Clinical Trial of Combined Fostamatinib and Paclitaxel in Ovarian Cancer

Phase I Clinical Trial of Combined Fostamatinib and Paclitaxel in Ovarian Cancer

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.

Study Overview

• Status: Completed
• Conditions: Ovarian Cancer
• Intervention / Treatment: Drug: Fostamatinib 100 mg bid and Paclitaxel; Drug: Fostamatinib 150 mg bid and Paclitaxel; Drug: Fostamatinib 200 mg bid and Paclitaxel

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.

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • District of Columbia
    • Washington, District of Columbia, United States, 20016
      • Sibley Memorial Hospital
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania Health System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: Fostamatinib 100 mg bid and Paclitaxel; Drug: Fostamatinib (oral; 100 mg bid) Drug: Paclitaxel (60-80 mg/m2); Other Names: Fostamatinib and Abraxane
Experimental: 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.	Drug: Fostamatinib 150 mg bid and Paclitaxel; Drug: Fostamatinib (oral; 150 mg bid) Drug: Paclitaxel (60-80 mg/m2); Other Names: Fostamatinib and Abraxane
Experimental: 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.	Drug: Fostamatinib 200 mg bid and Paclitaxel; Drug: Fostamatinib (oral; 200 mg bid) Drug: Paclitaxel (60-80 mg/m2); Other Names: Fostamatinib and Abraxane

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	First cycle (28 days) of treatment
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).	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	5 years
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.	5 years
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	First cycle (28 days) of treatment
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.	First cycle (28 days) of treatment
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.	First cycle (28 days) of treatment

Collaborators and Investigators

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborators: Rigel Pharmaceuticals; Allegheny Singer Research Institute (also known as Allegheny Health Network Research Institute)
• Investigators: Principal Investigator: Stéphanie Gaillard, MD, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Study record dates

Study Major Dates

• Study Start (Actual): April 3, 2018
• Primary Completion (Actual): August 9, 2022
• Study Completion (Actual): April 3, 2023

Study Registration Dates

• First Submitted: June 15, 2017
• First Submitted That Met QC Criteria: August 9, 2017
• First Posted (Actual): August 11, 2017

Study Record Updates

• Last Update Posted (Actual): October 24, 2024
• Last Update Submitted That Met QC Criteria: October 21, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: Phase I; Ovarian Cancer; Fostamatinib and Paclitaxel
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Endocrine System Diseases; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Neoplasms by Histologic Type; Genital Diseases, Female; Endocrine Gland Neoplasms; Neoplasms, Glandular and Epithelial; Ovarian Diseases; Adnexal Diseases; Genital Neoplasms, Female; Gonadal Disorders; Carcinoma; Carcinoma, Ovarian Epithelial; Ovarian Neoplasms; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Albumin-Bound Paclitaxel; Paclitaxel
• Other Study ID Numbers: J1708; IRB00271541 (Other Identifier: JHM IRB)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual participant data will not be shared.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No