Primary Objective:• To assess and compare efficacy of sacituzumab govitecan to TPC as measured by progression free survival (PFS) as determined by blinded independent central review (BICR) using Response Evaluation Criteria in Solid Tumors Version 1…
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Brief title
Condition
- Breast neoplasms malignant and unspecified (incl nipple)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary End Point (Primary Analysis)
PFS will be described using Kaplan Meier (K M) estimates. The primary analysis
of PFS for the comparison between treatment arms will be performed using a
stratified log rank test with the stratification factors used in the
randomization. Median PFS and its 95% CI as determined by the Brookmeyer and
Crowley method with log log transformation will be presented and the K M
estimates of PFS will be plotted over time. Hazard ratio of PFS and its 95% CI
will be estimated using Cox proportional hazards model stratified by the same
stratification factors used in the randomization.
Secondary outcome
Secondary End Points (Secondary Analyses)
OS will be described using K M estimates. The primary analysis of OS for
comparison between treatment arms will be performed using a stratified log rank
test with the same stratification factors used in the randomization. Median OS
and the associated 95% CI as determined by the Brookmeyer and Crowley method
with log log transformation will be presented. Hazard ratio and the associated
95% CI will be estimated using a Cox proportional hazards model stratified by
the same stratification factors used in the randomization.
ORR will be analyzed and compared between the treatment arms using the Cochran
Mantel Haenszel (CMH) test stratified by the stratification factors used in the
randomization. The 2 sided 95% CIs will be calculated using the Clopper
Pearson exact method.
CBR will be calculated with exact 95% CIs using the method of Clopper and
Pearson. CBR will be compared between treatment arms using a CMH test
stratified by the stratification factors used in the randomization. The
differences and odds ratios of these rates between treatment arms and 95% CIs
will be calculated respectively.
The K M estimates of median DOR and its 95% CI will be calculated for
responders (CR or PR) in each treatment arm.
Time to deterioration of global health status/QOL, pain, and fatigue domains as
measured by EORTC QLQ C30 will be analyzed similarly as the primary analysis of
PFS.
Safety Analyses
Safety analyses will be performed using the Safety Analysis Set and will be
summarized using descriptive statistics. Categorical variables will be
summarized by number and percentage. Continuous variables will be summarized
using number of subjects, mean, standard deviation, median, upper and lower
quartiles, and range (minimum and maximum).
Background summary
Subjects with hormonal receptor positive (HR+), human epidermal growth factor
receptor 2 (HER2) negative metastatic breast cancer (MBC) who have failed
approved or accepted treatments in the first and second line setting remain in
dire need of additional therapeutic approaches. The Trop-2 antigen is highly
expressed on most solid epithelial cancers, including MBC. Sacituzumab
Govitecan was developed by Immunomedics to treat these cancers by binding to
Trop-2 for targeted delivery of SN-38 directly to the tumor cell while
minimizing systemic exposure of SN-38 to decrease host toxicity. A Phase 1/2
trial in heavily treated patients with a variety of solid cancers, including
MBC, demonstrated that Sacituzumab Govitecan was therapeutically active when
given on Days 1 and 8 of repeated 21-day cycles (Immunomedics, Inc., data on
file). The Sacituzumab Govitecan safety profile is consistent with the
mechanism of action of SN-38 (gastrointestinal and myelosuppressive) and the
well-known safety profile of irinotecan, which has been in use for over 20
years (Camptosar USPI, 2018). The 10 mg/kg dose of Sacituzumab Govitecan
administered on Days 1 and 8 of
repeating 21-day cycles was selected for further clinical development with this
treatment schedule, including this Phase 3 study, based on the overall
tolerability and efficacy profile of this dosing regimen.
Study objective
Primary Objective:
• To assess and compare efficacy of sacituzumab govitecan to TPC as measured by
progression free survival (PFS) as determined by blinded independent central
review (BICR) using Response Evaluation Criteria in Solid Tumors Version 1.1
(RECIST 1.1) in subjects with HR+/HER2 MBC who have progressed after cyclin
dependent kinase (CDK) 4/6 inhibitor, endocrine therapy, taxane, and after at
least 2, but no more than 4 prior chemotherapy regimens for metastatic disease
Secondary Objectives:
• To assess and compare sacituzumab govitecan to TPC in overall survival (OS)
in subjects with HR+/HER2 MBC who have progressed after CDK 4/6 inhibitor,
endocrine therapy, taxane and at least 2, but no more than 4 prior chemotherapy
treatment regimens for metastatic disease
• To assess and compare objective (overall) response rate (ORR), duration of
response (DOR) and clinical benefit rate (CBR; complete response (CR)+partial
response (PR)+stable disease (SD) with a duration of >= 6 months) between
treatment arms as determined by local investigator review (LIR) and BICR using
RECIST 1.1
• To assess and compare the impact of treatment on time to deterioration (TTD)
of global health status/quality of life (QOL), pain, and fatigue domains as
measured by European Organization for the Research and Treatment of Cancer
(EORTC) quality of life of cancer patients, core questionnaire version 3.0 (QLQ
C30)
• To assess and compare the overall safety and tolerability
Exploratory Objectives:
• To assess and compare efficacy in a subset defined by tumor expression of
Trop 2 and to ascertain the role of expression of Trop 2 as a predictive
biomarker for response
• To identify candidate blood and tumor biomarkers as a predictive biomarker
for response
• To investigate the immunogenicity of sacituzumab govitecan with respect to
antidrug antibodies (ADA) testing and serum levels of sacituzumab govitecan
• To assess and compare the impact of treatment on the European Quality of Life
(EuroQOL) EQ 5D 5L instruments
• To assess and compare the impact of treatment on Health Related Quality of
Life (HRQOL) between treatment arms using the other domains of the EORTC QLQ C30
• To assess and compare the impact of treatment on treatment related symptoms
using a set of 9 relevant symptom concepts from the Patient Reported Outcomes
version of the Common Terminology Criteria for Adverse Events (PRO CTCAE*) item
library (decreased appetite, nausea, vomiting, constipation, diarrhea,
abdominal pain, shortness of breath, hair loss, and fatigue)
Study design
This is an open label, randomized, multicenter, international Phase 3 study to
compare the efficacy and safety of sacituzumab govitecan versus TPC in subjects
with metastatic or locally recurrent inoperable HR+/HER2 MBC who have
progressed after a CDK 4/6 inhibitor, endocrine therapy, a taxane, and at least
2, but no more than 4 prior chemotherapy regimens for metastatic disease.
Subjects will be randomized in a 1:1 ratio to either sacituzumab govitecan
(Investigational Arm A) or TPC (Control Arm B; i.e., eribulin, capecitabine,
gemcitabine, or vinorelbine). Randomization will be stratified based on prior
chemotherapy regimens for treatment of metastatic disease (two vs. three/four
lines), visceral metastasis (Y/N), and endocrine therapy in the metastatic
setting for at least 6 months (Y/N).
The study will be conducted in two phases, a Pre randomization Phase and a
Randomization Phase:
• The Pre randomization Phase will last no longer than 28 days and consists of
the following two periods:
* A Screening Period to establish study eligibility
* A Baseline Period to confirm eligibility and establish disease
characteristics prior to randomization and treatment
• The Randomization Phase will begin at the time of randomization of the first
subject and will end on the data cut off date for the final analysis of OS; the
Randomization Phase consists of the following two periods:
* A Treatment Period which begins at the time of randomization and ends with
the completion of the End of Treatment (EOT) visit, which will occur at least
30 days after the final dose of study treatment
* A Follow up Period which begins the day after the EOT visit and continues as
long as the subject is alive or until the data cut off date of the final
analysis of OS, unless the subject withdraws consent from the study or the
Sponsor terminates the study
An independent Data Safety Monitoring Committee (DSMC) will be convened at
regular intervals to assess the progress of this study and review safety.
Intervention
Sacituzumab Govitecan (10 mg/kg administered via intravenous [IV] injection on
Days 1 and 8 of repeating 21-day cycles) or TPC selected from one of the
following monotherapy treatment regimens administered for MBC, as per label or
National Comprehensive Cancer Network (NCCN) guidelines as per below (with dose
modifications if too toxic):
* Eribulin (1.23 mg/m2 IV on Days 1 and 8 of a 21-day cycle for European sites)
* Capecitabine (1000-1250 mg/m2 orally (PO) twice daily on Days 1-14 of a
21-day cycle)
* Gemcitabine (800-1200 mg/m2 IV on Days 1, 8, and 15 of a 28-day cycle)
* Vinorelbine (25 mg/m2 IV on Day 1 weekly). (Note: eligible subjects with
National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events
[CTCAE] grade 2 peripheral neuropathy should not be prescribed vinorelbine as
TPC)
Study burden and risks
Allergic Reactions (very common, occurring in more than 1 in 10 people)
including Infusion Related Reactions
Sometimes people have allergic reactions to sacituzumab govitecan, which can be
severe or life-threatening. This includes anaphylactic reaction (uncommon,
occurring in up to 1 in 100 people), which is a serious allergic reaction that
may cause an itchy rash, throat or tongue swelling, shortness of breath,
vomiting, lightheadedness, low blood pressure or death if not promptly treated.
Possible signs and symptoms of allergic reactions include:
• Rash or hives
• Having a hard time breathing
• Wheezing when you breathe
• Sudden change in blood pressure (making you feel dizzy or lightheaded)
• Swelling around the mouth, throat or eyes
• Fast pulse
• Sweating
Neutropenia (very common)
This is a condition where you have too few neutrophils, a type of white blood
cell, in your blood, resulting in increased risk of infections. These
infections can be severe, life-threatening, or deadly. Fever with neutropenia
(common, occurring in 1 to 10 in 100 people) may require antibiotics or other
medicines. Neutropenic colitis (inflammation of a part of the large intestine,
common) may be associated with infection.
Possible signs and symptoms of neutropenia or infections include:
• Fever
• Chills or sweating
• Sore throat, sores in the mouth, or a toothache
• Stomach pain
• Pain near the anus
• Pain or burning when urinating or urinating often
• Diarrhea or sores around the anus
• A cough or shortness of breath
Diarrhea (very common)
Diarrhea can be severe. Dehydration and in some cases acute kidney injury
(sudden kidney damage) have been observed.
Nausea and Vomiting (very common)
Patients who have the UGT1A1*28 Gene
Some patients may be genetically more likely to have certain side effects from
the medicine. You may be more likely to develop a condition in which the number
of white bloods cells called neutrophils is abnormally low (neutropenia)
earlier than in patients without the UGT1A1*28 gene. You may be more likely to
develop neutropenia, with or without fever, low level of red blood cells
(anemia) or other side effects after being given sacituzumab govitecan, than
those who do not have the gene. Inform your doctor if you know you have the
UGT1A1*28 gene.
Embryofetal Toxicity
Based on how sacituzumab govitecan works, it may cause harm to an unborn baby,
such as birth defects or death, when administered to a pregnant woman.
Sacituzumab govitecan contains a component that targets rapidly dividing cells,
may damage the genetic information within a cell, including cells that become
sperm, and therefore may harm an unborn baby (including mutations and birth
defects). The effects of sacituzumab govitecan in women trying to get pregnant
or are pregnant has not been studied.
As there is potential of harm to an unborn baby, women of childbearing
potential and men who are partners of women of childbearing potential enrolling
in this study should not be pregnant or get pregnant and must agree to the
contraception requirements for the study. Please refer to the Pregnancy section
of the informed consent form.
Older Patients
In previous clinical studies with HR+/HER2- breast cancer and bladder cancer,
patients who were 65 years and older stopped sacituzumab govitecan due to
harmful effects occurring at higher rates compared to younger patients.
However, overall, there were no differences in effectiveness.
Antibody Risks
Your body may develop its own antibodies against the sacituzumab govitecan that
is given in this study. In previous studies of patients treated with
sacituzumab govitecan, there was a low number of patients who developed
antibodies and the development of antibodies is not expected to impact the
effect of sacituzumab govitecan.
Other harmful effects reported in previous studies with sacituzumab govitecan
in more than 1 out of 10 people include:
• Low amount of red blood cells, also called anemia, which may cause fatigue or
may require a blood transfusion
• Low amount of white blood cells
• Decreased number of a type of white blood cell called *lymphocytes*
• Constipation
• Pain in the abdomen
• Fatigue (tiredness), feeling weak and having no energy
• Urinary tract infection which may cause frequent and painful urination
• Weight loss
• Decreased appetite
• Low blood magnesium
• Low potassium
• Low Phosphate level
• Dehydration (when your body does not have as much water and fluid as it
should)
• Joint pain
• Headache
• Dizziness
• Shortness of breath with or without exercise
• Cough
• Itching
• Hair loss
• Rash
In addition, in previous studies with sacituzumab govitecan, 1 to 10 in 100
people had these side effects:
• Decreased number of a type of blood cell that helps to clot blood (platelet),
causing bruising and/or bleeding
• Infection of the lungs
• Inflammation of the mouth and lips
• Indigestion
• Digestive disease in which stomach acid irritates the food pipe lining
• Swelling of the abdomen
• Upper abdominal pain
• Inflammation of the lining of the large intestine
• Chills
• Pain
• Upper respiratory tract infection, common cold
• Severe infection throughout the body
• Increase in an enzyme called alkaline phosphatase, which may be a sign of a
bone or liver problem
• Increase in length of time it takes for a blood clot to form
• High blood level of an enzyme called blood lactate dehydrogenase
• Low blood sodium
• Low calcium level
• High blood sugar level
• Change in sense of taste
• Difficulty sleeping
• Increase in levels of protein in the urine
• Bleeding from the nose
• Runny nose
• Nasal congestion
• Dry skin
• Rash which may look flat and discolored or small and raised and may be itchy
• Darkening of the skin
• Small, raised, acne-like bumps usually on the face, scalp, chest, or upper
back
• Low blood pressure
In previous studies with sacituzumab govitecan, 1 to 10 in 1000 people had this
side effect:
• Inflammation of the lining of the small intestine
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Age
Inclusion criteria
Subjects must meet all the following inclusion criteria:
1. Female or male subjects, adult or aged >=18 years at the time of signing the
informed consent form
2. Documented evidence of HR+/HER2- MBC confirmed by a local laboratory with
the most recently available or newly obtained tumor biopsy (preferably within
the last 12 months) from a locally recurrent or metastatic site(s) and defined
per American Society of Clinical Oncologists/College of American Pathologists
criteria as:
• HR+ (a tumor is considered HR+ if at least 1% of the cells examined have
estrogen and/or progesterone receptors)
• HER2- defined as immunohistochemistry <=2+ or fluorescence in situ
hybridization negative
3. Availability of archival tumor tissue in a formalin fixed, paraffin embedded
(FFPE) block (preferably within 12 months prior to consent) or newly acquired
biopsy (FFPE block) from a metastatic site. Note: Bone biopsies are not allowed
4. Refractory to or relapsed after at least 2, but no more than 4 prior
systemic chemotherapy regimens for metastatic disease. Adjuvant or neoadjuvant
therapy for early stage disease will qualify as one of the required prior
chemotherapy regimens if the development of unresectable, locally advanced, or
metastatic disease occurred within a 12-month period of time of the therapy.
Note: Treatments for bone metastases (eg, bisphosphonates, denosumab, etc.) and
hormonal therapy are not considered as prior systemic chemotherapy treatments
for advanced disease.
5. Should have been previously treated with:
• At least 1 taxane in any setting
• At least 1 prior anticancer hormonal treatment in any setting
• At least 1 CDK 4/6 inhibitor in any setting
6. Eligible for one of the chemotherapy options listed in the TPC arm
7. Documented disease progression after the most recent therapy by computed
tomography (CT)/magnetic resonance imaging (MRI)
8. At least 1 measurable target lesion according to RECIST 1.1 (bony disease
only is not allowed) that meets all of the following criteria:
• Lymph node lesion that measures at least >=1.5 cm in the short axis
• Non-nodal lesion that measures >=1.0 cm in the longest diameter in the plane
of measurement
• The lesion is suitable for repeat measurement using CT/MRI. Historical CT/MRI
scans performed within 28 days of C1D1 may be used as screening scans to
demonstrate eligibility as long as they meet minimum standards as separately
defined by the central imaging vendor.
• Lesions that have had external beam radiotherapy or locoregional therapy must
show radiographic evidence of disease progression based on RECIST 1.1 to be
deemed a target lesion.
• Brain CT/MRI must be conducted for subjects with a history of brain
metastasis. The subject must have had stable* brain metastasis for at least 4
weeks. Target lesions cannot be from brain.
* Stable brain metastasis is defined as the following:
* Prior local treatment by radiation, surgery, or stereotactic surgery
* Imaging - stable or decreasing size after such local treatment
* Clinically stable signs and symptoms for at least 4 weeks
* >=2 weeks from discontinuation of antiseizure medication
* Low and stable doses of corticosteroids <=20 mg prednisone or equivalent daily
are permitted
9. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
10. Adequate renal function: calculated creatinine clearance >=30 mL/minute
according to the Cockcroft and Gault formula
11. Adequate bone marrow function, defined as:
• Absolute neutrophil count (ANC) >=1,500 per mm3
• Hemoglobin >=9.0 g/dL
• Platelet count >=100,000 per mm3
Note: Blood transfusion or growth factor support is not allowed within 14 days
prior to screening labs.
12. Adequate liver function, defined as:
• Total bilirubin <=1.5× institutional upper limit of normal (IULN) or <=3 IULN
for patients with documented Gilbert*s syndrome Alanine aminotransferase (ALT),
and aspartate aminotransferase (AST) <=2.5× IULN (in the case of liver
metastases <=5× IULN), and serum albumin >=3 g/dL
• Alkaline phosphatase (ALP) <=5.0× IULN unless there are bone metastases, in
which case liver-specific ALP must be separated from the total and used to
assess liver function instead of total ALP
13. Resolution of all systemic anticancer therapy-related or radiation-related
toxicities to Grade 1 severity or lower, except for neuropathy (<=Grade 2) and
alopecia. Subjects with Grade 2 neuropathy are eligible, but should not receive
vinorelbine as TPC.
14. Females must not be lactating or pregnant at Baseline (as documented by a
negative beta human chorionic gonadotropin [β-hCG] or human chorionic
gonadotropin [hCG] test with a minimum sensitivity of 25 IU/L or equivalent
units of β-hCG [or hCG]). All females will be considered to be of childbearing
potential unless they are postmenopausal (amenorrhoeic for at least 12
consecutive months, in the appropriate age group, and without other known or
suspected cause) or have been sterilized surgically (i.e., bilateral tubal
ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at
least 1 month before dosing).
15. Females of childbearing potential must not have had unprotected sexual
intercourse within 30 days before study entry and must agree to use a highly
effective method of contraception (total abstinence [if it is her preferred and
usual lifestyle], a contraceptive implant, an oral contraceptive, or have a
vasectomized partner with confirmed azoospermia) throughout the entire study
period and for 120 days 6 months after study drug discontinuation. For sites
outside of the European Union (EU), it is permissible that if a highly
effective method of contraception is not appropriate or acceptable to the
subject, then the subject must agree to use a medically acceptable method of
contraception, ie, double barrier methods of contraception such as condom plus
diaphragm or cervical/vault cap with spermicide. If currently abstinent, the
subject must agree to use a highly effective method as described above if she
becomes sexually active during the study period or for 120 days after study
drug discontinuation. Females who are using hormonal contraceptives must have
been on a stable dose of the same hormonal contraceptive product for at least
28 days before dosing and must continue to use the same contraceptive during
the study and for 120 days after study drug discontinuation.
16. Male subjects who are partners of women of childbearing potential must use
a condom and spermicide and their female partners, if of childbearing
potential, must use a highly effective method of contraception (see methods
described above in Inclusion Criterion 15) beginning at least 1 menstrual cycle
prior to starting study drug, throughout the entire study period, and for 6 3
months after the last dose of study drug, unless the male subjects are totally
sexually abstinent or have undergone a successful vasectomy with confirmed
azoospermia or unless the female partners have been sterilized surgically or
are otherwise proven sterile. No sperm donation is allowed during the study
period and for 6 months after study drug discontinuation
17. Must be willing and able to comply with all aspects of the protocol
18. Must voluntarily agree to provide written informed consent
19. Could have received an unlimited number of prior endocrine, biological, or
targeted therapies in the absence of co administered chemotherapy; all of these
therapies must have been completed 14 days prior to randomization, except
biological therapy which must have been completed 28 days prior to
randomization
Exclusion criteria
Subjects who meet any of the following criteria will be excluded from the study:
1. Previous treatment with a topoisomerase 1 inhibitor as a free form or as
other formulations
2. Current enrollment in another clinical study or used any investigational
device or drug either within 5 half-lives or 28 days prior to randomization,
whichever is longer
3. Treatment with chemotherapy, radiation, or small molecule targeted therapy
within 2 weeks and biological therapy within 4 weeks prior to the first dose of
study treatment
4. Existing anticancer treatment-related AEs of Grade >=2 (except for alopecia
and Grade 2 neuropathy) according to NCI CTCAE v5.0
5. Any other malignancy that required treatment or has shown evidence of
recurrence (except for non-melanoma skin cancer or histologically-confirmed
complete excision of carcinoma in situ) during the 5 years prior to enrollment
in this study
6. History of significant cardiovascular disease, defined as:
• Congestive heart failure greater than New York Heart Association (NYHA) Class
II according to the NYHA Functional Classification
• Unstable angina or myocardial infarction within 6 months before enrollment
• Serious cardiac arrhythmia
7. Clinically-significant electrocardiogram (ECG) abnormality, including any of
the following:
• Marked Baseline prolonged QT/QTc interval (i.e., a repeated demonstration of
a QTc interval >500 ms) demonstrated on ECG at Screening.
• QTcF is calculated by Fridericia's formula
• History of risk factors for torsade de pointes (eg, heart failure,
hypokalemia, family history of long QT Syndrome)
8. Has known active central nervous system metastases and/or carcinomatous
meningitis. Subjects may participate provided they have stable brain
metastasis. All subjects with carcinomatous meningitis are excluded regardless
of clinical stability. Stable brain metastasis is defined in inclusion
criterion 8
9. Active hepatitis B virus (positive hepatitis B surface antigen) or active
hepatitis C virus (measurable viral RNA load with polymerase chain reaction)
infection
10. Scheduled surgery during the study, other than minor surgery which would
not delay study treatment
11. Has an active serious infection requiring antibiotics
12. Has active chronic inflammatory bowel disease (ulcerative colitis, Crohn*s
disease) and subjects with a history of bowel obstruction
13. Have received a live vaccine within 30 days of randomization
14. Known hypersensitivity or intolerance to any of the study drugs or any of
the excipients
15. Any medical or other condition which, in the opinion of the Investigator,
causes the subject to be medically unfit to receive sacituzumab govitecan or
unsuitable for any other reason
16. Is receiving any medication prohibited in combination with the study
treatment(s) as described in the respective product labels, unless medication
was stopped within 7 days prior to randomization
17. Locally-advanced MBC (stage IIIc) in subjects who are candidates for
curative intent therapy at the time of study enrollment.
18. If required per local guidelines, any subject with a blood uracil level >=
150 ng/mL is excluded from receiving capecitabine as TPC (Note: blood uracil
level will be assessed at Screening for all subjects eligible to be randomized
to capecitabine as TPC)
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 | EUCTR2018-004201-33-NL |
| ClinicalTrials.gov | NCT03901339 |
| CCMO | NL70250.068.19 |