Circulating CriPec docetaxel nanoparticles are designed to be in a higher degree than the original compound (docetaxel) to be trapped in tumor tissue due to the enhanced penetration and retention (EPR) effect. Subsequent release of docetaxel from…
ID
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoints for Part 1 are:
• The incidence of Grade 3 or 4 adverse events (AEs) defined as dose-limiting
toxicities Dose Limiting Toxicities (DLTs).
• PK parameters including:
o Plasma levels of total and released docetaxel up to 1 week after 1st
dose: Cmax, Tmax, AUClast, AUCinf, Thalf, lambda z, Cl and Vss in relation to
body surface area (m2) where applicable. Cmax, Tmax, AUClast, AUCinf, Thalf,
lambda z, Cl, and Vss will also be determined after the 2nd dose.
o Comparison of the PK profile of total and released docetaxel in
repeated dosing versus initial dosing.
The primary endpoints for Part 2 are:
• Safety and tolerability profile of CriPec docetaxel given every two weeks
(Q2W) including the incidence of Dose Limiting Toxicities (DLTs)
• PK parameters in Q2W dosing: plasma levels of total and released docetaxel
after single and repeated dosing.
The primary endpoints of Part 3 are:
• Safety and tolerability profile of CriPec docetaxel given Q3W including the
incidence of DLTs
• Plasma levels of total and released docetaxel after single and repeated
dosing of CriPec docetaxel given Q3W
Secondary outcome
The secondary endpoint for Part 1 is the response rate and duration of response
per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1.
The secondary endpoint for Part 2 is the response rate and duration of response
per RECIST Version 1.1.
The secondary endpoints for Part 3 are:
• Response rate and duration of response per RECIST Version 1.1.
• Level of total docetaxel in tumour tissue biopsies
Background summary
Cristal Therapeutics has developed a proprietary technology (CriPec) to
transform drug molecules into nanoparticulate compounds, thereby creating
nanomedicines that are believed to improve efficacy while maintaining
acceptable safety and tolerability profiles. With this technology, a
nanoparticle product containing docetaxel (CriPec docetaxel) has been designed.
CriPec docetaxel consists of docetaxel conjugated to a linker agent, and this
docetaxel-linker conjugate is covalently entrapped in a stabilised, CriPec
nanoparticle.
Docetaxel (Taxotere®) is a member of the taxane family. Docetaxel has
significant activity against several tumour types and is approved for the
treatment of locally advanced or metastatic breast, non-small cell lung cancer,
head and neck cancer, gastric cancer and hormone refractory metastatic prostate
cancer [Taxotere® label text 2014]. Docetaxel is active as single agent and it
has also demonstrated synergistic effects with other cytotoxic agents,
angiogenesis inhibitors, trastuzumab and radiation therapy. Docetaxel is
typically applied in 3-weekly i.v. schedules at doses ranging from 60 to 100
mg/m2, administered as a 1-hour infusion. The primary dose-limiting toxicity in
early studies of docetaxel was neutropenia, and even at the therapeutic doses
given in current practice, neutropenia persists as a frequent toxicity effect.
In addition, weekly i.v. schedules, instead of 3-weekly i.v. schedules, have
been used, as these schedules cause less hematologic toxicity and equal or even
better efficacy [Schuette 2005, Wailoo 2009]. Docetaxel treatment may cause
epiphora or excessive tearing. This toxicity can occasionally be dose-limiting
[Kintzel 2006]. Other toxicities seen with docetaxel include peripheral edema,
interstitial pneumonitis, asthenia, fatigue, nausea and vomiting. Furthermore,
the administration of Docetaxel is associated with severe hypersensitivity
reactions due to the excipient polysorbate 80 (Tween 80) in the pharmaceutical
formulation of Taxotere® [Engels 2007]. Docetaxel is metabolized extensively by
the cytochrome P450 CYP system, with the 3A family representing the major route
of inactivation.
Study objective
Circulating CriPec docetaxel nanoparticles are designed to be in a higher
degree than the original compound (docetaxel) to be trapped in tumor tissue due
to the enhanced penetration and retention (EPR) effect. Subsequent release of
docetaxel from the embedded particles are a local anti-tumor effect, while
exposure of non-tumor tissue to docetaxel remains limited. It is expected that
CriPec docetaxel shows a better systemic distribution and a higher accumulation
in the tumor as compared to docetaxel.
The primary objectives for Part 1 are:
• To evaluate the toxicity profile of escalating doses CriPec docetaxel and to
determine the MTD and the RP2D of CriPec docetaxel given every 3 weeks (Q3W)
• To characterize the PK profile of CriPec docetaxel
The secondary objective for Part 1 is:
• to assess early signs of anti-tumour activity of CriPec docetaxe l.
The primary objective for Part 2 are:
• To identify the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dosage
of CriPec docetaxel given every 2 weeks (Q2w)..
• To ensure absence of cumulative systemic accumulation of CriPec docetaxel
upon repeated administration
The secondary objective of Part 2 is:
• To asses early signs of anti-tumour activity (response rate + duration
of response) of CriPec docetaxel in patients with tumour types of which
treatment with taxane is an appropriate treatment option.
The primary objective for part 3 are:
• To confirm the RP2D of CriPec docetaxel given every 3 weeks (Q3W) with
premedication
• To ensure absence of cumulative systemic accumulation of CriPec docetaxel
upon repeated administration
The secundary objective for part 3 are:
• To assess early signs of anti-tumour activity (response rate + duration of
response) of CriPec docetaxel in patients with tumour types for which treatment
with a taxane is an appropriate treatment option.
• To evaluate the level of total docetaxel in tumour tissue biopsies
Study design
This is a three-part, open-label, safety, PK, and preliminary efficacy study of
CriPec docetaxel administered i.v. every 21 days (Q3W) in Part 1 in previously
treated patients with progressive, solid tumours and who have failed treatment
with standard systemic treatmentIn In Part 2 the dosage (dose level and
frequency) at which CriPec docetaxel can be given without cumulative toxicities
will be further optimized to reach a RP2D. Patients In Part 2, two dose
escalations will be done. First, approximately 12 patients in Part 2A will be
treated at escalating doses of CriPec docetaxel given Q2W. The dose escalation
process for CriPec docetaxel given Q2W will follow the same rules as in Part 1,
but has a DLT window of 8 weeks (2 cycles). To further prevent or mitigate skin
toxicity, in Part 2B a second dose escalation will be started at the MTD
defined in Part 2A, but these patients will receive premedication with oral
dexamethasone.
In Part 3 the RP2D of CriPec docetaxel Q3W determined in Part 1 will be
explored with premedication
Intervention
Upon completion of Cycle 1 and in the absence of progressive disease (PD) or
unacceptable toxicity, patients in all parts of the study may receive
additional cycles of treatment, with ongoing safety monitoring, beginning on
Day 1 of Cycle 2. CriPec docetaxel will be administered Q3W during this period
(21-day cycles). It should be the intention to treat a patient in all cycles at
the dose level assigned at Cycle 1.
For female patients at the beginning of every new cycle and at EOT a
pregnancytest will be performed.
Patients may continue to receive additional cycles of treatment until the
patient experiences disease progression, unacceptable toxicity, request by
patient or physician to discontinue treatment, death, or termination of the
study by the sponsor. The duration of patient participation may therefore vary.
Study visits should be scheduled relative to day 1 of each cycle.
All patients in Part 1 and 3 should return to the clinic for End of Treatment
(EOT) assessments 22 (±3) days after the last dose of CriPec docetaxel has been
administered.
If a patient has discontinued treatment due to abnormal blood values, these
will be followed up weekly until they have normalised.
Twenty-eight (±3) days after EOT a vital status visit will be conducted (for
Part I and Part 2). This visit may be conducted by telephone.
Study burden and risks
Docetaxel (Taxotere®) is an established anti-cancer drug and its toxicological
profile is well known. Docetaxel is the active ingredient of the CriPec
docetaxel nanoparticle formulation. The safety and efficacy of CriPec docetaxel
has not yet been studied in humans. However, preclinical studies have been
performed to determine the efficacy and safety of CriPec docetaxel prior to the
start of the phase I study. In toxicology studies it was demonstrated that
CriPec docetaxel has a similar toxicity profile as the active component with
the addition of vacuolation of reticuloendothelial macrophages by the
nanoparticle formulation. This is considered an adaptive change, but not a
toxic response. The minimum toxic dose in rats treated intermittently was
higher for CriPec docetaxel compared to Taxotere®. In preclinical efficacy
experiments CriPec docetaxel showed significant better tumour growth inhibition
and survival benefit in rodent xenografts with breast and gastric cancer
compared to regular docetaxel.
Safe and effective drug delivery of docetaxel to tumours remains challenging.
CriPec docetaxel is potentially capable of delivering more docetaxel within a
favourable therapeutic window. Based on the medical need, and the positive
outcome of the preclinical safety and efficacy studies of CriPec docetaxel,
clinical studies are necessary to evaluate CriPec docetaxel*s clinical
potential in the treatment of malignancies for which treatment with a taxane is
an appropriate treatment option.
Oxfordlaan 55
Maastricht 6229 EV
NL
Oxfordlaan 55
Maastricht 6229 EV
NL
Listed location countries
Age
Inclusion criteria
1. Age >= 18 years at signing of Informed Consent Form (ICF).
2. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1.
3. Estimated life expectancy of at least 12 weeks.
4. Ability and willingness to give written informed consent and to comply with the requirements of the study.
In addition to the above listed eligibility criteria, the following criteria are applicable:
Part 1
5. Patients with pathologically confirmed diagnosis of advanced, recurrent and progressive solid tumours that are refractory to standard therapy or for whom no standard therapy exists and with measurable or evaluable disease according to RECIST 1.1.
Part 2 and part 3
6. Patients with pathologically confirmed diagnosis of advanced, recurrent and progressive cancer with measurable disease according to RECIST 1.1 that are refractory to standard therapy or for whom no standard therapy exists and where treatment with a taxane is an appropriate treatment option
Exclusion criteria
A patient who meets ANY of the following criteria at screening and/or <=3 days of Cycle 1 Day 1 prior to Investigational Product administration (unless otherwise noted below) is not eligible for this study:
1. Less than 4 weeks since the last treatment of chemotherapy, biological therapy, immunotherapy or systemic radiotherapy (except palliative radiation delivered to <20% of bone marrow), and less than 6 weeks for nitrosoureas and mitomycin C prior to Cycle 1 Day 1.
2. Current or recent (within 4 weeks prior to Cycle 1 Day 1) treatment with another Investigational Product or participation in another investigational interventional study.
3. Symptomatic brain metastases.
4. Toxicities incurred as a result of previous anti-cancer therapy (radiation therapy, chemotherapy, or surgery) that have not resolved to <= grade 2 (as defined by CTCAE version 4.03).
5. Abnormal lab results which could indicate inadequate bone marrow function, as evidenced by any of the following at screening and/or <= 3 days of Cycle 1 Day 1 prior to Investigational Product :
* Absolute Neutrophil Count (ANC) < 1.5 x 109/L.
* Platelet count < 100 x 109/L.
* Haemoglobin < 6.0 mmol/L (< 9.6 g/dL).
The patient may not have received a transfusion or growth factors for these abnormalities in the 7 days prior to Cycle 1 Day 1.
Inadequate liver function as evidenced by any of the following at screening and/or <= 3 days of Cycle 1 Day 1 prior to Investigational Product Administration:
6. Serum (total) bilirubin > 1.5 x the Upper Limit of Normal (ULN) for the institution if no liver metastases (> 2 x ULN in patients with liver metastases).
7. AST or ALT > 2.5 x ULN if no liver metastases (> 5x ULN in patients with liver metastases).
8. Alkaline phosphatase levels > 2.5 x ULN if no liver metastases (> 5 x ULN in patients with liver metastases, or > 10 x ULN in patients with bone metastases).
9. International Normalized Ratio (INR) >1.3, consequence of reduced hepatic production of Vitamin K.
10. Hepatitis B surface antigen or hepatitis C positivity in combination with abnormal liver function tests as determined by the Investigator.
11. Medical history of:
* Non-alcoholic steatohepatitis (NASH).
* History of human immunodeficiency virus (HIV) antibody positive or use of antiretroviral therapy.
* Alcoholic and autoimmune hepatitis.
* Ischemic hepatitis, inadequate liver function due to cardiovascular dysfunction or impaired liver oxygenation (e.g. due to hypotension or right heart failure).
Inadequate renal function as evidenced by any of the following at screening and/or <= 3 days of Cycle 1 Day 1 prior to Investigational Product Administration:
12. Serum creatinine > 1.5 x ULN.
13. Estimated Glomerular Filtration Rate of < 50 mL/min/1.73m2 calculated by Modification of Diet in Renal Disease (MDRD) formula or creatinine clearance of < 50 mL/min calculated by Cockcroft-Gault.
Clinically significant (i.e. active) cardiovascular disease as evidenced by any of the following at screening and/or Cycle 1 Day 1 (unless otherwise noted below):
14. Stroke within 6 months prior to Cycle 1 Day 1.
15. Transient Ischemic Attack (TIA) within 6 months prior to Cycle 1 Day 1.
16. Myocardial infarction within 6 months prior to Cycle 1 Day 1.
17. Unstable angina.
18. New York Heart Association (NYHA) Grade II or greater Congestive Heart Failure at screening.
19. Serious cardiac arrhythmia requiring medication.
Other at screening and/or Cycle 1 Day 1 (unless otherwise noted below)::
20. Patients who are pregnant or breastfeeding.
21. Absence of effective means of contraception as of Cycle 1 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.
22. Major surgical procedure (including open biopsy and excluding central line intravenous catheter) within 28 days prior to Cycle 1 Day 1, or anticipation of the need for major surgery during the course of the study treatment.
23. Grade >=2 motor or sensory neuropathy symptoms (as defined by CTCAE version 4.03).
24. Known hypersensitivity to any of the Investigational Product*s excipients or taxanes.
25. History of drug or alcohol abuse in the opinion of the Investigator within 3 years before screening.
26. Evidence of any other medical conditions (such as psychiatric illness, infectious diseases, physical examination or laboratory findings) that may interfere with the planned treatment, affect patient compliance or place the patient at high risk for treatment-related complications.
27. Any active skin condition associated with impaired skin integrity exposing the patient at risk to develop skin toxicity
28. Current treatment with strong inhibitors and inducers of Cytochrome P450 family 3A (CYP3A)
Part 2B and Part 3:
29. Known hypersensitivity to dexamethasone or any other reason that would make the patient not eligible to receive dexamethasone
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 | EUCTR2014-004518-27-NL |
| ClinicalTrials.gov | NCT02442531 |
| CCMO | NL52166.078.15 |