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

NCT01173913 | Completed Phase 1

• 1 other identifier: N10BOM
• Study Type: interventional
• Target: 57
• Locations: 1 country
• Sites: 1

Brief Summary

Oral administration has many advantages above intravenously administrated drugs for patients. Up to now, oral administration of docetaxel as single agent has not been feasible due to low and variable bioavailability. This low systematic exposure to docetaxel can effectively be increased after co-administration of ritonavir. The department of pharmacy of the Slotervaart Hospital and Netherlands Cancer Institute developed a solid oral dosage form for docetaxel, ModraDoc001 10 mg capsules. Two other novel dosage forms of docetaxel with improved pharmaceutical characteristics, have been developed: ModraDoc003 10 mg tablets and ModraDoc004 10/50 mg tablets. The systemic exposure after administration of those forms is now being investigated.

Conditions

Cancer

Keywords

oral docetaxel; ModraDoc; pharmacokinetics; safety; MTD; DLT

Outcome Measures

Primary Outcomes (1)

• Number and percentage of Participants with Adverse Events

  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.

  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

Secondary Outcomes (4)

• Pharmacokinetics assessments

  Day 1 of week: 1, 2 and 3

• Number and percentage of Participants with Adverse Events

  during the study treatment and 30 days after the study discontinuation

• Radiological antitumor activity

  at least every six weeks

• Pharmacogenetic sampling

  Day 1 - predose

Study Arms (3)

ModraDoc001 10 mg capsules

EXPERIMENTAL

The optimal dose weekly bi-daily oral docetaxel - ModraDoc001 10 mg in combination with ritonavir will be determined with a classical dose escalation design. Approximately 24 patients will be enrolled depending on required number of dose levels before MTD is reached.

Drug: ModraDoc001 10mg capsules

ModraDoc003 10mg tablets and ModraDoc004 10/50 mg

EXPERIMENTAL

Both new oral dosage forms, ModraDoc003 10 mg tablets and ModraDoc004 10/50 mg tablets will be investigated to see whether these new formulations have comparable pharmacokinetic characteristics, in terms of systemic exposure to docetaxel, as ModraDoc001 10 mg capsule.

Drug: ModraDoc003 10mg tablets and ModraDoc004 10/50 mg

ModraDoc006 10 mg tablet

EXPERIMENTAL

The optimal dose weekly bi-daily oral docetaxel - ModraDoc006 10 mg in combination with ritonavir will be determined with a classical dose escalation design. Approximately 24 patients will be enrolled depending on required number of dose levels before MTD is reached.

Drug: ModraDoc006 10 mg tablet

Interventions

ModraDoc001 10mg capsules DRUG

Bi-daily administration. One cycle will last 7 days

ModraDoc001 10 mg capsules

ModraDoc003 10mg tablets and ModraDoc004 10/50 mg DRUG

The patients will receive 40 mg docetaxel and 200 mg ritonavir once daily as different dosage forms (ModraDoc001 10 mg capsules, ModraDoc003 10 mg tablets and ModraDoc004 10/50 mg tablets). Patients continue in Week 4 with 80 mg docetaxel (as ModraDoc001 10 mg capsules) in combination with 100 mg ritonavir once daily in a weekly schedule until progressive disease or adverse events, which require dose modifications or discontinuation of therapy, are observed.

ModraDoc003 10mg tablets and ModraDoc004 10/50 mg

ModraDoc006 10 mg tablet DRUG

Bi-daily administration. One cycle will last 7 days

ModraDoc006 10 mg tablet

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Histological or cytological proof of cancer
• Patients for whom no standard therapy of proven benefit exist
• 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.
• Age \_ 18 years
• Able and willing to give written informed consent
• Able and willing to undergo blood sampling for pharmacokinetics
• Life expectancy \_ 3 months allowing adequate follow up of toxicity evaluation and anti-tumor activity
• 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 x ULN
• 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 (palliative limited radiation for pain reduction is allowed)
• Able and willing to swallow oral medication

You may not qualify if:

• Patients with known alcoholism, drug addiction and/or psychotic disorders in the history that are not suitable for adequate follow up
• Women who are pregnant or breast feeding.
• 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).
• 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.
• Uncontrolled infectious disease or known HIV-1 or HIV-2 type patients
• Unresolved (\>grade 1) toxicities of previous chemotherapy
• Bowel obstructions or motility disorders that may influence the absorption of drugs
• Chronic use of H2-receptor antagonists or proton pump inhibitors
• Neurologic disease that may render a patient at increased risk for peripheral or central neurotoxicity
• Pre-existing neuropathy greater than CTC grade 1
• Symptomatic cerebral or leptomeningeal metastases
• 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.

Sponsors & Collaborators

• The Netherlands Cancer Institute: lead

Study Sites (1)

Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital

Amsterdam, 1066 CX, Netherlands

Location

Related Publications (1)

• Vermunt MAC, van der Heijden LT, Hendrikx JJMA, Schinkel AH, de Weger VA, van der Putten E, van Triest B, Bergman AM, Beijnen JH. Pharmacokinetics of docetaxel and ritonavir after oral administration of ModraDoc006/r in patients with prostate cancer versus patients with other advanced solid tumours. Cancer Chemother Pharmacol. 2021 Jun;87(6):855-869. doi: 10.1007/s00280-021-04259-5. Epub 2021 Mar 20.

  PMID: 33744986 DERIVED

Related Links

• Article on the study

MeSH Terms

Conditions

Neoplasms

Interventions

Tablets

Intervention Hierarchy (Ancestors)

Dosage Forms; Pharmaceutical Preparations

Study Officials

• JHM Schellens, MD, PhD

  The Netherlands Cancer Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 30, 2010
• First Posted: August 2, 2010
• Study Start: September 1, 2010
• Primary Completion: October 4, 2016
• Study Completion: January 26, 2017
• Last Updated: January 10, 2019

Record last verified: 2019-01

Locations

NL (1)