To perform a pilot study to determine the feasibility of conducting a two-arm phase I trial and to determine the recommended dose level for phase II (RP2D) study and assess the safety of the combination olaparib and melphalan in patients with…
ID
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary end point:
• Recommended phase II dose determined by the dose limiting toxicity (DLT)
graded using the NCI Common Terminology Criteria for Adverse Events (NCI CTCAE)
version 4
Secondary outcome
Secondary end points:
• Pharmacokinetics of the combination of olaparib and melphalan in two cohorts
• Pharmacodynamics: measuring PARP activity and γH2AX-RAD51 foci (plasma and
potential tumor)
• Assess objective response rates via RECIST in patients with measurable
disease
Background summary
Homologous recombination is an essential pathway for genomic integrity as it
repairs DNA double strand breaks error-free. Within this pathway BRCA1 and -2
play important roles. Inactivation of either of these genes predisposes
patients to cancer. Cancers associated with BRCA1 or -2 inactivation can*t
repair double strand breaks. These tumors are therefore more likely to benefit
from therapy that induces these lesions such as bifunctional alkylators and
Poly(ADP)Ribose Polymerase 1 (PARP1) inhibitors. Array CGH classifiers can
distinguish tumors that are associated with loss of BRCA1 or -2. In this trial
we will investigate feasibility of a combination of olaparib (a PARP1
inhibitor) and melphalan in BRCA1 or -2¬ mutation carriers or patients that
have a BRCA like CGH tumor.
Study objective
To perform a pilot study to determine the feasibility of conducting a two-arm
phase I trial and to determine the recommended dose level for phase II (RP2D)
study and assess the safety of the combination olaparib and melphalan in
patients with advanced solid tumors that have hallmarks of BRCA-1 or -2
deficiency.
Study design
This is a pilot open label phase I study assessing the orally administered
olaparib in combination with melphalan i.v. Two cohorts will be investigated.
In one cohort we will escalate melphalan in olaparib treated patients. In the
other cohort we will escalate the olaparib dose in melphalan-treated patients.
The study will consist of a dose escalation phase to establish the dose that
can safely be administered and is recommended for phase II testing. In an
expansion phase further safety and tolerability of the combination olaparib and
melphalan will be evaluated. To assess pharmacokinetics, single agent olaparib
will be administered on day 0 in cycle 1 as an internal control for PK.
Furthermore efficacy will be analyzed in a more restricted patient population
most likely to benefit from the combination. Allocation to cohorts occurs by
patient and physician preference until one of the cohorts is full.
Intervention
The dose escalation phase will follow a traditional 3+3 design in two cohorts.
In cohort 1 melphalan will be escalated on the background of an effective
olaparib dose. If after escalating melphalan to the current dose used for
treating multiple myeloma patients (25 mg/m2) no DLT has been observed olaparib
will be escalated to the currently recommended dose. If still no DLT has been
observed melphalan will be escalated beyond 25 mg/m2 following modified
Fibonnaci increments. In cohort 2 olaparib will be escalated in combination
with low dose melphalan. If no DLT occurs, melphalan will be increased to the
current single agent dose.
Study burden and risks
Patient will experience the side effects of the study treament with olaparib
and melphalan. Patients will be hospitalised for the first cycle of treatment
because of close monitoring of vital signs the first 2 hours after melphalan
infusion and for pharmacokinetic sampling.
In the first cycle patient will be seen on the out patient clinic on day 4, 8
and 15.
In the second and subsequent cycles patients will be seen on day 1 (dosing),
day 8 and 15.
Patient will be asked to participate in the optional investigations of
biomarker and pharmacogenetic research. This will include a tumor biopsy (3
timepoints), blood sampling ( 5 times x 10 ml) and urine sampling (4 times).
For these investigation as seperate informed consent will be asked.
Plesmanlaan 121
1066 CX Amsterdam
NL
Plesmanlaan 121
1066 CX Amsterdam
NL
Listed location countries
Age
Inclusion criteria
- Before patient registration, written informed consent must be given
- Male or female patients with a histologically or cytologically diagnosed metastatic or locally advanced malignant solid tumor having hallmarks of BRCA-1 or -2 deficiency:
o BRCA-1 or -2 mutation carriers with any tumor
o Breast cancer patients with a BRCA-likeCGH tumor
- Patients must have progressed despite standard therapy.
- Age > 18 years
- Performance status (PS): <2 (ECOG scale) and a life expectancy of at least 12 weeks
- Patients must be able to swallow oral medication.
- Female patients of childbearing age must have a negative urine or serum pregnancy test within 7 days prior to start of study.
- Laboratory requirements within 7 days prior to start of treatment:
Haematology:
-Haemoglobin >10.0 g/dl (6.2 mmol/l)
-absolute neutrophil count >1.5 x 109/L
-platelets >100 x 109/L;
Biochemistry:
-Total bilirubin : <1.25 x upper normal limit;
-AST (SGOT), ALT (SGPT) : <2.5 x upper limit of normal (ULN); in case of liver metastases < 5 * ULN
-Serum creatinine clearance >= 50 ml/min (Cockroft-Gault)
- Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
Exclusion criteria
- Patients having received any chemotherapy, radiotherapy (except for palliative reasons), biological therapy or investigational compound administered within four weeks prior to start of study treatment or patients not recovered from adverse events due to agents administered more than 4 weeks earlier.
- Patients having symptomatic brain metastases. A scan to confirm the absence of brain metastases is not required.
- Patients having gastrointestinal disorders likely to interfere with absorption of the study drug (e.g. partial bowel obstruction or malabsorption).
- Patients should not require treatment with inhibitors or inducers of Cytochrome P450 system.
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 | EUCTR2011-005278-46-NL |
| CCMO | NL39007.031.11 |