Solid Tumor, AdultPhase 1NCT05084456
Oral Docetaxel in Patients With Normal or Impaired Liver Function
A Phase 1 study testing ModraDoc006/r in people with Solid Tumor, Adult and Impaired Liver Function, run by Modra Pharmaceuticals at 1 site in Netherlands.
Trial summary
This is an open label, single centre pharmacological and safety study to define the safety and pharmacokinetics of ModraDoc006/r in a weekly dosing schedule in patients with impaired liver function who might have benefit from a weekly docetaxel regime. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Solid Tumor, Adult, Impaired Liver Function
- What is being tested?
- ModraDoc006/r
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 0 participants
- Where
- 1 siteNetherlands
- Study dates
- Jul 2017to Apr 2020
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Histological or cytological proof of cancer
- Patients who might benefit from a weekly (oral) docetaxel regime
- One of the following options regarding liver impairment:
- Normal liver function: Child-Pugh A classification and normal (<ULN) values of total bilirubin and ASAT/ALAT)
- Presence of liver impairment according to the following characteristics:
- Child-Pugh A and elevated (>ULN) values of total bilirubin and/or ASAT/ALAT (as described in table 3 or Appendix VI)
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- Child-Pugh B
- Age ≥ 18 years;
- Able and willing to give written informed consent;
- WHO performance status of 0, 1 or 2;
- Able and willing to undergo blood sampling for PK analysis;
- Life expectancy > 3 months;
- Minimal acceptable laboratory values defined as:
- Hb ≥ 6.0 mmol/L
- ANC of ≥ 1.5 x 109 /L
- Platelet count of ≥ 100 x 109 /L
- Renal function as defined by serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 mL/min (by Cockcroft-Gault formula);
- Negative pregnancy test (urine/serum) for female patients with childbearing potential;
- Able and willing to swallow oral medication
Who cannot join
- Severe liver impairment classified as Child-Pugh C
- Concomitant use of anticoagulant drugs that can or do alter the PT-INR
- Other causes of elevated bilirubin than intrinsic liver impairment (as described in appendix VII)
- 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.
- Bowel obstructions or motility disorders or gastrectomy that may influence the absorption of drugs
- Neurologic disease that may render a patient at increased risk for peripheral or central neurotoxicity
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- Patients with symptomatic brain metastases or with leptomeningeal metastases. Patients with brain metastases are allowed if they received adequate treatment, are asymptomatic in the absence of corticosteroid therapy and anticonvulsant therapy for at least 6 weeks. Radiotherapy for brain metastases must have been completed at least 4 weeks prior to start of study treatment. Brain metastases must be stable with verification by imaging (e.g. brain MRI or CT completed at screening).
- Unresolved > grade 1 toxicities of previous systemic therapy, except for alopecia
- Woman who are pregnant or breast feeding;
- Unreliable contraceptive methods. 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)
- Radio- or chemotherapy or any treatment with investigational drugs within the last 4 weeks prior to receiving the first dose of investigational treatment (palliative limited radiation for pain reduction is allowed);
- Uncontrolled infectious disease or known Human Immunodeficiency Virus HIV-1 or HIV-2 type patients;
- Patients with known alcoholism, drug addiction and/or psychiatric of physiological condition which in the opinion of the investigator would impair study compliance;
- 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;
- Legal incapacity
Trial locations and contacts
1 site in 1 country.
Netherlands1 site
Netherlands Cancer Institute - Antoni van Leeuwenhoek
Amsterdam, 1066 CX
About this study
Official title: Weekly Administration of (bi-)Daily Oral Docetaxel in Combination With Ritonavir in Patients With Normal or Impaired Liver Function
This is an open label, single centre pharmacological and safety study to define the safety and pharmacokinetics of ModraDoc006/r in a weekly dosing schedule in patients with impaired liver function who might have benefit from a weekly docetaxel regime. The safety of ModraDoc006 in combination with ritonavir for the patients with mild and moderate impaired liver function will be evaluated with a dose escalation design.
Read the detailed description
Oral administration of (anticancer) drugs has many advantages above intravenously administered compounds for patients. A major obstacle for development of an oral docetaxel formulation is the observed poor bioavailability of the drug after oral administration. This was efficiently improved in several pre-clinical and early clinical studies by co-administration of the CYP3A4 inhibitor ritonavir and by development of a new oral formulation of docetaxel (ModraDoc006).
Currently, treatment with ModraDoc006/r (i.e. oral docetaxel as tablets of 10 mg combined with a ritonavir dose of 100 mg) has been evaluated in several clinical trials at the NKI. In these trials, patients have been treated with ModraDoc006/r for a duration of up to 72 weeks.
Commonly observed toxicities of ModraDoc006/r in the phase I trials were nausea, vomiting, diarrhea and fatigue, mostly being of CTC (Common Toxicity Criteria) grade 1-2 severity and usually not interfering with the therapy. Frequently occurring toxicities of intravenously administered docetaxel, such as neutropenia, hypersensitivity reactions and peripheral polyneuropathy have rarely been observed with ModraDoc006/r.
The established recommended dose for further treatment with ModraDoc006/r is 30mg ModraDoc006 (combined with 100mg ritonavir) in the morning and 20 mg ModraDoc006 (combined with 100 mg ritonavir) in the afternoon, as a bidaily weekly schedule.
Impaired hepatic function The primary goal of this study is to explore the safety and pharmacokinetics of ModraDoc006/r in patients with mild or moderate liver impairment in order to be able to give appropriate and practical dose recommendations in daily clinical practice. According to the recommendations of the EMA and FDA guidelines, the Child-Pugh classification will be used in this study to define different classes of severity of liver impairment. However, patients with Child-Pugh class C score will not be included in the study, because of the expected poor performance status and survival and expected increased toxicity related to severely impaired organ function, for whom the use of ModraDoc006/r is considered contra-indicated.
Patients will receive oral docetaxel (as ModraDoc006 10 mg tablets) and ritonavir (100 mg tablet) once- or bi-daily, once a week in a fasted condition. After the end of the study period of twelve weeks patients will go off study and will immediately be offered the opportunity to embark on the roll over protocol N17DEX. This will ensure fully that the patient will receive ModraDoc006/r in the best interest without limitations.
- Conditions
- Solid Tumor, Adult, Impaired Liver Function
- Being tested
- ModraDoc006/r
- Medical subject headings
- Liver Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ModraDoc006/rDrug
Also called Oral docetaxel formulation
Treatment with weekly ModraDoc006 (oral docetaxel) 10mg tablets in combination with ritonavir 100mg tablets in fed or fasting condition
| Study group | Role | What they receive |
|---|---|---|
| Control | Experimental | ModraDoc006/r will be administered in a continuous weekly dose of 30-20 mg without dose escalation. This is the established recommended phase II dose for patients with normal liver function based on previous phase I trials. Receives: Drug: ModraDoc006/r |
| Child-Pugh class A | Experimental | ModraDoc006/r administration will start treatment with a weekly BID dose of 20-10mg ModraDoc006 in combination with ritonavir. If toxicity is acceptable, after 4 weeks an intra-patient dose-escalation will be initiated, followed by the second dose escalation after another 4 weeks. Receives: Drug: ModraDoc006/r |
| Child-Pugh class B | Experimental | ModraDoc006/r administration will start treatment with a weekly QD dose of 20mg ModraDoc006 in combination with ritonavir. If toxicity is acceptable, after 4 weeks an intra-patient dose-escalation will be initiated, followed by the second dose escalation after another 4 weeks. Receives: Drug: ModraDoc006/r |
What is being measured
The primary outcome is the main question the study is designed to answer.
The AUC of docetaxel (area under the curve)
The AUC of docetaxel given as bi-daily ModraDoc006 10 mg tablets in combination with ritonavir after administration in patients with normal and impaired liver function
Measured: Pharmacokinetic plasma sampling during 48 hours in Cycle 1 and Cycle 5 (each cycle is 7 days)
The hematological and non-hematological toxicity profile of oral docetaxel in combination with ritonavir
The number of CTCAE v.4.03 grade 3-4 toxicities during treatment with ModraDoc006/r
Measured: Safety and tolerance will be evaluated during the complete study treatment untill 28 days after the last intake, using the CTCAEv4.03 grading system
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Oct 2021
- Study startJul 2017 (estimated)
- Primary completionFeb 2020 (estimated)
- Study completionApr 2020 (estimated)
Why it stopped: Pending further development
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Solid Tumor, AdultStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Model description
- At least 6 evaluable patients will be included in every of the three groups: a) Controls (Child-Pugh class A with normal biochemical liver tests), b) Child-Pugh class A patients with impaired biochemical liver tests, c) Child-Pugh class B patients. Therefore a minimum of 18 evaluable patients will be included.
- Masking
- None (open label)
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- Modra Pharmaceuticals
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Serena Marchetti, MD/PhD, Principal investigator, The Netherlands Cancer Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05084456
- Sponsor's protocol ID
- N16DOL
- Status last verified
- Oct 2021
- First submitted
- 25 Mar 2019
- Last updated
- 19 Oct 2021
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 19 Oct 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Weekly Administration of (bi-)Daily Oral Docetaxel in Combination With Ritonavir in Patients With Normal or Impaired Liver Function
- ClinicalTrials.gov ID
- NCT05084456
- Acronym / sponsor ID
- N16DOL
- Conditions
- Solid Tumor, Adult, Impaired Liver Function
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: Pending further development
- Enrolment
- 0 participants (actual)
- Lead sponsor
- Modra PharmaceuticalsIndustry (pharma, biotech, devices)
- Study start
- Jul 2017 (estimated)
- Primary completion
- Feb 2020 (estimated)
- Study completion
- Apr 2020 (estimated)
- First posted
- 19 Oct 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This is an open label, single centre pharmacological and safety study to define the safety and pharmacokinetics of ModraDoc006/r in a weekly dosing schedule in patients with impaired liver function who might have benefit from a weekly docetaxel regime. The safety of ModraDoc006 in combination with ritonavir for the patients with mild and moderate impaired liver function will be evaluated with a dose escalation design.
Detailed description
Oral administration of (anticancer) drugs has many advantages above intravenously administered compounds for patients. A major obstacle for development of an oral docetaxel formulation is the observed poor bioavailability of the drug after oral administration. This was efficiently improved in several pre-clinical and early clinical studies by co-administration of the CYP3A4 inhibitor ritonavir and by development of a new oral formulation of docetaxel (ModraDoc006).
Currently, treatment with ModraDoc006/r (i.e. oral docetaxel as tablets of 10 mg combined with a ritonavir dose of 100 mg) has been evaluated in several clinical trials at the NKI. In these trials, patients have been treated with ModraDoc006/r for a duration of up to 72 weeks.
Commonly observed toxicities of ModraDoc006/r in the phase I trials were nausea, vomiting, diarrhea and fatigue, mostly being of CTC (Common Toxicity Criteria) grade 1-2 severity and usually not interfering with the therapy. Frequently occurring toxicities of intravenously administered docetaxel, such as neutropenia, hypersensitivity reactions and peripheral polyneuropathy have rarely been observed with ModraDoc006/r.
The established recommended dose for further treatment with ModraDoc006/r is 30mg ModraDoc006 (combined with 100mg ritonavir) in the morning and 20 mg ModraDoc006 (combined with 100 mg ritonavir) in the afternoon, as a bidaily weekly schedule.
Impaired hepatic function The primary goal of this study is to explore the safety and pharmacokinetics of ModraDoc006/r in patients with mild or moderate liver impairment in order to be able to give appropriate and practical dose recommendations in daily clinical practice. According to the recommendations of the EMA and FDA guidelines, the Child-Pugh classification will be used in this study to define different classes of severity of liver impairment. However, patients with Child-Pugh class C score will not be included in the study, because of the expected poor performance status and survival and expected increased toxicity related to severely impaired organ function, for whom the use of ModraDoc006/r is considered contra-indicated.
Patients will receive oral docetaxel (as ModraDoc006 10 mg tablets) and ritonavir (100 mg tablet) once- or bi-daily, once a week in a fasted condition. After the end of the study period of twelve weeks patients will go off study and will immediately be offered the opportunity to embark on the roll over protocol N17DEX. This will ensure fully that the patient will receive ModraDoc006/r in the best interest without limitations.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
- Model description
- At least 6 evaluable patients will be included in every of the three groups: a) Controls (Child-Pugh class A with normal biochemical liver tests), b) Child-Pugh class A patients with impaired biochemical liver tests, c) Child-Pugh class B patients. Therefore a minimum of 18 evaluable patients will be included.
| Arm | Type | Receives |
|---|---|---|
| Control | Experimental | Drug: ModraDoc006/rModraDoc006/r will be administered in a continuous weekly dose of 30-20 mg without dose escalation. This is the established recommended phase II dose for patients with normal liver function based on previous phase I trials. |
| Child-Pugh class A | Experimental | Drug: ModraDoc006/rModraDoc006/r administration will start treatment with a weekly BID dose of 20-10mg ModraDoc006 in combination with ritonavir. If toxicity is acceptable, after 4 weeks an intra-patient dose-escalation will be initiated, followed by the second dose escalation after another 4 weeks. |
| Child-Pugh class B | Experimental | Drug: ModraDoc006/rModraDoc006/r administration will start treatment with a weekly QD dose of 20mg ModraDoc006 in combination with ritonavir. If toxicity is acceptable, after 4 weeks an intra-patient dose-escalation will be initiated, followed by the second dose escalation after another 4 weeks. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (19 listed)
- Histological or cytological proof of cancer
- Patients who might benefit from a weekly (oral) docetaxel regime
- One of the following options regarding liver impairment:
- Age ≥ 18 years;
- Able and willing to give written informed consent;
Key exclusion criteria (15 listed)
- Severe liver impairment classified as Child-Pugh C
- Concomitant use of anticoagulant drugs that can or do alter the PT-INR
- Other causes of elevated bilirubin than intrinsic liver impairment (as described in appendix VII)
- 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.
- Bowel obstructions or motility disorders or gastrectomy that may influence the absorption of drugs
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ModraDoc006/rAlso: Oral docetaxel formulationTreatment with weekly ModraDoc006 (oral docetaxel) 10mg tablets in combination with ritonavir 100mg tablets in fed or fasting condition | Drug | Child-Pugh class A, Child-Pugh class B, Control |
Primary outcome
The AUC of docetaxel (area under the curve)
Time frame: Pharmacokinetic plasma sampling during 48 hours in Cycle 1 and Cycle 5 (each cycle is 7 days)
The AUC of docetaxel given as bi-daily ModraDoc006 10 mg tablets in combination with ritonavir after administration in patients with normal and impaired liver function
The hematological and non-hematological toxicity profile of oral docetaxel in combination with ritonavir
Time frame: Safety and tolerance will be evaluated during the complete study treatment untill 28 days after the last intake, using the CTCAEv4.03 grading system
The number of CTCAE v.4.03 grade 3-4 toxicities during treatment with ModraDoc006/r
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Oct 2021.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Serena Marchetti, MD/PhD principal investigator
The Netherlands Cancer Institute
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing ModraDoc006/r in people with Solid Tumor, Adult and Impaired Liver Function, run by Modra Pharmaceuticals at 1 site in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 19 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 19 Oct 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The AUC of docetaxel (area under the curve) (time frame: Pharmacokinetic plasma sampling during 48 hours in Cycle 1 and Cycle 5 (each cycle is 7 days)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Oct 2021.