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Weekly Administration of (bi-)Daily Oral Docetaxel in Combination With Ritonavir

Phase 1
Open (Enrolling)
Cancer Patients

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Trial Information

Weekly Administration of (bi-)Daily Oral Docetaxel in Combination With Ritonavir

The bioavailability of docetaxel is limited due to metabolising cytochrome P450 (CYP)
enzymes, which are abundantly present in the gastrointestinal tract.

Inhibition of CYP3A4 enzymes with ritonavir (an anti-retroviral drug) has in previously
conducted proof-of-concept and phase I trials, proven to enhance the bioavailability of oral

Oral administration of docetaxel has been investigated in five clinical trials, all
initiated by the Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital (NKI-AVL).
The department of pharmacy of the Slotervaart Hospital and Netherlands Cancer Institute
developed a solid oral dosage form for docetaxel, ModraDoc001 10 mg capsules. This
formulation has now been investigated in more than 40 patients in a first clinical study.
The preliminary results with ModraDoc001 10mg are promising and a linearity between systemic
exposure to docetaxel and the applied dose of ModraDoc001 10mg capsules is seen. In an
attempt to further improve and prolong the systemic exposure we will explore a twice daily
dosing schedule.

Two other novel dosage forms for docetaxel, ModraDoc003 10 mg tablets and ModraDoc004 10/50
mg tablets, were developed. Both are spray-dried solid dispersions of docetaxel pressed in
tablets. The distinction between both is that ritonavir is included in the co-formulation of
ModraDoc004 10/50 mg tablets (10 mg docetaxel and 50 mg ritonavir). Both dosage forms will
be investigated in arm B to see whether these new formulations have comparable
pharmacokinetic characteristics of docetaxel to the capsule formulation.

Arm A Arm A is a dose escalation study to establish the maximum tolerated dose (MTD)of
weekly bi-daily ModraDoc001 10 mg capsules. This study will be done with a classical dose
escalation design. The starting dose will be 40 mg BID. This dose is based on a safety of
weekly 80 mg single dose in the previously conducted study.

Arm B ModraDoc003 10 mg tablets and ModraDoc004 10/50 mg tablets will be investigated in arm
B to see whether these new formulations have comparable pharmacokinetic characteristics of
docetaxel to the capsule formulation od ModraDoc001 10 mg.

Another part of this study is the screening for 2 different polymorphism, C1236T (for
MDR1)and CYP3A4*1B. Polymorphic variants may influence the absorption and elimination of
docetaxel and ritonavir.

Inclusion Criteria:

1. Histological or cytological proof of cancer

2. Patients for whom no standard therapy of proven benefit exist

3. Patients who might benefit from treatment with docetaxel, e.g. advanced breast,
gastric, esophagus, bladder, ovarian cancer and non-small cell lung cancer, head and
neck cancers, prostate cancer and carcinoma of unknown primary site.

4. Age _ 18 years

5. Able and willing to give written informed consent

6. Able and willing to undergo blood sampling for pharmacokinetics

7. Life expectancy _ 3 months allowing adequate follow up of toxicity evaluation and
anti-tumor activity

8. Minimal acceptable safety laboratory values

- ANC of _ 1.5 x 109 /L

- Platelet count of _ 100 x 109 /L

- Hepatic function as defined by serum bilirubin _ 1.5 x ULN, ALAT and ASAT _ 2.5

- Renal function as defined by serum creatinine _ 1.5 x ULN or creatinine
clearance _ 50 ml/min (by Cockcroft-Gault formula).

9. WHO performance status of _ 2

10. No radio- or chemotherapy within the last 4 weeks prior to study entry (palliative
limited radiation for pain reduction is allowed)

11. Able and willing to swallow oral medication

Exclusion Criteria:

1. Patients with known alcoholism, drug addiction and/or psychotic disorders in the
history that are not suitable 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

4. Concomitant use of MDR and CYP3A modulating drugs such as Ca+-entry blockers
(verapamil, dihydropyridines), cyclosporine, quinidine, quinine, tamoxifen, megestrol
and grapefruit juice, concomitant use of HIV medications; other protease
inhibitors,(non) nucleoside analoga, St. Johns wort or macrolide antibiotics as
erythromycin and clarithromycin.

5. Uncontrolled infectious disease or known HIV-1 or HIV-2 type patients

6. Unresolved (>grade 1) toxicities of previous chemotherapy

7. Bowel obstructions or motility disorders that may influence the absorption of drugs

8. Chronic use of H2-receptor antagonists or proton pump inhibitors

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.

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Number and percentage of Participants with Adverse Events

Outcome Description:

The maximal tolerated dose (defined as the highest dose resulting in no more that 1/6 probability of causing a dose limiting toxicities defined in the protocol) of bi-daily ModraDoc001 10mg capsules with ritonavir will be assessed in Arm A. Weekly safety assessments for Arm A and Arm B: signs and symptoms/adverse events, physical examination, clinical laboratory tests (hematology, clinical chemistry and urinalysis), 12-lead ECG monitoring (Day 0, End of Th). The incidence of serious AEs (SAEs) and AE related to oral docetaxel and/or to ritonavir will be determined.

Outcome Time Frame:

AE will be collected during the study treatment and 30 days after discontinuation of the study treatment due to disease progression or unacceptable treatment related toxicity

Safety Issue:


Principal Investigator

JHM Schellens, MD, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

The Netherlands Cancer Institute


Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Study ID:




Start Date:

September 2010

Completion Date:

December 2011

Related Keywords:

  • Cancer Patients
  • oral docetaxel
  • ModraDoc
  • pharmacokinetics
  • safety
  • MTD
  • DLT