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Phase I Study of SNX-5422 Mesylate in Adults With Refractory Solid Tumor Malignancies and Lymphomas


Phase 1
18 Years
N/A
Not Enrolling
Both
Lymphoma, Neoplasms

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Trial Information

Phase I Study of SNX-5422 Mesylate in Adults With Refractory Solid Tumor Malignancies and Lymphomas


Background:

- Inhibitors of the chaperone protein Hsp90 are of current interest because of the
central role that Hsp90 plays in the maturation and maintenance of numerous proteins,
such as Her2, critical for tumor cell viability and growth.

- Disruption of Hsp90 function has been shown to cause degradation of multiple Hsp90
client proteins, leading to inhibition of several key signaling pathways. This in turn
results in inhibition of cellular proliferation.

Objectives:

- Determine the maximum tolerated dose (MTD) of SNX-5422 when administered twice a week
for 28 days.

- Characterize the safety profile of SNX-5422 when administered twice a week for 28 days.

- Investigate the effects of SNX-5422 on Hsp90 client proteins using pharmacodynamic (PD)
assays.

- Investigate the effects of SNX-5422 on tumor and lymphoma response using the National
Cancer Institute (NCI) Response Evaluation Criteria in Solid Tumors (RECIST) criteria)
and standardized lymphoma criteria, respectively.

- Determine the pharmacokinetic (PK) profile of SNX-2112 and its prodrug SNX-5422 in
humans.

Eligibility:

- Patients with histologically documented solid tumors and lymphoid malignancies
(lymphoma and CLL) whose disease has progressed following standard therapy, or who have
no acceptable standard treatment options.

- Patients with no major surgery, radiation, or chemotherapy within 4 weeks prior to
study enrollment, and who have recovered from toxicities from prior therapies to at
least eligibility levels.

Design:

This will be a Phase I dose escalation study to determine the MTD and recommended Phase II
dose of SNX-5422. SNX-5422 will be administered orally twice a week for 28 days in
continuous cycles until disease progression occurs or the patient meets off-study criteria.
Three to six patients will be enrolled at each dose level, and up to 6 additional patients
at the MTD, for a minimum of up to 36 patients and a maximum of 60 patients.

Inclusion Criteria


- INCLUSION CRITERIA:

Patients with histologically documented (by the NIH pathology department) solid tumors and
lymphoid malignancies (lymphoma and CLL) who are refractory to standard therapy or who
have no acceptable standard treatment options. Patients with lymphoid malignancies will be
eligible if their disease has progressed following 2 standard therapies (aggressive NHL),
and if their disease is considered refractory (for indolent NHL).

Patients must have measurable or evaluable disease.

Patients must have recovered to at least Grade less than or equal to1 toxicity levels due
to adverse events and/or toxicity of prior chemotherapy or biologic therapy. They must not
have had chemotherapy or biologic therapy within 4 weeks prior to entering the study (6
weeks for nitrosoureas or mitomycin C, or UCN-01). Patients must be greater than or equal
to 2 weeks since any prior administration of study drug in an exploratory IND/Phase Zero
study. Patients must be greater than or equal to 1 month since any prior radiation or
major surgery. However, patients receiving bisphosphonates for any cancer or undergoing
androgen deprivation therapy for prostate cancer are eligible for this therapy.

Age greater than or equal to 18 years

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

Life expectancy greater than 3 months

Patients must have normal or adequate organ and marrow function as defined below:

- Absolute neutrophil count greater than or equal to 1,500/milliliter

- Platelets greater than or equal to 100,000/milliliter

- Total bilirubin* within less than or equal to 1.5 times upper limit of normal

- AST (SGOT)/ALT (SGPT) less than or equal to 2.5 times institutional upper limit of
normal

- creatinine less than 1.5 times upper limit of normal

OR

- creatinine clearance greater than or equal to 60 mL/min (measured) for patients with
creatinine levels greater than or equal to 1.5 times upper limit of normal.

*we will allow patients with Gilbert's syndrome with total bilirubin up to 2.5 mg/dL

The effects of SNX-5422 on the developing human fetus are unknown. For this reason, women
of childbearing 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 2 months after discontinuation from the study. Women of
childbearing potential must have a negative pregnancy test in order to be eligible. Should
a woman become pregnant or suspect she is pregnant while participating in this study, she
should inform her treating physician immediately. Because there is an unknown but
potential risk for adverse events in nursing infants secondary to treatment of the mother
with SNX-5422, breastfeeding should be discontinued if the mother is treated with
SNX-5422.

Ability to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

Patients receiving any other investigational agents. Patients with symptomatic brain
metastases should be excluded from this clinical trial because of their poor prognosis and
because they often develop progressive neurologic dysfunction that would confound the
evaluation of neurologic and other adverse events. However, patients who have had
treatment for their brain metastases and whose brain metastatic disease status has
remained stable for at least 3 months without steroids may be enrolled at the discretion
of the principal investigator.

Uncontrolled medical illness including, but not limited to, ongoing or uncontrolled,
symptomatic congestive heart failure (AHA Class II or worse), uncontrolled hypertension,
unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations
that would limit compliance with study requirements.

HIV-positive patients receiving combination antiretroviral therapy are excluded from the
study because of possible PK interactions with SNX-5422. HIV positive patients not
receiving antiretroviral therapy are excluded due to the possibility that SNX-5422 may
worsen their condition and the likelihood that the underlying condition may obscure the
attribution of adverse events with respect to SNX-5422.

Chronic diarrhea.

Gastrointestinal diseases that could affect drug absorption, including postsurgical states
such as gastric bypass.

Gastrointestinal diseases that could alter the assessment of safety, including irritable
bowel syndrome, ulcerative colitis, Crohn's disease, or hemorrhagic coloproctitis.

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Determine the maximum tolerated dose (MTD) of SNX-5422 when administered twice a week for 28 days.

Authority:

United States: Federal Government

Study ID:

080091

NCT ID:

NCT00644072

Start Date:

March 2008

Completion Date:

June 2011

Related Keywords:

  • Lymphoma
  • Neoplasms
  • Hsp90 Inhibitor
  • Her2
  • Neoplasms
  • Advanced Cancer
  • Cancer
  • Solid Tumor
  • Lymphoma
  • Neoplasms
  • Lymphoma

Name

Location

National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892