Neoplasms, Ovarian, Ovarian Cancer
Conditions
Keywords
HYCAMTIN, ovarian cancer, recurrent, relapsed, carboplatin, topotecan, potentially platinum-sensitive
Brief summary
This study was designed to find the most effective and safest doses of both HYCAMTIN and CARBOPLATIN that can be given for the treatment of ovarian cancer. This study may allow researchers to determine the effectiveness of combining HYCAMTIN and CARBOPLATIN.
Interventions
DRUGtopotecan
HYCAMTIN at a dose of 2.0 mg/m2 on Days 1 and 8 every 21 days followed by carboplatin at AUC 5 on Day 1
DRUGCARBOPLATIN
HYCAMTIN at a dose of 2.0 mg/m2 on Days 1 and 8 every 21 days followed by carboplatin at AUC 5 on Day 1
Sponsors
GlaxoSmithKline
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subject must have baseline laboratory values as follows: * Hemoglobin 9.0 g/dL * Neutrophils 1,500/mm3 * Platelets 100,000/mm3 * Creatinine 1.5 mg/dL ( 133 mol/l) or creatinine clearance 60 mL/min * Serum bilirubin \< 2.0 mg/dL (\< 35 umol/L) * SGOT/AST, SGPT/ALT and alkaline phosphatase \< 2 times ULN if liver metastases are absent by abdominal CT or MRI or \< 5 times ULN if liver metastases are present * Subject is allowed to have received, but is not required to have received, one additional prior non-cytotoxic regimen for management of recurrent or persistent disease according to the following definition: Non-cytotoxic (biologic or cytostatic) agents include (but are not limited to) monoclonal antibodies, cytokines, and small-molecule inhibitors of signal transduction * Subject is female 18 years of age with an ECOG Performance Status of 0, 1 or 2 * Subject has recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer which was histologically confirmed at the time of the primary diagnosis * Subject has received one prior platinum-based chemotherapeutic regimen (containing either carboplatin or cisplatin) for the treatment of primary disease. Consolidation chemotherapy is not permitted * Subject's disease is considered potentially platinum-sensitive (i.e., have had a platinum-free interval following complete response to carboplatin or cisplatin of greater than 6 months) * Subject must have at least one measurable lesion as determined by diagnostic studies including CT or MRI or physical exam. Measurable disease must be accurately measured in at least one dimension (longest dimension to be recorded). Each lesion must be 20 mm in their longest dimension when measured by conventional techniques, including palpation, plain X-ray, CT and MRI, or 10 mm when measured by spiral CT. Palpable tumor masses that cannot be evaluated radiologically must have 2 diameters 20 mm. An attempt to document lesion size by ultrasound should be undertaken for palpable lesions not visualized on CT (or MRI). * The same diagnostic imaging method used to evaluate disease must be used throughout the study to evaluate lesions consistently * Stable blood, liver and renal functions. * Subjects of child-bearing potential must be practicing adequate contraception (e.g. oral contraceptives, diaphragm plus spermicide, or IUD) for at least 3 months prior to study start. The same contraceptive method should be used throughout the study and continue for at least 4 weeks after the end of the study
Exclusion criteria
* Pregnant or lactating. * Subject has received more than 1 prior chemotherapy regimen or a history of consolidation cytotoxic chemotherapy * Subject has concomitant or history of previous malignancies, with the exception of adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the subject has been disease-free for 5 years * Subject has brain metastases as documented by CT or MRI. Note: Asymptomatic subjects do not require CT or MRI to rule out brain metastases * Received previous treatment with HYCAMTIN. * Subject has received an investigational agent within 30 days or 5 half-lives (whichever is longer) prior to study entry * Received prior radiation therapy for ovarian cancer
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With the Indicated Response | From start of treatment to evidence of CR or PR (up to 39.3 weeks). | Overall response rate, as determined by radiologic evaluation (utilizing the World Health Organization \[WHO\] criteria and/or physical examination was measured. Complete response (CR: complete disappearance of all lesions), partial response (PR: \>50% decrease in the measurements of the largest lesions with no appearance of new lesions), stable disease (SD: no change in tumor size for at least 8 weeks) and progressive disease (PD: \>25% increase in measurements of lesions or appearance of new lesions). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response | From time of PR or CR to disease progression/death (up to 56.0 weeks) | Duration of response was calculated as the time from first documented PR or CR until disease progression or death. For participants who did not have disease progression or did not die, the date on which alternative anti-cancer therapy began was used, or the date of last contact (if sooner). The word used for such participants was censored. |
| Progression-free Survival | From start of treatment to disease progression/death (up to 67.7 weeks) | Progression-free survival (PFS) was calculated as the time from the start of treatment until disease progression or death. For participants who did not have disease progression or did not die, the date on which alternative anti-cancer therapy began was used, or the date of last contact (if sooner). The word used for such participants was censored. Although Time to Disease Progression was stated as an endpoint in the protocol, the definition given in the protocol (and used in the study) was that of PFS. As such, PFS was measured, not Time to Disease Progression. |
| Time to Response | From start of treatment to evidence of PR or CR (up to 39.3 weeks) | Time to response was calculated as the time from start of treatment until first evidence of partial response (PR; \>50% decrease in the measurements of the largest lesions with no appearance of new lesions) or complete response (CR; complete disappearance of all lesions). |
| The Number of Participants Classified as Responders in Cancer Antigen 125 (CA-125) | Baseline to end of study (up to 54.7 weeks). | CA-125 is a tumor marker, found in greater concentration in tumor cells than other cells of the body. Participants were classed as responders if their CA-125 level at the end of study was 50% or less of baseline. In addition, a confirmatory sample (taken at least 28 days after the first sample) must have also been 50% or less of baseline. |
| Time to Disease Progression | From start of treatment to disease progression/death | Although Time to Disease Progression was stated as an endpoint in the protocol, the definition given in the protocol (and used in the study) was that of Progression-free Survival. As such, Progression-free Survival was measured, not Time to Disease Progression. See the outcome measure entitled Progression-free Survival for data pertaining to time to disease progression. |
| Number of Participants Who Died From the Start of Treatment to Follow-up | From start of treatment to death (up to 110.4 weeks). | The number of participants who died from the start of treatment to follow-up was calculated. For participants who did not die, the date of last contact was used. The word used for such participants was censored. |
Countries
Canada, United States
Participant flow
Pre-assignment details
The run-in phase was conducted to find a safe dose of drug, before the treatment phase of the study began. Different doses were given to 22 participants (enrolled a few at a time) to find the safest dose. Once the safe dose was found, 55 new participants were enrolled in the treatment phase, and all were to start their treatment at this safe dose.
Participants by arm
| Arm | Count |
|---|---|
| Dose-finding Phase Starting dose of 2.0 milligrams (mg)/square meter (m2) topotecan (Days 1 and 8, every 21 days) and area under the curve (AUC) 5 carboplatin (Day 1 every 21 days) | 22 |
| Activity Assessment Phase Topotecan 2.5 mg/m2 (starting dose determined from the dose-finding phase) administered as a 30 minute intravenous (IV) infusion on Days 1 and 8, every 21 days. Carboplatin AUC 5 administered as a 30 minute IV infusion on Day 1, every 21 days. | 55 |
| Total | 77 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Run-in Phase | Adverse Event | 1 | 0 |
| Run-in Phase | Protocol Violation | 1 | 0 |
| Run-in Phase | Study Follow-up Stopped | 5 | 0 |
| Treatment Phase | Adverse Event | 0 | 1 |
| Treatment Phase | Lack of Efficacy | 0 | 3 |
| Treatment Phase | Lost to Follow-up | 0 | 3 |
| Treatment Phase | Study Follow-up Stopped | 0 | 34 |
| Treatment Phase | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Dose-finding Phase | Activity Assessment Phase | Total |
|---|---|---|---|
| Age Continuous | 63.8 years STANDARD_DEVIATION 10.94 | 62.2 years STANDARD_DEVIATION 11.13 | 62.6 years STANDARD_DEVIATION 11.03 |
| Number of participants with the indicated ECOG Performance Status Grade 0 | 15 participants | 42 participants | 57 participants |
| Number of participants with the indicated ECOG Performance Status Grade 1 | 7 participants | 9 participants | 16 participants |
| Number of participants with the indicated ECOG Performance Status Grade 2 | 0 participants | 4 participants | 4 participants |
| Race/Ethnicity, Customized African American/African Heritage | 2 participants | 2 participants | 4 participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Asian | 1 participants | 3 participants | 4 participants |
| Race/Ethnicity, Customized Missing | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized White | 19 participants | 48 participants | 67 participants |
| Sex: Female, Male Female | 22 Participants | 55 Participants | 77 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 20 / 22 | 54 / 55 |
| serious Total, serious adverse events | 6 / 22 | 12 / 55 |
Outcome results
Primary
Number of Participants With the Indicated Response
Overall response rate, as determined by radiologic evaluation (utilizing the World Health Organization \[WHO\] criteria and/or physical examination was measured. Complete response (CR: complete disappearance of all lesions), partial response (PR: \>50% decrease in the measurements of the largest lesions with no appearance of new lesions), stable disease (SD: no change in tumor size for at least 8 weeks) and progressive disease (PD: \>25% increase in measurements of lesions or appearance of new lesions).
Time frame: From start of treatment to evidence of CR or PR (up to 39.3 weeks).
Population: Intent-to-Treat (ITT) Population: all participants who received at least one dose of study drug
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Activity Assessment Phase | Number of Participants With the Indicated Response | Complete response | 6 participants |
| Activity Assessment Phase | Number of Participants With the Indicated Response | Partial response | 11 participants |
| Activity Assessment Phase | Number of Participants With the Indicated Response | Stable disease | 20 participants |
| Activity Assessment Phase | Number of Participants With the Indicated Response | Progressive disease | 7 participants |
| Activity Assessment Phase | Number of Participants With the Indicated Response | Not evaluable | 11 participants |
95% CI: [18.7, 43.1]
Secondary
Duration of Response
Duration of response was calculated as the time from first documented PR or CR until disease progression or death. For participants who did not have disease progression or did not die, the date on which alternative anti-cancer therapy began was used, or the date of last contact (if sooner). The word used for such participants was censored.
Time frame: From time of PR or CR to disease progression/death (up to 56.0 weeks)
Population: All participants who showed a tumor response (CR or PR).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Activity Assessment Phase | Duration of Response | 42.64 weeks |
Secondary
Number of Participants Who Died From the Start of Treatment to Follow-up
The number of participants who died from the start of treatment to follow-up was calculated. For participants who did not die, the date of last contact was used. The word used for such participants was censored.
Time frame: From start of treatment to death (up to 110.4 weeks).
Population: Intent-to-Treat (ITT) Population: all participants who received at least one dose of study drug
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Activity Assessment Phase | Number of Participants Who Died From the Start of Treatment to Follow-up | Died | 8 participants |
| Activity Assessment Phase | Number of Participants Who Died From the Start of Treatment to Follow-up | Censored | 47 participants |
Secondary
Progression-free Survival
Progression-free survival (PFS) was calculated as the time from the start of treatment until disease progression or death. For participants who did not have disease progression or did not die, the date on which alternative anti-cancer therapy began was used, or the date of last contact (if sooner). The word used for such participants was censored. Although Time to Disease Progression was stated as an endpoint in the protocol, the definition given in the protocol (and used in the study) was that of PFS. As such, PFS was measured, not Time to Disease Progression.
Time frame: From start of treatment to disease progression/death (up to 67.7 weeks)
Population: Intent-to-Treat (ITT) Population: all participants who received at least one dose of study drug
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Activity Assessment Phase | Progression-free Survival | 44.29 weeks |
Secondary
The Number of Participants Classified as Responders in Cancer Antigen 125 (CA-125)
CA-125 is a tumor marker, found in greater concentration in tumor cells than other cells of the body. Participants were classed as responders if their CA-125 level at the end of study was 50% or less of baseline. In addition, a confirmatory sample (taken at least 28 days after the first sample) must have also been 50% or less of baseline.
Time frame: Baseline to end of study (up to 54.7 weeks).
Population: Intent-to-Treat (ITT) Population: all participants who received at least one dose of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Activity Assessment Phase | The Number of Participants Classified as Responders in Cancer Antigen 125 (CA-125) | 23 participants |
Secondary
Time to Disease Progression
Although Time to Disease Progression was stated as an endpoint in the protocol, the definition given in the protocol (and used in the study) was that of Progression-free Survival. As such, Progression-free Survival was measured, not Time to Disease Progression. See the outcome measure entitled Progression-free Survival for data pertaining to time to disease progression.
Time frame: From start of treatment to disease progression/death
Population: Intent-to-Treat (ITT) Population: all participants who received at least one dose of study drug
Secondary
Time to Response
Time to response was calculated as the time from start of treatment until first evidence of partial response (PR; \>50% decrease in the measurements of the largest lesions with no appearance of new lesions) or complete response (CR; complete disappearance of all lesions).
Time frame: From start of treatment to evidence of PR or CR (up to 39.3 weeks)
Population: All participants who showed a tumor response (CR or PR).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Activity Assessment Phase | Time to Response | 6.57 weeks |