Ovarian Cancer
Conditions
Keywords
platinum-resistant
Brief summary
This trial will be a phase I dose-escalation study of lapatinib and paclitaxel for platinum-resistant ovarian cancer, which will establish the phase II dose for subsequent efficacy trials.
Detailed description
While ABCB1 (P-glycoprotein 1) upregulation after paclitaxel administration is well known, there is currently no clinically available method for preventing or overcoming it. To develop a therapy able to prevent ABCB1 upregulation and paclitaxel resistance, several ABCB1 inhibitors have been evaluated in combination with paclitaxel in preclinical model systems. Pulsed-dose lapatinib and paclitaxel are synergistic and inhibition of ABCB1 by lapatinib increases sensitivity to paclitaxel. Lapatinib is FDA approved, orally available, and previously studied in combination with weekly paclitaxel for breast cancer at doses of 1000mg to 1250mg daily (7000-8250mg per week). This trial will use twice-daily dosing of lapatinib at a starting dose of 750 mg for 2 days (1500mg a day and 3000mg weekly dose), which is less than half of the continuous dose and has been shown to achieve plasma concentrations at 48 hours that are associated with synergy. Therefore, these findings can be translated into a novel, well-tolerated, and convenient combination regimen with significant potential for clinical activity. This trial will be a phase I dose-escalation study of lapatinib and paclitaxel for platinum-resistant ovarian cancer, which will establish the phase II dose for subsequent efficacy trials.
Interventions
Participants will receive twice-daily Lapatinib, beginning two days prior to Paclitaxel treatment.
Sponsors
National Cancer Institute (NCI)
Frederick R. Ueland, M.D.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
* histologically or cytologically confirmed ovarian cancer who recur within 12 months of platinum-based chemotherapy * ECOG performance status less than or equal to 2 * Adequate organ and marrow function at baseline * ability to sign a written informed consent document
Exclusion criteria
* hypersensitivity to lapatinib or paclitaxel * uncontrolled intercurrent illness * receiving medications that inhibit or induce CYP3A4 * malabsorption syndrome * congestive heart failure * receiving any other anti-cancer investigational agents * baseline neuropathy greater than Grade 1
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival. | One year | Number of patients with progression-free survival at one year. |
| Number of Participants With Dose-limiting Toxicity | 4 weeks | Dose limiting toxicity (DLT) is calculated as the total number of patients experiencing DLTs divided by the total number treated. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Plasma Concentration of Lapatinib Cycle 1 | 15 days (on day 8 and 15) | Plasma concentrations of lapatinib will be measured on days 8 and 15 prior to paclitaxel administration |
| Change in Plasma Concentration of Lapatinib Cycle 2 | 15 days (on day 8 and 15) | Plasma concentrations of lapatinib will be measured on days 8 and 15 prior to paclitaxel administration |
| Change in Plasma Concentration of Lapatinib Cycle 3 | 15 days (on day 8 and 15) | Plasma concentrations of lapatinib will be measured on days 8 and 15 prior to paclitaxel administration |
Other
| Measure | Time frame | Description |
|---|---|---|
| ABCB1 Expression | 15 days (on day 1, 8 and 15) | Levels of ABCB1 expression (cell-free RNA) will be measured using Nanostring sequencing. |
Countries
United States
Participant flow
Pre-assignment details
Sixteen patients were evaluable for efficacy, toxicity, and response.
Participants by arm
| Arm | Count |
|---|---|
| Lapatinib - Group 1 Patients in this group will receive Lapatinib (750mg PO BID) and Paclitaxel (80mg/m2).
Lapatinib and Paclitaxel: Participants will receive twice-daily Lapatinib, beginning two days prior to Paclitaxel treatment. | 3 |
| Lapatinib - Group 2 Patients in this group will receive Lapatinib (1500mg PO BID) and Paclitaxel (80mg/m2).
Lapatinib and Paclitaxel: Participants will receive twice-daily Lapatinib, beginning two days prior to Paclitaxel treatment. | 6 |
| Lapatinib - Group 3 Patients in this group will receive Lapatinib (2000mg PO BID) and Paclitaxel (80mg/m2).
Lapatinib and Paclitaxel: Participants will receive twice-daily Lapatinib, beginning two days prior to Paclitaxel treatment. | 7 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Physician Decision | 1 | 1 | 2 |
Baseline characteristics
| Characteristic | Lapatinib - Group 1 | Total | Lapatinib - Group 3 | Lapatinib - Group 2 |
|---|---|---|---|---|
| Age, Continuous | 75 years | 67.5 years | 66 years | 64 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 16 Participants | 7 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 16 Participants | 7 Participants | 6 Participants |
| Region of Enrollment United States | 3 participants | 16 participants | 7 participants | 6 participants |
| Sex: Female, Male Female | 3 Participants | 16 Participants | 7 Participants | 6 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 3 | 6 / 6 | 2 / 7 |
| other Total, other adverse events | 3 / 3 | 6 / 6 | 7 / 7 |
| serious Total, serious adverse events | 1 / 3 | 0 / 6 | 0 / 7 |
Outcome results
Primary
Number of Participants With Dose-limiting Toxicity
Dose limiting toxicity (DLT) is calculated as the total number of patients experiencing DLTs divided by the total number treated.
Time frame: 4 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lapatinib - Group 1 | Number of Participants With Dose-limiting Toxicity | 0 Participants |
| Lapatinib - Group 2 | Number of Participants With Dose-limiting Toxicity | 1 Participants |
| Lapatinib - Group 3 | Number of Participants With Dose-limiting Toxicity | 1 Participants |
Primary
Progression-free Survival.
Number of patients with progression-free survival at one year.
Time frame: One year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lapatinib - Group 1 | Progression-free Survival. | 0 Participants |
| Lapatinib - Group 2 | Progression-free Survival. | 0 Participants |
| Lapatinib - Group 3 | Progression-free Survival. | 1 Participants |
Secondary
Change in Plasma Concentration of Lapatinib Cycle 1
Plasma concentrations of lapatinib will be measured on days 8 and 15 prior to paclitaxel administration
Time frame: 15 days (on day 8 and 15)
Population: Plasma lapatinib concentrations were analyzed among samples from patients who completed dosing for the assigned treatment arm and had blood drawn within 24 hours of the last lapatinib dose.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lapatinib - Group 1 | Change in Plasma Concentration of Lapatinib Cycle 1 | Day 8 | 2579 ng/ml | Standard Deviation 1620 |
| Lapatinib - Group 1 | Change in Plasma Concentration of Lapatinib Cycle 1 | Day 15 | 1630 ng/ml | Standard Deviation 590 |
| Lapatinib - Group 2 | Change in Plasma Concentration of Lapatinib Cycle 1 | Day 8 | 1593 ng/ml | Standard Deviation 2100 |
| Lapatinib - Group 2 | Change in Plasma Concentration of Lapatinib Cycle 1 | Day 15 | 2370 ng/ml | Standard Deviation 1910 |
| Lapatinib - Group 3 | Change in Plasma Concentration of Lapatinib Cycle 1 | Day 8 | 2490 ng/ml | Standard Deviation 1720 |
| Lapatinib - Group 3 | Change in Plasma Concentration of Lapatinib Cycle 1 | Day 15 | 2851 ng/ml | Standard Deviation 2160 |
Secondary
Change in Plasma Concentration of Lapatinib Cycle 2
Plasma concentrations of lapatinib will be measured on days 8 and 15 prior to paclitaxel administration
Time frame: 15 days (on day 8 and 15)
Population: Plasma lapatinib concentrations were analyzed among samples from patients who completed dosing for the assigned treatment arm and had blood drawn within 24 hours of the last lapatinib dose.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lapatinib - Group 1 | Change in Plasma Concentration of Lapatinib Cycle 2 | Day 8 | 2002 ng/ml | Standard Deviation 750 |
| Lapatinib - Group 1 | Change in Plasma Concentration of Lapatinib Cycle 2 | Day 15 | 2002 ng/ml | Standard Deviation 1120 |
| Lapatinib - Group 2 | Change in Plasma Concentration of Lapatinib Cycle 2 | Day 8 | 2987 ng/ml | Standard Deviation 2900 |
| Lapatinib - Group 2 | Change in Plasma Concentration of Lapatinib Cycle 2 | Day 15 | 3393 ng/ml | Standard Deviation 3940 |
| Lapatinib - Group 3 | Change in Plasma Concentration of Lapatinib Cycle 2 | Day 8 | 2951 ng/ml | Standard Deviation 2650 |
| Lapatinib - Group 3 | Change in Plasma Concentration of Lapatinib Cycle 2 | Day 15 | 2312 ng/ml | Standard Deviation 1490 |
Secondary
Change in Plasma Concentration of Lapatinib Cycle 3
Plasma concentrations of lapatinib will be measured on days 8 and 15 prior to paclitaxel administration
Time frame: 15 days (on day 8 and 15)
Population: Plasma lapatinib concentrations were analyzed among samples from patients who completed dosing for the assigned treatment arm and had blood drawn within 24 hours of the last lapatinib dose.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lapatinib - Group 1 | Change in Plasma Concentration of Lapatinib Cycle 3 | Day 8 | 1439 ng/ml | — |
| Lapatinib - Group 1 | Change in Plasma Concentration of Lapatinib Cycle 3 | Day 15 | 2242 ng/ml | Standard Deviation 1460 |
| Lapatinib - Group 2 | Change in Plasma Concentration of Lapatinib Cycle 3 | Day 8 | 1499 ng/ml | Standard Deviation 790 |
| Lapatinib - Group 2 | Change in Plasma Concentration of Lapatinib Cycle 3 | Day 15 | 1031 ng/ml | Standard Deviation 600 |
| Lapatinib - Group 3 | Change in Plasma Concentration of Lapatinib Cycle 3 | Day 8 | 2175 ng/ml | Standard Deviation 1790 |
| Lapatinib - Group 3 | Change in Plasma Concentration of Lapatinib Cycle 3 | Day 15 | 1824 ng/ml | Standard Deviation 1130 |
Other Pre-specified
ABCB1 Expression
Levels of ABCB1 expression (cell-free RNA) will be measured using Nanostring sequencing.
Time frame: 15 days (on day 1, 8 and 15)