The primary objective of the study is to assess the incidence of pathological complete response (pCR) in breast and ipsilateral axillary tissue after daily treatment with veliparib in combination with neoadjuvant carboplatin and paclitaxel followed…
ID
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms benign
- Breast disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Pathological Complete Response (pCR) will be defined by the absence of any
residual invasive cancer on hematoxylin and eosin evaluation of the resected
breast specimen and any resected lymph node tissue following completion of
neoadjuvant systemic therapy (i.e., ypT0/Tis ypN0 per AJCC staging system). The
co-primary efficacy analyses are defined by comparing pCR in two pairwise
comparisons of Arm A versus Arm B and Arm A versus Arm C. The percentage of
subjects with pCR will be calculated for each treatment arm and will be
compared between the active arm (Arm A) and each of the two control arms (Arm B
and C) by two pairwise comparisons (Arm A versus Arm B and Arm A versus Arm C)
using the Cochran-Mantel-Haenszel (CMH) test stratified by the stratification
factors (BRCA status, lymph node stage and planned schedule of
doxorubicin/cyclophosphamide administration) at the alpha = 0.05 significance
level. Both comparisons in the co-primary analyses need to be statistically
significant to claim efficacy of veliparib.
Secondary outcome
Event Free Survival (EFS):
Event Free Survival (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 invasive recurrence of breast cancer following curative surgery; a
new breast cancer; a new onset malignancy; or death as a result of any cause.
If a subject has not experienced above events, then the subject will be
censored at date of last available disease assessment. At the completion of
the study, EFS will be compared between the treatment arms by the two pairwise
comparison (Arm A versus Arm B and Arm A versus Arm C) using the log rank test,
stratified by the stratification factors, at the alpha = 0.05 significance
level. Only descriptive statistics will be calculated for EFS when the
analysis for the primary endpoint (pCR) is performed.
Overall Survival (OS):
Overall Survival (OS) will be defined as the number of days from the day the
subject is randomized to the date of the subject's death. All events of death
will be included, regardless of whether the event occurs while the subject is
still taking study drug, or after the subject discontinues study drug. If a
subject has not died, then the data will be censored at the date when the
subject is last known to be alive. At the completion of the study, OS will be
compared between the treatment arms by the two pairwise (Arm A versus Arm B and
Arm A versus Arm C) using the log rank test, stratified by the stratification
factors, at the alpha = 0.05 significance level. Only descriptive statistics
will be calculated for OS when the analysis for the primary endpoint (pCR) is
performed.
Breast Conservation Rate (BCR):
Breast Conservation Rate (BCR) will be defined as the rate at which subjects
are eligible for breast conservation after neoadjuvant therapy among subjects
for whom mastectomy was planned at diagnosis. The Breast Conservation Rate at
the pre-operative visit will be calculated for each treatment arm and will be
compared between the active arm (Arm A) and each of the two control arms (Arms
B and C) by two pairwise comparisons (Arm A versus Arm B and Arm A versus Arm
C) using the Cochran-Mantel-Haenszel (CMH) test stratified by the
stratification factors (BRCA status, lymph node stage and planned schedule of
doxorubicin/cyclophosphamide administration) at the alpha = 0.05 significance
level.
Background summary
Breast cancer is the most common cancer in women worldwide with approximately
1,380,000 new cases and 460,000 deaths estimated in 2008. Survival for early
invasive breast cancer is improved with the addition of chemotherapy and/or
radiotherapy to surgery for all but small, localized tumors. According to
global breast cancer care guidelines, neoadjuvant chemotherapy should contain
anthracyclines and taxanes. In breast cancer, administration of carboplatin to
previously untreated patients with metastatic disease results in response rates
of 20% to 50%. Paclitaxel in combination with carboplatin is also highly active
in breast cancer, with response rates of approximately 39% to 62% for
first-line treatment of metastatic disease. Consistent with the observation
that PARP activity may act as a resistance factor in some
tumors, PARP inhibitors have been shown in preclinical models to sensitize
tumors to a variety of DNA-damaging agents, including cross-linking
chemotherapy agents such as carboplatin and to ionizing radiation therapy.
Veliparib is a potent PARP inhibitor that delays the repair of DNA damage
induced by chemotherapeutics. Veliparib increases sensitivity of tumor cells to
DNA-damaging agents in vitro and
in vivo, and inhibits PARP in murine tumors in vivo, human peripheral blood
mononuclear cells (PBMCs) ex vivo, and human tumors ex vivo.
Study objective
The primary objective of the study is to assess the incidence of pathological
complete response (pCR) in breast and ipsilateral axillary tissue after daily
treatment with veliparib in combination with neoadjuvant carboplatin and
paclitaxel followed by doxorubicin + cyclophosphamide compared to two
neoadjuvant chemotherapy regimens (paclitaxel followed by doxorubicin +
cyclophosphamide; carboplatin and paclitaxel followed by doxorubicin +
cyclophosphamide) with matching placebo in subjects with triple negative breast
cancer.
The secondary objective of the study is to assess event free survival (EFS),
overall survival (OS) and the rate of eligibility for breast conservation after
therapy (BCR).
The tertiary objectives are to assess clinical response rate (CRR) at 12 weeks,
incidence of pCR plus minimal residual disease (defined as residual cancer
burden [RCB] class I), Eastern Cooperative Oncology Group (ECOG) performance
status, and breast cancer related quality of life (QoL).
Study design
This is a Phase 3, randomized, placebo-controlled, double-blinded,
multinational, multicenter study to evaluate the safety and efficacy of the
addition of veliparib and carboplatin in combination with standard neoadjuvant
chemotherapy compared to carboplatin in combination with standard neoadjuvant
chemotherapy compared to standard neoadjuvant chemotherapy in subjects with
previously untreated triple negative breast cancers who are candidates for
potentially curative surgery. Subjects will be stratified by BRCA status
(deleterious mutation in BRCA1 and/or BRCA2 gene; no BRCA mutation; or
unknown), lymph node stage (N0 versus N1-2) and planned schedule of
doxorubicin/cyclophosphamide administration (q2 weeks, also known as dose
dense, versus q3 weeks). Subjects with mutations of
uncertain clinical significance according to core laboratory testing will be
considered to have no BRCA gene mutation, and subjects with deleterious
mutations or suspected deleterious mutation according to core laboratory
testing will be considered to have a BRCA gene mutation.
Intervention
Approximately six hundred twenty-four (624) subjects will be randomized in a
2:1:1 ratio to one of the following three treatment arms:
Arm A) paclitaxel + carboplatin + veliparib followed by
doxorubicin/cyclophosphamide
Arm B) paclitaxel + carboplatin followed by doxorubicin/cyclophosphamide
Arm C) paclitaxel followed by doxorubicin/cyclophosphamide
Study burden and risks
From the I-SPY 2 study, a benefit of 20% absolute increase in pathologic
complete response (pCR) rate with veliparib combination therapy is assumed for
the design of the current trial. analysis demonstrated that in breast cancer
subgroups considered to have highly proliferating tumors, the pCR rate can
accurately discriminate between patients with good and poor
prognosis. The prognostic impact of the pCR rate was highest in triple negative
and in HER2-positive (nonluminal) tumors, with 3-year disease-free survival
rates in patients achieving pCR approximating 90%. The prognosis in patients
without pCR was comparable to that in patients receiving systemic treatment
after surgery, with 3-year disease-free survival rates approximating 55%. The
long-term outcome of these patients
suggests that a 20% increase in the pCR rate may lead to an improvement in
disease-free survival of approximately 47% (HR ~ 0.68), or an absolute
improvement in the recurrence-free survival rate of ~ 9.8% at 5 years.
Risks in this study include toxicity from the addition of veliparib and/or
carboplatin to standard therapy. Preliminary safety data for veliparib show the
most common AEs in the clinical studies evaluating veliparib in drug
combination studies were hematological toxicities, gastrointestinal events, and
other toxicities commonly associated with those known for each background
therapy. Standard clinical practices to manage these
toxicities are well established. Patients receiving veliparib in this study
will also receive carboplatin, and additional toxicity from the combination
must be considered versus the standard of care comparator paclitaxel followed
by AC. Limited published data suggest that carboplatin adds little severe
toxicity (increase in grade 3/4 anemia by 5% to 10%, low incidence of grade 3/4
thrombocytopenia) to a regimen containing taxane and doxorubicin in patients
with basal type breast cancer.
Knollstrasse 50
Ludwigshafen 67061
DE
Knollstrasse 50
Ludwigshafen 67061
DE
Listed location countries
Age
Inclusion criteria
1. Women >= 18 years of age.
2. Histologically confirmed invasive breast cancer by core needle or incisional biopsy (excisional
biopsy is not allowed). Clinical stage T2-3 N0-2 or T1 N1-2 by physical exam or radiologic studies.
At the time of presentation, subjects must be candidates for potentially curative surgery by surgeon's
assessment. Inflammatory breast cancer or neuroendocrine carcinoma is not allowed. If multiple
(up to 2) suspicious lesions are present, each must be biopsied to evaluate for invasive disease, and
all invasive lesions in the same breast must be triple-negative as defined below. Subjects with
synchronous bilateral invasive breast cancers are not eligible.
3. Documented BRCA germline mutation testing. All subjects regardless of BRCA mutation status
(i.e., wildtype BRCA or germline BRCA mutation) are eligible for study participation. If testing has
been performed by a laboratory other than the Sponsor core laboratory, subjects may be enrolled but must be re-tested by Sponsor core laboratory for confirmation of BRCA1 and/or BRCA2 germline mutation. Subjects who complete informed consent and screening procedures will not be denied protocol therapy due to delays in BRCA testing results. For those subjects who meet other enrollment criteria but have not received BRCA germline mutation testing results at the completion
of the screening period, randomization to a treatment group based on other stratification factors will
be permitted upon Sponsor approval. Subjects will be analyzed according to results of BRCA testing as described in the statistical methods.
4. ER-, PR-, and HER2-negative (triple-negative) cancer of the breast. Randomization based on local results will be permitted, and all results will be confirmed by central pathology reading.
Triple-negative tumors are defined as:
* For ER- and PR-negative: less than or equal to 1% tumor staining by immunohistochemistry
(IHC).
* HER2-negative disease, defined as IHC 0 - 1+ OR HER2-neu negative according to
ASCO-CAP guideline recommendations.
5. ECOG Performance status of 0 to 1.
6. Adequate organ function as follows:
* Bone Marrow: Absolute neutrophil count (ANC) >= 1500/mm3 (1.5 × 109/L); Platelets
>= 100,000/mm3 (100 × 109/L); Hemoglobin >= 9.5 g/dL (5.6 mmol/L); Leukocytes > 3,000/mm3;
* Renal Function: Calculated creatinine clearance >= 50 mL/min/1.73 m2 by the Cockroft-Gault
formula;
* Hepatic Function: Aspartate aminotransferase (AST) or alanine transaminase (ALT)
<= 2.5 × upper limit of normal (ULN); bilirubin <= 1.5 × ULN. Subjects with Gilbert's syndrome
may have a bilirubin > 1.5 × ULN, if no evidence of biliary obstruction exists;
* Activated Partial Thromboplastin Time (APTT) must be <= 1.5 × ULN and international
normalized ratio (INR) < 1.5 × ULN. Subjects on anticoagulant therapy will have an
appropriate APTT and INR as determined by the Investigator;
* Adequate cardiopulmonary reserve to undergo surgery with general anesthesia;
* Left ventricular ejection fraction greater than or equal to 50% by MUGA or echocardiogram.
7. Women must be determined to be not of childbearing potential (surgically sterile, or postmenopausal
defined as amenorrheic for at least 12 months) by the Investigator OR they must have a negative
serum pregnancy test prior to randomization. Women of childbearing potential must agree to use
adequate contraception (one of the following listed below) prior to study entry, while receiving
study treatment, and for 6 months (or per local labels) following completion of therapy:
* Total abstinence from sexual intercourse as the preferred lifestyle of the subject; periodic
abstinence is not acceptable;
* Sexual intercourse with only vasectomized partner;
* Double-barrier method (condoms, contraceptive sponge, diaphragm or vaginal ring with
spermicidal jellies or cream);
* Intra-Uterine Device (IUD).
8. Capability of understanding and complying with parameters as outlined in the protocol and able to sign and date the informed consent, approved by an Independent Ethics Committee
(IEC)/Institutional Review Board (IRB), prior to initiation of any screening or study-specific procedures.
9. Capability of taking oral medication.
Exclusion criteria
1. Previous anti-cancer treatment (cytotoxic chemotherapy, immunotherapy, biologic therapy,
radiotherapy or investigational agents) with therapeutic intent for current breast cancer.
2. Previous treatment with carboplatin, paclitaxel, doxorubicin, or cyclophosphamide.
3. Prior therapy with a Poly-(ADP-ribose)-Polymerase (PARP) inhibitor.
4. Concurrent treatment with an ovarian hormonal replacement therapy or with hormonal agents such
as raloxifene, tamoxifen or other selective estrogen receptor modulator (SERM). Subjects must
have discontinued use of such agents prior to beginning study treatment.
5. A history of seizure within 12 months prior to study entry.
6. Pre-existing neuropathy from any cause in excess of Grade 1.
7. Known history of allergic reactions to cremophor-containing medications, including Polyoxyl 35
Castor Oil.
8. Clinically significant uncontrolled condition(s) including but not limited to the following:
* Active infection;
* Symptomatic congestive heart failure;
* Unstable angina pectoris or cardiac arrhythmia;
* Myocardial infarction within last 6 months;
* Contraindications to surgery with general anesthetic or regional radiotherapy;
* Psychiatric illness/social situations that would limit compliance with study requirements;
* Hemorrhagic cystitis;
* Uncontrolled hypertension despite optimal medical management;
* Major surgery or significant traumatic injury, within 4 weeks of starting study treatment;
* History of Hepatitis B (HBV) or Hepatitis C (HCV) infection. Subjects with positive history of
HBV or HCV may undergo confirmatory testing if not performed within 3 months prior to
initiation of study treatment. Tested subjects with positive HBcAb or positive HCV RNA are
excluded; or
* Any medical condition which in the opinion of the Investigator places the subject at an
unacceptably high risk for toxicities.
9. A previous or concurrent cancer that is distinct in primary site or histology from the cancer under
study, except cervical carcinoma in situ, non-melanoma carcinoma of the skin, or in situ carcinoma
of the bladder. Any cancer curatively treated greater than 3 years prior to entry is permitted.
10. Pregnant or breastfeeding.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2013-002377-21-NL |
| CCMO | NL48946.029.14 |