Clinical Trial Results:
Phase I/II intra-patient dose escalation study of vorinostat in children with relapsed solid tumor, lymphoma or leukemia
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Summary
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EudraCT number |
2007-005537-11 |
Trial protocol |
DE |
Global end of trial date |
24 Mar 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
01 Feb 2019
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First version publication date |
01 Feb 2019
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Other versions |
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Summary report(s) |
Vorinostat_CTR |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
NCT-2007-11-02-1004
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01422499 | ||
WHO universal trial number (UTN) |
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Sponsors
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Sponsor organisation name |
University of Heidelberg
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Sponsor organisation address |
Im Neuenheimer Feld 672, Heidelberg, Germany, 69120
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Public contact |
Commercial Director Mrs. Irmtraut Gürkan, University of Heidelberg, Irmtraut.Guerkan@uni-heidelberg.de
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Scientific contact |
Clinical Trial Unit, Hopp-Kindertumorzentrum Heidelberg (KiTZ)
, 06221 567294, ruth.witt@kitz-heidelberg.de
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
27 Feb 2018
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
24 Mar 2017
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
Primary:
To determine a safe dose recommended (SDR) for the routine application of oral vorinostat (involving dose escalation) in children and adolescents (3-18 years) with relapsed/refractory solid tumor, lymphoma or leukemia. A SDR is defined as the highest dose with no ≥ grade 3 toxicity according to CTC criteria in no more than 1/50 patient in this study (for details refer chapter 2.1).
Secondary:
To determine the
-pharmacokinetics and the distribution of individual maximum tolerated doses (MTD), which is the maximum dose with no grade 3 or 4 toxicity according to CTC criteria.
-antitumor effectiveness of vorinostat as measured by treatment response rate. Response will be evaluated in each patient three months after start of treatment with the individual MTD.
- association of the histone deacetylase (HDAC)-inhibiting activity with the dose administered, toxicity, and treatment response.
-feasibility and safety
- duration of response in responding patients.
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Protection of trial subjects |
Continuous risk assessment: The toxicity associated with the starting dose chosen in this study will be continuously monitored using a Bayesian criterion with a noninformative prior and a binomial-beta model for the toxicity rate r. If, for the second and following patients, the posterior probability that r>10% is 90% or higher, the starting dose used for the following patients will be lowered by 50mg/m2. This decision process is repeated, i.e., it is applied to the lowered starting dose in an analogous way.
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Background therapy |
During vorinostat dose escalation and 3 months maintenance treatment at individual MTD, patients will receive a routine pediatric physical examination including vital signs, body weight, concomitant treatment and AEs once per week. Blood will be taken once per week for full blood counting including differential, serum electrolytes, glucose, AST, ALT, protein, bilirubin, LDH and creatinine. An ECG will be done at day 8 and 15 of vorinostat treatment and when the MTD is reached, to rule out QT-changes. Collection of blood and cerebrospinal fluid for pharmacokinetic evaluation will be done after 1 week of vorinostat treatment and at the time when individual MTD is established. This material will be sent to the reference pharmacokinetic laboratory. 3 months after start of vorinostat treatment at MTD, response will be evaluated by MRI imaging using the RECIST criteria and bone marrow cytology if indicated. In patients with neuroblastoma, a MIBG scan will also be performed and response additionally evaluated according to the International Neuroblastoma Response Critera (INRC). Furthermore, full blood counting including differential, serum electrolytes, glucose, AST, ALT, protein, bilirubin, LDH, creatinine, and tumor marker (if indicated). Biomarker (IL-6, IL-10, BMP4) will be determined at month 1 and 3 of MTD. Patients showing CR, PR, or SD on response evaluation will continue with vorinostat treatment for a maximum of 9 months or until disease progression. In these patients, tumor manifestations (MRI, tumor markers, bone marrow if indicated, MIBG) will be determined every three months until end of treatment (EOT). During this time, patients will receive routine pediatric oncological care including physical examination including body weight, full blood counting including differential, serum electrolytes, glucose, AST, ALT, protein, bilirubin, LDH and creatinine every 2 weeks. | ||
Evidence for comparator |
no comparator | ||
Actual start date of recruitment |
11 May 2012
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Germany: 50
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Worldwide total number of subjects |
50
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EEA total number of subjects |
50
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
26
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Adolescents (12-17 years) |
23
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Adults (18-64 years) |
1
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Recruitment of patients started in October 2011 and was continue until 50 patients will be enrolled. | ||||||||||||||||||||
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Pre-assignment
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Screening details |
After obtaining patient informed consent, screening evaluations and procedures must be performed within 14 days prior to initiating study drug treatment. | ||||||||||||||||||||
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Period 1
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Period 1 title |
overall trial (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||||
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Arms
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Arm title
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single-arm | ||||||||||||||||||||
Arm description |
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Arm type |
Experimental | ||||||||||||||||||||
Investigational medicinal product name |
Vorinostat study
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Investigational medicinal product code |
0006-0568-40
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Other name |
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Pharmaceutical forms |
Capsule, Capsule, hard
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Routes of administration |
Oral use
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Dosage and administration details |
Starting dose will be 180 mg/m²/d in children ≥ 3 years. The drug is provided as suspension of 50mg/ml or as capsules of 100 mg vorinostat and will be centrally distributed by the Department of Pharmacy, University of Heidelberg. A dosing schedule of vorinostat suspension or 100mg capsules based on body surface area is provided in the appendix section of the protocol.
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Baseline characteristics reporting groups
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Reporting group title |
overall trial
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Reporting group description |
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End points reporting groups
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Reporting group title |
single-arm
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Reporting group description |
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End point title |
Dose Limiting Toxicity [1] | ||||||||||||||||||||||||||||
End point description |
Number of Patients with DLT N at respective dose of Vorinostat (mg/m2/day) (N=50)
Number of Patients with at least one DLT observed
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End point type |
Primary
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End point timeframe |
dose escalation scheme was changed from 2 weekly to weekly
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The primary endpoint was the determination of a safe dose recommended (SDR) for the routine application of oral Vorinostat in children and adolescents. SDR was defined as the highest dose with no DLT (Dose Limiting Toxicity) in no more than 1/50 patient. According to this definition the SDR was 130 mg/m2/day. Disorders related to the Blood and lymphatic system were the most frequently reported DLTs. |
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Attachments |
Dose Limiting Toxicity(Preferred Terms) by Dosage DLT observed by Dosage - Safety Set |
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Adverse events information
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Timeframe for reporting adverse events |
All AEs reported by the subject or detected by the investigator, will be collected during the trial and must be documented on the appropriate pages of the CRF. AEs must also be documented until the completion of the trial
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
20.1
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Reporting groups
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Reporting group title |
overall trial
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Reporting group description |
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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18 Apr 2013 |
The patient cohort enrolled in this trial turned out to have progressive disease under first/secondline therapy predominantly. These patients require immediate onset of vorinostat treatment in order to increase the likelihood of therapy response before fatal outcome of the disease. Other pediatric relapse protocols (i.e. HIT REZ 2005 trial) therefore have two week time interval to previous treatment as inclusion criterion. Changing the inclusion criterion “1 months interval from previous treatment” to two weeks has a safety and an efficacy response evaluation aspect.
Safety: A 2 week interval is sufficiently long enough to ensure wash out of previous drug treatment, which in the case of valproic acid will additionally be ensured by determination of plasma drug levels. Also, the inclusion criteria “sufficient bone marrow, liver, kidney function etc.” ensures patient safety by enrolling only patients that show recovered organ functions from previous treatments.
Efficacy: Disease progression under previous treatment already proofs non-efficacy of previous treatment modality ensuring that response assessment of the study drug does not interfere with effects from previous treatments. |
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12 Jun 2014 |
Up to now we have included 35 patients into the trial and observed 3 responses. All responses occurred at very high doses (530 and 580mg/d/m²) and no responses at lower doses. The almost exclusive dose limiting toxicity (DLT) observed were reversible thrombocytopenia. After discontinuation of treatment, all side effects and symptoms (thrombocytopenia and other changes in blood counts, gastrointestinal symptoms, fatigue) completely resolved within 1 week which corresponds with observations in the literature (see protocol p. 21). In addition, preliminary PK analyses in the present trial demonstrate no accumulation of vorinostat in plasma and rapid clearance of the drug within 8h also at higher doses. Most patients haven’t reached higher dosage due to disease progression or DLT. Importantly, the occurrence of toxicities showed no correlation with the dose received. To give patients with poor life expectancy a chance to reach effective doses in a shorter time period without additional risk, dose escalation scheme was changed from 2 weekly to weekly. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/22915450 |
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