Primary Objective:- To demonstrate the superiority of palbociclib in combination with fulvestrant (with or without goserelin) over fulvestrant alone (with or without goserelin) in prolonging investigator-assessed PFS in women with HR+/HER2-negative…
ID
Source
Brief title
Condition
- Breast neoplasms malignant and unspecified (incl nipple)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Endpoint:
- Progression-Free Survival (PFS) as assessed by the Investigator.
Secondary outcome
Secondary Endpoints:
- Overall Survival (OS).
- 1-year, 2-year, and 3-year survival probabilities
Objective Response (OR): Complete Response (CR) or Partial Response (PR).
- Duration of Response (DR).
- Clinical Benefit Response (CBR): CR or PR or Stable Disease (SD) *24 weeks.
- Type, incidence, severity (as graded by the National Cancer Institute Common
Terminology Criteria for Adverse Events [NCI CTCAE] v4.0), seriousness and
relationship to study medications of Adverse Events (AEs) and any laboratory
abnormalities.
- Trough plasma concentration of palbociclib, fulvestrant and goserelin (if
applicable) in the subgroup of 40 patients included in the initial safety
review.
- PRO endpoints such as health related quality of life scores [EuroQol (EQ-5D)
Score; European Organisation for Research and Treatment of Cancer Quality of
Life Instrument (EORTC QLQ-C30); European Organisation for Research and
Treatment of Cancer Breast Cancer Module (EORTC QLQ-BR23);, minimally important
difference (MID) cut-off, and time to deterioration (TTD) composite endpoint.
- Tumor tissue biomarkers, including genes (eg, copy numbers of CCND1 and
CDKN2A, PIK3CA mutations), proteins (eg, Ki67, pRb, CCNE1), and RNA expression
(eg, cdk4, cdk6).
Background summary
HR+/HER2-negative breast cancer is the most common subset of breast cancer.1
Most patients are diagnosed at an early stage and remain relapse-free if
treated with a prolonged course of endocrine therapy. Unfortunately, not all
patients respond to first-line endocrine therapy (primary or de novo
resistance), and even patients who have a response will eventually relapse
(acquired resistance). About one-third of all HR+/HER2-negative patients,
diagnosed initially with early stage disease, experience disease recurrence. As
a result the HR+/HER2-negative subset is responsible for the majority of breast
cancer related deaths. The fundamental problem is that endocrine agents are
only partially effective, typically causing cell cycle arrest and tumor
dormancy rather than true cure. As a result, secondary resistance to endocrine
therapy is a major clinical challenge. In postmenopausal patients with
HR+/HER2-negative metastatic BC, aromatase inhibitors (AIs) have become the
treatment of choice in first-line therapy. On the contrary, most preor
perimenopausal women with HR+ breast cancer present with early stage disease
and are treated with the antiestrogen tamoxifen with or without ovarian
ablation (by surgery, chemotherapy or luteinizing hormone-releasing hormone
(LHRH) ) in the adjuvant setting. Upon initial presentation with metastatic
disease during premenopause, the recommended approach is to suppress ovarian
function (by ovarian ablation or luteinizing hormone-releasing hormone (LHRH)
agonist therapy), and then to concurrently follow post-menopausal treatment
guidelines, switching treatment from tamoxifen to AIs or fulvestrant. Thus, in
clinical practice so called *pre/perimenopausal* patients with HR+ metastatic
breast cancer will be rendered postmenopausal by the time of first line
treatment for advanced disease. Upon disease progression on hormonal therapy,
historically the treatment options have been
limited to a change in AIs (steroidal or nonsteroidal) or the use of the
estrogen-receptor (ER) antagonists fulvestrant and tamoxifen.
In the past few years the search for newer, non-endocrine related agents to
treat recurrent metastatic ER+ breast cancers has expanded to include agents
targeting the PI3K/mTOR pathway as well as cell cycle specific agents.
Everolimus, recently approved in advanced, recurrent disease, is an example of
the former,8 and palbociclib, is an example of the latter. In both cases,
successful development of molecular patient selection criteria has so far
proven to be elusive. More efficacious and safe therapeutic options are still
needed, particularly in molecularly selected patient populations. Thus,
HR+/HER2-negative breast cancer patients who have tumor progression following
endocrine therapies for metastatic disease, represent an important unmet
medical need, regardless of their menopausal status.
Study objective
Primary Objective:
- To demonstrate the superiority of palbociclib in combination with fulvestrant
(with or without goserelin) over fulvestrant alone (with or without goserelin)
in prolonging investigator-assessed PFS in women with HR+/HER2-negative
metastatic breast cancer whose disease has progressed on prior endocrine
therapy.
Study design
This is an international, multicenter, randomized, double-blind,
placebo-controlled, parallel-group, Phase 3 clinical trial with the primary
objective of demonstrating the superiority of palbociclib in combination with
fulvestrant (Faslodex*) over fulvestrant alone in in women with HR+,
HER2-negative metastatic breast cancer,regardless of their menopausal status,
whose disease has progressed after prior endocrine therapy. The safety between
the two treatment arms will also be compared. Pre- and perimenopausal women
must receive therapy with the LHRH agonist goserelin (Zoladex* or generic).
At least 417 patients will be randomization in a 2:1 ratio and stratified by
documented sensitivity to prior hormonal therapy (yes vs. no), menopausal
status at study entry (pre-/perivs. post menopausal), and presence of visceral
metastases (yes vs. no).
Patients will undergo tumor assessment at Week 8, and then every 8 weeks for
the first year, and then every 12 weeks, calculated from the date of
randomization. Patients will continue to receive assigned treatment until
objective Progressive Disease (PD), symptomatic deterioration, unacceptable
toxicity, death, or withdrawal of consent, whichever
occurs first. Crossover between treatment arms will not be allowed. Patients
showing RECIST-defined PD can continue with study treatment at the discretion
of the investigator as long as that is considered to be in the best interest of
the patient and no new anticancer treatment is initiated. In addition, should
palbociclib/placebo related toxicity mandate palbociclib/placebo
discontinuation, patients can continue to receive fulvestrant alone.
Patients discontinuing the active treatment phase (ie, discontinuing both
palbociclib/placebo and fulvestrant) will enter a follow-up phase during which
survival and new anti-cancer therapy information will be collected, initially
every 3 months and then every 6 months. An external data monitoring committee
(E-DMC) will perform an early review of safety data from the first 40
randomized patients in order to confirm safety and tolerability of the
combination. The early safety review by the E-DMC will also include
Pharmacokinetic (PK) data from the initial 40 randomized patients in order to
explore potential Drug-Drug-Interactions (DDIs) between fulvestrant, goserelin
(if applicable) and palbociclib.
The study will continue while these analyses and review are ongoing. In
addition, blood samples will be collected from all patients to assess trough
concentrations of palbociclib for exposure/response analysis for safety and
efficacy findings.
Patient Reported Outcomes (PRO) will be collected to evaluate health-related
quality of life and health status.
Intervention
Patients in Arm A (at least 278) will receive palbociclib 125 mg/day orally for
3 weeks followed by 1 week off plus fulvestrant 500 mg intramuscularly on Days
1 and 15 of Cycle 1, and then on Day 1 of each subsequent 28-day cycle.
Patients in Arm B (at least 139) will receive placebo orally daily for 3 weeks
followed by 1 week off plus fulvestrant 500 mg intramuscularly on Days 1 and 15
of Cycle 1, and then on Day 1 of each subsequent 28-day cycle.
In both arms, pre- and peri-menopausal women will also receive the LHRH agonist
goserelin (Zoladex* or generic).
Study burden and risks
Patiens will have to come to the hospital for a number of visits, depending on
the amount of treatment cycles they will undergo.
Patients will have to invest time as as specified in question J. Risks will be
side effects of study medication and prcedure related risks. Other things that
will be expected of patients are writen in the answer on question E4.
East 42nd Street 235
New York NY10017
US
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US
Listed location countries
Age
Inclusion criteria
Women 18 years of age or older, who are either:, - Postmenopausal, as defined
by at least one of the following criteria:, - Age * 60 years;, - Age <60
years and cessation of regular menses for at least 12 consecutive months with
no alternative pathological or physiological cause; and serum estradiol and FSH
level within the laboratory*s reference range for postmenopausal females;, -
Documented bilateral oophorectomy;, - Medically confirmed ovarian failure., OR,
- Pre/peri-menopausal, ie, not meeting the criteria for being postmenopausal.,
- Pre/perimeopausal women can be enrolled if amenable to be treated with the
LHRH agonist goserelin. Patients must have commenced treatment with goserelin
or an alternative LHRH agonist at least 4 weeks prior to randomization. But, if
patients have received an alternative LHRH agonist prior to study entry, they
must switch to goserelin for the duration of the trial., 2. Histologically or
cytologically proven diagnosis of breast cancer with evidence of metastatic or
locally advanced disease, not amenable to resection or radiation therapy with
curative intent., 3. Documentation of ER-positive and/or PR-positive tumor (*1%
positive stained cells) based on most recent tumor biopsy (unless bone-only
disease, see below) utilizing an assay consistent with local standards., 4.
Documented HER2-negative tumor based on local testing on most recent tumor
biopsy: HER2-negative tumor is determined as immunohistochemistry score 0/1+ or
negative by in situ hybridization (FISH/CISH/SISH) defined as a HER2/CEP17
ratio <2 or for single probe assessment a HER2 copy number <4., 5.
Patients must satisfy the following criteria for prior therapy:, - Progressed
during treatment or within 12 months of completion of adjuvant therapy with an
aromatase inhibitor if postmenopausal, or tamoxifen if pre- or perimenopausal.,
OR, - Progressed while on or within 1 month after the end of prior aromatase
inhibitor therapy for advanced/metastatic breast cancer if postmenopausal, or
prior endocrine treatment for advanced/metastatic breast cancer if pre- or
perimenopausal., One previous line of chemotherapy for advanced/metastatic
disease is allowed in addition to endocrine therapy., 6. Except where
prohibited by local regulations, all patients must agree to provide and have
available a formalin-fixed paraffin embedded (FFPE) tissue biopsy sample taken
at the time of presentation with recurrent or metastatic disease. A de novo
biopsy is required, if no archived tissue is available taken at the time of
presentation with recurrent/metastatic. The sole exception is those patients
with bone, only disease for whom provision of previous archival tissue only is
acceptable. Patients, who had surgery within the last 3 years (but without
neoadjuvant chemotherapy prior to surgery) and relapsed while receiving
adjuvant therapy, may provide a tumor specimen from that surgery., 7.
Measurable disease as defined by RECIST version 1.1, or bone-only disease.
Patients with bone-only metastatic cancer must have a lytic or mixed
lytic-blastic lesion that can be accurately assessed by CT or MRI. Patients
with bone-only disease and blastic-only metastasis are not eligible. Tumor
lesions previously irradiated or subjected to other loco, regional therapy will
only be deemed measurable if progression at the treated site after completion
of therapy is clearly documented., 8. Eastern Cooperative Oncology Group (ECOG)
performance status 0-1., 9. Adequate organ and marrow function defined as
follows:, - ANC *1,500/mm3 (1.5 x 109/L);, - Platelets *100,000/mm3 (100 x
109/L);, - Hemoglobin * 9 g/dL (90 g/L);, - Serum creatinine *1.5 x ULN or
estimated creatinine clearance * 60 ml/min as calculated using the method
standard for the institution;, - Total serum bilirubin *1.5 x ULN (<3ULN if
Gilbert*s disease);, - AST and/or ALT *3 x ULN (*5.0 x ULN if liver metastases
present);, - Alkaline phosphatase *2.5 x ULN (*5 x ULN if bone or liver
metastases present)., 10. Resolution of all acute toxic effects of prior
therapy or surgical procedures to National Cancer Institute (NCI) CTCAE Grade
*1 (except alopecia)., 11. Evidence of a personally signed and dated informed
consent document indicating that the patient (or a legal representative) has
been informed of all pertinent aspects of the study., 12. Patients who are
willing and able to comply with scheduled visits, treatment plan, laboratory
tests, and other study procedures.
Exclusion criteria
1. Prior treatment with any CDK inhibitor, or fulvestrant, or with everolimus,
or any agent whose mechanism of action is to inhibit the PI3K-mTOR pathway., 2.
Patients with advanced/metastatic, symptomatic, visceral spread, that are at
risk of life-threatening complications in the short term (including patients
with massive uncontrolled effusions [pleural, pericardial, peritoneal],
pulmonary lymphangitis, and over 50% liver involvement)., 3. Known active
uncontrolled or symptomatic Central Nervous System (CNS) metastases,
carcinomatous meningitis, or leptomeningeal disease as indicated by clinical
symptoms, cerebral edema, and/or progressive growth. Patients with a history of
CNS metastases or cord compression are eligible if they have been definitively
treated (eg, radiotherapy,, stereotactic surgery) and are clinically stable off
anticonvulsants and steroids for at least 4 weeks before randomization., 4.
Current use of food or drugs known to be potent CYP3A4 inhibitors, drugs known
to be potent CYP3A4 inducers (for examples, see the Prohibited Medications
section), and drugs that are known to prolong the QT interval., 5. Major
surgery, chemotherapy, radiotherapy, or other anti cancer therapy within 2
weeks before randomization. Patients who received prior radiotherapy to * 25%
of bone marrow are not eligible independent of when it was received., 6. Any
other malignancy within 3 years prior to randomization, except for adequately
treated basal cell or squamous cell skin cancer, or carcinoma in situ of the
cervix., 7. QTc interval >480 msec (based on the mean value of the
triplicate ECGs), family or personal history of long or short QT syndrome,
Brugada syndrome or known history of QTc prolongation or Torsade de Pointes.,
8. Any of the following within 6 months of randomization: myocardial
infarction, severe/unstable angina, ongoing cardiac dysrhythmias of NCI CTCAE
Grade *2, atrial fibrillation of any grade, coronary/peripheral artery bypass
graft, symptomatic congestive heart failure, cerebrovascular accident including
transient ischemic attack, or symptomatic pulmonary embolism., 9. Impairment of
gastro-intestinal (GI) function or GI disease that may significantly alter the
absorption of palbociclib, such as history of GI surgery with may result in
intestinal blind loops and patients with clinically significant gastroparesis,
short bowel syndrome, unresolved nausea, vomiting, active inflammatory bowel
disease or diarrhea of CTCAE Grade >1., 10. Prior hematopoietic stem cell or
bone marrow transplantation., 11. Known abnormalities in coagulation such as
bleeding diathesis, or treatment with anticoagulants precluding intramuscular
injections of fulvestrant or goserelin (if applicable)., 12. Known or possible
hypersensitivity to fulvestrant, goserelin, any of their excipients or to any
palbociclib/placebo excipients., 13. Known human immunodeficiency virus
infection., 14. Other severe acute or chronic medical or psychiatric condition,
including recent or active suicidal ideation or behavior, or laboratory
abnormality that may increase the risk associated with study participation or
investigational product administration or may interfere with the interpretation
of study results and, in the judgment of the investigator, would make the
patient inappropriate for entry into this study., 15. Patients who are
investigational site staff members directly involved in the conduct of the
trial and their family members, site staff members otherwise supervised by the
Investigator, or patients who are Pfizer employees directly involved in the
conduct of the trial., 16. Participation in other studies involving
investigational drug(s) (Phases 1-4) within 4 weeks before randomization in the
current study.
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 | EUCTR2013-002580-26-NL |
| CCMO | NL46083.028.13 |