Clinical trial NCT01581541: PU-H71 in Patients With Solid Tumors and Low-Grade Non-Hodgkin's Lymphoma That Have Not Responded to Standard 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Solid Tumors
Lymphoma
Keywords: Targeted Therapy
Solid Tumors
Lymphoma
Non-Hodgkin Lymphoma
Solid Tumor
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2012-04-20
Enrollment: 17
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

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 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.

Eligibility criteria: * 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.

Primary outcomes:
measure: Number of Participants With Cycle 1 Dose-limiting Toxicities (DLTs)
timeFrame: Cycle 1 (21 days)
measure: Number of Participants With Adverse Events Possibly, Probably, or Definitely Related to Study Drug
timeFrame: 3 years and two months and 11 days
measure: Maximum Tolerated Dose (MTD) of PU-H71
timeFrame: Cycle 1 (21 days)
Secondary outcomes:
measure: Number of Participants According to Best Response Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1)
timeFrame: Baseline and every 6 weeks up to 18 weeks
measure: Number of Days on Treatment
timeFrame: up to 126 days
measure: Maximum Observed Plasma Concentration (Cmax)
timeFrame: 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.
measure: Terminal Half-life (T1/2)
timeFrame: 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.
measure: Area Under the Concentration-Time Curve From Time 0 to 24 Hours [AUC(0-24)]
timeFrame: 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.
measure: Area Under the Concentration-Time Curve From Time 0 to Infinity [AUC(0-∞)]
timeFrame: 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.
measure: Urinary Excretion (%)
timeFrame: Every void post-treatment on day 1 of cycle 1
measure: Clearance
timeFrame: 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.
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: National Cancer Institute (NCI)
name: Alice P Chen, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
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citation: 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.
citation: 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.