PU-H71 in Patients With Solid Tumors and Low-Grade Non-Hodgkin's Lymphoma That Have Not Responded to Standard Treatment
| Status: | Terminated |
|---|---|
| Conditions: | Cancer, Lymphoma |
| Therapuetic Areas: | Oncology |
| Healthy: | No |
| Age Range: | 18 - 120 |
| Updated: | 10/6/2017 |
| Start Date: | April 26, 2011 |
| End Date: | September 3, 2014 |
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 an experimental drug used to treat cancer. It works by blocking a protein in
tumors. When this protein is blocked, it affects other proteins inside the cell that cancers
need to grow. Researchers want to study whether PU-H71 is a safe and effective way to treat
solid tumors and non-Hodgkin's lymphoma.
Objectives:
- To evaluate the safety and effectiveness of PU-H71 in solid tumors and non-Hodgkin's
lymphoma that have not responded to standard treatments.
Eligibility:
- Individuals at least 18 years of age who have solid tumors or non-Hodgkin's lymphoma that
have not responded to standard treatments.
Design:
- Patients will be screened with a physical exam, medical history, blood tests, and
imaging studies.
- Patients will receive PU-H71 as a 1-hour dose on days 1 and 8 of a 21-day cycle of
treatment. The first treatment cycle will be done in the hospital so that patients can
be monitored. The next treatment cycles will be done on an outpatient basis.
- Patients will have blood and urine tests and eye exams.
- Patients will provide tumor samples for study.
- Patients will have imaging studies to monitor tumor response to treatment.
- Patients will continue to take PU-H71 for as long as side effects remain tolerable and
their tumor or lymphoma does not worsen. Study researchers may adjust the dose if
needed.
- PU-H71 is an experimental drug used to treat cancer. It works by blocking a protein in
tumors. When this protein is blocked, it affects other proteins inside the cell that cancers
need to grow. Researchers want to study whether PU-H71 is a safe and effective way to treat
solid tumors and non-Hodgkin's lymphoma.
Objectives:
- To evaluate the safety and effectiveness of PU-H71 in solid tumors and non-Hodgkin's
lymphoma that have not responded to standard treatments.
Eligibility:
- Individuals at least 18 years of age who have solid tumors or non-Hodgkin's lymphoma that
have not responded to standard treatments.
Design:
- Patients will be screened with a physical exam, medical history, blood tests, and
imaging studies.
- Patients will receive PU-H71 as a 1-hour dose on days 1 and 8 of a 21-day cycle of
treatment. The first treatment cycle will be done in the hospital so that patients can
be monitored. The next treatment cycles will be done on an outpatient basis.
- Patients will have blood and urine tests and eye exams.
- Patients will provide tumor samples for study.
- Patients will have imaging studies to monitor tumor response to treatment.
- Patients will continue to take PU-H71 for as long as side effects remain tolerable and
their tumor or lymphoma does not worsen. Study researchers may adjust the dose if
needed.
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 lowgrade
non-Hodgkin's lymphoma (NHL).
- To establish the maximum tolerated dose (MTD) and the recommended phase 2 dose (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 peripheral blood mononuclear cells (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; Eastern Cooperative
Oncology Group (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.
- Pharmacokinetics (PK) and pharmacodynamics (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.
- Computed tomography (CT) scans will be performed at baseline and every 2 cycles (6
weeks) for restaging.
- Up to 100 patients may be treated.
-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 lowgrade
non-Hodgkin's lymphoma (NHL).
- To establish the maximum tolerated dose (MTD) and the recommended phase 2 dose (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 peripheral blood mononuclear cells (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; Eastern Cooperative
Oncology Group (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.
- Pharmacokinetics (PK) and pharmacodynamics (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.
- Computed tomography (CT) scans will be performed at baseline and every 2 cycles (6
weeks) for restaging.
- Up to 100 patients may be treated.
- INCLUSION CRITERIA:
- Patients must have histologically documented (confirmed at the Laboratory of
Pathology, National Cancer Institute (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 upper limit of
normal (ULN)
- Aspartate aminotransferase (AST)serum glutamic oxaloacetic transaminase
(SGOT)/alanine aminotransferase (ALT) serum glutamic pyruvic transaminase(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.
- Corrected QT interval (QTc) > 450 msec for men and > 470 msec for women.
- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible because of the potential for pharmacokinetics (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.
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
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