This study has been transitioned to CTIS with ID 2024-518036-36-01 check the CTIS register for the current data. To prove that the RECAP test has the potential of selecting patients who are sensitive to treatment with the PARP inhibitor talazoparib…
ID
Source
Brief title
Condition
- Breast neoplasms malignant and unspecified (incl nipple)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The aim of the current study is to assess the predictive potential of the RECAP
test for in vivo response to talazoparib treatment by investigating the
percentage of patients with HRD breast tumors with PFS on talazoparib
monotherapy of 4 months or longer. The main endpoint is thus the proportion of
patients with PFS at 4 months (PFS4).
Secondary outcome
Secondary endpoints are overall response rate (ORR), overall survival (OS)
among patients with HRD tumors treated with talazoparib. The negative
predictive value will be determined within the HRP group.
Background summary
Optimal patient selection for poly (adenosine diphosphate [ADP]-ribose)
polymerase (PARP) inhibitors (PARPi) and double strand break (DSB) inducing
chemotherapy is of great clinical importance. Although evidence is emerging
that the use of these therapies could be extended beyond germline BRCA1/2
mutated cancers, a gold standard test for predicting response to treatments
targeting homologous recombination(HR) is not yet available. Recently, we have
developed the REpair CAPacity (RECAP) test, a functional assay exploiting RAD51
(a DSB repair protein) foci formation after ex vivo irradiation of fresh breast
cancer tissue. This allows testing of the HR status on a real-time basis.
Within a cohort of 148 primary breast carcinomas (BrC), we found that 16% of
the tumors (n=24) were HR deficient (HRD) (Meijer et al, submitted/ under
review). Besides on primary BrC, we have also shown that execution of the
functional RECAP test on small core needle biopsies from metastatic BrC lesions
is achievable and produces robust and interpretable results for most patients
(93%) (unpublished data). Within an unselected cohort of metastatic BrCs
lesions, 32% (13 out of 41 biopsies) were HRD according to the RECAP test.
Molecular characterization of HRD tumors revealed BRCA1/2 germline (gBRCA)
mutations, somatic mutations, deletions and promotor methylation.
Interestingly, 31% of primary HRD and 46% of metastatic HRD BrCs lesions could
not be explained by any form of BRCA deficiency. Among non-BRCA HRD tumors,
one tumor harbored a PALB2 mutation. Thus, based on the HR phenotype rather
than BRCA germline status, more patients can be identified who are likely to
benefit from PARPi treatment. Furthermore, the RECAP test can also detect
reversion of the HRD phenotype in BRCA deficient tumors, that have been treated
with various DNA damaging chemotherapies that may have induced resistance, and
thereby prevent unnecessary treatment. Consequently, it is of the utmost
importance to determine the predictive value of the RECAP test for the in vivo
response to PARPi. Talazoparib is one of the most promising PARPi, given its
significant potency and superior PARP-trapping properties compared to other
PARPi.
Study objective
This study has been transitioned to CTIS with ID 2024-518036-36-01 check the CTIS register for the current data.
To prove that the RECAP test has the potential of selecting patients who are
sensitive to treatment with the PARP inhibitor talazoparib as measured by the
PFS rate at 4 months.
Study design
This is a single arm, prospective multicenter study among patients with
advanced breast cancer with proven HRD phenotype who will be treated with
talazoparib, a strong PARP inhibitor. After signing informed consent,
metastatic breast cancer patients will undergo an ultrasound (or CT-) guided
biopsy in order to obtain at least two biopsies from a metastatic lesion to
determine the HR status by the RECAP test and a blood withdrawal for
determination of ctDNA isolation. HRP patients will not receive talazoparib but
will be treated according to physicians choice. Therapy response will be part
of the follow-up. About 30% of screened patients will have an HRD tumor and
thus will be eligible to start talazoparib monotherapy until PD or unacceptable
side effects. The primary endpoint is PFS at four months. Additional endpoints
will be among others overall response rate and overall survival. Upon
progression, patients wil be kindly asked for consent to perform another biopsy
(optional) and blood withdrawal in order to prove reversibility of the RECAP
test outcome (from HRD to HRP) and explore potential mechanisms of resistance
(ctDNA changes). For example, BRCA reversion mutations have been associated
with Talazorparib resistance and can be identified in ctDNA.
Intervention
Talazoparib single agent, daily 1 mg orally
Study burden and risks
Burden for the patient will be minimal because only easily approachable
metastatic lesions will be offered for a biopsy. Bone and lung metastasis will
be excluded from this study to avoid risks and side effects. Expected but
confined effects will be mild pain and in the worst case a(n extended)
bleeding. Furthermore, talazoparib is an oral drug taken on a daily-base which
may lead to side effects. From previous studies, it is known that these are
overall mild and seldom result in premature end of study participation
Dr. Molenwaterplein 40
Rotterdam 3015 GD
NL
Dr. Molenwaterplein 40
Rotterdam 3015 GD
NL
Listed location countries
Inclusion criteria
• Age >=18 years
• WHO performance status 0-2
• Locally advanced breast cancer without curative intent or metastatic breast
cancer
* The breast cancer must be either
o high grade (Bloom & Richardson grade 3) ER positive (>10%) and HER2 negative
primary breast cancer, or
o triple negative (ER<10%, PR<10% and HER2 negative), or
o any Bloom & Richardson grading and receptor status and also
* at least one metastatic lesion must have a proven HRD phenotype based on a
RECAP test not treated with anticancer therapy thereafter or
* the patient must have a proven germline or somatic BRCA1 and/or BRCA2 mutation
• The site of the metastatic lesion (or primary tumor in case it is still in
situ) should be easily amendable for biopsy. NB lung metastases (high risk of
hemato/pneumo-thorax) and bone metastases (not suitable for RECAP test because
calcifications interfere with experimental procedures) are excluded. The local
guidelines will be used for stopping and restarting of anticoagulation.
Bilirubin <1.5 ULN (except elevated bilirubin due to Gilbert*s disease or a
similar syndrome involving slow conjugation of bilirubin) and both AST and ALT
<5x ULN in case a liver biopsy is planned.
• The tumor must be HRD, defined as HRD identified by the RECAP test determined
just before the start of potential Talazoparib treatment within this study or
just (also in case a proven germline BRCA1/2 mutation is present).
• Maximum of four prior lines of chemotherapy for advanced disease; Patients
who received platinum compounds are eligible if they have had at least a
progression free interval of four months.
• Measureable or evaluable disease according to RECIST 1.1 criteria (appendix 2)
• Life expectancy >= 3 months
• Hemoglobin >= 10 g/dL (6,2 mmol/L) and ANC of >= 1.5 x 109 /L
• Platelets >100 x 10e9/L
• Hepatic function as defined by total serum bilirubin <= 1. 5 x ULN (except
elevated bilirubin due to Gilbert*s disease or a similar syndrome involving
slow conjugation of bilirubin), ASAT and ALAT < 3 x ULN
• Renal function as defined by serum creatinine <= 1.5 x ULN or creatinine
clearance >= 50 mL/min (by Cockcroft-Gault formula);
• Negative pregnancy test (urine/serum) for female patients with childbearing
potential;
• Written informed consent
Exclusion criteria
• Any psychological condition potentially hampering compliance with the study
protocol
• Any treatment with investigational antitumor drugs within 28 days prior to
receiving the first dose of investigational treatment; or within 21 days for
standard chemotherapy; or within 14 days for weekly scheduled chemotherapeutic
regimens or endocrine therapy
• Radiotherapy within the last four weeks prior to receiving the first dose of
investigational treatment; except 1 or 2 x 8 Gy for pain palliation, then seven
days interval after the last radiation should be maintained
• Known persistent (>4 weeks) >= Grade 2 toxicity from prior cancer therapy
(except for alopecia grade 2)
• Symptomatic brain or leptomeningeal metastases. If adequately treated with
resection and/or irradiation and patients are at least four weeks completely
free of symptoms of these metastases without the use of corticosteroids,
patients could be eligible
• Women who have a positive pregnancy test (urine/serum) and/or who are
breastfeeding;
• Unreliable contraceptive methods. Women and men enrolled in this trial must
agree to use a reliable contraceptive method throughout the study (adequate
contraceptive methods are: intra-uterine devices or systems, condom or other
barrier contraceptive measures, sterilization and true abstinence)
• Concomitant use with P-gp inhibitors or inducers or BCRP inhibitors
• Any known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia
(AML)
• Uncontrolled infectious disease (such as Human Immunodeficiency Virus
HIV-1 or HIV-2 infection) or known active hepatitis B or C
• Recent myocardial infarction (< six months) or unstable angina
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 |
|---|---|
| EU-CTR | CTIS2024-518036-36-01 |
| EU-CTR | CTIS2024-518036-36-02 |
| EudraCT | EUCTR2018-002914-10-NL |
| CCMO | NL66856.078.18 |