Chemo-free BRCA-targeted Neoadjuvant Strategy

Sponsor

European Organisation for Research and Treatment of Cancer - EORTC (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05209529

Collaborator

AstraZeneca (Industry)

152

Enrollment

Arms

89.6

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

This is a multicenter randomized phase ll clinical trial to evaluate the pathological complete response (pCR) in the tumour burden (primary and lymph nodes) with olaparib alone or in the olaparib and durvalumab arm in TNBC patients candidate for neoadjuvant strategy showing a t/gBRCAmut or BRCAness/HRD profile.

Condition or Disease	Intervention/Treatment	Phase
TNBC - Triple-Negative Breast Cancer BRCA1 Mutation BRCA2 Mutation	Drug: olaparib Drug: Durvalumab	Phase 2

Detailed Description

Eligible patients will be registered for central testing of BRCA mutatinal status and HRD/BRCAness profile with central review of ER, PgR, TILs and PD-L1.

Eligible patients will be randomly assigned to either olparib or olaparib and durvalumab (=neoadjuvant treatment) in a 1:1 ratio. The treatment duration in both arms will last 16 weeks and both treatments are considered as experimental treatments in this study.

After completion of neoadjuvant systemic treatment, patients will undergo surgery and followed-up for 2 years after investigational drug discontinuation. After surgery, adjuvant treatment will be left at the investigator's decision.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

152 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Eligible patients after central screening are randomized to olaparib vs olaparib and durvalumabEligible patients after central screening are randomized to olaparib vs olaparib and durvalumab

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Neoadjuvant Olaparib and Durvalumab for Patients With BRCA-associated Triple Negative Breast Cancer

Anticipated Study Start Date :

Sep 1, 2022

Anticipated Primary Completion Date :

Sep 6, 2027

Anticipated Study Completion Date :

Feb 18, 2030

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Olaparib Olaparib treatment for a total of 16 weeks	Drug: olaparib olaparib 300 mg per os BID
Experimental: Olaparib and durvalumab Olaparib and durvalumab treatment for a total of 16 weeks	Drug: olaparib olaparib 300 mg per os BID Drug: Durvalumab durvalumab 1500 mg IV Q4 weeks

Arm

Intervention/Treatment

Experimental: Olaparib

Olaparib treatment for a total of 16 weeks

Drug: olaparib

olaparib 300 mg per os BID

Experimental: Olaparib and durvalumab

Olaparib and durvalumab treatment for a total of 16 weeks

Drug: olaparib

olaparib 300 mg per os BID

Drug: Durvalumab

durvalumab 1500 mg IV Q4 weeks

Outcome Measures

Primary Outcome Measures

pathological complete response (pCR) [5 years from first patient in]
pCR is defined as the absence of invasive residual disease in the breast and in the axillary lymph nodes (ypT0/is ypN0).

Secondary Outcome Measures

2-year overall survival (OS) rate [7.5 years from first patient in]
OS is defined as date of randomization to the date of death, whatever comes first

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria at registration:

Histologically confirmed, invasive TNBC, defined as:
ER and PR negative (not eligible for endocrine therapy) defined as immunohistochemistry (IHC) nuclear staining ≤ 10% AND
HER2 negative (not eligible for anti-HER2 therapy):
Early-stage disease, defined as cT1c-T2, N0-N1, M0
Medically fit for a neoadjuvant strategy and for radical surgery as by the investigator's decision
No prior systemic therapy nor definitive surgery for BC
Age ≥18 years
Women and men can be included
ECOG performance status (PS) 0-1

Exclusion Criteria at registration:

Previous treatment with a PARPi
Previous treatment with an anti-PD-1/PD-L1, anti-PD-L2 or anti-CTLA-4 antibody
Evidence of macroscopic distant metastases, investigated according to local institutional guidelines
Patients who underwent sentinel node biopsy before neoadjuvant therapy
History of previous invasive BC
Bilateral and/or multifocal and/or multicentric BC
Malabsorption syndrome or other chronic condition that would significantly interfere with enteral absorption
History of allogenic transplantation of bone marrow or an organ.
History of another primary malignancy.
Myelodysplastic syndrome/acute myeloid leukaemia or features suggestive of such.
Congenital long QT syndrome.
History of active primary immunodeficiency

Inclusion criteria at randomization:

Deleterious germline or somatic mutation in BRCA 1 and/or BRCA 2 or homologue repair deficiency (HRD) status as determined by central testing.
Tumour tissue available from primary tumour (fine needle aspiration cytology or lymph node metastasis tissue are not acceptable).
Normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined below:
Haemoglobin ≥ 10.0 g/dL with no blood transfusion in the past 28 days
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
Platelet count ≥ 100 x 109/L
AST (SGOT) and ALT (SGPT) ≤ 2.5 x ULN
Total bilirubin ≤ 1.5 x ULN (exception: higher bilirubin in patients with confirmed Gilbert's syndrome are allowed according to the investigator's decision)
Creatinine clearance estimated of ≥ 51 mL/min/1.73m2 using the MDRD equation
Body weight >30 kg
Participation in translational research is mandatory
Women of childbearing potential (WOCBP) must have a negative serum pregnancy test in the screening period and confirmed prior to treatment on day 1.
Female patients of childbearing/reproductive potential must use adequate birth control measures, as defined by the investigator, during the study treatment period and for at least 3 months after the last dose of treatment. A highly effective method of birth control is defined as a method which results in a low failure rate (i.e., less than 1% per year) when used consistently and correctly. Such methods include:
Intrauterine device (IUD)
Intrauterine hormone-releasing system (IUS)
Bilateral tubal occlusion
Vasectomized partner
Sexual abstinence (the reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient)
Male patients must use a condom during treatment and for 3 months after the last dose of study treatment when having sexual intercourse with a pregnant woman or with a woman of childbearing potential. Female partners of male patients should also use a highly effective form of contraception (see above) if they are of childbearing potential.
Female subjects who are breast feeding must discontinue nursing prior to the first dose of study treatment and until 3 months after the last study treatment.
Registration to a National Health Care System

Exclusion criteria at randomization:

Inability to swallow and/or retain oral tablets
Blood transfusion within 28 days
History of human immunodeficiency virus (HIV) (positive HIV 1/2-antibodies)
Active Hepatitis B or Hepatitis C
Active bacterial, viral, or fungal infection requiring systemic therapy
History of active tuberculosis (TB, Bacillus Tuberculosis)
History of idiopathic pulmonary fibrosis, drug-induced pneumonitis, organizing pneumonia, interstitial lung disease or evidence of active pneumonitis on screening (TAP-CT-scan)
History of aortic disease (aneurysm or dissection)
History of myasthenia gravis
Mean QT interval corrected for heart rate (QTc) ≥ 500ms using Fridericia's Correction
Uncontrolled intercurrent illness
Psychiatric illness/social situations or addiction (chronic alcoholism or drug addiction) that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.
Any other serious or uncontrolled illness or abnormality that, in the judgment of the investigator, limits compliance with study requirement, substantially increases risk of incurring AEs or compromises the ability to give written informed consent.
Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab.
Receipt of live attenuated vaccine within 30 days prior to the first dose of study treatment.
Any concurrent systemic chemotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment.
Any unresolved toxicity (Common Terminology Criteria for Adverse Event (CTCAE) grade ≥

caused by previous cancer therapy, excluding alopecia, vitiligo.

Patients with Grade ≥ 2 neuropathy will be evaluated on a case-by-case basis after consultation with the study physician.
Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with olaparib and/or durvalumab may be included only after consultation with the study physician.
Concomitant use of strong CYP3A inhibitors.The required washout period prior to starting study treatment (olaparib) is 2 weeks.
Concomitant use of strong CYP3A inducers. The required washout period prior to starting study treatment (olaparib) is 5 weeks for phenobarbital and 3 weeks for other agents.
Major surgery within 4 weeks prior to the first dose of study treatment. Patients must have recovered from the surgical procedure. Implanted port placement is not considered as a major surgery.
Known allergy or hypersensitivity to olaparib or durvalumab, or to any excipient.
Contraindication to MRI or to the contrast medium used for MRI (gadolinium).
Participation in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study
Female patients who are pregnant or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 3 months after the last dose of study treatment.