Primary objective:1. To evaluate the negative predictive value (NPV) of [68Ga]Ga-PentixaFor (PTF) PET at interim examination (after 6 ± 2 weeks of induction chemotherapy) for progression-free survival (PFS). Secondary objectives:2. To evaluate the…
ID
Source
Brief title
Condition
- Other condition
- Lymphomas non-Hodgkin's unspecified histology
Synonym
Health condition
Central Nervous system lymphoma
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy endpoint will be the NPV of [68Ga]Ga-PentixaFor (PTF) PET
at interim examination (after 6 ± 2 weeks of induction chemotherapy, PTF-PET2)
for the prediction of 16 (±1) month PFS.
Secondary outcome
Major secondary efficacy endpoints will be the PPV of PTF PET at interim
examination (PTF-PET2) for prediction of 16 (±1) month PFS; NPV and PPV of
PTF-PET at end-of-chemotherapy (PTF PET3) for prediction of 16 (±1) month PFS;
NPV and PPV of PTF-PET2 and PTF-PET3 for the prediction of complete response.
Exploratory analyses of the association between PTF PET variables (standardised
uptake value, tumour-to-background ratio, metabolic tumour volume) and PFS and
CR will be performed. Sensitivity of PTF-PET to detect CXCR4 overexpression
will be assessed. Agreement between PTF-PET and MRI concerning CNSL-suspicion
will be determined, and inter- and intra-reader agreement will be checked.
Background summary
The role of CXCR4/CXCL12 in CNS lymphoma is substantial: the tumour cells of
both primary and secondary CNS lymphoma are characterised by their strong and
consistent expression of this chemokine receptor and/or its ligand; moreover,
CXCR4/CXCL12 play a key role as neurotrophic factors.
Different therapeutic agents targeting CXCR4/CXCL12 are currently in clinical
development. Subsequently, various CXCR4-directed imaging tracers were
developed. PTF is being developed for CXCR4-directed imaging. The tracer shows
high affinity and selectivity for human CXCR4, rapid renal excretion, and very
low non-specific background accumulation, allowing sensitive and high-contrast
PET imaging of CXCR4-expressing tissues in vivo. Recent imaging studies have
confirmed that a CXCR4-based PET tracer accumulated in the brain of patients
with primary as well as of those with secondary CNS lymphoma.
In addition to the proposed indication, diagnosis of primary and secondary CNS
lymphoma, PentixaFor application in the future might include staging
(evaluating the extent of disease) and activities directed towards patient
selection for personalised therapeutic concepts such as CXCR4-directed
radio-ligand therapy and/or response assessment to anti-cancer therapy.
For CNS lymphoma, a major problem in therapy decisions is that it is not known
which patients need an additional consolidation therapy (high-dose chemotherapy
and/or radiation) if a (partial) remission is achieved. Both high-dose
chemotherapy and whole-brain irradiation are very toxic.
A staging method with a high negative predictive value (NPV) might be very
helpful for guiding the omission of consolidation therapies.
Moreover, a more precise staging method as compared with MRI might identify
relapses earlier and therefore improve therapy by prompting earlier
interventions.
Finally, a method with a high positive predictive value (PPV) might guide
escalation of therapy at an early stage of treatment.
Study objective
Primary objective:
1. To evaluate the negative predictive value (NPV) of [68Ga]Ga-PentixaFor (PTF)
PET at interim examination (after 6 ± 2 weeks of induction chemotherapy) for
progression-free survival (PFS).
Secondary objectives:
2. To evaluate the positive predictive value (PPV) of PTF PET at interim
examination (after 6 ± 2 weeks of induction chemotherapy) for PFS.
3. To evaluate the safety and tolerability of PTF PET imaging.
4. To evaluate the predictive values of PTF PET at the end of induction
chemotherapy for PFS.
5. To evaluate the predictive values of PTF PET at interim examination (after 6
± 2 weeks of induction chemotherapy) and end-of-chemotherapy-treatment for
complete response (CR).
6. To evaluate the predictive values of pre-treatment PTF PET imaging
parameters for PFS and CR.
7. To evaluate the predictive values of interim (after 6 ± 2 weeks of induction
chemotherapy) PTF PET imaging parameters for PFS and CR.
8. To evaluate the predictive values of changes between pre-treatment and
interim (after 6 ± 2 weeks of induction chemotherapy) PTF PET imaging
parameters for PFS.
9. To determine the sensitivity of pre-treatment PTF PET for CXCR4-positivity
in the fraction of patients from whom biopsy tissue is available, by using
histopathology (CXCR4 overexpression by immunohistochemistry, IHC) as the
reference standard on a patient basis.
10. To evaluate the diagnostic agreement between PTF PET and MRI at baseline
imaging on a patient level.
11. To evaluate the observer agreement of PTF PET (inter- and intra-reader
agreement).
Study design
This will be an open, single-arm, international, multicentre, phase II imaging
study to assess the predictive value of [68Ga]Ga PentixaFor PET imaging in
primary and isolated secondary central nervous system lymphoma (CNSL) patients
scheduled to undergo induction chemotherapy.
At each of three time points, each patient will receive two scans, a
CXCR4-directed PTF PET scan and an MRI scan. The time points are baseline
(before the initiation of induction chemotherapy), an interim scan (Week 6 ± 2
after the inception of induction chemotherapy) and a final scan in Week 12-18
(after the completion of induction chemotherapy).
After the three pairs of scans (PTF PET and MRI) have been performed the
patients will enter the follow-up phase of the study. This will comprise four
further MRI imaging procedures at 3 month intervals.
This is an imaging-only study, and the study procedures do not include any
therapeutic measures or decisions. Patients will be treated according to
*standard of care*.
Intervention
The study product is [68Ga]Ga-PentixaFor, otherwise referred to as PTF. It is a
positron emitter and is used in this study as a PET tracer. It will be
administered to each patient by bolus injection shortly before PET scanning. In
all, three PTF PET scans will be performed. The short decay half-life of 68Ga
will ensure an appropriately short exposure of the patients to radiation.
Imaging with [68Ga]Ga-PentixaFor PET/CT and MRI is planned for the following
time points:
1) Before the start of standard therapy (induction chemotherapy),
2) Halfway through standard therapy (induction chemotherapy) and
3) After the end of standard therapy (induction chemotherapy).
Study burden and risks
For the nature and extent of the burden and risks associated with
participation, please refer to section E.9.
Probably no short-term personal benefit for participating patients will be
gained in the study, but it may be that more accurate information about the
disease and treatment response can be obtained. In any case participation in
the study will deliver valuable information about whether imaging with
68Ga-PentixaFor PET/CT can provide additional information for CNS lymphoma
follow-up.
Bismarckstrasse 13
Würzburg 97080
DE
Bismarckstrasse 13
Würzburg 97080
DE
Listed location countries
Age
Inclusion criteria
All study patients must meet all the following criteria:
1.Written informed consent obtained according to international guidelines and
local laws by patient (or legally acceptable representative if the patient is
temporarily legally not competent owing to his/her disease). [Note: No invasive
study-specific procedures may be carried out until this consent has been given.]
2.Patient aged 18 years or above (either sex).
3.Histologically confirmed primary or secondary CNSL based on cytology/flow
cytometry of cerebrospinal fluid (CSF) or brain biopsy.
4.Disease exclusively located in the CNS (primary CNSL or secondary CNSL with
isolated CNS relapse). Subjects who had undergone allogeneic stem cell
transplant > 12 months prior to first dose of study drug, have no evidence
of active graft versus host disease, and are not on systemic immunosuppressive
therapy are allowed to participate in the study.
5.At least one measurable parenchymal lesion. [Note: parenchymal CNSL is a
*must*, and additional locations such as leptomeningeal disease are permitted.]
6.Previously untreated CNS disease.[Note: Previous or ongoing steroid treatment
is permitted. Prophylaxis chemotherapy is not necessary, as induction
chemotherapy will start within 72 hours after PTF-PET.]
7.At least one morphologically measurable lesion according to the IPCG criteria
(Appendix 1).
8.Patients scheduled to undergo induction chemotherapy based on one of the
following: High-dose methotrexate (HD-MTX)-based chemotherapy, ICE/DeVIC or
High-dose cytarabine (HD-AraC)-based chemotherapy.
9.ECOG performance status <= 2 for patients aged >=65 years;ECOG performance
status <= 3 for patients aged <65 years.
10.Life expectancy of at least 3 months, as estimated by the investigator.
11.For women of child-bearing potential: negative pregnancy test.
12.For sexually active female patients of child-bearing potential: The patient
agrees to take adequate contraceptive measures during study participation and
also agrees to continue use of this method for the duration of the study and
for 6 months after the last dose of PTF.
13.For male patients whose partner is of child-bearing potential: The patient
is willing to ensure that he and his partner use effective contraception during
the study and for 6 months after the last dose of PTF.
Exclusion criteria
Any patient meeting one or more of the following criteria will not be included:
1.Known hypersensitivity to [68Ga]Ga-PentixaFor or its components.
2.Contraindication for contrast-enhanced MRI as set out in the relevant
institutional guidelines (e.g., pacemaker, defibrillator, aneurysm clip, metal
in the body, renal insufficiency, severe claustrophobia etc.).
3.Contraindication for the use of gadolinium contrast for MRI.
4.Contraindication for PET according to institutional guidelines (weight-based,
e.g. weight > 180 kg).
5.Inability to lie still for the entire imaging time.
6.Systemic lymphoma manifestation (outside the CNS).
7.Presence of active infection at screening or history of serious infection
within the previous 6 weeks (except HIV infection: patients with HIV-associated
primary CNSL are considered eligible).
8.Administration of another investigational medicinal product within the 30
days (or 5 excretion half-lives, whichever period is the longer) before first
treatment with PTF.
[Note: Re screening may be performed to accept washout of prior agents.]
9.Current toxicity of Grade >2 from previous standard or investigational
therapies (grade according to the NCI Common Terminology Criteria for Adverse
Events, version 5.0 (CTCAE 5.0).
10.For female patients: Pregnancy (existing or intended) or breast-feeding.
11.Renal impairment: Both of the following: Estimated glomerular filtration
rate (eGFR) < 30 ml/min/1.73 m2 Creatinine clearance < 60 ml/min
12.Hepatic impairment: Both of the following: Aspartate aminotransferase (AST)
> 3 upper limit of normalAlanine aminotransferase (ALT) > 3 upper limit
of normal
13.Presence of any unstable systemic disease (including, but not limited to,
active infection, uncontrolled hypertension, unstable angina, congestive heart
failure, serious cardiac arrhythmia requiring medication, hepatic, renal or
metabolic disease.
14.Presence of psychiatric disease, alcohol abuse or any other medical
condition(s) that, in the opinion of the investigator, makes the patient unable
to comply with study procedures and visits.
15. Patient weight <= 48 kg
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 |
|---|---|
| EudraCT | EUCTR2021-001711-85-NL |
| ClinicalTrials.gov | NCT05222269 |
| CCMO | NL80452.000.22 |