Clinical trial NCT03246074
Conditions: Ovarian Cancer
Keywords: Phase I Ovarian Cancer Fostamatinib and Paclitaxel
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Start date: 2018-04-03; Completion date: 2023-04-03
Enrollment: 35 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

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.

Arms: arm 1: 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. arm 2: 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. arm 3: 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.
Interventions: intervention 1: Fostamatinib 100 mg bid and Paclitaxel intervention 2: Fostamatinib 150 mg bid and Paclitaxel intervention 3: Fostamatinib 200 mg bid and Paclitaxel
Intervention descriptions: intervention 1: Drug: Fostamatinib (oral; 100 mg bid)

Drug: Paclitaxel (60-80 mg/m2) intervention 2: Drug: Fostamatinib (oral; 150 mg bid)

Drug: Paclitaxel (60-80 mg/m2) intervention 3: Drug: Fostamatinib (oral; 200 mg bid)

Drug: Paclitaxel (60-80 mg/m2)

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
Title: Phase I Clinical Trial of Combined Fostamatinib and Paclitaxel in Ovarian Cancer 
 
NCT03246074 
 
Stephanie Gaillard, MD PhD 
 
Document Version: April 20, 2023 (v6.4) 


Phase I Clinical Trial of  
Combined Fostamatinib and Paclitaxel in Ovarian Cancer 
 
 
 
Protocol Chair 
Stephanie Gaillard, M.D., Ph.D. 
 
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins 
Administrative Offices: 
201 N Broadway, Room 10260 
Baltimore, MD 21287-0013 
Phone: 410-955-3774 
Fax: 410-614-9421 
Email:  Stephanie.gaillard@jhmi.edu 
 
Key Co-Investigators 
Ie-Ming Shih, Ph.D. 
Amanda N. Fader, M.D. 
Rebecca L. Stone, M.D. 
Danijela Jelovac, M.D. 
Deborah Armstrong, M.D. 
 
 
 
 
 
Collaborators 
Jeffrey Lin, M.D. 
Johns Hopkins at Sibley Memorial Hospital 
 
Lainie Martin, M.D. 
University of Pennsylvania 
 
Lead Site PI of  
Sibley Memorial Hospital 
Mary Wilkinson, M.D. 
 
Statistician 
Peng Huang, Ph.D. 
Marianna Zahurak, M.S. 
 
Supporters 
Rigel Pharmaceuticals, Inc. 
 
 
 
Protocol Version:   
April 20, 2023 (v 6.4) 
 
 
 
 


 
Phase I Fostamatinib and Paclitaxel in Ovarian Cancer 
Protocol Chair:  Stephanie Gaillard, M.D., Ph.D. 
 
 
 
 
 
 
 
 
Version:  April 27, 2022 (v 6.3) 
 
Page 2 
Table of Contents 
 
1. 
SUMMARY ........................................................................................................................................................ 4 
2. 
SCHEMA ............................................................................................................................................................ 4 
3. 
OBJECTIVES .................................................................................................................................................... 5 
3.1 
PRIMARY .......................................................................................................................................................... 5 
3.2 
SECONDARY ..................................................................................................................................................... 5 
3.3 
EXPLORATORY ................................................................................................................................................. 5 
4. 
BACKGROUND ................................................................................................................................................ 6 
4.1 
OVARIAN, FALLOPIAN TUBE, AND PRIMARY PERITONEAL CARCINOMA .......................................................... 6 
4.2 
FOSTAMATINIB ................................................................................................................................................. 6 
4.3 
PACLITAXEL ..................................................................................................................................................... 8 
4.4 
RATIONALE FOR THE COMBINATION OF FOSTAMATINIB AND PACLITAXEL ...................................................... 9 
4.5 
EXPLORATORY CORRELATIVE STUDIES BACKGROUND ................................................................................. 10 
5. 
PARTICIPANT SELECTION ........................................................................................................................ 11 
5.1 
INCLUSION CRITERIA ..................................................................................................................................... 11 
5.2 
EXCLUSION CRITERIA .................................................................................................................................... 13 
5.3 
INCLUSION OF WOMEN AND MINORITIES ....................................................................................................... 14 
6. 
REGISTRATION PROCEDURES ................................................................................................................ 15 
6.1 
RECRUITMENT ................................................................................................................................................ 15 
6.2 
REGISTRATION ............................................................................................................................................... 15 
6.3 
GENERAL GUIDELINES ................................................................................................................................... 15 
7. 
TREATMENT PLAN ...................................................................................................................................... 17 
7.1 
OVERVIEW ..................................................................................................................................................... 17 
7.2 
BLINDING AND RANDOMIZATION ................................................................................................................... 18 
7.3 
REGIMEN DESCRIPTION .................................................................................................................................. 18 
7.4 
DEFINITION OF DOSE-LIMITING TOXICITY ..................................................................................................... 19 
7.5 
GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES ............................................... 20 
7.6 
DURATION OF THERAPY ................................................................................................................................. 21 
7.7 
DURATION OF FOLLOW UP ............................................................................................................................. 21 
7.8 
CRITERIA FOR REMOVAL FROM STUDY .......................................................................................................... 21 
7.9 
ADDITIONAL INFORMATION ........................................................................................................................... 21 
8. 
DOSE DELAYS/MODIFICATIONS ............................................................................................................. 22 
8.1 
SUMMARY ...................................................................................................................................................... 22 
8.2 
DOSE MODIFICATIONS FOR HEMATOLOGIC TOXICITY ................................................................................... 22 
8.3 
DOSE MODIFICATIONS FOR NON-HEMATOLOGIC TOXICITY ........................................................................... 25 
8.4 
DOSE INTERRUPTION FOR SURGERY ............................................................................................................... 27 
8.5 
SPECIAL CONSIDERATIONS............................................................................................................................. 27 
9. 
PHARMACEUTICAL INFORMATION ...................................................................................................... 28 
9.1 
FOSTAMATINIB ............................................................................................................................................... 28 
9.2 
PACLITAXEL ................................................................................................................................................... 29 
9.3 
DRUG ACCOUNTABILITY ................................................................................................................................ 29 
10. 
CORRELATIVE STUDIES ............................................................................................................................ 30 
10.1 FOSTAMATINIB PHARMACOKINETICS ............................................................................................................. 30 


 
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10.2 PHARMACODYNAMIC ANALYSES ................................................................................................................... 30 
10.3 ADDITIONAL INFORMATION ........................................................................................................................... 31 
11. 
STUDY CALENDAR ...................................................................................................................................... 32 
12. 
MEASUREMENT OF EFFECT..................................................................................................................... 33 
12.1 DEFINITIONS .................................................................................................................................................. 33 
12.2 GUIDELINES FOR EVALUATION OF DISEASE ................................................................................................... 34 
12.3 LESION DOCUMENTATION .............................................................................................................................. 36 
12.4 RESPONSE CRITERIA ...................................................................................................................................... 37 
13. 
ADVERSE EVENTS ........................................................................................................................................ 41 
13.1 GENERAL ....................................................................................................................................................... 41 
13.2 DEFINITIONS .................................................................................................................................................. 41 
13.3 REPORTING PROCEDURES .............................................................................................................................. 43 
14. 
DATA AND SAFETY MONITORING .......................................................................................................... 45 
14.1 DATA MANAGEMENT ..................................................................................................................................... 45 
14.2 MEETINGS ...................................................................................................................................................... 45 
14.3 MONITORING AND AUDITING ......................................................................................................................... 46 
15. 
ADMINISTRATIVE PROCEDURES ........................................................................................................... 47 
15.1 PROTOCOL AMENDMENTS .............................................................................................................................. 47 
15.2 INFORMED CONSENT ...................................................................................................................................... 47 
15.3 ETHICS AND GOOD CLINICAL PRACTICE ........................................................................................................ 47 
15.4 REGULATORY AUTHORITIES .......................................................................................................................... 47 
16. 
COORDINATING CENTER & SITE RESPONSIBILITIES ..................................................................... 49 
16.1 PROTOCOL CHAIR .......................................................................................................................................... 49 
16.2 COORDINATING CENTER ................................................................................................................................ 49 
16.3 PARTICIPATING SITES..................................................................................................................................... 49 
17. 
STATISTICAL CONSIDERATIONS ............................................................................................................ 51 
17.1 STUDY DESIGN AND ENDPOINTS .................................................................................................................... 51 
17.2 SAMPLE SIZE/ACCRUAL RATE ....................................................................................................................... 53 
17.3 ANALYSIS OF OBJECTIVES ............................................................................................................................. 54 
17.4 REPORTING AND EXCLUSIONS ........................................................................................................................ 55 
REFERENCES .......................................................................................................................................................... 57 
APPENDICES ............................................................................................................................................................ 59 
APPENDIX A:  PERFORMANCE STATUS SCALE ............................................................................................ 60 
APPENDIX B:  INFORMATION ON POSSIBLE DRUG INTERACTIONS ....................................................... 61 
APPENDIX C:  STUDY DRUG DIARY – FOSTAMATINIB .............................................................................. 64 
 
 


 
Phase I Fostamatinib and Paclitaxel in Ovarian Cancer 
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1. SUMMARY 
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. 
 
2. SCHEMA 
 
 
 
 
 
Treat Q28 days to 
progression or toxicity 


 
Phase I Fostamatinib and Paclitaxel in Ovarian Cancer 
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3. OBJECTIVES 
3.1 
Primary  
3.1.1 To determine the safety, tolerability, and maximum tolerated dose (MTD) of fostamatinib 
when administered in combination with weekly paclitaxel 
3.2 
Secondary  
 
3.2.1 To estimate the objective response rate in the study population treated with the combination 
of fostamatinib and paclitaxel 
3.2.2 To estimate the progression-free survival in the study population treated with the 
combination of fostamatinib and paclitaxel 
3.2.3 To assess the pharmacokinetic (PK) profile of fostamatinib when combined with weekly 
paclitaxel 
3.3 
Exploratory  
3.3.1 To assess pharmacodynamic and predictive biomarkers of response from subject blood and 
tumor samples 
3.3.2 To develop patient-derived xenografts (PDX) models to (1) assess response to the 
individual study drugs or the combination, (2) evaluate biomarkers of tumor response, 
and (3) identify mechanisms of therapeutic resistance to these agents. 
 
 


 
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4. BACKGROUND 
4.1 
Ovarian, Fallopian Tube, and Primary Peritoneal Carcinoma 
Epithelial ovarian cancer is the most malignant of the gynecologic cancers, with a 5-year survival 
rate less than 50%.  Each year an estimated 22,000 women will be diagnosed with and 14,000 
women will die from the disease(1).  Because of similarities in histology, clinical behavior, and 
possibly tissue of origin, the treatment paradigm for fallopian tube and primary peritoneal 
carcinomas parallels those for epithelial ovarian cancers.  With aggressive therapy at diagnosis, 
including surgery and platinum based chemotherapy, more than 80% of women will have an initial 
complete response to therapy. Unfortunately these responses are infrequently durable and the 
majority of women with ovarian cancer develop recurrent, incurable disease. Responses to 
subsequent chemotherapeutic regimens shorten in duration over time because of progressive 
development of resistance to chemotherapy.  Platinum-resistant disease is defined as disease 
recurrence or progression within 6 months of cessation of platinum-based therapy (i.e. cisplatin or 
carboplatin).  For patients with platinum-resistant disease, platinum compounds are generally 
deemed to be ineffective.  Subsequent therapy is generally with a single-agent, often with a taxane, 
pegylated liposomal doxorubicin, gemcitabine, or topotecan.  Objective response rates to these 
agents are typically ~20% and median overall survival is less than 1 year(2-4).  Thus developing 
new treatment strategies, including identifying novel therapeutic targets, is an urgent need. 
4.2 
Fostamatinib 
4.2.1 Mechanism 
Fostamatinib (R788) is an orally dosed pro-drug of the ATP-competitive spleen tyrosine kinase 
(SYK) inhibitor, R406.  SYK is a non-receptor tyrosine kinase involved in immunoregulation and 
mediates diverse cellular responses including proliferation, differentiation, and cellular migration.  
Fostamatinib is in clinical development and has been (or is being) evaluated in clinical trials for 
the treatment of rheumatoid arthritis, immune thrombocytopenia, IgA nephropathy, hematologic 
malignancies, and solid tumors. 
 
4.2.2 Pre-Clinical Studies 
Fostamatinib and its active metabolite, R406, were shown to be effective in animal models of 
immune complex activation, arthritis, non-Hodgkin’s lymphoma and chronic lymphocytic 
leukemia.  In pre-clinical studies, R406/Fostamatinib was well tolerated; slight reduction in heart 
rate was noted at higher doses in a monkey cardiovascular study and mild behavioral hypoactivity 
was noted at higher doses in a rat CNS study(5).  In toxicology studies, long term exposure (4-39 
weeks) resulted in hematologic abnormalities, mild and fully reversible liver function test 
abnormalities, reproductive and/or developmental abnormalities.  The developmental 
abnormalities consisted of bone growth plate effects and odontodysplasia.  No mutagenic, 
clastogenic, or carcinogenic effects were identified. 
 
Pre-clinical pharmacokinetic (PK) studies demonstrated conversion of fostamatinib to R406 pre-
systemically, with little R788 detected in plasma(5).  The conversion is likely facilitated by 
phosphatases in the intestinal mucosa and the bioavailability of R406 in systemic circulation is 
estimated to be 40-60%. The elimination half-life ranged from 0.6-3.4 hours and R406 is 


 
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extensively metabolized by oxidation and conjugation reactions.  R406 is highly protein-bound in 
plasma and is preferentially and reversibly distributed to blood cells. 
 
4.2.3 Clinical Studies 
The clinical safety of fostamatinib has been established. Five phase 2 and three phase 3 trials have 
been conducted in patients with active rheumatoid arthritis(5).  Over 3,400 patients received 
fostamatinib or placebo for 1.5-12 months.  A statistically significant improvement in signs and 
symptoms as measured by the American College of Rheumatology 20 scale and functional 
improvement was found at doses of 100 and 150mg bid, however no benefit was found on bone 
erosion and joint destruction.  
 
Three studies have evaluated fostamatinib in cancer patients.  In a phase 1/2 study of patients with 
non-Hodgkin lymphoma and chronic lymphocytic leukemia, objective response rates were 22% (5 
of 23) for diffuse large B cell lymphoma and 55% (6 of 11) for chronic lymphocytic leukemia(6).  
Toxicities were tolerable and primarily consisted of diarrhea, fatigue, cytopenias, hypertension, 
and nausea.  Single-agent fostamatinib was evaluated in a small multi-cohort phase II trial for 
patients with selected solid tumors, predominantly colorectal cancer (22 of 37 patients)(7).  No 
objective responses were observed although disease stabilization rate was 27% in colorectal cancer 
patients. Grade 3/4 toxicities included transaminitis, hyperbilirubinemia, and hypertension. 
Baseline liver function abnormalities and liver metastases influenced risk of developing toxicity.  
Studies of fostamatinib in subjects with impaired hepatic or renal function have shown that 
systemic exposure to R406 was not clinically significantly altered(5).  Sixty-eight patients with 
relapsed or refractory DLBCL received fostamatinib in a two-arm, randomised, double-blinded 
manner at either 100 mg twice a day (BID) or 200 mg BID until disease progression or 
unacceptable toxicity. Grade 3/4 toxicities were infrequent and a 13% clinical benefit was 
observed(8). No study of fostamatinib in combination with chemotherapy has been performed to 
date. 
 
4.2.3.1 Human PK and Drug Metabolism Studies 
Similar to the animal studies, human PK studies have shown that R406 rapidly appeared in 
systemic circulation after administration of fostamatinib with a median tmax of 1 – 3 hours and a 
half-life of 12-19 hours(5). Oxidation and direct glucuronidation was the primary route of 
metabolism of R406.  Renal elimination was low. 
 
4.2.3.2 Metabolism, Drug Interactions, and Dietary Interactions 
R406 is metabolized by CYP3A4.  Inhibitors of CYP3A4 may slow the metabolism of R406, thus  
strong CYP3A4 inhibitors should not be co-administered with fostamatinib and moderate CYP3A4 
inhibitors and inducers should be used with caution.  Strong enzyme inducers should be administered 
with caution.  Fostamatinib was determined to be a weak CYP3A4 inhibitor and clinically 
significant interactions with CYP3A4 substrates are thought to be unlikely.  Fostamatinib is not 
expected to have effects on CYP2C8 substrates.  The PK and PD of warfarin were not significantly 
affected by fostamatinib.  There was no clinically relevant effect of ranitidine and statin 
medications on the PK of R406.   
 
Fostamatinib increased the exposure to the following: 


 
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 Ethinyl estradiol to a modest degree, however no interaction was identified between 
fostamatinib and levonorgestrel; 
 Rosuvastatin (2 fold by AUC) and simvastatin (1.7 fold by AUC); and  
 Digoxin geometric mean AUCss and Cmax,ss were increased by 37% and 70%, respectively. 
 
There was no clinically relevant effect of a high-fat/calorie meal.  Fostamatinib should not be taken 
with grapefruit juice or other food/drink known to inhibit CYP3A4.  
 
Fostamatinib inhibits UGT1A1, the sole enzyme responsible for bilirubin conjugation; this may 
increase unconjugated (indirect) bilirubin levels in some patients. The detection of elevated 
bilirubin, especially in the absence of any other LFT abnormalities, or signs or symptoms of liver 
impairment, suggests the (UGT1A1) effect of fostamatinib; in this case, continue the drug with 
regular LFT and fractionated bilirubin monitoring. 
 
4.2.3.3 Safety Profile  
The safety profile of fostamatinib has been studied in patients with rheumatoid arthritis and 
severely ill patients with lymphoma, chronically ill patients with ITP, and healthy subjects(5).  The 
predominant effects consistently were on blood pressure, neutrophil counts, GI complaints 
(especially diarrhea) and hepatic transaminase elevations, all of which were reversible and 
manageable. Lymphoma patients experienced more cytopenias and infections, consistent with 
extensive prior therapy and underlying disease.  In patients with solid tumors, baseline liver 
function abnormalities and liver metastases appeared to influence the development of 
hyperbilirubinemia and transaminitis(7).  However, the overall pattern of adverse events was 
consistent with a population of heavily pretreated patients with relapsed solid tumors of varying 
histologies.   
 
4.2.3.4 Rationale for Starting Dose and Dose Escalation Scheme 
The majority of patients who have been treated with fostamatinib have received doses of 150 – 
400 mg/day.  The recommended phase 2 dose for lymphoma patients was 200 mg bid.  In the solid 
tumor study, the MTD was 50 mg bid in patients with colorectal cancer, the majority of whom had 
liver involvement.  The MTD was not reached for the other tumor cohorts and the maximum dose 
administered was 200 mg bid.  Fostamatinib has not previously been combined with cytotoxic 
chemotherapy agents.  Fostamatinib is available in 100 mg and 150 mg tablet formulations.  For 
this phase I study, we plan to exclude patients with baseline liver function abnormalities.  Thus, 
we plan to start dosing fostamatinib at 100 mg bid in combination with paclitaxel.  If toxicities are 
acceptable in the first cohort we will increase the dose of fostamatinib by 50 mg bid per cohort 
until the maximum dose of 200 mg bid is reached. If toxicities in dose level 1 are not acceptable, 
we have allowed for a dose level -1 and dose level -2 which allow fostamatinib to be dose at 150mg 
daily and 100mg daily respectively.  
 
4.3 
Paclitaxel 
Paclitaxel is a taxane that stabilizes microtubules, inhibiting disassembly, resulting in disruption 
of cell replication and proliferation.  Although paclitaxel is typically given in front-line 
chemotherapy regimens for ovarian cancer, retreatment with paclitaxel, particularly on a weekly 


 
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schedule, is associated with response rates comparable to other chemotherapy agents used for 
platinum-resistant recurrent disease.  Several studies have evaluated the efficacy of the weekly 
administration of paclitaxel in platinum-resistant ovarian cancer and shown response rates ranging 
between 10 and 29%(4, 9-14).  In a Gynecologic Oncology Group (GOG) phase II study of weekly 
paclitaxel, 48 patients who had both platinum-resistant and paclitaxel-resistant disease were 
enrolled(15).  Patients were treated with paclitaxel 80 mg/m2/week for 12 consecutive weeks 
followed by 80 mg/m2/week for 3 consecutive weekly doses during each 4-week cycle until 
disease progression.  In this chemotherapy-resistant population, the objective response rate was 
20.9% with two complete responses (4.2%) and 8 partial responses (16.7%).  The median duration 
of response was 3.6 months with 2 durable responses >16 months.  Serious adverse events were 
relatively uncommon, with 21% experiencing grade 2 neuropathy, 4% grade 3 neuropathy, and 
8% grade 3 fatigue. 
 
Subsequent trials have administered paclitaxel either weekly for 4 doses in each 4 week cycle or 
weekly for 3 consecutive doses during each 4-week cycle(16, 17).  For this study, we have elected 
to administer paclitaxel 80mg/m2/week for 3 consecutive doses during each 4-week cycle while 
fostamatinib will be given continuously throughout each 4-week cycle. 
 
4.4 
Rationale for the Combination of Fostamatinib and Paclitaxel 
We first identified a potential role for the spleen tyrosine kinase (SYK) in ovarian cancer when in 
a proteomic analysis we found SYK levels to be increased in recurrent high-grade serous ovarian 
tumors compared to the primary tumors from the same patients(18).  SYK regulates adaptive 
immune receptor signaling, cell proliferation, differentiation, and survival of B-lymphocytes. SYK 
localizes to centrosomes(19) and several centrosome proteins are the substrates of SYK(20, 21). 
SYK has been reported as a candidate oncogene in B-cell leukemia, lymphomas, gastric 
carcinoma, and head and neck cancer(22-26). Expression levels of SYK are associated with 
increased cell motility and tumor progression in head and neck cancer(26), and peptides that block 
the substrate binding site of SYK induce apoptosis in B-precursor leukemia cells(27). 
Paradoxically, SYK expression may block tumor progression in breast cancer as loss of its 
expression is associated with poor prognosis and tumor metastasis(28). The evidence thus suggests 
that SYK can either negatively or positively regulate tumor development, depending on the 
biological context and tissue lineage. 
 
Consistent with the proteomic data above, we found higher levels of SYK and phosphorylated-
(activated-) SYK (p-SYK) are detectable in recurrent high-grade ovarian cancer tumors compared 
to patient-matched primary untreated tumors.  In studies in ovarian cancer cell lines, we 
demonstrated that inactivating SYK, using small compound inhibitors, such as R406 (the active 
form of fostamatinib) or SYK knockdown, selectively sensitized cells to the cytotoxic effects of 
paclitaxel, overcoming paclitaxel resistance (unpublished results).  This effect is likely a result of 
increased stabilization of microtubules with co-treatment of R406 and paclitaxel.  Furthermore, 
we have shown that the combination of R406 and paclitaxel suppressed the growth of ovarian 
tumor xenografts in mice with no overt signs of toxicity. 
 
Given the above data, we hypothesize that the addition of fostamatinib, the pro-drug of R406, to 
paclitaxel will have increased anti-tumor effects in patients with ovarian cancer.  We propose to 


 
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investigate the toxicity profile and to define the maximum tolerated dose and recommended phase 
II dose of the combination of fostamatinib and paclitaxel.  Following the determination of the 
MTD of the combination, we anticipate proposing a Phase 2 trial to evaluate the preliminary 
efficacy in participants with recurrent, platinum-resistant epithelial ovarian, fallopian tube, or 
primary peritoneal cancers. 
 
4.5 
Exploratory Correlative Studies Background 
This trial will also include correlative analyses designed to evaluate whether therapy is associated 
with changes in SYK expression or activity and whether plasma levels of fostamatinib and 
paclitaxel at the MTD inhibit proliferation of ovarian cancer cell lines. 
 
4.5.1 Immunohistochemistry of SYK, p-SYK, and Validated SYK Substrates 
In a retrospective evaluation of patient-matched primary and post-treatment recurrent tumors, we 
found elevated expression of SYK and p-SYK.  In ongoing work, we are identifying and validating 
SYK substrates in ovarian cancer cells.  To evaluate the utility of SYK or its substrates as 
predictive biomarkers for fostamatinib response, we will obtain pre- and post-treatment tumor 
tissue from participants.  Biopsy material will be obtained prior to treatment and at the end of cycle 
1 by CT- or ultrasound-guidance if it is clinically and safely feasible.  Expression levels of total 
SYK, p-SYK and other validated SYK substrates will be determined using immunohistochemistry 
and analyzed by digital imaging software.  Expression levels will be correlated with response to 
therapy. 
 
4.5.2 Inhibition Assays 
Plasma samples will be collected from patients at the time of the biopsies outlined above (prior to 
initiation of treatment and at the end of cycle 1). For these assays, two index ovarian cancer cell 
lines (SKOV3TR and MPSC1TR) that express abundant SYK and p-SYK will be grown in 3-D 
cultures. The cells will be incubated with plasma samples collected from patients and cell cycle 
analysis or BrdU incorporation assays will be performed 12 hrs after incubation. Plasma collected 
at the end of the first cycle is expected to have a greater anti-proliferative effect than pre-treatment 
plasma. Inhibition of proliferation by plasma samples containing R406 would support the 
hypothesis that the MTD is effective in inhibiting ovarian cancer growth. Peripheral blood 
mononuclear cells (PBMCs) will also be analyzed for SYK activity in samples before and after 
fostamatinib treatment. 
4.5.3 Development of PDX Models to Assess Response to and Identify Mechanisms of 
Resistance to Fostamatinib Therapy 
Patient-derived xenografts (PDXs) have become an important platform to explore new biomarkers, 
treatments, and mechanisms of resistance to cancer therapy. Tumor tissue, from Johns Hopkins 
participants only who opt to participate via concurrent consent to this study and a companion 
protocol (IRB00184241/SKCCC#J18117), will be sent to Champions Oncology, Inc. for 
development of PDXs under the Champions TumorGraft™ program. The Champions 
TumorGraft™ program implants human tumor tissue into immune-deficient mice to produce 
patient-derived PDX. Successful PDX models will be sent back to the investigators for exploratory 
studies. The models will be used to (1) assess response to the individual study drugs or the 


 
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combination, (2) evaluate biomarkers of tumor response, and (3) identify mechanisms of 
therapeutic resistance to these agents.  
 
5. PARTICIPANT SELECTION 
5.1 
Inclusion Criteria 
5.1.1 
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.  
5.1.2 Patients must have measurable disease, according to RECIST v1.1.  Measurable disease is 
defined as at least one lesion that can be accurately measured in at least one dimension 
(longest diameter to be recorded for non-nodal lesions) as ≥20 mm with conventional 
techniques or as ≥10 mm with spiral CT scan, MRI, or calipers by clinical exam.  To be 
considered pathologically enlarged and measurable, a lymph node must be ≥15 mm in short 
axis when assessed by CT scan or MRI (CT scan slice thickness recommended to be no 
greater than 5 mm).  See Section 12 for the evaluation of measurable disease. 
5.1.3 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.  
5.1.4 Patients must have the ability to take oral medications. 
5.1.5 Females, age ≥18 years.  Because no dosing or adverse event data are currently available 
on the use of fostamatinib in combination with weekly paclitaxel in patients <18 years of 
age, children are excluded from this study, but will be eligible for future pediatric trials. 
5.1.6 ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A). 
5.1.7 Life expectancy of greater than 3 months 
 


 
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5.1.8 Patients must have normal organ and marrow function as defined below: 
Leukocytes
≥3,000/mcL
Absolute Neutrophil Count
≥1,000/mcL
Platelets
≥100,000/mcL
Total Bilirubin
≤institutional upper limit of normal (ULN)
AST(SGOT) or ALT(SGPT) 
≤3 × institutional ULN
Bilirubin
≤1.5 × institutional ULN
PT/INR 
≤1.5 × institutional ULN (or an in-range INR, usually 
between 2 and 3 if a patient is on a stable dose of 
therapeutic warfarin)
Creatinine 
-OR- 
Glomerular Filtration Rate 
≤1.5 x institutional ULN 
-OR- 
≥60 mL/min/1.73 m2 for patients with creatinine levels 
above 1.5 x institutional ULN
5.1.9 Patients with a diagnosis of hypertension are required to have adequate blood pressure 
control prior to enrollment, defined as blood pressure ≤ 140/90 mmHg. 
5.1.10 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 including for one month after last dose of fostamatinib.  Should a 
woman become pregnant or suspect she is pregnant while she is participating in this study, 
she should inform her treating physician immediately.   
5.1.11 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. 
5.1.12 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. 
5.1.13 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. 
5.1.14 Patients with treated brain metastases are eligible if follow-up brain imaging after 
central nervous system (CNS)-directed therapy shows no evidence of progression. 
5.1.15 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 


 
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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.  
5.1.16 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. 
5.1.17 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. 
5.1.18 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. 
5.1.19 Ability to understand and the willingness to sign a written informed consent document. 
 
5.2 
Exclusion Criteria 
5.2.1 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. 
5.2.2 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).  
5.2.3 Patients who are currently receiving or have previously received any other investigational 
agents within 3 weeks prior to entering the study. 
5.2.4 Patients with known, untreated brain metastases, as progressive neurologic dysfunction 
may develop that would confound the evaluation of neurologic and other adverse events. 
5.2.5 Patients with Grade 2 or greater neuropathy.  
5.2.6 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. 
5.2.7 Strong CYP3A4 inhibitors or inducers should not be used within 3 days of Day 1 dosing 


 
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until the end of study.  Moderate CYP3A4 inhibitors or inducers should be used with 
caution. 
Because the lists of these agents are constantly changing, it is important to regularly 
consult a frequently updated list such as http://medicine.iupui.edu/ 
clinpharm/ddis/table.aspx; medical reference texts such as the Physicians’ Desk 
Reference may also provide this information.  As part of the enrollment/informed consent 
procedures, the patient will be counseled on the risk of interactions with other agents, and 
what to do if new medications need to be prescribed or if the patient is considering a new 
over-the-counter medicine or herbal product.   
5.2.8 Uncontrolled intercurrent illness including, but not limited to, the following: 
 ongoing or active infection, including latent tuberculosis infection, 
 clinically significant GI disease (such as active Crohn’s disease or ulcerative 
colitis), 
 recent or significant cardiovascular disease (defined as any major CV event within the 
previous 6 months including myocardial infarction, unstable angina, cardiac 
arrhythmia, stroke, PE, or New York Heart Association Class III or IV heart failure),  
 history of liver function abnormality requiring investigation, drug induced liver 
injury, chronic liver disease, excessive alcohol consumption or chronic alcohol-
induced disease,  
 psychiatric illness/social situations that would limit compliance with study 
requirements, or 
 any other severe acute or chronic medical condition or laboratory abnormality that 
may increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the patient inappropriate for entry into 
this study 
5.2.9 Pregnant women are excluded from this study because of the potential for teratogenic or 
abortifacient effects of fostamatinib. 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. 
5.3 
Inclusion of Women and Minorities 
Individuals of all races and ethnic groups are eligible for this trial. There is no bias towards age or 
race in the clinical trial outlined. This trial is open to the accrual of women only as ovarian cancer 
affects only females. 
 
 


 
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6. REGISTRATION PROCEDURES 
6.1 
Recruitment 
Patients will be recruited through the gynecologic cancer clinics at each of the participating 
centers.  
6.2 
Registration 
Subjects will be registered with the study coordinator at the coordinating center (Johns Hopkins) 
once an informed consent form is signed. After eligibility is established, the coordinating center 
study coordinator will assign a study number. Subjects will not begin protocol-specified treatment 
until eligibility is confirmed and the patient is assigned a study number. 
 
After eligibility is established at the participating institution, the study staff will register patients 
with the Coordinating Center at Johns Hopkins. The following is required to be submitted for 
successful registration: 
 
 Registration forms 
 Copy of subject consent 
 Copies of the following source documents:  
- 
Diagnostic pathology report(s), including receptor status 
- 
Laboratory reports, including hematology, chemistries as per the eligibility 
criteria and pregnancy test, if applicable 
- 
CT and/or MRI imaging confirming sites of disease, including measurable or 
evaluable disease 
- 
Other documents, if requested 
 
Upon review of the registration documents, the Coordinating Center at Johns Hopkins will confirm 
successful registration by return email and/or fax to the local study team/designee. 
 
Study treatment cannot begin until the patient is registered with the Coordinating Center. 
 
Subjects who sign a consent form, but do not initiate protocol treatment for any reason (i.e., 
subjects who are screen failures), will be replaced and will not count towards our accrual goal. 
 
6.2.1 Participating sites 
The Protocol Chair at the Coordinating Center will maintain a list of the contact information for 
all participating sites. Each participating site will keep on file an Federalwide Assurance (FWA) 
with Office for Human Research Protections (OHRP). 
6.3 
General Guidelines 
It is preferred that registration not occur more than 28 days prior to the planned day 1 of 
treatment; registration and confirmation of eligibility may occur outside this window in the event 
that required eligibility and baseline assessment windows will be maintained. In the event a 


 
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subject’s day 1 is delayed for unforeseeable reasons and a baseline assessment(s) fall outside the 
intended window, it is expected that these be repeated and reviewed by the Coordinating Center 
prior to treatment unless explicit approval is given by the Protocol Chair or her designee. 
 
 


 
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7. TREATMENT PLAN 
7.1 
Overview 
Treatment will be administered on an outpatient basis.  Potential risks and appropriate dose 
modifications are described in Section 8.  No investigational or commercial agents or therapies 
other than those described below may be administered with the intent to treat the patient's 
malignancy. 
 
Participants will receive paclitaxel on Days 1, 8 and 15 of each cycle and fostamatinib at a fixed 
oral dose twice daily throughout each 28-day cycle.  The dose of fostamatinib will be determined 
by the enrollment dose level.  Given the mTPI design, dose-escalation decisions will be made 
based on the three dosing intervals, where the underdosing interval corresponds to dose escalation 
(E), overdosing interval corresponds to dose de-escalation (D), and proper dosing corresponds to 
staying at the current dose (S). The initial dose level will be Level 1 of Table 1.  Participants will 
be individually continually assessed for DLT.  The associated dose-escalation decisions are 
presented in Table 2. For illustration, suppose a cohort of 3 patients is at the current dose.  
 
 If 0 of 3 patients have a DLT, the decision is E (= escalate to the next dose);  
 if 1 of 3 patients has a DLT, the decision is S (= stay at the current dose level with an 
additional 3 patients);  
 if 2 of 3 patients have a DLT, the decision is D (= de-escalate to the next lower dose (or 
DL-1 if the current dose is DL1);  
 if 3 of 3 patients experience a DLT, the decision is DU (= de-escalate to the next lower 
dose and never return to the current dose as it has been deemed unacceptably toxic).  
 
The trial will terminate when the lowest dose is above the MTD or when 6 patients have been 
treated at the highest dose. A minimum of 6 patients will be treated at the MTD.   
 
Dose Level 
Dose* 
Paclitaxel (mg/m2) 
Days 1, 8, & 15 of 28 day cycle 
Fostamatinib (mg) 
continuous 
Level -2 
80 
100 QDay 
Level -1 
80 
150 QDay 
Level  1 
80 
100 BID 
Level  2 
80 
150 BID 
Level  3 
80 
200 BID 
Table 1: Dose Levels.  .  
 
 
 


 
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No. of patients 
experiencing a DLT 
No. of Patients Treated at Current Dose Level 
3
6
9
12
15
18
0
E 
E 
E 
E 
E 
E 
1
S 
E 
E 
E 
E 
E 
2
D 
S 
S 
E 
E 
E 
3
DU 
S 
S 
S 
S 
E 
4
DU 
S 
S 
S 
S 
5
DU 
DU 
S 
S 
S 
6
DU 
DU 
D 
S 
S 
7
DU 
DU 
S 
S 
8
DU 
DU 
DU 
S 
9
DU 
DU 
DU 
DU 
Table 2: Dose-escalation decision rules based on the mTPI design with a cohort size of 3 for a maximum sample size 
of 18 patients and target DLT risk of 30%. E = Escalate to the next higher dose; S = Stay at the current dose; D = De-
escalate to the next lower dose; DU = De-escalate and the current dose is unacceptably toxic; DLT = dose limiting 
toxicity. 
7.2 
Blinding and Randomization  
This is a non-blinded, non-randomized study; dose levels will be assigned as above.  
7.3 
Regimen Description 
7.3.1 Fostamatinib 
Fostamatinib should be taken twice daily (approximately 12 hours apart) without interruption at 
approximately the same times each day. Participants are to be instructed to return all unused 
fostamatinib. A record of the number of tablets dispensed to and returned by each participant must 
be maintained. If a participant forgets to take a dose of fostamatinib, they should take the missed 
dose within four hours of that scheduled dose. If it is more than four hours from the time they were 
scheduled to take that dose, they should wait until the next dose.  Participants must not make up 
the missed dose at the next dose. 
 
If a participant vomits after taking a fostamatinib dose, the participant should be instructed not to 
retake the dose, but should instead resume dosing at the next scheduled dose.  If vomiting persists, 
the participant should be instructed to contact the investigator. 
 
The patient will be requested to maintain a medication diary of each dose of fostamatinib.  The 
medication diary (see Appendix C) will be returned to clinic staff at the end of each cycle.  
7.3.2 Paclitaxel 
Intravenous paclitaxel should be administered according to the following schedule: 
 
 80 mg/m2 (60mg/m2 if dose is modified for toxicity), weekly, on Days 1, 8, and 15 (± 2 
days) of a 28-day cycle, given as a one-hour intravenous infusion. 
 


 
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Prior to administration of the paclitaxel infusion, participants should be pre-medicated with a 
suggested regimen of (a) dexamethasone, (b) diphenhydramine, and (c) a H2 blocker according to 
local practice.  Recommendations for pre-medication are as follows: 
 
 20 mg dexamethasone sodium phosphate orally, 12 and six hours prior to the paclitaxel 
infusion, OR dexamethasone 10 mg IV in 50 ml D5W over 15 min, 30 min prior to 
paclitaxel, 
 25-50 mg diphenhydramine orally OR by IV administration, 30 to 60 minutes prior to the 
beginning of the paclitaxel infusion, and  
 150 mg ranitidine orally OR 50 mg ranitidine by IV administration, 30 to 60 minutes prior 
to the beginning of the paclitaxel infusion 
 
Additional information can be found in the prescribing information for paclitaxel [Taxol Package 
Insert, 2007].  NOTE:  This is a suggested premedication regimen; established standard of care at 
each institution may be used as long as it is clearly documented in the medical record and reported 
with the research data.   
 
With permission of the primary investigator, administration of paclitaxel through a local oncology 
infusion center will be allowed for cycles 2 and beyond, if in the best interest of the patient, and if 
the local oncology infusion center agrees to be in contact with the study investigators/staff, adhere 
to protocol measures, and provide information regarding infusion administration and any other 
study procedures performed. 
 
Regimen Description 
Agent 
Premedications/Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Paclitaxel 
Suggested premedications: 
dexamethasone, 
diphenhydramine, and a H2 
blocker prior to Paclitaxel
**  in 250 cc 
D5W 
IV over 1 hour  
Days 1, 8, 
and 15 
28 days  
(4 weeks) 
 
 
 
Fostamatinib 
Take with water. Fostamatinib 
can be taken with or without 
food.
**  tablet 
PO twice daily 
approximately 12 
hours apart 
Daily 
throughout 
cycle
**Doses as appropriate for assigned dose level.
Table 3 Regimen Description. 
7.4 
Definition of Dose-Limiting Toxicity 
Any grade 2 liver function toxicity (see criteria below), and clinically significant grade 3 or 4 
toxicities, including any toxicity that requires delay of treatment for greater than 14 days, will be 
considered a DLT except for the following: 
Hematologic Toxicities: 
 Grade 3 or 4 neutropenia lasting less than 7 days (excluding febrile neutropenia) 
 Grade 3 uncomplicated thrombocytopenia lasting less than 7 days with no evidence 
of bleeding 
 Grade 3 or 4 decreased total WBC 


 
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Non-Hematologic Toxicities: 
 Grade 3 fatigue persisting less than 7 days 
 Grade 3 nausea, vomiting, or diarrhea that can be controlled by medication within 
48 hours 
 Grade 3 hyperglycemia, hypophosphatemia, hyponatremia, or hypocalcemia that is 
responsive to medical therapy within 24 hours 
 Grade 3 dehydration that responds to medical intervention within 24 hours 
 Grade 3 hypertension that is controlled within 1 week of diagnosis 
 
Per FDA guidance for drug-induced liver injury (DILI), the following liver function 
toxicities based upon Hy’s Law will be considered a DLT if: 
 AST or ALT >8 x ULN; or 
 AST or ALT >3 x ULN and total bilirubin >2 x ULN, with no elevation of alkaline 
phosphatase; or  
 ALT or AST >3xULN with the appearance  of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)  
AND 
 No other reason(s) for these abnormalities or pre-existing liver disease.32,33 
 
Any increase in bilirubin, with or without liver enzymes increases, should prompt an assessment 
of the fractionated bilirubin. Fostamatinib inhibits UGT1A1, the sole enzyme responsible for 
bilirubin conjugation; this may increase unconjugated (indirect) bilirubin levels in some patients. 
The detection of elevated bilirubin, especially in the absence of any other LFT abnormalities, or 
signs or symptoms of liver impairment, suggests the (UGT1A1) effect of fostamatinib; in this case, 
continue the drug with regular LFT and fractionated bilirubin monitoring. 
 
The window for monitoring DLTs is the first 4 weeks (28 days) of protocol treatment.   
 
Management and dose modifications associated with the above adverse events are outlined in 
Section 8. 
 
Dose escalation will proceed within each cohort according to the dose-escalation decision rules in 
Table 2. Dose-limiting toxicity (DLT) is defined above.  
 
7.5 
General Concomitant Medication and Supportive Care Guidelines 
In general, concomitant medications and therapies deemed necessary for the supportive care and 
safety of the participant are allowed, provided their use is documented in the subject records and 
on the appropriate case report form. If toxicity occurs, the appropriate treatment will be used to 
ameliorate signs and symptoms (including anti-emetics for nausea and vomiting, anti-diarrheals 
for diarrhea, and anti-pyretics and anti-histamines for drug fever). All supportive measures for 
optimal medical care will be given during the period of study.  
 
Because there is a potential for interaction of Fostamatinib with other concomitantly administered 
drugs through the cytochrome P450 system, the case report form must capture the concurrent use 


 
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of all other drugs, over-the-counter medications, or alternative therapies.  The Principal 
Investigator should be alerted if the patient is taking any agent known to affect or with the potential 
to affect selected CYP450 isoenzymes. Appendix B presents guidelines for identifying 
medications/substances that could potentially interact with the study agent(s). 
 
7.6 
Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of the 
following criteria applies: 
 
 Disease progression, 
 Intercurrent illness that prevents further administration of treatment, 
 Unacceptable adverse event(s), 
 Patient decides to withdraw from the study, or 
 General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator. 
 
NOTE:  If a patient discontinues agent administration for any reason other than disease 
progression, ongoing radiologic evaluations to document progression are requested at least every 
12 weeks after discontinuation of therapy.   
 
7.7 
Duration of Follow Up 
Patients will be followed for 4 weeks after discontinuation of study treatment or until death, 
whichever occurs first.  Patients removed from study for unacceptable adverse event(s) will be 
followed until resolution or stabilization of the adverse event. 
 
7.8 
Criteria for Removal from Study 
Patients will be removed from study when toxicity monitoring is completed, as is described above, 
or one of the following: 
 
 Subject withdraws consent. 
 Subject is lost to follow-up. 
 Study is canceled for any reason. 
 
NOTE:  The reason for removal from the study and date must be cleared documented in the 
records.   
 
7.9 
Additional Information 
Subjects may be given parking vouchers (if applicable) to cover parking costs during the study, 
depending on the preferences of each participating site. No other subject remuneration is planned. 
 
 
 


 
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8. DOSE DELAYS/MODIFICATIONS 
8.1 
Summary 
Treatment will be modified based on toxicity, defined per CTCAE v4.03, as described below for 
all participants receiving paclitaxel and fostamatinib. Dose adjustments will be made as outlined 
in Table 4. A maximum of two dose reductions is allowed for each patient, if feasible based upon 
the initially assigned dose level. Patients experiencing toxicity (hematologic or non-hematologic) 
that meets criteria for further dose reduction, after this maximum, will be removed from study 
therapy. 
 
After 4 cycles, individualized modifications to the treatment plan, especially paclitaxel, may be 
considered to increase tolerability with permission of the primary investigator. 
 
Study Drug 
Initial Dose level 
1 level reduction 
2 level reduction 
Paclitaxel 
80mg/m2 
60mg/m2 
Remove from study* 
Fostamatinib 
100mg QDay 
Consider decrease in paclitaxel only, or remove from study* 
150mg QDay 
100mg QDay 
Consider decrease in paclitaxel only, or 
remove from study* 
100mg BID 
150mg QDay 
100mg QDay 
150mg BID 
100mg BID 
150mg QDay 
200mg BID 
150mg BID 
100mg BID 
Table 4 Dose Reduction Parameters. 
 
8.2 
Dose Modifications for Hematologic Toxicity 
 
8.2.1 Initial treatment modifications will consist of cycle delay and/or dose reduction as 
indicated below. The use of hematopoietic cytokines and protective reagents are restricted 
as noted:  
 
 Patients will NOT receive prophylactic growth factors [filgrastim (G-CSF), 
sargramostim (GM-CSF), pegfilgrastim (Neulasta)] unless they experience recurrent 
neutropenic complications after treatment modifications specified below.  
 
 Patients will NOT receive prophylactic thrombopoietic agents. 
 


 
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 Patients may receive erythropoietin (EPO), iron supplements, and/or transfusions as 
clinically indicated for management of anemia. Treating physicians should be aware of 
prescribing information for the erythropoiesis stimulating agents (including Aranesp, 
Epogen and Procrit) which note that there is a potential risk of shortening the time to 
tumor progression or disease-free survival, and that these agents are administered only 
to avoid red blood cell transfusions. They do not alleviate fatigue or increase energy. 
They should not be used in patients with uncontrolled hypertension. They can cause an 
increased incidence of thrombotic events in cancer patients on chemotherapy. The 
updated 
package 
inserts 
should 
be 
consulted 
(http://www.fda.gov/Medwatch/safety/2007/safety07.htm).  
 
8.2.2 Treatment decisions will be based on the absolute neutrophil count (ANC) rather than the 
total white cell count (WBC). 
 
8.2.3 Subsequent cycles of therapy will not begin (Day 1 of each cycle) until the ANC is ≥ 1000 
cells/mcl and the platelet count is ≥ 100,000/mcl. Therapy will be delayed for a maximum 
of two weeks until these values are achieved. Patients who fail to recover adequate counts 
within a two-week delay will be removed from study therapy.  
Day 8 and Day 15 paclitaxel treatment will not be given unless ANC is ≥ 1000 cells/mcl 
and the platelet count is ≥ 75,000/mcl. If Day 8 or Day 15 paclitaxel is held, it should not 
be made up.  
 
8.2.4 Patients requiring greater than one dose reductions of paclitaxel during Cycle 1 for any 
cause will result in discontinuation of study treatment. If patients require more than two 
dose reductions of the fostamatinib, fostamatinib will be discontinued (with continuation 
of paclitaxel, if appropriate, until unacceptable toxicity or progression of disease). 
 
 
 


 
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8.2.5 Dose Modification Tables 
For hematologic toxicity dose reduction of both drugs may be required. Please review both 
Tables 5 and 6 below. 
8.2.5.1 Paclitaxel Dose Modification for Hematologic Toxicity: 
ANC1
PLT 
ACTION FOR PACLITAXEL 
Day 1  
<1000  
< 100,000  
Delay. Monitor counts at least 
weekly until adequate for treatment.  
 
Restart when counts are adequate 
for treatment; reduce one dose level. 
 
If counts do not recover after 2 
weeks delay, remove from study. 
Day 8 
< 1000 
< 75,000 
Hold dose 
Day 15 
< 1000 
< 75,000 
Hold dose 
1For febrile neutropenia, and/or documented grade 4 neutropenia persisting 
greater than or equal to 7 days, reduce paclitaxel by one dose level on 
subsequent cycles.  
Table 5 Paclitaxel dose modification for hematologic toxicity. 
 
8.2.5.2 Fostamatinib Dose Modification for Hematologic Toxicity: 
 
Thrombocytopenia/ 
Neutropenia/ 
Anemia1 
GRADE
ACTION FOR FOSTAMATINIB 
Grades 1 or 2 
No interruption in treatment; maintain current dose. 
Grades 3 or 4 
Interrupt treatment until toxicity is ≤grade 2; reduce 
one dose level. 
 
If no recovery to ≤grade 2 or recurrent grade 3 or 4, 
discontinue fostamatinib. 
 
Maximal interruption is 2 weeks.
1The dose delays and modifications for anemia apply only to anemia secondary to 
hemorrhage or bleeding.  No specific dose delays or dose reductions are required for anemia 
due to other causes, but the investigator should dose delay and dose-decrease, if he/she feels 
it is necessary, in a manner consistent with good medical practice. 
Table 6 Fostamatinib dose modification for hematologic toxicity. 
 
 
 


 
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8.3 
Dose Modifications for Non-Hematologic Toxicity 
The following sections address the management of non-hematologic toxicities arising over the 
course of treatment on study. 
8.3.1 Management of Hypertension 
 
Toxicity 
Grade 
Paclitaxel 
Fostamatinib 
Hypertension 
Grade 1 
(sBP: 120-139 or dBP:80-89) 
No change 
No change; however for systolic between 
130-139 or diastolic between 80-89 
mmHg, anti-hypertensive therapy should 
be initiated for patients with increased 
cardiovascular risk 
Grade 2 
(sBP: 140-159, dBP: 90-99, or 
symptomatic increase by 
>20mmHg diastolic) 
No change 
No change; however, initiate anti-
hypertensive therapy, titrate as necessary. 
Monitoring per physician. If BP can not 
be controlled after an optimal trial of up 
to 2 antihypertensive medications, 
consider 1 dose reduction. 
Grade 3  
(sBP ≥160, or dBP≥100) 
No change 
Hold Fostamatinib until ≤Grade 2. 
Monitoring per physician. If BP can not 
be controlled after an optimal trial of up 
to 2 antihypertensive medications, 
consider 1 dose reduction when sBP ≤159 
and dBP≤99. 
Grade 4 
(urgent intervention required, 
including hospitalization for 
symptomatic HTN) 
No change 
Permanently discontinue fostamatinib. 
Monitoring as recommended by 
physician. 
Table 7.1 Dose Modifications for Hypertension 
8.3.2 Management of Nausea, Vomiting, or Diarrhea 
Toxicity 
Grade 
Paclitaxel 
Fostamatinib 
Nausea/Vomiting/
Diarrhea  
Grade 1/2 
No change 
No change 
Persistent Grade 3 or Grade 4 
(unresponsive to maximum medical 
management) 
Hold until resolved to ≤ 
Grade 1 and reduce 1 
dose level.  
Hold until resolved to ≤ Grade 1 and 
reduce to next lower dose level.  
Table 8.2 Dose Modifications for Nausea, Vomiting, or Diarrhea 


 
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8.3.3 Management of Elevated AST, ALT, or Bilirubin 
Bilirubin/AST/AL
T elevations 
AST or ALT Grade 1 (≤3xULN), 
bilirubin Grade ≤1 (<1.5xULN) 
No change 
No change 
Consider stopping concomitant 
medications that may be contributing to 
LFT abnormalities (e.g. statins) 
AST or ALT Grade 2 (>3-5xULN), 
bilirubin Grade ≤1 (<1.5xULN) 
and asymptomatic 
No change 
Recheck q72hr until AST or ALT Grade 
1 (≤3xULN), then follow weekly until 
stable. 
If worsens, follow guidance below. 
If remains elevated x 2 weeks, reduce to 
next lower dose level, recheck q72hr until 
AST or ALT Grade 1 (≤3xULN), then 
follow weekly until stable. 
AST or ALT Grade 2 (>3-5xULN), 
bilirubin Grade ≤1 (<1.5xULN) 
and symptomatic (e.g., nausea, 
vomiting, abdominal pain) 
No change 
Hold and recheck q72hr until AST or 
ALT Grade 1 (≤3xULN).  
Restart at next lower dose level and 
follow LFTs weekly until stable. 
AST or ALT Grade 3/4 (>5xULN), 
bilirubin Grade ≤1 (≤1.5xULN) 
Hold, recheck q72hr 
until AST or ALT 
Grade 1 (≤1.5xULN). 
If resolves, restart same 
dose level. 
If persists >2wks, 
discontinue study 
treatment. 
Hold, recheck q 72hr until AST or ALT 
Grade 1 (≤1.5xULN). 
If resolves, restart at next lower dose 
level. 
If persists >2wks, discontinue study 
treatment. 
AST or ALT Grade 2 (>3-5xULN), 
bilirubin Grade >1 (>1.5xULN) 
Discontinue study treatment. Recheck q72hr until AST or ALT 
Grade 1 (≤3xULN) and bilirubin Grade ≤1 (≤1.5xULN). 
Isolated elevated conjugated 
(direct) bilirubin >2xULN 
Hold and evaluate for other potential causes. If unable to identify 
other potential cause, discontinue study treatment, recheck q72hr 
until <1.5xULN. 
Isolated elevated unconjugated 
(indirect) bilirubin  
No change 
Continue fostamatinib with frequent 
monitoring since isolated increase in 
unconjugated (indirect) bilirubin may be 
due to UGT1A1 inhibition. 
Table 9.3 Dose Modifications for Elevated AST, ALT, or Bilirubin 
8.3.4 Management of Peripheral Neuropathy 
Peripheral 
neuropathy 
≥Grade 2 
Hold until resolved to ≤ 
Grade 1 and reduce 1 
dose level for next 
cycle. 
No change 
Table 10.4 Dose Modifications for Peripheral Neuropathy 


 
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8.3.5 Management of other clinically significant toxicities not-specifically addressed above 
Other clinically 
significant 
adverse events not 
mentioned 
elsewhere1 
Grade 1/2 
No change 
No change 
Grade 3/4 
Hold until resolved to ≤ 
Grade 1 and reduce by 
one dose level for next 
cycle 
Hold until resolved to ≤ Grade 1 and 
reduce to next lower dose level for next 
cycle 
1If treatment is held for a non-hematologic grade 3/4 adverse event not described above both drugs should be dose-reduced unless 
the toxicity can be clearly attributed to paclitaxel or fostamatinib specifically. 
Table 11 Dose Modifications for Other Clinically Significant Toxicities 
 
8.4 
Dose Interruption for Surgery 
 
8.4.1 Fostamatinib 
It is recommended that fostamatinib is stopped 5 days prior to elective surgery and restarted 
when the surgical wound has healed. If emergency surgery is performed fostamatinib 
should be withheld until the wound has healed. 
 
8.4.2 Paclitaxel 
It is recommended that paclitaxel be held for at least 4 weeks after any major surgery (e.g. 
laparotomy, laparoscopy, thoracotomy, video assisted thorascopic surgery).  There is no 
restriction on minor procedures (e.g. central venous access catheter placement, ureteral 
stent placement or exchange, paracentesis, thoracentesis). 
8.5 
Special Considerations 
Any consideration to modification of the above dose modification guidelines may be permitted 
after discussion/approval with the Protocol Chair/designee. 
 
 


 
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9. PHARMACEUTICAL INFORMATION 
9.1 
Fostamatinib 
9.1.1 Classification 
Fostamatinib is an investigational agent supplied to investigators by Rigel Pharmaceuticals, Inc. 
9.1.2 Formulation 
Fostamatinib will be supplied as 100 and 150 milligram (mg) tablets.   
9.1.3 Storage and Stability 
Fostamatinib is stored at room temperature, protected from light.   
9.1.4 Supply 
Rigel Pharmaceuticals, Inc. will supply Fostamatinib for use in this clinical trial. A study-specific 
supply will be given to all subjects.  
9.1.5 Adverse Effects 
The most common side effects of Fostamatinib include the following:   
 
Incidence of Common (≥5%) Adverse Reactions from Double-
Blind Clinical Studies (C788-047 and C788-048)5  
Preferred Term 
All Grades (%) 
Diarrheaa
31
Hypertensionb
28
Nausea
19
Dizziness
11
ALT Increased
11
AST Increased
9
Respiratory Infectionc
11
Rashd
9
Abdominal Paine
6
Fatigue
6
Chest Pain
6
Neutropeniaf
6
ALT = Alanine Aminotransferase; AST= Aspartate Aminotransferase 
a. Includes diarrhea and frequent bowel movement. 
b. Includes hypertension, blood pressure (BP) increased, BP diastolic abnormal, and BP 
diastolic increased. 
c. Includes upper respiratory tract infection, respiratory tract infection, lower respiratory 
tract infection, and viral upper respiratory tract infection. 
d. Includes rash, rash erythematous, and rash macular. 
e. Includes abdominal pain and abdominal pain upper. 
f. Includes neutropenia and neutrophil count decreased. 


 
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9.2 
Paclitaxel 
9.2.1 Classification 
Paclitaxel is an antimicrotubule agent.  It promotes microtubule assembly and stabilizes tubulin 
polymers by preventing their depolarization, resulting in the formation of extremely stable and 
nonfunctional microtubules, and consequently inhibition of many cell functions. 
9.2.2 Formulation 
Paclitaxel is supplied as 30mg (5ml), 100mg (16.7ml), and 300mg (50ml) multidose vials.  Each 
ml of sterile nonpyrogenic solution contains 6mg paclitaxel, 527mg of purified Cremophor EL 
(polyoxyethylated castor oil) and 49.7% (v/v) dehydrated alcohol, USP. 
9.2.3 Storage and Stability 
Please refer to the package insert for standard preparation instructions 
9.2.4 Supply 
Paclitaxel is commercially available.  
9.2.5 Adverse Effects 
The most common (> 10% frequency) adverse events associated with weekly paclitaxel are 
anemia, nausea, fatigue, and peripheral neuropathy (4). Please refer to the package insert for 
common adverse effects. 
9.3 
Drug Accountability 
The research pharmacy will keep records for Fostamatinib receipts, dispensation, and destruction 
as per standard practice at each institution for supplied agents. 
 


 
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10. CORRELATIVE STUDIES 
 
10.1 Fostamatinib Pharmacokinetics 
To measure the pharmacokinetics of fostmatinib, blood will be collected in a sodium heparin 
vacutainer on days 1, 8, and 15 of the first cycle. Blood draws will occur pre-treatment and at the 
following times after administration: 
 
Timing of Pharmacokinetic Analyses During Cycle 1 of Treatment 
Cycle 1 Day 1 
Cycle 1 Day 8 
Cycle 1 Day 15 
Prior to administration 
1 hour post administration 
3 hours post administration 
6 hours post administration
Prior to administration 
Prior to administration 
 
Samples will be frozen at -80oC and sent in batches to Rigel Pharmaceuticals for analysis. 
 
10.2 Pharmacodynamic Analyses 
 
10.2.1 Immunohistochemistry of SYK, p-SYK, and Validated SYK Substrates 
In a retrospective evaluation of patient-matched primary and post-treatment recurrent tumors, we 
found elevated expression of SYK and p-SYK.  In ongoing work, we are identifying and validating 
SYK substrates in ovarian cancer cells.  To evaluate the utility of SYK or its substrates as 
predictive biomarkers for fostamatinib response, we will obtain pre- and post-treatment tumor 
tissue from at least 75% of participants.  Biopsy material will be obtained prior to treatment and at 
the end of cycle 1 by CT- or ultrasound-guidance if it is clinically and safely feasible.  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. Expression levels of total SYK, p-SYK and other validated SYK 
substrates will be determined using immunohistochemistry and analyzed by digital imaging 
software.  Expression levels will be correlated with response to therapy. 
 
10.2.2 Inhibition Assays 
Plasma samples will be collected from patients at the time of the biopsies outlined above (prior to 
initiation of treatment and at the end of cycle 1).  For these assays, two index ovarian cancer cell 
lines (SKOV3TR and MPSC1TR) that express abundant SYK and p-SYK will be grown in 3-D 
cultures. The cells will be incubated with plasma samples collected from patients and cell cycle 
analysis or BrdU incorporation assays will be performed 12 hrs after incubation. Plasma collected 
at the end of the first cycle is expected to have a greater anti-proliferative effect than pre-treatment 
plasma.  Inhibition of proliferation by plasma samples containing R406 would support the 
hypothesis that the MTD is effective in inhibiting ovarian cancer growth. Peripheral blood 
mononuclear cells will be analyzed for SYK activity in samples before and after fostamatinib 
treatment. 


 
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10.2.3 Modeling Tumor Response to Fostamatinib +/- Paclitaxel in PDX Models 
Tumor tissue, from participants who opt to participate, will be sent to Champions Oncology, Inc. 
for development of PDXs under the Champions TumorGraft™ program. The Champions 
TumorGraft™ program implants human tumor tissue into immune-deficient mice to produce 
patient-derived PDX. Successful PDX models will be used by the study investigators to (1) 
assess response to the individual study drugs or the combination, (2) evaluate biomarkers of 
tumor response, and (3) identify mechanisms of therapeutic resistance to these agents.  
 
The procedural protocols pertaining to the above correlative studies are being optimized, thus 
explicit instructions for handling, preserving, and shipping the specimens will be provided 
in the laboratory manual once finalized.   
10.3 Additional Information 
Submission of data for Genome Wide Association Studies (GWAS) is not currently planned; 
however, subjects will be asked for permission in the informed consent process. A revision to the 
protocol and/or any regulatory approvals will be secured prior to any GWAS submission or 
inclusions in the future, if applicable. 
 
 
 


 
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11. STUDY CALENDAR 
Pre-study evaluations are to be conducted within 4 weeks prior to start of protocol therapy.  In the event 
that the patient’s condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior 
to initiation of therapy. 
 
Timing of on-treatment evaluations:  
 
Labs for Day 1 of each cycle may be performed up to 3 days prior to the cycle.   
 
Radiologic evaluations should be done every 8 weeks (+/- 3 days). If stable disease or response to 
therapy is documented after Cycle 4, imaging can then continue every three (3) cycles thereafter. 
Imaging can be done at a shorter interval per provider discretion.  
 
Procedure 
Pre-Study 
Cycle 1 
Cycle 2-Beyondi 
Off Studyc 
Day 
1 
Day  
8 
Day 
15 
Day 
22 
Day 
1 
Day  
8 
Day 
15 
Day 
22 
Fostamatinib
A: twice daily continuously
A: twice daily continuously 
Paclitaxel
B
B
B
B
B
B
Informed Consent
X 
Demographics
X
Medical History
X
Physical Exam
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Vital Signs, Height (Baseline Only)
X
X
X
X
X
X
X
X
X
Weight
X
X
X
X
Performance Status
X
X
X
X
CBC w/Diff, Plts
X
Xf
X
X
X
X
X
X
X
Serum Chemistrya
X
Xf
X
X
X
X
X
CA125g
Xf 
X
B-HCG
Xb
PT/INR
X
EKG 
X
Concurrent Medications
X
X ................................................................... X
Adverse Event Evaluation
X ................................................................... X
X
Radiologic Evaluation/  
Tumor Measurements
X 
Radiologic measurements should be performed every 8 weeks.   
See Section 12.2 for additional information.
X 
Biopsyj 
X
Xd
 
Plasma
X
Xe 
PK Analyses
Xe
X
X
PBMC Collection
Xe 
Xe
A: 
Fostamatinib:  Dose as assigned; administered orally BID continuously throughout the 28 day cycle.  A Study Drug Diary (Appendix 
C) must be completed by subjects with each dose/cycle and collected by the study staff.   
B: 
Paclitaxel:  Dose as assigned; administered IV on Days 1, 8, and 15 of each 28 day cycles 
a: 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, 
total protein, SGOT [AST], SGPT [ALT], sodium. 
b: 
Serum pregnancy test (women of childbearing potential only). 
c: 
Off-study evaluation; subjects who discontinue therapy for a reason other than disease progression should continue to be followed for 
radiologic evaluation/tumor measurements about every 12 weeks until disease progression.  


 
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d:      Biopsy should be obtained during week 4 of cycle 1. 
e:      Plasma to be obtained at the time of biopsy. PK analyses are pre- and post-dosing on C1D1. PBMC Collection performed pre-dose. 
f:       If C1D1 labs are performed within 7 days prior to start of therapy, they do not need to be repeated. CA125 does not need to be  
 repeated if performed within 28 days. 
g:      Per standard of care 
h: In order to minimize the need for research-only in-person visits, telemedicine visits may be substituted for in person clinical trial visits or 
portions of clinical trial visits where determined to be appropriate and where determined by the investigator not to increase the participants 
risks. Prior to initiating telemedicine for study visits the study team will explain to the participant, what a telemedicine visit entails and 
confirm that the study participant is in agreement and able to proceed with this method. Telemedicine acknowledgement will be obtained in 
accordance with the Guidance for Use of Telemedicine in Research. In the event telemedicine is not deemed feasible, the study visit will 
proceed as an in-person visit. Telemedicine visits will be conducted using HIPAA compliant method approved by the Health System and 
within licensing restrictions. 
i: Administration of paclitaxel through a local oncology infusion center will be allowed for cycles 2 and beyond, if in the best interest of the 
patient, and if the local oncology infusion center agrees to be in contact with the study investigators/staff, adhere to protocol measures, and 
provide information regarding infusion administration and any other study procedures performed. 
j: Biopsies (prior to treatment and prior to C2) are required from at least 75% of participants.
12. MEASUREMENT OF EFFECT 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guidelines 
(version 1.1). Changes in the largest diameter (unidimensional measurement) of the tumor lesions 
and the short axis measurements in the case of lymph nodes are used in the RECIST guideline. 
The Protocol Chair (or designee) may choose to review cases at Johns Hopkins.  
 
In addition, if a formal re-read for RECIST measurements is performed, but the results are not 
available prior to the scheduled start of the next cycle, treatment should continue based upon 
review of the routine/clinical radiologist report of the status of disease (i.e., response, stability or 
progression). In the event that a RECIST re-read would have changed the treatment decision for 
the subject, if known prior, the Protocol Chair/designee should be consulted and course of action 
clearly documented in the medical record. If it is in the best interests of the subject to continue on 
study, this is permissible. These cases will be reviewed in detail at the time of study analyses. 
 
The schedule of evaluations will occur per the Study Calendar.  
12.1 Definitions  
12.1.1 Measurable Disease 
 
 A non-nodal lesion is considered measurable if its longest diameter can be accurately 
measured as 2.0 cm with chest x-ray, or as ≥1.0 cm with CT scan, CT component of a 
PET/CT, or MRI.  
 A superficial non-nodal lesion is measurable if its longest diameter is ≥ 1.0 cm in diameter 
as assessed using calipers (e.g. skin nodules) or imaging. In the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended. 
 A malignant lymph node is considered measurable if its short axis is >1.5 cm when 
assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm). 
 
NOTE: Tumor lesions in a previously irradiated area are only considered measurable disease 
in the event that there is evidence of post-radiation progression. 


 
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12.1.2 Non-Measurable Disease 
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm [<1 cm] 
or pathological lymph nodes with ≥10 to <15 mm [≥1 to <1.5 cm] short axis), are considered non-
measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed 
by CT or MRI), are considered as non-measurable. 
 
NOTE: “Cystic lesions” thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-cystic 
lesions are present in the same subject, these are preferred for selection as target lesions. In 
addition, lymph nodes that have a short axis <1.0 cm are considered non-pathological (i.e., normal) 
and should not be recorded or followed. 
12.2 Guidelines for Evaluation of Disease 
12.2.1 Measurement Methods  
 
 All measurements should be recorded in metric notation (i.e., decimal fractions of 
centimeters) using a ruler or calipers. 
 The same method of assessment and the same technique must be used to characterize each 
identified and reported lesion at baseline and during follow-up. For subjects having only 
lesions measuring at least 1 cm to less than 2 cm must use CT imaging for both pre- and 
post-treatment tumor assessments.  
 Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used at the same evaluation to assess the antitumor effect of a treatment.  
12.2.2 Modalities for Measurable Disease  
 
 Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness. CT is preferred; MRI is also acceptable in certain situations (e.g., for body 
scans). 
 
Diagnostic quality CT is expected (with oral and IV contrast); any deviations from this 
must be approved by the Protocol Chair/designee in advance. (See note below regarding 
contrast allergy). 
 
 
 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 
type and site of disease. Furthermore, as with CT, the modality used at follow-up should 
be the same as was used at baseline and the lesions should be measured/assessed on the 


 
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same pulse sequence. It is beyond the scope of the RECIST guidelines to prescribe specific 
MRI pulse sequence parameters for all scanners, body parts, and diseases. Ideally, the same 
type of scanner should be used and the image acquisition protocol should be followed as 
closely as possible to prior scans. Body scans should be performed with breath-hold 
scanning techniques, if possible. 
 
NOTE: If prior to enrollment it is known a subject is not able to undergo CT scans with IV 
contrast due to allergy or renal insufficiency, the decision as to whether a non-contrast CT 
or MRI (with or without IV contrast) should be used to evaluate the subject at baseline and 
follow-up should be guided by the anatomic location(s) of the disease. For subjects who 
develop contraindications to contrast after baseline contrast CT is done, the decision as to 
whether non-contrast CT or MRI (enhanced or non-enhanced) should be performed should 
also be based on the anatomic location of the disease and should be optimized to allow for 
comparison to the prior studies if possible. Each case should be discussed with the 
radiologist and Protocol Chair/designee to determine if substitution of these other 
approaches is possible and, if not, the subject may be considered not evaluable from that 
point forward.  
 
 Chest X-Ray: Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT scans are preferable. 
 
 Clinical Lesions: For superficial non-nodal lesions, physical examination is acceptable, but 
imaging is preferable, if both can be done. Clinical lesions will only be considered 
measurable when they are superficial (e.g., skin nodules and palpable lymph nodes) and 
≥10 mm (≥1 cm) diameter as assessed using calipers (e.g., skin nodules). In the case of 
skin lesions, documentation by color photography, including a ruler to estimate the size of 
the lesion, is recommended. 
 
 Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as 
a method of measurement. Ultrasound examinations cannot be reproduced in their entirety 
for independent review at a later date and, because they are operator dependent, it cannot 
be guaranteed that the same technique and measurements will be taken from one 
assessment to the next. If new lesions are identified by ultrasound in the course of the study, 
confirmation by CT or MRI is advised. If there is concern about radiation exposure at CT, 
MRI may be used instead of CT in selected instances. 
 
 PET-CT: If the site can document that the CT performed as part of a PET-CT is of identical 
diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion of 
the PET-CT can be used for RECIST measurements and can be used interchangeably with 
conventional CT in accurately measuring cancer lesions over time with approval from the 
Protocol Chair/designee.  
 
 FDG-PET: FDG-PET scanning is allowed to complement CT scanning in assessment of 
progressive disease [PD] and particularly possible 'new' disease. A ‘positive’ FDG-PET 
scanned lesion is defined as one which is FDG avid with an update greater than twice that 


 
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of the surrounding tissue on the attenuation corrected image; otherwise, an FDG-PET 
scanned lesion is considered ‘negative.’ New lesions on the basis of FDG-PET imaging 
can be identified according to the following algorithm:  
 
o Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
o No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this 
is PD. If the positive FDG-PET at follow-up is not confirmed as a new site of 
disease on CT, additional follow-up CT scans are needed to determine if there is 
truly progression occurring at that site (if so, the date of PD will be the date of the 
initial abnormal FDG-PET scan). If the positive FDG-PET at follow-up 
corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD. 
o FDG-PET may be used to upgrade a response to a CR in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring. The use of FDG-PET in this circumstance should be 
prospectively described in the protocol and supported by disease-specific medical 
literature for the indication. However, it must be acknowledged that both 
approaches may lead to false positive CR due to limitations of FDG-PET and 
biopsy resolution/sensitivity. 
 
NOTE: A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an 
uptake greater than twice that of the surrounding tissue on the attenuation corrected 
image. 
12.2.3 Additional Considerations 
 
 Tumor markers alone cannot be used to assess response. If markers are initially above the 
upper normal limit, they must normalize for a subject to be considered in complete clinical 
response.  
 The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or stable 
disease is mandatory to differentiate between response or stable disease (an effusion may 
be a side effect of the treatment) and progressive disease. 
 Cytologic and histologic techniques can be used to differentiate between PR and CR in rare 
cases (e.g., residual lesions in tumor types such as germ cell tumors, where known residual 
benign tumors can remain.) 
12.3 Lesion Documentation 
12.3.1 Target Lesions 
 
 Measurable lesions: up to a maximum of 5 lesions, representative of all involved organs, 
should be identified as “Target Lesions” and recorded and measured at baseline. These 
lesions can be non-nodal or nodal (as defined), where no more than 2 lesions are from the 


 
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same organ and no more than 2 malignant nodal lesions are selected.  
 
NOTE: If fewer than 5 target lesions and target lymph nodes are identified (as there often 
will be), there is no reason to perform additional studies beyond those specified in the 
protocol to discover new lesions.  
 
 Target lesions and target lymph nodes should be selected on the basis of their size, be 
representative of all involved sites of disease, but in addition should be those that lend 
themselves to reproducible repeated measurements. It may be the case that, on occasion, 
the largest lesion (or malignant lymph node) does not lend itself to reproducible 
measurements in which circumstance the next largest lesion (or malignant lymph node) 
which can be measured reproducibly should be selected.  
 
 Baseline Sum of Diameters (BSD): A sum of the longest diameter for all target lesions plus 
the sum of the short axis of all the target lymph nodes will be calculated and reported as 
the baseline sum of dimensions (BSD). The BSD will be used as reference to further 
characterize any objective tumor response in the measurable dimension of the disease.  
 
 Post-Baseline Sum of the Diameters (PBSD): A sum of the longest diameter for all target 
lesions plus the sum of the short axis of all the target lymph nodes will be calculated and 
reported as the post-baseline sum of dimensions (PBSD). If the radiologist is able to 
provide an actual measure for the target lesion (or target lymph node), that should be 
recorded, even if it is below 0.5 cm. If the target lesion (or target lymph node) is believed 
to be present and is faintly seen but too small to measure, a default value of 0.5 cm should 
be assigned. If it is the opinion of the radiologist that the target lesion or target lymph node 
has likely disappeared, the measurement should be recorded as 0 cm. 
 
 The minimum sum of the diameters (MSD) is the minimum of the BSD and the PBSD. 
12.3.2 Non-Target Lesions & Non-Target Lymph Nodes 
Non-measurable sites of disease including any measurable lesions over and above the 5 target 
lesions should be identified as non-target lesions or non-target lymph nodes and should also be 
recorded at baseline. Measurements of these lesions are not required, but the presence, absence, or 
in rare cases unequivocal progression of each should be noted throughout follow-up.  
12.4 Response Criteria 
12.4.1 Overview 
All target lesions, as well as non-target lesions must be measured on re-evaluation at evaluation 
time points. Specifically, a change in objective status to either a PR or CR cannot be done without 
re-measuring target lesions and target lymph nodes.  
 
NOTE: Non-target lesions and non-target lymph nodes should be evaluated at each assessment, 
especially in the case of first response or confirmation of response. In selected circumstances, 
certain non-target organs may be evaluated less frequently. For example, bone scans may need to 


 
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be repeated only when complete response is identified in target disease or when progression in 
bone is suspected. 
12.4.2 Evaluation of Target Lesions 
 
 Complete Response (CR): Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm (<1 cm). 
 
 Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters. 
 
 Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if that 
is the smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm (0.5 cm). (NOTE: The appearance of 
one or more new lesions is also considered progression.) 
 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. 
12.4.3 Evaluation of Non-Target Lesions & Non-target Lymph Nodes 
 
 Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumor marker level. All lymph nodes must be non-pathological in size (<10 mm [<1 cm] 
short axis). 
 
NOTE: If tumor markers are initially above the upper normal limit, they must normalize 
for a subject to be considered in complete clinical response. 
 
 Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
 
 Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal progression should not normally 
trump target lesion status. It must be representative of overall disease status change, not a 
single lesion increase. 
 
NOTE: To achieve “unequivocal progression” on the basis of non-target disease there must 
be an overall level of substantial worsening in non-target disease such that, even in 
presence of CR, PR or SD in target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy. A modest “increase” in the size of one or 
more non-target lesions is usually not sufficient to qualify for unequivocal progression 
status. The designation of overall progression solely on the basis of change in non-target 
disease in the face of CR, PR or SD of target disease is therefore expected to be rare. In 
order for a PD to be assigned on the basis of non-target lesions, the increase in the extent 
of the disease must be substantial even in cases where there is no measurable disease at 


 
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baseline. If there is unequivocal progression of non-target lesion(s), then at least one of the 
non-target lesions must be assigned a status of “Worsened”. Where possible, similar rules 
to those described above for target lesions for assigning PD following a CR for the non-
target lesion response in the presence of non-target lesions nodal lesions should be applied. 
12.4.4 Symptomatic Deterioration 
Subjects with global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time, and not either related to study treatment or 
other medical conditions, should be reported as PD due to “symptomatic deterioration.” Every 
effort should be made to document the objective progression even after discontinuation of 
treatment due to symptomatic deterioration. A subject is classified as having PD due to 
“symptomatic deterioration” if any of the following occur that are not either related to study 
treatment or other medical conditions: 
 
 Weight loss >10% of body weight 
 Worsening of tumor-related symptoms 
 Decline in performance status of >1 level on ECOG scale 
12.4.5 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). The subject's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
 
 For Subjects with Measurable Disease at Baseline:  
 
Target Lesions & 
Target Lymph Nodes 
Non-Target Lesions & 
Non-Target Lymph Nodes 
New Sites of 
Disease 
Overall 
Objective Status 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
CR 
Non-CR/Non-PD 
No 
PR 
CR/PR 
Not All Evaluated* 
No 
PR** 
SD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
SD 
Not all Evaluated 
CR 
Non-CR/Non-PD 
No 
Not Evaluated 
(NE) 
PD 
Unequivocal PD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
Yes or No 
PD 
CR/PR/SD/PD/Not all 
Evaluated 
Unequivocal PD 
Yes or No 
PD 
CR/PR/SD/PD/Not all 
Evaluated 
CR 
Non-CR/Non-PD 
Yes 
PD 


 
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Not All Evaluated* 
 
 For Subjects with Non-Measurable/Evaluable Disease Only at Baseline:  
 
Non-Target Lesions 
New Lesions 
Overall Objective Status 
CR
No
CR
Non-CR/Non-PD
No
Non-CR/Non-PD
UNK/Not All Evaluated*
No
Indeterminate
Unequivocal progression
Yes or No
PD
Any
Yes
PD
 
* NOTE: This study uses the protocol RECIST v1.1 template dated 2/16/2011. For data collection and 
analysis purposes the objective status changed from SD to PR in the NCCTG protocol RECIST v1.1 
template as of 2/16/2011 and to match RECIST v1.1 requirements. 
12.4.6 Duration of Response 
12.4.6.1 Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are met for CR 
or PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
 
12.4.6.2 Duration of Stable Disease 
Stable disease is measured from the start of the treatment until the criteria for progression are met, 
taking as reference the smallest measurements recorded since the treatment started, including the 
baseline measurements.  
12.4.7 Progression-Free Survival 
Progression-free survival (PFS) is defined as the time from the initiation of the study treatment 
until the date of objective disease progression or death (by any cause in the absence of 
progression). 
12.4.8 Response Review 
There is no independent or central review of the radiology assessments planned for this trial. It is 
the responsibility of each Principal Investigator to ensure that tumor assessments are reported per 
the RECIST 1.1 criteria outlined above. The Protocol Chair (or her designee) may choose to review 
select cases. 
 
 
 
 


 
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13. ADVERSE EVENTS 
13.1 General 
This study will use the descriptions and grading scales found in the revised National Cancer 
Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 for adverse 
event reporting that can be found at http://ctep.cancer.gov/reporting/ctc.html. 
 
Information about all adverse events, whether volunteered by the subject, discovered by 
investigator questioning, or detected through physical examination, laboratory test or other means, 
will be collected, recorded, and followed as appropriate.  
 
All adverse events experienced by subjects will be collected from the time of first dose of study 
medication, throughout the study and until the final study visit. Subjects continuing to experience 
toxicity believed to be related to fostamatinib after discontinuation of the study may be contacted 
for additional assessments until the toxicity has resolved or is deemed irreversible. 
 
The Coordinating Center may periodically request that de-identified AE logs and deviation logs 
from participating site be submitted via email to the Coordinating Center, such as for annual 
continuing review. 
13.2 Definitions 
13.2.1 Adverse Event (AE): An adverse event is any undesirable sign, symptom or medical 
condition occurring after starting study drug (or therapy) even if the event is not considered 
to be related to the study. 
 
Medical conditions/diseases present before starting study treatment are only considered 
adverse events if they worsen after starting study treatment (any procedures specified in 
the protocol).  
 
Abnormal laboratory values or test results constitute adverse events only if they induce 
clinical signs or symptoms or require therapy. 
13.2.2 Serious Adverse Event (SAE): A serious adverse event is an untoward sign, symptom, or 
medical condition which:  
 
 results in death; 
 is immediately life-threatening; 
 requires inpatient hospitalization or prolongation of existing hospitalization; 
 results in persistent or significant disability/incapacity; 
 is a congenital anomaly/birth defect; 
 jeopardizes the subject and requires medical or surgical intervention to prevent; or one 
of the outcomes listed above. 
 


 
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The definition of serious adverse event (experience) also includes important medical event. 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require intervention to prevent one of the other outcomes listed in the 
definition above. These should also usually be considered serious. Examples of such events 
are intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse. 
 
Events not considered to be serious adverse events are hospitalizations for: 
 routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition, or for elective procedures 
 elective or pre-planned treatment for a pre-existing condition that did not worsen 
 emergency outpatient treatment for an event not fulfilling the serious criteria outlined 
above and not resulting in inpatient admission 
 respite care 
 
A hospitalization planned before the start of the study agent(s) and/or for a preexisting 
condition that has not worsened does not constitute a serious adverse event (e.g., elective 
hospitalization). A hospitalization for a social reason in the absence of an adverse event 
also does not meet the criteria for a serious adverse event. 
13.2.3 Expectedness 
 Unexpected Adverse Event: An adverse event is considered unexpected when it 
varies in nature, intensity or frequency from information provided in the current 
adverse event list, the Investigator’s Brochure, the package insert or when it is not 
included in the informed consent document as a potential risk 
 Expected (Known) Adverse Event: Expected adverse events are those that have 
been previously identified as resulting from administration of the agent. For the 
purposes of this study, an adverse event is considered expected when it appears in 
the current adverse event list, the Investigator’s Brochure, the package insert or is 
included in the informed consent document as a potential risk. 
13.2.4 Attribution 
The relationship of all adverse events and serious adverse events to study medication will be 
assessed by an investigator and assigned as follows: 
 
 Definite: The AE is clearly related to the study treatment. An adverse event which has a 
timely relationship to the administration of the investigational agent, follows a known 
pattern of response, for which no alternative cause is present.  
 Probable: The AE is likely related to the study treatment. An adverse event, which has a 
timely relationship to the administration of the investigational agent, follows a known 


 
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pattern of response, but for which a potential alternative cause may be present.  
 Possible: The AE may be related to the study treatment An adverse event, which has a 
timely relationship to the administration of the investigational agent, follows no known 
pattern of response, but a potential alternative cause does not exist. 
 Unlikely: The AE is doubtfully related to the study treatment. An adverse event which 
does not have a timely relationship to the administration of the investigational agent, 
follows no known pattern of response, does not reappear or worsen after re-administration 
of the investigational drug/agent (if applicable), and for which there is evidence that it is 
related to a cause other than the investigational agent. 
 Unrelated: The AE is clearly NOT related to the study treatment. An adverse event, for 
which there is evidence that it is definitely related to a cause other than the investigational 
agent. In general, there is no timely relationship to the administration of the investigational 
agent, or if there is a timely relationship, the event does not follow a known pattern of 
response, and there is an alternative cause.  
13.3 Reporting Procedures 
13.3.1 General 
All adverse events will be captured on the appropriate study-specific case report forms (CRFs).  
13.3.2 Serious Adverse Events 
13.3.2.1 General  
All serious adverse events, regardless of causality to study drug, will be reported to the Principal 
Investigator and/or the Study Coordinator at each institution, and also to the Coordinating Center. 
 
All serious adverse events must be reported to the Coordinating Center within 1 business day after 
the investigator becomes aware of the event. Events should be reported using a MedWatch form 
(3500) as available on the FDA website (see link below).  
 
Follow-up information must also be reported within 1 business day of receipt of the information 
by the investigator. 
 
The Coordinating Center will disseminate information regarding serious adverse events to the 
participating sites within 5 days of review of the information by the Protocol Chair (or her designee 
in the event of extended absence) only in the case that the event(s) is believed to be related (i.e., 
possibly, probably, or definitely) related to the study medication. The Coordinating Center will be 
responsible for reporting of events to the FDA and supporters, as appropriate (outlined below). 
13.3.2.2 Pregnancy 
If a female subject becomes pregnant while receiving investigational therapy, the pregnancy must 
also be reported in the same time frame as a serious adverse event. In addition, any occurrence of 
pregnancy within 6 months after the last dose of investigational drug must also be reported. 
Follow-up to obtain the outcome of the pregnancy should also occur. Abortion, whether accidental, 
therapeutic, or spontaneous, should additionally always be classified as serious, and expeditiously 


 
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reported.  
13.3.3 Institutional Review Board 
All adverse events and serious adverse events will be reported to the IRB per current institutional 
standards. If an adverse event requires modification of the informed consent, these modifications 
will be provided to the IRB with the report of the adverse event. If an adverse event requires 
modification to the study protocol, these modifications will be provided to the IRB as soon as is 
possible. 
13.3.4 Food and Drug Administration (FDA) 
In this trial, unexpected adverse events believed to be definitely, probably, or possibly related to 
the medications will be reported to the Food and Drug Administration via MedWatch (using the 
online form available at https://www.accessdata.fda.gov/scripts/medwatch/; by telephone 1-800-
FDA-1088; 
or 
by 
fax 
1-800-FDA-0178 
using 
form 
available 
at 
http://www.fda.gov/medwatch/report/hcp.htm). The Coordinating Center will be responsible for 
correspondence regarding adverse events with the FDA for all participating sites. 
13.3.5 Rigel Pharmaceuticals, Inc.   
All adverse events and serious adverse events will be reported to Rigel Pharmaceuticals, Inc., as 
required.  
 
 
 


 
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14. DATA AND SAFETY MONITORING 
14.1 Data Management 
All information will be collected on study-specific case report forms by the study staff at each 
institution. The necessary forms will be provided to each site by the Coordinating Center.  
 
The completed forms will be forwarded to the Coordinating Center for central review and inclusion 
in the study dataset with relevant source documentation as outlined in the case report forms. The 
data submission schedule is as follows: 
 
At the time of registration:  
- 
Registration Form 
- 
Informed Consent Form (signed by the subject) 
- 
Eligibility Checklist 
- 
Source documents related to eligibility and registration 
 
Within 2 weeks after registration: 
- 
Baseline study case report forms 
- 
Pertinent source documents 
 
Within 2 weeks after completion of each cycle: 
- 
On study case report forms by cycle 
- 
Pertinent source documents 
 
Within 2 weeks after 30 day follow-up: 
- 
On study case report forms 
- 
Pertinent source documents 
 
Every 3-6 months during follow-up: 
- 
Follow-up case report forms 
- 
Pertinent source documents (if necessary) 
 
All study data will be reviewed for completeness and accuracy by the Protocol Chair. The Principal 
Investigator (or his/her designee) at each respective institution is responsible for review, and 
ensuring the completeness and accuracy, of the data generated by his/her institution. The study 
data will also be periodically reviewed by the Sidney Kimmel Comprehensive Cancer Center 
Clinical Research Office. 
14.2 Meetings 
Scheduled meetings will take place as needed with the medical oncology co-investigators and The 
Coordinating Center will schedule teleconferences to take place approximately every three (3) 
months, or more frequently depending on the rate of accrual, and will include the Protocol Chair 


 
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and Principal Investigators from each site. The following study team members involved with the 
conduct of the trial will be included as appropriate: study coordinators, data managers, research 
nurses, sub-investigators, collaborators (if applicable), and statistician. 
 
During these meetings matters related to the following will be discussed: enrollment rate relative 
to expectation, characteristics of subjects, retention of subjects, adherence to protocol (potential or 
real protocol violations), validity and integrity of the data, shipment of research/blood samples, 
and progress of data for objectives. 
 
A summary of the items discussed at each teleconference will be prepared by the Coordinating 
Center and forwarded to each participating site.  
14.3 Monitoring and Auditing 
This study is being reviewed by the United States Food and Drug Administration (FDA) and will 
require an IND; sponsored by a Johns Hopkins investigator (Dr. Stephanie Gaillard).   
 
This study will be monitored per the SKCCC Data Safety Monitoring Plan with monitoring 
completed by the SKCCC Clinical Research Office Quality Assurance (CRO QA) group.    The 
study conduct will additionally be reviewed at least annually by the SKCCC’s Clinical Research 
Review Committee (CRC) and Data and Safety Monitoring Committee (DSMC); with continual 
oversight by the Johns Hopkins Medicine Institutional Review Board (JHM-IRB). 
 
As above, all data will be sent to the Coordinating Center for central collation and review. There 
are no formal on-site evaluations planned by the Coordinating Center; however, these may occur 
depending on site accrual rate, identified problems or concerns, or other reasons, as appropriate. 
 
 
 


 
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15. ADMINISTRATIVE PROCEDURES 
15.1 Protocol Amendments 
Any changes to the protocol or consent document will be made in the form of an amendment and 
must be approved by the IRB before implementation. Any modifications to the protocol or consent 
will also be reviewed and approved by sponsoring agencies, as required. Amendments will be 
distributed by the coordinating center of the lead institution (Johns Hopkins) to all affiliate sites 
upon approval by the Johns Hopkins IRB. 
15.2 Informed Consent 
An investigator will explain to each subject the nature of the study, its purpose, procedures 
involved, expected duration, potential risks and benefits. Each subject will be informed that 
participation in the study is voluntary and that she may withdraw from the study at any time, and 
that withdrawal of consent will not affect her subsequent medical treatment. This informed consent 
will be given by means of a standard written statement and will be submitted for IRB approval 
prior to use. No patient will enter the study before her informed consent has been obtained. In 
accordance with the Health Insurance Portability and Accountability Act (HIPAA), the written 
informed consent document (or a separate document to be given in conjunction with the consent 
document) will include a subject authorization to release medical information to the study sponsor 
and supporting agencies and/or allow these bodies, a regulatory authority, or Institutional Review 
Board access to subjects’ medical information that includes all hospital records relevant to the 
study, including subjects’ medical history. 
15.3 Ethics and Good Clinical Practice 
This study must be carried out in compliance with the protocol and Good Clinical Practice, as 
described in: 
 
1. ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996. 
2. US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 
and 56 concerning informed consent and IRB regulations). 
3. Declaration of Helsinki, concerning medical research in humans (Recommendations 
Guiding Physicians in Biomedical Research Involving Human Subjects, Helsinki 1964, 
amended Tokyo 1975, Venice 1983, Hong Kong 1989, Somerset West 1996). 
 
The investigator agrees to adhere to the instructions and procedures described in it and thereby to 
adhere to the principles of Good Clinical Practice that it conforms to. 
15.4 Regulatory Authorities 
15.4.1 Institutional Review Board 
Information regarding study conduct and progress will be reported to the Institutional Review 
Board (IRB) per the current institutional standards of each participating center. 
15.4.1.1 JHM Single IRB 


 
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Johns Hopkins Medicine is serving as the single IRB for this study. It is the preference of Johns 
Hopkins Medicine IRB to use the SMART IRB reliance agreement as the basis of reliance. The 
SMART IRB master reliance agreement was created in 2016 to harmonize and streamline the 
IRB review process for multisite studies. It enables reliance on a study-by-study basis, clearly 
defines roles and responsibilities of relying institutions and reviewing IRBs, and eliminates the 
need to sign reliance agreements for each study [e.g., a non-SMART IRB agreement]. 900+ 
institutions have already signed onto this agreement and are actively using it as the basis of 
reliance for multisite projects. Sites that will rely on JHM IRB are still responsible for 
conducting a local context review prior to the start of research at their site and for following any 
local and institutionally required policies as it applies to research at their site [e.g., reporting of 
unanticipated problems]. 
15.4.2 Food and Drug Administration (FDA) 
This trial does not involve an Investigational New Drug (IND) application and no reporting is 
required with regards to the clinical trial outlined at this time.  
 


 
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16. COORDINATING CENTER & SITE RESPONSIBILITIES 
16.1 Protocol Chair 
The Protocol Chair is responsible for performing the following tasks: 
 
 
Coordinating, developing, submitting, and obtaining approval for the protocol as well as 
its subsequent amendments. 
 
Assuring that all participating institutions are using the correct version of the protocol. 
 
Taking responsibility for the overall conduct of the study at all participating institutions 
and for monitoring the progress of the study. 
 
Reviewing and ensuring reporting of Serious Adverse Events (SAE). 
 
Reviewing data from all sites. 
16.2 Coordinating Center 
The Coordinating Center is responsible for performing the following tasks: 
 
 
Ensuring that IRB approval has been obtained at each participating site prior to the first 
patient registration at that site, and maintaining copies of IRB approvals from each site. 
 
Managing central patient registration. 
 
Collecting and compiling data from each site. 
 
Establishing procedures for documentation, reporting, and submitting of AE’s and SAE’s 
to the Protocol Chair, and all applicable parties. 
 
Facilitating audits by securing selected source documents and research records from 
participating sites for audit, or by auditing at participating sites. 
16.3 Participating Sites 
Participating sites are responsible for performing the following tasks: 
 
 
Following the protocol as written, and the guidelines of Good Clinical Practice (GCP). 
 
Submitting data to the Coordinating Center. 
 
Registering all patients with the Coordinating Center by submitting patient registration 
form, and signed informed consent promptly. 
 
Providing sufficient experienced clinical and administrative staff and adequate facilities 
and equipment to conduct a collaborative trial according to the protocol. 
 
Maintaining regulatory binders on site and providing copies of all required documents to 
the Coordinating Center. 
 
Collecting and submitting data according to the schedule specified by the protocol. 
 
Additional information for participating sites: 
16.3.1 Staffing 
The participating sites will provide experienced staff, and adequate equipment and facilities to 
support this clinical trial. The participating sites will also be responsible for research staff training 
in computer applications, human subjects research, and HIPAA compliance, as well as the 


 
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continuing education in these areas as required by local institutional standards. 
16.3.2 Documentation 
Each participating site is responsible for submitting copies of all relevant regulatory 
documentation to the Coordinating Center. The required documents include, but are not limited to 
the following: local IRB approvals (i.e., protocol, consent form, amendments, participant 
brochures and recruitment material, etc.), IRB membership rosters, summary of unanticipated 
problems or protocol deviations, and documentation of expertise of the investigators. The 
Coordinating Center will provide each participating site with a comprehensive list of the necessary 
documents. It is the responsibility of the participating sites to maintain copies of all documentation 
submitted to the Coordinating Center. 
 
The requirements for data management, submissions, and monitoring are outlined below. 
16.3.3 Confidentiality 
All unpublished information that the Coordinating Center gives to the investigator shall be kept 
confidential and shall not be published or disclosed to a third party without the prior written 
consent of the Protocol Chair (or her designee). 
16.3.4 Record Retention 
Following closure of the study, each participating center will maintain a copy of all site study 
records in a safe and secure location. The Coordinating Center will inform the investigator at each 
site at such time that the records may be destroyed. 
16.3.5 Publication 
It is understood that any manuscript or releases resulting from the collaborative research will be 
circulated to all participating sites prior to submission for publication or presentation. The Protocol 
Chair will be the final arbiter of the manuscript content. 
16.3.6 Additional Information 
Each participating site is responsible for submitting additional information as requested by the 
Protocol Chair (or her designee). The Coordinating Center may terminate the study at a 
participating site in the event that these conditions are not followed. 
 
 


 
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17. STATISTICAL CONSIDERATIONS 
17.1 Study Design and Endpoints 
This is a phase I, open-label, 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. The dose-escalation part of the study will enroll a maximum of 18 subjects who 
will be administered a combination of fostamatinib and paclitaxel. Three dose levels of 
fostamatinib have been identified with a fixed dosage of paclitaxel (Section 7.1). Dose escalation 
will follow a modified toxicity probability interval (mTPI) design(29, 30). This design uses a 
Bayesian statistical framework with a beta-binomial model to guide dose escalation to the highest 
dose level for which the risk of dose-limiting toxicity (DLT) lies within an acceptable range.  The 
range is effectively a window around a pre-specified target risk.  The decision rule for dose 
escalation leads to escalation if the probability is high that the current dose level is below the 
acceptable range.  If the study data suggest that the risk of DLT with the current dose is above the 
acceptable range, the rule calls for de-escalation.  If the data suggest that the current dose’s risk of 
DLT is most likely in the acceptable range, the rule calls for staying at this dose.  The probability 
a dose level’s risk of DLT is in each of the three intervals is updated as information from treated 
patients accrues.  Essentially, the Bayesian calculations compute the posterior probabilities that 
the risk of DLT lies in each of three intervals, and the procedure leads to choosing the dose level 
with the highest probability of having a risk of DLT near the target.  Effectively, the chosen dose 
level (MTD) will also have the highest probability of having a risk of DLT in the acceptable region. 
Depending on the number of patients needed to identify the MTD (see Section 17.1.5), an 
expansion cohort of patients will be enrolled to receive weekly paclitaxel in combination with 
fostamatinib at the MTD to ensure the safety of the combination and to further explore clinical and 
biological effects of the therapy. 
 
17.1.1 Primary Endpoint 
Definition of the dose limiting toxicities of the combination of fostamatinib and weekly 
paclitaxel graded based on CTCAE 4.03 and determination of the MTD of fostamatinib when 
administered in combination with paclitaxel. The risk and severity of toxicities of the 
combination will be recorded. 
 
17.1.2 Secondary Endpoints 
 The objective response rate in the study population treated with the combination of 
fostamatinib and paclitaxel. 
 The progression-free survival in the study population treated with the combination of 
fostamatinib and paclitaxel. 
 The pharmacokinetic (PK) profile of fostamatinib when combined with weekly 
paclitaxel 
 
17.1.3 Exploratory Endpoints 
 Pharmacodynamic and predictive biomarkers of response from subject blood and tumor 
samples. 
 


 
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17.1.4 Dose Escalation 
Given the mTPI design, dose-escalation decisions will be made based on the three dosing intervals, 
where the underdosing interval corresponds to dose escalation (E), overdosing interval 
corresponds to dose de-escalation (D), and proper dosing corresponds to staying at the current dose 
(S). For this study, we consider  
 
1) cohorts of size 3, 
2) dose escalation starts at dose-level 1 (DL1),  
3) the target DLT risk is 30%,  
4) an associated range of DLT risks believed to be acceptable (essentially equivalent to the 
target of 30%) is 25-35% (i.e., target DLT risk ± 5%) and,  
5) a dose would be excluded if the posterior probability of risk of DLT being larger than 30% 
is 95% or higher; 
6) the maximum number of patients in the dose-escalation part is 18.  
 
The associated dose-escalation decisions are presented below.  
 
No. of patients 
experiencing a DLT 
No. of Patients Treated at Current Dose Level 
3
6
9
12
15
18
0
E 
E 
E 
E 
E 
E 
1
S 
E 
E 
E 
E 
E 
2
D 
S 
S 
E 
E 
E 
3
DU 
S 
S 
S 
S 
E 
4
DU 
S 
S 
S 
S 
5
DU 
DU 
S 
S 
S 
6
DU 
DU 
D 
S 
S 
7
DU 
DU 
S 
S 
8
DU 
DU 
DU 
S 
9
DU 
DU 
DU 
DU 
Dose-escalation decision rules based on the mTPI design with a cohort size of 3 for a maximum sample size of 18 
patients and target DLT risk of 30%. E = Escalate to the next higher dose; S = Stay at the current dose; D = De-
escalate to the next lower dose; DU = De-escalate and the current dose is unacceptably toxic; DLT = dose limiting 
toxicity 
 
For illustration, suppose a cohort of 3 patients are at the current dose.  
 
 If 0 of 3 patients have a DLT, the decision is E (= escalate to the next dose);  
 if 1 of 3 patients has a DLT, the decision is S (= stay at the current dose level with an 
additional 3 patients);  
 if 2 of 3 patients have a DLT, the decision is D (= de-escalate to the next lower dose (or 
DL-1 if the current dose is DL1);  
 if 3 of 3 patients experience a DLT, the decision is DU (= de-escalate to the next lower 
dose and never return to the current dose as it has been deemed unacceptably toxic).  
 
The trial will terminate when the lowest dose is above the MTD, the last dose is much lower than 
the MTD or a pre-specified maximum sample size is reached. If the MTD is established as one of 
the 3 dose levels, a minimum of 6 patients will be treated at the MTD. The table below presents 


 
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the operating characteristics of the proposed design for this trial under different scenarios of 
hypothetical risks of DLT based on 2000 simulations. 
 
Operating Characteristics of the Design 
Target DLT Risk = 0.30 
Dose 
Avg. Fraction 
Experiencing a DLT 
Avg. Total 
Sample Size 
1
2
3
None
Scenario 1 
0.202
16.4
True DLT risk
0.05
0.15
0.35
Selection probability
0.015
0.349
0.380
0.257
Avg. # of patients treated
3.9
6.5
6.0
Scenario 2 
0.269
17.5
True DLT risk
0.10
0.30
0.50
Selection probability
0.152
0.640
0.141
0.0675
Avg. # of patients treated
5.8
8.7
3.0
Scenario 3 
0.238
17.1
True DLT risk
0.10
0.25
0.40
Selection probability
0.097
0.537
0.228
0.139
Avg. # of patients treated
5.4
7.9
3.9
Scenario 4 
0.110
13.5
True DLT risk
0.05
0.10
0.15
Selection probability
0.008
0.099
0.186
0.707
Avg. # of patients treated
3.7
4.7
5.0
Scenario 5 
True DLT risk
0.01
0.20
0.35
0.211
16.4
Selection probability
0.004
0.439
0.323
0.234
Avg. # of patients treated
3.5
7.4
5.5
 
17.1.5 Expansion Cohort 
An expansion cohort will be enrolled only if the MTD is established as one of the 3 dose levels. 
The sample size of the expansion cohort is planned to be up to 15. A maximum of 18 patients may 
be treated at the MTD. Monitoring the safety of fostamatinib at the MTD in combination with 
weekly paclitaxel will continue with this expansion cohort (see table above regarding dose decision 
making) to ensure that the DLT risk of the combination therapy does not convincingly exceed 
30%. Clinical activity and correlative outcomes will also be explored.  
 
17.2 Sample Size/Accrual Rate 
 
17.2.1 Summary 
The accrual rate for this study is expected to be 1-2 patient per month. The study will enroll up to 
18 patients who will be administered the combination of fostamatinib and paclitaxel. The 
maximum sample size in the dose-escalation part of the study is expected to be up to 18 patients. 
Once the MTD is established, accrual may continue as a dose expansion at this dose with the 
objective of studying additional patients at the MTD as long as the total study accrual does not 
exceed 30.  
 
17.2.2 Early Stopping Guidelines for Safety in an Expansion Cohort 
For dose expansion at the MTD to a maximum of accrual of 18, toxicity will be monitored 
continually in the expansion cohort. If the risk of DLT convincingly exceeds 35%, the upper bound 


 
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of the acceptable risk range, we will temporarily halt the study pending dose modification. 
Specifically, a Bayesian toxicity monitoring rule will suggest suspending enrollment to the 
expansion cohort if the posterior probability of risk being larger than 0.35 is 70% or higher. The 
prior for this monitoring rule is beta (1.5, 3.5), representing the risk of DLT has mean of 30%, 
which falls in the acceptable risk range, and there is 90% probability that this risk is between 4.6% 
and 65%. The stopping rules for safety and the operating characteristics under different scenarios 
of hypothetical actual sample sizes based on 5000 simulations are as below. 
 
No. patients 
experiencing a DLT
4 
5 
6 
7 
8 
Out of 
7
8-10
11-13
14-15
16-18
 
Actual sample 
size
True risk of 
DLT
Prob. declaring 
regimen too toxic
Avg. sample size 
12
0.25
10.8%
11.6
0.30
19.7%
11.2
0.35
31.1%
10.8
0.40
43.4%
10.3
0.45
58.5%
9.7
0.50
70.8%
9.1
15
0.25
13.4%
14.2
0.30
23.6%
13.6
0.35
36.5%
12.8
0.40
52.9%
11.8
0.45
66.8%
10.8
0.50
79.5%
9.9
18
0.25
14.6%
16.8
0.30
26.2%
15.8
0.35
41.2%
14.6
0.40
56.8%
13.3
0.45
72.1%
11.8
0.50
84.4%
10.5
 
17.3 Analysis of Objectives 
 
17.3.1 Analysis of Primary Objective  
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. The proportion of dose limiting 
toxicities at each dose level will be reported with exact binomial proportions and 95% confidence 
intervals. All toxicities will be reported by type and grade using NCI CTCAE version 4.03. 
 
17.3.2 Analysis of Secondary Objectives  
Objective response rate will be estimated with an exact 95% confidence interval. Progression-free 
survival (PFS) will be described by the method of Kaplan and Meier. Median PFS will be estimated 


 
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along with its 95% confidence interval. Descriptive statistics will be used to summarize 
pharmacokinetic marker profile. 
 
17.3.3 Analysis of Exploratory Objectives  
Immunostaining intensities of SYK, p-SYK, and other substrate markers from biopsy samples 
before and after fostamatinib and paclitaxel treatment will be compared using paired t-tests after 
proper data transformation. Linear dose-response modeling will be performed using a mixed 
effects model for change in immunostaining intensity using dose as a continuous explanatory 
variable with biopsy time, dose, and time-by-dose interaction as fixed effects.  
 
PDX mice will be randomized into 4 groups and treated with either vehicle, R406, paclitaxel, or 
R406 + paclitaxel according to previously published protocol (31). Tumor size and percent Tumor 
Growth Inhibition (%TGI) in response to treatment will be reported as a mean ± SE. ANOVA will 
be used to compare %TGI among four groups. If the null hypothesis of no difference is rejected at 
significance level alpha=0.05, pairwise comparison will be conducted to identify different pairs. 
Mean differences will be estimated along with 95% CI, and response rates will be reported along 
with their respective confidence intervals. Using growth inhibition of more than 60% as definitive 
response, a secondary analysis will use logistic regression to evaluate differences in definitive 
response rates between treatment groups. P-values < 0.05 will be considered statistically 
significant. Both continuous (%TGI) and binary (%TGI >60%) measures will be used as response 
variables in linear and logistic regression models, and covariates will include phosphorylation 
levels of expressions from SYK, pSYK, and candidate substrates, clinical and pathological features 
of the tumors from which the xenografts were derived. For each PDX model, the target effect size 
is f=1.35 which was observed from over 67% of preliminary cell line essays. To control false 
discovery rate of 10%, we need n=6 mice/group to reach 80% power to detect difference between 
combination therapy and single agent. This sample size also gives over 90% power to reject the 
null hypothesis in ANOVA at a two-sided significance level of 0.05. 
 
17.4 Reporting and Exclusions 
17.4.1 Evaluable for Toxicity 
All subjects will be evaluable for toxicity from the time of their first dose of fostamatinib.   
17.4.2 Evaluable for Objective Response 
Only those subjects who have measurable disease present at baseline, have received at least one 
cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response.  
These subjects will have their response classified according to the definitions stated below.   
 
NOTE:  Subjects who exhibit objective disease progression prior to the end of cycle 1 will also be 
considered evaluable. 
17.4.3 Evaluable for Non-Target Disease Response 
Patients who have lesions present at baseline that are evaluable but do not meet the definitions of 
measurable disease, have received at least one cycle of therapy, and have had their disease re-


 
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evaluated will be considered evaluable for non-target disease.  The response assessment is based 
on the presence, absence, or unequivocal progression of the lesions. 
 


 
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REFERENCES 
 
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15. 
Gynecologic Oncology G, Markman M, Blessing J, Rubin SC, Connor J, Hanjani P, et al. 
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Xue L, Wang WH, Iliuk A, Hu L, Galan JA, Yu S, et al. Sensitive kinase assay linked 
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25. 
Nakashima H, Natsugoe S, Ishigami S, Okumura H, Matsumoto M, Hokita S, et al. 
Clinical significance of nuclear expression of spleen tyrosine kinase (Syk) in gastric cancer. 
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26. 
Luangdilok S, Box C, Patterson L, Court W, Harrington K, Pitkin L, et al. Syk tyrosine 
kinase is linked to cell motility and progression in squamous cell carcinomas of the head and 
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27. 
Uckun FM, Ek RO, Jan ST, Chen CL, Qazi S. Targeting SYK kinase-dependent anti-
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Coopman PJ, Do MT, Barth M, Bowden ET, Hayes AJ, Basyuk E, et al. The Syk tyrosine 
kinase suppresses malignant growth of human breast cancer cells. Nature. 2000;406(6797):742-
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29. 
Ji Y, Liu P, Li Y, Bekele BN. A modified toxicity probability interval method for dose-
finding trials. Clinical trials (London, England). 2010;7(6):653-63. 
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Ji Y, Wang SJ. Modified toxicity probability interval design: a safer and more reliable 
method than the 3 + 3 design for practical phase I trials. Journal of clinical oncology : official 
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31. 
Yu Y, Gaillard S, Phillip JM, Huang TC, Pinto SM, Tessarollo NG, et al. Inhibition of 
Spleen Tyrosine Kinase Potentiates Paclitaxel-Induced Cytotoxicity in Ovarian Cancer Cells by 
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32. 
Temple, R.  Hy’s law: predicting serious hepatotoxicity. Pharmacoepidemiology and Drug 
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33. Reuben, A.  Hy’s Law.  Hepatology 39(2):574-8 (2004). 
 
 
 
 
APPENDICES 
 
A 
Performance Status Scale 
B 
Information on Possible Drug Interactions 
C 
Study Drug Diary – Fostamatinib 
 


 
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APPENDIX A:  PERFORMANCE STATUS SCALE 
 
 ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade
Descriptions
Percent
Description
0 
Normal activity.  Fully active, able 
to 
carry 
on 
all 
pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease.
90 
Able to carry on normal activity; 
minor signs or symptoms of disease.
1 
Symptoms, 
but 
ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or 
sedentary 
nature 
(e.g., 
light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work.
2 
In 
bed 
<50% 
of 
the 
time.  
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities.  Up and about more 
than 50% of waking hours.
60 
Requires occasional assistance, but is 
able to care for most of his/her needs.
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance.
30 
Severely disabled, hospitalization 
indicated.  Death not imminent.
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any self-
care.  Totally confined to bed or 
chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent.
10 
Moribund, 
fatal 
processes 
progressing rapidly.
5
Dead.
0
Dead.
 
 
 


 
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APPENDIX B:  INFORMATION ON POSSIBLE DRUG INTERACTIONS  
Information on Possible Interactions with Other Agents for Patients and Their Caregivers 
and Non-Study Healthcare Team 
 
Fostamatinib interacts with many drugs that are processed by your liver.  Because of this, it is very 
important to tell your study doctors about all of your medicine before you start this study.  It is 
also very important to tell them if you stop taking any regular medicine, or if you start taking a 
new medicine while you take part in this study.  When you talk about your medicine with your 
study doctor, include medicine you buy without a prescription at the drug store (over-the-counter 
remedy), or herbal supplements such as St. John’s wort.  
 
Many health care prescribers can write prescriptions.  You must also tell your other prescribers 
(doctors, physicians’ assistants or nurse practitioners) that you are taking part in a clinical trial. 
Bring this paper with you and keep the attached information card in your wallet.  These are 
the things that you and they need to know:  
 
Fostamatinib interacts with (a) certain specific enzyme(s) in your liver.  
 The enzyme(s) in question is CYP3A4 which is an enzyme that metabolizes drugs in order 
to be cleared from your system.  
 Fostamatinib must be used very carefully with other medicines that need these liver 
enzymes to be effective or to be cleared from your system.  
 You and healthcare providers who prescribe drugs for you must be careful about adding or 
removing any drug in this category.  
 Before you start the study, your study doctor will work with your regular prescriber to 
switch any medicines that are considered “strong inducers/inhibitors or substrates of 
CYP3A4.” 
 Your 
prescribers 
should 
look 
at 
this 
web 
site 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx or consult a medical reference to see 
if any medicine they want to prescribe is on a list of drugs to avoid.   
 Please be very careful!  Over-the-counter drugs have a brand name on the label—it’s 
usually big and catches your eye.  They also have a generic name—it’s usually small and 
located above or below the brand name, and printed in the ingredient list.  Find the generic 
name and determine, with the pharmacist’s help, whether there could be an adverse 
interaction.   
 Be careful: 
o If you take acetaminophen regularly:  You should not take more than 4 grams a day 
if you are an adult or 2.4 grams a day if you are older than 65 years of age.  Read 
labels carefully!  Acetaminophen is an ingredient in many medicines for pain, flu, 
and cold. 
o If you drink grapefruit juice or eat grapefruit:  Avoid these until the study is over.  
o If you take herbal medicine regularly:  You should not take St. John’s wort while 
you are taking Fostamatinib. 
o Other medications or foods that should not be taken while on this study include: 
 


 
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CYP3A4 Inhibitors
CYP3A4 Inducers
Amiodarone 
Erythromycin  
Isoniazid  
Norfloxacin 
Troleandomycin 
Chloramphenicol 
Fluconazole 
Itraconazole  
Norfluoxetine  
Verapamil 
Cimetidine  
Fluvoxaimine  
Ketoconazole  
Ritonavir 
Ciprofloxacin  
Grapefruit Juice  
Mifepristone  
Rotonavir 
Clarithromycin  
Imatinib  
Nefazodone  
Seville Oranges 
Diltiazem  
Indinavir  
Nelfinavir  
Star Fruit
Barbiturates  
Efavirenz  
Nevaripine  
Pioglitazone  
Rifampin 
Carbamazepine  
Modafinil  
Phenytoin  
Rifabutin  
St. John’s Wort 
 
Other medicines can be a problem with your study drugs.  
 
 You should check with your doctor or pharmacist whenever you need to use 
an over-the-counter medicine or herbal supplement.  
 
 Your regular prescriber should check a medical reference or call your study 
doctor before prescribing any new medicine for you.  Your study doctor’s 
name is  
 
 
_____________________________________  
 
and he or she can be contacted at  
 
_____________________________________ 
 
 


 
Phase I Fostamatinib and Paclitaxel in Ovarian Cancer 
Protocol Chair:  Stephanie Gaillard, M.D., Ph.D. 
 
 
 
 
 
 
 
 
Version:  April 27, 2022 (v 6.3) 
 
Page 63 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
INFORMATION ON POSSIBLE DRUG INTERACTIONS  
You are enrolled on a clinical trial using the experimental agent 
Fostamatinib.  Fostamatinib interacts with drugs that are processed 
by your liver.  Because of this, it is very important to: 
 Tell your doctors if you stop taking regular medicine or if you start 
taking a new medicine. 
 Tell all of your prescribers (doctor, physicians’ assistant, nurse 
practitioner, pharmacist) that you are taking part in a clinical trial. 
 Check with your doctor or pharmacist whenever you need to use 
an over-the-counter medicine or herbal supplement. 
 
Fostamatinib interacts with a specific liver enzyme called CYP3A4, 
and must be used very carefully with other medicines that interact 
with this enzyme.  
 Before you start the study, your study doctor will work with your 
regular prescriber to switch any medicines that are considered 
“strong inducers/inhibitors or substrates of CYP3A4.” 
 Before prescribing new medicines, your regular prescribers should 
go to http://medicine.iupui.edu/clinpharm/ddis/table.aspx for a 
list of drugs to avoid, or contact your study doctor.   
 Your study doctor’s name is _____________________________ 
and can be contacted at _________________________________.  


 
Phase I Fostamatinib and Paclitaxel in Ovarian Cancer 
Protocol Chair:  Stephanie Gaillard, M.D., Ph.D. 
 
 
 
 
 
 
 
 
Version:  April 27, 2022 (v 6.3) 
 
Page 64 
APPENDIX C:  STUDY DRUG DIARY – FOSTAMATINIB 
This is a medication diary on which you are to record the number of fostamatinib tablet(s) you 
take each day. The instructions on how to take the fostamatinib are below. 
 
Use the calendar to record date, time and number of tablet(s) taken each day. You will start taking 
____ tablets of fostamatinib twice a day for 28 days. (It is possible your doctor may reduce the 
amount of fostamatinib you take while participating in this study. Your doctor will discuss the new 
treatment plan with you at that time.) A 28-day period of time is called a cycle. These cycles will 
be repeated as long as your tumor is not growing and you are not experiencing any unacceptable 
side effects. Each medication diary sheet should last you 4 weeks (one cycle). Medication should 
be taken as instructed without skipping any days. If you have missed a dose please mark “0” in the 
slot for that dose. If your doctor changes the amount of fostamatinib you take, please be sure to 
write down the correct number of pills and correct amount taken in the columns below. 
 
How to take Fostamatinib: 
Tablet(s) should be taken twice daily at approximately the same time each day.  Tablets should be 
taken with approximately 1 cup (240mL) of water. Tablets should be swallowed whole and should 
not be crushed or broken.  
 
What to do if you forget a dose: 
If you forget to take a dose of fostamatinib, you can take the missed dose within four hours of the 
scheduled dose. If it is more than four hours from the time you were scheduled to take that dose, 
you should wait until the next day to take the next dose.  You should not take two doses at one 
time to make up for a missed dose.  If you vomit after taking a fostamatinib dose, you should not 
to retake the dose, but should instead resume dosing at the next scheduled dose.  If vomiting 
persists, please contact the study physician or research nurse. 
 
If you develop any side effects, please write side effects the day they occurred and anything else 
you would like to tell the doctor in the comments section. 
 
Please note: You must not take Grapefruit juice or St. John’s Wort while on this study. 
 
Bring any unused tablets, empty medication containers, and your completed diary to your next 
appointment.  
 
 
Note to staff: Please give patient a medication diary at initial enrollment and at the start of every cycle. Instruct patient 
how to complete the medication diary. If they are taking the first pill at a visit complete the log with them. Remind 
them they must bring the log back at each visit along with pill bottles even if empty.  
 


 
Phase I Fostamatinib and Paclitaxel in Ovarian Cancer 
Protocol Chair:  Stephanie Gaillard, M.D., Ph.D. 
 
 
 
 
 
 
 
 
Version:  April 27, 2022 (v 6.3) 
 
Page 65 
Medication Diary – Fostamatinib 
 
Participant Initials: ______ Study ID: _________ Cycle Number: ____ Day 1 Date: __________ 
 
Dose/Number of tablets to take at each dose:  _________________________________________  
 
 
INSTRUCTIONS: 
1. Complete one form per cycle of therapy. 
2. Record the date, the number of tablets of you took, and when you took them. 
3. Please record comments or side effects in the Comments section. 
4. Please return the forms to your physician/research nurse prior to the next cycle of therapy. 
 
Day 
Date 
Time of AM dose 
# of tablets 
Time of PM dose 
# of tablets 
Comments 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
 
6 
 
 
 
 
 
 
7 
 
 
 
 
 
 
8 
 
 
 
 
 
 
9 
 
 
 
 
 
 
10 
 
 
 
 
 
 
11 
 
 
 
 
 
 
12 
 
 
 
 
 
 
13 
 
 
 
 
 
 
14 
 
 
 
 
 
 
15 
 
 
 
 
 
 
16 
 
 
 
 
 
 
17 
 
 
 
 
 
 
18 
 
 
 
 
 
 
19 
 
 
 
 
 
 
20 
 
 
 
 
 
 
21 
 
 
 
 
 
 
22 
 
 
 
 
 
 
23 
 
 
 
 
 
 
24 
 
 
 
 
 
 
25 
 
 
 
 
 
 
26 
 
 
 
 
 
 
27 
 
 
 
 
 
 
28 
 
 
 
 
 
 
 
Reviewed by:  ____________________________________    Date:  __________________