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

NCT01581541 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: 11015011-C-0150
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Solid Tumors; Lymphoma

Keywords

Targeted Therapy; Solid Tumors; Lymphoma; Non-Hodgkin Lymphoma; Solid Tumor

Outcome Measures

Primary Outcomes (3)

• Number of Participants With Cycle 1 Dose-limiting Toxicities (DLTs)

  A DLT was defined as an adverse event that occurred during cycle 1, was thought to be related to study drug administration, and met one of the following criteria: grade ≥ 3 non-hematologic toxicities (except diarrhea, nausea, vomiting without maximal supportive therapy; alopecia), grade 4 hematologic toxicities (except lymphopenia), and grade 2 ocular toxicity that did not resolve to ≤ grade 1 within 2 weeks. Occurrence of a DLT resulted in a dose reduction following resolution to grade ≤ 2. No more than 2 dose reductions were allowed per patient on study.

  Cycle 1 (21 days)

• Number of Participants With Adverse Events Possibly, Probably, or Definitely Related to Study Drug

  Severity of adverse events were graded using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Grade 1 Mild adverse event (AE), Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, and Grade 5 Death related to AE.

  3 years and two months and 11 days

• Maximum Tolerated Dose (MTD) of PU-H71

  The MTD is the dose level at which no more than 1 of 6 patients experience DLT during the first cycle of treatment, and the dose below that at which at least 2 (of ≤ 6) patients have DLT as a result of the drug.

  Cycle 1 (21 days)

Secondary Outcomes (8)

• Number of Participants According to Best Response Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1)

  Baseline and every 6 weeks up to 18 weeks

• Number of Days on Treatment

  up to 126 days

• Maximum Observed Plasma Concentration (Cmax)

  Before the start of infusion, 30 minutes after the start of infusion, 5 minutes before completion of infusion, and at 1.5, 2, 3, 4, 7, 10, and 24 hours after the start of infusion on day 1 during cycle 1.

• Terminal Half-life (T1/2)

  Before the start of infusion, 30 minutes after the start of infusion, 5 minutes before completion of infusion, and at 1.5, 2, 3, 4, 7, 10, and 24 hours after the start of infusion on day 1 during cycle 1.

• Area Under the Concentration-Time Curve From Time 0 to 24 Hours [AUC(0-24)]

  Before the start of infusion, 30 minutes after the start of infusion, 5 minutes before completion of infusion, and at 1.5, 2, 3, 4, 7, 10, and 24 hours after the start of infusion on day 1 during cycle 1.

Study Arms (1)

PU-H71

EXPERIMENTAL

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

Drug: PU-H71

Interventions

PU-H71 DRUG

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.

PU-H71

Eligibility Criteria

• Age: 18 Years - 120 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• Zuehlke A, Johnson JL. Hsp90 and co-chaperones twist the functions of diverse client proteins. Biopolymers. 2010 Mar;93(3):211-7. doi: 10.1002/bip.21292.

  PMID: 19697319 BACKGROUND

• Fukuyo Y, Hunt CR, Horikoshi N. Geldanamycin and its anti-cancer activities. Cancer Lett. 2010 Apr 1;290(1):24-35. doi: 10.1016/j.canlet.2009.07.010. Epub 2009 Oct 21.

  PMID: 19850405 BACKGROUND

• Chavany C, Mimnaugh E, Miller P, Bitton R, Nguyen P, Trepel J, Whitesell L, Schnur R, Moyer J, Neckers L. p185erbB2 binds to GRP94 in vivo. Dissociation of the p185erbB2/GRP94 heterocomplex by benzoquinone ansamycins precedes depletion of p185erbB2. J Biol Chem. 1996 Mar 1;271(9):4974-7. doi: 10.1074/jbc.271.9.4974.

  PMID: 8617772 BACKGROUND

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Lymphoma; Lymphoma, Non-Hodgkin

Interventions

9H-purine-9-propanamine, 6-amino-8-((6-iodo-1,3-benzodioxol-5-yl)thio)-N-(1-methylethyl)-

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Results Point of Contact

• Title: Dr. Shivaani Kummar
• Organization: Stanford University School of Medicine

skummar@stanford.edu

650-724-9084

Study Officials

• Alice P Chen, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: April 19, 2012
• First Posted: April 20, 2012
• Study Start: April 26, 2011
• Primary Completion: September 3, 2014
• Study Completion: September 3, 2014
• Last Updated: October 4, 2017
• Results First Posted: October 4, 2017

Record last verified: 2017-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)