PU-H71 in Patients With Solid Tumors and Low-Grade Non-Hodgkin s Lymphoma That Have Not Responded to Standard Treatment

This study is currently recruiting participants. (see Contacts and Locations)
Verified December 2013 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by:
National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:
NCT01581541
First received: April 19, 2012
Last updated: July 25, 2014
Last verified: December 2013
  Purpose

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.

Condition Intervention Phase
Solid Tumors
Lymphoma
Drug: PU-H71
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I Study of the Hsp90 Inhibitor, PU-H71, in Patients With Refractory Solid Tumors and Low-Grade Non-Hodgkin's Lymphoma

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • To establish the safety and tolerability of PU-H71 administered on a once weekly, 2 weeks out of 3 schedule.
  • To establish the MTD and the RP2D of PU-H71.

Secondary Outcome Measures:
  • 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.

Estimated Enrollment: 100
Study Start Date: April 2011
Estimated Study Completion Date: April 2015
Estimated Primary Completion Date: April 2015 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: PU-H71
    N/A
Detailed Description:

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.
  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01581541

Contacts
Contact: Deborah E Allen, R.N. (301) 402-5640 allendeb@mail.nih.gov
Contact: Shivaani Kummar, M.D. (301) 435-0517 kummars@mail.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    (888) NCI-1937      
Sponsors and Collaborators
Investigators
Principal Investigator: Shivaani Kummar, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
ClinicalTrials.gov Identifier: NCT01581541     History of Changes
Other Study ID Numbers: 110150, 11-C-0150
Study First Received: April 19, 2012
Last Updated: July 25, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Targeted Therapy
Solid Tumors
Lymphoma
Non-Hodgkin Lymphoma
Solid Tumor

Additional relevant MeSH terms:
Lymphoma
Lymphoma, Non-Hodgkin
Neoplasms
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases

ClinicalTrials.gov processed this record on August 18, 2014