,000/mm3 (>= 100 GI/L)] without transfusion within 2 weeks
prior to screening laboratory sample collection.
c. Hemoglobin >= 9 g/dL (>= 90 g/L) without transfusion within 2 weeks prior to
screening laboratory sample collection.
d. Activated partial thromboplastin time (aPTT) <= 1.2 × upper limit of normal
(ULN) and prothrombin time (PT) <= × 1.2 ULN or International Normalized Ratio
(INR) <= 1.3 without anticoagulation therapy (INR <= 3 if on stable oral
coumarin-based anticoagulant).
e. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <= 3 ×
ULN. Note: Subjects with hepatic metastases and ALT and AST > × 3 ULN may be
allowed at the discretion of the Investigator.
f. Total bilirubin <= 1.5 × ULN (for subjects with known Gilbert*s disease,
total bilirubin <= 3 × ULN).
g. Serum creatinine <= 1.5 × ULN or calculated creatinine clearance >= 45 mL/min
(>= 0.75 mL/sec) using the Cockcroft-Gault equation
h. Urine protein creatinine ratio (UPCR) <= 1.0.
8. Capable of understanding and complying with the protocol requirements and
must have signed the informed consent document.
9. Sexually active fertile subjects and their partners must agree to highly
effective methods of contraception (defined in Appendix E) during the course of
the study and for the following durations after the last dose of treatment
(whichever is later).
• 7 months after the last dose of XB002 for women of childbearing potential
(WOCBP) and 4 months after the last dose of XB002 for men.
• 5 months after the last dose of nivolumab for WOCBP.
• 6 months after the last dose of bevacizumab for WOCBP.
• Male subjects with female partners of childbearing potential must agree to
use a condom until 4 months after the last dose of XB002.
10. Female subjects of childbearing potential must not be pregnant at
screening. Female
subjects are considered to be of childbearing potential unless one of the
following criteria
is met: permanent sterilization (hysterectomy, bilateral salpingectomy, or
bilateral
oophorectomy) or documented postmenopausal status.
Exclusion criteria
1. Receipt of any tissue factor-targeting antibody drug conjugate or auristatin
derivate-based antibody drug conjugate.
2. Receipt of any chemotherapy or anticancer antibody (eg, anti-VEGF mAb,
antibody-drug conjugate, or PD-1/PD-L1 mAb) within 21 days (nitrosoureas or
mitomycin within 42 days) before first dose of study treatment.
3. Receipt of any type of small molecule kinase inhibitor (including
investigational kinase inhibitors) within 2 weeks before first dose of study
treatment.
4. Receipt of any anticancer hormonal therapy within 2 weeks or within 5
half-lives of the agent, whichever is shorter, before first dose of study
treatment. Note: Concomitant use of a luteinizing hormone-releasing hormone
(LHRH) agonist (eg, leuprolide, goserelin) or antagonist (eg, relugolix) is
permitted.
5. Radiation therapy within 2 weeks before first dose of study treatment.
Subjects with clinically relevant ongoing complications (eg, radiation induced
esophagitis or pneumonitis) from prior radiation therapy are not eligible. See
inclusion criteria #4 for relevant details.
6. Known brain metastases or cranial epidural disease unless adequately treated
with radiotherapy and/or surgery (including radiosurgery) and stable for at
least 4 weeks before first dose of study treatment. Note: Eligible subjects
must be neurologically asymptomatic and without corticosteroid treatment at the
time of first dose of study treatment.
7. The subject has uncontrolled, significant intercurrent or recent illness.
8. Major surgery (eg, GI surgery, removal or biopsy of brain metastasis) within
4 weeks before first dose of study treatment. Minor surgery (eg, simple
excision, tooth extraction, port placement) within 7 days before first dose
unless discussed with and approved by the Sponsor. Complete wound healing from
surgery must have occurred and any surgery related AEs must have resolved
before the first dose. Subjects with clinically relevant ongoing complications
from prior surgery are not eligible.
9. Corrected QT interval calculated by the Fridericia formula (QTcF) > 480 ms
per electrocardiogram (ECG) within 4 weeks before first dose of study treatment
(see Section 5.7.7 for Fridericia formula) Note: If a single ECG shows a QTcF
with an absolute value > 480 ms, two additional ECGs at intervals of
approximately 3 minutes must be performed within 30 minutes after the initial
ECG, and the average of the three consecutive results for QTcF must be <= 480 ms
for the subject to be eligible.
10. History of psychiatric illness likely to interfere with ability to comply
with protocol requirements or give informed consent.
11. Pregnant or lactating females.
12. Previously identified allergy or hypersensitivity to components of the
study treatment formulations or history of severe infusion-related reactions
(IRRs) to monoclonal antibodies.
13. Another unresolved malignancy or a malignancy that is considered to be
cured within 2 years before first dose of study treatment. Note: Subjects with
superficial non-melanoma skin cancers, or localized, low grade tumors deemed
cured and not treated with systemic therapy, within 2 years before first dose
of study treatment are eligible.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2023-508267-69-00 |
| EudraCT | EUCTR2021-006543-10-NL |
| ClinicalTrials.gov | NCT04925284 |
| CCMO | NL81905.068.22 |