Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Breast Neoplasms

Breast Diseases

Skin Diseases

All Drugs and Chemicals

Estrogens

Mitogens

Progesterone

MammaTyper™ will be used to assess tumor material of patients treated with neo-adjuvant therapy.

MammaTyper™ is an in vitro molecular diagnostic test for the quantitative detection of the biomarkers estrogen receptor (ESR1), progesterone receptor ( PgR), Human epidermal growth factor receptor 2 (HER2) and proliferation antigen Ki-67 on the basis of the values of the messenger ribonucleic acid (mRNA).

MammaTyper™

This is a prospective examination of ribonucleic acid (RNA) extracted from tumor material of breast cancer patients treated with a neo-adjuvant therapy. The RNA will be analysed for expression of estrogen receptor (ER 1), progesterone receptor (PgR), HER2 and Ki-67 with MammaTyper™.

According to the determined values for the individual parameters at least 4 subtypes can be distinguished to date

* Luminal A-type
* Luminal B-type
* HER2-type
* Triple-negative-type As non-clinical endpoint, the agreement of new subtyping with Immunohistochemical methods will be evaluated.

As clinical objective, the 5 year Distant metastasis free survival (DMFS) and Overall survival (OS) will be reevaluated according to the new subtyping.

Tumor material collected from patients who received neoadjuvant therapy either with four cycles of doxorubicin 60 mg/m² plus pemetrexed 500 mg/m² on day 1 every 21 days followed by four cycles of docetaxel 100 mg/m² on day 1 every 21 days or four cycles of doxorubicin 60 mg/m² plus cyclophosphamide 600 mg/m² on day 1 every 21 days followed by four cycles of docetaxel 100 mg/m² on day 1 every 21 days will be re-analyzed with the MammaTyper Kit. The Kit is an in-vitro molecular diagnostic test for molecular subtyping of breast cancers into Luminal A \& B, HER2 and Triple negative. It allows quantitative detection of the RNA expression status of the genes for estrogen receptor (ESR1), PgR, HER2 and Ki-67 on the basis of their mRNA present in the samples. This prospective diagnostic study will investigate the subtyping-results of the MammaTyper™ analysis and will compare them to the subtyping of the former immunohistochemical analysis performed. Based on the MammaTyper™-subtypes the efficiency of the therapy regimen and the outcome will be re-evaluated from the patient data.

Re-Examination of Tumor Material and Re-Evaluation of Patient Data From Patients Treated With Neo-adjuvant Therapy

Evaluation of the MammaTyper Kit, Ref 90020/90021 Performed on Clinical Material Obtained From Patients With Early Breast Cancer: Re-Examination of Tumor Material and Re-Evaluation of Patient Data From Patients Treated With Neo-adjuvant Therapy

For each MammaTyper and immunohistochemical based subtype categorization, percent agreement, positive and negative percent agreement as well as kappa-statistics are calculated.

Assessed as rate of patients in subgroup Luminal A with 5 year OS vs. rate of patients in combined subgroups with 5 year OS based on MammaTyper subtyping

Assessed as rate of patients with complete response and Ki-67 determination according to MammaTyper and visual scoring assessment

Assessed as rate of patients with 5 year OS and high or low expression of ESR1 mRNA

BioNTech Diagnostics GmbH

Antineoplastic Agents

Bone Density Conservation Agents

Amino Acids

Trastuzumab

Paclitaxel

Tamoxifen

Letrozole

Albumin-Bound Paclitaxel

Lapatinib

Tubulin Modulators

Antimitotic Agents

Antineoplastic Agents, Immunological

Aromatase Inhibitors

Enzyme Inhibitors

Estrogen Antagonists

Estrogen Receptor Antagonists

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

Estrogen Receptor Modulators

Selective Estrogen Receptor Modulators

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Tyrosine

For a total of 18 weeks, HR-negative patients will be given dual blockade consisting of daily lapatinib at 1000 mg and trastuzumab at a loading dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks.

For a total of 18 weeks, HR-positive patients will be given letrozole (2.5 mg daily) or tamoxifen (20 mg daily) with concurrent dual blockade consisting of daily lapatinib at 1000 mg and trastuzumab at a loading dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks.

Letrozole or tamoxifen will be prescribed according to patient's menopausal status

Endocrine Therapy

Only administrated if tumor progression is observed by US on week 6

Antonio Llombart, MD, PhD

Aleix Prat, MD, PhD

Javier Cortés, MD, PhD

Non-randomized, open label, multicentric translational research study in women with untreated invasive breast carcinoma eligible for primary surgery (Stage I-IIIA).

The aim of PAMELA is to test the hypothesis that PAM50 HER2-enriched (HER2-E) subtype better predicts response to neoadjuvant dual anti-HER2 blockade, with or without endocrine therapy, compared to traditional clinical HER2 classification. Furthermore, we posit that characterization of gene expression patterns may identify profiles of those who may be safely spared chemotherapy.

PAMELA is a non-randomized, open label, multicentric translational research study of neoadjuvant dual HER2 blockade therapy without chemotherapy. Although efficacy and safety will be investigated, the primary goal is to identify profiles predictive of clinical benefit from targeted therapy. Eligible patients must be women with untreated primary HER2-overexpressing and/or amplified breast tumors of more than 1 cm in diameter amenable to definitive surgery (stage I-IIIA).

The PAMELA study is designed to test the hypothesis that the PAM50 HER2-E subtype is able to predict clinical response to neoadjuvant dual HER2 blockade with lapatinib and trastuzumab, with or without endocrine therapy, assessed by pathological complete response in the breast (pCRB) rate at the time of surgery, compared to traditional clinical HER2 classification. Furthermore, we posit that characterization of gene expression patterns may identify profiles of those who may be safely spared chemotherapy.

Patients will first undergo screening, tumor measurement, and mandatory collection of core tumor biopsies for central determination of HER2 and HR status. These biopsies will be used to determine gene expression patterns once the patient is included in the study. Patients will be treated with dual HER2 blockade consisting of lapatinib and trastuzumab for a total of 18 weeks. Patients who are HR-positive will also be given endocrine therapy, letrozole or tamoxifen depending on their menopausal status, for the same 18 weeks. If tumor progression is observed by ultrasound (US) at week 6, tumors will be identified as resistant, and paclitaxel will be added to dual HER2 blockade, maintaining trastuzumab at the same original dose and reducing lapatinib dose for safety reasons. In those patients with HR-positive disease, endocrine therapy will be withdrawn in order to avoid its adverse interactions with chemotherapy.

Two weeks after the first administration of study medication, all patients will undergo mandatory repeat tumor tissue acquisition that will be used for secondary endpoint assessment.

Post treatment tissue acquisition will be obtained at the time of surgery from the specimen excised.

US of the breast and axillary lymph nodes will be performed at baseline, Day 14, week 6, and prior to surgery, and will be correlated with pCR. If tumor progression is observed on week 6, the US will be repeated on week 10 to discard the progression continues despite the addition of paclitaxel at neoadjuvant regimen.

Mammography is required at baseline and prior to surgery, but will not be used for the objective response assessment.

Treatment will be given until definitive surgery, clinical signs of disease progression after paclitaxel addition, unacceptable toxicity or withdrawal of patient consent.

Breast surgery will be carried out 1 to 3 weeks after completion of dual HER2 blockade with or without endocrine therapy, and 2 to 3 weeks after completion of paclitaxel plus dual HER2 blockade, should it had been initiated for progressive disease.

Following surgical excision, adjuvant treatment will be as per investigator´s choice and local standards of care outside the scope of this protocol.

End of study is 30 days (±14 days) after surgery with a safety follow-up visit.

PAM50 HER2-enriched Phenotype as a Predictor of Response to Dual HER2 Blockade in HER2-positive Early Breast Cancer

PAMELA: PAM50 HER2-enriched Phenotype as a Predictor of Early Response to Neoadjuvant Lapatinib Plus Trastuzumab in Stage I to IIIA HER2-positive Breast Cancer

Comparison between the PAM50 HER2-E versus non HER2-E cases to achieve pCRB from dual HER2 blockade with lapatinib and trastuzumab at the time of surgery

Comparison between the PAM50 HER2-E versus non HER2-E cases to achieve pCRBL from dual HER2 blockade with lapatinib and trastuzumab at the time of surgery

Correlation between PAM50 HER2-E cases and RCB status (0-I versus II-III) after dual HER2 blockade with lapatinib and trastuzumab at the time of surgery

Comparison of the changes in the percentage of Ki67-positive cells in Luminal versus non-Luminal subtypes after 14 days of dual HER2 blockade plus endocrine therapy

Compare significant changes in gene expression from baseline to Day 14 in the entire study population and separately, in the HR-negative and HR-positive patients

In all patients and in those with HR-positive and HR-negative disease

Correlation between the PAM50 ROR and pCR and/or RCB after dual HER2 blockade with lapatinib and trastuzumab at the time of surgery

Identification of gene expression changes that correlate with pCRB or RCB after dual HER2 blockade treatment

Frequency of adverse events (AE)(assessed by CTCAE v.4.03), including the following parameters:

* All reported AEs and serious AEs
* Neutropenia Grade 3/4
* Febrile neutropenia Grade 3/4
* Neuropathy Grade 3/4
* Myalgia/arthralgia
* Cardiotoxicity (Grade 3/4 or NYHA Class III or IV)
* Frequency of dose reductions and dose delays due to treatment toxicity

Novartis

SOLTI Breast Cancer Research Group

Triple Negative Breast Neoplasms

Olaparib

Adavosertib

Poly(ADP-ribose) Polymerase Inhibitors

All randomized patients will receive Olaparib monotherapy 300 mg twice daily (BD).

All randomized patients will receive Olaparib 300 mg twice daily+Ceralasertib 160 mg once daily (OD).

All randomized patients will receive Olaparib 200 mg BD +adavosertib 150 mg BD. Following the discontinuation of adavosertib+olaparib treatment arm on 18 April 2019, patients receiving treatment with adavosertib+olaparib treatment were offered the opportunity to continue treatment on olaparib monotherapy at the approved dose (300 mg bd).

Two (2) 150 mg olaparib tablets should be taken at the same time each day, approximately 12 hours apart with one glass of water (approximately 250 mL).

Olaparib Continuous (28-Day cycle) 300 mg BD.

Patients will be administered Ceralasertib OD at 160 mg from Day 1 to Day 7 (inclusive) of every 28-day cycle.

Ceralasertib 160 mg OD + olaparib continuous 300 mg BD (28-day cycle).

Patients will be administered adavosertib BD at 150mg from Day 1 to Day 3 and Day 8 to Day 10.

Adavosertib 150 mg BD + olaparib 200 mg BD (21-day cycle).

Andrew Tutt, MB ChB PhD

This study is to assess the efficacy and safety of olaparib monotherapy versus olaparib in combination with an inhibitor of ATR (Ataxia-Telangiectasia Mutated (ATM) and Rad3-related protein kinase (Ceralasertib \[AZD6738\]) and olaparib monotherapy versus olaparib in combination with an inhibitor of WEE1 (adavosertib \[AZD1775\]) in second or third line setting in patients with Triple-negative breast cancer (TNBC) prospectively stratified by presence/absence of qualifying tumour mutation in genes involved in the homologous recombination repair (HRR) pathway. Treatment arms are olaparib monotherapy, olaparib+ Ceralasertib and olaparib+adavosertib. The study subject population will be divided into Stratum A, Stratum B, and Stratum C. Due to the different schedules of administration of each of the treatment options as well as their different toxicity profiles, the study is not blinded. Study has two stage consent process- stage 1 consent (molecular screening for HRR defects) and stage 2 consent (main study). Patients with TNBC and with known qualifying BRCAm, non BRCAm HRRm and non HRRm status will be offered the option of consenting to the main part of the study within the 28-day screening period. Following the ISRC meeting on 17 April 2019 a recommendation was made to close the adavosertib+olaparib treatment arm across all biomarker strata. Patients receiving treatment with adavosertib+olaparib treatment were offered the opportunity to continue treatment on olaparib monotherapy at the approved dose (300 mg bd). Following the closure of this arm the total number of patients randomised will be lower (approximately 350 patients). Approximately 300 patients will be randomised (using randomisation ratio 1:1) to 2 ongoing treatment arms plus an additional 47 patients to a 3rd arm (olaparib+adavosertib) prior to the arm being discontinued.

This is a prospective, open label, randomised, multi-centre Phase 2 study that will assess the efficacy and safety of olaparib monotherapy versus olaparib in combination with an inhibitor of ATR (Ceralasertib) and olaparib monotherapy versus olaparib in combination with an inhibitor of WEE1 (adavosertib) in second or third line setting in patients with TNBC prospectively stratified by presence/absence of qualifying tumour mutation in genes involved in the HRR pathway.

Eligible patients will be randomised by a ratio 1:1:1 to treatment Arm 1: olaparib continuous in a 28-day cycle, Arm 2: Ceralasertib Days 1-7 with olaparib continuous in a 28-day cycle or Arm 3: adavosertib Days 1-3 and 8-10 with olaparib continuous in a 21-day cycle. Following the ISRC meeting on 17 April 2019 a recommendation was made to close the adavosertib+olaparib treatment arm across all biomarker strata. Following closure of this arm the randomisation ratio will be 1:1 to olaparib monotherapy or Ceralasertib+olaparib. Patients who were receiving treatment with adavosertib+olaparib treatment were offered the opportunity to continue treatment on olaparib monotherapy at the approved dose (300 mg bd).

The study subject population will be divided into Stratum A (patients with mutations in BRCA1 or BRCA2 (Breast cancer susceptible gene mutation (BRCAm)), Stratum B (patients with mutations in any of the other genes involved in the HRR pathway and no mutation in BRCA1 and no mutation in BRCA2), and Stratum C (patients with no detected tumour mutations in any of the HRR genes). Within each stratum A, B and C, there will be further stratification by whether the patient received prior platinum-based therapy.

In the olaparib monotherapy treatment arm as well as in the Ceralasertib+olaparib treatment arm, patients will be administered olaparib bd at 300 mg continuously. Two (2) 150 mg olaparib tablets will be taken at the same time each day, approximately 12 hours apart with one glass of water (approximately 250 mL). In the adavosertib+olaparib treatment arm, patients will be given olaparib 200 mg bd (2 x 100 mg tablets twice a day) and adavosertib 150 mg bd from Day 1 to Day 3 (inclusive) and Day 8 to Day 10 (inclusive) of every 21-day cycle. Ceralasertib will be supplied as 20 mg, 80 mg, or 100 mg film coated tablets. Patients will be administered Ceralasertib od at 160 mg from Day 1 to Day 7 (inclusive) of every 28-day cycle. A total of 160 mg of Ceralasertib tablets will be taken at the same time on each day of dosing with approximately 250 mL of water. Adavosertib will be supplied as capsules containing 25 mg, 50 mg, 75 mg, 100 mg, or 200 mg of drug substance. Adavosertib will be taken with approximately 250 mL of water approximately 2 hours before or 2 hours after food. Olaparib, Ceralasertib and adavosertib will be provided by AstraZeneca.

Primary outcome measures (progression free survival \[PFS\]) will be analysed for the 3 patient populations BRCAm, Non BRCAm HRRm (Homologous Recombination Repair gene mutation) and Non HRRm. Secondary outcome measures will be analysed in 2 patient populations HRRm and All for PFS, Objective response rate (ORR) and overall survival (OS) will be analysed in all 5 patient populations. DoR, and tumour change will be analysed in BRCAm, Non BRCAm HRRm, and Non HRRm patient populations. Tumour and germline mutation status will be analysed only in the all patient population. PK outcome measures will be analysed only in the all patient population. Blinded Independent Central Review (BICR) of radiological imaging data will be carried out using RECIST version 1.1 and Investigator assessments will also be analysed for sensitivity purposes.

Given the study treatment design (monotherapy and 2 different combination therapies will be employed) neither patients nor Investigators will be blinded to study treatment.

To Assess Safety and Efficacy of Agents Targeting DNA Damage Repair With Olaparib Versus Olaparib Monotherapy.

A Phase II, Open Label, Randomised, Multi-centre Study to Assess the Safety and Efficacy of Agents Targeting DNA Damage Repair in Combination With Olaparib Versus Olaparib Monotherapy in the Treatment of Metastatic Triple Negative Breast Cancer Patients Stratified by Alterations in Homologous Recombinant Repair (HRR)-Related Genes (Including BRCA1/2) (VIOLETTE).

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Progression-free survival was defined as time from randomization until the date of objective disease progression or death, regardless of whether the patient withdrew from randomized therapy or received another anti-cancer therapy prior to progression. Progression was determined by Blinded independent central review (BICR) using Response Evaluation Criteria In Solid Tumours Version (RECIST 1.1). Patients who had not progressed or died at the time of analysis were censored at the time of the latest date of assessment from their last evaluable RECIST assessment. If patients had no evaluable visits or baseline data, the patient was censored at Study Day 1, unless death occurred within 17 weeks i.e., death within 17 weeks was relative to randomization. Here, the study patient population was stratified as follows: Breast cancer susceptible gene mutation (BRCAm) patients; non BRCAm homologous recombination repair gene mutation (HRRm) patients; non HRRm patients.

Progression-free survival was defined as time from randomization until the date of objective disease progression or death, regardless of whether the patient withdrew from randomized therapy or received another anti-cancer therapy prior to progression. Progression was determined by the site Investigator. Patients who had not progressed or died at the time of analysis were censored at the time of the latest date of assessment from their last evaluable RECIST 1.1 assessment. If patients had no evaluable visits or baseline data, the patient was censored at Study Day 1, unless death occurred within 17 weeks i.e., death within 17 weeks was relative to randomization. Here, the study patient population was stratified as follows: BRCAm patients; non BRCAm HRRm patients; non HRRm patients.

Progression-free survival was defined as time from randomization until the date of objective disease progression or death, regardless of whether the patient withdrew from randomized therapy or received another anti-cancer therapy prior to progression. Progression was determined by BICR using RECIST 1.1. Patients who had not progressed or died at the time of analysis were censored at the time of the latest date of assessment from their last evaluable RECIST assessment. If patients had no evaluable visits or baseline data, the patient was censored at Study Day 1, unless death occurred within 17 weeks i.e., death within 17 weeks was relative to randomization. Here, the study patient population was presented as follows: HRRm and all enrolled patients.

The objective response was defined as patients with at least one BICR assessed visit response of CR or PR. For sensitivity analysis, objective response was defined as the patients with at least one visit response of CR or PR based on Investigator data. These are unadjusted percentages of responders (100 \* number of responders / number of patients in full analysis set). The objective response was assessed per RECIST 1.1 guidelines for: measurable lesions (measured at baseline as ≥ 10 mm in the longest diameter (except lymph nodes which must have short axis ≥ 15 mm) using CT or MRI, non-measurable lesions (all other lesions, including small lesions (longest diameter \<10 mm or pathological lymph nodes with ≥10 to \<15mm short axis at baseline), based on target lesions \[TL\] (maximum of 5 measurable lesions (with a maximum of 2 lesions per organ), non-target lesions \[NTL\] (lesions (or sites of disease) not recorded as TL should be identified as NTL at baseline) and any new lesions.

The ORR was defined using BICR data to define a visit response of CR or PR, with denominator defined as number of patients in FAS. For sensitivity analysis, ORR is defined as the percentage of patients with at least one investigator-assessed visit response of CR or PR, with denominator defined as number of patients in FAS. These are summarized using adjusted response rates, which are computed with a logistic regression including factors study treatment and prior platinum-based therapy (no, yes), i.e. these response rates are adjusted for prior platinum-based therapy, which is one of the randomisation stratification factors. The adjusted response rates have been presented as a percentage of patients.

The DoR was defined as the time from the date of first documented response according to BICR data until date of documented progression according to BICR data or death in the absence of disease progression. For sensitivity analysis, DoR was defined as the time from the date of first documented response according to Investigator assessment until date of documented progression according to Investigator assessment or death in the absence of disease progression. Here, the median DoR and the 25th and 75th percentile of DoR are presented. The DoR from onset of response was calculated using Kaplan-Meier technique. Here, the study patient population was stratified as follows: BRCAm patients; non BRCAm HRRm patients; non HRRm patients.

Tumour size was the sum of the longest diameters of the target lesions (TLs). The percentage change in TL tumour size at Week 16 was obtained for each patient as follows (considering a visit window around the scheduled day of the Week 16 assessment): (TL at Week 16 minus TL at baseline) divided by (TL at baseline) multiplied by 100. Here, the percentage change data have been reported as per BICR and as per sensitivity analysis per investigator assessments. Here, the study patient population was stratified as follows: BRCAm patients; non BRCAm HRRm patients; non HRRm patients.

Overall survival was defined as the time from the date of randomisation until death due to any cause. Any patient not known to have died at the time of data cut-off was censored based on the last recorded date on which the patient was known to be alive. Here, the study patient population was stratified as follows: BRCAm patients; non BRCAm HRRm patients; non HRRm patients.

Plasma drug concentrations of olaparib are evaluated to assess exposure to olaparib in all patients.

Plasma drug concentrations of ceralasertib and adavosertib are evaluated to assess exposure to ceralasertib and adavosertib in all patients.

Treatment-emergent adverse events reported after treatment with olaparib monotherapy, the combination of ceralasertib and olaparib or the combination of adavosertib and olaparib. The data includes adverse events (AEs) with an onset or worsening date on or after the date of first dose and up to and including 30 days following the date of last dose of study medication.

AstraZeneca

Full analysis set population is used for All-cause Mortality as death formed part of efficacy. However, safety analysis set is used for serious adverse events and non-serious adverse event as the adverse events form part of safety and not efficacy.

Randomized patients received olaparib monotherapy 300 mg twice daily (BD) \[28-day cycle\], until objective radiological disease progression as per Response Evaluation Criteria In Solid Tumours Version (RECIST 1.1) as assessed by the Investigator or until any other discontinuation criteria were met.

Olaparib Monotherapy

Randomized patients received ceralasertib 160 mg once daily (OD) from Days 1 to 7 and olaparib 300 mg twice daily (28-day cycle), until objective radiological disease progression as per RECIST 1.1 as assessed by the Investigator or until any other discontinuation criteria were met.

Olaparib + Ceralasertib

Randomized patients received adavosertib 150 mg BD from days 1 to 3 and days 8 to 10 and olaparib 200 mg BD (21-day cycle), until objective radiological disease progression as per RECIST 1.1 as assessed by the Investigator or until any other discontinuation criteria were met. The adavosertib dose was reduced from 175 mg to 150 mg BD through implementation of clinical study protocol (CSP) version 5.0.

Olaparib + Adavosertib

Total

Age, Continuous

<40 Years

>=40 to <50 Years

>=50 to <65 Years

>=65 to <75 Years

>=75 Years

Age, Customized

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Full analysis set: All randomized patients were analyzed according to the randomization scheme, regardless of the treatment they actually received.

The interpretation of efficacy results of the adavosertib + olaparib arm and comparison with the olaparib monotherapy arm and ceralasertib + olaparib arm is limited due to the lower number of patients with available data in the adavosertib + olaparib arm, the nature of the analysis (intent-to-treat), and the fact that some of the patients switched from adavosertib + olaparib treatment to olaparib monotherapy.

Global Clinical Lead

BRCAm patients

non BRCAm HRRm patients

non HRRm patients

All randomized patients were analyzed according to the randomisation scheme, regardless of the treatment they actually received. Here, number analyzed reflects number of patients enrolled in each stratum per treatment arm.

Progression-free Survival Per Stratum (BICR)

All randomized patients were analyzed according to the randomisation scheme, regardless of the treatment actually they received. Here, number analyzed reflects number of patients enrolled in each stratum per treatment arm.

Progression-free Survival Per Stratum (Sensitivity Analysis)

HRRm patients per BICR

All patients per BICR

All randomized patients were analyzed according to the randomization scheme, regardless of the treatment they actually received. Here, number analyzed reflects number of patients enrolled in each stratum per treatment arm.

Progression-free Survival (Per BICR)

BRCAm patients per BICR

non BRCAm HRRm patients per BICR

non HRRm patients per BICR

BRCAm patients per sensitivity analysis

non BRCAm HRRm per sensitivity analysis

non HRRm per sensitivity analysis

Number of Patients With Objective Response (Per BICR and Per Sensitivity Analysis)

Objective Response Rate (ORR) (Per BICR and Per Sensitivity Analysis)

All randomized patients were analyzed according to the randomization scheme, regardless of the treatment they actually received. Here, number analyzed reflects number of patients with objective response.

Duration of Response (DoR) [Per BICR and Per Sensitivity Analysis]

All randomized patients were analyzed according to the randomization scheme, regardless of the treatment they actually received. Here, number analyzed reflects the number of patients with an observed or imputed value for the percentage change from baseline at week 16.

Percentage Change From Baseline in Target Lesion Tumour Size [Per BICR and Per Sensitivity Analysis]

Overall Survival (OS)

Pharmacokinetic (PK) analysis set included patients who have received at least one dose of study medication per the protocol and for whom there was at least one reportable PK concentration.

Plasma Drug Concentrations of Olaparib

PK analysis set included patients who have received at least one dose of study medication per the protocol and for whom there was at least one reportable PK concentration.

Plasma Drug Concentrations of Ceralasertib and Adavosertib

Any AE

Any AE causally related to olaparib

Any AE causally related to non-olaparib

Any AE causally related to non-olaparib and olaparib

Any AE with outcome = death

Any AE with outcome = death, causally related to olaparib

Any AE with outcome = death, causally related to non-olaparib

Any AE with outcome = death, causally related to non-olaparib and olaparib

Any SAE

Any SAE causally related to olaparib

Any SAE causally related to non-olaparib

Any SAE causally related to non-olaparib and olaparib

Any AE leading to discontinuation of study treatment

AEs leading to reduction of study treatment

AEs leading to reduction of olaparib

AEs leading to reduction of non-olaparib

AEs leading to reduction of non-olaparib and olaparib

The safety analysis set included all patients who received at least one dose of randomized treatment according to the treatment they actually received.

Number of Patients With Treatment Emergent Adverse Events (TEAEs)

Overall Study

Antirheumatic Agents

Anti-Infective Agents

Docetaxel

Pertuzumab

Cyclophosphamide

Doxorubicin

Liposomal doxorubicin

Epirubicin

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Anti-Bacterial Agents

Antibiotics, Antitubercular

Doxorubicin liposome（PLD）35 mg/m2 Cyclophosphamide（CTX）600 mg/m2 Trastuzumab：first cycle 8mg/kg，then 6mg/kg Pertuzumab：first cycle 840mg，then 420mg Docetaxel（DOC）75 mg/m2 every 3 weeks paclitaxel (PTX) 175 mg/m2 every 3 weeks or paclitaxel (PTX) 80 mg/m2 every week albumin-bound paclitaxel 260 mg/m2 or albumin-bound paclitaxel 100 mg/m2 every week

Epirubicin（EPI）90 mg/m2 Cyclophosphamide（CTX）600 mg/m2 Trastuzumab：first cycle 8mg/kg，then 6mg/kg Pertuzumab：first cycle 840mg，then 420mg Docetaxel（DOC）75 mg/m2 every 3 weeks paclitaxel (PTX) 175 mg/m2 every 3 weeks or paclitaxel (PTX) 80 mg/m2 every week albumin-bound paclitaxel 260 mg/m2 or albumin-bound paclitaxel 100 mg/m2 every week

Doxorubicin liposome

paclitaxel (PTX) 175 mg/m2 every 3 weeks or paclitaxel (PTX) 80 mg/m2 every week

albumin-bound paclitaxel 260 mg/m2 or albumin-bound paclitaxel 100 mg/m2 every week

Paclitaxel-albumin

Wen Xia, MD

Breast cancer is the most common malignant tumor in women. EC-TH is one of the standard chemotherapy regimens for HER-2 positive early breast cancer(EBC). Earlier use of trastuzumab may improve DFS rate. In this study, the investigators want to find out whether ACH-TH regimen compared with the EC-TH regimen in HER2+ EBC could improve the pCR rate in neoadjuvant chemotherapy.

We update protocol in Sep 2020, because Pertuzumab is approveled by Chinese goverment and coverd by national insurance, dual target therapy with Trastuzumab and Pertuzumab is the standard therapy for neoadjuvant therapy of HER2-positive EBC patients.

Breast cancer is the most common malignant tumor in women. EC-TH is one of the standard chemotherapy regimens for HER-2 positive early breast cancer(EBC). Earlier use of trastuzumab could improve the DFS rate in HER2+ EBC. But due to the cardio-toxicity of both anthracycline and trastuzumab, the investigators usually avoid using these two drugs synchronously. The guidelines do not recommend ECH-TH regemin because of cardiac adverse effect. Doxorubicin liposome(A) has equivalent effect as anthracycline in advaced breast cancer(ABC), lower cardiac toxicity and could be combined use with trastuzumab. In this study, the investigators want to find out whether ACH-TH regimen compared with the EC-TH regimen in HER2+ EBC could improve the pCR rate in neoadjuvant chemotherapy.

We update protocol in Sep 2020, because Pertuzumab is approveled by Chinese goverment and coverd by national insurance, dual target therapy with Trastuzumab and Pertuzumab is the standard therapy for neoadjuvant therapy of HER2-positive EBC patients. So now we want to compare ACHP-THP regimen compared with the EC-THP regimen in HER2+ EBC could improve the pCR rate in neoadjuvant chemotherapy.

ACHP-THP vs EC-THP as Neoadjuvant Therapy for HER2-positive EBC

A Multi-center Randomized Phase II Study of Doxorubicin Liposome Versus Epirubicin Plus Cyclophosphamide Combined With Trastuzumab and Pertuzumab(HP), Followed by Taxon Plus HP as Neoadjuvant Therapy for HER2-positive Early Breast Cancer

Pathological complete response (pCR) in the breast tissue and the lymph node tissue will be assessed upon completion of pre-operative systemic therapy and definitive surgery.

CRR is defined as the proportion of subjects with complete or partial radiographic response of the primary tumor as determined by the central imaging vendor.

EFS will be defined as the time from random assignment to documentation of the first of the following events: discontinuation of study therapy due to protocol-defined progression prior to surgery; local, regional, or distant recurrence of breast cancer following curative surgery; a new breast cancer; another new onset malignancy; or death as a result of any cause.

OS will be defined as the number of days from the day the subject is randomized to the date of the subject's death.

Incidence of chemotherapy-induced cardiotoxicity, according to NCI-CTCAE 4.03 version.

The EuroQol EQ-5D is a 6-item instrument designed to assess health status in terms of a single index value or utility score. It contains 5 descriptors of current health state (mobility, self-care, usual activities, pain or discomfort, and anxiety or depression) with each dimension having 3 levels of function (1=no problem, 2=some problem, and 3=extreme problem). The scores on the 5 descriptors are summarized to create a single summary score. An overall utility score is calculated based on these domains, with a range score from 0 (worse health scenario) to a maximum of 1.0 (best health scenario).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Re-Examination of Tumor Material and Re-Evaluation of Patient Data From Patients Treated With Neo-adjuvant Therapy	NCT02449993	Breast Cancer	MammaTyper™	18 Years - 70 Years	BioNTech Diagnostics GmbH
PAM50 HER2-enriched Phenotype as a Predictor of Response to Dual HER2 Blockade in HER2-positive Early Breast Cancer	NCT01973660	Breast Cancer	Lapatinib Trastuzumab Endocrine Thera... Paclitaxel	18 Years -	SOLTI Breast Cancer Research Group
To Assess Safety and Efficacy of Agents Targeting DNA Damage Repair With Olaparib Versus Olaparib Monotherapy.	NCT03330847	Metastatic Trip...	Olaparib Contin... Ceralasertib 16... Adavosertib 150...	18 Years - 130 Years	AstraZeneca
ACHP-THP vs EC-THP as Neoadjuvant Therapy for HER2-positive EBC	NCT04172259	Breast Cancer Neoadjuvant Che...	Doxorubicin lip... Cyclophosphamid... Trastuzumab Docetaxel Epirubicin Pertuzumab Paclitaxel Paclitaxel-albu...	18 Years - 70 Years	Sun Yat-sen University
Anti-HER2 Therapy in Patients of HER2 Positive Metastatic Carcinoma of Digestive System	NCT03185988	Targeted Therap... HER2 Biliary Tract C... Esophageal Squa... Colorectal Canc...	chemotherapy in... chemotherapy in... chemotherapy in... chemotherapy in...	18 Years - 75 Years	Peking University
Re-Examination of Tumor Material and Re-Evaluation of Patient Data From Patients Treated With Neo-adjuvant Therapy	NCT02449993	Breast Cancer	MammaTyper™	18 Years - 70 Years	BioNTech Diagnostics GmbH
A Trial Using ARV-471 or Anastrozole in Post-Menopausal Women With Breast Cancer Prior to Surgery	NCT05549505	Breast Cancer	ARV-471 Anastrozole Surgical resect...	18 Years -	Arvinas Inc.
Binary Oncolytic Adenovirus in Combination With HER2-Specific Autologous CAR VST, Advanced HER2 Positive Solid Tumors	NCT03740256	Bladder Cancer Head and Neck S... Cancer of the S... Lung Cancer Breast Cancer Gastric Cancer Esophageal Canc... Colorectal Canc... Pancreatic Aden... Solid Tumor	CAdVEC	18 Years -	Baylor College of Medicine

Spots Global Cancer Trial Database for human epidermal growth factor receptor 2