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JOURNAL ONKOLOGIE – STUDIE
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Study of Neoadjuvant Olaparib Monotherapy and Olaparib and Durvalumab Combination in HER2 Negative BRCAm Breast Cancer

Rekrutierend

NCT-Nummer:
NCT05498155

Studienbeginn:
November 2022

Letztes Update:
27.11.2023

Wirkstoff:
Neoadjuvant Olaparib monotherapy group

Indikation (Clinical Trials):
Breast Neoplasms

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 2

Sponsor:
AstraZeneca

Collaborator:
-

Studienleiter

Anitra Fielding, MBChB
Study Director
AstraZeneca

Kontakt

AstraZeneca Clinical Study Information Center
Kontakt:
Phone: 1-877-240-9479
E-Mail: information.center@astrazeneca.com» Kontaktdaten anzeigen

Studienlocations
(3 von 67)

Research Site
40225 Düsseldorf
(Nordrhein-Westfalen)
GermanyRekrutierend» Google-Maps
Research Site
45130 Essen
(Nordrhein-Westfalen)
GermanyRekrutierend» Google-Maps
Research Site
30625 Hannover
(Niedersachsen)
GermanyRekrutierend» Google-Maps
Research Site
69120 Heidelberg
(Baden-Württemberg)
GermanyRekrutierend» Google-Maps
Research Site
50931 Köln
(Nordrhein-Westfalen)
GermanyRekrutierend» Google-Maps
Research Site
48149 Muenster
(Nordrhein-Westfalen)
GermanyRekrutierend» Google-Maps
Alle anzeigen

Studien-Informationen

Detailed Description:

The investigation of olaparib as monotherapy or olaparib in combination with durvalumab in

patients with early stage BRCAm, oestrogen receptor (ER)-negative or ER-low, human epidermal

growth factor receptor 2 (HER2)-negative breast cancer who are candidates for neoadjuvant

therapy supports the ongoing effort to identify novel agents and new drug combinations that

can improve pathological complete response (pCR) rates and event-free survival (EFS). In

patients at a lower risk (T1b-c/N0) of disease recurrence and a higher chance for cure,

monotherapy olaparib may provide adequate neoadjuvant treatment. In contrast, monotherapy

olaparib may be inadequate neoadjuvant treatment for those patients at a higher risk (T2/N0

or T1/N1) of recurrence, and the addition of an immune checkpoint inhibitor (ICI) to the

neoadjuvant regimen may improve long-term outcomes as was seen in KEYNOTE-522 and GeparNuevo.

However, the risk of irreversible immune-mediated adverse events (AEs) of the endocrine

system due to ICI use supports the use of ICIs only in the cohort of patients at higher risk

for disease recurrence. For both the lower and higher risk groups, the study treatments have

the potential for the development of de-escalation strategies in this disease setting where

traditional chemotherapy regimens may be avoided altogether.

While assessment of the efficacy of the combination of olaparib and durvalumab is ongoing,

there are sufficient safety data available to develop a safety and tolerability profile for

the combination.

Ein-/Ausschlusskriterien

Inclusion Criteria:

- Males or Females ≥18 years

- Minimum body weight of 30 kg

- Capable of giving signed informed consent.

- Male and Female participants of childbearing potential must use effective methods of

contraception

- Histologically confirmed, newly diagnosed, primary, operable, nonmetastatic invasive

breast cancer with the following characteristics:

--ER-negative or ER-low defined as IHC nuclear staining ≤10%

- HER2-negative (not eligible for anti-HER2 therapy) defined as:

- IHC 0, 1+ without in situ hybridization OR

- In situ hybridization non-amplified with ratio less than 2.0 OR

- In situ hybridization average HER2 copy number < 6 signals/cells

- Clinical TNM staging (per AJCC 8th Edition) as follows:

- T1b (>5 mm but ≤10 mm), N0, no known metastases (M0 or MX); OR

- T1c (>10 mm but ≤20 mm), N0, no known metastases (M0 or MX); OR

- T1 (>1 mm but ≤20 mm), N1, no known metastases (M0 or MX); OR

- T2 (>20 mm but ≤50 mm), N0, no known metastases (M0 or MX).).

- Documented deleterious or suspected deleterious mutation in BRCA1 or BRCA2 from local

BRCA testing using either a germline or tumour test.

- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

- Participants must have adequate organ and bone marrow function

- Participant must be willing to undergo a baseline research biopsy prior to start of

study treatment.

- Participant must be willing to have any leftover tumour tissue/FFPE from the

diagnostic biopsy submitted for research purposes, if available.

Exclusion Criteria:

- Any evidence of other diseases (such as severe or uncontrolled systemic diseases or

active, uncontrolled infections, including but not limited to, uncontrolled

ventricular arrhythmia, uncontrolled hypertension, recent [within 3 months] myocardial

infarction, uncontrolled major seizure disorder, renal transplant, active bleeding

diseases, unstable spinal cord compression, superior vena cava syndrome, extensive

interstitial bilateral lung disease on High Resolution Computed Tomography scan

- Refractory nausea and vomiting, chronic gastrointestinal disease likely to interfere

with absorption of the study medication, inability to swallow the formulated product

- History of another primary malignancy except for malignancy treated with curative

intent with no known active disease for ≥5 years before the first dose of study

intervention and of low potential risk for recurrence

- Participants with MDS or AML

- For higher risk (Cohort B) participants only: Active or prior documented autoimmune or

inflammatory disorders (including inflammatory bowel disease [eg, colitis or Crohn's

disease], diverticulitis [with the exception of diverticulosis], systemic lupus

erythematosus, sarcoidosis, granulomatosis with polyangiitis, Graves' disease,

rheumatoid arthritis, hypophysitis, uveitis, etc), autoimmune pneumonitis, and

autoimmune myocarditis

- Known active hepatitis infection, positive hepatitis C antibody, hepatitis B virus

surface antigen or hepatitis B virus core antibody

- Known to have tested positive for human immunodeficiency virus unless currently on

effective anti-retroviral therapy with an undetectable viral load within 6 months

- History of arrhythmia (multifocal premature ventricular contractions, bigeminy,

trigeminy, ventricular tachycardia), which is symptomatic or requires treatment

(Common Terminology Criteria for Adverse Events [CTCAE] Grade 3), symptomatic or

uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained

ventricular tachycardia

- Participant must not have had any prior treatment for the current breast cancer,

including surgery, chemotherapy, hormonal therapy, radiation, or experimental therapy

- For higher risk (Cohort B) participants only: Prior exposure to anti-PD1, anti-PD-L1,

or anti-CTLA4 agents (ICIs); OR an agent directed to other co-inhibitory or

co-stimulatory T-cell receptors

- Any concurrent anticancer treatment

- Major surgical procedure (excluding placement of vascular access, local surgery of

isolated lesions, or diagnostic staging) within 2 weeks of the first dose of study

intervention

- For higher risk (Cohort B) participants only: Current or prior use of

immunosuppressive medication within 14 days before the first dose of durvalumab.

- Concomitant use of:

- Known strong cytochrome P450 (CYP3A) inhibitors or moderate CYP3A inhibitors

within 2 weeks prior to first dose of study intervention

- Known strong CYP3A inducers or moderate CYP3A inducers .The required washout

period prior to starting study therapy is 5 weeks for enzalutamide or

phenobarbital and 3 weeks for other agents

Studien-Rationale

Primary outcome:

1. To evaluate the efficacy, measured by pCR (pathological complete response) rate, of olaparib monotherapy and olaparib plus durvalumab combination therapy, as assessed by central pathology review. (Time Frame - Approx. 4 to 6 months):
pCR is defined as ypT0/Tis ypN0 (ie, no invasive residual in breast and the axillary lymph nodes on evaluation of the complete resected breast specimen and all sampled regional lymph nodes) following completion of neoadjuvant systemic therapy.



Secondary outcome:

1. To evaluate the efficacy, measured by pCR rate, of olaparib monotherapy and olaparib plus durvalumab combination therapy as assessed by local pathology review (Time Frame - Approx. 4 to 6 months):
pCR is defined as ypT0/Tis ypN0 (ie, no invasive residual in breast and the axillary lymph nodes on evaluation of the complete resected breast specimen and all sampled regional lymph nodes) following completion of neoadjuvant systemic therapy.

2. To evaluate the efficacy, measured by RCB (residual cancer burden), of olaparib monotherapy and olaparib plus durvalumab combination therapy as assessed by central pathology review (Time Frame - Approx. 4 to 6 months):
RCB index value using 6 variables to categorize response in 1 of 4 classes: RCB 0 (pCR), I (minimal RCB), II (moderate RCB), and III (extensive RCB).

3. To evaluate the efficacy, measured by RCB, of olaparib monotherapy and olaparib plus durvalumab combination therapy as assessed by local pathology review (Time Frame - Approx. 4 to 6 months):
RCB index value using 6 variables to categorize response in 1 of 4 classes: RCB 0 (pCR), I (minimal RCB), II (moderate RCB), and III (extensive RCB).

4. To evaluate the efficacy of olaparib monotherapy and olaparib plus durvalumab combination therapy in terms of change from baseline tumour volume. Tumour volume will be assessed by local radiology review. (Time Frame - Approx. 4 to 6 months):
Percentage change in tumour volume from baseline after 3 cycles of treatment will be measured using MRI. Baseline is defined as the most recent measurement prior to the first administration of study intervention. Percent change from baseline is defined as: (Difference in value between post-baseline volume and baseline volume) divided by baseline volume and multiplied by 100.

5. To evaluate the efficacy of olaparib monotherapy and olaparib plus durvalumab combination therapy in terms of change from baseline tumour volume. Tumour volume will be assessed by local radiology review. (Time Frame - Approx. 4 to 6 months):
Percentage change in tumour volume from baseline after 6 cycles of treatment will be measured using MRI. Baseline is defined as the most recent measurement prior to the first administration of study intervention. Percent change from baseline is defined as: (Difference in value between post-baseline volume and baseline volume) divided by baseline volume and multiplied by 100.

6. To evaluate the efficacy of olaparib monotherapy and olaparib plus durvalumab combination therapy by assessment of EFS (event-free survival). (Time Frame - Approx. 3 years):
EFS is defined as time from the first dose of study intervention administration to any of the following events: progression of disease that precludes surgery, local or distant recurrence after surgery, second primary malignancy (breast or other invasive cancers), or death due to any cause.

7. Safety and tolerability profile of olaparib monotherapy and olaparib plus durvalumab combination therapy by assessment of advers events and seriuos advers events (AEs/SAEs) (Time Frame - Through study completion, around 15 months for single patient):
Graded according to the Common Terminology Criteria for Adverse Event (CTCAE) grade and changes in CTCAE grade

8. The number of participants with adverse events /serious adverse events of olaparib monotherapy and olaparib plus durvalumab combination therapy. (Time Frame - Through study completion, around 15 months for single patient):
Data will include clinical observations, ECG parameters, haematology / clinical chemistry, vital signs assessed as the number of participants with adverse events.

9. Safety and tolerability profile of olaparib monotherapy when given as adjuvant therapy to participants who achieve pCR by assessment of AEs/SAEs (Time Frame - Through study completion, around 15 months for single patient):
Graded according to the Common Terminology Criteria for Adverse Event (CTCAE) grade and changes in CTCAE grade

10. The number of participants with adverse events / serious adverse events of olaparib monotherapy when given as adjuvant therapy to participants who achieve pCR. (Time Frame - Through study completion, around 15 months for single patient):
Data will include clinical observations, ECG parameters, haematology / clinical chemistry, vital signs assessed as the number of participants with adverse events.

11. Systolic blood pressure (SBP), diastolic blood pressure (DBP) (Time Frame - Through study completion, around 15 months for single patient):
millimeter of mercury (mmHg)

12. Body Temperature (Time Frame - Through study completion, around 15 months for single patient):
Celsius (°C)

13. Pulse rate (heart rate) (Time Frame - Through study completion, around 15 months for single patient):
Beats per minute (BPM)

14. Weight (Time Frame - Through study completion, around 15 months for single patient):
Kilograms (kg)

Studien-Arme

  • Experimental: Cohort A
    Cohort A will consist of a lower-risk population of participants with HER2-negative ER-negative or ER-low defined as having a tumour size >5 mm and ≤20 mm and N0 (T1b-c/N0).
  • Experimental: Cohort B
    Cohort B will consist of a higher-risk population of participants with HER2-negative ER-negative or ER-low defined as having a tumour size of >20 mm but ≤50 mm and N0 (T2/N0), or having a tumour size of >1 mm but ≤20 mm and N1 (T1/N1).

Geprüfte Regime

  • Neoadjuvant Olaparib monotherapy group (Cohort A):
    Neoadjuvant olaparib monotherapy (300 mg BID) for four to six 28-day cycles.
  • Neoadjuvant combination therapy with olaparib plus durvalumab (Cohort B):
    Neoadjuvant combination therapy with olaparib (300 mg BID) plus durvalumab (1500 mg IV Q4W) for four to six 28-day cycles.

Quelle: ClinicalTrials.gov


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