Fallopian Tube Cancer, Ovarian Cancer
Conditions
Keywords
Asymptomatic, Clinical trial, Phase II, GM-CSF, Immunotherapy
Brief summary
Granulocyte macrophage colony-stimulating factor (GM-CSF) is an immunostimulant and preliminary data suggests it may change the natural history of prostate cancer and melanoma. This study looks at ability of GM-CSF to alter disease progression in women who have recurrent but asymptomatic recurrence of their ovarian cancer.
Detailed description
This is an open labeled, single arm phase II study of GM-CSF, sargramostim delivered daily without a break in a population of healthy and fit women with evidence of recurrent but asymptomatic mullerian malignancy (such as ovarian cancer, fallopian tube cancer, or primary peritoneal cancer). The main goal is to determine the time to treatment termination due to disease progression or toxicity.
Interventions
DRUGGM-CSF, sargramostim
GM-CSF subcutaneous injection
Sponsors
Dana-Farber Cancer Institute
Bayer
Massachusetts General Hospital
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have a history of histologic or cytologic diagnosis of primary ovarian, primary peritoneal or tubal carcinoma. * Patients must be asymptomatic from their cancer. * Patients must have evidence of recurrent carcinoma, as determined by: * A rising cancer antigen 125 (CA-125) serum level greater than 35 U/mL or two successive rising values with the most recent value at least 3 times the nadir value. * Or evidence of evaluable or measurable disease by x-ray or computed tomography (CT) scan. * Patients may not receive concurrent antineoplastic therapy. All hormonal therapy used as a treatment modality (i.e. tamoxifen, arimidex, etc) must be stopped prior to treatment on protocol. * Age \> 18 years. * Eastern Cooperative Oncology Group (ECOG) performance status \< 2.
Exclusion criteria
* Known severe hypersensitivity to GM-CSF. * Other coexisting malignancies or malignancies diagnosed within the last 5 years, with the exception of basal cell carcinoma or cervical cancer in situ or concurrent superficial or stage IB endometrial carcinoma. * Concomitant use of anti-neoplastic therapy. * Treatment with a non-FDA approved or investigational drug within 30 days before Day 1 of trial treatment. * Any unresolved chronic toxicity greater then Common Toxicity Criteria (CTC) grade 2 from previous anticancer therapy (except alopecia). * Serum creatinine level greater than CTC grade 2 \[1.5 x upper limit normal (ULN)\]. * Pregnancy or breast feeding (women of childbearing potential). * Severe or uncontrolled systemic disease (e.g., unstable or uncompensated respiratory, cardiac, hepatic, or renal disease) as judged by the investigator. * Significant clinical disorder or laboratory finding that makes it potentially unsafe for the subject to participate in the trial as judged by the investigator. * Patients currently receiving other investigational antineoplastic agents, on systemic chemotherapy or under radiation therapy treatment. * Patients with clinical and/or radiographic evidence of current or impending bowel obstruction. * Performance status \< 1. * Ability to understand and the willingness to sign a written informed consent document.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Median Time to Treatment Termination (TTT) | Up to 460 days | TTT is the median time in days to discontinuing treatment with GM-CSF, sargramostim (treatment termination) e.g. time on study until progression of disease, unacceptable adverse effects, bowel obstruction, development of new ascites or pleural effusions, initiation of systemic chemotherapy, participant death, development of co-morbid diseases which make participant continuation on the trial unsafe in the judgment of the principal investigator or the treating physician or withdrawal of consent by the participant. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Time to Progression (TTP) | Up to 60 months | TTP was defined as the median time in days from trial entry until progressive disease (PD) was documented as defined by RECIST criteria. PD was defined of at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. In participants with no measurable disease who had an informative cancer antigen-125 (CA-125), PD was defined as a rise of \> 50% over Baseline, confirmed by a subsequently higher value at least 21 days later. |
| Tumor Response Rate (RR) | Up to 60 months | RR is the percentage of patients with response as assessed by the investigator using Response Evaluable Criteria in Solid Tumors (RECIST) and CA-125 Rustin criteria. Complete Response (CR) is the disappearance of all target and non-target lesions and normalization of CA-125. Partial Response (PR) is at least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD; in patients with no measurable disease with an informative CA-125, the 75% definitions by Rustin is used. Stable Disease is neither sufficient shrinkage for PR nor increase for PD, taking as reference the smallest sum LD since the treatment start. PD is at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since treatment start or the appearance of one or more new lesions; in patients with no measurable disease with an informative CA-125, PD is defined as a rise of \> 50% over baseline, confirmed by a higher value 21 days later. |
| Number of Participants With Adverse Events (Toxicity) Grade 3 or 4 | Up to 460 days | Adverse Events (previously toxicity) were graded according the National Cancer Institute (NCI) Common Toxicity Criteria (CTC), version 3.0. The total number of participants with adverse events graded 3 (severe) or 4 (life-threatening or disabling) are reported. |
Other
| Measure | Time frame |
|---|---|
| Change From Baseline of Anti-Trag Antibodies | Up to 60 months |
Participant flow
Recruitment details
Granulocyte macrophage colony-stimulating factor (GM-CSF) Phase II recruitment from oncology clinic.
Pre-assignment details
Phase II
Participants by arm
| Arm | Count |
|---|---|
| GM-CSF, Sargramostim All enrolled eligible participants who participated in Cohort 1 or Cohort 2 of the study.
In Cohort 1 participants received GM-CSF, sargramostim 250 μg/m\^2 subcutaneous injection daily on days 1 to 14 in a 28-day cycle until disease progression or unacceptable toxicity for a median of 3 cycles.
In Cohort 2 participants received GM-CSF, sargramostim 150 μg/m\^2 subcutaneous injection daily for 28 days in a 28-day cycle until disease progression or unacceptable toxicity for a median of 3 cycles. GM-CSF, sargramostim dose escalation was permitted up to 250 μg/m\^2 per day if applicable based on toxicity and white blood cell count. | 72 |
| Total | 72 |
Baseline characteristics
| Characteristic | GM-CSF, Sargramostim |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 23 Participants |
| Age, Categorical Between 18 and 65 years | 49 Participants |
| Age, Continuous | 60 years STANDARD_DEVIATION 9.15 |
| Region of Enrollment United States | 72 participants |
| Sex: Female, Male Female | 72 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 35 / 35 | 37 / 37 |
| serious Total, serious adverse events | 2 / 35 | 5 / 37 |
Outcome results
Primary
Median Time to Treatment Termination (TTT)
TTT is the median time in days to discontinuing treatment with GM-CSF, sargramostim (treatment termination) e.g. time on study until progression of disease, unacceptable adverse effects, bowel obstruction, development of new ascites or pleural effusions, initiation of systemic chemotherapy, participant death, development of co-morbid diseases which make participant continuation on the trial unsafe in the judgment of the principal investigator or the treating physician or withdrawal of consent by the participant.
Time frame: Up to 460 days
Population: After initial analysis, it was clear that the schedule did not significantly impact the immune response and that the actual white cell count (WCC) was the best correlate predictor of change in CA125, and so the cohorts were combined for an overall analysis. 1 participant withdrew consent and was not included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| GM-CSF, Sargramostim | Median Time to Treatment Termination (TTT) | 78 days |
Secondary
Median Time to Progression (TTP)
TTP was defined as the median time in days from trial entry until progressive disease (PD) was documented as defined by RECIST criteria. PD was defined of at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. In participants with no measurable disease who had an informative cancer antigen-125 (CA-125), PD was defined as a rise of \> 50% over Baseline, confirmed by a subsequently higher value at least 21 days later.
Time frame: Up to 60 months
Population: No analysis was performed. No data was reported for TTP in the clinical chart that was found to be reliable or consistent in the absence of proper computed tomography (CT) surveillance.
Secondary
Number of Participants With Adverse Events (Toxicity) Grade 3 or 4
Adverse Events (previously toxicity) were graded according the National Cancer Institute (NCI) Common Toxicity Criteria (CTC), version 3.0. The total number of participants with adverse events graded 3 (severe) or 4 (life-threatening or disabling) are reported.
Time frame: Up to 460 days
Population: After initial analysis, it was clear that the schedule did not significantly impact the immune response and that the WCC was the best correlate predictor of change in CA125, and so the cohorts were combined for an overall analysis. 1 participant withdrew consent and was not included in the analysis.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| GM-CSF, Sargramostim | Number of Participants With Adverse Events (Toxicity) Grade 3 or 4 | Thrombocytopenia | 2 Participants |
| GM-CSF, Sargramostim | Number of Participants With Adverse Events (Toxicity) Grade 3 or 4 | Musculoskeletal pain | 9 Participants |
| GM-CSF, Sargramostim | Number of Participants With Adverse Events (Toxicity) Grade 3 or 4 | Fatigue | 3 Participants |
| GM-CSF, Sargramostim | Number of Participants With Adverse Events (Toxicity) Grade 3 or 4 | Abnormal liver function test | 2 Participants |
| GM-CSF, Sargramostim | Number of Participants With Adverse Events (Toxicity) Grade 3 or 4 | Vomiting | 2 Participants |
| GM-CSF, Sargramostim | Number of Participants With Adverse Events (Toxicity) Grade 3 or 4 | Metabolic | 2 Participants |
| GM-CSF, Sargramostim | Number of Participants With Adverse Events (Toxicity) Grade 3 or 4 | Small bowel obstruction | 2 Participants |
| GM-CSF, Sargramostim | Number of Participants With Adverse Events (Toxicity) Grade 3 or 4 | Myelodysplasia | 1 Participants |
| GM-CSF, Sargramostim | Number of Participants With Adverse Events (Toxicity) Grade 3 or 4 | Urticaria | 1 Participants |
| GM-CSF, Sargramostim | Number of Participants With Adverse Events (Toxicity) Grade 3 or 4 | Abdominal pain | 1 Participants |
| GM-CSF, Sargramostim | Number of Participants With Adverse Events (Toxicity) Grade 3 or 4 | Palpitations | 1 Participants |
| GM-CSF, Sargramostim | Number of Participants With Adverse Events (Toxicity) Grade 3 or 4 | Hypertension | 1 Participants |
| GM-CSF, Sargramostim | Number of Participants With Adverse Events (Toxicity) Grade 3 or 4 | Changes in bowel habit | 1 Participants |
| GM-CSF, Sargramostim | Number of Participants With Adverse Events (Toxicity) Grade 3 or 4 | Diverticulitis | 1 Participants |
| GM-CSF, Sargramostim | Number of Participants With Adverse Events (Toxicity) Grade 3 or 4 | Gout | 1 Participants |
| GM-CSF, Sargramostim | Number of Participants With Adverse Events (Toxicity) Grade 3 or 4 | Macular tuft | 1 Participants |
| GM-CSF, Sargramostim | Number of Participants With Adverse Events (Toxicity) Grade 3 or 4 | Nausea sinus | 1 Participants |
| GM-CSF, Sargramostim | Number of Participants With Adverse Events (Toxicity) Grade 3 or 4 | Bradycardia | 1 Participants |
| GM-CSF, Sargramostim | Number of Participants With Adverse Events (Toxicity) Grade 3 or 4 | Headache | 1 Participants |
Secondary
Tumor Response Rate (RR)
RR is the percentage of patients with response as assessed by the investigator using Response Evaluable Criteria in Solid Tumors (RECIST) and CA-125 Rustin criteria. Complete Response (CR) is the disappearance of all target and non-target lesions and normalization of CA-125. Partial Response (PR) is at least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD; in patients with no measurable disease with an informative CA-125, the 75% definitions by Rustin is used. Stable Disease is neither sufficient shrinkage for PR nor increase for PD, taking as reference the smallest sum LD since the treatment start. PD is at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since treatment start or the appearance of one or more new lesions; in patients with no measurable disease with an informative CA-125, PD is defined as a rise of \> 50% over baseline, confirmed by a higher value 21 days later.
Time frame: Up to 60 months
Population: After initial analysis, it was clear that the schedule did not significantly impact the immune response and that the actual WCC was the best correlate predictor of change in CA125, and so the cohorts were combined for an overall analysis. 1 participant withdrew consent and was not included in the analysis.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| GM-CSF, Sargramostim | Tumor Response Rate (RR) | Complete Response | 1 Participants |
| GM-CSF, Sargramostim | Tumor Response Rate (RR) | Partial Response | 0 Participants |
| GM-CSF, Sargramostim | Tumor Response Rate (RR) | Stable Disease | 20 Participants |
| GM-CSF, Sargramostim | Tumor Response Rate (RR) | Progressive Disease | 50 Participants |
Other Pre-specified
Change From Baseline of Anti-Trag Antibodies
Time frame: Up to 60 months
Population: This outcome measure was originally posted as a secondary outcome measures but was actually an exploratory endpoint. No data was collected.