This study has been transitioned to CTIS with ID 2023-507170-41-00 check the CTIS register for the current data. Primary:Phase I: • To identify the maximum tolerated dose (MTD) and/or Recommended Phase II dose (RP2D) of [177Lu]-NeoB Phase IIa:•…
ID
Source
Brief title
Condition
- Other condition
- Miscellaneous and site unspecified neoplasms malignant and unspecified
Synonym
Health condition
Advanced solid tumors known to overexpress GRPR
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Efficacy:
Tumor assessment per RECIST v1.1, RANO (applicable for GBM only)
Key safety assessments:
Incidence and severity of Adverse Events (AEs) and Serious Adverse Events
(SAEs), including changes in laboratory values, vital signs, and
Electrocardiograms (ECGs) for [177Lu]-NeoB; Incidence and severity of Adverse
Events (AEs) and Serious Adverse Events (SAEs) for [68Ga]-NeoB.
Secondary outcome
Other:
PK for all patients as well as distribution and radiation dosimetry for at
least the first 3 patients treated at each dose level of [177Lu]-NeoB in phase
I, the first 6 patients treated in cohorts A, B, and C, and all patients
treated in cohort D in Phase IIa.
Background summary
Gastrin-releasing-peptide (GRP) is a bombesin-like peptide growth factor
implicated in the regulation of numerous central and peripheral functions. By
binding to an extracellular GRP receptor (GRPR), it activates an intracellular
G-protein that triggers further downstream events. Beside its physiological
widespread role, GRP has been demonstrated to be a potent mitogen for normal
and neoplastic tissues and may be involved in growth dysregulation and
carcinogenesis. In fact, upregulation of GRP/GRPR has been reported in several
cancers, including colon, stomach, pancreas, gastrointestinal (GI), uterus,
ovaries, head and neck squamous cell cancer and in various central nervous
system (CNS) malignancies with the strongest signal been observed for
gastrointestinal stromal tumors (GIST), breast, lung (small cell and non-small
cell), prostate cancer and glioblastoma (GBM).
Peptide receptor agonists have initially been the GRPR ligands of choice for
tracer development. However, more recently, GRPR antagonists have demonstrated
greater tumor uptake and better image contrast.
The ligand NeoB, a high affinity antagonist for GRPR, can be radiolabelled with
either Gallium 68, for diagnostic use, or with Lutetium 177, for therapy.
[68Ga]-NeoB has already been assessed in a Phase I/IIa clinical trial aimed at
evaluating the safety, biodistribution, dosimetry and preliminary diagnostic
performance of [68Ga]-NeoB in patients with advanced Tyrosine Kinase Inhibitor
(TKI)-treated Gastro Intestinal Stromal Tumor (GIST) (EudraCT Number:
2016-002053-38).
[68Ga]-NeoB was well tolerated, no related adverse events have been reported in
this study.
Additionally, a Phase II study was recently conducted to evaluate the
preliminary diagnostic performance of [68Ga]-NeoB in adult patients with
malignancies known to overexpress GRPR (EudraCT Number: 2017-003432-37), and no
adverse events related to [68Ga]-NeoB were reported.
Study objective
This study has been transitioned to CTIS with ID 2023-507170-41-00 check the CTIS register for the current data.
Primary:
Phase I:
• To identify the maximum tolerated dose (MTD) and/or Recommended Phase II dose
(RP2D) of [177Lu]-NeoB
Phase IIa:
• Cohort A, B, C: To assess the Disease Control Rate (DCR) of [177Lu]-NeoB at
the RP2D
• Cohort D: To assess the PK as well as the biodistribution and radiation
dosimetry of [177Lu]-NeoB in patients with moderately impaired renal function
Secondary:
Phase I:
• To assess the PK as well as the biodistribution and radiation dosimetry of
each dose level of [177 Lu]-NeoB
• To assess the preliminary anti-tumor activity of [177Lu]-NeoB
Phase IIa:
• Cohort A, B, C: To assess quality of life of patients via EORTC QLQ-C30
Questionnaire
• Cohort A, B, C: To assess the PK as well as the biodistribution and radiation
dosimetry of [177Lu]-NeoB
• Cohort A, B, C: To further assess the anti-tumor activity of [177Lu]-NeoB
Phase I and IIa:
• To characterize the safety and tolerability of [177Lu]-NeoB
• To further characterize the safety and tolerability of [68Ga]-NeoB
Exploratory Objectives:
Phase I:
• To evaluate the biodistribution of [68Ga]-NeoB and [177Lu]-NeoB
Phase IIa:
• Cohort D: To further assess the anti-tumor activity of [177Lu]-NeoB
Phase I and IIa:
• To compare SUVr ranges with qualitative [68Ga]-NeoB uptake to define as
positive or negative on GRPR overexpressing tumor lesions
Study design
This is a Phase I study which consists of a dose escalation. The design of the
Phase I, open label dose finding study was chosen to establish a safe and
tolerated dose of [177Lu]-NeoB to be used in Phase IIa in patients with
selected advanced solid tumors known to overexpress GRPR and with [68Ga]-NeoB
lesion uptake.
The dose escalation will follow a Bayesian optimal interval (BOIN) design. Dose
escalation decisions will be based on a synthesis of all relevant data
available from all dose levels evaluated in the ongoing study.
Only patients with a [68Ga]-NeoB tumor lesion uptake, as defined in inclusion
criteria, on PET/CT or PET/MRI scan performed at screening will be enrolled
into the study and will receive treatment with [177Lu]-NeoB. The methodology to
discriminate [68Ga]-NeoB uptake as positive or negative on tumor lesions is
described in the Imaging Acquisition Manual.
Since [68Ga]-NeoB is not approved yet and is therefore considered as an IMP2 in
this protocol, a safety follow-up will be performed via phone call in an
interval of 2(+1) days after [68Ga]-NeoB administration.
An interval of at least 2 weeks between [68Ga]-NeoB and [177Lu]-NeoB
administration is required.
A total of up to 7 dose levels in the dose escalation of [177Lu]-NeoB will be
evaluated. At each cohort/dose level of at least 3 patients will be enrolled at
the same time. This is deemed acceptable due to the advanced tumor status of
the population, the low dose of 1.85 GBq (50 mCi) in cycle 1 Cohort 1 and the
safety margin (40% and 20% of the estimated cumulative dose) applied in Cohorts
2 and 3. The dosimetry data obtained from three evaluable patients in cycle 1
Cohort 1 will be used to establish the Estimated Cumulative Dose (ECD). This
ECD will be used to define the dose of subsequent cycles for patients treated
in Cohort 1 as described in Section 6.4.3 of the Protocol.
For further information please refer to the protocol.
Intervention
The IV administration of [68Ga]-NeoB 50 µg, kit for radiopharmaceutical
preparation (IMP2), administered 1 time.
The IV administration and subsequent dose escalation and -modification of
[177Lu]-NeoB (IMP1), administered 2/3 times.
See the protocol section 6 for a detailed description on dose determination and
administration in relation to the different cohorts.
Study burden and risks
Subjects will be asked to come to the doctor*s study site between 15-20 times
over about 15 months. In addition, subjects will be called twice over the phone
at the end of the study to check if they have some side effects linked to the
study treatment and to know what type of new treatment they are taking. Each
visit should take about 2 hours except the visits where subjects will receive
the study products and will have body scans for which the visit will be longer.
For the first treatment administration of [177Lu]-NeoB, subjects will have to
stay at the hospital all day with an overnight until the day after.
These visits also include physical examinations, electrical tracing of the
heart (ECG), echocardiograms, body scans, vital signs measurements and taking
blood and urine samples.
When taking blood samples the subject might experience pain, lightheaded,
additional bleeding (at the site of blood draw), temporary discomfort,
bruising, and infection (rarely).
During ECG's the subject may experience temporary discomfort (pulling skin/hair
when removing the sensors), develop minor skin irritation from the ECG patch
adhesive.
Slow intravenous infusion; for practical and radioprotection reasons, a cannula
is inserted through the skin into a vein. The insertion feels like a sharp
scratch and the related risks are infection, inflammation of the vein,
infiltration, extravasation and embolism.
The potential risks issued from [177Lu]-NeoB are of two types: radioactivity
side effects and risks related to the nature of drug.
The most common radioactivity side-effects expected in patients being treated
with [177Lu]-NeoB is the decrease of blood cells, most importantly, red blood
cells, platelets, and other blood cells such as white blood cells. A decrease
in the various blood cell types may put one at risk for bleeding, fatigue,
shortness of breath, and infection.
The radioactive substance may affect other organs, especially pancreas, kidneys
and bone marrow. To check the possible adverse effects of treatment with the
[177Lu]-NeoB on these organs, the function of these organs will be assessed
throughout the study duration by taking blood and urine tests.
Other secondary effects could be nausea and vomiting - usually during the first
24 hours and abdominal pain - during the treatment administration. Possible
delayed (> first 24 hours) side effects of the radiation include fatigue and
temporary hair loss. Other sides-effects reported are: irritation at the
injection site, diarrhea or constipation, slow or fast heart-beat, abnormal
liver function, loss of appetite, loose feces (stools), shortness of breath.
PET (Positron Emission Tomography): one will receive an intravenous injection
of a radioactive substance ([68Ga]-NeoB) and between 1 hour and 3 hours later
one will lie still on a bed while the PET machine takes pictures of the body
for about 15 minutes. The risks of this procedure are related to the
radioactive substance: the radioactivity will disappear by itself soon after
the end of the exam; the amount of radiation of this procedure is similar to
that from a CT scan exam.
SPECT (Single-Photon Emission Computed Tomography): if one is among the first 3
patients included in each cohort of the first part of the study (Phase I), one
will receive via intravenous injection a radioactive substance ([177Lu]-NeoB),
and will lie on a bed while the SPECT machine takes pictures of the body. The
risks of this procedure are related to the radioactive substance: the
radioactivity will disappear by itself progressively after the end of the exam;
the amount of radiation of this procedure is similar to that from a CT scan
exam.
CT (Computed Tomography): the CT scan is often combined with the SPECT or PET
and is low-dose CT scan. The contribution of low-dose CT scan will result in a
theoretical radiation dose of 7 mSv max. Other risks of this procedure are only
related to the IV (nausea for a short time and, in rare cases, allergic
reactions).
MRI (Magnetic Resonance Imaging): the MRI can be used as an alternative to the
CT scan, especially if your tumor lesions are located in the brain. During the
scan, a MRI contrast (a type of dye) will be injected into a vein in the arm.
The dye will be injected through the cannula that is already in place or a new
one. The risks of this procedure are only related to the dye injection (nausea
for a short time and, in rare cases, allergic reactions).
Considering the risks, precautions, possible benefits, and the situation of
possible participants; the benefit-risk balance of administering [177Lu]-NeoB
within the overall clinical context defined in the clinical trial appears to
weight in favor of patient*s benefit.
See protocol section 4 for a full description on the risks and benefits.
Rue de la Tour de lîle 4
Geneva 1204
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Rue de la Tour de lîle 4
Geneva 1204
CH
Listed location countries
Age
Inclusion criteria
1. Signed informed consent must be obtained prior to participation in the
study.,
2. Adult patients (age >= 18 years old) with any of the following advanced or
metastatic solid tumors:
• For Phase I: breast cancer, lung cancer, prostate cancer, GIST, GBM
• For Phase IIa:
a. Cohort A: Breast cancer with histology as follows: HR- positive with ER >
10% of nuclei stain, HER-2 negative and HER-2 low based on current practice and
medical history.
b. Cohort B: Prostate cancer
c. Cohort C: GIST
d. Cohort D: patients affected by any advanced/metastatic solid tumor type
suspected to overexpress GRPR including recurrent GBM, and with moderate
impaired renal function defined as creatinine clearance (calculated using the
Cockcroft-Gault formula, or measured) >= 30mL/min and < 60mL/min.,
3. At least one measurable lesion per RECIST 1.1 RANO (applicable for GBM only)
criteria detected on the low-dose CT/MRI (for GBM MRI only) acquired together
with the [68Ga]-NeoB PET. The same identified measurable lesion shows
[68Ga]-NeoB uptake on PET/CT or PET/MRI. If the only matching lesion is located
in the bone, the patient will still be eligible.,
4. Patients for whom no standard therapy is available, tolerated or appropriate
in both Phase I and Phase IIa. Specifically in the Phase IIa breast cancer
cohort, patients need to have completed at least one prior treatment of
endocrine therapy (including CDk4/6i) and at least one prior chemotherapy
(unless contraindicated) in the metastatic setting. Patients with prior
treatment with trastuzumab deruxtecan, alpelisib or elascestrant are also
eligible. In case of confirmed presence of deleterious or suspected deleterious
germline BRCA1 or BRCA2 mutation, the patient must also have already received a
PARP inhibitor based therapy.
5. Patient Eastern Cooperative Oncology Group (ECOG) performance status:
For phase I: <= 2
For phase IIa: <= 1
Exclusion criteria
1. Patients who have not had resolution, except where otherwise stated in the
inclusion/ exclusion criteria, of all clinically significant toxic effects of
prior systemic cancer therapy, surgery, or radiotherapy to Grade <=1 (except for
alopecia).
2. Creatinine clearance (calculated using Cockcroft-Gault formula, or measured):
a. < 60 mL/min or serum creatinine >1.5 x ULN* for Phase I and Phase IIa
(Cohort A, B and C)
b. <30 mL/min and >= 60 mL/min for Phase IIa (Cohort D)
3. Platelet count of < 75 x 10^9/L*.
4. Absolute neutrophil count (ANC) < 1.0 x 10^9/L*.
5. Hemoglobin < 9 g/dL*.
6. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 x
upper limit of normal (ULN) if no demonstrable liver metastases or > 5 x ULN in
the presence of liver metastases*.
7. Total bilirubin > 1.5 x ULN, except for patients with documented Gilbert*s
syndrome who are eligible if total bilirubin <= 3 x ULN*.
8. Serum amylase and/or lipase > 1.5 x ULN*.
9. Known or expected hypersensitivity to [177Lu]-NeoB, [68Ga]-NeoB or any of
their excipients.
10. Impaired cardiac function or clinically significant cardiac disease,
including any of the following:
* Clinically significant and/or uncontrolled heart disease such as congestive
heart failure requiring treatment (New York Heart Association (NHYA) grade >=
2), uncontrolled arterial hypertension or clinically significant arrhythmia
* LVEF < 50% as determined by echocardiogram (ECHO)*
* QTcF >470 msec for females and QTcF >450 msec for males on screening
electrocardiogram (ECG) or congenital long QT syndrome
* Acute myocardial infarction or unstable angina pectoris < 3 months prior to
[177LU]-NeoB (IMP1) administration.
11. Patients with diabetes mellitus not stable under current treatment as
judged by the investigator, or with hyperglycemia >= CTCAE version 5.0 grade 2*.
12. Patients with history of or ongoing acute or chronic pancreatitis.
13. Concurrent bladder outflow obstruction or unmanageable urinary incontinence.
14. Administration of a radiopharmaceutical with therapeutic intent within a
period corresponding to 10 half-lives of the radionuclide used prior to
injection of [68Ga]-NeoB.
15. Prior External Beam Radiation Therapy (EBRT) to more than 25% of the bone
marrow.
16. [223Ra]-therapy within the context of diffuse bone or bone marrow
involvement (i.e. "superscan" defined as bone scintigraphy in which there is
excessive skeletal radioisotope uptake [>20 bone lesions] in relation to soft
tissues along with absent or faint activity in the genitourinary tract due to
diffuse bone/bone marrow metastases).
18. Patients who have received prior systemic anti-cancer treatment within the
following time frames:
* Cyclical chemotherapy within a period that is shorter than the cycle length
used for that treatment (e.g. 6 weeks for nitrosourea, mitomycin-C) prior to
starting [177Lu]-NeoB treatment
* Biologic therapy (e.g. antibodies), continuous or intermittent small molecule
therapeutics, or any other investigational agents within a period which is <= 5
T1/2 or <= 14 days (whichever is shorter) prior to starting [177Lu]-NeoB
treatment.
19. History of somatic or psychiatric disease/condition that may interfere with
the objectives and assessments of the study.
20. Malignant disease, other than that being treated in this study. Exceptions
to this exclusion include the following: malignancies that were treated
curatively and have not recurred within 2 years prior to [177Lu]-NeoB
treatment; completely resected basal cell and squamous cell skin cancers; any
malignancy considered to be indolent and that has never required therapy; and
completely resected carcinoma in situ of any type.
21. Pregnant or breast-feeding women
22. Women of child-bearing potential, defined as all women physiologically
capable of becoming pregnant, are not allowed to participate in this study
UNLESS they are using highly effective methods of contraception throughout the
study and for 7 months after study drug discontinuation. Highly effective
contraception methods are discussed in the protocol.
23. Use of other investigational drugs within 30 days prior to informed consent
signature.
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 | CTIS2023-507170-41-00 |
| EudraCT | EUCTR2018-004727-37-NL |
| ClinicalTrials.gov | NCT03872778 |
| CCMO | NL69020.078.19 |