We will develop a bi-daily low-dose metronomic treatment schedule with paclitaxel in a convenient oral formulation and test whether this therapy has significant anti-angiogenic and anti-tumor activity.
ID
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To determine the safety and feasibility of LDM bi-daily oral paclitaxel (as
ModraPac005 tablets) in combination with boosting agent ritonavir.
Secondary outcome
• To determine the optimal biological recommended dose (OBDRD) of bi-daily oral
paclitaxel in combination with ritonavir.
• To determine the maximal tolerated dose (MTD, or maximal safe dose) to assess
the safety range.
• Pharmacokinetics of paclitaxel and ritonavir in this schedule.
• To preliminary asses the efficacy of LDM treatment, measured by PFS, response
rates, duration of response and duration of disease control.
• To establish the effect of functional genetic polymorphisms in six genes
(SLCO1B3, ABCB1, ABCC2, CYP3A4, CYP3A5 and CYP2C8, C1236T (for MDR1) and
CYP3A4*1B, on the pharmacokinetics of oral paclitaxel and ritonavir.
• To determine the effect of a high-fat meal on the exposure of ModraPac005/r
Background summary
In classical dose-intensive oncolytic therapy it is believed that the highest
tolerable dose-intensity (MTD) will result in the highest anti-tumor activity.
An alternative is *low dose metronomic (LDM) chemotherapy*, i.e. chronic
administration of oncolytic drugs at relatively low, non-toxic doses on a
frequent administration schedule with no drug-free breaks. Unlike
dose-intensive therapy directly aimed at tumor cell kill, the main target is
dividing endothelial cells of the growing vasculature of a tumor.
Administration of dose-intensive chemotherapy may not lead to optimal
anti-tumor activity, but often exposes patients unnecessarily to severe
side-effects. In fact, it will probably thwart the anti-vasculogenetic capacity
of the therapy.
Based on preclinical data, the taxane paclitaxel is considered to be an ideal
drug to use for the concept of metronomic therapy, if repeated oral dosing
would be possible. We are the first to have successfully developed an oral
treatment strategy for paclitaxel, for which we recently developed a novel
capsule formulation of paclitaxel. In combination with the oral boosting agent
ritonavir high apparent bioavailability of oral paclitaxel is achieved when
given as a drinking solution, or in a capsule/tablet formulation. This strategy
has turned out to be safe and active upon prolonged once weekly BID dosing of
patients with various types of solid tumors at MTD. A capsule preparation has
thus far been used. A novel tablet formulation (ModraPac005 tablet) has been
produced, a tablet has advantages, since these are better produceble and
therefore easier to incorporate in a possible fase II study. The novel tablet
formulation will be implemented in the dose expansionfase when available.
Study objective
We will develop a bi-daily low-dose metronomic treatment schedule with
paclitaxel in a convenient oral formulation and test whether this therapy has
significant anti-angiogenic and anti-tumor activity.
Study design
Dose-escalation of paclitaxel
The OBD of paclitaxel in combination with ritonavir will be determined by dose
escalation. Three patients will be assigned to each dose level. On a predefined
day the patient will start receiving oral paclitaxel BID, dosed according to
the escalation schedule and 100 mg ritonavir (see *dose escalation and study
treatment*). This regime will be continued until progressive disease or until
adverse events, which require dose modifications or discontinuation of therapy,
are observed. Three weeks will be seen as one course. Weekly physical
examination, blood hematology and blood chemistry parameters will guide the
safety of the treatment. If one patient of the first three at a defined
dose-level experiences dose limiting toxicity (DLT), the number of patients
treated at this dose level will be expanded to a maximum of six. The dose
escalation will continue if none of the additional patients experiences a DLT.
The safety range (*Therapeutic Window*) of this schedule will be determined by
assessing the MTD, defined as the highest safe bi-daily dose of oral paclitaxel
using classical clinical and laboratory endpoints (the dose-level at which
maximally one out of six patients develops a DLT).
Expansion phase
At the dose-level of the expected OBD the number of patients treated at this
dose will be expanded to a maximum of twelve. In this phase the effect if food
intake on the pharmacokinetic results will be analysed. If the pharmacokinetic
results are not affected by the intake of food, then the treatment of future
patients can be more convenient by removal of the obligated fasted state around
the bidaily intake of the tablets.
Intervention
Only patients who fulfil all in- and exclusion criteria can enroll in this
study and can receive this therapy.
Study burden and risks
Patients participating will be hospitalized during the first day of treatment.
Blood will be drawn for pharmacokinetic research, hematology, and serum
chemistry (see *Pharmacokinetics*). The patient will have to visit the hospital
once every week.
Patients are at risk for paclitaxel related side effects.
Plesmanlaan 121
Amsterdam 1066 CX
NL
Plesmanlaan 121
Amsterdam 1066 CX
NL
Listed location countries
Age
Inclusion criteria
- Patients with histological or cytological proof of cancer who might benefit from treatment with paclitaxel
- Patients for whom no standard therapy of proven benefit exist;- Age =/> 18 years;- Able and willing to give written informed consent;- Able and willing to undergo blood sampling for pharmacokinetics and pharmacodynamics;- Life expectancy =/> 3 months allowing adequate follow up of toxicity evaluation and anti-tumor activity;- Minimal acceptable safety laboratory values;a. ANC of =/> 1.5 x 109 /L;b. Platelet count of =/> 100 x 109 /L;c. Hepatic function as defined by serum bilirubin </= 1.5 x ULN, ALAT and ASAT </= 2.5 x ULN;d. Renal function as defined by serum creatinine </= 1.5 x ULN or creatinine clearance =/> 50 ml/min (by;Cockcroft-Gault formula).;- WHO performance status of </= 2;- No radio- or chemotherapy within the last 4 weeks prior to study entry ;- Able and willing to swallow oral medication;for expansion phase: able and willing to consume a high-fat meal
Exclusion criteria
1. Patients with known alcoholism, drug addiction, psychotic disorders in the history and/or other reasons, for which they are not amenable for adequate follow up.;2. Women who are pregnant or breast feeding. ;3. Both men and women enrolled in this trial must agree to use a reliable contraceptive method throughout the study (adequate contraceptive methods are: condom, sterilization, other barrier contraceptive measures preferably in combination with condoms). ;4. Concomitant use of MDR and CYP3A modulating drugs such as Ca+ entry blockers (verapamil, dihydropyridines), cyclosporine, (non) nucleoside analoga, St. Johns worth, macrolide antibiotics as erythromycin and clarithromycin, quinidine, quinine, tamoxifen, megestrol, grapefruit juice, concomitant use of HIV medications or other protease inhibitors. ;5. Uncontrolled infectious disease or known HIV-1 or HIV-2 type patients;6. Unresolved (>grade 1) toxicities of previous chemotherapy, excluding alopecia;7. Known allergic reaction against contrast agents;8. Bowel obstructions or motility disorders that may influence the absorption of drugs;9. Neurologic disease that may render a patient at increased risk for peripheral or central neurotoxicity;10. Pre-existing neuropathy greater than CTC grade 1;11. Symptomatic cerebral or leptomeningeal metastases;12. Evidence of any other disease, neurological or metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or puts the patient at high risk for 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
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In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2010-021525-13-NL |
| CCMO | NL33122.031.10 |