Primary:The primary objective of this study is to demonstrate that the overall progression-free survival (PFS) of 8 cycles of intermittent (2 times 4 cycles) chemotherapy (paclitaxel) is not inferior in efficacy, compared to 8 continuous cycles of…
ID
Source
Brief title
Condition
- Breast neoplasms malignant and unspecified (incl nipple)
- Breast disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Overall PFS of first treatment line for the continuous treatment arm is defined
as the time from randomization to the documented first progression as defined
by the investigator, or to death due to any cause; for the intermittent
treatment arm is defined as the time from randomization to the documented final
progression as defined by the investigator in first-line intermittent
treatment, or to death due to any cause.
Secondary outcome
Secondary:
* Changes in the RAND 36 quality of life scale will be measured and information
about the social status of patients will be collected.
* Safety and tolerability.
Other:
* Overall PFS of second treatment line for the continuous treatment arm is
defined as the time from start of second-line treatment to the documented first
progression as defined by the investigator, or to death due to any cause;
for the intermittent treatment arm is defined as the time from start of
second-line treatment to the documented final progression as defined by the
investigator in second-line intermittent treatment, or to death due to any
cause.
* PFS-1 in first treatment line calculated from randomization to the documented
first progression as defined by the investigator or to death due to any cause;
* PFS-2 in first treatment line calculated from start of treatment with the
fifth cycle of first-line chemotherapy to the documented final progression as
defined by the investigator in first treatment line, or to death due to any
cause;
lculated using a standard cost method.* PFS-1 in second treatment line
calculated from start of second-line treatment to the documented first
progression, as defined by the investigator, or to death due to any cause;
* PFS-2 in second treatment line calculated from start of treatment with the
fifth cycle of second-line chemotherapy to the documented final progression as
defined by the investigator in second treatment line, or to death due to any
cause;
* TTF in first treatment line is defined as the time from randomization to
treatment discontinuation for any reason, including disease progression,
treatment toxicity, patient or physician preference, or death, whichever comes
first.
* TTF in second treatment line is defined as the time from start of second-line
treatment to treatment discontinuation for any reason, including disease
progression, treatment toxicity, patient or physician preference, or death,
whichever comes first.
* ORR calculated as the proportion of patients with a best overall response of
confirmed Complete Response (CR) and Partial Response (PR).
* DOR calculated as the time from the date of first documented CR or PR to the
first documented progression or death due to underlying cancer.
* OS calculated as the time from the date of randomization to the date of death
due to any cause or the date of last contact.
* Direct medical costs will be calculated using a standard cost method.
Background summary
In The Netherlands, approximately 13.000 women will present with breast cancer
each year. Locally recurrent or metastatic breast cancer is expected to
develop in one third of these women. For almost 30 years chemotherapy in breast
cancer has been continuously developed. However, in spite of the availability
of several chemotherapeutic agents, median survival after the development of
metastatic disease is generally 2-4 years. The sequential single-agent mono
chemotherapy for most patients in the absence of imminent visceral crisis is an
acceptable standard of care and the addition of novel agents targeting
angiogenesis has resulted in improvement of progression free survival of these
patients.
The optimal duration of chemotherapeutic treatment for metastatic breast cancer
is still a matter of debate. Continuous chemotherapy administration regimens
would be justified if there was a proven prolongation in survival. Possible
gain in the duration of remission has to be weighed against the side-effects of
treatment. In several studies, continuous chemotherapy, administered until
disease progression was evident, has been compared with shorter duration
chemotherapy consisting of intermittent therapy, or using an
induction/maintenance approach. Results from 5 studies indicate no clinical
advantage for giving uninterrupted continuous or induction plus maintenance
chemotherapy in patients with metastatic breast cancer. In two studies it was
concluded that continuous chemotherapy is better than intermittent chemotherapy
or induction only chemotherapy in patients with advanced breast cancer.
Study objective
Primary:
The primary objective of this study is to demonstrate that the overall
progression-free survival (PFS) of 8 cycles of intermittent (2 times 4 cycles)
chemotherapy (paclitaxel) is not inferior in efficacy, compared to 8 continuous
cycles of chemotherapy (paclitaxel), both in combination with bevacizumab, in
first line treatment of patients with HER2/neu negative, incurable, metastatic
or unresectable locally advanced breast cancer.
Secondary:
The secondary objectives of this study are:
* To compare the overall PFS of second line treatment of 8 continuous cycles of
chemotherapy with non-pegylated liposomal doxorubicin or capecitabine with 8
cycles of intermittent (2 times 4 cycles) chemotherapy with non-pegylated
liposomal doxorubicin or capecitabine;
* To assess PFS associated with the first set of 4 chemotherapy cycles (PFS-1)
and, if applicable, to assess PFS associated with the second set of 4
chemotherapy cycles (PFS-2) of the intermittent chemotherapy treatment arm,
both in first treatment line, combined with bevacizumab, and in second
treatment line;
* To compare the Time to Treatment Failure (TTF) between 8 continuous cycles of
chemotherapy with 8 cycles of intermittent (2 times 4 cycles) chemotherapy in
first treatment line, combined with bevacizumab, and in second treatment line;
* To compare the objective Overall Response Rate (ORR) between 8 continuous
cycles of chemotherapy with 8 cycles of intermittent (2 times 4 cycles)
chemotherapy in first treatment line, combined with bevacizumab, and in second
treatment line;
* To compare the Duration of Objective Response (DOR) between 8 continuous
cycles of chemotherapy with 8 cycles of intermittent (2 times 4 cycles)
chemotherapy in first treatment line, combined with bevacizumab, and second
treatment line; For the intermittent chemotherapy schedule the first DOR and,
if applicable, second DOR in the same treatment line will be accumulated;
* To compare Overall Survival (OS) between 8 continuous cycles of chemotherapy
with 8 cycles of intermittent (2 times 4 cycles) chemotherapy;
* To compare the Safety between 8 continuous cycles of chemotherapy with 8
cycles of intermittent (2 times 4 cycles) chemotherapy;
* To compare the Quality of Life (QoL) between 8 continuous cycles of
chemotherapy with 8 cycles of intermittent (2 times 4 cycles) chemotherapy;
* To compare the Pharmacoeconomics between 8 continuous cycles of chemotherapy
with 8 cycles of intermittent (2 times 4 cycles) chemotherapy.
Study design
Patients will be randomized to two treatment arms. In Arm A, patients will
receive 8 continuous cycles of chemotherapy in first and second line treatment.
In Arm B, patients will receive 8 cycles of intermittent (2 times 4 cycles)
chemotherapy in first and second line treatment.
In first line treatment, patients in both study arms will receive paclitaxel
and bevacizumab continued with bevacizumab only until Progressive Disease (PD)
or unacceptable toxicity, whichever comes first.
As second line treatment patients will receive non-pegylated liposomal
doxorubicin (Myocet®) or capecitabineThere are two exceptions to this:
* Patients that have received a prior maximum cumulative dose of > 300 mg/m2
for doxorubicin or > 600 mg/m2 for epirubicin. They will receive capecitabine.
* Patients that based on other protocol criteria (e.g. deterioration of cardiac
function) are not suitable candidates for 2nd line treatment with non-pegylated
liposomal doxorubicin. They will receive capecitabine.
Arm A
1st line:
* Paclitaxel and bevacizumab: 8 cycles, unless PD or unacceptable toxicity
occurs earlier.
* Bevacizumab until PD or unacceptable toxicity
* At PD patients will go to the 2nd treatment line.
2nd line:
* Non-pegylated liposomal doxorubicin or capecitabine:
8 cycles, unless PD or unacceptable toxicity occurs earlier.
* At PD patients will go to the 3rd treatment line. If possible, it is advised
to cross-over from 2nd line non-pegylated liposomal doxorubicin to 3rd line
capecitabine or from 2nd line capecitabine to 3rd line non-pegylated liposomal
doxorubicine.
Arm B
1st line:
* Paclitaxel and bevacizumab: 4 cycles, unless PD or unacceptable toxicity
occurs earlier.
* Bevacizumab until PD or unacceptable toxicity
* At PD < 3 months after last administration of paclitaxel patients will go to
the 2nd treatment line.
* At PD * 3 months after last administration of paclitaxel, patients will
receive another 4 cycles of paclitaxel and bevacizumab.
* Bevacizumab until the next PD or unacceptable toxicity
* At the next PD patients will go to the 2nd treatment line.
2nd line:
* Non-pegylated liposomal doxorubicin or capecitabine: 4 cycles, unless PD or
unacceptable toxicity occurs earlier.
* At PD < 3 months patients will go to the 3rd treatment line. If possible, it
is advised to cross-over from 2nd line non-pegylated liposomal doxorubicin to
3rd line capecitabine or from 2nd line capecitabine to 3rd line non-pegylated
liposomal doxorubicine.
* At PD * 3 months after last administration of non-pegylated liposomal
doxorubicin or capecitabine, patients will receive another 4 cycles of
non-pegylated liposomal doxorubicin or capecitabine.
* At the next PD patients will go to the 3rd treatment line.
Intervention
During first-line treatment paclitaxel and bevacizumab are given according to
the following schedules:
* Paclitaxel: 90 mg/m2 IV on days 1, 8 and 15 every 28 days
* Bevacizumab: 10 mg/kg IV on days 1 and 15 every 28 days
In Arm A and B, regardless discontinuation of paclitaxel, treatment with
bevacizumab should be continued until progression or unacceptable toxicity.
After discontinuation of paclitaxel bevacizumab is continued as follows:
* Bevacizumab: 15 mg/kg IV on day 1 every 21 days
The following schedules are followed for 2nd line treatment:
* Non-pegylated liposomal doxorubicin (Myocet®): 60 mg/m2 IV on day 1 every 21
days; or
* Capecitabine 1000 mg/m2 twice daily Per Os (P.O.) for two weeks followed by a
one-week rest period
Study burden and risks
The treatment and assessments are concurrent with the standard treatment. In
principle the patient does not have to undergo any extra assessments.
Risks:
* Toxicity due to the medication
* Reaction to the use of contrast fluid (used for CT/MUGA scans)
* Side effects of blood sampling
The above mentioned risks are the result of treatment and assessments which the
patient would undergo regardless of whether she would participate in the study
or not.
Plesmanlaan 125
Amsterdam 1066 CX
NL
Plesmanlaan 125
Amsterdam 1066 CX
NL
Listed location countries
Age
Inclusion criteria
1. Female patients * 18 years old.;2. Patients with HER2/neu negative, incurable, metastatic or unresectable locally advanced breast cancer, who are candidates for chemotherapy. ;3. Patients with measurable or evaluable-only disease by Response Evaluation Criteria in Solid Tumors (RECIST 1.1) criteria as determined by the investigator.;4. Documented Estrogen Receptor (ER) / Progesteron Receptor (PR) status.;5. HER2/neu-negative disease as determined by immunohistochemistry or Fluorescence In Situ Hybridization (FISH).;6. Patients with an ECOG Performance Status * 2.;7. Life expectancy of * 12 weeks.;8. Signature of Informed Consent Form by patient
Exclusion criteria
Prior Treatment:;1. Previous chemotherapy for HER2/neu negative, incurable, metastatic or unresectable locally advanced breast cancer. ;2. Prior hormonal therapy for HER2/neu negative, incurable, metastatic or unresectable locally advanced breast cancer that has not been discontinued 1 week before start of study treatment.;3. Prior adjuvant/neo-adjuvant chemotherapy within 6 months prior to first study treatment. However, if the prior adjuvant/neo-adjuvant chemotherapy was taxane based, patients are excluded if they received their last chemotherapy within12 months prior to first study treatment. ;4. Prior radiotherapy covering more than 30% of marrow-bearing bone. ;5. Patients that have received recent radiation therapy that are not recovered from any significant (Grade * 3) acute toxicity prior to study treatment.;6. Prior therapy with bevacizumab, sorafenib, sunitinib, or other VEGF pathway-targeted therapy.;Current Treatment:;7. Chronic daily treatment with aspirin (* 325 mg/day) or clopidogrel (* 75 mg/day).;8. Chronic daily treatment with corticosteroids (dose of * 10 mg/day methylprednisolone or equivalent), with the exception of inhaled steroids.;9. Current or recent (within 30 days of first study treatment) treatment with another investigational drug or participation in another investigational study.;Hematology, coagulation and biochemistry;10. Inadequate bone marrow function: Absolute Neutrophil Count (ANC): < 1.5 x 109/L, or platelet count <100 x 109/L or hemoglobin < 6 mmol/L. ;11. Inadequate liver function, defined as: ;* Serum (total) bilirubin > 2 x the Upper Limit of Normal (ULN) for the institution; ;* Aspartaat-Amino-Transferase/ Serum Glutamic Oxaloacetic Transaminase (ASAT/SGOT) or Alanine-Amino-Transferase/ Serum Glutamic Pyruvic Transaminase (ALAT/SGPT) > 2.5 x ULN (> 5 x ULN in patients with liver metastases);;* Alkaline phosphatase levels > 2.5 x ULN (> 5 x ULN in patients with liver metastases, or > 10 x ULN in patients with bone metastases).;12. Inadequate renal function, defined as: ;*Serum creatinine > 1.5 x ULN;*Creatinine clearance < 50 mL/min (Calculated according to Cockroft and Gault);;*Urine dipstick for proteinuria > 2+. ;13. Patients not receiving anticoagulant medication who have an International Normalized Ratio (INR) > 1.5 or an activated Partial Thromboplastin Time (aPTT) > 1.5 x ULN within 7 days prior to first study treatment. Note: Patients receiving full dose oral or parenteral anticoagulants may be included in the study as long as anticoagulant dosing has been stable for at least two weeks prior to study entry and the appropriate coagulation monitoring tests are within local therapeutic limits.
Other:
14. Known CNS disease, except for treated brain metastases. Treated brain metastases are defined as: having no evidence of progression or haemorrhage after treatment and no ongoing requirement for dexamethasone, as ascertained by clinical examination and brain imaging (MRI or CT) during the screening period. Anticonvulsants (stable dose) are allowed. Treatment for brain metastases may include whole brain radiotherapy (WBRT), radiosurgery (RS; Gamma Knife, LINAC, or equivalent) or a combination as deemed appropriate by the treating physician. Patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to day 1 are excluded. A brain or MRI scan is required within 28 days prior to day 1 if the presence of untreated brain metastases is suspected.
15. Patients with concurrent active malignancy other than: breast cancer; adequately treated non melanoma skin cancer; or other non-invasive carcinoma or in situ neoplasm, provided that the patient is disease free for > 3 years.
16. Pregnant or lactating females. Serum pregnancy test to be assessed within 7 days prior to study treatment start, or within 14 days with a confirmatory urine pregnancy test within 7 days prior to study treatment start.
17. Women of childbearing potential (defined as <2 years after last menstruation and not surgically sterile) not using effective, non-hormonal means of contraception (intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly).
18. Major surgical procedure (including open biopsy) within 28 days prior to the first study treatment, or anticipation of the need for major surgery during the course of the study treatment.
19. Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to day 1.
20. Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months prior to day 1.
21. Any previous venous thrombo-embolism > CTC Grade 3.
22. History of haemoptysis (*1/2 teaspoon of bright red blood per episode) within 1 month prior to day 1.
23. History or evidence of inherited bleeding diathesis or coagulopathy with the risk of bleeding.
24. Uncontrolled hypertension (systolic > 150 mm Hg and/or diastolic > 100 mm Hg).
25. Clinically significant (i.e. active) cardiovasculair disease defined as:
* Cerebro Vascular Accident (CVA)
* Stroke within * 6 months prior to prior to day 1
* Myocardial infarction within * 6 months prior to day 1
* Unstable angina
* New York Heart Association (NYHA) Grade II or greater
* Congestive Heart Failure (CHF)
* Serious cardiac arrhythmia requiring medication
* Relevant pathologic findings in ECG.
26. Inadequate left ventricular ejection fraction at baseline. LVEF by MUGA or ECHO must be * 50% and should be performed within 4 weeks prior to randomization if cardiac failure is suspected.
27. History of abdominal fistula, Grade 4 bowel obstruction or gastrointestinal perforation, intra-abdominal abscess within 6 months of randomization.
28. Serious non-healing wound, peptic ulcer or bone fracture.
29. Known hypersensitivity to any of the study drugs or excipients.
30. Hypersensitivity to Chinese hamster ovary cell products or other recombinant human or humanized antibodies.
31. Evidence of any other medical conditions (such as psychiatric illness, physical examination or laboratory findings) that may interfere with the planned treatment, affect patient compliance or place the patient at high risk from treatment-related complications.
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 | EUCTR2010-021519-18-NL |
| CCMO | NL33091.060.10 |