Overview

Talazoparib Maintenance Therapy in Triple-negative Breast Cancer

Status:
Not yet recruiting
Trial end date:
2024-03-01
Target enrollment:
0
Participant gender:
Female
Summary
The investigators propose a randomized phase II clinical trial of talazoparib maintenance therapy in TNBC patients whose tumor showed clinical benefit (platinum-sensitivity) to first- or second-line platinum-based chemotherapy (monotherapy or combination with other agents). Patients are eligible when they meet at least one of two following platinum-sensitivity criteria: 1. They should have received 6 tri-weekly doses or 18 weekly doses of platinum-based therapy in non-progression status (at least stable disease) at the time of enrollment; 2. They should remain in complete or partial response status after 4-6 tri-weekly doses or 12-18 weekly doses of platinum-based chemotherapy. Eligible patients are enrolled to the trial within 4 to 8 weeks after last chemotherapy and 1:1 randomized to receive talazoparib versus placebo maintenance therapy. The primary endpoint is PFS by RECIST 1.1 after randomization. The secondary endpoints include OS, time from randomization to second progression or death (PFS2), and objective response rate (ORR) by RECIST 1.1, adverse events by CTCAE 5.0 criteria, quality of life evaluated by EORTC-QLQ-C30, and EuroQoL EQ-5D.
Phase:
Phase 2
Accepts Healthy Volunteers?
No
Details
Lead Sponsor:
Yonsei University
Treatments:
Talazoparib
Criteria
Inclusion Criteria:

1. Histologically or cytologically confirmed TNBC patients receiving first- or
second-line chemotherapy for recurrent, metastatic, or unresectable disease. The
triple-negative breast cancer is defined as ER negative, PR negative, and HER2
negative receptor status

- ER and PR negative defined as IHC nuclear staining < 1% AND

- HER2 negative defined as:

1. IHC 0, 1+ without ISH OR

2. IHC 2+ and ISH non-amplified (average HER2 gene copy number < 4 signals/cell
using single-probe ISH or HER2/CEP17 ratio < 2.0 and average HER2 gene copy
number < 4 signals/cell in dual-probe ISH) OR

3. ISH non-amplified without IHC

2. Female patients with ≥19 years of age

3. Patients on first- or second-line platinum-based (cisplatin or carboplatin)
chemotherapy regimen for recurrent, metastatic, or unresectable TNBC showing
platinum-sensitivity during chemotherapy

- The platinum-based chemotherapy can be either monotherapy or combination doublet
chemotherapy of carboplatin or cisplatin with following combination partners:
Paclitaxel, Docetaxel, Gemcitabine, Eribulin, Vinorelbine, Capecitabine, and
Nab-paclitaxel.

- For the patient who recurred within 12 months after the last dose of
(neo)adjuvant chemotherapy for operable stage breast cancer, the (neo)adjuvant
chemotherapy will be considered as one line of chemotherapy.

- The combined targeted therapy agents including bevacizumab will be allowed but
should be discontinued before randomization.

The platinum sensitivity is determined as follows,

- Remaining stable disease after 6 tri-weekly doses or 18 weekly doses of
platinum-based therapy (stable disease after 6 cycles)

- Remaining complete or partial response status after 4-6 tri-weekly doses or 12-18
weekly doses of platinum-based chemotherapy (partial or complete response after
4-6 cycles)

4. Patients who can receive germline BRCA1/2 mutation test or patients with previously
known germline BRCA1/2 mutation status.

5. Provision of informed consent prior to any study specific procedures

6. Measurable disease and/or non-measurable or no evidence of disease assessed at
baseline by CT as defined by RECIST 1.1

7. Patients who have received platinum as potentially curative treatment for a prior
cancer (eg ovarian cancer) or as adjuvant/neoadjuvant treatment for breast cancer are
eligible with at least 12 months elapsed between the last dose of curative
platinum-based treatment and initiation of the platinum-based chemotherapy for
recurrent, metastatic, or unresectable breast cancer.

8. ECOG performance status 0 or 1

9. Adequate organ function within 14 days before enrollment for treatment A. Absolute
neutrophil count (ANC) ≥ 1500 cells/mm3 B. Platelets ≥ 100,000 cells/mm3 C. Hemoglobin
≥ 9.0g/dL with no blood transfusions (packed red blood cells) in the past 7 days D.
Bilirubin ≤ 2.0 x ULN E. AST (SGOT) ≤ 3 x ULN (5.0 x ULN if hepatic metastases) F. ALT
(SGPT) ≤ 3 x ULN (5.0 x ULN if hepatic metastases) G. Creatinine clearance ≥ 30mL/min
as calculated using the Cockcroft-Gault equation or serum creatinine ≤ 1.5 ULN

10. 12-Lead electrocardiogram (ECG) with normal tracing or non-clinically significant
changes that do not require medical intervention

11. QTc interval ≤470 msec and without history of Torsades de pointes

12. Not pregnant or nursing, fertile patients must use effective contraception 2 weeks
before, during, and for 7 months after completion of study treatment

- A fertile female patient whose result of the urine test or serum pregnancy test
was negative within 72 hours of the first dose. If the test results are positive
or not-confirmatory negative, a serum pregnancy test should be performed.

- The fertile women are required to use proper contraception (inscribed in 11.13
section) during clinical trials and up to seven months after final
administration, or agree to be surgically infertile or to stop having
heterosexual sex.

The definition of infertile women is as follows, and the woman who do not fall under
this category are judged to be fertile women.

- Women who have undergone infertility surgery (bilateral tubal resection,
bilateral oophorectomy, or uterine resection)

- Women aged 55 or older who have no natural menstruation for more than 12 months
before random assignment

- Women under the age of 55 with no natural menstruation and a menopause follicle
hormone (FSH) concentration of 30 IU/L (or meet the standards of post-menopausal
in the local lab) for a period of more than 12 months before randomization

13. No other concurrent severe and/or uncontrolled medical disease which could compromise
study participation

14. Adequate treatment washout period before enrollment are below Treatment Washout Period
Major surgery ≥ 4 weeks Radiation therapy ≥ 4 weeks (if palliative stereotactic
radiation therapy ≥ 2 weeks)

15. For patients with Germline BRCA1/2 mutations, the patients whose use of PARP
inhibitors outside this clinical trial after the treatment of the platinum
chemotherapy is inappropriate, impossible, or difficult to implement due to the
patient's rejection, judged by the investigator or the patient for various reasons
(including economic reasons)

Exclusion Criteria:

1. Progression of tumor between start of platinum-based chemotherapy for recurrent,
metastatic, or unresectable TNBC and randomization.

2. Severe Cardiac disease (e.g., uncontrolled hypertension, congestive cardiac failure,
ventricular arrhythmias, active ischemic heart disease, myocardial infarction within
the past year)

3. Current active hepatic or biliary disease (except for Gilbert syndrome, asymptomatic
gallstones, liver metastasis or stable chronic liver disease per investigator
assessment).

4. Any previous treatment with a PARP inhibitor, including talazoparib

5. Clinically significant uncontrolled medical conditions are not permitted that would
limit ability to comply with study procedures, and any other medical condition that
places the patient at unacceptable risk of toxicity.

6. Presence of symptomatic CNS metastases or CNS metastases that require local
CNS-directed therapy (such as radiotherapy or surgery). Patients with treated brain
metastases should be neurologically stable (for 4 weeks post treatment and prior to
study enrollment) and without steroid therapy over physiologic dose (> 10mg
prednisolone/day) for at least 2 weeks before administration of study drug.

7. Concomitant use of known potent CYP3A4/5 inhibitors such as ketoconazole,
itraconazole, ritonavir, indinavir, saquinavir, telithromycin, clarithromycin and
nelfinavir.

8. Known active hepatitis B or C infection

9. Significantly altered mental status prohibiting the understanding of the study, or
with psychological, familial, sociological, or geographical condition potentially
hampering compliance with the study protocol and follow-up schedule.

10. Multiple primary malignancies within 5 years, except adequately resected non-melanoma
skin cancer, curatively treated in-situ disease, other solid tumors curatively
treated, or contralateral breast cancer.

11. Patients unable to swallow orally administered medication and patients with
gastrointestinal disorders likely to interfere with absorption of the study
medication.

12. Patients who are pregnant or nursing, or plan to be pregnant during the scheduled
clinical trial period from the screening visit to 7 months after the last
administration of the medication.

13. Previous allogeneic bone marrow transplant.

14. Patients with a known hypersensitivity to talazoparib or any of the excipients of the
product.

15. Patients who received live-attenuated vaccination with 30 days before the first
administration of study drug

16. Unresolved systemic active infection

17. Patients with history of HIV infection