Weekly administration of Oral Docetaxel in combination with Ritonavir

Oral administration has many advantages above intravenously administrated drugs
for patients. However, oral bioavailability is frequently low and variable. The
bioavailability of docetaxel and paclitaxel are limited due to metabolising
cytochrome P450 (CYP) enzymes and p-glycoprotein (a transporter enzyme), which
are abundantly present in the gastrointestinal tract. Inhibition of CYP3A4
enzymes with ritonavir, (an anti-retroviral drug) has in a previously conducted
proof-of-concept trial, shown to enhance the bioavailability of oral docetaxel
and possibly also from paclitaxel.

To determine the maximum tolerated dose (MTD), dose limiting toxicities (DLT),
and optimal dose of docetaxel that can safely be administered to patients with
cancer in a weekly schedule.

amendment 1
The objective of the first amendment is to determine the effect of a second
ritonavir dose 4 hours post-dose on the pharmacokinetics of docetaxel.

amendment 2
THe objective of the second amendment is to determine the systemic exposure of
the new oral docetaxel formulation (ModraDoc001 capsules) in combination with
ritonavir.

amendment 3
The results of Arm C justify to continue the development of an oral
docetaxel/rionavir regimen with ModraDoc001 capsules instead of the liquid
formulation. therefore we would like to continue in Arm A and B with the
capsule formulation, ModraDoc001 capsules. therefore we would like to continue
in doselevel 2 of Arm A, the dose escalating part of the study, with the
capsule formulation instead of the liquid formulation. Patients treated in Arm
B receive in each course 30 mg ModraDoc001 capsules.

Amendment 4:
Is it necessary to administer the novel oral formulation of docetaxel,
ModraDoc001 capsules, with a booster to enhance the systemic exposure?
-Are there other, frequently used CYP3A4 inhibitors (ketoconazole, Grapefruit
juice) that also increase the systemic exposure of oral docetaxel (ModraDoc001
capsules)?
-Has ritonavir a similar effect on the apparent bioavailability of paclitaxel?
These questions will be addressed in Arm D, E and F.

Amendment 5:
-Can claritromycin, a macrolide antibacterial agent and strong CYP3A inhibitor,
enhance the systemic exposure to docetaxel and paclitaxel after oral
administration?
-Can ketoconazole enhance the systemic exposure to oral paclitaxel?
These questions relate to the extent of the concept of boosting docetaxel and
paclitaxel by inhibition of CYP3A.

The formulation of oral paclitaxel currently used has a few disadvantages. Due
to its main excipients, alcohol and cremophor, it has a bad taste and it also
has a limited shelf life. The department of pharmacy of the Slotervaart
hospital and Netherlands Cancer Institute developed an improved formulation.
This new formulation, ModraPac001 capsules, will be investigated in part C to
see whether this new formulation has comparable pharmacokinetic characteristics
to the orally administered iv formulation.

Amendment 6:
In arm K, the influence of a double ritonavir dose (200 mg) will be
investigated. The combination of oral docetaxel in combination with ritonavir
has been investigated thoroughly. However, to assess the optimal ritonavir
dose, the impact of higher ritonavir doses needs to be assessed.
An important issue to address is whether the final formulation for both
docetaxel and paclitaxel should be coated with an enteric protective coat. The
influence of an enteric coat on the bioavailability is investigated. This
concerns arms L and M of the protocol.

amendment 7:
in Arm A i.v. docetaxel is given on week 1. this is omitted in doselevel 5 and
higher.

amendment 8:
doselevel 6 will be 60 mg ModraDoc001 in combination with 200 mg RTV.
addition of arm L: 100 or 200 mg RTV in combination with oral paclitaxel.
study arms with coated modraDoc001 capsules are removed from the protocol.

amendment 9:
addition of pharmacogenetic analysis

amendment 10:
switch from ritonavir capsules to ritonavir tablets.

amendment 11:
physical exam once every two weeks instead of weekly.

amendmet 13:
To determine the systemic exposure of the oral docetaxel formulation
(ModraDoc005 tablets) in combination with ritonavir.
To determine dose limiting toxicities (DLT) and recommended dose (RD) of
docetaxel (ModraDoc005 tablets) that can safely be administered to patients
with cancer in a weekly schedule.

amendment14:
To determine the systemic exposure of the oral docetaxel formulation
(ModraDoc006 tablets) in combination with ritonavir.
To determine dose limiting toxicities (DLT) and recommended dose (RD) of
docetaxel (ModraDoc006 tablets) that can safely be administered to patients
with cancer in a weekly schedule.

Arm A
The optimal dose of docetaxel in combination with ritonavir will be determined
by dose escalation. Three patients are assigned to each dose level.
On day 1 of the first week, each patient receives docetaxel 20 mg iv and
ritonavir 100 mg.
On the first day of the second and every subsequent week, the patient receives
ritonavir and oral docetaxel, dosed according to the dose escalation schedule.
This regime will be continued weekly until progressive disease or until adverse
events, which require dose modifications or discontinuation of therapy, are
observed. In doselevel 2 patients receive 40 mg ModraDoc001 capsules instead of
the liquid formulation.
In doselevel 5 and higher, patients will not receive iv docetaxel. Patients
immediately start with oral docetaxel. PK samples will be drawn during the
first and second week.

Arm B:
The patients are randomized into two groups. The first group receives:
* Cycle 1, Day1: 20 mg docetaxel in combination with 100 mg RTV
* Cycle 2, Day 1: 20 mg docetaxel in combination with 100 mg RTV and 100 mg RTV
4 hours post-dose.
Each cycle lasts 7 days.
Cycle 1 and 2 are reversed for the second randomization group.
Patients continue in cycle 3 with 30 mg docetaxel in combination with 100 mg
RTV in a weekly schedule until progressive disease or adverse events, which
require dose modifications or discontinuation of therapy, are observed. This
dose is the starting dose of the dose escalating trial, arm A.
The first two patients were treated according to the above schedule, patiented
treated after approval of amendment 3 will be treated in each course with 30 mg
ModraDoc001 capsules.

Arm C:
A new oral formulation of docetaxel will be investigated in part C. The
patients are randomized into two groups. The first group receives:
* Cycle 1, Day 1: 30 mg docetaxel in combination with 100 mg RTV
* Cycle 2, Day 1: 30 mg ModraDoc001 capsules in combination with 100 mg RTV.
* Cycle 3, Day 1: 30 mg ModraDoc001 capsules in combination with 100 mg RTV.
Each cycle lasts 7 days.
Cycle 1 and 3 are reversed for the second randomization group.
Patients continue in cycle 4 with 30 mg docetaxel (i.v. formulation) in
combination with 100 mg RTV in a weekly schedule until progressive disease or
adverse events, which require dose modifications or discontinuation of therapy,
are observed. This dose is the starting dose of the dose escalating trial, arm
A.

Arm D, E and Arm G:
Different CYP3A4 modulating agents are investigated in these arms:
* Cycle 1, Day 1: 30 mg ModraDoc001 capsules
* Cycle 2, Day 1: 30 mg ModraDoc001 capsules in combination with 100 mg
ritonavir
* Cycle 3, Day 1: 30 mg ModraDoc001 capsules in combination with 400 mg
ketoconazole
Each cycle lasts 7 days.
Cycle 2 and 3 are reversed for the second randomization group.

in Arm E: patients are treated with 2 glasses of grapefruit juice instead of
ketoconazole (simultaneously and 1 hour after ModraDoc001 capsulesintake).

Arm G: patients do not receive ModraDoc001 capsules without booster (due to
poor results of ModraDoc001 capsules alone, when administered without booster).
Patients reveive 1000 mg claritromycine instead of 400 mg ketoconazole

Patients continue in cycle 4 or cycle 3 (arm G) with 30 mg docetaxel
(ModraDoc001 capsules) in combination with 100 mg RTV in a weekly schedule
until progressive disease or adverse events, which require dose modifications
or discontinuation of therapy, are observed.

Arm K:
In total, 4 patienten will be randomzied into 2 groups. group1 will recieve the
schedule depicted below. Cycle 1 and 2 are reveresed for the second
randomization group.
Cycle1 day 1: 30 mg ModraDoc001 capsules and 100 mg ritonavir
Cycle2 day 1: 30 mg ModraDoc001 capsules and 200 mg ritonavir

Arm L:
In total, 4 patienten will be randomzied into 2 groups. group1 will recieve the
schedule depicted below, the second group receives first the second cycle and
subsequently the first cours.
Cycle1 day 1: 30 mg ModraDoc001 capsules and 100 mg ritonavir
Cycle2 day 1: 30 mg ModraDoc002 capsules and 100 mg ritonavir

Patients assigned to arm K or L continue in cycle 3 with 40 mg docetaxel
(ModraDoc001 capsules) in combination with 100 mg RTV in a weekly schedule
until progressive disease or adverse events, which require dose modifications
or discontinuation of therapy, are observed.


Arm F, H and I:
Different CYP3A4 modulating agents are investigated in these arms, arm F:
* Cycle 1, Day 1: 100 mg paclitaxel po in combination with 15mg/kg cyclosporin
A po
* Cycle 2, Day 1: 100 mg paclitaxel in combination with 100 mg ritonavir
Each cycle lasts 7 days.
Cycle 1 and 2 are reversed for the second randomization group.

In arm H and I patients follow the same schedule as for arm F. Except, instead
of cyclosporin A, patients recveive 1000 mg claritromycine in arm H and 400 mg
ketoconazole in arm I.

Arm M: Has not been opened for patients, no patients have been recruited, in
amendment 13 a new arm M has been introduced
In total, 4 patienten will be randomzied into 2 groups. group1 will recieve the
schedule depicted below, the second group receives first the second cycle and
subsequently the first cours.
Cycle1 day 1: 30 mg Modrapac001 and 100 mg ritonavir
Cycle2 day 1: 30 mg Modrapac002 and 100 mg ritonavir


In Arm F, H, I, J and M: Patients continue in cycle 3 with a weekly 1-hour
infusion schedule of 90 mg/m2 paclitaxel until progressive disease or adverse
events, which require dose modifications or discontinuation of therapy, are
observed.

Arm M: after amendment 13
Dose escalation cohor with ModraDoc005, 3-13 patient per dose level, with a
maximum of 18 patients in this arm M.

Arm N: introduced in amendment 14
Dose escalation cohor with ModraDoc006, 3-13 patient per dose level, with a
maximum of 18 patients in this arm N.

The safety profile for oral administrated docetaxel is expected to be similar
as intravenously administered docetaxel. Gastrointestinal side effects might
occur more frequently due to the oral route of administration.
Twenty-five patients treated in a phase II trial with weekly oral docetaxel 100
mg and cyclosporine 15 mg/m2 were evaluable for respons and toxicity. The main
toxicities were: neutropenia, diarrhea, nail toxicity and fatigue.

Ritonavir has been administered to healthy volunteers at oral doses of 600 mg
at 12 hour intervals. Vomiting, nausea and abdominal pain occur frequently
especially during the first few weeks of therapy but only at the highest doses.
These ritonavir side effects correlate with ritonavir plasma levels. Thus, the
expected burden andf risks associated with ritonavir are low.

Side effects from cyclosporin and ketoconazole are not expected. both drugs are
administrated only once, while sideeffects generally are observed when
administered on a continues base.
Possible side effects from claritromycine are diarrhea and vomitting.
Overall, the risks associated with the study procedures are low. For most
people, needle punctures for blood samples do not cause any serious problems.
However, this procedure may cause bleeding, bruising, discomfort, infections
and or pain at the needle site.