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Phase I Study of the Hsp90 Inhibitor, PU-H71, in Patients With Refractory Solid Tumors and Low-Grade Non-Hodgkin's Lymphoma


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Solid Tumors, Lymphoma

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Trial Information

Phase I Study of the Hsp90 Inhibitor, PU-H71, in Patients With Refractory Solid Tumors and Low-Grade Non-Hodgkin's Lymphoma


Background:

-PU-H71 is a synthetic HSP90 inhibitor which can bind both open and closed conformations of
HSP90. It demonstrates extended tumor retention and client protein degradation, while being
rapidly cleared from normal tissues. It has shown complete tumor responses and retained
sensitivity to retreatment in vivo.

Primary Objectives:

- To establish the safety and tolerability of PU-H71 administered on a once weekly, 2
weeks out of 3 schedule, in patients with refractory solid tumors and low-grade
non-Hodgkin s lymphoma (NHL).

- To establish the MTD and the RP2D of PU-H71 administered on a once weekly, 2 weeks out
of 3 schedule, in patients with refractory solid tumors and low-grade NHL.

- To determine the pharmacokinetics of PU-H71 administered on a once weekly, 2 weeks out
of 3 schedule, in patients with refractory solid tumors and low-grade NHL.

Secondary Objectives:

- To perform pharmacodynamic studies to ascertain PU-H71 effect on HSP70 in tumor tissue,
serum, and PBMCs at the MTD.

- To perform pharmacodynamic studies to ascertain PU-H71 effect on HSP90 client proteins
in tumor tissue at the MTD.

Eligibility:

-Study participants must have histologically confirmed solid tumor malignancy or low-grade
non-Hodgkin s lymphoma that has progressed or recurred after at least one line of
chemotherapy or for which no standard treatment option exists; no therapy within 4 weeks
prior to entering the study; age greater than or equal to 18 years; ECOG less than or equal
to 2; life expectancy > 3 months; and adequate organ and marrow function. Patients entering
on the expansion cohort at the MTD must have disease amenable to biopsy with willingness to
undergo pre- and post-treatment biopsies.

Study Design:

- This study will follow a modified accelerated titration design (Simon et al., 1997).

- The accelerated phase ends when 1 patient experiences a dose-limiting toxicity or 2
patients experience Grade 2 drug-related toxicity during the first cycle; after which
the study will follow the standard 3 + 3 design.

- PU-H71 will be administered intravenously over one hour, once weekly, 2 weeks out of 3,
(i.e., on days 1 and 8) every 21 days.

- PK and PD studies will be conducted during cycle 1. Up to 10 additional patients will
be entered at the MTD to further define toxicity and perform PD studies at this dose;
pre- and post-treatment tumor biopsies will be mandatory for these patients.

- CT scans will be performed at baseline and every 2 cycles (6 weeks) for restaging.

- Up to 100 patients may be treated.

Inclusion Criteria


- INCLUSION CRITERIA:

- Patients must have histologically documented (confirmed at the Laboratory of
Pathology, NCI) solid tumor malignancy or low-grade non-Hodgkin s lymphoma that is
metastatic or unresectable, for which standard curative measures do not exist, or
whose disease has progressed or recurred following at least one line of standard
therapy.

- Patients must have measurable or evaluable disease.

- Patients must have completed any chemotherapy, radiation therapy, or biologic therapy
greater than or equal to 4 weeks prior to entering the study (6 weeks for
nitrosoureas or mitomycin C).

Patients must be greater than or equal to 2 weeks since any prior administration of a
study drug in a Phase 0 study (also referred to as a pre-Phase I study where a
sub-therapeutic dose of drug is administered). Patients must have recovered to eligibility
levels from prior toxicity or adverse events. Patients receiving bisphosphonates for any
cancer are eligible to participate.

- Age greater than or equal to 18 years.

- An Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to
2.

- Life expectancy > 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/microL

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

- Total bilirubin less than or equal to 1.5 times institutional ULN

- AST (SGOT)/ALT (SGPT) less than or equal to 2.5 times institutional ULN

- Creatinine < 1.5 times ULN; OR

- Measured creatinine greater than or equal to 60 mL/minute for patients with
clearance creatinine levels greater than or equal to 1.5 times ULN

- The effects of PU-H71 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 completion of study.
Women of childbearing potential must have a negative pregnancy test within 72 hours
of enrollment in order to be eligible. Should a woman become pregnant or suspect she
is pregnant while she or her partner is participating in the study, the treating
physician should be notified immediately. Because there is an unknown but potential
risk to nursing infants secondary to treatment of the mother with PU-H71,
breastfeeding should be discontinued if the mother is treated with PU-H71.

- During the expansion phase of the protocol, patients must have:

- Disease amenable to biopsy

- Willingness to undergo pre- and post-treatment tumor biopsies

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

EXCLUSION CRITERIA:

- Patients with known brain metastases or carcinomatous meningitis are excluded from
this clinical trial, with the exception of patients whose brain metastatic disease
status has remained stable for greater than or equal to 3 months after treatment of
the brain metastases.

- Patients with clinically significant intercurrent illnesses, including but not
limited to, symptomatic congestive heart failure, unstable angina pectoris,
uncontrolled cardiac arrhythmia, or psychiatric illness/social situations that would
limit compliance with study requirements.

- QTc > 450 msec for men and > 470 msec for women.

- HIV-positive patients on combination antiretroviral therapy are ineligible because of
the potential for PK interactions with PU-H71.

- Pregnant women are ineligible because the effects of PU-H71 on the developing human
fetus are unknown. Breastfeeding should be discontinued if the mother is treated with
PU-H71 since there is an unknown but potential risk for adverse events in nursing
infants.

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

To establish the safety and tolerability of PU-H71 administered on a once weekly, 2 weeks out of 3 schedule.

Principal Investigator

Shivaani Kummar, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)

Authority:

United States: Federal Government

Study ID:

110150

NCT ID:

NCT01581541

Start Date:

April 2011

Completion Date:

April 2014

Related Keywords:

  • Solid Tumors
  • Lymphoma
  • Targeted Therapy
  • Solid Tumors
  • Lymphoma
  • Non-Hodgkin Lymphoma
  • Solid Tumor
  • Lymphoma
  • Lymphoma, Non-Hodgkin
  • Neoplasms

Name

Location

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