Breast Cancer
Conditions
Keywords
Metastatic, HR positive, ER positive
Brief summary
Ganetespib is a drug that may stop cancer cells from growing. This drug has been used in other research studies and laboratory experiments. It has also been studied in phase I trials, where the appropriate dosing has been determined. Ganetespib is considered an "HSP90 inhibitor". By blocking HSP90, ganetespib is thought to reduce the ability of cancer cells to become resistant to treatment. Fulvestrant is a hormonal therapy that works by attaching to estrogen receptors. In doing so, it can block the effect of estrogen on cancer cells. In addition, fulvestrant causes a decrease in the number of estrogen receptors. Fulvestrant is a drug that is approved by the FDA for treatment of metastatic, hormone receptor positive breast cancer, based upon the results of phase III clinical trials. In the laboratory, adding ganetespib to fulvestrant appears to improve its effectiveness. It is not known whether this is true in humans. In this research study, we are evaluating the effect of the addition of ganetespib to fulvestrant in participants with hormone receptor-positive, metastatic breast cancer.
Detailed description
Because no one knows which of the study options is best, you will be "randomized" into one of the study groups: Arm A: Fulvestrant or Arm B: Fulvestrant plus Ganetespib. You will have a one-third chance of being placed in Arm A and a two-thirds chance of being placed in Arm B. If you are initially placed in Arm A but your disease progresses, you will have the option of receiving the combination of fulvestrant plus ganetespib as part of Arm C. You will undergo the following procedures during the research study: study drug(s), blood tests, clinical exams and scans/imaging tests.
Interventions
DRUGFulvestrant
DRUGGanetespib
Sponsors
Dana-Farber Cancer Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Participants were randomized 2:1 B Fulvestrant+Ganetespib:A Fulvestrant
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed invasive breast cancer that is metastatic or unresectable locally advanced * Estrogen and/or progesterone receptor positive breast cancer * HER2 negative * Measurable disease is required (effective 4/30/14: all non-measurable \[evaluable\] disease slots have been filled) * Endocrine resistant breast cancer * May have received up to one prior line of chemotherapy for metastatic or unresectable locally advanced breast cancer * May have initiated bisphosphonate therapy prior to start of protocol therapy * Must be at least 2 weeks from prior chemotherapy or radiotherapy * ECOG performance status of 0 or 1 * Availability of tissue block from initial breast cancer diagnosis and/or metastatic recurrence * For subjects with biopsy-accessible disease, must be willing to undergo a required on-treatment research biopsy * Adequate IV access
Exclusion criteria
* Pregnant or breastfeeding * Prior treatment with HSP90 inhibitor * Prior treatment with fulvestrant * Concurrent treatment with commercial agents or other agents with the intent to treat the participant's malignancy * Untreated or progressive brain metastases * Pending visceral crisis, in the opinion of the treating investigator * History of allergic reactions attributed to compounds of similar chemical or biologic composition to fulvestrant or ganetespib * Uncontrolled intercurrent illness * Other malignancies within 3 years
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) | Disease was assessed radiographically every 2 cycles for year 1 and every 2-4 cycles longer-term. Participants in this study cohort were followed for survival up to 4 years from treatment end. | PFS based on Kaplan-Meier is defined as the time from study entry to the earliest documentation of disease progression (PD) or death. Participants alive without evidence of PD are censored at the date of last disease assessment. Participants who receive non-protocol anti-cancer therapy before disease progression are censored at time of last disease assessment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Grade 3-4 Toxicity Rate | AEs were assessed every cycle on treatment (weeks 2-3 on cycle 1). Median treatment duration was 4 cycles/~4 months on each arm. Maximum treatment duration was 41 cycles (Arm A) and 42 cycles (Arm B) which approximates 38 months. | All grade 3-4 adverse events (AE) with treatment attribution of possibly, probably or definite based on NCI Common Toxicity Criteria for Adverse Events version 4 (CTCAEv4) as reported on case report forms were counted to calculate the percentage of participants experiencing at least one treatment-related grade 3 or 4 AE of any type on treatment. |
| Objective Response Rate (ORR) | Disease was assessed radiographically every 2 cycles for year 1 and every 2-4 cycles thereafter on treatment. Maximum treatment duration was 41 cycles (Arm A) and 42 cycles (Arm B) which approximates 38 months. | ORR was defined as the percentage of participants with measurable disease at baseline achieving complete response (CR) or partial response (PR) based on RECIST 1.1 criteria on treatment. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions. |
| Clinical Benefit Rate (CBR) | Disease was assessed radiographically every 2 cycles for year 1 and every 2-4 cycles thereafter on treatment. Maximum treatment duration was 41 cycles (Arm A) and 42 cycles (Arm B) which approximates 38 months. | CBR was defined as the percentage of participants with measurable disease at baseline achieving complete response (CR), partial response (PR), or stable disease (SD) for 24 weeks or longer based on RECIST 1.1 criteria on treatment. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PD is at least a 20% increase in sum LD of target lesions (smallest sum LD reference), new lesions, and/or unequivocal progression of existing non-target lesions. Stable disease (SD) is defined as any condition not meeting the above criteria. SD needed to be a minimum 24 weeks in duration. |
| Overall Survival (OS) | Participants were followed long-term for survival every 3 months from the end of treatment until death, lost to follow-up or up to 4 years from treatment end. Median survival follow-up was 28 months for the study cohort. | OS based on Kaplan-Meier is defined as the time from study entry to death or date last known alive or censored at date last known alive. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORNancy U Lin, MD
Dana-Farber Cancer Institute
Participant flow
Recruitment details
Participants were enrolled between June 2012 and June 2015
Participants by arm
| Arm | Count |
|---|---|
| ARM A - Fulvestrant Fulvestrant: 500 mg administered by intramuscular injection on days 1 and 15 of cycle 1, day 1 of cycle 2 and each subsequent cycle; cycle duration is 28 days Eligible participants on Arm A were allowed to crossover to Arm B upon disease progression. Treatment continued for Arm A participants until 2nd disease progression. | 15 |
| Arm B - Fulvestrant+Ganetespib Fulvestrant: 500 mg administered by intramuscular injection on days 1 and 15 of cycle 1, day 1 of cycle 2 and each subsequent cycle; cycle duration is 28 days Ganetespib: 200 mg/m2 administered intravenously on days 1, 8 and 15 of each 28 day cycle
Arm B participants whose disease was at a minimum stable could elect to discontinue ganetespib after 6 cycles or stay on combination treatment until disease progression. Otherwise, Arm B participants taken off ganetespib for toxicity were to remain on single agent fulvestrant until disease progression. | 35 |
| Total | 50 |
Baseline characteristics
| Characteristic | ARM A - Fulvestrant | Arm B - Fulvestrant+Ganetespib | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 6 Participants | 7 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants | 29 Participants | 43 Participants |
| Age, Continuous | 57 years | 52 years | 53 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants | 34 Participants | 49 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) White | 15 Participants | 30 Participants | 45 Participants |
| Region of Enrollment United States | 15 Participants | 35 Participants | 50 Participants |
| Sex: Female, Male Female | 15 Participants | 34 Participants | 49 Participants |
| Sex: Female, Male Male | 0 Participants | 1 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 11 / 15 | 15 / 35 | 6 / 7 |
| other Total, other adverse events | 15 / 15 | 35 / 35 | 7 / 7 |
| serious Total, serious adverse events | 2 / 15 | 11 / 35 | 0 / 7 |
Outcome results
Primary
Progression-Free Survival (PFS)
PFS based on Kaplan-Meier is defined as the time from study entry to the earliest documentation of disease progression (PD) or death. Participants alive without evidence of PD are censored at the date of last disease assessment. Participants who receive non-protocol anti-cancer therapy before disease progression are censored at time of last disease assessment.
Time frame: Disease was assessed radiographically every 2 cycles for year 1 and every 2-4 cycles longer-term. Participants in this study cohort were followed for survival up to 4 years from treatment end.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| ARM A - Fulvestrant | Progression-Free Survival (PFS) | 3.7 months |
| Arm B - Fulvestrant+Ganetespib | Progression-Free Survival (PFS) | 3.6 months |
p-value: 0.79Log Rank
Secondary
Clinical Benefit Rate (CBR)
CBR was defined as the percentage of participants with measurable disease at baseline achieving complete response (CR), partial response (PR), or stable disease (SD) for 24 weeks or longer based on RECIST 1.1 criteria on treatment. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PD is at least a 20% increase in sum LD of target lesions (smallest sum LD reference), new lesions, and/or unequivocal progression of existing non-target lesions. Stable disease (SD) is defined as any condition not meeting the above criteria. SD needed to be a minimum 24 weeks in duration.
Time frame: Disease was assessed radiographically every 2 cycles for year 1 and every 2-4 cycles thereafter on treatment. Maximum treatment duration was 41 cycles (Arm A) and 42 cycles (Arm B) which approximates 38 months.
Population: The analysis dataset is comprised of all enrolled participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ARM A - Fulvestrant | Clinical Benefit Rate (CBR) | 33.3 percentage of participants |
| Arm B - Fulvestrant+Ganetespib | Clinical Benefit Rate (CBR) | 34.3 percentage of participants |
Secondary
Grade 3-4 Toxicity Rate
All grade 3-4 adverse events (AE) with treatment attribution of possibly, probably or definite based on NCI Common Toxicity Criteria for Adverse Events version 4 (CTCAEv4) as reported on case report forms were counted to calculate the percentage of participants experiencing at least one treatment-related grade 3 or 4 AE of any type on treatment.
Time frame: AEs were assessed every cycle on treatment (weeks 2-3 on cycle 1). Median treatment duration was 4 cycles/~4 months on each arm. Maximum treatment duration was 41 cycles (Arm A) and 42 cycles (Arm B) which approximates 38 months.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ARM A - Fulvestrant | Grade 3-4 Toxicity Rate | 100 percentage of participants |
| Arm B - Fulvestrant+Ganetespib | Grade 3-4 Toxicity Rate | 100 percentage of participants |
| Arm A - Crossover Fulvestrant+Ganetespib | Grade 3-4 Toxicity Rate | 100 percentage of participants |
Secondary
Objective Response Rate (ORR)
ORR was defined as the percentage of participants with measurable disease at baseline achieving complete response (CR) or partial response (PR) based on RECIST 1.1 criteria on treatment. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions.
Time frame: Disease was assessed radiographically every 2 cycles for year 1 and every 2-4 cycles thereafter on treatment. Maximum treatment duration was 41 cycles (Arm A) and 42 cycles (Arm B) which approximates 38 months.
Population: The analysis dataset is comprised of all enrolled participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ARM A - Fulvestrant | Objective Response Rate (ORR) | 20.0 percentage of participants |
| Arm B - Fulvestrant+Ganetespib | Objective Response Rate (ORR) | 14.3 percentage of participants |
p-value: 0.68Fisher Exact
Secondary
Overall Survival (OS)
OS based on Kaplan-Meier is defined as the time from study entry to death or date last known alive or censored at date last known alive.
Time frame: Participants were followed long-term for survival every 3 months from the end of treatment until death, lost to follow-up or up to 4 years from treatment end. Median survival follow-up was 28 months for the study cohort.
Population: The analysis dataset is comprised of all enrolled participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ARM A - Fulvestrant | Overall Survival (OS) | 25.9 months |
| Arm B - Fulvestrant+Ganetespib | Overall Survival (OS) | 29.2 months |