Ovarian Cancer
Conditions
Keywords
Phase I, Ovarian Cancer, Fostamatinib and Paclitaxel
Brief summary
This research is being done to test the safety of the combination of the study drugs fostamatinib and paclitaxel. This study tests different doses of the drugs to see which doses are safest in people with ovarian cancer when given together.
Detailed description
This is a phase I, open-label, non-randomized multicenter dose-escalation study with the primary objective to determine the maximally tolerated dose (MTD) of fostamatinib when administered with weekly paclitaxel in women with recurrent platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer. Between 8 and 18 adult female subjects will be enrolled and receive weekly paclitaxel in combination with increasing doses of fostamatinib. There will be three dosing regimens of fostamatinib (100 mg bid, 150 mg bid, and 200mg bid) selected based on the FDA approved doses and prior phase I studies of single agent fostamatinib. Dose-escalation will follow a modified toxicity probability interval (mTPI) design. In this study, up to 18 adult female subjects will be enrolled and receive weekly paclitaxel in combination with fostamatinib at the MTD of the combination; at least 6 patients will receive fostamatinib plus paclitaxel at the MTD. A total of up to 30 patients will be enrolled in this study.
Interventions
DRUGFostamatinib 100 mg bid and Paclitaxel
Drug: Fostamatinib (oral; 100 mg bid) Drug: Paclitaxel (60-80 mg/m2)
DRUGFostamatinib 150 mg bid and Paclitaxel
Drug: Fostamatinib (oral; 150 mg bid) Drug: Paclitaxel (60-80 mg/m2)
DRUGFostamatinib 200 mg bid and Paclitaxel
Drug: Fostamatinib (oral; 200 mg bid) Drug: Paclitaxel (60-80 mg/m2)
Sponsors
Rigel Pharmaceuticals
Allegheny Singer Research Institute (also known as Allegheny Health Network Research Institute)
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
* Inclusion Criteria 1. Patients must have histologically or cytologically confirmed epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. Histologic documentation (via the pathology report) of the original primary tumor is required. 2. Patients must have measurable disease, according to RECIST v1.1. 3. Patients must have recurrent, platinum-resistant disease (defined as having relapsed within 6 months of last platinum-containing regimen) or be unable to receive further platinum therapy. There is no limit on the number of prior treatment regimens; however, patients may not have previously received weekly paclitaxel in the recurrent setting. Previous dose dense paclitaxel as initial therapy is allowable. 4. Patients must have the ability to take oral medications. 5. Females, age ≥18 years. 6. ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A). 7. Life expectancy of greater than 3 months. 8. Patients must have normal organ and marrow function. 9. Patients with a diagnosis of hypertension are required to have adequate blood pressure control prior to enrollment, defined as blood pressure ≤ 140/90 mmHg. 10. The effects of fostamatinib on the developing human fetus are unknown. For this reason, women of childbearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately. 11. Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial if the anti-retroviral therapy is not an excluded concurrent medication. 12. For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated and the suppressive therapy is not an excluded concurrent medication. 13. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load and the HCV therapy is not an excluded concurrent medication. 14. Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression. 15. Patients who are willing and able to comply with the protocol and study procedures. Tumor biopsy or paracentesis for tumor cells before therapy (at baseline) and after initiation of treatment (before Cycle 2) for at least 75% of subjects if this is clinically and safely feasible to do so. For patients who have had tumor tissue sampled within 6 months of enrollment and no intervening anti-neoplastic therapy, archived tissue may satisfy the requirement of the pre-treatment biopsy with permission of the protocol chair. 16. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial, with permission of the protocol chair. 17. Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better. 18. The effects of fostamatinib on the developing human fetus are unknown. For this reason and because spleen tyrosine kinase inhibitors as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. 19. Ability to understand and the willingness to sign a written informed consent document. *
Exclusion criteria
1. Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study. Hormonal therapy directed at the malignant tumor must be discontinued at least one week prior to registration. 2. Patients who have not recovered (CTCAE v4.03 grade ≤1) from adverse events due to agents administered more than 4 weeks earlier, unless those events are deemed to have returned to baseline, are irreversible, or are unlikely to develop into a life-threatening condition at the permission of the Protocol Chair (e.g., alopecia). 3. Patients who are currently receiving or have previously received any other investigational agents within 3 weeks prior to entering the study. 4. Patients with known untreated brain metastases, as progressive neurologic dysfunction may develop that would confound the evaluation of neurologic and other adverse events. 5. Patients with Grade 2 or greater neuropathy. 6. History of allergic reactions attributed to compounds of similar chemical or biologic composition to fostamatinib or paclitaxel. Patients who are able to tolerate paclitaxel on a desensitization protocol will be allowed. 7. Strong CYP3A4 inhibitors or inducers should not be used within 3 days of Day 1 dosing until the end of study. Moderate CYP3A4 inhibitors or inducers should be used with caution. 8. Uncontrolled intercurrent illness 9. Pregnant women are excluded from this study because the potential for teratogenic or abortifacient effects of fostamatinib are unknown. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with fostamatinib, breastfeeding should be discontinued if the mother is treated with fostamatinib. These potential risks may also apply to other agents used in this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety and Tolerability of Fostamatinib | First cycle (28 days) of treatment | The number of dose limiting toxicities (DLTs) at each dose level will be reported. All toxicities will be reported by type and grade using NCI CTCAE version 4.03. |
| Maximum Tolerated Dose (MTD) of Fostamatinib | 28 days | The MTD will be determined as the dose level with the highest probability of having a risk of DLT in the acceptable region based on the mTPI dose-escalation design. Measured at 28 days (DLT period). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetic (PK) Profile of Fostamatinib When Combined With Weekly Paclitaxel - Tmax | First cycle (28 days) of treatment | Tmax (hours) was used to summarize pharmacokinetic marker profile for fostamatinib. Tmax (hours): Time to reach maximum plasma concentration of R406, the active meta |
| Objective Response Rate in the Study Population Treated With the Combination of Fostamatinib and Paclitaxel | 5 years | Number of participants within each objective response as seen on imaging/RECIST 1.1. Per response evaluation criteria in solid tumors criteria (RECIST v1.1) for target lesions: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. |
| Pharmacokinetic (PK) Profile of Fostamatinib When Combined With Weekly Paclitaxel - Area Under the Curve (AUC) 0-6hours | First cycle (28 days) of treatment | AUC0-6h (ng\*h/mL) was used to summarize pharmacokinetic marker profile for fostamatinib. AUC0-6h (ng\*h/mL): Area under the concentration-time curve for R406 up to 6 hours post-dosing. |
| Pharmacokinetic (PK) Profile of Fostamatinib When Combined With Weekly Paclitaxel - Cmax | First cycle (28 days) of treatment | Cmax (ng/mL) was used to summarize pharmacokinetic marker profile for fostamatinib. Cmax (ng/mL): Maximum plasma concentration of R406. |
| Progression-free Survival in the Study Population Treated With the Combination of Fostamatinib and Paclitaxel | 5 years | Progression-free survival (PFS) will be described by the method of Kaplan and Meier. Median PFS in months will be estimated along with its 95% confidence interval. Per response evaluation criteria in solid tumors (RECIST v1.1), Progressive Disease (PD) is defined as at least a 20% increase in the sum of diameters of target lesions, appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. |
Countries
United States
Participant flow
Pre-assignment details
35 participants were consented. 8 were screen failures. 27 were assigned to study arms.
Participants by arm
| Arm | Count |
|---|---|
| Fostamatinib 100 mg Bid and Paclitaxel Participants will receive paclitaxel on Days 1, 8 and 15 of each cycle and fostamatinib at a fixed oral dose of 100mg twice daily throughout each 28-day cycle.
Fostamatinib 100 mg bid and Paclitaxel: Drug: Fostamatinib (oral; 100 mg bid)
Drug: Paclitaxel (60-80 mg/m2) | 6 |
| Fostamatinib 150 mg Bid and Paclitaxel Participants will receive paclitaxel on Days 1, 8 and 15 of each cycle and fostamatinib at a fixed oral dose of 150mg twice daily throughout each 28-day cycle.
Fostamatinib 150 mg bid and Paclitaxel: Drug: Fostamatinib (oral; 150 mg bid)
Drug: Paclitaxel (60-80 mg/m2) | 3 |
| Fostamatinib 200 mg Bid and Paclitaxel Participants will receive paclitaxel on Days 1, 8 and 15 of each cycle and fostamatinib at a fixed oral dose of 150mg twice daily throughout each 28-day cycle.
Fostamatinib 200 mg bid and Paclitaxel: Drug: Fostamatinib (oral; 200 mg bid)
Drug: Paclitaxel (60-80 mg/m2) | 18 |
| Total | 27 |
Baseline characteristics
| Characteristic | Total | Fostamatinib 100 mg Bid and Paclitaxel | Fostamatinib 150 mg Bid and Paclitaxel | Fostamatinib 200 mg Bid and Paclitaxel |
|---|---|---|---|---|
| Age, Continuous | 62.12 years | 62.9 years | 62.1 years | 62.0 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 25 Participants | 5 Participants | 3 Participants | 17 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 | 3 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 0 Participants | 0 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 1 Participants | 0 Participants | 1 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 | 17 Participants | 5 Participants | 2 Participants | 10 Participants |
| Sex: Female, Male Female | 27 Participants | 6 Participants | 3 Participants | 18 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 | 0 / 6 | 0 / 3 | 1 / 18 |
| other Total, other adverse events | 6 / 6 | 3 / 3 | 18 / 18 |
| serious Total, serious adverse events | 3 / 6 | 0 / 3 | 7 / 18 |
Outcome results
Primary
Maximum Tolerated Dose (MTD) of Fostamatinib
The MTD will be determined as the dose level with the highest probability of having a risk of DLT in the acceptable region based on the mTPI dose-escalation design. Measured at 28 days (DLT period).
Time frame: 28 days
Population: Participants included in the dose-escalation are reported
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fostamatinib 100 mg Bid and Paclitaxel | Maximum Tolerated Dose (MTD) of Fostamatinib | 200 milligrams |
Primary
Safety and Tolerability of Fostamatinib
The number of dose limiting toxicities (DLTs) at each dose level will be reported. All toxicities will be reported by type and grade using NCI CTCAE version 4.03.
Time frame: First cycle (28 days) of treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fostamatinib 100 mg Bid and Paclitaxel | Safety and Tolerability of Fostamatinib | 0 Dose Limiting Toxicities (DLTs) |
| Fostamatinib 150 mg Bid and Paclitaxel | Safety and Tolerability of Fostamatinib | 0 Dose Limiting Toxicities (DLTs) |
| Fostamatinib 200 mg Bid and Paclitaxel | Safety and Tolerability of Fostamatinib | 1 Dose Limiting Toxicities (DLTs) |
Secondary
Objective Response Rate in the Study Population Treated With the Combination of Fostamatinib and Paclitaxel
Number of participants within each objective response as seen on imaging/RECIST 1.1. Per response evaluation criteria in solid tumors criteria (RECIST v1.1) for target lesions: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Time frame: 5 years
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Fostamatinib 100 mg Bid and Paclitaxel | Objective Response Rate in the Study Population Treated With the Combination of Fostamatinib and Paclitaxel | Partial Response (PR) | 1 Participants |
| Fostamatinib 100 mg Bid and Paclitaxel | Objective Response Rate in the Study Population Treated With the Combination of Fostamatinib and Paclitaxel | Stable Disease (SD) | 0 Participants |
| Fostamatinib 100 mg Bid and Paclitaxel | Objective Response Rate in the Study Population Treated With the Combination of Fostamatinib and Paclitaxel | Progressive Disease (PD) | 1 Participants |
| Fostamatinib 100 mg Bid and Paclitaxel | Objective Response Rate in the Study Population Treated With the Combination of Fostamatinib and Paclitaxel | Non-Evaluable (NE) | 4 Participants |
| Fostamatinib 150 mg Bid and Paclitaxel | Objective Response Rate in the Study Population Treated With the Combination of Fostamatinib and Paclitaxel | Non-Evaluable (NE) | 0 Participants |
| Fostamatinib 150 mg Bid and Paclitaxel | Objective Response Rate in the Study Population Treated With the Combination of Fostamatinib and Paclitaxel | Partial Response (PR) | 0 Participants |
| Fostamatinib 150 mg Bid and Paclitaxel | Objective Response Rate in the Study Population Treated With the Combination of Fostamatinib and Paclitaxel | Progressive Disease (PD) | 2 Participants |
| Fostamatinib 150 mg Bid and Paclitaxel | Objective Response Rate in the Study Population Treated With the Combination of Fostamatinib and Paclitaxel | Stable Disease (SD) | 1 Participants |
| Fostamatinib 200 mg Bid and Paclitaxel | Objective Response Rate in the Study Population Treated With the Combination of Fostamatinib and Paclitaxel | Non-Evaluable (NE) | 2 Participants |
| Fostamatinib 200 mg Bid and Paclitaxel | Objective Response Rate in the Study Population Treated With the Combination of Fostamatinib and Paclitaxel | Stable Disease (SD) | 5 Participants |
| Fostamatinib 200 mg Bid and Paclitaxel | Objective Response Rate in the Study Population Treated With the Combination of Fostamatinib and Paclitaxel | Progressive Disease (PD) | 4 Participants |
| Fostamatinib 200 mg Bid and Paclitaxel | Objective Response Rate in the Study Population Treated With the Combination of Fostamatinib and Paclitaxel | Partial Response (PR) | 7 Participants |
Secondary
Pharmacokinetic (PK) Profile of Fostamatinib When Combined With Weekly Paclitaxel - Area Under the Curve (AUC) 0-6hours
AUC0-6h (ng\*h/mL) was used to summarize pharmacokinetic marker profile for fostamatinib. AUC0-6h (ng\*h/mL): Area under the concentration-time curve for R406 up to 6 hours post-dosing.
Time frame: First cycle (28 days) of treatment
Population: 1 patient at the 100 mg dose and 1 patient at the 200 mg did not have all PKs drawn and were not included in the PK analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fostamatinib 100 mg Bid and Paclitaxel | Pharmacokinetic (PK) Profile of Fostamatinib When Combined With Weekly Paclitaxel - Area Under the Curve (AUC) 0-6hours | 2265.7 ng*h/mL | Standard Deviation 1328.7 |
| Fostamatinib 150 mg Bid and Paclitaxel | Pharmacokinetic (PK) Profile of Fostamatinib When Combined With Weekly Paclitaxel - Area Under the Curve (AUC) 0-6hours | 4067.3 ng*h/mL | Standard Deviation 1177.8 |
| Fostamatinib 200 mg Bid and Paclitaxel | Pharmacokinetic (PK) Profile of Fostamatinib When Combined With Weekly Paclitaxel - Area Under the Curve (AUC) 0-6hours | 3958.8 ng*h/mL | Standard Deviation 2104.1 |
Secondary
Pharmacokinetic (PK) Profile of Fostamatinib When Combined With Weekly Paclitaxel - Cmax
Cmax (ng/mL) was used to summarize pharmacokinetic marker profile for fostamatinib. Cmax (ng/mL): Maximum plasma concentration of R406.
Time frame: First cycle (28 days) of treatment
Population: 1 patient at the 100 mg dose and 1 patient at the 200 mg did not have all PKs drawn and were not included in the PK analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fostamatinib 100 mg Bid and Paclitaxel | Pharmacokinetic (PK) Profile of Fostamatinib When Combined With Weekly Paclitaxel - Cmax | 803.4 ng/ML | Standard Deviation 452 |
| Fostamatinib 150 mg Bid and Paclitaxel | Pharmacokinetic (PK) Profile of Fostamatinib When Combined With Weekly Paclitaxel - Cmax | 1309.3 ng/ML | Standard Deviation 599.7 |
| Fostamatinib 200 mg Bid and Paclitaxel | Pharmacokinetic (PK) Profile of Fostamatinib When Combined With Weekly Paclitaxel - Cmax | 1187.2 ng/ML | Standard Deviation 784 |
Secondary
Pharmacokinetic (PK) Profile of Fostamatinib When Combined With Weekly Paclitaxel - Tmax
Tmax (hours) was used to summarize pharmacokinetic marker profile for fostamatinib. Tmax (hours): Time to reach maximum plasma concentration of R406, the active meta
Time frame: First cycle (28 days) of treatment
Population: 1 patient at the 100 mg dose and 1 patient at the 200 mg did not have all PKs drawn and were not included in the PK analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fostamatinib 100 mg Bid and Paclitaxel | Pharmacokinetic (PK) Profile of Fostamatinib When Combined With Weekly Paclitaxel - Tmax | 1.96 hours | Standard Deviation 2.26 |
| Fostamatinib 150 mg Bid and Paclitaxel | Pharmacokinetic (PK) Profile of Fostamatinib When Combined With Weekly Paclitaxel - Tmax | 1.69 hours | Standard Deviation 1.13 |
| Fostamatinib 200 mg Bid and Paclitaxel | Pharmacokinetic (PK) Profile of Fostamatinib When Combined With Weekly Paclitaxel - Tmax | 1.9 hours | Standard Deviation 1.1 |
Secondary
Progression-free Survival in the Study Population Treated With the Combination of Fostamatinib and Paclitaxel
Progression-free survival (PFS) will be described by the method of Kaplan and Meier. Median PFS in months will be estimated along with its 95% confidence interval. Per response evaluation criteria in solid tumors (RECIST v1.1), Progressive Disease (PD) is defined as at least a 20% increase in the sum of diameters of target lesions, appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.
Time frame: 5 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fostamatinib 100 mg Bid and Paclitaxel | Progression-free Survival in the Study Population Treated With the Combination of Fostamatinib and Paclitaxel | 1.445 Months |
| Fostamatinib 150 mg Bid and Paclitaxel | Progression-free Survival in the Study Population Treated With the Combination of Fostamatinib and Paclitaxel | 1.81 Months |
| Fostamatinib 200 mg Bid and Paclitaxel | Progression-free Survival in the Study Population Treated With the Combination of Fostamatinib and Paclitaxel | 4.305 Months |