The present study is aimed at identifying the specific routes of PM01183 excretion and elimination following its administration to patients with advanced tumors. Also, the study design may allow the identification and quantification, if possible, of…
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 and the time course of excretion of PM01183 in
adult patients with advanced cancer.
- To identify PM01183 metabolites formed in adult patients with
advanced cancer.
Secondary outcome
- To determine, if feasible, the concentration of as many PM01183 metabolites
as possible in body fluids.
- To evaluate, if possible, whether cytochrome P450 (CYP) and/or nuclear
receptors and drug transporter genotypes, responsible for PM01183 metabolism,
are related to major differences in the patient*s exposure to PM01183.
- To characterize the safety profile and feasibility of PM01183 in patients
with advanced cancer.
Background summary
PM01183 (lurbinectedin) is a novel synthetic tetrahydroisoquinoline
structurally related to ecteinascidins. PM01183 is a new Chemical Entity that
binds the DNA leading to the formation of DNA double-strand breaks (DSBs). The
binding to DNA is likely occurring in the minor groove region and induces
apoptosis and delayed progression through the cellular phase S/G2. PM01183 also
induces the specific degradation of transcribing RNA Pol II in several human
tumor cell lines.
In vitro, PM01183 demonstrated cytotoxic effects against a broad selection of
tumor types with half maximal inhibitory concentration (IC50) values in the
range of 1-10 nM. Although selectivity was also seen, a clustering of sensitive
tumors has not been identified. PM01183 also exhibited antitumor activity
against different murine models of xenografted human-derived tumor types.
PM01183 has been tested as a single agent or in combination with different
drugs in solid tumors; while antitumor activity in hematological tumors was
deemed negligible, PM01183 has shown activity in different solid tumors; some
of the most responsive tumor types were breast, small cell lung cancer (SCLC),
ovarian and endometrial cancer.
Based on current clinical data, the toxicity of PM01183 is predictable,
reversible and manageable. The most relevant toxicity is reversible
myelosuppression with a nadir occurring in the middle of the second week after
Day 1 infusion in an every-three-week cycle; overall, the incidence of febrile
neutropenia (FN) is below 20% in all ongoing Phase II trials.
Study objective
The present study is aimed at identifying the specific routes of PM01183
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 PM01183-related metabolites
formed in patients with advanced tumors.
Study design
This is a Phase I, open-label, uncontrolled, pharmacology study to characterize
the mass balance of PM01183 administered as 1 hour (h) intravenous (i.v.)
infusion every three weeks (q3wk) (one cycle = three weeks). The patient will
have to stay in the research unit up to a minimum of eight days. The first dose
of PM01183 will be radiolabeled with 14C1; subsequent doses of PM01183, up to a
maximum of eight cycles, will not be radiolabeled. PM01183 will be administered
to six evaluable patients for the primary endpoint and for a maximum of eight
cycles, while considered to be on the patient*s best interest or until: disease
progression (PD), unacceptable toxicity, intercurrent 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 study, more than two PM01183 dose reductions
due to AEs related to PM01183 (unless clear benefit has been documented and
always with the Sponsor*s agreement) or any other reason at the physician*s
judgment that precludes PM01183 continuation.
If the patient responds to treatment or achieves stable disease (SD) after
eight treatment cycles, treatment with PM01183 may continue outside this study
under a Compassionate Use Program at the same dose based on Investigator*s
decision and upon agreement with the Sponsor. Should the patient continue under
a Compassionate Use Program, the treating center must request authorization to
the relevant Health Authorities and notify the Sponsor in due time.
Intervention
This is a Phase I, open-label, uncontrolled, pharmacology study to
characterize the mass balance of PM01183 administered as 1 hour (h) intravenous
(i.v.) infusion every three weeks (q3wk) (one cycle = three weeks). The patient
will have to stay in the research unit up to a minimum of eight days. The first
dose of PM01183 will be radiolabeled with 14C1; subsequent doses of PM01183, up
to a maximum of eight cycles, will not be radio-labelled.
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 will
resolve soon after the patient stops taking PM01183. In some cases, they can be
serious, long lasting, or may not resolve. There is also a very small risk of
death.
During previous clinical studies, the following side effects related to PM01183
have been observed, usually moderate in intensity and reversible:
Very common (observed in >= 10% of patients):
- Anemia: A condition in which there is a lower-than-normal number of red blood
cells. It may result in symptoms like fatigue, palpitations, dizziness or
malaise. It might require red blood cell transfusions.
- Thrombocytopenia: A condition in which there is a lower-than-normal number of
platelets in the blood. It may result in easy bruising and excessive bleeding
from wounds or bleeding in mucous membranes and other tissues.
- Leukopenia: A condition in which there is a lower-than-normal number of white
blood cells (leukocytes) in the blood. It may increase the risk of infection.
- Neutropenia: A condition in which there is a lower-than-normal number of
neutrophils (a type of white blood cell). It may increase the risk of
potentially serious infections.
- Febrile neutropenia or neutropenic infection (severe infection while your
defenses are low, which may require hospitalization and intravenous antibiotic
therapy).
- Abnormal blood tests related to liver function. Usually not associated with
clinical symptoms.
- Nausea: A feeling of sickness or discomfort in the stomach that may come with
an urge to vomit.
- Vomiting.
- Fatigue: A condition marked by extreme tiredness and inability to function
due to lack of energy and strength, weakness.
- Diarrhea: Frequent and watery bowel movements.
- Constipation: A condition in which stool becomes hard, dry and difficult to
pass, and bowel movements do not happen very often. Other symptoms may include
painful bowel movements and feeling bloated, uncomfortable, and sluggish.
- Anorexia: An abnormal loss of appetite.
- Abdominal pain or discomfort.
Common (observed in >= 1% but < 10% of patients):
- Sores (stomatitis) in the mouth or inflammation within your digestive system
(mucositis) that may or may not be painful. Associated pain, if any, may result
in difficulty eating and drinking.
- Fever, chills or the sensation of temperature increase without fever.
- Headache.
- Dyspnea: Difficulty in breathing or shortness of breath.
- Weight loss.
- Liquid/fluid retention (edemas).
- Changes in the taste of food (dysgeusia).
- Peripheral neuropathy: Numbness or diminished sensation to pressure, which
may hamper normal daily activities such as dressing and undressing.
- Skin alterations: Such as rash and/or dry skin.
- Insomnia.
- Phlebitis or local infusion site reactions: Inflammation (redness, swelling,
pain, and heat) of a vein through which PM01183 is administered.
- Alopecia: Hair loss may occur; however, it is rarely extensive with PM01183
treatment alone; hair usually grows again after treatment discontinuation.
- Hiccups.
- Cough.
- Epistaxis (nose bleeds).
- Dyspepsia (indigestion or heartburn).
- An increased risk in the frequency and/or duration of common infections due
to a transient decrease in the ability of your immune system to fight
microorganisms (bacterial, virus, fungi). It may include infections such as
nasopharingitis, rhinitis, pneumonia, vaginitis and urinary infections, among
others.
- Hypotension (low blood pressure) with or without dizziness or malaise when
you change posture rapidly.
- Tachycardia (faster-than-normal heart rate) with or without palpitations
(feeling the beats of your heart).
- Musculoskeletal and/or joint pain.
- Changes in blood laboratory parameters (e.g., glucose, sodium, potassium,
magnesium, calcium, creatinine or uric acid) might be found in some cases and
may require specific management.
Uncommon but potentially serious adverse events (observed in approximately 1%
of patients):
- Pneumonia or pneumonitis (pulmonary infection or inflammation).
- Hypertension.
- Serious infections and/or sepsis (severe infection caused by microorganisms,
especially bacteria, in the blood or tissues), which require intravenous
antibiotic treatment and hospital admission for adequate management.
- Liver, renal, respiratory or multi organ impairment, which may require ICU
admission in order to adequately manage it.
- Cardiac impairment, which may result in liquid retention, less tolerance to
exercise and difficulty breathing, especially when lying in bed at night
(orthopnea).
- Dehydration.
- Jaundice (yellowish coloration of the skin, eyes and mouth with or without
darker coloration of urine).
- Muscular pain and/or weakness associated with abnormal muscular function
blood tests.
- Extravasation, the spread of the drug out of the vein during its
administration, may result in redness and pain in less serious cases or may
lead to serious tissue injury and ulceration, at least theoretically. Only one
patient has reported extravasation with PM01183, which resulted in a mild
reaction and was successfully treated with anti-inflammatory treatment without
requiring any surgery; the patient recovered completely without complications.
Some of these adverse events have been observed rarely; however, they might be
serious and some might even be life-threatening, and thus require prompt
hospitalization for adequate management. Most patients suffering these adverse
events have recovered completely with adequate treatment; however, there is a
risk that some patients may not fully recover or that recovery might take
several weeks.
Reproductive risks: Because the effects of PM01183 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.
Patient should not nurse (breast-feed) a baby while on this study and also for
six months after treatment discontinuation. Consequently, the patient and
their partner must agree on using a highly effective method of contraception to
avoid pregnancy throughout the treatment period and for six months after
treatment discontinuation. Highly effective methods of contraception include
intrauterine device (IUD), oral contraceptives, subdermal implant, bilateral
tubal occlusion or vasectomy.
Should pregnancy of their 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 (Madrid) 28770
ES
Avda. de los Reyes 1
Colmenar Viejo (Madrid) 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 minimum of eight days.
3) Patients with histologically/cytologically confirmed solid malignant disease (not recorded in the exclusion criteria), for which no standard therapy would reasonably be expected to result in cure or palliation.
4) Age >= 18 years.
5) Body Surface Area (BSA) >= 1.56 m2.
6) Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) <= 2.
7) Adequate organ function as reflected by:
a) Neutrophil count >= 1.5 x 10^9/L.
b) Platelet count >= 100 x 10^9/L.
c) Hemoglobin >= 9 g/dL (5.6 mmol/L).
d) Albumin >= 3.0 g/dL.
e) Calculated creatinine clearance (CrCL) >= 30 mL/min (using the Cockcroft and Gault*s formula).
f) Serum total bilirubin <= upper limit of normality (ULN) or, direct bilirubin < ULN if total bilirubin is > ULN and as long as total bilirubin <= 1.5 ULN.
g) Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) <= 3.0 x ULN.
h) Creatinine phosphokinase (CPK) <= 2.5 x ULN.
i) Left ventricular ejection fraction (LVEF) by echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan within normal range (according to
institutional standards).
8) Recovery to grade < 1 from any adverse event (AE) derived from previous treatment (alopecia of any grade and peripheral neuropathy [PN] grade < 2 are allowed).
9) Women of childbearing potential must have a negative serum pregnancy test before entering the study. Both women and men must agree to use a highly effective method of contraception throughout the treatment period and for six months after treatment discontinuation. Highly effective methods of contraception include intrauterine contraceptive device (IUD), oral contraceptives, subdermal implant, bilateral tubal occlusion or vasectomy.
10) Patients must carry a central venous catheter.
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) Limitation of the patient*s ability to comply with the treatment or follow-up
protocol.
e) Any other major illness that, in the Investigator*s judgment, will substantially
increase the risk associated with the patient*s participation in this study. This
includes but is not limited to, any significant disease such as significant
cardiovascular, pulmonary, endocrine, renal, neurological or psychiatric
disorder.
2) Symptomatic, progressive or corticosteroid-requiring documented brain metastases
or leptomeningeal disease (controlled and stable or non-progressing brain
metastases without steroids are allowed).
3) Patients with the following tumors:
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) Limitation of the patient*s ability to comply with the treatment or follow-up protocol.
e) Any other major illness that, in the Investigator*s judgment, will substantially increase the risk associated with the patient*s participation in this study. This includes but is not limited to, any significant disease such as significant cardiovascular, pulmonary, endocrine, renal, neurological or psychiatric disorder.
2) Symptomatic, progressive or corticosteroid-requiring documented brain metastases or leptomeningeal disease (controlled and stable or non-progressing brain metastases without steroids are allowed).
3) Patients with the following tumors:
a) Colorectal cancer.
b) Primary CNS tumors.
4) Women who are pregnant or breast-feeding.
5) High transfusion requirements (> two packages or units of red blood cells and/or one platelet transfusion) within 30 days prior to inclusion in the study.
6) Chemotherapy, radiotherapy, immunotherapy or molecular targeted cancer therapy within four weeks prior to the start of PM01183 administration (six weeks for mitomycin C, nitrosourea therapy, temozolomide and other minor groove binders). This restriction does not apply to steroids and/or
bisphosphonates.
7) Major surgical procedure within the last eight weeks prior to the first PM01183 administration.
8) Wide-field radiotherapy (> 25% of bone marrow [BM] reserve) within 12 months prior to administration of PM01183 (pelvic radiation is considered 25% BM reserve).
9) Known hypersensitivity to any of the excipients used.
10) Participation in another clinical study 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. Total radioactivity exposure from the
current study and any previous 14C study must not exceed 5 mSv.
11) Tumoral or other conditions affecting the gastrointestinal (GI) tract or near the GI tract expected to induce total or partial occlusion of the GI transit.
12) Presence or history of inflammatory bowel disease or digestive tract fistulae.
13) Significant constipation (defined as < one deposition every two days or need of laxatives).
14) Any condition resulting in clinically evident obstruction of the urinary tract.
15) A history of 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) Consumption of Hypericum perforatum (Saint John*s wort) herbal extracts from at least seven days prior to the first dose of study medication.
18) History of alcoholism.
19) Any condition that could interfere with the accurate assessment and recovery of radiocarbon 14C.
20) Prior allogenic, syngeneic or autologous BM transplantation or stem cell transplantation.
21) 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 | EUCTR2016-000800-27-NL |
| CCMO | NL59571.031.16 |