Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Blood and Lymph Conditions

Immune System Diseases

Rare Diseases

Carcinoma, Non-Small-Cell Lung

Carcinoma

Lung Neoplasms

Lymphoma

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Carcinoma, Bronchogenic

Bronchial Neoplasms

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Lymphosarcoma

All Drugs and Chemicals

Amino Acids

Alectinib

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

Alectinib plasmaconcentration will be blinded untill the end of the trial. No intervention based on the alectinib plasmaconcentrion will be performed. In case of unacceptable toxicity (i.e. unbearable or persistent grade 2 toxicity and grade 3/4 toxicity), the alectinib dose can be reduced by 150mg BID.

In case of an alectinib plasmaconcentration Cmin \<435 ng/mL, determined by TDM, and manageable toxicity, the alectinib dose will be increased with 150mg BID up to a maximum of 900mg BID. In case of unacceptable toxicity (i.e. unbearable or persistent grade 2 toxicity and grade 3/4 toxicity), the alectinib dose can be reduced by 150mg BID.

M.B. Muntinghe-Wagenaar, Msc

B. Besse, PhD

M.M. van den Heuvel, PhD

L.E.L. Hendriks, PhD

A.J. de Langen, PhD

S.M.S. Hashemi, Msc

E.F. Smit, PhD

A.C. Dingemans, PhD

A.J. van der Wekken, PhD

The ADAPT ALEC randomized controlled trial (RCT) is performed in patients with Anaplastic Lymphoma Kinase (ALK) positive non-small cell lung cancer (NSCLC). The RCT will compare the use of Therapeutic Drug Monitoring (TDM) and dose increases if alectinib 35 ng/Ml (arm A) with standard of care (arm B).

The ADAPT ALEC trial is a phase IV, RCT in patients with ALK positive NSCLC treated with alectinib. A longer median progression free survival (mPFS) is expected in patients treated with standard dose alectinib when minimum plasma concentrations (Cmin) of alectinib exceed 435 ng/mL. The ADAPT ALEC trial will investigate whether using therapeutic drug monitoring (TDM) and increasing the dose of alectinib in patients with Cmin \<435 ng/mL, will raise the mPFS. We will compare mPFS in the subgroup of patients with an alectinib Cmin \<435 ng/mL using TDM and dose increases (arm A) to fixed dosing/standard of care (arm B).

Both study-arms will receive oral alectinib (Alecensa®, Roche). In arm A (TDM arm), the alectinib dose will be increased if Cmin \<435 ng/mL and manageable toxicity. In both arms, alectinib dose can be reduced based on toxicity.

The alectinib Cmin for patients treated in arm B (standard dose arm) will be blinded to participants and care providers

Comparison of Standard Dose Alectinib to Alectinib in Adjusted Dose Based on Alectinib Bloodlevels

Standard Dosed Alectinib Versus Therapeutic Drug Monitoring Guided Alectinib Dosing

Individual participant data that underlie the results will only be shared upon reasonable request from the Principal Investigator at the UMCG, who will discuss the request with the ADAPT ALEC study team.

PFS is measured from start of treatment to progressive disease, death or lost to follow-up.Patients who did not die or progress, or lost to follow-up, will be censored at their last available date.

The percentage of succesfull TDM interventions, in which successful is defines as tartget attainment and manageable toxicity.

ORR is the percentage of patients with partial response or complete response, according to RECIST v1.1, of the total treated population.

mOS is defined as time from randomization to death from any cause in the total population.

PFS is measured from start of treatment to progressive disease in the brain, death or lost to follow-up. Patients who did not die or progress, or lost to follow-up, will be censored at their last available date.

This will be estimated by pill counts of returned medication as well as a patient diary on drug intake.

AE's will be defined using CTCAE v5.0. Number of AE's in the subgroups of patients with Cmin \<435 ng/mL compared to Cmin \>= 435 ng/ML, and in patients who did and who did not receive a TDM-guided dose increase.

Mean change from baseline in EORTC QLQ-C30 and QLQ-LC13 scores

Mean change from baseline in EQ-5D-5L score

The ICER is the final outcome of the comparative cost-effectiveness analysis performed using a health-state transition model to compare costs and effectiveness between both study arms.

Alectinib M4 plasmaconcentrations in relation to alectinib plasma concentrations

Amsterdam University Medical Center

Erasmus Medical Center

Maastricht University Medical Center

Radboud University Medical Center

The Netherlands Cancer Institute

Leiden University Medical Center

University Medical Center Groningen

Antineoplastic Agents

Sorafenib

In this phase I study patients are treated with high-dose, pulsatile sorafenib in escalating AUC0-12h cohorts.

In new dosing schedule of sorafenib is investigated in this study: high-dose, pulsatile sorafenib

sorafenib

Henk MW Verheul, MD PhD

Sorafenib is an oral anticancer drug and inhibits multiple protein kinases important for tumor growth and metastases, including VEGFR, PDGFR, and RAF kinases. In daily clinical practice it is currently used at a dose of 400 mg twice daily in a continuous schedule. In this phase I study patients will be treated with a new dosing schedule of sorafenib: i.e. a high-dose, pulsatile schedule. The tolerability and safety of this new schedule is examined in exposure escalation cohorts based on a target plasma AUC0-12h (area under the curve). Exposure escalation cohorts are used instead of conventional dose escalation cohorts because the effect of a drug is dependent of its AUC levels and large differences in plasma sorafenib AUC0-12h have previously been shown between patients treated at the same dose level. Using pharmacokinetic monitoring, the sorafenib dose will be adjusted to a target plasma AUC0-12h. The escalation cohorts consist of 3-6 patients per exposure level starting with a target plasma sorafenib AUC0-12h level of 25-50 mg/L/h. After the determination of the maximum tolerated AUC0-12h, 10 additional patients will be entered into an expansion cohort. In the expansion cohort the patients will be treated with a weekly pulse of sorafenib at the maximum tolerated AUC0-12h for further assessment of safety and preliminary exploration of efficacy.

Rationale: Preclinical research showed improved efficacy of sorafenib when given in a high-dose, pulsatile schedule compared with conventional (lower dose) continuous scheduling as a result of higher peak concentrations in the tumor. In this phase I study patients will be treated with high-dose, pulsatile sorafenib in exposure escalation cohorts. Exposure escalations cohorts are based on a target plasma AUC0-12h (area under the curve) and are used instead of conventional dose escalation cohorts because the effect of a drug is dependent of its AUC levels and large differences in plasma sorafenib AUC0-12h have previously been shown between patients treated at the same dose level.

Primary Objectives:

* To determine the maximum tolerated plasma AUC0-12h of high-dose sorafenib administered in a weekly, pulsatile schedule.
* To assess the safety and tolerability of high-dose, pulsatile sorafenib.

Secondary Objectives:

* To determine the pharmacokinetic behaviour of sorafenib and its major active metabolite pyridine N-oxide when administered in a weekly, pulsatile schedule.
* To determine a recommended phase II plasma AUC0-12h of high-dose sorafenib in a weekly pulsatile schedule.
* Preliminary assessment of the efficacy of high-dose, pulsatile sorafenib administered at the maximum tolerated plasma AUC0-12h.
* To determine skin and intratumoral concentrations of sorafenib and their correlation with plasma and whole blood concentrations.
* To select 1-2 optimal time points from the AUC0-12h data to determine sorafenib exposure using a finger puncture.

Study design: A single center, open-label, phase I study of high-dose, pulsatile sorafenib administered in exposure escalation cohorts.

Study population: Adult patients with locally advanced or metastatic disease for whom no standard therapy exists.

Treatment: Patients will be treated in exposure escalation cohorts with high-dose sorafenib administered in a weekly pulsatile schedule. Using pharmacokinetic monitoring, the sorafenib dose will be adjusted to a target plasma AUC0-12h. The escalation cohorts consist of 3-6 patients per exposure level starting with a target plasma sorafenib AUC0-12h level of 25-50 mg/L/h. After the determination of the maximum tolerated AUC0-12h, 10 additional patients will be entered into an expansion cohort. In the expansion cohort the patients will be treated with a weekly pulse of sorafenib at the maximum tolerated AUC0-12h for further assessment of safety and preliminary exploration of efficacy.

Sorafenib Administered Using a High-dose, Pulsatile Regimen: a Phase I Exposure Escalation Study

Sorafenib Administered Using a High-dose, Pulsatile Regimen in Patients With Advanced Solid Malignancies: a Phase I Exposure Escalation Study

Toxicity is graded according to National Cancer Institute Common Toxicity Criteria for Adverse Events version 4.0.

In an expansion cohort, 10 extra patients will be treated with high-dose, pulsatile sorafenib administrated at the maximum tolerated AUC. Before treatment and every 8 weeks during treatment CT thorax and abdomen will be performed and evaluated according to RECIST version 1.1.

Biopsies are only mandatory in the patients included in the expansion cohort. Concentrations are measured in biopsies using LC/MS/MS.

Finger punctures are only mandatory in de patients included in the expansion cohort. The results of the finger puncture will be compared with plasma and whole blood venous PK samples used for the AUC0-12h. The aim is to simplify full pharmacokinetic AUC sampling and to develop a method that can easily guide dose-adjustments based on sorafenib exposure.

Amsterdam UMC, location VUmc

Prof. Dr. MD PhD

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Prostatic Neoplasms

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

Abiraterone Acetate

Hormones

Hormone Antagonists

Cytochrome P-450 Enzyme Inhibitors

Abiraterone acetate standard dose

Abiraterone acetate escalated dose

Jerome ALEXANDRE, MD PhD

The purpose of this study is to test whether a dose escalation up to 2000 mg per day of abiraterone acetate is feasible and lead to disease stabilization in castration-resistant metastatic prostate cancer patients who experience disease progression within the first 6 months of abiraterone actetate at standard dose (1000 mg/d) and have a plasma abiraterone concentration below 8.5 ng/mL.

It is a non-comparative phase 2 study in which patients will be included in two successive steps. Patients with mCRPC will be included in the first step and treated with standard dose (1000 mg/day) of ABI + prednisone /prednisolone (10 mg/d) according to the summary of product characteristics and monitored for trough ABI plasma level each month for 3 months.

In the second step intrapatient ABI dose escalation (2000 mg/day) + prednisone/prednisolone (10 mg/d) will be realized for patients from the first step experiencing progressive disease within 6 months of ABI standard dose and with mean ABI plasma level during the first three months \< 8.5 ng/mL

Metastatic castration-resistant prostate cancer (mCRPC) causes approximately 307,500 deaths annually worldwide. mCRPC has been defined as a clinical state in which, despite suppressed circulating testosterone levels lower than 50 ng/dL, the androgen receptor axis is reactivated. This reactivation is mainly due to the multiple signaling mechanisms in prostate cancer cells along with their microenvironment.

Thus, research efforts aimed at identifying new strategies to inhibit the androgen receptor axis. Abiraterone acetate (ABI) is a first-in-class inhibitor of cytochrome (CYP) 17A1, a critical enzyme for extra-gonadal and testicular androgen syntheses. ABI has shown impressive efficacy in treatment of mCRPC. ABI plus low-dose prednisone was first shown to improve survival in mCRPC patients pre-treated with docetaxel, and the combination therapy has since been approved for this purpose. Moreover, ABI plus low-dose prednisone resulted in prolonged overall survival (OS) as compared with placebo plus prednisone in docetaxel-naive patients. In these patients, ABI was associated with a median progression free survival of 16 months and median overall survival of 35 months. However, around 40% of patients do not experience PSA response to ABI therapy at 3 months. This parameter has been consistently identified as a surrogate parameter of time to progression.

As ABI is an oral agent that is subject to both inter- and intra-individual variability in bioavailability, its pharmacokinetics might be a critical parameter for its anticancer activity.

Investigators first established a simple method to mesure plasma ABI concentration by HPLC. They then conducted a prospective observational study in which they aimed to explore the relationship between ABI trough concentration and PSA response in mCRPC patients and to identify the critical determinants for its activity.

73 mCRPC patients, in whom treatment with ABI was indicated, were recruited from December 2012 to December 2014 in the oncology department of Cochin Hospital in Paris, France. The plasma concentration of ABI was determined at baseline, and then one (M1), two (M2) and three (M3) months after treatment initiation. The primary study objective was to investigate the relationship between ABI mean plasma trough concentration (ABI Cmin) and PSA response. PSA response was defined as a PSA decline of at least 50% after receiving ABI for 3 months.

In multivariate analysis, ABI Cmin was the only factor independently associated with PSA response: OR=1.12, \[1.0-1.3\], P=0.03. Based on these results, they established an optimal threshold of ABI C min by building a ROC curve. The treshold value of 8.45 ng/mL was associated with a specificity of and sensitivity of 70% \[49-84\] and 79% \[63-81\], respectively.

As plasma ABI exposure is a key element of PSA response, it supports the exploration of benefits of a pharmacokinetically-guided dosing strategy for ABI.

In a phase I trial, the recommended dose of ABI was 1000 mg per day as a plateau of endocrine effects was reported at doses greater than 750 mg. However, to their knowledge, no data regarding the effect of ABI on tissue androgens are available, and no dose limiting toxicity was identified up to 2000 mg per day which support the rational of a dose-escalation strategy. In a phase 2 study, 41 mCRPC patients received 1000 mg twice a day of ABI (2000 mg/day) and the tolerance profile appeared similar than with lower dose.

In this phase II trial, investigators aim to confirm the preliminary results presented above in a larger population. Moreover, their objective is to test whether a dose escalation up to 2000 mg per day is feasible and lead to disease stabilization in progressive patients within the first 6 months of treatment.

Study of Dose Escalation of Abiraterone Actetate in Prostate Cancer

Intra-individual Dose Escalation of Abiraterone Acetate According to Its Plasma Concentration in Patients With Progressive Castration-resistant Metastatic Prostate Cancer

The proportion of patients who do not experience progressive disease (defined by PSA and/or radiographic progression) among those receiving ABI at a dose of 2000 mg / day + prednisone/prednisolone after failure of standard dose (1000 mg/day).

Incidence of underexposure to ABI (mean plasma concentration \< 8.5 ng/mL) in patients treated at standard dose (1000 mg / day) and identification of inter- and intra-individual variability factors of plasma levels of ABI

The adherence will be evaluated using two tools: the french version of the Girerd survey filled by the patient at 12 weeks and a personal treatment log book indicating daily times of drug administration

The adherence will be evaluated using two tools: the french version of the Girerd survey filled by the patient at 24 weeks and a personal treatment log book indicating daily times of drug administration

PSA response rate is defined as the proportion of patients with a decrease of ≥ 50% in the PSA concentration from the pretreatment baseline value, confirmed after ≥ 3 weeks by an additional PSA evaluation

Time from inclusion to progression or death in patients treated at escalated dose Disease progression is defined as either PSA or radiologic progression as described above

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Comparison of Standard Dose Alectinib to Alectinib in Adjusted Dose Based on Alectinib Bloodlevels	NCT05525338	Drug Monitoring Carcinoma, Non-... Lung Cancer Anaplastic Lymp... Anaplastic Lymp...	Alectinib	18 Years -	University Medical Center Groningen
Comparison of Standard Dose Alectinib to Alectinib in Adjusted Dose Based on Alectinib Bloodlevels	NCT05525338	Drug Monitoring Carcinoma, Non-... Lung Cancer Anaplastic Lymp... Anaplastic Lymp...	Alectinib	18 Years -	University Medical Center Groningen
Comparison of Standard Dose Alectinib to Alectinib in Adjusted Dose Based on Alectinib Bloodlevels	NCT05525338	Drug Monitoring Carcinoma, Non-... Lung Cancer Anaplastic Lymp... Anaplastic Lymp...	Alectinib	18 Years -	University Medical Center Groningen
Sorafenib Administered Using a High-dose, Pulsatile Regimen: a Phase I Exposure Escalation Study	NCT02636426	Neoplasms	sorafenib	18 Years -	Amsterdam UMC, location VUmc
Study of Dose Escalation of Abiraterone Actetate in Prostate Cancer	NCT03458247	Prostate Cancer	Abiraterone ace... Abiraterone ace...	18 Years -	Assistance Publique - Hôpitaux de Paris

Spots Global Cancer Trial Database for drug monitoring