Breast Cancer, Triple Negative Breast Cancer
Conditions
Brief summary
This is a 3-arm study stratified by plasma ctDNA. Patients with residual TNBC disease after pre-operative therapy will be assigned to 1 of 3 Arms based on plasma ctDNA positivity and genomic marker(s).
Detailed description
Participants that are plasma ctDNA positive with a genomic target will be assigned to one of the three groups in Arm 1 and receive genomically directed therapy. * Arm 1a: DNA Repair pathway = talazoparib + capecitabine (CLOSED) * Arm 1b: Immunotherapy pathway = pembrolizumab + capecitabine (CLOSED) * Arm 1c: PI3K Pathway = inavolisib + capecitabine ---\> +/- standard of care pembrolizumab * Arm 1d: DNA Repair + Immunotherapy = talazoparib + capecitabine +/- standard of care pembrolizumab Participants that are plasma ctDNA positive without a genomic target will be assigned to Arm 2 and receive capecitabine and pembrolizumab or treatment of physician's choice. Participants that are plasma ctDNA negative will be assigned to Arm 3 and receive any of the following based on patient and physician decision: no therapy/observation, capecitabine and pembrolizumab or treatment of physician's choice.
Interventions
DRUGCapecitabine
Capecitabine 1000 mg/m2 BID Orally 14 days on and 7 days off Cycle = 21 days; Total of 8 cycles
DRUGTalazoparib
Talazoparib Cycle 1: 0.75 mg then Cycle 2-8: 1 mg Cycle = 21 days; Total of 8 cycles
DRUGPembrolizumab
Per standard of care.
DRUGInavolisib
Inavolisib Cycle 1: 6 mg then Cycle 2-8: 9mg Orally 21 days on Cycle = 21 days; Total of 8 cycles
Sponsors
Genentech, Inc.
Pfizer
Foundation Medicine
Indiana University
Vera Bradley Foundation for Breast Cancer
Bryan Schneider, MD
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
General Inclusion Criteria * Written informed consent and HIPAA authorization for release of personal health information. NOTE: HIPAA authorization may be included in the informed consent or may be obtained separately. * Age ≥ 18 years at the time of consent. * ECOG Performance Status 0 or 1 within 28 days prior to study registration. * Must have histologically or cytologically confirmed triple negative (ER-/PR-/HER2-) invasive breast cancer per pathology report. NOTE: ER and PR will be considered negative if ≤ 10% 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 clinical stage I-III at diagnosis (AJCC 8th edition) based on initial evaluation by physical examination and/or breast imaging prior to neoadjuvant chemotherapy. * Must have completed preoperative (neoadjuvant) chemotherapy for this index case. 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 registration. Bisphosphonate use is allowed. * Subjects who received pembrolizumab in the neoadjuvant setting are eligible and may continue treatment during the screening process. Subjects assigned to Arm 1 will require a 3 week wash out period prior to initiation of study treatment. Subjects may resume pembrolizumab to complete the planned year of therapy (17 cycles) after completion of study therapy based on investigator discretion. Subjects assigned to Arm 2 and Arm 3 may continue pembrolizumab treatment during the study based on investigator discretion. Total duration of pembrolizumab treatment should not be extended beyond 17 cycles. * 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 invasive disease in the breast measuring at least 1 cm. The presence of DCIS without invasion does not qualify as residual disease in the breast. * Any macroscopic, (≥ 2mm) residual, lymph node involvement regardless of primary tumor site involvement (includes no residual disease in the breast). * Residual cancer burden (RCB) score 2 or 3. * Must have completed definitive resection of primary tumor. Participants must begin assigned arm therapy no later than 96 days from the last local therapy. NOTE: Negative margins for both invasive and ductal carcinoma in situ (DCIS) are desirable, however participants with positive margins may enroll if the study site treatment team believes no further surgery is possible and participant 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. * Breast Radiotherapy * Radiotherapy is required for participants who underwent breast-conserving therapy, including lumpectomy or partial mastectomy unless deemed inappropriate by the treating provider. * Post mastectomy radiation is at the discretion of the treating physician. * If radiation was given prior to surgery, additional radiation after surgery is not required. * In all cases participants must begin arm assigned therapy no later than 96 days from the last local therapy * Any acute toxicity must have resolved to grade \< 2 prior to starting arm specific therapy. * Must consent to allow submission of blood and archived tumor tissue sample from definitive surgery for next generation sequencing of the tumor. Tumor block is preferred however 14 slides + 1H&E can be submitted if necessary. NOTE: Due to possible false positives, ctDNA should not be drawn before completing radiation or less than 14 days from surgery if radiation is not required. * Adequate laboratory values must be obtained within 28 days prior to study registration. * Hemoglobin (Hgb) ≥ 9.0 g/dL * Platelets ≥ 100 K/mm3 * Absolute neutrophil count (ANC) ≥ 1.5 K/mm3 * Calculated creatinine clearance of ≥ 50 cc/min using the Cockcroft-Gault formula * Bilirubin ≤ 1.5 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 ULN * Alanine aminotransferase (ALT, SGPT) ≤ 2.5 ULN * Women of childbearing potential and their partners and male subjects and their partners must be willing to use effective contraception (as outlined in protocol) from the time consent is signed until after protocol therapy discontinuation based on package insert or investigator brochure guidelines (See protocol for timeframes). * Women of childbearing potential must have a negative urine or serum pregnancy test at screening and within 7 days prior to study registration. Women should be counseled regarding acceptable birth control methods to utilize. 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. NOTE: Women are considered not of childbearing potential if they are surgically sterile (they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy), or they are postmenopausal for at least 12 consecutive months. * Women must not be breastfeeding from the time of treatment initiation until the number of days after protocol therapy discontinuation based on package insert or investigator brochure guidelines (See protocol for timeframes). Inclusion Criteria for Patients Assigned to Arm 1c ONLY -Adequate laboratory values must be obtained within 21 days prior to starting arm therapy. * Fasting total glucose ≤ 126 mg/dL * HbA1C ≤ 5.7% * Cholesterol \< 300 mg/dL; 10.34 mmol/L * Triglycerides \< 300 mg/dL; 3.42 mmol/L General
Exclusion criteria
* Clinically significant infections as judged by the treating physician. * 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. * HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of registration are eligible for this trial. NOTE: Patients without a known history of being HIV positive do not require testing at screening. Patients who are known to be HIV positive will require testing as described to be eligible for this trial. Testing should be considered standard of care. * Patients with evidence of chronic hepatitis B virus (HBV) infection, with undetectable HBV viral load within 6 months of registration are eligible for this trial. They should be on suppressive therapy, if indicated. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, the HCV viral load must be undetectable within 6 months of registration to be eligible for this trial. NOTE: Patients without a known history of being hepatitis positive do not require testing at screening. Patients who are known to be hepatitis positive will require testing as described to be eligible for this trial. Testing should be considered standard of care. * Participants with unstable angina or a myocardial infarction within 12 months of study registration. * 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. * Inability to swallow pills. * Evidence of significant uncontrolled concomitant disease that could affect compliance with the protocol, safety of participation, or interpretation of results. This includes significant liver disease (such as cirrhosis, uncontrolled major seizure disorder, or superior vena cava syndrome) or any other serious medical condition or abnormality in clinical laboratory tests that meet these criteria in the investigator's opinion. * History of severe allergic, anaphylactic, or other hypersensitivity reactions to any of the study medications being used in this study. * Treatment with any investigational agent within 30 days prior to study registration.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| ARM 1c: Disease Free Survival (DFS) at 2 Years | 2 years | DFS is defined as the duration of time from arm assignment to time of a DFS event, defined as local failure (invasive), regional failure, distant failure, contralateral breast cancer (invasive or non-invasive), or death from any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| ARM 3:Disease Free Survival (DFS) at 2 Years | 2 years | DFS is defined as the duration of time from arm assignment to time of a DFS event, defined as local failure (invasive), regional failure, distant failure, contralateral breast cancer (invasive or non-invasive), or death from any cause. |
| Overall Disease Free Survival (DFS) | Up to 29 months | Comparison of overall DFS in Arms 1c, 2, 3. DFS is defined as the duration of time from arm assignment to time of a DFS event such as local failure (invasive), regional failure, distant failure, contralateral breast cancer (invasive or non-invasive), or death from any cause |
| Overall Distant Disease Free Survival (DDFS) | Up to 29 months | DDFS is defined as the duration of time from arm assignment to time of recurrence of breast cancer outside the breast and/or death from any cause. |
| ARM 2: Disease Free Survival (DFS) at 2 Years | 2 years | DFS is defined as the duration of time from arm assignment to time of a DFS event, defined as local failure (invasive), regional failure, distant failure, contralateral breast cancer (invasive or non-invasive), or death from any cause. |
| Overall Survival (OS) at 5 Year | 5 years | Overall survival is defined as the time from date of treatment start until death from any cause. |
| Number of Participants With Adverse Events | Up to 16 months | Adverse events (regardless of relationship with study drug) will be assessed using the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) criteria v5 |
| 1-year Disease Free Survival (DFS) | 1 year | Compare 1-year DFS in Arms 1c, 2, 3. DFS is defined as the duration of time from arm assignment to time of a DFS event, defined as local failure (invasive), regional failure, distant failure, contralateral breast cancer (invasive or non-invasive), or death from any cause |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm 1c: ctDNA Positive Genomically Directed - PI3K Pathway Arm 1c: Patients who are ctDNA-positive and harbor a genomic target. PI3K Pathway = inavolisib + capecitabine ---\> +/- standard of care pembrolizumab | 1 |
| Arm 2: ctDNA Positive - Standard of Care Arm 2 subjects have plasma ctDNA positive but do not have a genomically driven treatment option. Treatment of physician's choice will be given with consideration for capecitabine and pembrolizumab. Dose, schedule and duration of treatment to be determined by treating physician.
Capecitabine: Capecitabine 1000 mg/m2 BID Orally 14 days on and 7 days off Cycle = 21 days; Total of 8 cycles
Pembrolizumab: Per standard of care. | 4 |
| Arm 3: ctDNA Negative - Physician's Choice Arm 3 subjects have plasma ctDNA negative. Treatment of patient and physician's choice will be given with consideration for capecitabine and pembrolizumab. Dose, schedule and duration of treatment to be determined by treating physician.
Capecitabine: Capecitabine 1000 mg/m2 BID Orally 14 days on and 7 days off Cycle = 21 days; Total of 8 cycles
Pembrolizumab: Per standard of care. | 46 |
| Total | 51 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Eligibility criteria not meet | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Arm 3: ctDNA Negative - Physician's Choice | Arm 2: ctDNA Positive - Standard of Care | Arm 1c: ctDNA Positive Genomically Directed - PI3K Pathway |
|---|---|---|---|---|
| Age, Continuous | 51 years | 51 years | 55 years | 47 years |
| ECOG Performance Status ECOG = 0 | 40 Participants | 37 Participants | 2 Participants | 1 Participants |
| ECOG Performance Status ECOG = 1 | 10 Participants | 8 Participants | 2 Participants | 0 Participants |
| ECOG Performance Status Missing | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 5 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 46 Participants | 41 Participants | 4 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 13 Participants | 12 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 37 Participants | 33 Participants | 3 Participants | 1 Participants |
| Region of Enrollment United States | 51 participants | 46 participants | 4 participants | 1 participants |
| Sex: Female, Male Female | 51 Participants | 46 Participants | 4 Participants | 1 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 1 / 4 | 4 / 46 |
| other Total, other adverse events | 1 / 1 | 3 / 4 | 33 / 46 |
| serious Total, serious adverse events | 0 / 1 | 1 / 4 | 3 / 46 |
Outcome results
Primary
ARM 1c: Disease Free Survival (DFS) at 2 Years
DFS is defined as the duration of time from arm assignment to time of a DFS event, defined as local failure (invasive), regional failure, distant failure, contralateral breast cancer (invasive or non-invasive), or death from any cause.
Time frame: 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1c: ctDNA Positive Genomically Directed - PI3K Pathway | ARM 1c: Disease Free Survival (DFS) at 2 Years | 100 Percentage of participants |
Secondary
1-year Disease Free Survival (DFS)
Compare 1-year DFS in Arms 1c, 2, 3. DFS is defined as the duration of time from arm assignment to time of a DFS event, defined as local failure (invasive), regional failure, distant failure, contralateral breast cancer (invasive or non-invasive), or death from any cause
Time frame: 1 year
Population: In accordance with the Statistical Analysis Plan, the analysis population for the endpoint Disease free survival was defined as all patients who received at least one dose of study treatment and have had at least one post baseline disease assessment or die before first assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1c: ctDNA Positive Genomically Directed - PI3K Pathway | 1-year Disease Free Survival (DFS) | 100 Percentage of participants |
| Arm 2: ctDNA Positive - Standard of Care | 1-year Disease Free Survival (DFS) | 0 Percentage of participants |
| Arm 3: ctDNA Negative - Physician's Choice | 1-year Disease Free Survival (DFS) | 79.8 Percentage of participants |
Secondary
ARM 2: Disease Free Survival (DFS) at 2 Years
DFS is defined as the duration of time from arm assignment to time of a DFS event, defined as local failure (invasive), regional failure, distant failure, contralateral breast cancer (invasive or non-invasive), or death from any cause.
Time frame: 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1c: ctDNA Positive Genomically Directed - PI3K Pathway | ARM 2: Disease Free Survival (DFS) at 2 Years | 0 Percentage of participants |
Secondary
ARM 3:Disease Free Survival (DFS) at 2 Years
DFS is defined as the duration of time from arm assignment to time of a DFS event, defined as local failure (invasive), regional failure, distant failure, contralateral breast cancer (invasive or non-invasive), or death from any cause.
Time frame: 2 years
Population: In accordance with the Statistical Analysis Plan, the analysis population for the endpoint Disease free survival was defined as all patients who received at least one dose of study treatment and have had at least one post baseline disease assessment or die before first assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1c: ctDNA Positive Genomically Directed - PI3K Pathway | ARM 3:Disease Free Survival (DFS) at 2 Years | 40.2 Percentage of participants |
Secondary
Number of Participants With Adverse Events
Adverse events (regardless of relationship with study drug) will be assessed using the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) criteria v5
Time frame: Up to 16 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1c: ctDNA Positive Genomically Directed - PI3K Pathway | Number of Participants With Adverse Events | 1 Participants |
| Arm 2: ctDNA Positive - Standard of Care | Number of Participants With Adverse Events | 3 Participants |
| Arm 3: ctDNA Negative - Physician's Choice | Number of Participants With Adverse Events | 42 Participants |
Secondary
Overall Disease Free Survival (DFS)
Comparison of overall DFS in Arms 1c, 2, 3. DFS is defined as the duration of time from arm assignment to time of a DFS event such as local failure (invasive), regional failure, distant failure, contralateral breast cancer (invasive or non-invasive), or death from any cause
Time frame: Up to 29 months
Population: In accordance with the Statistical Analysis Plan, the analysis population for the endpoint Disease free survival was defined as all patients who received at least one dose of study treatment and have had at least one post baseline disease assessment or die before first assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1c: ctDNA Positive Genomically Directed - PI3K Pathway | Overall Disease Free Survival (DFS) | 27.7 Months |
| Arm 2: ctDNA Positive - Standard of Care | Overall Disease Free Survival (DFS) | 8.1 Months |
| Arm 3: ctDNA Negative - Physician's Choice | Overall Disease Free Survival (DFS) | 23.1 Months |
Secondary
Overall Distant Disease Free Survival (DDFS)
DDFS is defined as the duration of time from arm assignment to time of recurrence of breast cancer outside the breast and/or death from any cause.
Time frame: Up to 29 months
Population: In accordance with the Statistical Analysis Plan, the analysis population for the endpoint Disease free survival was defined as all patients who received at least one dose of study treatment and have had at least one post baseline disease assessment or die before first assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1c: ctDNA Positive Genomically Directed - PI3K Pathway | Overall Distant Disease Free Survival (DDFS) | 27.7 Months |
| Arm 2: ctDNA Positive - Standard of Care | Overall Distant Disease Free Survival (DDFS) | 8.1 Months |
| Arm 3: ctDNA Negative - Physician's Choice | Overall Distant Disease Free Survival (DDFS) | 23.1 Months |
Secondary
Overall Survival (OS) at 5 Year
Overall survival is defined as the time from date of treatment start until death from any cause.
Time frame: 5 years
Population: In accordance with the Statistical Analysis Plan, the analysis population for the endpoint 5 -years Overall survival was defined as all patients who received at least one dose of study treatment and have follow-up up to 5 years. Because of the early termination, 5-year overall survival was not reached by any subjects.