The present study is aimed at identifying the specific routes of plitidepsin excretion and elimination following its administration to patients with advanced tumors. Also, the study design may allow the identification and quantification, if possible…
ID
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
• To obtain the mass balance of plitidepsin in adult patients with advanced
cancer.
• To identify the metabolites of plitidepsin formed in adult patients with
advanced cancer.
Secondary outcome
• To determine, if possible, the concentration of as many plitidepsin
metabolites as feasible in body fluids.
• To assess, if possible, whether cytochrome P450 (CYP) and/or UDP
glucoronosyltransferase (UGT) enzyme genotypes, responsible for the metabolism
of plitidepsin, are related to major differences in the availability of
plitidepsin.
• To characterize the safety profile and feasibility of plitidepsin in patients
with advanced cancer.
Background summary
This is an open-label, non-randomized, pharmacological study to characterize
the mass balance of plitidepsin administered as a 3-hour (h) intravenous (i.v.)
infusion fortnightly (Day [D] 1 and D15) every four weeks (q4wk). The first
administered dose of plitidepsin will be radiolabeled with 14C; additional
doses of plitidepsin will not be radiolabeled. Plitidepsin will be administered
to six evaluable patients for a maximum of six cycles or until disease
progression (PD), unacceptable toxicity, consent withdrawal or while it is
considered to be in their best interest.
Study objective
The present study is aimed at identifying the specific routes of plitidepsin
excretion and elimination following its administration to patients with
advanced tumors. Also, the study design may allow the identification and
quantification, if possible, of any potential plitidepsin-related metabolite
formed in patients with advanced tumors.
Study design
A total of six evaluable patients are expected to be treated with at least one
plitidepsin infusion.
Patients will receive the study medication(s) for a maximum of six cycles and
while it is considered to be in their best interest. Specifically, treatment
will continue for a maximum of six cycles or until:
• PD.
• Unacceptable toxicity.
• Inter-current illness of sufficient magnitude to preclude safe continuation
of the study.
• Patient*s refusal and/or non-compliance with study requirements.
• A protocol deviation with an effect on the risk/benefit ratio of the clinical
trial.
• Dose omissions >= 2 plitidepsin infusions due to AEs related to plitidepsin.
Intervention
A total of six evaluable patients are expected to be treated with at least one
plitidepsin infusion.
Patients will receive the study medication(s) for a maximum of six cycles
For the first cycle radiolabeled plitidepsin will be administered.
Study burden and risks
Everyone taking part in the study may have side effects and will be carefully
watched. However, doctors do not know all side effects that may happen. Not all
patients will experience them and they may be mild or very serious. Many of
them will resolve soon after the patient will stop taking Aplidin®. In some
cases, they can be serious, long lasting, or may not resolve. There is also a
very small risk of death.
Based on experience from previous clinical trials, the occurrence of several
side effects related to Aplidin® have been observed, usually moderate in
intensity and reversible:
Likely (observed in >= 10% of patients):
* The most important side effect of Aplidin® concerns the muscles. It consists
either of several short periods of muscular cramps or long-lasting muscular
pain, mostly over shoulders and hips. Usually, these effects are not severe and
do not need any treatment. Sometimes, it can be associated with muscular
weakness and/or changes in blood tests (indicating muscular damage) that,
exceptionally, can be severe. After stopping Aplidin® infusions, these effects
usually resolve within two to three weeks.
* It is also very common to have some degree of transient fatigue, loss of
appetite (anorexia), nausea and vomiting, diarrhea, and changes in blood tests
related to liver function (blood transaminases, indicating liver damage).
Usually they do not cause any symptom and resolve completely.
Common (observed in >=1% but in less than 10% of patients):
* Aplidin® injections tend to produce local irritation when administered into a
blood vessel in the arm or hand. Therefore, infusion into a larger vein through
a small subcutaneous venous access device that is permanently implanted is
better; this procedure consists of minor surgery, usually with local
anesthesia. This catheter is widely used in patients receiving other types of
chemotherapy. The risks of a subcutaneous port are infection, clots and,
rarely, kinks or rupture; if the needle is not properly inserted, fluids can
leak into the tissue around the port. Occasionally, acute local pain over the
catheter area appears during the administration of Aplidin®, or shortly
afterwards. If your doctors should consider that a permanent catheter is not
appropriate for you, it will be possible to infuse Aplidin® through a vein in
the arm or hand, using a higher volume of fluids for diluting the drug, as it
has been recently demonstrated that the frequency of complications between both
infusion types (catheter versus peripheral vein) is not significantly different.
* Allergic reactions consisting of fever, shivering, skin rash and even
difficulty to breathe may occur. Severe reactions have been observed in less
than 5% of the patients treated to date. If severe allergic reactions occur,
you will not be able to receive any further infusions of Aplidin®.
* Occasionally, some patients may have gastrointestinal disturbances, such as
constipation, heartburn, inflammation of the mouth, abdominal pain, and taste
disturbances.
Rare (observed in less than 1% of patients) but potentially serious:
* Severe effects on the blood cells are uncommon. Mild decreases in the number
of white blood cells and platelets have been observed. However, there is always
a possibility of having a severe decrease in the number of all blood cells,
which can make you more vulnerable to have infections or bleeding.
* Other events that have been less frequently observed in patients in whom
Aplidin® was administered are: changes in the levels of glucose in the blood,
renal function impairment, cardiac impairment (mainly arrhythmia, palpitations
and pulse acceleration), and blood clots in veins or lung embolism. Very
infrequently (less than 1% of patients), Aplidin® may induce irreversible
toxicities that may eventually have a fatal outcome.
Reproductive risks: Because the effects of Aplidin® during pregnancy have never
been addressed formally in animals or in humans, we cannot exclude at this time
whether its use may be harmful or deleterious in this situation. Therefore, the
patient should not become pregnant or have a baby while participating in this
study, and for at least six months after discontinuation of study treatment.
the patient should not nurse (breast-feed) a baby while on this study and also
for six months after treatment discontinuation. Consequently, the patient and
his/her partner must agree on using an effective contraception method to avoid
pregnancy during the course of the study and for six months after
discontinuation.
Should pregnancy of the female partner occur, she will be asked to sign a
release of information form to allow the collection of information on the
progress of the pregnancy and its outcome. The study doctor will make this
information available to the Sponsor of the study for safety monitoring
(follow-up).
Avda de los Reyes 1
Colmenar Viejo (Mardrid) 28770
ES
Avda de los Reyes 1
Colmenar Viejo (Mardrid) 28770
ES
Listed location countries
Age
Inclusion criteria
1) Voluntarily signed and dated written informed consent (IC), obtained from the patient prior to any specific study procedure.
2) Patient*s availability to stay in the research unit up to a maximum of ten days.
3) Patients with histologically/cytologically confirmed diagnosis of advanced cancer (i.e., solid tumors, lymphomas and multiple myelomas) refractory to standard therapy or for whom no standard therapy exists or patients who have refused standard therapy.
4) Age >= 18 years.
5) Body Surface Area (BSA) >= 1.4 m².
6) Eastern Cooperative Oncology Group (ECOG) performance status (PS) score < 2.
7) Adequate bone marrow, renal, hepatic, and metabolic function (assessed <= 7 days before inclusion in the study):
a) Platelet count >= 100 x 109/L, hemoglobin >= 5.58 mmol/L and absolute neutrophil count (ANC) >= 1.0 x 109/L.
b) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <= 3 x the upper limit of normal (ULN).
c) Total bilirubin <= 1.0 x ULN or direct bilirubin <= 1.0 x ULN when total bilirubin is above the ULN.
d) Calculated creatinine clearance (CrCl) >= 45 mL/minute (by means of Cockcroft and Gault*s formula).
e) Creatine phosphokinase (CPK) <= 2.5 x ULN.
f) Albumin >= 30 g/L.
8) Recovery to grade <= 1 from any adverse event (AE) derived from previous treatment (excluding alopecia of any grade and peripheral neuropathy grade <= 2).
9) Left ventricular ejection fraction (LVEF), by echocardiogram (ECHO) or multiple-gated acquisitions (MUGA) >= 50%.
10) Women of childbearing potential must have a negative serum pregnancy test before study entry. Both men and women must agree to use a medically acceptable method of contraception throughout the treatment period and for six months after discontinuation of treatment. Acceptable methods of contraception include: intrauterine contraceptive device (IUD), oral contraceptives, subdermal implant and double barrier (condom with a contraceptive sponge or contraceptive suppository).
Exclusion criteria
1) Concomitant diseases/conditions:
a) History or presence of unstable angina, myocardial infarction, valvular heart disease or congestive heart failure within the last 12 months.
b) Symptomatic arrhythmia or any arrhythmia requiring ongoing treatment, and/or prolonged QT-QTc grade>= 2.
c) Active uncontrolled infection.
d) Myopathy or any clinical situation that causes significant and persistent elevation of CPK (> 2.5 x ULN in two different determinations performed one week apart).
e) Limitation of the patient*s ability to comply with the treatment or follow-up protocol.
f) Any other major illness that, in the Investigator*s judgment, will substantially increase the risk associated with the patient*s participation in this study.
2) Symptomatic, progressive or corticosteroid-requiring documented brain metastases or leptomeningeal disease. Controlled and stable brain metastases without steroids are allowed.
3) Patients diagnosed with CNS tumors or leukemia.
4) Women who are pregnant or breast-feeding.
5) High transfusion requirements (> 2 packages of red blood cells and/or 1 platelet transfusion) in the 30 days prior to inclusion in the study.
6) Chemotherapy, radiotherapy, immunotherapy, or molecular targeted cancer therapy within the previous four weeks of the given drug, prior to the start of trial medication or concomitantly within this trial. This restriction does not apply to steroids and bisphosphonates.
7) Major surgical procedure within the last eight weeks prior to the start of trial medication.
8) Clinically relevant non-malignant disease, which in the Investigator's opinion would exclude the subject from the trial, such as significant cardiovascular, pulmonary, endocrine, renal and neurological disease or psychiatric disorder.
9) Known hypersensitivity to any of the excipients used.
10) Participation in another clinical trial or concomitant treatment with any investigational product in the 30-day period prior to inclusion in the study and/or participation in a 14C study within the last six months prior to screening for the current study. The total radioactivity exposure from the current study and the previous 14C study must be less than 5 mSv.
11) Tumoral or other conditions affecting the gastrointestinal tract or close to the gastrointestinal tract that may be expected to induce total or partial occlusion of the gastrointestinal transit.
12) Presence of, or history of, inflammatory bowel disease or digestive tract fistulae.
13) Significant constipation (defined as <1 deposition every 2 days or need for laxatives)
14) Any condition resulting in clinically evident obstruction of the urinary tract.
15) A history or regular use of tobacco- or nicotine-containing products within three months prior to screening.
16) Consumption of red wine, Seville oranges, grapefruit or grapefruit juice from two days prior to the first dose of study medication.
17) History of alcoholism.
18) Any condition that could interfere with the accurate assessment and recovery of radiocarbon [14C].
19) Unwillingness or inability to follow the procedures outlined in the protocol.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2013-005011-26-NL |
| CCMO | NL49614.031.14 |