The primary objectives of this study is to determine whether uptake of 89Zr CriPec® docetaxel in tumour lesions can be detected and quantified
ID
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms benign
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint of this study is detection (visual and quantitative) of
89Zr CriPec® docetaxel in tumour lesions (the long axis diameter of a visually
assessable and quantifiable lesion must be * 2 cm) .
The five largest lesions will be used for evaluation:
- Visually: present/absent; present being as focally enhanced uptake on the PET
scan with optimal contrast (2-96 h post injection).
- Quantitatively: same tumour lesions measured in Standardized Uptake Value
(SUV) using tumour volumes of interest (VOI). % Injected dose (ID)/ml above
background and above blood will be determined.
To prevent undetectable uptake due to size the short axis diameter of at least
one measurable lesions must be * 2 cm for each patient. Liver lesions may be
excluded for analysis if excessive sequestering of 89Zr CriPec® docetaxel in
healthy liver is observed.
Secondary outcome
The secondary endpoints of the study are:
* Dosimetry of 89Zr CriPec® docetaxel:
o Organ dose (mSv) - recorded for each organ
o Effective dose (mSv) * a single value for each subject
* Define the optimal time point for PET imaging after 89Zr CriPec® docetaxel
administration
* Pharmacokinetics of 89Zr CriPec® docetaxel and total docetaxel
* Biodistribution of low dose dose89Zr CriPec® docetaxel before and after
administration of therapeutic dose of CriPec® docetaxel (quantified with %ID
89Zr CriPec® docetaxel)
* Adverse Effects using Common Terminology Criteria Adverse Events, version 4.0
(CTCAE 4.0)
* Correlation between side effects of CriPec® docetaxel and uptake of 89Zr
CriPec® docetaxel in normal tissue
* The correlation between tumour (quantification measures of) targeting of 89Zr
CriPec® docetaxel and response to therapy.
Background summary
Nanoparticle compounds, such as CriPec® docetaxel are designed to have an
improved efficacy while maintaining acceptable safety and tolerability profiles
compared to the standard docetaxel. The hypothesis is that these compounds stay
longer in circulation than the native drug, and therefore docetaxel accumulates
in tumour lesions due to the retention of docetaxel in the nanoparticle (the
enhanced penetration and retention effect (EPR)). Subsequent release of
docetaxel from the entrapped particles will allow a local anti-tumour effect,
whilst docetaxel exposure in non-tumour tissue will remain limited. It is
expected that CriPec® docetaxel has a better systemic distribution as compared
to docetaxel including a higher accumulation in the tumour. Indeed, as
described in preclinical experiments in rats, the Cmax and AUC following the
administration of CriPec docetaxel was approximately 150-200 times greater than
the Cmax and AUC of total docetaxel following the administration of docetaxel
at the same dose.
In order to prove that this mechanism of action indeed leads to selective
accumulation in tumour lesions in the patient, this study will investigate in
vivo imaging of the entire patient using 89Zr labelled CriPec® docetaxel.
PET imaging with 89Zr labelled tracers in patients have been described for many
different monoclonal antibodies (Jauw 2016). PET imaging is a feasible way of
obtaining quantitative information on the levels of drug present in normal as
well as tumour tissues throughout the body simultaneously and at multiple time
points without being as invasive as multiple biopsies. Nanoparticles have
similar half-life as mAb, the long lived tracer 89Zr (t* = 78 h) is ideally
suited to label CriPec® docetaxel. In a non-clinical qualification study,
CriPec® docetaxel was conjugated to the chelator Desferal and subsequently
radiolabelled with 89Zr using procedures described previously [Perk 2006].
Please see the IMPD for further details.
The purpose of this proof-of-concept study is to determine uptake of 89Zr
CriPec® docetaxel in tumour lesions of patients with solid tumours with
histological types for which treatment with a taxane is an appropriate option.
The initial aim will be to establish if low dose 89Zr CriPec® docetaxel
accumulation in tumour lesions can be determined in the first 3 patients. In
these same patients linearity of 89Zr CriPec® docetaxel PK at low dose and
during treatment with CriPec® docetaxel at the RP2D of 60 mg/m2 will be
determined. In addition, unlabelled CriPec® docetaxel will be administered at
variable doses (2-5 patients per cohort) before low dose of 89Zr CriPec®
docetaxel to investigate the existence of a sink and gain further information
on in vivo PK of 89Zr CriPec® docetaxel. Dose levels will be chosen based on
the results obtained so far. In case of negative results (no visual tumour
uptake of 89Zr CriPec® docetaxel in tumour lesions >2 cm outside the liver) in
the first 3 patients, the study will be discontinued.
Study objective
The primary objectives of this study is to determine whether uptake of 89Zr
CriPec® docetaxel in tumour lesions can be detected and quantified
Study design
A clinical phase I, open-label, immune-PET study with [89Zr] CriPec® docetaxel
in patients with solid tumours to assess biodistribution and tumour
accumulation of [89Zr] CriPec® docetaxel
After inclusion an [18F]-FDG PET scan will be performed to delineate viable
tumour lesions. On day 1, patients will receive a low dose of [89Zr] CriPec®
docetaxel (corresponding to approximately 0.1-2 mg docetaxel) followed by
maximally 3 [89Zr]-PET scans (timing of PET scan can be adapted depending on
results obtained, within timeframe of 2 h * 9 days after administration) to
evaluate biodistribution and tumour uptake. Two weeks later, the patients will
receive unlabelled CriPec® docetaxel up to the RP2D that was determined to be
safe in the phase I NAPOLY trial (CT-CL01), immediately followed by a second
low dose of [89Zr] CriPec® docetaxel and maximally 3 [89Zr]-PET scans (timing
of PET scan can be adapted depending on results obtained, within timeframe of 2
hrs * 9 days after administration) to evaluate biodistribution and tumour
uptake with therapeutic dosage.
Patients will continue to receive unlabelled CriPec® docetaxel every 3 weeks at
the RP2D determined in the NAPOLY trial until disease progression, unacceptable
toxicity, or discontinuation for any other reason.
Intervention
All patients will undergo a fluorodeoxyglucose (FDG)-PET scan within 14 days
before Run-in Day 1 to identify metastatic lesions and to precisely demarcate
viable tumour tissue.
The first 3 patients will undergo 3 whole-body PET scans at 2 (for dosimetry
purposes), 48 and 96 h after the first dose of 89Zr CriPec® docetaxel (where
t=0 is the time of administration of 89Zr CriPec® docetaxel) and 2 whole body
PET scans at 48 and 96 h after the second dose of 89Zr CriPec® docetaxel.
The next patients will undergo 2-3 PET scans after each administration of 89Zr
CriPec® docetaxel, with a maximum of 5 89Zr PET scans/patient, < 9 days after
each administration. The timing of these PET scan will be determined based on
the data gathered in the first 3 patients.
PK assessments:
Whole blood and plasma concentrations of 89Zr CriPec® docetaxel and plasma
concentrations of total docetaxel will be measured and PK parameters in whole
blood and plasma (Cmax, AUC, CL, Vss and t1/2), respectively will be calculated
in the first 3 patients.
Study burden and risks
For the patient the total dose administration of 2 times 37 MBq of 89Zr CriPec®
docetaxel is expected to be around 40 mSv. Low dose CT scans used for
attenuation correction will give an additional dose of 3 mSv for low dose CT.
The radiation dose from an FDG-PET scan is usually around 4 mSv, with 3 mSv for
low dose CT. The total effective dose is expected to be around 62 mSv for the
first three patients. As a comparison, natural cosmic radiation exposure in the
Netherlands during is 2,5 mSv per year.
The side effects of CriPec docetaxel are the same as for the known chemotherapy
docetaxel:
Increased risk of gettinf an infection, breathlessness, tiredness and weakness
(fatigue) during and after treatment, hair loss, skin rash, fluid build up,
discoloured fingernails.
Soreness, redness and peeling of skin on hand and feet, sore mouth, diarrhoea,
peripheral sensitive neuropathy, allergic reactions, watery eyes.
De Boelelaan 1117
Amsterdam 1081HV
NL
De Boelelaan 1117
Amsterdam 1081HV
NL
Listed location countries
Age
Inclusion criteria
1. Age older or equal to 18 years
2. A pathologically confirmed diagnosis of advanced, recurrent and progressive
cancer that is refractory to standard therapy or for which no standard therapy
exists and where treatment with a taxane is an appropriate treatment option
3. Measurable or evaluable disease according to RECIST criteria v.1.1. Patient
must have at least one measurable lesion with a long axis diameter of > 2 cm.
4. Performance status (WHO scale/ECOG) smaller or equal than 2
5. Estimated life expectancy of at least 12 weeks
6. Toxicities incurred as a result of previous anti-cancer therapy (radiation
therapy, chemotherapy, or surgery) must be resolved to * grade 2 (as defined by
CTCAE version 4.0)
7. ANC equal or> 1.5 x 109/L; platelets equal or > 100 x 109/L; Haemoglobin
equal or >* 6.0 mmol/L ( equal or >* 9.6 g/dL)
8. Creatinine ** 1.5 x upper limit of normal (ULN); or creatinine clearance
equal or > 60 mL/min (Cockcroft-Gault)
9. Serum bilirubin ** 1.5 x ULN; alkaline phosphatase, ASAT and ALAT ** 2.5 x
ULN, unless related to liver metastases, in which case ** 5 x ULN is allowed
10. Written informed consent according to local guidelines
Exclusion criteria
* Less than 4 weeks since the last treatment with other anti-cancer therapies,
(i.e. endocrine therapy, immunotherapy, radiotherapy, chemotherapy, etc.), less
than 8 weeks for cranial radiotherapy, and less than 6 weeks for nitrosoureas
and mitomycin C prior to first study treatment
* A history of grade 2 or higher skin toxicity as a result of prior treatment
with taxanes
* If excessive sequestering of 89Zr CriPec ® docetaxel in healthy liver is
observed in the first 3 patients, patients with only liver lesion will not be
eligible
* Current or recent (within 28 days of first study treatment) treatment with
another investigational drug or participation in another investigational study
* Current malignancies at other sites, with exception of adequately treated
cone-biopsied in situ carcinoma of the cervix uteri and basal or squamous cell
carcinoma of the skin
* Major surgical procedure (including open biopsy, excluding central line IV
and port-a-cath) within 28 days prior to the first study treatment, or
anticipation of the need for major surgery during the course of the study
treatment
* Uncontrolled hypertension (systolic > 150 mm Hg and/or diastolic > 100mm Hg)
* Grade *2 motor or sensory neuropathy symptoms (as defined by CTCAE version
4.03)
* Known hypersensitivity to any of the study drugs or excipients or taxanes
* Any active skin condition associated with impaired skin integrity exposing
the patient at risk to develop skin toxicity
* Clinically significant (i.e. active) cardiovascular disease defined as:
* Stroke within * 6 months prior to first study treatment;
* Transient Ischemic Attack (TIA) within * 6 months prior to first study
treatment;
* Myocardial infarction within * 6 months prior to first study treatment;
* Unstable angina;
* New York Heart Association (NYHA) Grade II or greater Congestive Heart
Failure (CHF);
* Serious cardiac arrhythmia requiring medication;
* Clinically relevant pathologic findings in electrocardiogram (ECG);
* Left Ventricle Ejection Fraction (LVEF) by MUGA or ECHO < 50%
13. Patients who are pregnant or breastfeeding
14. Absence of effective means of contraception as of Run-in Day 1 in female
patients of childbearing potential (defined as <2 years after last menstruation
and not surgically sterile) or in male patients who are not surgically sterile
and who have female partners of childbearing potential
15. Evidence of any other medical conditions (such as psychiatric illness,
infectious diseases, drug or alcohol abuse, physical examination or laboratory
findings) that may interfere with the planned treatment, affect patient
compliance or place the patient at high risk from treatment-related
complications
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 | EUCTR2017-0034664-1-NL |
| ClinicalTrials.gov | NCT03712423 |
| CCMO | NL63373.029.17 |