Randomized Controlled Trial of Genomically Directed Therapy in Patients With Triple Negative Breast Cancer

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Basic Trial Information

PhaseTypeStatusAgeTrial IDs
Phase IITreatmentActive18 and overBRE12-158
NCI-2015-00307, NCT02101385

Trial Description


This study will test the theory that therapy designed for each individual's tumor will

improve outcomes over standard of care in a population that needs a better standard.

Further Study Information

OUTLINE: This is a multi-center trial.


DNA from archived tumor samples collected at the time of surgery (residual disease post

neoadjuvant chemotherapy) will be extracted and sequenced. The resulting sequencing data

will be interrogated for known genomic drivers of sensitivity or resistance to existing FDA

approved agents.


Realizing that optimal treatment recommendations cannot be made based on sequencing data

alone, the CGTB will be responsible for the final treatment recommendation. The CGTB will

consider the genomic data along with the patient's prior treatment history, ongoing

toxicities, and comorbidities. Preference will be given to the treatment identified by the

sequencing data unless a significant clinical or safety contraindication exists for that

therapy. All participants and investigators will be blinded to sequencing results and CGTB

deliberations until the time of relapse.


Participants with a CGTB recommendation will be randomized to Experimental Arm A

(genomically directed monotherapy) or Control Arm B (standard therapy).


Participants randomized to Experimental Arm A will receive an FDA approved drug at standard

dose for four cycles (12-16 weeks total duration, depending on cycle length). Clinical and

laboratory monitoring and dose-reductions will follow the FDA package insert guidelines.


1. PIK3CA, PTEN: Everolimus

2. TOP2A: Doxorubicin

3. PARP1, BRCA1: Cisplatin and Olaparib

4. VEGFA: Bevacizumab

5. TYMP: Capecitabine

6. SSTR2: Octreotide

7. MGMT: Temozolomide

8. MYC: Paclitaxel

9. EGFR: Cetuximab

10. COX2: Celecoxib

11. hENT: Gemcitabine

12. MET: Crizotinib

CONTROL ARM B (STANDARD THERAPY); Recently, a randomized phase III trial of over 900

HER2-negative patients demonstrated an improvement in disease-free survival (DFS) and

overall survival (OS) for the addition of 8 cycles of capecitabine in the post-neoadjuvant

setting. The hazard ratios were also significant in the triple negative subgroup. Thus,

capecitabine can be considered a standard option in this setting. As this represents only a

single trial (with prior data not demonstrating benefit for the addition of capecitabine in

the neoadjuvant nor adjuvant settings in unselected patients), observation can be considered

an option as directed by the treating physician. While not recommended, other therapies can

be used as deemed appropriate by the treating physician.

In the event of disease progression on the control arm, patient sequencing results will be

forwarded to the treating physician.


Participants may have no CGTB recommendation either because 1) sequencing did not identify a

matched drug or 2) the matched drug was contraindicated. These participants will be assigned

to Control Arm B and treated as described above for Control Arm B. As the outcome of

participants without an 'actionable' genomically directed therapy may differ, the primary

analysis will include only participants randomized to Control Arm B.

Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 14 days prior

to study registration

Life Expectancy: Not Specified

Adequate laboratory values must be obtained within 14 days prior to study registration:


Hemoglobin (Hgb) ≥ 9.0 g/dL

Platelets ≥ 100 K/mm3

Absolute neutrophil count (ANC) ≥ 1.5 K/mm3


Bilirubin ≤ 1.5 x ULN (except in participants with documented Gilbert's disease, who

must have a total bilirubin ≤ 3.0 mg/dL)

Aspartate aminotransferase (AST, SGOT) ≤ 2.5 x ULN

Alanine aminotransferase (ALT, SGPT) ≤ 2.5 x ULN


Calculated creatinine clearance of ≥ 50 cc/min using the Cockcroft-Gault formula


Left ventricular ejection fraction within normal limits obtained within 30 days prior

to study registration. NOTE: Participants with an unstable angina or myocardial

infarction within 12 months of study registration are excluded.

No clinically significant arrhythmia or baseline ECG abnormalities in the opinion of

the treating physician

Eligibility Criteria

Inclusion Criteria:

Must have histologically or cytologically confirmed triple negative (ER-/PR-/HER2-)

invasive breast cancer, clinical stage I-III at diagnosis (AJCC 6th edition) based on

initial evaluation by physical examination and/or breast imaging prior to study

registration. NOTE: ER, PR and HER2 status will be confirmed by central pathology

review prior to randomization. ER and PR will be considered negative if ≤ 1% of cells

stain weakly positive. HER2 will be considered negative if scored 0 or 1+ by

immunohistochemistry (IHC) or 2+ by IHC associated with a fluorescence in situ

hybridization (FISH) ratio of < 2.0 or < 6 copies per cell.

Must have completed preoperative (neoadjuvant) chemotherapy. NOTE: Acceptable

preoperative regimens include an anthracycline or a taxane, or both. Participants who

received preoperative therapy as part of a clinical trial may enroll. Participants

may not have received adjuvant chemotherapy after surgery prior to randomization.

Bisphosphonate use is allowed.

Must have completed definitive resection of primary tumor. The most recent surgery

for breast cancer must have been completed at least 14 days prior (but no more than

84 days prior) to study registration. NOTE: Negative margins for both invasive and

ductal carcinoma in situ (DCIS) are desirable, however participants with positive

margins may enroll if the treatment team believes no further surgery is possible and

patient has received radiotherapy. Participants with margins positive for lobular

carcinoma in situ (LCIS) are eligible. Either mastectomy or breast conserving surgery

(including lumpectomy or partial mastectomy) is acceptable.

Must have significant residual invasive disease at the time of definitive surgery

following preoperative chemotherapy. Significant residual disease is defined as at

least one of the following:

Residual Cancer Burden (RBC) classification II or III6

Residual invasive disease in the breast measuring at least 2 cm. The presence of

DCIS without invasion does not qualify as residual disease in the breast.

Residual invasive disease in the breast measuring at least 1cm with any lymph

node involvement (does not include metastases in lymph node which are only

detected by immunohistochemistry).

Any lymph node involvement that results in 20% cellularity or greater regardless

of primary tumor site involvement (includes no residual disease in the breast).

Must have an FFPE tumor block with tumor cellularity of 20% or greater. NOTE: Prior

to randomization, the tumor cellularity will be confirmed by central pathology review

and percent values will be double checked at Paradigm (a Next Generation Sequencing



Whole breast radiotherapy is required for participants who underwent

breast-conserving therapy, including lumpectomy or partial mastectomy.

Participants must have completed radiotherapy at least 14 days prior (but no

more than 84 days prior) to study registration.

Post-mastectomy radiotherapy is required for all participants with a primary

tumor ≥ 5 cm or involvement of ≥ 4 lymph nodes. For participants with primary

tumors < 5 cm or with < 4 involved lymph nodes, provision of post-mastectomy

radiotherapy is at the discretion of the treating physician. Study registration

must occur within 84 days of completion of radiation.

For radiation required prior to surgery, the participant must register within 84

days of surgery. Also, participants in this situation would not be required to

have additional post-mastectomy radiation therapy.

For those participants who do not require radiation, registration must be within

84 days of surgery.

Age ≥ 18 years at the time of consent.

Written informed consent and HIPAA authorization for release of personal health

information. HIPAA authorization may be included in the informed consent or may be

obtained separately. NOTE: Central pathology review may be conducted any time after

definitive surgery. Consenting participants may be pre-registered to the study and

proceed with central pathology review before full eligibility has been confirmed.

However ALL of the eligibility criteria must be met and formal study registration

completed prior to submission of the sample for sequencing.

Must consent to allow submission of adequate archived tumor tissue sample from

definitive surgery for genomic assessment of tumor.

Must consent to collection of whole blood samples for genomic analysis

Women and men of childbearing potential must be willing to use an effective method of

contraception (e.g. hormonal or barrier method of birth control; abstinence) from the

time consent is signed until 4 weeks after protocol therapy discontinuation.

Women of childbearing potential must have a negative pregnancy test within 30 days

prior to study registration. Women should be counseled regarding acceptable birth

control methods to utilize from the time of screening to start of treatment. If prior

to treatment after discussion with the subject it is felt by the treating physician

there is a possibility the subject is pregnant a pregnancy test should be repeated.

Women of childbearing potential must have a negative pregnancy test within 30 days prior

to study registration.

Women must not be breastfeeding.

Exclusion Criteria:

No stage IV (metastatic) disease, however no specific staging studies are required in

the absence of symptoms or physical exam findings that would suggest distant disease.

No treatment with any investigational agent within 30 days prior to study


No history of chronic hepatitis B or or untreated hepatitis C.

No clinically significant infections as judged by the treating physician.

No active second malignancy (except non-melanomatous skin cancer or incidental

prostate cancer found on cystectomy): Active second malignancy is defined as a

current need for cancer therapy or a high possibility (> 30%) of recurrence during

the study. Previous contralateral breast cancer is allowable unless it meets "active"

criteria as stated above.

Trial Contact Information

Trial Lead Organizations / Sponsors / Collaborators

Bryan Schneider, MD

  • Hoosier Cancer Research Network
  • Vera Bradley Foundation for Breast Cancer
  • Walther Cancer Institute
  • Strategic Research Initiative Grant through IUSCC

Trial Sites



University of Alabama at Birmingham Cancer Center

Carla Isadora Falkson
Ph: 205-975-2693
Email: cfalkson@uab.edu

Carla Isadora Falkson
Principal Investigator


Emory University/Winship Cancer Institute

Elisavet Paplomata
Email: epaplom@emory.edu

Elisavet Paplomata
Principal Investigator


University of Chicago Comprehensive Cancer Center

Rita Nanda
Ph: 773-702-6149

Rita Nanda
Principal Investigator


Indiana University/Melvin and Bren Simon Cancer Center

Bryan Paul Schneider
Ph: 317-274-6473
Email: bpschnei@iupui.edu

Bryan Paul Schneider
Principal Investigator

Link to the current ClinicalTrials.gov record.
NLM Identifier NCT02101385

Note: Information about participating sites on pharmaceutical industry trials may be incomplete. Please visit the ClinicalTrials.gov record via the link above for more information about participating sites.