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A Broad Multi-Histology Phase II Study of the Multi-Kinase Inhibitor R935788 (Fostamatinib Disodium) in Advanced Colorectal, Non-Small Cell Lung, Head and Neck, Hepatocellular and Renal Cell Carcinomas and Pheochromocytoma and Thyroid Tumors

Phase 2
18 Years
Not Enrolling
Head and Neck Neoplasms, Pheochromocytoma, Colorectal Neoplasms, Carcinoma, Non-Small-Cell Lung, Carcinoma, Renal Cell

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Trial Information

A Broad Multi-Histology Phase II Study of the Multi-Kinase Inhibitor R935788 (Fostamatinib Disodium) in Advanced Colorectal, Non-Small Cell Lung, Head and Neck, Hepatocellular and Renal Cell Carcinomas and Pheochromocytoma and Thyroid Tumors


- R935788 (fostamatanib disodium) is a kinase inhibitor with activity in vitro against
several kinases known to be mutated or aberrantly expressed in malignant cells.

- Anticancer drugs that target multiple kinases are of particular interest because tumors
may rely on several different kinase pathways for survival.

- R935788 has shown promising activity in the NCI 60-cell line panel against colon
cancer, non-small cell lung cancer, and renal cell carcinoma cell lines, as well as in
two renal cell xenograft models. R935788 is orally absorbed in tumor-bearing mice at
concentrations that achieve antitumor activity and are not associated with observable

- Phase I studies in patients with immune thrombocytopenic purpura, rheumatoid arthritis
and lymphoma have demonstrated safety with a continuous dosing schedule, and a maximum
tolerated dose (MTD) has been established.


- To determine the clinical response of R935788 administered orally twice a day on a
continuous schedule in patients with colorectal carcinoma, pheochromocytoma,
follicular, medullary, or papillary thyroid cancer, non-small cell lung cancer,
hepatocellular carcinoma, carcinoma of the head and neck, and renal cell carcinoma.

- To evaluate the safety of R935788 in patients with various solid tumors.

- To determine the effects of R935788 on circulating tumor cells, circulating endothelial
cells and levels of phosphorylated AKT and extracellular-signal regulated kinase (ERK)
in tumor samples.

- To evaluate the biochemical response to R935788 therapy in patients with thyroid
malignancies and pheochromocytoma.


- Patients with histologically documented pheochromocytoma, follicular, medullary, or
papillary thyroid cancer, colorectal cancer, non-small cell lung carcinoma (excluding
squamous cell histology), hepatocellular carcinoma, carcinoma of the head and neck, as
well as renal cell carcinoma) whose disease has progressed after any therapy or who
have no acceptable standard treatment options.

- Radiation or chemotherapy is not permitted within 4 weeks prior to study enrollment.

- Patients must have recovered from toxicities of prior therapies to at least eligibility


-This is an open-label, Phase II study of R935788. Patients will receive R935788 orally
twice a day in 28-day cycles without interruption. Imaging studies will be obtained every 2
cycles. Following a limited dose escalation portion in each stratum, a two stage design will
be used, the initial stage of which will consist of 15 to 21 patients depending on tumor
type in each of 7 strata.

Inclusion Criteria


- 3.1.1 Subjects must have histologically documented solid tumors: pheochromocytoma,
follicular or papillary thyroid, colorectal, non-small cell lung (excluding squamous
cell histology), hepatocellular, head and neck or renal cell origin, whose disease
has progressed after any number of prior therapies or who have no acceptable standard
treatment options.

- Patients with follicular or papillary thyroid cancer will be eligible if they have
metastatic or unresectable, locally advanced disease which is refractory to, or not
suitable for, I therapy.

- Diagnosis of malignancy must be confirmed by the Laboratory of Pathology at the
Clinical Center, National Institutes of Health (NIH), prior to patient enrollment.

- 3.1.2 Patients must have measurable disease, defined as at least one lesion that can
be accurately measured in at least one dimension (longest diameter to be recorded) as
greater than or equal to 20 mm with conventional techniques or as greater than or
equal to 10 mm with spiral computed tomography (CT) scan.

- 3.1.3 Life expectancy of greater than 3 months.

- 3.1.4 Eastern Cooperative Oncology Group (ECOG) performance status less than or equal
to 2 (Karnofsky greater than or equal to 60%).

- 3.1.5 Subjects must have normal organ and marrow function as defined below:

- absolute neutrophil count greater than or equal to 1,500/mcL

- platelets greater than or equal to 100,000/mcL

- total bilirubin within less than or equal to 1.5 institutional upper limit of normal

- aspartate aminotransferase (AST) serum glutamic oxaloacetic
transaminase(SGOT),alanine aminotransferase (ALT)/serum glutamic pyruvic
transaminase(SGPT) less than or equal to 2.5 times ULN

- creatinine < 1.5 times ULN


- creatinine clearance greater than or equal to 60 mL/min/1.73 m^2 for patients with
creatinine levels greater than or equal to 1.5 times institutional upper limit of

- 3.1.6 The effects of R935788 on the developing human fetus are unknown. For this
reason, women of child-bearing potential and men must agree to use adequate
contraception (hormonal or barrier method of birth control or abstinence) prior to
study entry, for the duration of study participation, and for 1 month after
discontinuation of the study. Women of child bearing potential must have a negative
pregnancy test in order to be eligible. Should a participant or a participant's
partner become pregnant or suspect she is pregnant while participating in this study,
the participant should inform the Research Team immediately.

- 3.1.7 Ability to understand and the willingness to sign a written informed consent

- 3.1.8 Age greater than or equal to 18 years. Because no dosing or adverse event data
are currently available on the use of R935788 in patients < 18 years of age, children
are excluded from this study, but may be eligible for future pediatric Phase I

- 3.1.9 Patients with diagnosis of hypertension should have their blood pressure
adequately controlled by medical therapy (adequate control of hypertension for the
purposes of this trial is defined as systolic blood pressure < 150 mmHg or diastolic
pressure < 90 mmHg).

- 3.1.10 Patients with head and neck cancer who are unable to swallow and who are
gastrostomy tube (G-tube) dependent will have the tablets dissolved in water or
orange juice followed by a free water or orange juice flush.


- 3.2.1 Subjects who have had chemotherapy, biotherapy, or radiotherapy within 4 weeks
prior to entering the study, or those who have not recovered from adverse events due
to prior therapy.

- A time period of greater than or equal to 2 weeks must have elapsed since a patient
was administered any investigational agent as part of a Phase 0 study (also referred
to as an early Phase I study or pre-Phase I study where a sub-therapeutic dose of
drug is administered) at the principal investigator's (PI's) discretion, and patients
should have recovered from any toxicity from prior therapy to eligibility levels.

- 3.2.2 Patients must not have other current malignancies, other than basal cell skin
cancer, squamous cell skin cancer, in situ cervical cancer, ductal or lobular
carcinoma in situ of the breast.

- Patients who have undergone primary therapy for a prior diagnosis of cancer and are
disease free for at least 3 years prior to study entry will be included in the trial.

- 3.2.3 Patients may not be receiving any other investigational agents.

- 3.2.4 Subjects with known brain metastases are excluded with the exception of those
whose brain metastatic disease status has remained stable for at least 3 months since
treatment of the brain metastases without steroids (except for maintenance
replacement doses) or antiseizure medications.

- Patients cannot be taking enzyme-inducing anti-seizure medications (e.g., phenytoin,
carbamazepine, phenobarbital, primidone, oxcarbamazepine); other seizure medications
that are not considered enzyme-inducing would be permissible.

- 3.2.5 Because there is an unknown but potential risk for adverse events in nursing
infants secondary to exposure to this agent, women who are breast feeding are
ineligible for this study.

- 3.2.6 Patients receiving medications known to induce/inhibit cytochrome P450 3A4
(CYP3A4) will be excluded from this study.

- Patients who must initiate treatment with a CYP3A4 inhibitor while receiving R935788
will be carefully monitored.

- Inhibitors of CYP3A4 include but are not limited to:

- amiodarone,

- clarithromycin,

- erythromycin,

- imatinib,

- troleandomycin,

- ritonavir,

- indinavir,

- fluconazole,

- itraconazole,

- and ketoconazole.

- Patients should also avoid grapefruit and grapefruit juice during participation in
the study.

- Patients will also be required to keep a study diary to record any side effects that
occur during the study and any other medications taken.

- 3.2.7 Subjects with clinically significant illnesses which would compromise
participation in the study, including, but not limited to: unstable or serious
medical conditions (ongoing or active infection, symptomatic congestive heart failure
[AHA Class II or worse], unstable angina pectoris, cardiac arrhythmia, or psychiatric
illness/social situations that would limit compliance with study requirements) are
excluded due to the possibility that the underlying condition may obscure the
attribution of effect and adverse events with respect to the study medication and may
limit study compliance.

- 3.2.8 Patients with hepatocellular cancer (HCC) may have underlying chronic
infectious hepatitis as long as there is no evidence of hepatic failure and they meet
the eligibility criteria.

- 3.2.9 Human immunodeficiency virus (HIV)-positive patients on combination
antiretroviral therapy are ineligible because of the potential for pharmacokinetic
interactions with R935788.

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Response Rate

Outcome Description:

Response is assessed by the RECIST (response criteria in solid tumors)criteria. A complete response (CR) is disappearance of all target lesions , partial response (PR) is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, progressive disease (PD) is at least a 20% increase in the sum of the LD of target lesions, and stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.

Outcome Time Frame:

24 months

Safety Issue:


Principal Investigator

Shivaani Kummar, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)


United States: Federal Government

Study ID:




Start Date:

April 2009

Completion Date:

January 2012

Related Keywords:

  • Head and Neck Neoplasms
  • Pheochromocytoma
  • Colorectal Neoplasms
  • Carcinoma, Non-Small-Cell Lung
  • Carcinoma, Renal Cell
  • Multi-Kinase Inhibitor
  • Neoplasms
  • Advanced Cancer
  • Kidney Cancer
  • Liver Cancer
  • Pheochromocytoma
  • Non-Small Cell Lung Cancer
  • Colorectal Cancer
  • Head and Neck Cancer
  • Neoplasms
  • Carcinoma
  • Thyroid Neoplasms
  • Carcinoma, Non-Small-Cell Lung
  • Carcinoma, Renal Cell
  • Colorectal Neoplasms
  • Head and Neck Neoplasms
  • Pheochromocytoma



National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda, Maryland  20892