Primary objective· • To investigate the safety and tolerability and establish either the dose of KU-0059436 which causes inhibition of PARP in combination with an active dose of carboplatin or the maximum tolerated dose (MTD) of KU-0059436 in…
ID
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety data, including laboratory parameters and adverse events, will be
collected for all patients in order to determine the toxicity, reversibility of
toxicity, and dose limiting toxicity of orally administered KU-0059436 when
given in combination with i.v. carboplatin, in combination with i.v. paclitaxel
and carboplatin and in combination with i.v. paclitaxel.
Secondary outcome
Although tumour response is not the primary endpoint of this study, patients
with measurable disease will be assessed by RECIST criteria. Pharmacokinetic
data will also be collected.
Background summary
Preliminary results from an ongoing phase I study (EudraCT 2005-001435-29) have
illustrated that KU-0059436 can effectively inhibit the PARP enzyme.
Inhibition of PARP affects the repair of DNA damage. Whilst the ability to
repair DNA is desirable in most cases, in cancer therapy it may enable tumour
cells to recover from chemotherapy thus preventing effective treatment.
The potential to effectively inhibit the DNA repair in tumour cells following
cytotoxic agents may potentiate the effects of chemotherapy and lead to better
responses in some tumours. This concept is supported by the preclinical
studies.
Carboplatin exerts its cytotoxic and therapeutic effect primarily by forming
intrastrand and DNA adducts with adjacent guaninine residues in tumour cell
DNA, thereby inhibiting tumour growth.
A combination of carboplatin with KU-0059436 may be an effective anti-cancer
combination and warrants further investigation.
The paclitaxel / carboplatin combination is standard treatment for advanced
ovarian cancer. It has also been found to give a high response rate in patients
with metastatic / recurrent triple negative breast cancer, including patients
with prior exposure to taxanes and those with large volume disease. It is
therefore expected that the addition of paclitaxel to the KU-0059436 and
carboplatin administration will lead to the best possible clinical outcome for
these patients.
Study objective
Primary objective·
• To investigate the safety and tolerability and establish either the dose of
KU-0059436 which causes inhibition of PARP in combination with an active dose
of carboplatin or the maximum tolerated dose (MTD) of KU-0059436 in combination
with paclitaxel / carboplatin and validate this in specific patient populations.
Secondary objectives·
• To identify the Dose Limiting Toxicity (DLT) of the combination of KU-0059436
and paclitaxel / carboplatin.·
• To determine the plasma pharmacokinetic profile of:
- KU-0059436 alone
- KU-0059436 in combination with carboplatin
- KU-0059436 in combination with paclitaxel / carboplatin
- KU-0059436 in combination with paclitaxel
• To investigate the pharmacodynamic profile over time in surrogate tissue of
KU-0059436 when given in combination with a paclitaxel/carboplatin (TC) doublet.
• To determine the safety profile of KU-0059436 in combination with paclitaxel
given at two dose levels.
To enable a preliminary assessment of the anti-tumour activity of KU-0059436
when given in combination with paclitaxel / carboplatin in specific patient
populations.
• To determine the safety and tolerability profile of the KU-0059436
Melt-Extrusion (tablet) formulation in combination with a paclitaxel /
carboplatin (TC) doublet.
Exploratory objective·
•To investigate exploratory biomarkers in whole blood, serum, urine and tumour
biopsies (on treatment and historical) to ascertain if there are any which
differentiate treatment effects, and to investigate their correlation with
disease progression/response to therapy or an improved understanding of the
disease.
Study design
This is an open-label multi-centre, phase I study of KU-0059436 when
administered orally in combination with carboplatin and in combination with
paclitaxel / carboplatin.
The study consists of a dose escalation phase to establish the appropriate dose
to be used in the dose expansion phase. The dose expansion phase of the study
will establish the safety and tolerability of the established dose.
The dose escalation phase consists of 3 parts:
Part I: KU-0059436 (continuous) + carboplatin
Part IIa: KU-0059436 (continuous) + paclitaxel / carboplatin
Part IIb: KU-0059436 (continuous) + paclitaxel
Part III: KU-0059436 (discontinuous) + paclitaxel / carboplatin - this part of
the study will only be initiated if a dose of carboplatin AUC 5 or above cannot
be achieved in part II.
Part IV: KU-0059436 (discontinuous) + paclitaxel / carboplatin - this part of
the study will only be initiated if the 1st expansion dose is not appropriate
for futher phase II/III studies.
Intervention
Dose escalation phase:
Part I:
Cycle 1 will be of 28 days* duration. KU-0059436 will be administered twice
daily for 28 days. Carboplatin will be administered on day 8. All subsequent
cycles will be of 21 days* duration with carboplatin being administered on day
1 at least 1 hour after the patient has taken their KU-0059436 capsules.
Starting dose is 50 mg bd KU-0059436 and 4 mg/ml.min Carboplatine
Part IIa:
Cycle 1 will be of 28 days' duration and all subsequent cycles will be of 21
days' duration. KU-0059436 will be administered twice daily for 28 days.
Paclitaxel, followed by carboplatin, will be administered on day 8, at least 1
hour after the patient has taken their KU-0059436 capsules. All subsequent
cycles, KU-0059436 will be administered twice daily for 21 days, with
paclitaxel and carboplatin administration on day 1. In case 50 mg KU-0059436
twice daily is not tolerated then 50 mg KU-0059436 once daily may be tested in
a dose escalating scheme.
Starting dose of KU-0059436 and carboplatin is the maximum tolerated dose of
Part I. Starting dose of paclitaxel is 90 mg/m2.
Part IIb:
Cycle 1 will be of 35 days* duration. KU-0059436 will be administered twice
daily for 28 days. Paclitaxel will be administered on days 8, 15 and 22, at
least 1 hour after intake of the KU-0059436 capsules. All subsequent cycles
will be of 28 days* duration with paclitaxel being administered on day 1, 8 and
15 at least 1 hour after the patient has taken their KU-0059436 capsules
Starting dose is 100 mg bd KU-0059436 and 80 mg/m2 paclitaxel
Part III:
Each cylce will be of 21 days' duration. KU-0059436 capsules or tablets will be
administered once or twice daily for a certain number of days in the cycle,
followed by a rest period. Paclitaxel and carboplatin will be administered on
day 1, at least 1 hour after the patient has taken their KU-0059436
capsule/tablet.
Starting dose of KU-0059436 and paclitaxel is the maximum tolerated dose of
Part II. Starting dose of carboplatin will be 4 mg/ml.min.
Part IV: (will only be initiated if the 1st expansion dose is not appropriate
for further phase II/III studies)
Each cylce will be of 21 days' duration. KU-0059436 capsules or tablets will be
administered once or twice daily for a certain number of days in the cycle,
followed by a rest period. Paclitaxel and carboplatin will be administered on
day 1, at least 1 hour after the patient has taken their KU-0059436
capsule/tablet. Other discontinuous KU-0059436 schedules consisting of
KU-0059436 (capsule or tablet) administered for any pre-defined number of days,
up to 20 days, within each treatment cycle may be explored with carboplatin and
paclitaxel.
Starting dose of KU-0059436 will be determined by the Investigators and the
sponsor. Starting dose of carboplatin will be 4 mg/ml.min and of paclitaxel
will be 175 mg/m2.
Expansion Phase (following part III and/or part IV of the study):
Each cycle will be of 21 days' duration. The maximum tolerated dose established
in Part III will be selected for dose expansion.
In the event that carboplatin/paclitaxel is permanently discontinued on the
basis of carboplatin/paclitaxel related toxicity or patients have completed the
required treatment course, treatment with KU-0059436 may continue alone, at the
discretion of the Investigator and in consultation with the sponsor. The
optimal recommended monotherapy dose is 400 mg b.d. continuously.
Study burden and risks
Screening procedures: medical history, physical exam, vital signs (pulse, blood
pressure, respiratory rate, temperature), ECOG preformance status, ECG, CT scan
or NMRI of the thorax and abdomen, chest X-ray, hematology and biochemistry
test, biomarker, urine test and pregnancy test
Before start of chemotherapy: hematology and biochemistry test, physical exam,
urine test, adverse event assessment and concomitant medication. During
treatment CT scan or NMRI of the chest and abdomen will done every 2 cycles.
During cycle 1 the patient will come weekly to the clinic (day 8, 15 and 22)
for hematology and biochemistry test, adverse event assessment and concomitant
medication. Patients participating in part IIb will need to come twice a week
for hematology and biochemistry tests.
Additional pharmacokinetic blood samples will be taken on day 1, 4 and 8. Also
two pharmacokinetic blood samples will be taken on day 9 (24 hours after
paclitaxel and/or carboplatin administration) and on day 10 (48 hours after
Carboplatin administration).
In part III pharmacokinetic blood samples will be taken before treatment on day
1 of cycle 1 and periodically over about 8 hours. Depending on the treatment
schedule, further pharmacokinetic samples may be taken on day 2 and day 8 of
cycle 1. Certain treatment schedules may result in a sample being taken on day
18. In that case no samples will be taken on day 2 and day 8.
Pharmacodynamic blood samples will be taken before treatment on day 1 of cycle
1 and periodically over about 4 hours on day 1 of cycle 1. Depending on the
treatment schedule, further pharmacodynamic blood sampling may occur on days 2,
8, 10-12 and 15 of cycle 1 and before treatment on day 1 of cycle 2. Certain
treatment schedules may result in a sample being taken on day 18. In that case,
no pharmacodynamic samples will be taken on days 2 and 8.
During the subsequent cycles the patient will need to come weekly to the clinic
(day 8 and 15) for hematology and biochemistry test, adverse event assessment
and concomitant medication.
At the last visit: physical exam, vital signs, ECOG, ECG, CT scan or NMRI of
the chest and abdomen, hematology and biochemistry test, urine test, adverse
event assessment and concomitant medication.
Building 411A, Floor 4
Sodertalje S-151 85
SE
Building 411A, Floor 4
Sodertalje S-151 85
SE
Listed location countries
Age
Inclusion criteria
1. Full informed consent
2. Dose escalation phase: male or female patients with a histologically or cytologically diagnosed malignant solid tumour
Non-randomised dose expansion phase: female patients with histologically or cytologically diagnosed metastatic triple-negative breast cancer (platinum naive) and female patients with histologically or cytologically diagnosed ovarian cancer, where further treatment with platinum based chemotherapy is indicated.
Randomised dose expansion phase: female patients with histologically or cytologically diagnosed measurable metastatic breast cancer and female patients with histologically or cytologically diagnosed measurable ovarian cancer, where further treatment with platinum based chemotherapy is indicated.
3. Adequate bone marrow, hepatic and renal function, including the following:
a. hemoglobin >= 10.0 g/dl, ANC >= 1500x10 6/l, platelets >= 100.000x10 6/l;
b. total bilirubin <= 1,25 x upper normal limit
c. AST (SGOT), ALT (SGPT) ,= 2,5 x upper normal limit
d. creatinine <= 1,5 x upper normal limit
4. Creatinine clearance (Cockcroft-Gault) within normal range (> 60 ml/min)
5. Age >= 18 years
6. PS <= 2
7. Female patients with reproductive potential must have a negative urine or serum pregnancy test within 7 days of start of study.
8. The patient is willing to comply with the protocol for the duration of the study, including hospital visits for treatment and scheduled follow-up visits and examinations.
9. Life expectancy of at least 12 weeks.
Exclusion criteria
1. Any chemotherapy, radiotherapy (except for palliative reasons), endocrine therapy or immunotherpay within 4 weeks prior to study entry (or a longer period depending on the defined characteristics of the agents used). Patients may continue the use of biphosphonates for bone disease and corticosteroids provided the dose is stable before and during the study. Heavily pre-treated patients (> 2 courses of previous chemotherapy and/or extensive irradiation leading to bone marrow deficiency) will be excluded from the study.
Bone marrow deficiency is defined as the occurence of one or other of the events below:
- treatment delay in previous chemotherapy courses due to bone marrow toxicity.
- previous chemotherapy courses requiring growth factor support.
2. Dose escalation phase: more than 2 previous courses of platinum-containing chemotherapy
Non-randomised dose expansion phase: more than 2 courses of platinum-containing chemotherapy, except for metastatic triple negative breast cancer patients who must have had no previous platinum-containing chemotherapy.
Randomised dose expansion phase: patients where platinum therapy is not indictaed
3. Major surgery within 4 weeks of starting the study and patients must have recovered from the effects major surgery.
4. Patients with an active second primary cancer, except adequately treated basal skin cancer or carcinoma in-situ of the cervix. An active second primary cancer is defined as one with a disease free interval of <3 years
5. Pre-existing peripheral neuropathy > grade 1.
6. Any co-existing medical condition that in the investigator's judgement will substantially increase the risk associated with the patient's participation in the study.
7. Psychiatric disorders or altered mental status precluding understanding of the informed consent process and/or compliance with the study protocol.
8. Symptomatic or known brain metastases.
9. Gastrointestinal disorders likely to interfere with absorption of the study drug.
10. Patients who are unable to swallow oral medication.
11. Patients with a history of allergic reactions to carboplatin, platinum containing compounds or mannitol.
12. Persistent toxicities (grade 2 or greater) from any cause.
13. Pregnant or breast-feeding women.
14. Patients with hepatic disease, e.g. patients with known serologically positive Hepatitis B or Hepatitis C as they may be more at risk of toxicity from KU-0059436.
15. Immunocompromised patients, e.g. patients who are known to be serologically positive for HIV.
16. Treatment with any investigational product during the last 30 days
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 | EUCTR2007-000939-26-NL |
| CCMO | NL16955.031.07 |